Dispersões sólidas como estratégia para melhorar a biodisponibilidade oral de drogas pouco solúveis em água

dispersões sólidas como estratégia para melhorar a biodisponibilidade oral de drogas pouco solúveis em água
As dispersões sólidas são uma das estratégias mais promissoras para melhorar a biodisponibilidade oral de drogas pouco solúveis em água. Ao reduzir o tamanho de partícula do fármaco ao mínimo absoluto e, portanto, melhorar a humidificação do fármaco, a biodisponibilidade pode ser significativamente melhorada. São geralmente apresentados como produtos amorfos, principalmente obtidos por dois métodos diferentes principais, por exemplo, derretimento e evaporação do solvente. Recentemente, foram incluídos agentes tensioactivos para estabilizar as formulações, evitando assim a recristalização do fármaco e potenciando sua solubilidade. Novos processos de fabricação para obter dispersões sólidas também foram desenvolvidos para reduzir as desvantagens do processo inicial. Nesta revisão, pretende-se discutir os recentes avanços relacionados à área de dispersões sólidas.
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Avisos de pesquisa científica internacional.
Estratégias de Formulação para Melhorar a Biodisponibilidade de Drogas Mal Absorvidas com Ênfase Especial em Sistemas Auto-Emulsionantes.
1 Departamento de Farmacêutica, Parul Institute of Pharmacy, Limda, Waghodia, Vadodara, Gujarat 391760, Índia.
2 Departamento de Química e amp; Bioquímica, Universidade Laurentiana, 935 Ramsey Lake Road, Sudbury, ON, Canadá P3E 2C6.
Recebido 1 de outubro de 2013; Aceito em 13 de novembro de 2013.
Editores acadêmicos: J. Reynisson, S. Simovic e A. S. Zidan.
Copyright © 2013 Shweta Gupta et al. Este é um artigo de acesso aberto distribuído sob a Licença de Atribuição de Commons, que permite uso, distribuição e reprodução sem restrições em qualquer meio, desde que o trabalho original seja devidamente citado.
Os candidatos de drogas pouco solúveis em água estão se tornando mais prevalentes. Estimou-se que aproximadamente 60-70% das moléculas do fármaco são insuficientemente solúveis em meio aquoso e / ou têm uma permeabilidade muito baixa para permitir a sua absorção adequada e reprodutível a partir do trato gastrointestinal (TGI) após administração oral. Os cientistas de formulação devem adotar várias estratégias para aumentar sua absorção. As formulações lipídicas são uma abordagem promissora para combater os desafios. Neste artigo de revisão, são discutidas potenciais vantagens e desvantagens de várias técnicas convencionais e as abordagens mais recentes especificamente os sistemas auto-emulsionantes. Vários componentes dos sistemas auto-emulsionantes e seus critérios de seleção são críticos. As tentativas de vários cientistas para transformar os sistemas de libertação de fármaco auto-emulsionantes líquidos (SEDDS) para SEDDS sólidos por adsorção, secagem por pulverização, liofilização, granulação em fusão, extrusão e assim por diante para formular várias formas de dosagem como cápsulas auto-emulsionantes, comprimidos, peletes de libertao controlada, esferas, microesferas, nanopartulas, supositios, implantes e assim por diante tamb foram incluos. A formulação de SEDDS é uma estratégia potencial para fornecer novas moléculas de fármaco com biodisponibilidade aumentada, apresentando principalmente baixa solubilidade aquosa. O sistema auto-emulsionante oferece várias vantagens em relação a outros sistemas de administração de fármacos com potencial para resolver vários problemas associados a fármacos de todas as classes do sistema de classificação biofarmacêutica (BCS).
1. Introdução.
Várias estratégias têm sido amplamente investigadas para melhorar a biodisponibilidade de medicamentos mal absorvidos, a fim de aumentar sua eficácia clínica quando administrados por via oral. Estima-se que entre 40% e 70% de todas as novas entidades químicas identificadas em programas de descoberta de drogas sejam insuficientemente solúveis em meio aquoso [1,2]. O aumento na proporção de candidatos pouco solúveis é frequentemente atribuído a melhorias na tecnologia de síntese, o que permitiu o desenho de compostos muito complicados e uma mudança na estratégia de descoberta de uma abordagem chamada fenotípica para uma abordagem baseada em metas [3]. . Várias propriedades físico-químicas que contribuem para a fraca solubilidade de vários fármacos incluem a sua estrutura complexa, tamanho, alto peso molecular, alta lipofilicidade, ligação H composta ao solvente, ligação H intramolecular, ligação H intermolecular (embalagem de cristal), cristalinidade, polimorfismo formas, estado de carga iônica, pH e forma de sal [4].
A regra de cinco de Lipinski foi amplamente proposta como um modelo preditivo qualitativo para a avaliação da absorção de compostos mal absorvidos. Na configuração de descoberta, “a regra de 5” prediz que a má absorção ou permeação é mais provável quando há mais de 5 doadores de ligação de H, aceitadores de ligação de 10 H, o peso molecular é maior que 500 e o Log P calculado é maior do que 5. A regra de cinco só detém para compostos que não são substratos para transportadores ativos e mecanismos de efluxo [5]. Assim, a avaliação in vivo de novos fármacos candidatos em modelo animal é realizada para avaliar a absorção de drogas. Drogas mal absorvidas representam um desafio para os cientistas da formulação para desenvolver formas de dosagem adequadas que podem aumentar sua biodisponibilidade.
Em termos gerais, fármacos pouco solúveis podem ser formulados em três formas diferentes para superar o desafio de formulações sólidas de absorção de sólidos cristalinos, formulações amorfas e formulações lipídicas [6].
1.1. Formulações sólidas cristalinas.
A modificação das propriedades fisicoquímicas, tais como a formação de sal e a micronização do composto cristalino para aumentar a área superficial e, portanto, a dissolução pode ser uma abordagem para melhorar a taxa de dissolução do fármaco. O tamanho de partícula de cerca de 2-5 μ m pode ser conseguido por micronização usando um moinho a jato de ar. A tecnologia nanocristal pode reduzir o tamanho de partícula cristalina para 100-250 nm, usando moagem de bolas [7], tecnologias de gás denso [8], e assim por diante. No entanto, esses métodos têm suas próprias limitações. Por exemplo, a formação de sal de compostos neutros não é viável. A redução do tamanho das partículas pode não ser desejável em situações em que a dificuldade de molhabilidade e manuseio são experimentadas para pós muito finos [9].
1.2. Formulações amorfas.
As formulações amorfas incluem "soluções sólidas" que podem ser formadas usando uma variedade de tecnologias, incluindo secagem por pulverização e extrusão por fusão [9-11]. As formulações amorfas podem incluir agentes tensioactivos e polímeros que proporcionam actividade de superfície durante a dispersão.
Outras estratégias de formulação que são mais popularmente adotadas para aumentar a biodisponibilidade de tais medicamentos incluem a complexação com ciclodextrinas [12], formulação de conjugados poliméricos [13], nanopartículas, nanopartículas lipídicas sólidas (SLN) [14], uso de potenciadores de permeação e surfactantes [15].
1.3. Formulações lipídicas.
Nos últimos anos, um grande interesse se concentrou nos sistemas de suporte baseados em lipídios. A abordagem mais popular é a incorporação do componente ativo e pouco solúvel ativo em veículos lipídicos inertes, como óleos, dispersões de surfactantes [16], dispersões sólidas, nanopartículas lipídicas sólidas, emulsões, microemulsões, nanoemulsões, formulações auto-emulsionantes (SEF), micro / formulações nanoemulsificantes [17], e lipossomas [18]. A Tabela 1 fornece uma breve indicação das principais estratégias de formulação e as principais vantagens e desvantagens de cada abordagem [6].
2. Formulações lipídicas.
As formulações lipídicas para administração oral de drogas são um grupo diversificado de formulações com uma ampla gama de propriedades. A utilidade de solubilizar formulações baseadas em lipidos para melhorar a absorção gastrointestinal (GI) de fármacos hidrofóbicos fracamente solúveis em água está bem documentada na literatura. Estes geralmente consistem em um fármaco dissolvido em uma mistura de excipientes (5 classes de excipientes) com grande variedade de propriedades físico-químicas que variam de óleos de triglicerídeos puros, mono - e diglicéridos e proporção substancial de surfactantes lipofílicos ou hidrofílicos e co-solventes. A Tabela 2 fornece o amplo sistema de classificação para várias formulações lipídicas [19].
O principal mecanismo de ação pelo qual uma formulação lipídica leva à biodisponibilidade melhorada geralmente evita o processo de dissolução lenta que limita a biodisponibilidade de drogas hidrofóbicas a partir de formas de dosagem sólidas. De preferência, a formulação permite que o medicamento permaneça em estado dissolvido durante todo o seu trânsito no GIT. O fármaco para absorção pode ser aumentado pela formulação do fármaco como solubilizante dentro de uma dispersão coloidal. Este objetivo pode ser alcançado através da formulação do fármaco em um sistema auto-emulsionante. Entre as várias abordagens, o sistema auto-emulsionante de administração de fármacos ganhou mais atenção devido à biodisponibilidade oral aumentada, possibilitando redução na dose, perfis temporários mais consistentes de absorção de drogas, alvos seletivos de drogas para janela de absorção específica em GIT e proteção de droga (s) do ambiente hostil no intestino [17].
2.1. Tipos de Sistemas Auto-Emulsionantes: Sistema de Distribuição de Medicamentos Auto-Emulsionante, Auto-Microemulsionante e Auto-Nanoemulsificante (SEDDS, SMEDDS e SNEDDS)
SEDDSs, SMEDDSs e SNEDDSs são misturas isotrópicas fisicamente estáveis ​​de óleo, surfactante, co-tensoativo e substância de fármaco solubilizada que forma rápida e espontaneamente óleo fino em emulsões de água, microemulsões ou nanoemulsões, respectivamente, quando introduzidas em fases aquosas sob agitação suave. Assim, as formulações auto-emulsionantes são prontamente dispersas no trato gastrointestinal, onde a motilidade do estômago e do intestino delgado fornece a agitação necessária para a emulsificação.
