The peroral route is the most commonly employed route for the administration of medications. Due to the limitations associated with peroral route such as extensive first-pass metabolism and hydrolysis of acid-labile drugs, the potential use of other routes of drug administration, such as the buccal route, is being investigated. Drug-containing dosage forms like tablets, gels, solutions, and patches are placed in the buccal pouch. If the drug has the appropriate physicochemical properties, or advantageous modifications can be made to the membrane permeability or to the local environment, absorption of the active drug into the blood circulation is expected to occur. Drug delivery via the buccal mucosa possesses many advantages over the other routes and is rapidly emerging as an alternate route of delivery for certain drugs, such as those that undergo extensive first-pass metabolism. The buccal mucosa appears to be better in terms of permeability, surface area, patient compliance, etc., when compared to the other mucosal and transdermal routes of delivery (1
). Frequent exposure to food materials and rapid cell turnover make the buccal mucosa more resistant to tissue damage and irritation compared to other mucosal routes of administration. Hence, the buccal route of diffusant delivery is a logical alternative delivery route for diffusants which undergo extensive degradation in the stomach and the liver (2
The assessment of the permeability of diffusants across the buccal mucosa is usually conducted in vitro
using porcine buccal tissue and a diffusion assembly. Porcine buccal mucosa is closest to that of human in terms of structure, composition, and permeability than any other animal (8
). It is widely recognized that temperature must be controlled during in vitro
buccal permeation studies (11
). However, individual laboratories have used different controlled temperatures, such as room temperature (25°C) (10
), 30°C (1
), 34°C (15
), or physiological temperature (37°C) (21
). In the literature, the use of ambient or room temperature (25°C) for permeation studies has been justified by stating that diffusant permeation is not significantly different at body and ambient temperatures (14
). It is also stated that since diffusant permeation occurs by simple diffusion across the oral mucosa, it is not affected by metabolic inhibitors (14
Many investigators use Franz diffusion cells to carry out buccal permeation studies. The receiver chambers of these diffusion cells are typically maintained at 37°C while the donor chamber is kept at ambient temperature, typically 22–24°C (31
). Such an experimental setup for in vitro
permeation studies across the buccal mucosa does not mimic the in vivo
condition. Both the donor and receiver chamber must be maintained at a constant temperature of 37°C to mimic the in vivo
environment. Maintaining temperatures other than 37°C could potentially lead to significant differences in permeability, making it impractical to compare results from different studies and also difficult to correlate in vitro
and in vivo
permeability data. Hence, the present authors considered it important to investigate the effect of experimental temperature on diffusant permeability.
One may, in general, anticipate an increase in diffusant permeability with an increase in experimental temperature, but the nature of the kinetic relationship is hard to predict. For example, does permeability increases linearly or exponentially with temperature? The mechanism whereby permeability increases with temperature is also unclear, i.e., does permeability increase due to a change in the barrier structure (for example subtle changes in the chemical nature, but not the physical integrity, of the barrier) or to an overt change in the physical integrity of the buccal mucosa?
Apart from the effect of temperature on the results of experimental permeation studies, there is also the potential for heat-enhanced drug delivery via the buccal route; using suitable temperature modulated drug delivery devices. Over the past few years, attention has been focused on overcoming the problems associated with buccal drug delivery. One of the prime limitations facing buccal delivery is poor absorption when compared to the sublingual route of drug delivery. The success of a buccal drug delivery system depends on the ability of the drug to permeate the mucosal barrier at a concentration high enough to achieve its desired therapeutic effect. The buccal mucosa acts as a barrier to the permeation of exogenous material across the tissue. Transport across the buccal epithelium is via passive diffusion; active transport is rare, vitamin B12 being a notable exception. Various approaches including chemically assisted methods (e.g., penetration enhancers and supersaturated systems) or physically assisted techniques (e.g., ultrasound, iontophoresis, and microneedles) have been studied to overcome the barrier properties and to increase the rate and extent of diffusant absorption across the buccal mucosa.
Chemical penetration enhancers are being extensively studied to improve the delivery of diffusants across the buccal mucosa. However, the major limitation of these efficient permeation enhancers is the toxicity associated with their use. Hence, alternative methods of enhancing permeation, which are safe as well as effective, need to be investigated. One possible means to achieve this enhancement is to apply heat locally to increase the temperature in the buccal region.
The enhancing effect of heat on transdermal and transvaginal absorption has been well documented (44
), but its effect on the buccal mucosa has not been fully explored. Some investigators have shown an approximate doubling of transdermal flux with each 6–8°C increase in temperature from 10°C to 60°C (46
). Another investigation studied the effect of increase in temperature on the permeability of selected B-agonist across primary hamster cheek pouch cultures (54
). A similar effect on diffusant transport across the buccal mucosa has not been investigated, so in this study, tranbuccal permeability of model diffusants were also studied at 7°C increase. If the permeability of a diffusant across the buccal mucosa is significantly enhanced with a relatively small increase in temperature, the principle of permeation enhancement with elevated temperature can be used to develop practical buccal drug delivery systems. Permeation enhancement with heat may be safer than the use of hazardous and toxic penetration enhancers.
Before it can be used as a means of permeation enhancement, however, studies should be performed to characterize the effects of temperature on both the penetrant and the tissues to which it is applied. For example, while it may be acceptable to use higher temperatures (≥45°C) in the in vitro
studies, the prolonged use of such temperatures in drug delivery devices may cause patient discomfort. It has been shown in the case of certain transdermal formulations that burns (scalds) have occurred when subjects were exposed to temperatures in excess of 60°C for a short period (55
The main objective of this work was to evaluate the influence of temperature on porcine buccal mucosal permeation of model diffusants of differing lipophilicities. The studied diffusants, with their log D (distribution coefficient) values at pH 6.8, are: buspirone (2.8), bupivacaine (2.5), antipyrine (0.39), and caffeine (−0.07). Such studies may provide a basis for designing buccal drug delivery systems that utilize transient temperature increases as the mechanism of permeation enhancement.
It is most likely that the effect of temperature on permeation across the buccal mucosa follows a relationship similar to the Arrhenius equation as given below (56
|DT||the diffusion coefficient at a certain temperature (square centimeters per second)|
|D0||the theoretical maximum diffusion coefficient at infinite temperature (kelvin) (arbitrary value, preexponential factor)|
|EA||activation energy of diffusion (joules per mole)|
|R||the universal gas constant (83144 joules per mole kelvin)|
|T||the temperature of interest (kelvin)|
The activation energy can be defined as the energy used to counter the cohesive forces of the membrane in order to facilitate the diffusion process.
In this case, the permeability of a diffusant may be expressed as follows:
|Papp||apparent permeability of the diffusant at the temperature of interest|
|K||partition coefficient of the diffusant|
|h||thickness of the membrane|
Combining Eqs. 1
, we get
Assuming that the partition coefficient and the thickness of the membrane remain constant over the range of temperature studied, the following relationship can be derived from Eq. 3
This suggests that the apparent permeability of the diffusant increases exponentially with temperature. A plot of log of apparent permeability versus
absolute temperature will yield a linear relationship. The energy necessary for the permeant to break the restraining bonds and to diffuse, similar to energy of activation (EA
), can be determined from the slope of this plot. The activation energy provides a measure of the resistance of the buccal mucosa to diffusion of the permeant. In general, the value of the activation energy is a function of both the diffusing permeant and the diffusion pathway (57
The enhancement in permeability with increase in temperature is given by a ratio known as the enhancement factor (EF). It is calculated using the equation: