Cyclodextrins and ternary complexes: technology …

1 Article Brazilian Journal of Pharmaceutical Sciences vol. 47, n. 4, , 2011. Cyclodextrins and ternary complexes : technology to improve solubility of poorly soluble drugs Janisse Crestani de Miranda1, T rcio Elyan Azevedo Martins1, Francisco Veiga2, Humberto Gomes Ferraz1,*. 1. Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of S o Paulo, 2 Faculty of Pharmacy, University of Coimbra Cyclodextrins (CDs) are cyclic oligosaccharides composed of D-glucopyranoside units linked by glycosidic bonds. Their main property is the ability to modify the physicochemical and biological characteristics of low-soluble drugs through the formation of drug:CD inclusion complexes .

2 Inclusion complexation requires that host molecules fit completely or partially within the CD cavity. This adjustment is directly related to the physicochemical properties of the guest and host molecules, easy accommodation of guest molecules within the CD cavity, stoichiometry, therapeutic dose, and toxicity. However, dosage forms may achieve a high volume, depending on the amount of CD required. Thus, it is necessary to increase solubilization efficiency in order to use smaller amounts of CD. This can be achieved by adding small amounts of water-soluble polymers to the system.

3 This review addresses aspects related to drug complexation with CDs using water-soluble polymers to optimize the amount of CD used in the formulation in order to increase drug solubility and reduce dosage form volume. Uniterms: Cyclodextrins . ternary complexes . Drugs/complexation. Water-soluble polymers/use. Drugs/. solubility. Inclusion complexe. Ciclodextrinas (CDs) s o oligossacar deos c clicos, compostos por unidades D-glicopiranos dicas ligadas entre si por meio de liga es glicos dicas e sua principal propriedade est na capacidade de alterar as caracter sticas f sico-qu micas e biol gicas de f rmacos com baixa solubilidade por meio da forma o de complexos de inclus o f rmaco:CD.

4 Para a forma o dos complexos de inclus o a mol cula hospedeira necessita ajustar-se total ou parcialmente no interior da cavidade da CD, onde este ajuste est diretamente ligado a propriedades f sico-qu micas da mol cula h spede e hospedeira, facilidade de alojamento da mol cula h spede no interior da cavidade da CD, estequiometria, dose terap utica e toxicidade. No entanto, as formas farmac uticas podem atingir um elevado volume, em fun o da quantidade de CD requerida, sendo necess rio aumentar sua efici ncia de solubiliza o para que seja poss vel utilizar menores quantidades das mesmas.

5 Isso pode ser obtido com a inclus o de pequenas quantidades de pol meros hidrossol veis ao sistema. Nessa revis o, s o abordados aspectos relacionados complexa o de f rmacos com ciclodextrinas empregando-se pol meros hidrossol veis para otimiza o da quantidade de CD utilizada na formula o, com a finalidade de aumentar a solubilidade do f rmaco e reduzir o volume das prepara es. Unitermos: SCiclodextrinas. Complexos tern rios. F rmacos/complexa o. Pol meros hidrossol veis/. uso. F rmacos/solubilidade. Complexos de inclus o. INTRODUCTION safe and effective dosage formulation, because prepara- tion, absorption and even the biological activity of a drug Among several factors, solubility in water is of are all dependent on its solubility.

6 However, the amount paramount importance in the development of a sufficiently of lipophilic molecules used in treatment is relatively high and tends to increase, considering that many different *Correspondence: H. G. Ferraz. Departamento de Farm cia, Faculdade de drugs have low solubility (Lipinski, 2000; Grant, Zhang, Ci ncias Farmac uticas USP. Av. Prof. Lineu Prestes, 580 - Cidade Univer- sit ria, 05508-900 - S o Paulo - SP, Brasil. E-mail: 2011). 666 J. C. Miranda, T. E. A. Martins, F. Veiga, H. G. Ferraz Thus, use of Cyclodextrins (CDs) is one of several (Loftsson et al.)

7 , 1996). The mechanism involved in in- technologies available to improve the solubility of poorly creasing CD complexation efficiency in the presence of water-soluble drugs. The most remarkable property of CDs water-soluble polymers is not yet fully understood; how- is their ability to modify the physicochemical character- ever, it is believed that water-soluble polymers can reduce istics of molecules that are accommodated within their CD mobility and increase the complex solubility (Veiga internal cavity to form the so-called inclusion complexes et al.

8 , 2006). The addition of water-soluble polymers has (Loftsson, Brewster, 1997; Tsai et al., 2010). been shown to increase drug bioavailability and cause an Typical characteristics of formulations containing up to 80% reduction in the amount of CD required (Lofts- inclusion complexes include a faster dissolution rate and son, Fridriksd ttir, 1998; Mura et al., 2001). shorter drug release time, as well as more efficient absorp- The purpose of this study is to outline the relevance tion. This translates into greater oral bioavailability of of using CDs to improve the solubility of poorly water- the drugs involved and an increase in biological activity, soluble drugs, with special emphasis on their structural which may result in a reduction in drug dosage (Valle, characteristics, physicochemical properties, productive 2004; Garnero et al.

9 , 2010). processes, toxicity, derivatives, and use in the pharmaceu- However, the use of CDs is limited in some cases, tical industry. Despite the recognized benefits of ternary because guest molecules need to fit completely or partially (drug:CD:water-soluble polymer) complexes , there have within the CD cavity. This adjustment is directly related been no reviews on the subject in the scientific literature. to the physicochemical properties of the guest and host This review addresses aspects related to drug complex- molecules, easy accommodation of guest molecules within ation with CDs using water-soluble polymers to increase the CD cavity, stoichiometry, therapeutic dose, and CD drug solubility and reduce dosage form volume.

10 Toxicity (Loftsson, Brewster, 1997). An increase in formulation volume represents a criti- Cyclodextrins (CDs). cal stage in the applicability of CD inclusion complexes . We can consider that 1 g of a solid complex corresponds to CDs are cyclic oligosaccharides composed of D- 100-250 mg of a drug (when the molecular weights of the glucopyranoside units (glucose) linked by glycosidic drug and the CD are 200-400 g/mol and 1200-1500 g/mol, bonds. They are obtained from biotechnological processes respectively). Therefore, the use of CDs in oral solid dosage involving the enzymatic degradation of corn starch and of- forms is limited to drug doses less than 200 mg that have fer greater yield with 6, 7 and 8 units of glucose, known as good complexation properties (Loftsson, Brewster, 1996).