As vantagens potenciais dos sistemas auto-emulsionantes incluem 100% de capacidade de aprisionamento de drogas, formulação fisicamente estável (também pode ser preenchida em cápsulas), não é necessário passo de dissolução, formação de tamanho de gotícula submicrónico, aumentando assim a área de superfície de absorção, aumento de taxa e extensão de absorção e, portanto, maior biodisponibilidade. Os SEDDS fornecem medicamentos BCS Classe II de forma eficaz. Eles também têm potencial para a entrega efetiva de BCS classe III, BCS classe IV e drogas suscetíveis hidrolisticamente. Eles fornecem proteção contra a degradação gástrica. Além disso, eles fornecem um perfil temporal consistente com dosagem reduzida, frequência de dosagem. Eles são fáceis de fabricar e ampliar. Também direciona a distribuição de drogas no sistema linfático.
Os SEDDSs foram descritos como sistemas que produzem emulsões com um tamanho de gotícula entre 100 e 300 nm, enquanto os SMEDDSs formam microemulsões transparentes com um tamanho de gotícula inferior a 50 nm [20]. No entanto, SEDDS geralmente se refere a todos os tipos de sistemas auto-emulsionantes, a menos que seja descrito de outra forma, enquanto SNEDDSs descrevem sistemas que formam nanoemulsões após dispersão em meios aquosos [21].
Quando comparados com as emulsões, que são formas dispersas sensíveis e metaestáveis, estas formulações auto-emulsionantes são fisicamente estáveis, fáceis de fabricar e são adequadas para administração oral como forma de dosagem unitária em cápsulas de gelatina mole ou dura devido à natureza anidra. Assim, para compostos de fármacos lipofílicos que exibem absorção limitada na taxa de dissolução, esses sistemas podem oferecer uma melhora na taxa e extensão da absorção e resultar em perfis de sangue-tempo mais reprodutíveis. Sendo anidros, esses sistemas também oferecem um grande potencial para a formulação e administração de drogas suscetíveis hidrolisticamente. SEDDS também são encontrados para aumentar a permeabilidade intestinal e minimizar o efeito do pH na absorção de drogas [22].
Embora o mecanismo primário pelo qual essas formulações sejam pensadas para melhorar a absorção de drogas é através da eliminação da necessidade de solubilização de fármacos pré-absorvente no trato gastrointestinal (GIT), outros mecanismos podem incluir proteção contra degradação química e enzimática localizada no ambiente aquoso do GIT e promoção do transporte de drogas linfáticas, que contorna o metabolismo hepatico de primeira passagem [2]. A Figura 1 fornece o diagrama esquemático do transporte de drogas intestinais a partir de formulações à base de lipídeos através do portal e as rotas linfáticas mesentéricas [23].
As características físico-químicas da substância fármaco, os próprios excipientes lipídicos e a dispersibilidade da formulação in vivo determinarão a absorção do fármaco no GIT, bem como o grau de participação das vias linfáticas venosa e mesentérica portal no medicamento global absorção.
2.2. Seleção de Excipientes em Formulações Auto-Emulsionantes.
A consideração principal na escolha de excipientes apropriados para qualquer formulação à base de lipídeos é a identificação de um excipiente ou a sua combinação possuindo a capacidade de solubilizar toda a dose de medicamento num volume aceitável para administração oral unitária. A auto-emulsificação demonstrou ser específica para a natureza do par de óleo / surfactante; a concentração de surfactante e a relação óleo / surfactante; e a temperatura a que ocorre a auto-emulsificação [33]. Em apoio a estes fatos, também foi demonstrado que apenas combinações de excipientes farmacêuticos muito específicos poderiam levar a sistemas auto-emulsionantes eficientes. O fármaco também deve ser fisicamente e quimicamente estável na formulação e as características de liberação do fármaco devem permanecer constantes durante a vida útil da formulação. O último requisito depende da estabilidade física e química dos excipientes que devem ser cuidadosamente monitorizados durante o desenvolvimento da formulação. O excipiente deve ser escolhido da lista de excipientes "GRAS" geralmente considerados como seguros publicados pela USFDA ou de outros ingredientes inativos aprovados e publicados pelas agências reguladoras. Os principais excipientes em um sistema auto-emulsionante incluem os lipídios (óleos), surfactantes e co-tensoativos. Alguns exemplos de vários excipientes utilizados em diferentes produtos comerciais são apresentados na Tabela 3.
2.2.1. Lípidos / Óleos.
O óleo representa um dos excipientes mais importantes nas formulações auto-emulsionantes porque pode solubilizar quantidades marcantes do fármaco lipofílico, facilitar a auto-emulsificação e aumentar a fração de fármaco lipofílico transportado através do sistema linfático intestinal, aumentando assim a absorção a partir do Trato GI dependendo da natureza molecular do triglicerídeo [16, 46]. Apesar do potencial considerável que esses excipientes de lipídios oferecem, muito poucas formulações lipídicas atingiram o mercado farmacêutico. Isso pode ser devido à informação insuficiente sobre a química física relativamente complexa de lipídios e preocupações sobre a farmacologia farmacológica e a estabilidade física formulada. Além dessas preocupações, a interação de uma formulação à base de lipídios com o ambiente gastrintestinal e seu impacto na absorção de drogas também é importante [2]. Por exemplo, os lípidos digestíveis demonstraram ser intensificadores consideravelmente mais eficientes da absorção de fármaco pouco solúvel, em comparação com os lípidos não digeríveis (por exemplo, parafina líquida). O comprimento da cadeia de ácidos gordos do lípido também influencia a absorção do fármaco [47]. Ambos os óleos de triglicerídeos de cadeia longa e média com diferentes graus de saturação foram utilizados para o projeto de formulações auto-emulsionantes. Os óleos comestíveis que representam a escolha lógica e preferida do excipiente lipídico para o desenvolvimento de SEDDS não são freqüentemente selecionados devido à sua fraca capacidade de dissolver grandes quantidades de drogas lipofílicas. Óleos vegetais modificados ou hidrolisados ​​têm sido amplamente utilizados, uma vez que estes excipientes formam bons sistemas de emulsificação com um grande número de surfactantes aprovados para administração oral e exibem melhores propriedades de solubilidade do fármaco [48]. Eles oferecem vantagens formulativas e fisiológicas, e seus produtos de degradação se assemelham aos produtos finais naturais da digestão intestinal. Novos derivados de cadeia média semi-sintética, que podem ser definidos como compostos anfifílicos com propriedades de surfactantes, substituem progressivamente e efetivamente os óleos de triglicerídeos de cadeia média regular nos sistemas auto-emulsionantes de administração de fármacos [49].
Os lipídios exercem seus efeitos possivelmente através de vários mecanismos complexos que podem levar à alteração nas propriedades biofarmacêuticas do fármaco, como aumento da taxa de dissolução do fármaco e solubilidade no fluido intestinal, proteção do fármaco por degradação química e enzimática em as gotículas de óleo e a formação de lipoproteínas que promovem o transporte linfático de drogas altamente lipofílicas [48].
A quantidade de lípidos contidos numa formulação também influencia a absorção do fármaco principalmente através da solubilização no TGI e potencialmente através da activação da digestão dos lípidos do GI, resultando no aumento da secreção do sumo e da bílis pancreãticos [50]. Assim, o impacto de qualquer formulação baseada em lipídeos nos processos de digestão lipídica deve ser considerado, particularmente quando unidades de dosagem múltiplas de uma formulação à base de lipídeos são administradas como uma dose única, o que é comum para muitos medicamentos anti-HIV.
2.2.2. Tensioactivos.
As propriedades auto-emulsionantes requerem a incorporação de quantidades relativamente grandes de tensioactivo na formulação, em adição ao veículo veículo de fármaco oleoso. Os surfactantes podem melhorar a afinidade entre os lipídios e a membrana intestinal ou aumentar a permeabilidade da membrana intestinal. Os surfactantes aumentam a permeabilidade dividindo-se na membrana celular e perturbando a organização estrutural da bicamada lipídica levando ao aprimoramento da permeação [51]. Portanto, a maioria dos medicamentos são absorvidos através da via transcorrular passiva. Eles também exercem seus efeitos de aumento da absorção aumentando a taxa de dissolução do medicamento. Vários compostos que exibem propriedades tensioactivas podem ser empregados para o projeto de sistemas auto-emulsionantes, sendo os mais recomendados os surfactantes não iónicos com valores de equilíbrio hidrófilo-lipofílico (HLB) relativamente elevados [2, 51, 52]. A segurança é um dos principais fatores determinantes na escolha de um surfactante. Os emulsionantes de origem natural (por exemplo, lecitina, monoglicéridos de cadeia média de Akoline (MCM) e Peceol) são normalmente preferidos, uma vez que são considerados mais seguros do que os tensioactivos sintéticos. No entanto, estes excipientes têm eficiência de auto-emulsificação limitada [49]. Vários derivados de óleo vegetal, como Acrosyl (derivado do óleo de rícino), ainda estão sendo encontrados para dar auto-emulsificação óptima [53]. Os tensioactivos não iónicos são normalmente preferidos em relação às suas contrapartes iónicas devido a perfis de segurança mais favoráveis ​​e maior estabilidade da emulsão em uma gama mais ampla de pH e força iónica. Além disso, os surfactantes não iónicos podem produzir mudanças reversíveis na permeabilidade da mucosa intestinal [51], facilitando ainda mais a absorção do medicamento coadministrado. Os surfactantes hidrófobos podem penetrar nas membranas causando mudanças na fluidez e permeabilidade da membrana. Geralmente as cadeias de alquilo simples são mais penetrantes, então os surfactantes volumosos, como os polissorbatos e os etoxilatos de triglicerídeos, são menos tóxicos. Normalmente, a concentração de surfactante varia entre 30 e 60% da formulação total para formar SEDDS estável [33]. É muito importante determinar a concentração de surfactante adequadamente, pois grandes quantidades de surfactantes podem causar irritação gastrintestinal. No entanto, o tamanho extremamente pequeno de gotículas lipídicas produzidas pelas formulações de SMEDDS e SNEDDS promove um rápido esvaziamento estomacal e ampla dispersão em todo o TGI, minimizando a exposição a altas concentrações de surfactantes locais e, assim, reduzindo o potencial de irritação. O surfactante envolvido na formulação de SEDDS deve ter um HLB e uma hidrofilicidade relativamente elevados para permitir a dispersão rápida e fácil no fluido GI aquoso como uma emulsão óleo-em-água muito fina e, portanto, boa performance auto-emulsionante pode ser alcançada [2 ]. O uso de misturas de surfactantes para atingir o valor do balanço hidrófilo-lipofílico (HLB) necessário para a emulsificação tem sido comprovadamente provido de propriedades auto-emulsionantes superiores em relação ao uso de um único agente tensioactivo possuindo o HLB desejado [54]. Um ou mais co-solventes são frequentemente adicionados à formulação para auxiliar na solubilização de altas concentrações do fármaco. Os surfactantes são de natureza anfifílica e podem dissolver ou solubilizar quantidades relativamente elevadas de compostos de fármacos hidrofóbicos. Existe uma relação entre o tamanho da gota e a concentração do surfactante em uso. Em muitos casos, o aumento da concentração de surfactante pode levar a gotículas com menor tamanho médio de gotícula. Isso poderia ser explicado pela estabilização das gotículas de óleo como resultado da localização das moléculas de surfactantes na interface óleo-água. Por outro lado, em alguns casos, o tamanho médio das gotículas pode aumentar com o aumento das concentrações de surfactante [55]. Esse fenômeno poderia ser atribuído à ruptura interfacial provocada pela penetração de água aumentada nas gotículas de óleo mediadas pela concentração aumentada de surfactante e levando a ejeção de gotículas de óleo na fase aquosa. Tentativas foram feitas para avaliar a toxicidade de excipientes farmacêuticos e formulações SEDDS ou SMEDDS in vitro em monocamadas de células Caco-2 [20, 56].
2.2.3. Cosurfactantes.
A produção de uma formulação auto-emulsionante ideal requer concentrações relativamente elevadas (geralmente superiores a 30% p / p) de agentes tensioactivos. A adição de co-tensoativos ajuda na auto-emulsificação. A presença dos co-tensoativos diminui o estresse de flexão da interface e permite ao filme interfacial uma flexibilidade suficiente para assumir diferentes curvaturas necessárias para formar nanoemulsões em uma ampla gama de composição [57]. Os solventes orgânicos como o etanol, o propileno glicol (PG) e o polietilenoglicol (PEG) são adequados para administração oral e permitem a dissolução de grandes quantidades de surfactante hidrofílico ou o fármaco na base lipídica. Por outro lado, os álcoois e outros co-solventes voláteis têm a desvantagem de se evaporarem nas cápsulas da gelatina mole ou cápsulas de gelatina dura e selada na formulação auto-emulsionante convencional que leva à precipitação do fármaco. Assim, formulações livres de álcool também foram projetadas [49], mas sua capacidade lipofílica de dissolução de drogas pode ser limitada.
3. Mecanismo de Auto-Emulsificação.
O mecanismo pelo qual a auto-emulsificação ocorre ainda não é bem entendido. Foi sugerido por Reiss que a auto-emulsificação ocorre quando a mudança de entropia que favorece a dispersão é maior do que a energia necessária para aumentar a área de superfície da dispersão [58]. A energia livre de uma formulação de emulsão convencional é uma função direta da energia necessária para criar uma nova superfície entre as duas fases (fases de óleo e água) e pode ser descrita por.
onde é a energia livre associada ao processo (ignorando a energia livre da mistura), o número de gotículas, o raio dos glóbulos e a energia interfacial.
As duas fases da emulsão tendem a se separar com o tempo para reduzir a área interfacial e, portanto, a energia livre dos sistemas. Os agentes emulsionantes convencionais estabilizam as emulsões resultantes da diluição aquosa formando uma monocamada em torno das gotículas da emulsão, reduzindo a energia interfacial e formando uma barreira à coalescência. Em contraste, a emulsificação ocorre espontaneamente com formulações auto-emulsionantes porque a energia livre necessária para formar a emulsão é baixa e positiva ou negativa [17, 49]. A emulsificação que requer pouca energia de entrada envolve a desestabilização através da contração de regiões interfaciais locais. É necessário que a estrutura interfacial não mostre resistência contra o cisalhamento da superfície para que a emulsificação ocorra. A Figura 2 mostra a apresentação esquemática do mecanismo que ocorre durante a adição de água no SEDDS de forma simplificada.
A facilidade de emulsificação foi sugerida para estar relacionada à facilidade de penetração de água nas várias fases de cristal líquido (LC) ou gel formadas na superfície da gota. A interface entre o óleo e as fases contínuas aquosas é formada após a adição de uma mistura binária (óleo / surfactante não iónico) à água. Isto é seguido pela solubilização da água dentro da fase oleosa como resultado da penetração aquosa através da interface. Isso ocorrerá até que o limite de solubilização seja alcançado próximo à interfase. Uma penetração aquosa adicional levará à formação da fase LC dispersa. Eventualmente, tudo o que está em estreita proximidade com a interface será LC, cuja quantidade real depende da concentração de surfactante na mistura binária. Assim, após uma suave agitação do sistema auto-emulsionante, a água penetrará rapidamente nos núcleos aquosos e levará à interrupção da interface e à formação de gotículas. Como conseqüência da formação da interface LC em torno das gotículas de óleo, as formulações auto-emulsionantes tornam-se muito estáveis ​​para a coalescência. Estudos detalhados também foram realizados para determinar o envolvimento da fase LC no processo de formação de emulsões [31, 33, 59]. Além disso, foram utilizadas análises de tamanho de partícula e espectroscopia dielétrica de baixa freqüência (LFDS) para examinar as propriedades auto-emulsionantes de uma série de Imwitor 742 (uma mistura de mono - e diglicéridos de ácidos caprílico e caprílico) / Tween 80 [60]. Os resultados sugeriram que pode haver uma relação complexa entre a formação de LC e a formação de emulsões. Além disso, a presença do composto do medicamento pode alterar as características da emulsão, provavelmente por interação com a fase LC. No entanto, a correlação entre a formação de LC e a emulsificação espontânea ainda não foi estabelecida.
4. Abordagens mais recentes do sistema de entrega de medicamentos auto-emulsionantes.
Os sistemas auto-emulsionantes de administração de fármacos oferecem vantagens para enfrentar os desafios da solubilidade e absorção de drogas; o próximo desafio continua sendo a entrega do medicamento em uma forma de dosagem aceitável. As formas de dosagem oral são a via de administração de fármaco preferida, e as formulações lipídicas oferecem flexibilidade para formas de dosagem oral porque podem ser formuladas como soluções, formas semi-sólidas e sólidas. Os sistemas convencionais auto-emulsionantes de administração de fármacos, no entanto, são principalmente preparados em uma forma líquida, o que pode produzir algumas desvantagens, por exemplo, baixa estabilidade, precipitação irreversível de drogas / excipientes, grande volume de dose, dificuldade de manipulação e portabilidade e poucas escolhas de formas de dosagem.
Para resolver esses problemas, SEDDSs sólidos (S-SEDDSs) foram investigados como abordagens alternativas. Tais sistemas requerem a solidificação de sistemas auto-emulsionantes líquidos em pós para produzir várias formas de dosagem sólidas (cápsulas SE, comprimidos SE, peletes SE, contas SE, e assim por diante). O SEDDS líquido pode ser convertido em forma de dosagem sólida sem afetar a propriedade de liberação de drogas. A emulsificação automática acontece no GIT pelo conteúdo divulgado. Assim, os S-SEDDS combinam as vantagens do SEDDS (isto é, solubilidade e biodisponibilidade melhoradas) com as formas de dosagem sólidas (por exemplo, alta estabilidade e reprodutibilidade, forma de dosagem compacta, facilidade de manipulação e portabilidade e melhor conformidade do paciente). Conhecendo as vantagens das formas farmacêuticas sólidas, os S-SEDDSs têm sido amplamente investigados nos últimos anos, pois freqüentemente correspondem a alternativas mais eficazes às SEDDS líquidas convencionais. Exemplos incluem o desenvolvimento de S-SEDDS de Dexibuprofeno [36], Nimodipina [45] e Hidroclorotiazida [28]. Do ponto de vista das formas de dosagem, S-SEDDSs significam formas de dosagem sólidas com propriedades de auto-emulsão. Os S-SEDDSs concentram-se na incorporação de ingredientes SE líquidos / semi-sólidos em pós / nanopartículas por diferentes técnicas de solidificação.
O conceito de super-SNEDDS de fármaco pouco solúvel Simvastatina também foi investigado. Super-SNEDDSs (200% de carga de drogas) foram produzidos submetendo os pré-concentrados SNEDDS a um ciclo de aquecimento e resfriamento. A biodisponibilidade relativa do fármaco a partir de super-SEDDDS aumentou significativamente (180 ± 53,3%) em comparação com SNEDDS convencional. Absorção prolongada ao longo do intestino delgado foi observada [61]. Em um estudo anterior também, o SEDDS supersaturável foi projetado, usando uma pequena quantidade de HPMC (hidroxipropilmetilcelulose ou outros polímeros) na formulação para evitar a precipitação do fármaco gerando e mantendo um estado supersaturado in vivo. Este sistema continha uma quantidade reduzida de um surfactante, minimizando os efeitos colaterais GI e [62].
Para aumentar a biodisponibilidade oral de fármacos com alta solubilidade e baixa permeabilidade, também são investigadas emulsões duplas de água-em-óleo-em-água (w / o / w). Uma nova formulao, sistemas de administrao de fmacos auto-emulsionantes duplos (SDEDDS) foram formulados por mistura de surfactantes hidroficos e emulss de ua em eo (a / o). O SDEDDS pode emulsionar espontaneamente para emulsões duplas / emulsões duplas no ambiente gastronómico misto aquoso, com drogas encapsuladas na fase de água interna das emulsões duplas [63].
