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Many drug candidates are poorly water-soluble. Microenvironmental pH (pHM) modification in buccal/sublingual dosage forms has attracted increasing interest as a promising pharmaceutical strategy to enhance the oral mucosal absorption of drugs with pH-dependent solubility. Optimizing drug absorption at the oral mucosa using pHM modification is considered to be a compromise between drug solubility and drug lipophilicity (Log D)/permeation. To create a desired pHM around formulations during the dissolution process, a suitable amount of pH modifiers should be added in the formulations, and the appropriate methods of pHM measurement are required.
- microenvironmental pH modification
- buccal/sublingual dosage form
- solubility
1. Introduction
Buccal/Sublingual administration is an attractive route to achieve systemic drug delivery. It offers advantages such as circumventing the hepatic first-pass metabolism and chemical/biological drug degradation associated with oral administration, the quick onset of drug action, ease of administration and relatively high level of patient compliance [1][2][3][4][1,2,3,4]. In general, formulations such as mucoadhesive films, patches, tablets, gels, etc., have been employed for buccal/sublingual drug delivery, which could increase the contact time between drugs and the oral mucosa. Among the various physicochemical properties of the drug candidates, aqueous solubility and lipophilicity (Log D)/permeation are two crucial factors affecting drug absorption at the oral mucosa. A good drug candidate should be soluble in human saliva, and possess enough lipophilicity to permeate the epithelium at the oral mucosa [3]. However, it is estimated that over 40% of drugs on the market are poorly water-soluble [5], which could lead to a slow drug release. Generally, poorly water-soluble drugs are weakly ionizable drugs, which might have pH-dependent solubility and/or pH-dependent lipophilicity (Log D)/permeation. Therefore, pH plays a crucial role in the absorption of those drugs in the oral cavity.
Microenvironmental pH (pHM) modification is widely used in oral solid dosage forms to increase the dissolution of poorly water-soluble drugs with pH-dependent solubility in the gastrointestinal (GI) tract, and this approach creates a microenvironment with an ideal pH level in the vicinity and inside the solid dosage forms by adding pH modifiers to the formulations [6][7][8][9][6,7,8,9]. It has been demonstrated that pHM modification is an effective way to increase drug dissolution and enhance drug absorption in the GI tract [7][10][11][12][7,10,11,12]. Typically, the pH rapidly changes from highly acidic in the stomach to neutral in the small intestine. Under fasted-state conditions, the gastric pH range is between 1.7 and 4.7, and the pH in the small intestine slightly increases from 5.9 in the proximal parts to 7.8 in distal parts for the human subjects [13]. The physiological environment for drug dissolution in the oral cavity is different compared to that in the GI tract. The pH range for unstimulated human saliva is 6.2 to 7.6 and the average salivary pH is 6.8 [14][15][14,15]. The neutral pH environment, without dramatic shifts, is beneficial to create a desired pHM. Additionally, the limited volume (average 0.8 to 1.1 mL) and the low secretion rate of human saliva (0.35 to 2.00 mL/min) [16][17][16,17] could lead to a slow release of the pH modifiers from the formulations and, hence, to maintaining the ideal pHM. Therefore, the oral cavity provides a suitable physiological environment for pHM modifications. pHM might not only affect drug release from formulations, but also drug permeation across the oral mucosa. Generally, pH modifiers could modulate pHM both in and in the vicinity of the buccal/sublingual formulations and affect the drug ionization, and thereby influence the drug permeation across the oral mucosa. Thus, pHM modification in buccal/sublingual dosage forms might be an effective strategy to enhance the absorption of drugs with pH-dependent solubility or/and permeation.
where Cs is the drug solubility at a given pH and CS0 is the intrinsic solubility of the drug.
According to the “Solubility-pH” equations, a slight shift in the pH might lead to a significant change in the drug solubility. Theoretically, decreasing the pH could improve the solubility of a weakly basic drug by increasing the concentration of ionized drug in the solution. When most of the dissolved drug substance remains in its ionized form, a further decrease in the pH has little effect on its solubility, and the drug solubility approaches a plateau level in the pH-solubility profile. A suitable pH level at the surface of a solid formulation exposed to dissolution media could increase the local drug concentration (Cs) and, consequently, enhance the drug dissolution and release (dCdt
) from the solid formulation.
The mechanism of drug transport across the oral epithelium is similar to that across the other epithelia in the human body. Generally, both the transcellular and paracellular pathways are involved in this process [3][21][22][23][24][3,21,22,23,24]. For the drugs transported mainly via the transcellular route, drug permeation across the oral mucosa might be affected by the pH at the oral mucosa. According to the pH-partition theory, the neutral forms of drugs are more permeable (lipophilic) than the ionized species; therefore, a pH shift not only affects the dissociation of weakly ionizable drugs, but also the drug permeation across biological membranes (Figure 1) [25][26][25,26].
2. Concept of Microenvironmental pH (pHM) Modification in the Buccal/Sublingual Dosage Forms
2.1. Theory: pH-Dependent Dissolution and Permeation
Drug dissolution/release from buccal/sublingual formulations is one of the crucial factors affecting drug absorption at the oral mucosa. The relationship between the pH, drug solubility and dissolution rate has been elucidated using the Nernst-Noyes-Whitney equation [18] (Equation (1)) and the “solubility-pH” equations (take monoacidic drugs and monobasic drugs as examples) [19][20][19,20] (Equations (2) and (3)), as described below: where is the dissolution rate, D is the diffusion coefficient, S is the surface area of solid exposed, V is the volume of dissolution media, h is the thickness of the diffusion layer, Cs is the concentration (saturated) of drug at the solid surface and Cb is the concentration of drug in the bulk medium.
where Cs is the drug solubility at a given pH and CS0 is the intrinsic solubility of the drug.
According to the “Solubility-pH” equations, a slight shift in the pH might lead to a significant change in the drug solubility. Theoretically, decreasing the pH could improve the solubility of a weakly basic drug by increasing the concentration of ionized drug in the solution. When most of the dissolved drug substance remains in its ionized form, a further decrease in the pH has little effect on its solubility, and the drug solubility approaches a plateau level in the pH-solubility profile. A suitable pH level at the surface of a solid formulation exposed to dissolution media could increase the local drug concentration (Cs) and, consequently, enhance the drug dissolution and release (dCdt
) from the solid formulation.
The mechanism of drug transport across the oral epithelium is similar to that across the other epithelia in the human body. Generally, both the transcellular and paracellular pathways are involved in this process [3][21][22][23][24][3,21,22,23,24]. For the drugs transported mainly via the transcellular route, drug permeation across the oral mucosa might be affected by the pH at the oral mucosa. According to the pH-partition theory, the neutral forms of drugs are more permeable (lipophilic) than the ionized species; therefore, a pH shift not only affects the dissociation of weakly ionizable drugs, but also the drug permeation across biological membranes (Figure 1) [25][26][25,26].
Figure 1.
Illustration of pH-partition theory.
2.2. pH
max
Concept
A pH
max
concept defined as the pH value at which a given drug has a maximal aqueous solubility and the sum of its ionized species and unionized species in solution is at a maximum [27]. Modulating the saliva pH at the sublingual mucosa to the pH
max
by adding buffering agents in sublingual formulations was expected to lead to a maximal potential absorption. The pH
max
concept was proven to be valuable in the case of a propranolol sublingual tablet with buffering agents, which achieved a higher absorption in human subjects than the conventional non-buffered tablet. However, previous studies regarding the metroprolol buccal tablet and gel did not support the pH
max
concept. A specific pH level (rather than pH
2.3. Microenvironmental pH Modification in Buccal/Sublingual Dosage Forms
The aim of pH
) also led to the highest buccal absorption of metroprolol [28,29].
2.3. Microenvironmental pH Modification in Buccal/Sublingual Dosage Forms
The aim of pH
M
modification is to enhance the absorption of a given drug by influencing its solubility and permeability. Upon pH
M
modification in buccal/sublingual dosage forms, a small space exists between the formulation and the mucous membrane when the formulation is attached the oral mucosa. Typically, a drug must have a sufficient aqueous solubility to be released from the formulation and dissolved in the space, before permeating through the membrane of the oral mucosa. The pH of the space and the pH inside the formulation could be modified by adding pH modifiers into the formulation, which might affect the drug release (caused by the changes in drug solubility), drug solubility in the space and drug permeation across the mucosa by influencing the drug dissociation (
Figure 2
). In general, the drug, pH modifier and mucoadhesive polymer are the main components of the pH
M
modifying buccal/sublingual formulations.
Figure 2. Schematic drawing of drug permeation across oral mucosa from the buccal/sublingual formulation.
