Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Review
New Drug Delivery Systems for Stable Oral Absorption: Theory, Strategies, and Applications
Satomi Onoue
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2024 Volume 47 Issue 11 Pages 1797-1803

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Abstract

The oral dosage route still remains the most common and preferred route for drug administration due to convenient handling, high patient compliance, and cost-effectiveness. However, the oral absorption of drugs can be a complex process depending upon: (i) physicochemical properties of the drug (e.g., pKa, lipophilicity, solubility), (ii) pharmaceutical factors (e.g., dosage form), and (iii) physiological factors (e.g., gastrointestinal pH values, gastric emptying rate, gastric and intestinal pH, metabolism). Oral administration of drugs sometimes leads to poor and/or variable oral bioavailability, possible leading to unstable clinical outcomes. To offer stable and improved pharmacokinetic behavior of drugs, a number of formulation approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of drugs. To provide new formulation platforms for better and safe medication, it is considered essential to understand the physicochemical, biochemical, metabolic, and biological barriers which limit overall drug bioavailability in more detail. The review article considers several crucial factors affecting oral absorption of drug substances. This article also describes the recent progress in formulation approaches to achieve stable and improved biopharmaceutical properties of orally-taken drugs.

1. INTRODUCTION

Conventional oral dosage forms, including pills, capsules, caplets, and tablets, have been widely used for clinical treatment of various diseases due to non-invasiveness, convenience of self-administration, compactness, and ease of manufacturing. While the oral route is convenient, the oral absorption of drugs can be theoretically influenced by conditions in the gastrointestinal (GI) tract of patients, such as pH and volume of GI fluids, gastric emptying and small intestinal transit time, and food intake.1) Drugs need to be dissolved in the GI fluid to facilitate drug absorption and ensure the effectiveness of drug treatment, although the transition in GI conditions sometimes has a major impact on the dissolution behavior of drugs.2) Recently, many drug candidates have shown poor aqueous solubility, and hence the solubility of a drug substance is one of the critical factors influencing drug dissolution and oral bioavailability. Especially for Biopharmaceutical Classification System (BCS) class II compounds with high permeability and low solubility, drug absorption is often limited by drug solubility and dissolution,3) and thereby the oral bioavailability of such drugs tends to be affected by patients’ conditions. The morphology and physiology of the GI tract can also be influenced by multiple factors, such as age, sex, ethnicity, genome, or the disease state of the treated patient.4) In some conditions, there were significant transitions of gastric emptying and the small intestinal transit time, and these physiological changes can significantly alter the kinetics of drug absorption, as well as the total amount of the drug absorbed.5) These physiological changes would affect the pharmacokinetic behavior of orally-taken drugs, possibly resulting in inconsistent clinical efficacy with wide variability.6)

So far, a number of efforts have been made to establish various pharmaceutical technologies for more stable pharmacokinetic behavior and clinical outcomes, that include solid dispersion (SD), microparticles, micelles, microenvironmental pH-modifiers, nanocrystals, and cyclodextrin complexation.7) There have been numerous studies demonstrating the enhanced drug dissolution and oral absorption of drugs by these methods. Briefly, microenvironmental pH-modifier approaches could achieve pH-independent dissolution behavior of drug substances,2) so that they would provide stable medication even though the gastric condition of patients could change. Other formulation systems such as micelles and solid dispersions showed consistent oral absorption of drugs with no significant influences of food intake.8) Accumulated experience and knowledge obtained from these previous studies would promote formulation design and development of oral dosage forms. The present article was focused on several formulation approaches to achieve stable oral absorption and/or improve biopharmaceutical properties of drugs. Herein, we reviewed several key factors affecting the pharmacokinetic behavior of drugs, and the concept of several delivery options in order to improve dissolution, and application examples are provided.

