Revisiting dispersible milk-drug tablets as a solid lipid formulation in the context of digestion

Abstract

Oral delivery of dispersible tablets is a preferred route of administration for paediatrics due to ease of administration and dose control. Milk has gained interest as a drug delivery system due to its ability to dissolve poorly water-soluble drugs. There are no reports of milk tablet formulations being assessed in the context of lipid digestion, which is critical in influencing orally administered drug solubility and bioavailability. Milk-drug tablets were formulated by blending freeze-dried bovine milk or infant formula with the poorly water-soluble drug cinnarizine, which were directly compressed. Tablet strength, friability and dispersibility were quantified and synchrotron X-ray scattering was used to determine the lipid liquid crystalline phases formed during in vitro digestion of dispersed tablets and their effects on drug solubilisation. Tableting had a significant impact on the self-assembly of lipids in redispersed milk tablets whereas no effect was seen for infant formula tablets. Incorporation of the disintegrant poly(vinylpolypyrrolidone) to reduce tablet dispersion times promoted the formation of hexagonal liquid crystalline phases upon digestion but had minimal effect on drug solubilisation. These findings show that similar to the use of liquid milk, the formulation of milk-drug tablets can be used to improve solubilisation of poorly water-soluble drugs.

Keywords: Dispersible tablet; Drug solubilisation; In vitro digestion; Milk; Self-assembly; X-ray scattering.

Graphical abstract

Fig. 1

Formulation of dispersible freeze-dried milk/infant formula-drug tablets using freeze-dried milk or infant formula and cinnarizine as the drug. Tablet characteristics were studied using pharmacopeial methods, while lipid self-assembly and drug solubilisation during digestion were studied using in situ X-ray diffraction.

Fig. 2

(a) Appearance of freeze-dried milk/infant formula-cinnarizine tablets and (b) thickness of freeze-dried milk tablets, left = without PVPP, right = with PVPP.

Fig. 3

Turbidity as a function of time for (a) freeze-dried milk-cinnarizine tablet and (b) infant formula-cinnarizine tablet with increasing amounts of PVPP added.

Fig. 4

SAXS profiles for the digestion of (a) freeze-dried milk, (b) freeze-dried milk tablets, (c) infant formula before tableting and (d) infant formula tablets after the addition of lipase over 40 min at pH 6.5, 37 °C. “1″ represents the bicontinuous cubic Im3m phase, with peak q ratios of √2: √4: √6, “2” refers to the cubic Pn3m phase with peak q ratios of √2: √3: √4, “3” is annotated as hexagonal phase with peak q ratios of 1: √3: √4 and “4” represents the lamellar phase with peak q ratios of 1: 2: 3.

Fig. 5

(a) SAXS profiles from the end of digestion of freeze-dried milk tablets (reproduced from Fig. 4b at time = 40 min) and freeze-dried milk-cinnarizine tablets. “1” represents the bicontinuous cubic Im3m phase, “2” refers to the cubic Pn3m phase, “3” is annotated as hexagonal and “4” represents the lamellar phase. Trends in lattice parameters as a function of digestion time of the phases formed from the self-assembly of milk lipids from (b) freeze-dried milk tablets and (c) freeze-dried milk-cinnarizine tablets.

Fig. 6

(a) SAXS profiles from the end of digestion of infant formula tablets (reproduced from Fig. 4d at time = 40 min) and infant formula-cinnarizine tablets. “3” is annotated as hexagonal and “4” represents the lamellar phase. Trends in lattice parameters as a function of digestion time of the phases formed from the self-assembly of lipids from (b) infant formula tablets and (c) infant formula-cinnarizine tablets.

Fig. 7

SAXS profiles from the end of digestion of (a) freeze-dried milk tablets with and without PVPP and (b) infant formula tablets with and without PVPP. “1” represents the bicontinuous cubic Im3m phase, “3” is annotated as hexagonal and “4” represents the lamellar phase.

Fig. 8

SAXS profiles during in vitro digestion of (a) freeze-dried milk-cinnarizine tablets and (b) infant formula-cinnarizine tablets between q = 1.20 and 1.50 Å⁻¹. The peak at 1.32 Å⁻¹ is characteristic for cinnarizine. Residual peak area of cinnarizine (represented by the green and black hollow squares) and titrated FFA released (indicated by the orange and blue hollow circles) of (c) freeze-dried milk-cinnarizine tablets with and without PVPP and (d) infant formula-cinnarizine tablets with and without PVPP. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)