Development and evaluation of physical and release properties of a tablet formulation containing dry hydroethanolic extract from Lippia alba leaves

Highlights

• An immediate-release tablet formulation with Lippia alba extract was developed.

• Suitable physical properties of tablets were assured using dry granulation manufacturing.

• Drug content and release profile were studied using acteoside as chemical marker.

• Amounts of acteoside released in acid medium were higher than 80 % in 20 min.

Abstract

The development of an immediate-release solid formulation which contains natural products is a challenge considering several variables. These include the physical properties of the drug, the complex composition of the herbal extracts, and its ability to be released in the body. The present study describes the development and characterization of an immediate-release tablet formulation of a hydroethanolic extract of Lippia alba (Mill.) N. E. Br. dried leaves which possess potential gastroprotective properties and sedative effects. L. alba is a Brazilian herb known as “cidreira,” and the ethnopharmacological use of the leaf infusion has been reported in many South and Central America countries. However, no study has considered phytotherapeutics containing extracts of this herb. To achieve this goal, 14 solid formulations were produced using direct compression, wet granulation, or dry granulation. These were characterized by physical tests, such as average weight, friability, hardness, and disintegration tests. The tablet formulation produced by the dry granulation of 100 mg of the L. alba extract exhibited better physical properties, and it was characterized using acteoside (verbascoside) as a chemical marker, presenting 6.9 % w/w of acteoside content per tablet, corresponding to 41.3 mg of this constituent per unit. This formulation dissolves rapidly in simulated gastric fluid without enzymes, achieving amounts >80 % after 20 min. Thus, an immediate-release tablet formulation with L. alba extract was successfully prepared.

Introduction

Lippia alba (Mill.) N.E. Brown (Verbenaceae) is an aromatic shrub widely distributed throughout Central and South America (Hennebelle et al., 2008b). Its infusion is reported in many ethnopharmacological surveys as a sedative (Di Stasi et al., 2002; Guzmán et al., 2014; Rodrigues and Guedes, 2006), for digestive troubles (Di Stasi et al., 2002; Girón et al., 1991; Heinrich et al., 1992; Oliveira et al., 2006; Pinto et al., 2006; Rodrigues and Guedes, 2006; Toscano González, 2006), hypertension (Di Stasi et al., 2002; Oliveira et al., 2006; Rodrigues and Guedes, 2006), and to treat general respiratory ailments (Di Stasi et al., 2002; Girón et al., 1991; Oliveira et al., 2006; Toscano González, 2006).

Various in vivo and in vitro studies have confirmed these ethnopharmacological observations of L. alba preparations, notably their gastroprotective properties and effects on the central nervous system (CNS). In this context, an infusion of L. alba leaves prevents gastric ulcerations induced by indomethacin in rats (Pascual et al., 2001). The essential oils obtained from the linalool and citral chemotypes of L. alba exhibit antispasmodic effects by non-competitively inhibiting muscarinic receptors mediated by acetylcholine (Blanco et al., 2013). Moreover, limonene, one of the major components of L. alba essential oil, presents gastroprotective effects in in vivo pharmacological models of ethanol and indomethacin-induced ulcers (Rozza et al., 2011).

Many studies have demonstrated the CNS sedative, anxiolytic, myorelaxant, anticonvulsive (Soares, 2001), and anesthetic effects of L. alba (Souza et al., 2017). The myorelaxant effect has been demonstrated by the rotarod test (Vale et al., 2002, 1999). The anxiolytic effect can be evaluated by the elevated T-maze (Hatano et al., 2012; Vale et al., 1999) and the open-field test (Vale et al., 2002, 1999). Sedative activity has been demonstrated as pentobarbital-induced sleeping time in mice (Vale et al., 2002; Zétola et al., 2002) and a decrease in rectal temperature (Vale et al., 2002, 1999).

The flavonoids and phenylpropanoids found in L. alba, which are present in all chemotypes, are responsible for the neurosedative properties. These components present inhibitory affinity to the CNS benzodiazepine (BZD) and γ-aminobutyric acid type A (GABA_A) receptors and more specifically, luteolin-7-O-diglucuronide is the most active compound according to Hennebelle et al. (2008a). Furthermore, acteoside (verbascoside) is the major compound found in the extracts of all L. alba chemotypes (Gomes et al., 2019; Timóteo et al., 2015). The authors preliminary in silico molecular modeling studies have suggested the high affinity of acteoside for the γ-aminobutyric acid (GABA) receptor and GABA-transaminase (Zimmermann et al., 2019). Moreover, this compound exhibits a high affinity to benzodiazepine, dopamine, and morphine receptors (Daels-Rakotoarison et al., 2000). Thus, acteoside is proposed in this study as a chemical marker for plant species, as this substance has been used as a quality control reference for herbal products. The chemical structure of acteoside is shown in Fig. 1.

Previous studies have demonstrated that a hydroethanolic extract (80 % EtOH) of leaves obtained from the L. alba myrcene-citral chemotype inhibit GABA uptake and GABA binding in a dose-dependent manner, which may explain the anticonvulsant properties of L. alba (Neto et al., 2009). Moreover, sedative and myorelaxant activities are observed in mice dosed with L. alba liquid and spray-dried ethanolic leaf extracts. Interestingly, the most significant effects were observed with a higher ethanol percentage (80 % EtOH) compared to hydroethanolic solutions with 40 and 60 % ethanol (Zétola et al., 2002).

The development of a phytotherapeutic formulation is described in the current study given the extensive use of L. alba preparations. Thus, a dry hydroethanolic extract of L. alba (Mill.) N. E. Br. from leaves was incorporated into a tablet formulation with potential gastroprotective properties and sedative effects. However, the development of an immediate-release solid formulation containing a natural product is a challenge considering many variables, such as the absortion ability, and the complex composition of the herbal extract, which requires chemical markers for further characterization. Acteoside was chosen as the chemical marker. Among the 14 solid formulations evaluated, one was selected based on quality control parameters.