2. PHYSIOLOGICAL FACTORS AFFECTING PHARMACOKINETIC BEHAVIOR

2.1. pH

Physiological pH and the acid-base dissociation constant (pKa) are key determinants of the pharmacokinetics of orally-taken drugs when considering the effects of ionization or protonation (Table 1). In particular, pH in the GI tract is important for the dissolution of drugs with pH-dependent solubility, and gastric acidity could be variable due to endogenous or exogenous factors. pH of the stomach is basically approx. 1.0–3.0 in cases of healthy adults,9) and mainly regulated by the secretion of gastric acid. Infection by Helicobacter pylori could cause suppression of gastric acid secretion, resulting in hypochlorhydria with a high pH of more than 5.0.10) One of the major exogenous factors for suppression of gastric juice is administration of a drug for gastroesophageal reflux disease, including proton pump inhibitors and H2 blockers. The increase of gastric pH could reduce the oral bioavailability of weakly basic drugs, including dipyridamole,11,12) levothyroxine,13) and posaconazole.14) In contrast, acidic beverages could markedly decrease gastric pH, leading to increased oral bioavailability of weakly basic drugs, including itraconazole15) and posaconazole.14) In terms of intestinal pH, it has been reported that the cecal pH of Crohn’s disease patients after ileocecal resection was 0.9 pH units higher than healthy patients.16) Although the variability of the intestinal pH tends to influence the absorption of drugs with pH-dependent solubility, information regarding the relationship is limited.

Table 1. Factors Changing Physiological Parameters in Gastrointestinal Tract and Their Effects on the Drug Absorption

Physiological parametersEndogenous factorsExogenous factorsEffects on absorptionReported drugs
Gastrointestinal pHHypochlorhydria,23)
Crohn’s disease16)
Food 
Drug: PPIs antacid, H2 blocker 
Acidic beverage
Increasing/decreasing dissolved drugDipyridamole12)
Itraconazole15)
Levothyroxine13)
Posaconazole14)
Water volumeAging12)Water volume 
Food
Increasing/decreasing dissolved drugDanazole19)
Nifedipine20)
Gastric emptying timeAging,22)
Parkinson’s disease,23)
Diabetes25)
Food 
Drug: metoclopramide, propantheline
Delayed Tmax 
Increasing/decreasing dissolved drug
Gefitinib21)
Levodopa23)
Meloxicam24)
Metformin26)
Small intestinal transit timeDiabetes,25)
Crohn’s disease,16)
Liver cirrhosis28)
Drug: propanthelineIncreasing/decreasing drug exposureMetformin26)
Contents in gastrointestinal tractSecretion of bile acidFoodIncreasing/decreasing dissolved drugCabozantinib31)
Danazol19)
Itraconazole8)

2.2. Water Volume

In general, the water volume in the GI tract affects the disintegration of tablets, dispersion, and dissolution rate of drugs17) (Table 1). Especially, the oral bioavailability of hydrophobic drugs with low solubility could be markedly reduced with a low water volume in the GI tract. Secretion in the GI tract of the elderly may decrease, resulting in smaller water volume in the GI tract than in younger people.18) However, the most influential factor affecting water volume in the GI tract might be drinking water, and the increased rate of area under the curve (AUC) after administration of danazole with drinking water of 800 mL to that of 200 mL was 155%.19) In terms of variability of drug absorption, Cmax of nifedipine, a BCS class II drug with low solubility and high permeability, exhibited lower variability in cases of drug administration with a greater volume of drinking water.20)

2.3. Gastric Emptying Time

Gastric emptying is closely associated with movement of the drug from the stomach to small intestine where many drugs could be absorbed; therefore, oral absorption of drug substances can also be markedly affected by the gastric emptying time (GET)/rate (GER) (Table 1). Gradual transition of a drug caused by slow GER directly increases drug contact with the absorption site, possibly resulting in increased oral bioavailability of drugs; however, rapid GER can decrease the oral bioavailability of gefitinib with its low solubility.21) One of the main reasons for the variability of gastric motility is aging,22) the same as for other physiological parameters. Interestingly, delayed GER can be observed in patients with Parkinson’s disease, possibly due to lewy pathology in the enteric nervous system and partially discrete brainstem nuclei, and variability of Tmax of levodopa could occur in Parkinson’s disease patients with different gastric emptying rate.23) Severe acute pain could suppress the nervus vagus, thereby influencing gastrointestinal secretion and motility, and this physiological change might result in poor and delayed oral absorption.24)

