Multipolymeric monolayered mucoadhesive films for drug therapy.
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Date
2007
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Abstract
The use of the oral cavity membranes as sites of drug administration has been a topic of increasing interest for the past decade. The buccal route, in particular, offers several advantages over the per oral route and may prove to be a viable alternative to other routes for drug delivery, as it bypasses hepatic first pass metabolism, thereby improving the systemic bioavailability of the administered drug. A controlled drug release formulation may further enhance the therapeutic efficacy of a buccal drug delivery system. Propranolol HCI (PHCI), a non-selective p-blocker, primarily advocated in the treatment of hypertension, has a short half-life (3 - 6 hours) and is also subjected to extensive hepatic first-pass metabolism following oral administration, resulting in a low oral bioavailability, therefore rendering it an ideal candidate for buccal drug delivery. For optimal controlled release and mucoadhesivity of a buccal delivery system containing PHCI, the blending of polymers and drug of opposing solubilities may be required for the formation of monolayered films. The aim of this study was therefore to formulate and characterise multipolymeric monolayered mucoadhesive films containing drug and polymer/s of opposing solubilities for the buccal delivery of PHCI. First, preparation parameters for the formation of monolayered multipolymeric films (MMFs) and homopolymeric PHCI films comprising drug and polymer/s of opposing solubilities, i.e. Chitosan (CHT) and Poly(D,L-lactide-co-glycolide) (PLGA) by an emulsification/casting/solvent evaporation method were investigated. MMFs could be prepared at all homogenisation speeds (6000, 9000, 12000, 15000 rpm) and times (1, 5, 15, 25 minutes). The films showed micromatrices embedded in the film matrix due to the inclusion of the PLGA polymer. Increased homogenisation speed and time resulted in a reduction in the size of the micromatrices. Phase separation occurred at temperatures below 20 °C. Emulsifiers employed in the study (Poly(vinylalcohol) (PVA) and Tween 80®) adversely affected the morphology and appearance of the film and were therefore not considered feasible for inclusion in the formulation. The preparation parameters identified for emulsification without phase separation and the subsequent generation of monolayered films, without phase separation during solvent evaporation and drying, were emulsification at 20 °C and homogenisation at 9500 rpm for 15 minutes. It was discovered through preliminary investigations and a comprehensive literature search that the conventional film casting method of film preparation suffered from poor drug content uniformity. To address this problem of non-uniformity, a specially designed silicone-molded tray (SMT) for film casting was prepared and evaluated in terms of enhancing drug content uniformity. These investigations confirmed that the SMT with teflon-coated perspex inserts provided a reproducible method for the preparation of both homopolymeric and multipolymeric (including drug and polymers of similar and opposing solubilities) films that met drug content uniformity requirements (assay values were within 92-107.5%) and also reduced the variability in mucoadhesivity (p=0.2922), drug release [fi values = 92.76, 90.99 and 86.06) and film thickness for all three trays. The final phase of this study involved the identification of a suitable polymeric blend for the preparation of MMFs comprising hydrophilic and hydrophobic polymers for the controlled buccal delivery of PHCI and subsequent characterisation of these films in terms of their physicochemical/mechanical properties. Initial investigations of different polymers for the formation of homopolymeric films showed that the combination of drug and polymer/s of opposing ionic states was not possible due to complexation. PHCI film formation as homopolymeric films was achievable with hydrophilic polymers, Hydroxypropylmethylcellulose (HPMC) and CHT, and hydrophobic polymers, Ethylcellulose (EC) and Eudragit® RSI00 (EUD100). It was also found that combining PHCI, a hydrophilic drug, with a hydrophilic polymer (CHT or HPMC) failed to retard drug release (> 80% at 1 hour), whilst the release of PHCI from a homopolymeric film comprising a hydrophobic polymer (EC or EUD100) was retarded. A PHCIiEUDlOO (1:10) film provided controlled release but was too retarded (< 67% at 8 hours) for the purposes of this study. Hence, the polymeric content of the formulation was altered by the addition of a hydrophilic polymer CHT, to obtain the desired controlled release profile. A PHCI:EUD100:CHT (1:10:0.5) polymeric blend (MMF) was found to be suitable for the controlled release of PHCI and was reproducible in terms of drug content uniformity (p=0.1964), drug release [h values = 83.18; 82.03 and 71.19) and mucoadhesivity (p=0.9971). Drug release followed Higuchi's square-root model (r2=0.9426). Scanning electron microscopy revealed that the addition of CHT to the PHCI:EUD100 (1:10) film formulation rendered it more textured, which contributed to the faster drug release observed with the PHCI:EUD100:CHT (1:10:0.5) MMF. Swelling and erosion studies indicated that maximal swelling of the films occurred after 1 hour and 28.26% of the film eroded during the 8 hour test period. The system also demonstrated acceptable mucoadhesivity and mechanical properties. The surface pH of the films also remained constant at neutral pH throughout the study. The data obtained in this study confirmed the potential of this multipolymeric monolayered film system as a promising candidate for the controlled buccal delivery of PHCI. Key words: Films; Buccal; Multipolymeric; Mucoadhesive; Controlled drug release; Propranolol HCI
Description
Thesis (M. Med. Sc.) - University of KwaZulu-Natal, 2007.
Keywords
Drug therapy., Mucoactive agents., Theses--Pharmacy and pharmacology.