3. Properties of Saliva Associated with pH Modification
The main functions of saliva are to maintain oral health and help to build and maintain the health of hard and soft tissues. Approximately 99% of saliva is water, and the other 1% consists of a variety of electrolytes and proteins [30][31]. Regarding buccal/sublingual drug delivery, saliva provides a water-rich environment that facilitates in the drug dissolution and release from buccal/sublingual formulations before the drugs permeate through the membrane of oral mucosa [32]. To achieve a successful pH
The main functions of saliva are to maintain oral health and help to build and maintain the health of hard and soft tissues. Approximately 99% of saliva is water, and the other 1% consists of a variety of electrolytes and proteins [30,31]. Regarding buccal/sublingual drug delivery, saliva provides a water-rich environment that facilitates in the drug dissolution and release from buccal/sublingual formulations before the drugs permeate through the membrane of oral mucosa [32]. To achieve a successful pH
M
modification in buccal/sublingual formulations, some properties of saliva should be taken into consideration during the formulation design.
3.1. pH and Buffer Capacity of Saliva
Human saliva has been reported to have a pH range of 6.2–7.6 [14]. The composition of saliva secreted from different regions differs, leading to different saliva pH. The pH in the palate, the floor of the mouth, the buccal mucosa and the tongue, in humans, have been reported to be 7.3, 6.5, 6.3 and 6.8, respectively [33]. The flow of saliva with a buffer capacity resisting pH shift could remove acidic and basic foods on the oral mucosa, maintaining the pH in the oral cavity near neutrality in a long term. The bicarbonate, the phosphate and the protein buffer systems in the whole saliva are the major systems contributing to the buffer capacity, and their concentration and buffer capacity are dependent on the secretion rate of saliva [34][35][36].
3.2. Secretion Rate of Saliva and Thickness of Salivary Film
Human saliva has been reported to have a pH range of 6.2–7.6 [14]. The composition of saliva secreted from different regions differs, leading to different saliva pH. The pH in the palate, the floor of the mouth, the buccal mucosa and the tongue, in humans, have been reported to be 7.3, 6.5, 6.3 and 6.8, respectively [33]. The flow of saliva with a buffer capacity resisting pH shift could remove acidic and basic foods on the oral mucosa, maintaining the pH in the oral cavity near neutrality in a long term. The bicarbonate, the phosphate and the protein buffer systems in the whole saliva are the major systems contributing to the buffer capacity, and their concentration and buffer capacity are dependent on the secretion rate of saliva [34,35,36].
3.2. Secretion Rate of Saliva and Thickness of Salivary Film
Saliva is a complex mixture secreted by salivary glands. There are three pairs of major glands: the parotid, submandibular and sublingual glands, and numerous minor salivary glands [37]. Salivary secretion continues throughout the day, with an average total volume of 500–600 mL. Previous studies have reported that the mean flow rate of unstimulated human saliva and stimulated human saliva is 0.35 mL/min and 2 mL/min, respectively [16][38][16,38].4. Drug Candidate and pH Modifier for Buccal/Sublingual Dosage Forms
4.1. Drug Candidate
The low drug loading capacity of buccal/sublingual formulations and the limited absorption area in the oral cavity are two main limitations for buccal/sublingual drug delivery. Thus, drug candidates should be high potency to achieve successful therapeutic efficacy. In addition, suitable drug candidates must not cause local irritation and toxicity at oral mucosa. Regarding physicochemical properties, high lipophilicity (log P (octanol/water) > 2), fairly good water-solubility and small molecular size (less than 800 Da) are typically considered as ideal parameters for drug candidates, as described previously [3]. The extent of different drug transport pathways across the epithelium depends on the drug physicochemical properties [39][40][43,44]. Typically, drug candidates with high lipophilicity can move across the lipid-rich epithelial cell membrane with relative ease. Fairly good water solubility allows for the fast drug release of buccal/sublingual formulations and drug diffusion across the hydrophilic cytoplasm of cells and paracellular passage. Macromolecules can be delivered via the oral mucosa, e.g., buccal insulin spray (Generex Oral-lyn®) was approved by Food and Drug Administration (FDA) for the treatment of patients under the Investigational New Drug (IND) program [41][42][43][45,46,47]. However, the number of marketed buccal/sublingual macromolecules is very small. However, over 40% of marketed drugs and approximately 90% of drug candidates are reported to be poorly water-soluble [5], and most of them are weakly ionizable drugs, indicating that their solubility and/or permeability across the lipid-rich epithelium are pH-dependent [44][45][46][47][49,50,51,52]. Typically, the ionic form of a drug is more water soluble than its non-ionic form. A change in the pH might influence the ratio of the ionized form of the dissolved drug, according to the Henderson-Hasselbach equation (Equation (4)) [48][53]. When the difference in the water solubility (and/or lipophilicity) between the two forms is big enough, a slight pH change might have a significant effect on the drug solubility. Therefore, drug candidates suitable for pHM modification should have pH-dependent solubility and/or pH-dependent lipophilicity and be poorly soluble at physiological pH in the oral cavity.4.2. pH Modifier