4.1. Técnicas de Solidificação para Transformar Liquid SEDDS em Solid-SEDDS (S-SEDDS)
Os SEDDSs sólidos estão sendo desenvolvidos a partir de SEDDS líquido / semisólido principalmente por adsorção em veículos sólidos [64], secagem por pulverização [45], liofilização [65], extrusão por fusão [66] e tecnologia de nanopartículas. Tais pós / nanopartículas, que são referidas como nanopartículas SE / emulsões secas / dispersões sólidas, são usualmente processadas adicionalmente em outras formas de dosagem de SE sólido ou, alternativamente, enxertadas em cápsulas (isto é, cápsulas SE). As cápsulas SE também incluem as cápsulas nas quais SEDDSs líquidos / semi-sólidos são preenchidos diretamente sem nenhum excipiente solidificante. Outras formas de dosagem de SE sólido que emergiram nos últimos anos incluem bolotas / comprimidos SE, microsferas / nanopartículas de SE e supositórios de SE / implantes [67].
4.1.1. Adsorção em transportadores sólidos.
Os pós de fluxo livre podem ser obtidos a partir de formulações líquidas de SE por adsorção em veículos sólidos. O processo de adsorção é simples e envolve apenas a adição da formulação líquida sobre transportadores inertes e a mistura em um liquidificador. O pó resultante pode então ser preenchido directamente em cápsulas ou, alternativamente, misturado com excipientes adequados antes da compressão em comprimidos. SEDDS pode ser adsorvido em níveis elevados (até 70% p / p) em veículos adequados [64]. Os transportadores sólidos podem ser substâncias inorgânicas microporosas, substâncias adsorventes inorgânicas coloidais de área superficial elevada, polímeros reticulados ou adsorventes de nanopartículas, por exemplo, silica, silicatos, trisilicato de magnésio, silicato de cálcio microporoso de silicato de magnésio e alumínio (Florite TM RE) hidróxido de magnésio, talco, crospovidona, carboximetilcelulose de sódio reticulada e metacrilato de polimetilo reticulado. O pó auto-emulsificante foi preparado por adsorção do SEDDS líquido na neusilina como veículo para melhorar a solubilidade do cloridrato de lercanidipina fracamente solúvel [35]. Os polímeros reticulados criam um ambiente favorável para sustentar a dissolução da droga. Os adsorventes de nanopartículas compreendem dióxido de silício poroso [36], nanotubos de carbono, nanohorns de carbono, carvão e assim por diante.
4.1.2. Secagem por pulverização.
In this technique, the liquid SEDDS is added to a solution of suitable solid carrier with stirring to obtain the o/w emulsion. This is then atomized into a spray of droplets in a drying chamber, where the volatile phase (e. g., the water contained in an emulsion) evaporates, forming dry particles under controlled temperature and airflow conditions [36, 45]. Such particles can be further prepared into tablets or capsules. The atomizer, the temperature, the most suitable airflow pattern, and the drying chamber design are selected according to the drying characteristics of the product and powder specification. Solid state emulsions are reported by Myers and Shivley (1993). Shivley has used sucrose and mineral oil for preparing solid state emulsions [68].
4.1.3. Lyophilization Technique.
Lyophilization or freeze-drying involves transfer of heat and mass to and from the product under preparation. Freeze drying of an oil-in-water emulsion can be an alternative method for the production of dry emulsions. Lyophilization has been thought as a molecular mixing technique where the drug and carrier are codissolved in a common solvent, frozen, and sublimed to obtain a lyophilized molecular dispersion. The potential applications of lyophilization in manufacturing of solid dispersions have successfully been investigated [65, 69, 70]. A slow cooling rate and addition of amorphous cryoprotectants has been reported to have the best stabilizing effects during lyophilization of oil-in-water emulsions [71]. Maltodextrins are also useful matrix forming agent in the formulation of freeze-dried tablets [28].
4.1.4. Melt Granulation.
Melt granulation is a technique in which powder agglomeration is obtained through the addition of a lipid as binder that melts or softens at relatively low temperatures. Melt granulation offers several advantages over the conventional wet granulation, since the liquid addition and the subsequent drying phase are omitted. Furthermore, it is also a good alternative to the use of solvent. The main parameters that control the granulation process are impeller speed, mixing time, binder particle size, and the viscosity of the binder. A wide range of solid and semisolid lipids can be applied as meltable binders. For example, Gelucires, a family of vehicles derived from the mixtures of mono-/di-/triglycerides and polyethylene glycols (PEG) esters of fatty acids, is able to increase the dissolution rate compared with PEG usually used before, probably owing to its SE property. Other lipid-based excipients evaluated for melt granulation to create solid SES include lecithin, partial glycerides, or polysorbates. In all cases, the lipidic excipients used must be semisolid at room temperature [66].
4.1.5. Melt Extrusion/Extrusion Spheronization.
Melt extrusion is a solvent-free process that allows high drug loading (60%), as well as content uniformity. Extrusion is a procedure of converting a raw material with plastic properties into a product of uniform shape and density, by forcing it through a die under controlled temperature, product flow, and pressure conditions. The size of the extruder aperture will determine the approximate size of the resulting spheroids. The extrusion-spheronization process is commonly used in the pharmaceutical industry to make uniform sized spheroids (pellets). The extrusion-spheronization process requires the following steps: dry mixing of the active ingredients and excipients to achieve a homogenous powder; wet massing with binder; extrusion into rope-like extrudate; spheronization from the extrudate to spheroids of uniform size; drying; sifting to achieve the desired size distribution and coating [34, 66].
4.2. Problems Associated with the Solidification Technologies.
There are various challenges associated with the solidification technologies. Examples of such problems include the following. (1) Amount of solidifying excipients may affect the release of the drug. (2) Nature of the excipients used may affect the drug absorption. (3) Probability of irreversible phase separation on reconstitution. (4) Clogging of spray nozzles due to oil content in spray-drying method. (5) Degradation of drug during solidification process. (6) Reduction in drug loading capacity. (7) Difficulty in ensuring content uniformity. (8) Probability of residual solvents used during granulation.
4.3. Approaches to Overcome the Problems Associated with Solidification Technologies.
(1) In order to reduce the amount of solidifying excipients required for transformation of SEDDS into solid dosage forms, a gelled SEDDS has been developed. Colloidal silicon dioxide (Aerosil 200) was selected as a gelling agent for the oil-based systems, which served the dual purpose of reducing the amount of required solidifying excipients and aiding in slowing down of the drug release [72]. (2) After administration of capsules containing conventional liquid SE formulations, emulsion droplets form and subsequently disperse in the GI tract to reach sites of absorption. However, if irreversible phase separation of the emulsion occurs, an improvement of drug absorption cannot be expected. (a) For handling this problem, sodium dodecyl sulfate was added into the SE formulation [73]. (b) With the similar purpose, the supersaturatable SEDDS was designed, using a small quantity of HPMC (or other polymers) in the formulation to prevent precipitation of the drug by generating and maintaining a supersaturated state in vivo . This system contains a reduced amount of a surfactant, thereby minimizing GI side effects [62]. (3) Self-emulsifying solid dispersions . These involve the dispersion of drug in self-emulsifying solid excipients. These excipients have the potential to increase the absorption of poorly water-soluble drugs relative to previously used PEG solid dispersions and may also be filled directly into hard gelatin capsules in the molten state, thus obviating the former requirement for milling and blending before filling. SE excipients like Gelucire1 44/14, Gelucire150/02, Labrasol1, Transcutol1, and tocopheryl polyethylene glycol 1000 succincte (TPGS) have been widely used in this field [10, 11, 26, 69].
5. Dosage Forms from Self-Emulsifying Systems.
5.1. Self-Emulsifying Capsules.
Capsule filling is the simplest and the most common technology for the encapsulation of liquid, semisolid, or solid SE formulations for the oral route. The advantages of capsule filling are simplicity of manufacturing, suitability for highly potent low-dose drugs, and high drug loading (up to 50% w/w) potential.
For liquid formulations, it involves a two-step process: filling the formulation into the capsules followed by sealing of the body and cap of the capsule, by banding or microspray sealing. Besides liquid SEDDS filling, the solid-SEDDS obtained by various techniques described above like spray drying, freeze drying, and so forth can be filled in the capsules. After administration of capsules containing conventional liquid SE formulations or the solid-SE formulations, emulsion/nanoemulsion/microemulsion droplets form and subsequently disperse in the GI tract to reach sites of absorption [19].
5.2. Self-Emulsifying Tablets.
Combinations of lipids and surfactants have presented great potential of preparing SE tablets that have been widely researched. Nazzal et al. developed self-nanoemulsified tablet dosage form of Ubiquinone [67]. First, the self-nanoemulsion system containing the Ubiquinone was prepared; this nanoemulsion was absorbed on granular materials and then compressed to form tablets. Polyethylene oxide successfully illustrated its suitability for controlled-release matrices. The resultant SE tablets consistently maintained a higher active ingredient concentration in blood plasma over the same time frame compared with a nonemulsifying tablet. The newest advance in the research field of SE tablet is the SE osmotic pump tablet, in which the elementary osmotic pump system was chosen as the carrier of SES. This system has outstanding features such as stable plasma concentrations and controllable drug release rate, allowing a bioavailability of 156.78% relative to commercial carvedilol tablets [74].
5.3. Self-Emulsifying Sustained/Controlled-Release Pellets.
Pellets are multiple unit dosage form which possess many advantages over conventional solid dosage forms, such as flexibility in manufacturing, reduction of intrasubject and intersubject variability of plasma profiles, and minimizing GI irritation without lowering drug bioavailability [75]. Thus, it is very interesting to combine the advantages of pellets with those of SEDDS by SE pellets. SE controlled-release pellets were prepared by incorporating drugs into SES that enhanced their rate of release and then by coating the pellets with a water-insoluble polymer which reduced the rate of drug release. Pellets can be prepared by extrusion/spheronization. The combinations of coating and SES could control in vitro drug release and provide a range of release rates [76].
In some investigations, solid self-emulsifying drug delivery systems (solid-SEDDS) were prepared by means of a wet granulation process in a lab-scale high shear mixer in order to improve the dissolution rate of a poorly water-soluble drug. The conventional liquid granulation binder was replaced with an oil-in-water microemulsion, loaded with the drug [34, 42].
5.4. Self-Emulsifying Beads.
Self-emulsifying system can be formulated as a solid dosage form by using minimum amounts of solidifying excipients. Patil and Paradkar investigated loading SES into the microchannels of porous polystyrene beads (PPB) using the solvent evaporation method. PPB has complex internal void structures typically produced by copolymerizing styrene and divinylbenzene. It is inert and stable over a wide range of pH, temperature and humidity. PPB was found to be potential carriers for solidification of SES, with sufficiently high SES to PPB ratios required to obtain solid form. Bead size and pore architecture of PPB were found to affect the loading efficiency and in vitro drug release from SES-loaded PPB [77]. In another study, floating alginate beads containing SEDDS of tetrahydrocurcumin were developed to increase drug solubility and prolong gastric residence time. Use of different proportions of sodium alginate, calcium chloride, and water soluble pore former (polyvinyl alcohol-polyethylene glycol copolymer) in bead formulations was found to have different effects on the floating abilities and in vitro drug release rate [78].
5.5. Self-Emulsifying Sustained-Release Microspheres.
Solid SE sustained-release microspheres were prepared by using the quasi-emulsion-solvent-diffusion method of the spherical crystallization technique. Zedoary turmeric oil (ZTO) exhibited potent pharmacological actions. With ZTO as the oil phase, ZTO release behaviour was controlled by the ratio of hydroxypropyl methylcellulose acetate succinate to Aerosil 200 in the formulation. The plasma concentration-time profiles achieved after oral administration of such microspheres to rabbits showed bioavailability of 135.6% with respect to the conventional liquid SEDDS [79].
5.6. Self-Emulsifying Nanoparticles.
Nanoparticle techniques are useful in the production of SE nanoparticles. Solvent injection is one of these techniques. In this method, the lipid, surfactant, and drugs are melted together and injected dropwise into a stirred nonsolvent. The resulting SE nanoparticles are filtered out and dried. This approach yielded nanoparticles (about 100 nm) with a high drug loading efficiency of 74% [80].
A second technique is that of sonication emulsion-diffusion-evaporation. The mixture of polylactide-co-glycolide (PLGA) and O-carboxymethyl-chitosan (O-CMC) had a SE effect, with no need to add another surfactant stabilizer. Eventually the 5-FU and plasmid encapsulation efficiencies were found to have 94.5% and 95.7%, respectively, and the 5-FU release activity from the nanoparticles was found to have sustained for three weeks [81].
Trickler et al. developed a novel nanoparticle drug delivery system consisting of chitosan and glyceryl monooleate for the delivery of Paclitaxel. These chitosan/GMO nanoparticles, with bioadhesive properties and increased cellular association, were prepared by multiple emulsion (o/w/o) solvent evaporation methods. The SE property enhanced the solubility of Paclitaxel and provided a foundation for chitosan aggregation, meanwhile causing near 100% loading and entrapment efficiencies of Paclitaxel. These advantages allow the use of lower doses of Paclitaxel to achieve an efficacious therapeutic window, thus minimizing the adverse side effects associated with chemotherapeutics like Paclitaxel [82].
5.7. Self-Emulsifying Phospholipid Suspension (SEPS)
Self-emulsifying phospholipid suspension (SEPS) consisting of high amount of phospholipids has the ability to keep the drug in solubilized form in vivo , which is essential for bioavailability enhancement. Phospholipids are endogenous lipid with efficient in vivo emulsification capability. These require relatively low amount of surfactant/cosurfactant and thus posing less health problems [83].
5.8. Self-Emulsifying Suppositories.
Some investigators proved that S-SEDDS could increase not only GI adsorption but also rectal/vaginal adsorption [84]. The drugs, which do not easily achieve therapeutic plasma concentrations by oral route, may obtain satisfactory therapeutic levels for chronic hepatic diseases by either vaginal or rectal SE suppositories. There are a few such patented products too.
Self-microemulsifying suppositories of β - artemether have been formulated and evaluated with the objective of faster onset of action and prolonged effect when administered by rectal route [85].
5.9. Self-Emulsifying Implants.
Research into SE implants has greatly enhanced the utility and application of S-SEDDS. As an example, 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine) is a chemotherapeutic agent used to treat malignant brain tumors. However, its effectiveness was affected by its short half-life. In order to enhance its stability compared with that released from poly(d, l-lactide-co-glycolide) (PLGA) wafer implants, SES was formulated with tributyrin, Cremophor RH 40 (polyoxyl 40 hydrogenated castor oil), and Labrafil 1944 (polyglycolyzed glyceride). Then the self-emulsified carmustine was fabricated into wafers with flat and smooth surface by compression molding. Ultimately, SES increased in vitro half-life of carmustine up to 130 min. In vitro release of carmustine from SE PLGA wafers was prolonged up to 7 days. Such wafers had higher in vitro antitumor activity and were less susceptible to hydrolysis than those wafers devoid of SES [86].
6. Physicochemical Characterization Parameters for Self-Emulsifying Formulations.
6.1. % Transmittance.
The primary means of self-emulsification assessment is visual evaluation [87]. To avoid any subjective variations, the % transparency of the resulting micro/nanoemulsion obtained on dilution/reconstitution of the self-emulsifying formulations is measured using UV-visible spectrophotometer [22].
6.2. Globule Size and PDI.
The globule size of the emulsion is a crucial factor in self-emulsification performance because it determines the rate and extent of drug release as well as absorption [54, 88, 89]. It has been reported that the particle size distribution is one of the most important characteristics of the in vivo fate of drug emulsion [37]. The globule size of the reconstituted formulations is most commonly measured using Malvern Zeta Sizer based on the principle of dynamic light scattering (DLS).
6.3. Robustness to Dilution.
Robustness to dilution is important for SEDDS/SNEDDS to ensure that the emulsion/nanoemulsion formed have similar properties at different dilutions to achieve uniform drug release profile and to ensure that the drug will not get precipitated at higher dilutions in vivo which may significantly retard the absorption of the drug from the formulation [49, 90]. The SEDDSs should be evaluated by diluting them at different dilutions and investigating their effect on the properties of the formed emulsion/nanoemulsion [22].
6.4. Zeta Potential.
This is used to identify the charge of the droplets. The charge of the oil droplets of SEDDS is a property that should be assessed [46]. Generally, the increase in electrostatic repulsive forces between the nanoemulsion droplets prevents the coalescence of nanoemulsion droplets. On the contrary, a decrease of electrostatic repulsive forces causes phase separation. The zeta potential of the reconstituted SEDDS is commonly measured using Malvern Zeta Sizer Nano based on the electrophoresis and electrical conductivity of the formed nanoemulsion.
6.5. Effect of pH.
The pH of the aqueous phase has considerable influence on the phase behaviour of the spontaneously emulsifying systems [33, 84]. In view of this, the effect of the pH of the aqueous phase on the resultant nanoemulsion should also be investigated.
6.6. Effect of Temperature.
Self-emulsification has been shown to be specific to the temperature at which self-emulsification occurs [33, 52]. Hence, the effect of temperature on the globule size can also be investigated [22].
6.7. Viscosity.
The viscosity of the liquid SEDDS is useful to assess its ability to be filled in the hard or soft gelatin capsules. If the system has very low viscosity, it may enhance the probability of leakage from the capsule and the system with too high viscosity may create problem in pourability [91].
6.8. Centrifugation Test.
This test can be used to determine the stability of the SEDDS after emulsion formation. For this, the samples diluted with distilled water are centrifuged at specified rpm for specified time and then examined for the phase separation [92, 93].
6.9. Dye Solubilization Test.
The characterization of self-emulsifying drug delivery system can be made utilizing dye solubilization [49]. This test is used to identify the nature of the formed nanoemulsion and its continuous phase. For this, the water-soluble dye is sprinkled onto the surface of the prepared nanoemulsion. By observing the dispersion of dye or the clump formation, the nature of the internal, external phase of the emulsion can be determined.
6.10. Cloud Point Measurement.
The cloud point is a necessary factor in SEDDS consisting of nonionic surfactants. When the temperature is higher than the cloud point, an irreversible phase separation will occur and the cloudiness of the preparation would have a bad effect on drug absorption, because of the dehydration of its ingredients. Hence, the cloud point for SNEDDS should be above 37°C, which will avoid phase separation occurring in the gastrointestinal tract [22, 94, 95].
6.11. Transmission Electron Microscopy.
The morphology of the nanoemulsion obtained from SEDDS is investigated using transmission electron microscopy.
7. Conclusions.
Advancement of the technologies and design and development of new chemical moieties having targeting potential is leading to emergence of new drug molecules having therapeutic effect but unfavourable physicochemical properties for their drug absorption in the body. This is becoming the greatest challenge to the formulation scientists to efficiently deliver such drug molecules mostly exhibiting poor aqueous solubility.
Lipidic formulations are promising approach for various categories of drug molecules having challenging drug properties. Among the various lipid formulations, the self-emulsifying delivery systems offer additional advantages of higher stability, suitability for hydrolytically susceptible drugs, high drug loading capacity, potential for oral drug delivery (solid-SEDDS), ease of manufacture and scale-up, and so forth, if suitably formulated with proper selection of excipients.
SEDDSs are mostly investigated for the BCS class II drugs having low aqueous solubility for their bioavailability enhancement and have shown promising success. They have the potential to solve the problems associated with drugs of all other classes of BCS also as summarized in Table 4. Some studies have already been performed with positive results. More investigations are needed to get better insight in the field.
