Vilayat A. Sayeed is Director, Division of Chemistry III.

Vilayat A. Sayeed

Taste may be subjective, but it is crucial to patient compliance, particularly for pediatric treatments. This article reviews methods used to improve and assess pharmaceutical palatability.

Articles

Taste may be subjective, but it is crucial to patient compliance, particularly for pediatric treatments.

Assessing and Improving the Palatability of Pharmaceuticals

The oral mucosal lining offers a preferable route for the local and systemic administration of certain drugs and for the treatment of some diseases (see 

) (1). This route has several distinct advantages over the enteral and parenteral routes of drug delivery due to its rich blood supply, rapid onset of action, enhanced bioavailability, avoidance of the first pass and food effects, increased patient compliance, and ease of self-medication. Over the years, a number of products taking advantage of oral mucosal drug delivery have been introduced in the market.

	Oral mucosal drug absorption is governed by (a) the permeability of the oral mucous membrane and the anatomy of the underlying tissues, (b) the physicochemical properties of the drugs, and (c) the formulation design. The focus of this review is on the latter two points, as an understanding of these elements enables the selection of drug candidates suitable for oral mucosal delivery and optimizes drug delivery.

					Buprenorphine hydrochloride and naloxone hydrochloride

	The oral cavity has four distinct regions that can absorb drugs-the sublingual, buccal, gingival, and palatal regions. These regions differ from one another in histological structure and biochemical composition of the mucosal membrane, and their ability to retain the dosage form long enough to allow complete drug absorption. The sublingual membrane on the floor of the mouth under the tongue and the buccal membrane lining the cheeks are commonly used for systemic drug delivery.

	The mucosal lining consists of three distinct layers. The outermost layer is the epithelial membrane, which consists of stratified squamous epithelial cells and has a protective barrier function. The innermost layer of the epithelial membrane is called the basement membrane that replenishes the epithelium. Below the epithelium lies the lamina propria followed by the submucosa. The lamina propria is a hydrated and less dense layer of connective tissue containing collagen and elastic fibers. The oral submucosa is also richly supplied with blood vessels.

	Following absorption through the mucous membrane in the sublingual region, the drug instantly diffuses into venous blood. The venous blood from the sublingual region of the oral cavity drains into a common trunk, which then drains via the internal jugular vein, the subclavian vein, and the brachiocephalic vein directly into the superior vena cava (2, 3). Thus, venous return from these regions enters the systemic circulation, bypassing the pre-systemic drug elimination, unlike in oral administration. Direct drainage into systemic circulation results in immediate systemic availability of the drug and rapid onset of action. It should be noted that smoking, which causes vasoconstriction, may affect drug absorption.

	Permeability of the oral mucosa and drug absorption

	The salivary glands present in the oral cavity secrete saliva that has a pH of 5.5-7.0. Saliva consists of proteins and carbohydrate complexes called mucus and enzymes such as amylase and carboxylesterase. Mucus is negatively charged at the physiological pH, forming a cohesive gelatinous film on all oral cavity surfaces. This cohesiveness permits mucoadhesion of the drug to the epithelial tissue leading to drug absorption (4, 5).

	The epithelial membrane is 100–200 µm thick in the sublingual region and 500–600 µm thick in the buccal region (6). The epithelial membrane in both regions is non-keratinized. The permeability of the mucosa varies from region to region in the oral cavity depending on thickness and degree of keratinization of the epithelial membrane (7).

	Membrane-coating granules deposited at the apical surfaces of the epithelial cells and neutral lipids, such as ceramides and acylceramides, impart a barrier function to keratinized epithelium resulting in decreased permeability. Conversely, cholesterol, cholesterol esters, and glucosyl ceramides in the non-keratinized epithelial cells of the sublingual and buccal regions render it permeable to drug absorption (8).

	The profuse blood supply, combined with the relative thinness and higher permeability of the sublingual mucosa, permits rapid absorption and desirable bioavailability of certain drugs following sublingual administration. Thus, the sublingual mucosa is a suitable site for achieving a clinically effective drug concentration in a shorter period of time when rapid onset of action is desired. For this reason, rapidly dissolving sublingual tablets are highly effective for the emergency treatment of angina, breakthrough cancer pain, or migraine.

	It should be noted that the sublingual region is constantly washed by saliva and by movements of the tongue, and thus is not suitable for the prolonged retention of a drug-delivery system. On the other hand, the buccal mucosa is not continuously affected by saliva or by tongue movements and is suitable for prolonged retention of dosage forms such as mucoadhesive sustained drug-delivery systems.

	Commercially available sublingual tablets

	Presently, a small number of commercially available drugs use the sublingual mucosa for drug administration. These drugs are used for the emergency treatment of angina pectoris, hypertensive crises, breakthrough cancer pain, and migraine. The buccal route has been exploited for hormone replacement therapy. 

 lists some of the approved drugs that are available as sublingual tablets (9).

