Formulation of an oral dosage form utilizing the properties of cubic liquid crystalline phases of glyceryl monooleate Ref.: European Journal of Pharmaceutics and Biopharmaceutics 53 (2002) 343–352 Introduction: GMO: FDA -approved food additive, The unique properties of cubic liquid crystalline phases formed from GMO systems have been utilized for the preparation of controlled release systems and in topical and mucosal drug delivery systems due to their adhesive properties.

Investigated model drug: Furosemide (diuretic). Disadvantage of conventional dosage forms: low bioavailability and short period of peak diuresis. Suggested solutions: Sustained release formulations (showed reduced bioavailability of the drug in comparison with immediate release dosage forms), Modified release dosage form having a longer gastric residence time (a correlation was made between gastrointestinal transit and furosemide).

Aim: Investigation of the cubic liquid crystalline phases of GMO to formulate an oral drug delivery system for furosemide. Furosemide when dispersed in GMO and filled into hard gelatin capsules is expected, when exposed to gastrointestinal fluids at body temperature, to swell forming the cubic liquid crystalline phase. The system is expected: To produce sustained release, To be retained in the stomach through its bioadhesive nature.

Glyceryl Monooleate Also known as monoolein or GMO Polar lipid, insoluble but swallable in water, Semisolid, melting point deg.

Methods 1.Preparation of different GMO mixtures a. Preparation of GMO-drug mixtures: GMO > melt (at 45deg in water bath)> add furosemide, PEG 400 and trisodium phosphate (TSP)> continuous mixing > complete dispersion. Store at 5 C in a dark place. b. Samples for phase diagram construction: GMO in glass vials>melt> add warm aqueous media (water, or simulated intestinal fluids without enzymes (SIF) or simulated gastric fluids without enzymes (SGF)) >mix. c. Samples for additives effect on the cubic phase formation: GMO in glass vials>melt> add additives > add warm distilled sufficient to form the cubic phase. Store the well closed samples (b, c) at 37 C in a dark place for 12 h in order to reach equilibrium conditions before testing.

Identification of GMO phases Observation of viscosities and optical properties changes upon heating at constant rate (4 C/ min) on a hot stage connected to polarizing microscope. Results: Reversed micellar phase (L2): clear liquid and isotropic. Cubic phase: very viscous gel and isotropic Other phases were less viscous than the cubic liquid crystalline phase and look radiant when viewed between crossed polarizers. Lamellar phase (La) had a pattern of ‘oily streaks’ and Maltese crosses; Reversed hexagonal phase: fan-like textures. The results proved that the cubic phase of GMO would exist at body temperature in the presence of gastrointestinal fluid.

Fig. 1. Phase diagrams of (a) GMO/distilled water system, (b) GMO/SIF system, (c) GMO/SGF system. SIF, simulated intestinal fluid; SGF, simulated gastric fluid; L2, reversed micellar phase; La, lamellar phase; C, cubic phase; HII, reversed hexagonal phase.

Fig. 2. Phase diagram of GMO containing 5% furosemide in water.

Observation of the melting behavior of GMO: furosemide and their mixtures using a hot-stage microscope at 4 C/min heating rate. Thermal analysis: DSC thermograms of GMO, furosemide each alone and in mixtures were recorded at heating rate of 10 C/min. For mixtures containing furosemide and GMO, the endothermic event attributed to the melting o GMO was not affected by the presence of furosemide.

Partitioning of furosemide between aqueous test solutions and GMO in the cubic liquid crystalline form: known concentration of furosemide + test solution placed in a 100-ml stoppered conical flask in a shaker water bath maintained at 37.0 deg., protected from light to avoid photodegradation of Furosemide, Add One gram of GMO to each flask with continuous shaking, At selected time interval, withdraw 5-ml aliquots, were filter, through a 0.45-mm membrane filter and measure furosemide concentration (spectrophotometrically). Runs were done in triplicate.

The apparent lipid bilayer/water partition coefficient of furosemide versus the corresponding pH value (at 37 C).

Dissolution tests: Samples accurately weighed containing the equivalent of 40 mg furosemide were filled into hard gelatin transparent capsule size (0) and used for dissolution testing within 24 h of preparation. Dissolution tests were carried out in triplicates using USP apparatus II (paddle) (protected from light).

Release rates of furosemide from GMO containing different drug loadings in comparison with an immediate release furosemide capsule using SGF at 37 C

Effect of changing the pH of the dissolution medium on the release rate of furosemide from formula containing furosemide/TSP/PEG 400/ GMO (5:5:10:80) using apparatus I; 100 rpm.

Conclusion ……… A formula containing furosemide/TSP/PEG 400/GMO in the ratio 5:5:10:80, respectively, was found to have optimum properties concerning release characteristics and mucoadhesion. However, future work needs to b concentrated on the evaluation of in vivo mucoadhesive studies on the selected formulation.