The challenges associated with the formulation of self-emulsifying system include the selection of right excipients with consideration of their solvent capacity, miscibility, chemical stability, capsule compatibility, self-dispersibility, regulatory issues, and so forth. The major excipients required for their formulation are the oil, surfactant, and the cosurfactant for liquid self-emulsifying systems. The criteria for the selection of the combination of excipients for SEDDS formulations should include their solubilising capacity for the required dose of drug, ability to self-emulsify the system when in contact with the gastric fluid (by use of phase diagram), their regulatory approval state for oral use with consideration of their permitted concentration, and so forth. The material used for transforming liquid SEDDS to solid forms should be inert, compatible and should not affect the emulsifying properties and the release profile of the drug.
The various techniques employed for the solidification may also affect the product quality. Various authors have reported insignificant effect on the emulsification properties of solid-SEDDS prepared by spray drying, free drying (lyophilisation), or the adsorption and extrusion technique with respect to the corresponding liquid SEDDS [34, 36, 45, 65]. Spray drying may be preferred because of their capability to produce smooth surfaced, well separated spherical particles at a rapid rate. But it may not be suitable for thermolabile drugs where lyophilization technique may be beneficial.
Another challenge associated with the SEDDS is that their in vivo assessment is difficult in small animals owing to the small volume of gastric fluid in comparison to the humans which may not be sufficient for proper self-emulsification. One can foresee a good scope for the growth of the self-emulsifying drug delivery systems in near future, provided some means are developed for the estimation of their in vivo performance. There is a need for the agents which have even better self-emulsifying properties at lower concentrations to minimize any possibility of undesired effects like gastric irritation which may be associated with this system of drug delivery due to comparatively higher amount of surfactant and co-surfactant used in their formulation. A lot of investigations have been done in the field, yet there is a need for the more predictive in vitro models for predicting the changes involving the drug in SEDDS in the gut, so that the fate of the drug in vivo can be more reliably monitored. Future research may involve human bioavailability studies as well.
List of Abbreviations.
Conflict of Interests.
The authors declare that there is no conflict of interests regarding the publication of this paper.

Pharmaceutical Solid Dispersion Technology: A Strategy to Improve Dissolution of Poorly Water-Soluble Drugs.
Author(s): Shobhit Kumar, Satish K. Gupta. Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Delhi - Roorkee Highway, NH-58, Baghpat Crossing, Meerut-250005, U. P. Índia.
Journal Name: Recent Patents on Drug Delivery & Formulation.
Oral bioavailability is the major problem when a poorly water-soluble active agent is delivered via oral route. To overcome such problems, solid dispersion systems have been demonstrated in literature to enhance the dissolution property of poorly water-soluble drugs. In the present review, the important aspects to be considered during preparation of solid dispersion systems viz., properties of polymer and preparation techniques of solid dispersion which affect the dissolution rate are discussed. Formulation and evaluation techniques for solid dispersions have been described. The final section of article highlights the recent patents and studies related to solid dispersion systems.
Keywords: Bioavailability, carrier, dissolution rate, polymers, solid dispersions.
Recent Patents on Drug Delivery & Formulation.
Title: Pharmaceutical Solid Dispersion Technology: A Strategy to Improve Dissolution of Poorly Water-Soluble Drugs.
Author(s): Shobhit Kumar and Satish K. Gupta.
Affiliation: Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Delhi - Roorkee Highway, NH-58, Baghpat Crossing, Meerut-250005, U. P. Índia.
Keywords: Bioavailability, carrier, dissolution rate, polymers, solid dispersions.
Abstract: Oral bioavailability is the major problem when a poorly water-soluble active agent is delivered via oral route. To overcome such problems, solid dispersion systems have been demonstrated in literature to enhance the dissolution property of poorly water-soluble drugs. In the present review, the important aspects to be considered during preparation of solid dispersion systems viz., properties of polymer and preparation techniques of solid dispersion which affect the dissolution rate are discussed. Formulation and evaluation techniques for solid dispersions have been described. The final section of article highlights the recent patents and studies related to solid dispersion systems.

Improved Bioavailability of Poorly Water-Soluble Drug Curcumin in Cellulose Acetate Solid Dispersion.
Shuxin Wan Yingqian Sun Xiuxiang Qi Fengping Tan Email author.
Curcumin (Cur), one of the most widely used natural active constituents with a great variety of beneficial biological and pharmacological activities, is a practically water-insoluble substance with a short biologic half-life. The aim of this study was to develop a sustained-release solid dispersion by employing water-insoluble carrier cellulose acetate for solubility enhancement, release control, and oral bioavailability improvement of Cur. Solid dispersions were characterized by solubility, in vitro drug release, Fourier transform infrared spectroscopy, X-ray diffractometry, and differential scanning calorimetry studies. The in vivo performance was assessed by a pharmacokinetic study. Solid-state characterization techniques revealed the amorphous nature of Cur in solid dispersions. Solubility/dissolution of Cur was enhanced in the formulations in comparison with pure drug. Sustained-release profiles of Cur from the solid dispersions were ideally controlled in vitro up to 12 h. The optimized formulation provided an improved pharmacokinetic parameter ( C max = 187.03 ng/ml, t max = 1.95 h) in rats as compared with pure drug ( C max = 87.06 ng/ml, t max = 0.66 h). The information from this study suggests that the developed solid dispersions successfully enhanced the solubility and sustained release of poorly water-soluble drug Cur, thus improving its oral bioavailability effectively.
Notas.
ACKNOWLEDGMENTS.
Xiuxiang Qi acknowledges the National Science Foundation for Post-doctoral Scientists of China (grant no. 20090450761) for the financial support. The authors also thank Miss Xiling Zhao for revising the English text.
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Shuxin Wan 1 Yingqian Sun 1 Xiuxiang Qi 1 Fengping Tan 1 Email author 1. Tianjin Key Laboratory of Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology Tianjin University Tianjin People’s Republic of China.
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SOLID DISPERSION: A NOVEL MEANS OF SOLUBILITY ENHANCEMENT.
RUBENDRA KURMI 1 , DINESH KUMAR MISHRA* 1 , DINESH KUMAR JAIN 1.
1 IPS Academy, College of Pharmacy Indore (M. P.) Pin 452012.
Received: 20 Oct 2015 Revised and Accepted: 14 Aug 2015.
Poor solubility of drugs is a major challenge in the formulation development. Solid dispersion is introduced as a novel means for enhancement of solubility. Solid dispersion may be defined as a set of solid products comprising of at least two diverse components, usually hydrophilic matrix and hydrophobic drug. This matrix may be crystalline or amorphous in nature. As per biopharmaceutical classification system class II drugs are with low solubility and high permeability and are the promising candidates for improvement of solubility as well as bioavailability by means of solid dispersion. Practical aspects pertaining to preparation of solid dispersions, like the selection of carrier, drugs molecular arrangement in these preparations are discussed in this article. Proposed article highlights the various preparation techniques of solid dispersion, characterization, available recent technologies, marketed preparation, future prospective etc.
Keywords: Matrix, Solubility, Carrier, Solid dispersion.
© 2016 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (creativecommons/licenses/by/4.0/)
The simple and easy way of administration of the drug is through oral route. The oral dosage forms have many benefits compared to other dosage forms like greater stability, accurate dosage, smaller bulk and ease of production. The oral route has been considered as most common and preferred route owing to convenience and easy administration. As a patient’s prospect, swallowing a dosage form is a comfortable means of taking medication [1, 2]. Solubility is a major challenge for certain drugs to develop a suitable formulation for administration of drugs orally like Griseofulvin, Digoxin, Phenytoin, Sulphathiazole and Chloramphenicol. With the recent advent of high-throughput screening of potential therapeutics, the numerous drug candidates with poor solubility has increased severely and their formulation for oral delivery poses great challenge to formulation scientists in the pharmaceutical industry [3, 4]. Major problem encountered during oral delivery of certain active agents is poor bioavailability due to inadequate drug absorption. Therefore pharmaceutical research is mainly focused on two prime areas: first to improve the oral bioavailability of active agents including solubility enhancement and dissolution rate of poorly water-soluble drugs and secondly to enhance the permeability of poorly permeable drugs. In the Biopharmaceutical Classification System (BCS) (table 1) drugs with high membrane permeability and low aqueous solubility are categorized as Class II drugs. Therefore, solid dispersion (SD) technologies are particularly useful in the improvement of oral absorption as well as the bioavailability of BCS class II drugs [5].
Table 1: General BCS for orally administered drugs.
The Solubility is the property of a liquid, solid, or gaseous chemical substance called solute to dissolve in a liquid, solid, or gaseous solvent to obtain a homogeneous solution of the solute in the solvent. The solubility of any substance basically depends on the solvent used in temperature and pressure as shown in (table 2) [6].
Table 2: Solubility aspect of parameter.
Part of solvent required per part of solute.
From 100 to 1000.
Very slightly soluble.
From 1000 to 10,000.
Importance of solubility.
Solubility is one of the significant parameters to attain a preferred concentration of drug in systemic circulation for providing a therapeutic response. Oral intake is the most suitable and frequently employed route of drug delivery owing to its ease of administration, high patient compliance, cost effectiveness, least sterility constraints, and flexibility in the design of dosage form. The oral bioavailability depends on several factors including aqueous solubility, drug permeability, dissolution rate, first-pass metabolism, pre-systemic metabolism, and susceptibility to efflux mechanisms [7].
Factors affecting solubility.
The solubility depends on the physical form of the solid, the nature and composition of the solvent medium as well as temperature and pressure of system [8, 9].
It is very much related to solubility and affects surface area to volume. If the particle size is reduced, this ratio gets increased. Greater the surface area greater the interaction with the solvent occurs.
The effect of particle size on solubility can be described by [10].
S, is the solubility of infinitely large particles.
S 0, is the solubility of fine particles.
V, is molar volume.
R, is the radius of the fine particle.
T, absolute temp in °K.
R, universal gas constant.
Usually, solubility of a solid solute is increased due to increase in temperature.
An increase in pressure causes an increase in solubility and vice versa for gaseous solutes while for solid and liquid solutes it has no effect on solubility [11].
(d) Nature of the solute and solvent.
Nature of solute and solvent affect solubility. For example, one gram of lead chloride can be dissolved in 100 grams of water at room temperature; while 200 grams of zinc chloride can be dissolved. This vast difference in solubility is due to the difference in the nature.
Molecular size is also affects the solubility. The bigger the molecule or greater the molecular weight, the less soluble will be the compound. In the case of organic compounds, the quantity of carbon branching will lead to increase in solubility as more branches reduce the size of the molecule [12, 13].
It is known that like dissolve like. Generally polar solute dissolves in polar solvents while non-polar solute dissolves in non-polar solvents. Polar solute compound is having both ends to the molecule positive as well as negative. For polar solvent, the positive end of it attracts negative end of the solute molecule. This type of interaction is known as dipole-dipole interaction [14].
The capacity for a substance to crystallize in more than one crystalline form is a polymorphism. It is possible that all crystals can crystallize in different forms or polymorphs. If the change from one polymorph to another is reversible, the process is called enantiotropy. If the system is monotropic, there is a transition point above the melting points of both polymorphs. Polymorphs can vary in melting point. Since the melting point of the solid is related to solubility, so polymorphs will have different solubility [15, 16].
Techniques for solubility enhancement.
There are various techniques that help in increasing the solubility of drugs are as follows [1, 17].
1. Salt formation.
II. Physical modifications.
1. Particle size reduction.
2. Modification of the crystal habit.
4. Solubilization by surfactants.
5. Drug dispersion in carriers.
There are various techniques for solubility enhancement. Solid dispersion is one of the best approaches for solubility enhancement. The term SD refers to a set of solid products comprising of at least two diverse components, usually hydrophilic matrix and a hydrophobic drug. The matrix may be crystalline or amorphous, and the drug can be dispersed in either form [2, 7, 18, 19].
1. Improved drug bioavailability and change in water solubility are possible.
2. More efficient than particle size reduction techniques, since the latter have a particle size reduction limit around 2–5 mm which frequently is not enough to improve considerably the drug solubility or drug release in the small intestine [20].
3. Increase in dissolution rate and extent of absorption and reduction in pre-systemic metabolism.
4. Transformation of liquid form of drug into solid form.
5. Parameters, such as carrier molecular weight and composition, drug crystallinity and particle porosity and wettability, when successfully controlled, can produce improvements in bioavailability [2, 21].
1. Changes in crystallinity and a decline in dissolution rate with aging [22].
2. Moisture and temperature have deteriorating effect on SD than on physical mixtures.
3. Some SD may not lend them to easy handling because of tackiness.
4. Drawback of SD is their poor scale-up for the purposes of manufacturing [23, 24].
Researchers have classified SD on various bases, but usually, it can be classified as follows (fig. 1)[2].
On the basis of carrier employed.
SD can be prepared employing various types of hydrophilic carriers. These carriers or polymers affects the final properties of SD including, its state, drug release kinetics, dissolution profile, stability profile, etc. Hence taking in to the consideration the above-mentioned facts, SDmay be further subdivided into three types: [25, 26].
This type of system causes the chances of mixture eutectic development which releases the drug as microcrystals and ultimately improves the solubility. In continuation to successful SD of drugs like Sulphathiazole and Chloramphenicol preparation using urea and sugar as crystalline carrier systems. Hence, SD which is developed by using crystalline carriers is designated as “FGSD” [27].
Fully synthetic polymers include povidone (PVP), polyethylene glycols (PEG) and polymethacrylates. Natural product based polymers are mainly composed by cellulose derivatives, such as hydroxypropylmethylcellulose (HPMC), ethyl cellulose or hydroxypropyl cellulose or starch derivates, like cyclodextrins [17, 28].
Example: Surface active self-emulsifying carriers: Poloxamer 408, Tween 80, and Gelucire 44/141 [20].
Two compounds which are completely miscible in the liquid state leads to simple eutectic mixture formation but only to a very limited extent in the solid state (fig. 2) [29]. This is usually prepared by rapid solidification of fused melt of two components that shows complete liquid miscibility but negligible solid-solid solution [12, 17].
Fig. 2: Simple eutectic mixture phase diagram.
Amorphous precipitation in crystalline matrix.
This is similar to simple eutectic mixtures but only difference is that drug gets precipitated out in an amorphous form.
When two components crystallize together in a homogeneous single phase considered as solid solution. They are of two types: Substitutional solid solutions, interstitial solutions. Solid solutions can generally attain quicker dissolution rate than the corresponding eutectic mixture [10, 30].
Glass solutions and suspensions.
A homogeneous system which consists of solid solute dissolved in a solid solvent is known as glass solutions. Mixed/heterogeneous groups of crystals are formed because both components crystallize simultaneously. A homogeneous system in which the drug molecule is suspended in a glassy carrier is termed as glass suspensions. Glassy state in glass solution and glass suspension is characterized by transparency and brittleness below the glass transition temperature [14, 19, 31].
PEG compounds can be obtained after reaction of ethylene glycol and ethylene oxide. Molecular weights above 300000 are known to as polyethylene oxides [17, 21, 32].
The complexity of glycerides advances by manipulation of the terminal hydroxyl and phosphate associated head groups to form phospholipids. Commonly used phospholipid head groups are choline, ethanolamine, serine, inositol, inositol phosphate, and glycerol esters [20, 21, 33].
It is soluble in water, ethanol, chloroform and isopropyl alcohol and molecular weight ranges from 10000 to 700000. SD prepared by melt method is not suitable for PVP because it melts at a very high temperature above 275 and gets decomposed [17, 22]. The effect of molecular weight of PVP on the rate of dissolution of a drug is more consistent than for PEG. An increase in molecular weight of PVP will decrease the dissolution rate of most drugs. An increase in viscosity of PVP solution due to an increase in molecular weight decreases diffusion of drug molecules from the surface of viscous material into the dissolution medium, lower molecular weight PVP has a short swelling time prior to dissolution resulting in an increase in dissolution rate of the polymer and drug [4, 34].
They are mainly used to enrich solubility, chemical protection, masking of taste and better handling by the transformation of liquids into solids by entrapment.
Selection of solvent for SD.
The solvent to be included for the formulation of SD should have the following criteria as shown in (table 3) [17, 6].
Table 3: List of solvent for SD.
Melting and solvent evaporation methods are the two major processes of preparing SD.
In this method drug is dissolved in a suitable liquid solvent. Then, the solution is incorporated directly into the melt of polyethylene glycol obtainable below 70 °c, without removing the liquid solvent. It has been shown that without significant loss of its solid property 5-10% (w/w) of the liquid compound could be incorporated into polyethylene glycol 6000 [2, 10, 35]. This method consists of the physical mixture of drug and carrier preparation followed by heating until it gets melted. Finally obtained solid mass is then crushed and sieved. Additionally supersaturation of drug or solute can be achieved by quenching the melt quickly from a high temperature [17, 36]. This method is also known as fusion method. Although numerous compounds either drugs or carriers gets decomposed or evaporate during the process due to elevated temperature. Oxidative degradation of drug or carrier can be avoided possibly by heating the physical mixture in a sealed container or melting it under vacuum or in the presence of inert gas like nitrogen [23].
Solvent evaporation method.
The solvent evaporation method consists of the solubilization of the drug and carrier in a volatile solvent that is later evaporated as shown in (fig. 3). The thermal breakdown of drugs or carriers can be stopped, since organic solvent evaporation occurs at low temperature [37]. A basic process of preparing SD of this type consists of dissolving the drug and the polymeric carrier in a common solvent, such as ethanol, chloroform, a mixture of ethanol and dichloromethane. Normally, the resulting films are pulverized and milled [2, 26].
Fig. 3: Preparation of solid dispersion by solvent evaporation method.
Melting solvent method (melt evaporation)
Melt evaporation leads to the development of SD by dissolution of drug in a appropriate solvent followed by incorporation of solution directly into the melt of polyethylene glycol, which is then evaporated until a clear, solvent free film is left. The obtained film is dried further till constant weight. The film is further dried to constant weight [7, 38]. This technique possesses unique advantages of fusion as well as solvent evaporation methods.
Hot melt extrusion method.
In this method extruder is utilized for intense mixing of components. The components of the extruder are barrel, hopper, a kneading screw, heating jacket, and a die[39]. Generally physical mixture of both the carrier and drug is introduced into the hopper then passed through screw and finally it is extruded from the die (fig. 4). The advantage of the method is to get various shapes and designs of the heated drug-matrix mixture into ophthalmic inserts, implants, or oral dosage form [17, 26].
Other advantage like the continuous production of SD is possible so that large-scale production can easily be achieved. The product produced by this method can easily be handled because any shape can be adopted [40]. Like other methods, miscibility of drug and matrix also creates a problem. Thermolabile compounds can be degraded due to the production of heat generated by the extruder [5, 7].
This is sometimes used interchangeably as the melt method that is appropriate only when the crystalline substances are used as the starting materials. Hence, generally fusion term is chosen [27]. The first SD was developed by this method for pharmaceutical applications. This was a mixture of sulfathiazole and urea which fused and later cooled to get the final dispersion. The eutectic composition was chosen in order to attain to attain concurrent crystallization of drug and matrix during cooling [2, 29, 41].
Supercritical fluid methods.
These methods are generally applied with carbon dioxide, which is used either as a solvent for drug and matrix or as an anti-solvent. While supercritical CO2 is used as solvent, matrix and drug are dissolved and sprayed through nozzle, into an expansion vessel with lowerpressure, and particles are immediately formed (fig. 5)[23, 42]. The mixture causes rapid cooling. In this technique it does not involve the use of organic solvents and since CO2 is considered environmentally friendly, this technique is referred to as ‘solvent free’. The technique is rapid expansion of supercritical solution [28].
Fig. 5: Schematic diagram for supercritical fluid technology [9]
This method was developed in 1920 in which the manufacture of milk powder was one of the first applications of spray drying. Presently, this technique is having great utility in pharmaceutical industry owing to rapid drying and specific characteristics such as particle size and shape of the final product. In this method atomization of suspensions or solutions into fine droplets is done and drying of particles that may lead to the formation of solid particles [14]. This process permits production of fine, dust free powder [29, 43].
This process consists of dissolving the drug and carrier in a common solvent, which is immersed in liquid nitrogen until it is fully frozen. Then, the frozen solution is further lyophilized [1]. The main advantage of this technique is that the drug exposed to minimum thermal stress and low risk of phase separation. Freeze drying technique is poorly explored for making SD [30, 44].
In this technique the drug and carrier are dissolved in a common solvent, frozen and sublimed to attain a lyophilized molecular dispersion [31, 45].
The enhancement in dissolution rate because of SD formation, relative to pure drug, varies from as high as 400 fold to less than two-fold. The increase in dissolution rate can be attributed to myriad factors and it is very difficult to show the experimentally importance of one factor in comparison to other. SD improves the dissolution rate of poorly water-soluble drugs by following mechanisms [17, 46].
Reduction in particle size Improvement in wettability and dispersibility Change in crystalline form of drug to amorphous form Reduction in aggregation and agglomeration of drug particles.
Table 4: Applications of pharmaceutical field.
Dissolution rate enhancement.
Celecoxib, hydrocortisone, ibuprofen, diazepam.
Mucoadhesive drug delivery.
Mouth dissolving tablet(MDT)
Hydrocortisone, carbamazepine, 5-aminosalicylic acid, curcumin.
Dry powder for reconstitution.
Diclofenac sodium, indometahcin, ketoprofen, nifedipine.
Orodispersible tablets (ODT)
Acelofenac, indomethacin, promethazine hydrochloride.
Contribution in the field of SD.
Various milestones and turning point in the field of solubility enhancement achieved through usage of SDtechnique since it was put before by Sekiguchi and Obi in1961 is tabulated below (table 5)
Table 5: Historical turning point in the field of SD technology.
Studied absorption behavior of eutectic mixture of sulphathiazole and compared with.
ordinary sulphathiazole. It was assumed that this new type of formulation could be utilized for better therapeutic effect.
Demonstrated a simple and precise method for the preparation of SD and solid solution. It was.
concluded that that solid solution may enhance the drug dissolution.
Described the preparation of an aqueous colloidal dispersion of carotene by solvent evaporation.
method with polyvinyl pyrrolidone (PVP) as hydrophilic carrier. Analytical data showed that.
carotene is molecularly dispersed in SD improved solubility.
Studied a method for the preparation of Griseofulvin SD with marked increment in solubility.
Reigelman and Chiou.
Reported that the absorption in body fluids of poorly soluble drugs can be enhanced by forming a.
glassy solid matrix of a carrier and the drug.
Reported the invention related to a novel galenic form of verapamil with excellent bioavailability.
Described a novel thermal-mechano-chemical process for preparation of S.
Reported the solvent free and temperature independent approach for the formulation of SD.
using the twin screw extruder. The resulting SD was found to be superior in terms of its performance and stability.
They introduced one of the pharmaceutical SD compositions comprising of an HIV protease inhibitor.
as drug and peg as carrier system. The SD claimed to effectively cure HIV; as it was able to enhance.
the solubility and hence the bioavailability of drug.
Described a simple solvent evaporation method for the.
production of SD, comprising of at least one therapeutic agent. It was found that the SD enhances the.
solubility of drug in aqueous media.
Reported a method for oral administration of mTOR inhibitors especially in case of oral cancer patient SD.
Expressed the composition and therapeutic use of water dispersible molecular SD constituting of.
sparingly water soluble drug or any salt in particulatable lipidic matrix.
Demonstrated a method of preparation of disintegrant free orodispersible tablet containing SD.
Reported a method of preparation of reconstituted powder for oral administration of Etravirine for.
safe and effective management of HIV via SD technology.
Reported a tactful employment of SD technique for the preparation of intravaginal ring.
containing a homogenously distributed drug.
Reported a method of preparation of solid dosage form comprising of SD, containing an anti-HIV.
drug with hydrophilic polymer of low glass transition temperature approx 50 °C.
Reviewed the SD a strategy for improving the solubility of.
poorly soluble drugs.
Reviewed SD and its possible approaches for improvement of drug solubility.
Explored the possibility of SD in pharmaceutical drug development from basics to clinical applications.
Reviewed the various preparation techniques for SD, characterization and compiled some of the recent technology transfers.
Kommavarapu et al.
Gave an overview of SD for solubility and bioavailability enhancement of poorly aqueous soluble drugs.
Table 6: Marketed products of SD.
Pendinal pharm inc.
Hepatitis type b.
The physical nature of SD can be characterized by various methods. Single method is not sufficient to furnish the complete information rather a combination of two or more techniques is needed [32, 47].
Thermal analysis X-ray diffraction method Spectroscopic method Modulated temperature differential scanning calorimetric Environmental scanning electron microscopy Dissolution testing Dissolution rate method Microscopic method Thermodynamic method [4]
Thermal analysis techniques.
The thermal analysis comprises a group of techniques in which a physical property of a substance is measured as a function of temperature while the substance is subjected to a controlled temperature programmed [48]. In differential thermal analysis (DTA), the temperature difference existing between a sample and an inert reference material is measured. [1, 33].
This method can be used to determine the arrangement of atoms within a crystal. In this method X-ray beam hit a crystal and diffracts into many directions. A crystallographer can produce a three-dimensional picture of the density of electrons within the crystal from the angles and intensities of these diffracted beams. The mean positions of the atoms in the crystal can be determined from this electron density [34, 49].
It is the study of the interaction between radiation and matter as a function of wavelength (λ). Conventionally, spectroscopy referred to as the use of visible light dispersed according to its wavelength, e. g. by a prism [50]. Later on the concept was further extended to comprise the measurement of a quantity as a function of either wavelength or frequency [35, 51].
Environmental scanning electron microscopy.
The morphology of the spray-dried ternary SD can be characterized with a Philips XL30 ESEM FEG environmental scanning electron microscope operating at 25 kV accelerating voltage and a vacuum[52]. The samples were sprayed on double-sided carbon tape that was mounted on conventional SEM stubs [36, 37, 53].
Applications of sd in pharmaceutical field.
Apart from absorption enhancement, the SDcould have numerous other pharmaceutical applications, which need to be explored [32]. Currently, they have been applied successfully to develop orodispersible tablets, mouth dissolving tablets, enhancement of dissolution rate, mucoadhesive drug delivery, dry powder for reconstitution, controlled drug delivery (table 4)[19, 54].
Application of SD is not restricted only to laboratory scale, but it has been applied successfully on a commercial scale. Various products available at commercial scale are listed below table 6 [69, 27].
The enhancement of oral bioavailability of poorly water-soluble drugs remains one of the most challenging aspects of drug development. Successful development of SD system for preclinical, clinical and commercial use has been feasible in recent years due to the availability of surface active carriers and self-emulsifying carriers. These significantly help to improve the bioavailability and bioequivalence. Finally it is asserted that if the manufacturing of SD are properly controlled and validated then it can be suitably propelled on commercial scale and various cost-effective dosage form can be launched.
The most frequent concerns with SD have been the ability to scale-up the manufacturing method, the physical stability of the dispersion, and the amount of carrier needed to facilitate the required increase in the release rate. When a high carrier/drug ratio must be used, the amount of dispersion required to administer the usual dose of the drug may be too high to produce a tablet or capsule that can be easily swallowed. The higher the unit dose of the drug, the more likely this problem is to occur. Another aspect that must be considered is the correlation between in vitro and in vivo results. Dispersions with a rapid in vitro release rate may fail to improve the oral bioavailability if the in vitro test conditions do not adequately simulate the gastrointestinal conditions, or if there is some specific interaction between the carrier and a component of the GI. Several products containing SD are already on the market and the number is expected to increase dramatically in the next years.

Improved Bioavailability of Poorly Water-Soluble Drug Curcumin in Cellulose Acetate Solid Dispersion.
Shuxin Wan Yingqian Sun Xiuxiang Qi Fengping Tan Email author.
Curcumin (Cur), one of the most widely used natural active constituents with a great variety of beneficial biological and pharmacological activities, is a practically water-insoluble substance with a short biologic half-life. The aim of this study was to develop a sustained-release solid dispersion by employing water-insoluble carrier cellulose acetate for solubility enhancement, release control, and oral bioavailability improvement of Cur. Solid dispersions were characterized by solubility, in vitro drug release, Fourier transform infrared spectroscopy, X-ray diffractometry, and differential scanning calorimetry studies. The in vivo performance was assessed by a pharmacokinetic study. Solid-state characterization techniques revealed the amorphous nature of Cur in solid dispersions. Solubility/dissolution of Cur was enhanced in the formulations in comparison with pure drug. Sustained-release profiles of Cur from the solid dispersions were ideally controlled in vitro up to 12 h. The optimized formulation provided an improved pharmacokinetic parameter ( C max = 187.03 ng/ml, t max = 1.95 h) in rats as compared with pure drug ( C max = 87.06 ng/ml, t max = 0.66 h). The information from this study suggests that the developed solid dispersions successfully enhanced the solubility and sustained release of poorly water-soluble drug Cur, thus improving its oral bioavailability effectively.
Notas.
ACKNOWLEDGMENTS.
Xiuxiang Qi acknowledges the National Science Foundation for Post-doctoral Scientists of China (grant no. 20090450761) for the financial support. The authors also thank Miss Xiling Zhao for revising the English text.
Referências.
Informações sobre direitos autorais.
Autores e afiliações.
Shuxin Wan 1 Yingqian Sun 1 Xiuxiang Qi 1 Fengping Tan 1 Email author 1. Tianjin Key Laboratory of Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology Tianjin University Tianjin People’s Republic of China.
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