2.4. Small Intestinal Transit Time

Since the main drug absorption site is the small intestine, the small intestinal transit time (SITT) can also affect the absorption of orally-taken drugs (Table 1). A previous investigation demonstrated that the absorption of metformin, a drug for the treatment of type 2 diabetes,25) could change in accordance with SITT, and the AUC value of metformin was increased to approx. 120% in patients receiving propantheline to delay SITT, compared with patients without such treatment.26) Patients with diabetes sometimes exhibit abnormal GI conditions, possibly resulting in rapid SITT.27) SITT might be accelerated in patients with liver cirrhosis,28) possibly due to portal vein and intestinal wall blood stasis, and patients with Crohn’s disease who have undergone ileocecal resection.16) However, it is still unclear how liver dysfunction could affect the activity of the gastrointestinal tract, possibly with the opposite result of accelerating SITT.29) The absorption profile of drugs with low permeability or a narrow absorption window in the GI tract could be variable in patients with changed SITT.

2.5. Food Effect

Concomitant food intake might affect the pharmacokinetic behavior of orally-taken drugs, and food can alter the oral bioavailability of drugs by various mechanisms, including delayed gastric emptying, stimulated bile flow, altered pH value in the gastrointestinal tract, increased splanchnic blood flow, changes in the luminal metabolism of a drug substance, and physical or chemical interaction with a dosage forms or drug substances.30) Food effects on the oral bioavailability of drug substances can have clinically significant consequences,8,19,31) leading to variations in efficacy and toxicity; therefore, the oral absorption profile of orally-taken drugs should be confirmed under fasting and fed conditions (Table 1). As a positive food effect, it may accelerate solubilization of orally-taken drugs with poor solubility, possibly due to the secretion of bile acids and lipidic moieties in foods.14) In contrast, negative food effects could be observed for weakly basic drugs.32) Under fed conditions, the gastric pH increases up to approx. 3.0–5.0, higher than that in the fasting state, and precipitation of weak basic drugs might occur in the stomach with a higher pH range, resulting in decreased oral bioavailability. Gastric emptying can also be delayed by food intake, and the food effect is likely to be correlated with the number of calories in food.33) Thus, the food effect can be reflected in alterations in both the absorption rate and absorption extent, from the perspective of pharmacokinetics.

