The effect of carbomer 934P and different vegetable oils on physical stability, mechanical and rheological properties of emulsion-based systems containing propolis

Highlights

• Carbomer amount and vegetal oil type were studied to prepare emulsion for propolis delivery.

• Passion fruit, sweet almond and andiroba oils were used to prepare emulsion systems.

• Carbopol 934P 1% (w/w) resulted the best systems for delivery propolis or by-product extract.

• Propolis extract yielded more structured and soft systems with improved mechanical properties.

Abstract

Semi-solid emulsion systems constitute important platforms for drug delivery, due to the easiness of administration, increasing residence time and also improve the drug availability. They are usually stabilized by emulsifiers and hydrophilic polymers may be used to form a tridimensional network in the hydrophilic phase resulting in a structure than can disperse the hydrophobic phase and the drug. These systems can be administered by oral, parenteral, and topical routes as platforms for delivery of biologically active agents from different origins such as mineral, animal or vegetal. Propolis has a complex chemical composition and displays many important biological activities (antibacterial, fungicidal, antioxidant, antiviral, anti-inflammatory, immunostimulant, anti-cancer, antiulcer, hypotensive and cytostatic). Propolis ethanolic extract (PE) and extract of propolis by-product (BPE) are usually utilized in therapeutics. In this work, three vegetable oils (passion fruit, andiroba and sweet almond oils) were used to develop emulsion-systems composed of Carbopol 934P (C934P) for propolis delivery. The mechanical and rheological properties of formulations were investigated to select potential emulsion systems. A factorial design was employed to determine the influence of C934P concentration and the different vegetable oils on the physicochemical characteristics of systems, considering the presence of PE or BPE. Emulsion systems displayed physicochemical stability and mechanical characteristics dependent of C934P 1% (w/w). Formulations displayed pseudoplastic flow behavior and viscoelasticity dependent of vegetable oil type, temperature and type of propolis extract. The results indicated that the PE resulted in a more structured emulsion system due to the greater content of resin and gum than the BPE. Emulsion systems displayed softness and are worthy of investigation intended the administration on the skin and mucous membranes.

Introduction

Semi-solid systems are based on the dispersion of one or more types of molecules on a suitable dispersant medium resulting in a product displaying important rheological and mechanical characteristics (e.g. pseudoplastic behavior, thixotropy and cohesiveness), which are desirable for pharmaceutical applications on skin or mucous membranes [1,2]. These systems can be attractive pharmaceutical dosage forms to be used as modified drug delivery systems and extending their residence time and improving the drug bioavailability [[3], [4], [5]]. The topical administration of drugs on the skin has a great interest constituting an attractive alternative to conventional oral therapy, due to the possibility of a more efficient treatment based on the local action of the drug, avoiding the effect of first-pass metabolism, in addition to promoting greater patient compliance and reduction of side effects [[6], [7], [8]].

Emulsion systems are coarse or colloidal dispersions of varying consistency and may contain one or more biologically active substances. It is composed of at least two phases of immiscible liquids, in which one of them is dispersed, in the form of small droplets (internal or dispersed phase) in the other (external or continuous phase). They are usually stabilized by the surfactant/emulsifier action of one or more agents [9,10]. Moreover, hydrogels consist of a liquid part confined within a polymeric matrix formed by gelling substances such as agar, gelatin, cellulose derivatives, poloxamers, and carbomers. Hydrogels can modify the drug delivery, display bioadhesion and evaporate forming a thin adhesive film [9,10]. However, they have not been found to be effective for the delivery of the hydrophobic drugs [11,12].

When semi-solid systems are obtained from the combination of gels and emulsions, they can be called of emulgels [11,12]. Some polymers can display complex functions as emulsifiers and thickeners due to their gelling capacity. Thus, they can allow the formation of more stable emulsions by decreasing surface and interfacial tension and increasing the viscosity of the aqueous phase as well [11].

Emulgels can show good rheological properties being easy to spread, easily removable (because they are not greasy), emollient, water soluble, long shelf life and pleasant appearance [[11], [12], [13]]. These systems can be administered by vaginal, buccal, and topical routes as platforms for delivery of biologically active agents from different origins such as mineral, animal or vegetal [[11], [12], [13], [14]].

Carbomers are composed of acrylic acid chains reticulated by allyl sucrose or pentaerythritol allyl ethers [[16], [17], [18], [19], [20], [21]]. They have the ability to swell ten times their original size to form a gel, when exposed at pH 4.0 to 6.0. The carboxyl groups present in the acrylic acid chain are responsible for several of their characteristics, such as gel formation due to ionization of the chains and electrostatic repulsion of the negatively charged groups when neutralized, thus being able to release the drug molecules at the site of action. However, pedant carboxylic acid groups at low pH values remain non-ionized and retain the drug inside [19,[22], [23], [24], [25]]. The ability to absorb water, hydrate and swell, maintaining the reticulated structure and the insolubility in water, makes the carbomers excellent bio/mucoadhesive polymers [26]. Some studies have evaluated the toxicity of this type of polymer and demonstrated low toxicity and low irritant potential. Therefore, carbomers are widely accepted as a bioadhesive in many applications [19,21,23] and several types are reported and differentiated by the degree of reticulation and manufacturing conditions [18,23]. Carbopol 934P (934P) is highly cross-linked with excellent stability at high viscosities, which confers excellent bioadhesive and viscoelastic properties. Its designation “P” refers to the pharmaceutical grade because it has a low residual benzene content [23,27].

Propolis (PRP) is a complex mixture, produced by bees of the species Apis mellifera L. from the collection of resinous materials, harvested from the vegetation around the hive. The word “propolis” is derived from Greek language and means “in defense of the city” [28]. The bees add salivary secretions and enzymes to the collected vegetable material [29,30] and the gum-resin is used by them to protect the comb, sealing gaps, from insects, microorganisms and dirt [31,32]. PRP chemical composition is complex and directly related to the flora around the hive, which may vary from region to region in the same territory [33,34]. It consists of approximately 50–60% resinous compounds and gums, 30–40% waxes, 5–10% volatile oils and aromatic acids, 5% balsams and pollen grains and 5% various other substances such as polyphenols (flavonoids and phenolic acids), vitamins, minerals and impurities [33,35,36]. The diversity of biological activities of PRP ranges from antibacterial, fungicidal, antioxidant, antiviral, anti-inflammatory, immunostimulant, anti-cancer, antiulcer, hypotensive and cytostatic [31,37,38], as well as there are reports of tissue regenerating and healing action in ulcers and anesthetic action [36,37].

PRP is usually processed and the ethanolic extract obtained (PE) can be used as a final or intermediary dosage form and incorporated into pharmaceutics, beverages and cosmetics [3,27,37]. Moreover, the residue obtained from this extraction is called by-product (BP), and its ethanolic extract (BPE) shows properties similar to PE [[39], [40], [41]]. The complex chemical composition of PRP limits the number of dosage forms to be used as platforms for topical administration of its extracts. A good dispersion of PRP constituents is dependent of physicochemical characteristics of the system. Therefore, the development of an emulgel system for PRP delivery by topical route constitutes a good strategy.

Vegetable oils are used as organic solvents to prepare emulgels [[11], [12], [13], [14]]. In the present work, three vegetable oils (passion fruit, andiroba and sweet almond oils) were used to develop emulgels composed of C934P for delivery of PRP extracts. The mechanical and rheological properties of systems were investigated to select potential emulsion systems. A factorial design was employed to determine the influence of C934P concentration and the different vegetable oils on these physicochemical characteristics of systems, considering the presence of PE or BPE.