	Potential drug candidates for oromucosal delivery

	The literature is full of studies that have demonstrated the enhanced potential of several drugs when administered via oromucosal route. However, this potential has not been fully utilized commercially in developing drugs for oromucosal delivery. The following examples illustrate superior therapeutic management when drugs were administered via the oromucosal route as compared to oral administration.

	In a comparative effectiveness study of sublingual captopril, nifedipine, and prazosin, it was reported that sublingual captopril may be a better alternative to sublingual nifedipine in treating hypertensive emergencies based on less side effects (10). Another study has shown that sublingually administered captopril and nifedipine are effective in the treatment of hypertensive emergencies; however, for severe forms of hypertension, this study recommends sublingual nifedipine (11).

	Sublingual administration of verapamil has exhibited significantly higher maximum plasma concentration of the drug (C

), a faster absorption rate, and greater bioavailability as compared to its oral administration (12). It has also been shown to produce a rapid and significant reduction in ventricular rate (13). Sublingual administration of furosemide was shown to offer a therapeutic advantage over the oral route of administration (14).

	Oromucosal administration of midazolam was compared with the rectal administration of diazepam for the emergency treatment of acute febrile and afebrile (epileptic) seizures in children (15). Oromucosal midazolam was found to be more effective than the rectal diazepam.

	The sublingual tablets of buprenorphine and naloxone have shown useful results for the treatment of opiate addiction (16). The study has proposed office-based treatment of addiction using sublingual administration of these drugs.

	Zolmitriptan is used for the treatment of migraine and cluster headaches. A sublingual formulation of zolmitriptan exhibited faster absorption and higher drug exposure as compared to subcutaneous injection and is expected to be highly efficient for the emergency treatment of these conditions (17).

	In a randomized, double-blind clinical trial, comparing 40 mg of sublingual piroxicam with a 75 mg intramuscular injection of diclofenac for the emergency treatment of acute renal colic, sublingual piroxicam was found as effective as the intramuscular diclofenac (18).

	Self-injected epinephrine is used for the treatment of anaphylaxis. In a study, sublingual epinephrine resulted in rapid absorption and higher peak plasma concentration in animal models when compared to self-injected epinephrine. The study proposed sublingual epinephrine as an alternative to self-injected epinephrine (19, 20).

	Estrogens in menopausal women with cardiovascular disease have been shown to produce coronary and peripheral vasodilation, reduction of vascular resistance, and improvement of endothelial function. Sublingual estrogens have exhibited faster drug absorption (i.e., shorter T

) than orally administered forms (21, 22).

	The sublingual administration of vaccines may be used against various infectious diseases. Preclinical studies have found that sublingual vaccines can be highly immunogenic and may protect against influenza virus and Helicobacter pylori (23–25).

	Development of sublingual tablet formulations

	For optimal sublingual formulation development, it is necessary to understand the mechanism of drug absorption, physicochemical and mechanical properties of the drug, function of the excipients in the formulation, and taste-masking techniques for better patient compliance.

 Following sublingual administration, the drugs are absorbed across the mucous membrane by one of the following mechanisms:

	Although the process of passive diffusion is spontaneous, the rate of diffusion is dependent on the molecular weight and solubility of the drug, concentration gradient, temperature, the surface area of the membrane, and the proximity of the molecule to the membrane. When a drug exists in its unionized form in saliva, it is absorbed by passive diffusion. Physical models have been proposed to describe drug absorption from saliva through the lipid bilayer of the mucous membrane into systemic circulation (26–29). The rate of drug absorption across the mucous membrane is directly related to its partition coefficient (30). Some compounds, such as glutamic acid, L-ascorbic acid, nicotinic acid, and thiamine, are transported via a carrier-mediated process (31–34).

	Lipids present in the oral mucous membrane offer the main barrier to the permeability of hydrophilic drugs. On the other hand, well-hydrated connective tissues provide resistance to lipophilic drugs. Thus, the potential transport path across the oral mucous membrane may be either polar or non-polar. Non-polar molecules cross through the lipid regions of the epithelium, while polar molecules travel through ionic channels present in the intercellular spaces of the epithelium, or aqueous pores present in the epithelial cells. For this reason, an understanding of a drug’s lipophilic or hydrophilic nature during the developmental stage of the drug product appears to be the most useful index for evaluating its suitability for absorption across the oral mucosa.

Physicochemical properties of drugs. Table II

 lists the physicochemical properties of some commercially available drugs administered sublingually. These properties of the drugs facilitate their absorption by passive diffusion through the oral mucosa. Partition coefficients and ionization constants of several drugs are described in the literature (35–38).


					Physicochemical properties of sublingually administered drugs.

This review highlights relevant physicochemical drug properties and formulation design considerations critical to quality and performance of the sublingual tablets.