3. FORMULATION DESIGN BASED ON BIOPHARMACEUTICS CLASSIFICATION SYSTEM

The BCS has been considered a useful tool for decision-making in formulation development from a biopharmaceutical point of view.34) It categorizes drug substances into one of four categories based on their solubility and intestinal permeability, and these four categories are defined as follows: high solubility/high permeability (class I), low solubility/high permeability (class II), high solubility/low permeability (class III), and low solubility/low permeability (class IV) (Fig. 1). A drug substance is considered “highly permeable” when the extent of absorption in humans is determined to be 90% or more of an administered dose. A drug substance is considered “highly soluble” when the highest dose strength is soluble in 250 mL or less of aqueous media over the pH range of 1–7.5 at 37 °C. Recently, the concept of BCS has drawn considerable attention as it is available for formulation design.35,36) Classification of drug candidates based on BCS can provide an indication of the difficulty of development. For BCS class I drugs, there is no rate-limiting step for oral absorption. Immediate-release solid oral dosage forms, such as conventional tablets or capsule formulations, are commonly designed to ensure rapid dissolution in the gastrointestinal tract. In contrast, the bioavailability of a BCS class II drug is rate-limited by its dissolution, so that even a small increase in the dissolution rate sometimes results in a large increase in bioavailability.37) Therefore, enhancement of the dissolution rate of a drug is thought to be a key factor for improving the bioavailability of BCS class II drugs. For example, increases in the saturation solubility and effective surface area have a positive impact on the dissolution rate of drugs, and these factors could be increased by efforts in preformulation studies and formulation design. Crystal modification,38) particle size reduction,39) self-emulsification,40) pH modification,41) and amorphization42) are considered to be effective for improving the dissolution behavior of BCS class II drugs. For BCS class III drugs with high solubility and low permeability,43) the use of permeation enhancers, such as fatty acids, bile salts, surfactants, and polysaccharides, might result in enhanced clinical outcomes since the bioavailability of BCS class III drugs is rate-limited by the membrane permeability in the gastrointestinal tract. BCS class IV drugs exhibit challenging molecular properties such as low solubility and low permeability. Since both solubility and permeability are rate-limiting steps for absorption, it is considered that physiological factors, such as the gastric emptying and gastrointestinal transit times, markedly influence the absorption of BCS class IV drugs. So far, formulation approaches similar to those for BCS class II drugs have been practically applied to BCS class IV drugs, even though the absorption could be limited by poor permeability after dissolving in the gastrointestinal tract. The viable formulation options based on BCS are summarized in Fig. 1.

Fig. 1. Biopharmaceutics Classification System and Viable Formulation Options Based on It

Reproduced with kind permission of Elsevier, from International Journal of Pharmaceutics, 420 (1), 2006, 1–10, Fig. 1, Copyright (2011) by Elsevier.

4. DELIVERY OPTIONS TO ACHIEVE STABLE ORAL ABSORPTION

4.1. Microenvironmental pH-Modifier

Microenvironmental pH modification in solid dosage forms is considered to be an alternative option for an ionizable drug to improve the solubility and dissolution rate. The pH change significantly influences the saturation solubility of an ionizable drug by dissociation.6) The incorporation of pH modifiers in the dosage form can alter the microenvironmental pH. Microenvironment is a term used to represent a microscopic layer surrounding a solid particle in which the solid forms a saturated solution of adsorbed water. The microenvironmental pH would affect the performance of the solid dosage form, such as the chemical stability of the drug substance and dissolution profile. Microenvironmental pH modification has also been widely used in oral solid dosage forms to achieve pH-independent dissolution in the GI tract, as well as increase the solubility of poorly water-soluble drugs.44)

Selection and optimization of counter-ions would be one of the key considerations for formulation design with the microenvironmental pH-modification approach. For weakly basic drugs, organic acids have often been used as acidifiers, such as citric, fumaric, succinic, and tartaric acids. In particular, citric acid has been applied to many formulations. In our previous investigation, a granule formulation of dipyridamole was prepared by employing fumaric acid as a microenvironmental pH-modifier.2) Poor and inconsistent systemic exposure of dipyridamole was noted early after oral administration of dipyridamole in a rat model of hypochlorhydria; however, the pharmacokinetic behavior of a new dipyridamole formulation with fumaric acid under hypochlorhydria was almost identical to that of dipyridamole in normal rats. Given the improved systemic exposure early after oral administration in the hypochlorhydric rats, the new formulation of dipyridamole with the pH-modification approach might promote better clinical outcomes in patients with hypochlorhydria.

Commercialization of research achievements has also been attempted in pharmaceutical industries over the last few decades, and formulation studies with the pH-modification approach led to the successful development of various solid dosage forms, e.g., matrix tablets, pellets, SD formulations, and conventional Immediate-release formulations.6) Some products have already been introduced onto the market, e.g., Persantin® SR (dipyridamole sustained-release formulation) and Cipro® XR (ciprofloxacin extended-release tablets). The pH-modifiers added to these formulations could modulate the dissolution behavior of chemicals with pH-dependent solubility, thereby offering improved and stable therapeutic potential and more favorable clinical outcomes.