There are a few concerns about the excipients used in pharmaceutical formulations. A pH modifier can only be considered as a pharmaceutical excipient if it has been demonstrated to be safe for human beings. So far, various pH modifiers have been applied in the food and pharmaceutical industries. The Generally Recognized as Safe (GRAS) list of the FDA lists some safe pH modifiers that have been added to food. In addition, various pH modifiers recommended for oral liquids have been collected in the United States Pharmacopeia (USP). However, the specific pH modifiers for buccal/sublingual formulations were not referenced. The pH modifiers collected in the USP [49][67] and their maximum potency per unit dose used in solid oral and buccal/sublingual formulations in the database of Inactive Ingredient Search for Approved Drug Products Search, provided by the FDA [50][68]. The pH modifiers can be divided into three categories: acidifying agents, alkalizing agents and buffering agents. Currently, only a few pH modifiers, were applied in the commercial buccal/sublingual formulations approved by the FDA. pH modifiers demonstrated without local irritation and toxicity to oral mucosa could also be potential choices for the buccal/sublingual dosage forms.5. Methods for Microenvironmental pH Measurement
5.1. pH Electrode Approach
The most common method to determine the pHM is the pH electrode approach. As the previous studies described [51][52][53][54][55][56][57][57,77,78,79,80,81,82], formulations (e.g., tablets, film and patch) were allowed to swell in a limited volume of buffer solution (at neutral pH) at room temperature for a certain period. Subsequently, the pH on the surface of the formulations was determined using a pH electrode. Mucoadhesive buccal films containing ornidazole were allowed to swell in 4 mL of phosphate buffer (pH 6.8 ± 0.1) at room temperature for 120 min and the surface pH was measured using an electrode pH meter [52][77].5.2. Computer-Enhanced Color Images Method
To gain more information on the pHM change during the dissolving process of the fentanyl tablet, a computer-enhanced color images (of pH paper) method was used to record the pHM as it varied over the surface of the swelling tablet [58][54]. The schematic view of the setup and the computer-enhanced color images of pH paper are shown in Figure 3. A piece of pH paper was placed over a tablet. The tablet with the pH paper was held between two microscope slides, and a small volume of deionized water was applied to the pH paper. The tablet was rapidly wetted by the water that permeated the pH paper. As the tablet swelled, the pH paper was digitally photographed at different time intervals. The pH over the distinct regions of the tablet surface were then determined from the digital images and in comparison to the reference pH standards. The pHM decreased from 7.0 to 5.0, and then gradually increased to around 6.0 during the first 5 min of the dissolving process [58][54].Figure 3.
Schematic view of the setup of the computer-enhanced color images method.
5.3. UV/Vis Imaging Method
In a previous works, an UV/Vis imaging method with an agarose hydrogel mimicking the fluid on the surface of the buccal mucosa was constructed. The effect of the malic acid dose on the pH
M during the initial dissolution of the buccal films, and the information related to film the swelling and possible drug precipitation in the films were monitored using this method [59]. The agarose hydrogel contained agarose (0.5%
during the initial dissolution of the buccal films, and the information related to film the swelling and possible drug precipitation in the films were monitored using this method [58]. The schematic view of the UV/Vis imaging setup is shown in Figure 4. The agarose hydrogel contained agarose (0.5%
w
/
v
), bromothymol blue (pH indicator, 6.29 × 10
−5
M) and a buffer solution, simulating the human saliva pH and buffer capacity. A buccal film was attached on the agarose hydrogel, and the absorbance change of the pH indicator in the hydrogel at a wavelength of 610 nm was monitored during the swelling of the film. To relate the absorbance of bromothymol blue to the pH in the hydrogel, an absorbance-pH profile was constructed as a calibration curve. Based on the calibration curve, the pH during the swelling of the buccal film could be measured.
