In vitro, ex vivo and in vivo evaluation of taste masked low dose acetylsalicylic acid loaded composite wafers as platforms for buccal administration in geriatric patients with dysphagia

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Abstract

This study reports the development and characterization of taste masked, freeze-dried composite wafers for potential oral and buccal delivery of low dose aspirin (acetylsalicylic acid) to prevent thrombosis in elderly patients with dysphagia. The wafers were formulated by combining metolose (MET) with carrageenan (CAR), MET with chitosan (CS) at low molecular weight or CAR with CS using 45% v/v ethanol as solvent for complete solubilization of acetylsalicylic acid. Each wafer contained 75 mg of acetylsalicylic acid and sweetener (sucralose, stevia or aspartame) with a drug: sweetener ratio of 1:1 w/w. The formulations were characterized for physical properties using texture analyzer (hardness and mucoadhesion), scanning electron microscopy (SEM), X-ray diffractometry (XRD), Fourier transform infrared (FTIR) spectroscopy, swelling capacity, and in vitro drug dissolution. Further, permeation studies with three different models (Permeapad™ artificial barrier, EpiOral™ and porcine buccal mucosa) using HPLC, cell viability using MTT assay and in vivo taste masking evaluation using human volunteers were undertaken. The sweeteners increased the hardness and adhesion of the wafers, XRD showed the crystalline nature of the samples which was attributed to acetylsalicylic acid, SEM confirmed a compacted polymer matrix due to recrystallized acetylsalicylic acid and sweeteners dispersed over the surface. Drug dissolution studies showed that acetylsalicylic acid was rapidly released in the first 20 min and then continuously over 1 h. EpiOral™ had a higher cumulative permeation than porcine buccal tissue and Permeapad™ artificial barrier, while MTT assay using Vero cells (ATCC® CCL-81) showed that the acetylsalicylic acid loaded formulations were non-toxic. In vivo taste masking study showed the ability of sucralose and aspartame to mask the bitter taste of acetylsalicylic acid and confirm that acetylsalicylic acid loaded MET:CAR, CAR:CS and MET:CS composite wafers containing sucralose or aspartame have potential for buccal delivery of acetylsalicylic acid in geriatric patients with dysphagia.

Introduction

The buccal region of the oral mucosa cavity offers an attractive route of administration for systemic drug delivery. The oral cavity is highly acceptable by patients as the mucosa is relatively permeable with a rich blood supply, it is robust and shows short recovery times after stress or damage (Rathabone and Hadgraft, 1991). In addition, the oral mucosa route bypasses first pass metabolism by delivering the drug directly into the bloodstream. These factors make the oral mucosa a very attractive and feasible site for systemic drug delivery (Shojaei, 1998). Further, there has been an increased interest in novel drug delivery systems, over the past few decades, to improve safety, efficacy and patient compliance and increase the product patent life cycle (Panda et al., 2012, Boateng, 2017). Fast dissolving and sustained release lyophilized wafers and films are examples of formulations for oral and buccal mucosa drug delivery and can be used for various classes of drugs (Peh and Wong, 1999).

Acetylsalicylic acid (commonly referred to as aspirin) has anti-thrombin action, which inhibits clot formation, thus reducing the rate of heart attacks and strokes. Such administration for the purpose of reducing the clotting action of platelets, is referred to as ‘low-dose aspirin’ (usually administered as a single tablet containing 75 mg of the drug). Acetylsalicylic acid acts as an acetylating agent and causes an irreversible inhibition of cyclooxygenase (COX)-1 which is an essential enzyme for the production of thromboxane A2 (TxA2) in the platelets and supresses the generation of prostaglandin H2, which is a precursor of TxA2. TxA2 is a powerful stimulant of platelet aggregation and use of acetylsalicylic acid inactivates these platelets (Hovens et al., 2006). Advantages of acetylsalicylic acid over other ‘blood thinners’ such as warfarin, include low cost, once-daily administration and no need for dose monitoring (Mekaj et al., 2015).

Low dose acetylsalicylic acid is recommended for people with heart or vascular disease and patients who have had heart bypass surgery (British Medical Association, 2014) and most people who suffer from these problems are older (geriatric) patients, who usually also present with other chronic conditions. The impact of demographic ageing is likely to be of major significance in the coming decades, due to low birth rates and higher life expectancy. Older people generally require more prescribed medicines due to the presence of multiple conditions such as dysphagia (difficulty in swallowing). This occurs when the swallowing physiology changes with advancing age due to reduction in the muscle mass and connective tissue elasticity, resulting in the loss of strength and motion. These changes reduce the effective and efficient flow of materials, such as food and medications through the upper aero digestive tract (Sura et al., 2012).

Freeze-dried wafers are usually prepared by freeze-drying a polymeric solution or gel in an appropriate solvent (usually water). Freeze drying of water-soluble polymers produces shaped materials of highly porous nature that can be turned back to gels and solutions when they come into contact with fluids such as saliva. Lyophilized wafers can easily be applied to mucosa surfaces and they offer advantages over semi solid polymer gels and solvent cast films (Boateng et al., 2010). Semi solid polymer gels flow easily after application, while wafers can maintain their swollen gel structure for a longer period and therefore longer residence times (Matthews et al., 2005) to allow for effective drug absorption.

Freeze dried wafers are preferred over chewable acetylsalicylic acid tablets because the latter contains sorbitol which causes diarrhoea and flatulence. In addition the flavouring agents present in chewable tablets may cause ulcers in the oral cavity and the prolonged chewing may cause pain in the facial muscles which may increase the risk of poor adherence, medication errors or reduced patient quality of life. This is because of a loss of muscle strength in the mouth and throat regions, which makes it difficult for geriatric patients to chew. Further, these chewable tablets also show fragile (poor mechanical strength) and granular characteristics and therefore careful handling is required (Renu et al., 2015, Farias and Boateng, 2018).

This paper reports the formulation design and development of composite polymer based lyophilized wafers, taste masked with sweeteners, for potential buccal delivery of acetylsalicylic acid to geriatric patients and improved compliance from masking the bitter taste of the drug. The formulations were initially characterized for their physico-chemical properties (resistance to compression – ‘hardness’ and mucoadhesion), crystallinity, internal and surface morphology and chemical interactions. Drug dissolution and permeation studies using three different models (EpiOral™, porcine buccal tissue and Permeapad™ an artificial buccal membrane) were performed for the optimized acetylsalicylic acid loaded and taste masked wafers using HPLC and finally the in vivo taste masking of acetylsalicylic acid by sucralose and aspartame was investigated using healthy adult human volunteers.

Section snippets

Materials

Metolose (MET) grade type (60SH), viscosity (4000 cP) and MW (1261.4 g/mol) was obtained as a gift from Shin Etsu (Stevenage, Hertfordshire, UK), gelatin from porcine skin, MW (10,000 g/mol), mucin from bovine submaxillary glands, MW (4000 kDa), MTT [3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide] reagent, dimethyl sulfoxide (DMSO) and acetyl salicylic acid were purchased from Sigma-Aldrich (Gillingham, UK). Κappa carrageenan [(CAR) (low viscosity grade NF 911, MW < 100,000 Da, 25%

Optimization of taste masked DL wafers

Taste is a crucial factor which determines the palatability of oral dosage forms and patient compliance (Gala and Chauhan, 2014). Therefore, the taste masked DL formulations were optimized by their physical and chemical properties as well as their taste. Table 1 shows all the taste masked DL formulations. Commonly used pharmaceutical and food sweeteners, sucralose, aspartame and stevia were used in the development of taste masked DL wafers with a drug: sweetener ratio of 1:1. After freeze

Conclusions

The functional properties of taste masked DL wafers for geriatric delivery, have been characterized. Wafers comprising sucralose and aspartame showed higher hardness compared to their corresponding non-taste masked wafers which was reflected in the SEM, swelling capacity and porosity results. However, adding the sweeteners increased the rate of release compared to the BDL formulations. Both sucralose and aspartame showed similar effect in masking the bitter taste of acetylsalicylic acid while

CRediT authorship contribution statement

Smirna Farias: Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft. Joshua S. Boateng: Conceptualization, Methodology, Project administration, Resources, Software, Supervision, Writing - review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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