4.2. Amorphous Solid Dispersion

Amorphous solid dispersion (ASD) is defined as a distribution of active ingredients in molecular and amorphous forms surrounded by inert carriers,45) and ASD has been used for poorly water-soluble pharmaceutical compounds. With the ASD approach, the dissolution behavior of a drug substance can be improved by disarranging its crystalline lattice to produce a higher energy state of the amorphous form. Marked enhancement of the saturated solubility of an amorphous drug may lead to a significant improvement of oral bioavailability. ASD formulations can be manufactured by spray drying, melt extrusion, lyophilization, and use of supercritical fluids with polymeric carriers and/or surfactants.7) Despite their attractive characteristics, amorphous drugs tend to be chemically and physically less stable than crystalline forms. The transformation from amorphous to crystalline forms in ASD formulations would lead to a reduction of oral bioavailability of the incorporated drugs. Suitable polymers could stabilize ASD and prevent drugs from crystallizing and provide improved physical stability under a variety of accelerated stability conditions, such as elevated temperature and relative humidity. Therefore, careful consideration should be made for the selection of suitable polymers.

Several studies demonstrated that ASD technology can offer rapid dissolution and supersaturation of various poorly-soluble compounds, including itraconazole, nobiletin, and tacrolimus.46) Also, the ASD formulation approach could offer stable and improved pharmacokinetic behavior of orally-taken drug substances such as non-steroidal anti-inflammatory drugs (NSAIDs) and carvedilol.46,47) In general, the analgesic activity of NSAIDs tends to be positively correlated with the plasma concentration, so the onset of NSAID action could be delayed in patients with severe pain because of decreases in gastric fluid secretion and motility by suppression of the vagus nerve.24) In our previous study, after the oral administration of crystalline meloxicam, a 69% reduction in AUC0–4 was observed between normal and propantheline-pretreated rats with impaired gastric motility.46) For an orally-dosed ASD formulation of meloxicam with hydroxypropylmethylcellulose (HPMC), there were approx. 9- and 12-fold increases of AUC0–4 in normal and propantheline-pretreated rats, respectively, in comparison with crystalline meloxicam. Interestingly, the ASD formulation of meloxicam with Eudragit® E PO was found to be less effective, although it showed significant improvement in dissolution behavior of meloxicam even at a gastric pH value. According to the results from infrared spectroscopic study, there were potent interactions between meloxicam and Eudragit® E PO, and this might partly explain the marked attenuation of meloxicam absorption. In addition, after the oral administration of carvedilol in a rat model of hypochlorhydria, there was a 34.4% reduction in the systemic exposure of carvedilol compared with that in normal rats. However, for the orally-dosed ASD formulation of carvedilol, there was no significant difference in pharmacokinetic behavior between normal and hypochlorhydric rats.47) These observations, taken together with outcomes from previous investigations,7) suggest that the ASD approach may be a viable dosage option to achieve reliable medication.

4.3. Self-micellizing Solid Dispersion (SMSD)

Previously, our group proposed the concept of SMSD as a new solubilizing technology to improve oral absorption of poorly water-soluble drugs.48) SMSD can be defined as an SD system using an amphiphilic polymer, and, compared with the conventional SD system, the SMSD system could achieve superior solubilizing potential for poorly soluble compounds because of its self-micellization property due to the amphiphilic polymer with encapsulation of a lipophilic drug through hydrophobic interaction (Fig. 2). When the SMSD approach was applied to tranilast49) and cyclosporine A48) with the use of poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) [poly(MPC-co-BMA)] as an amphiphilic polymer, there was marked improvement in the dissolution behavior of the SMSD formulations compared with those of crystalline or amorphous powders. In aqueous media, evident formation of nanoparticles was observed, and NMR spectroscopic analysis was indicative of molecular interaction between the drug and poly(MPC-co-BMA). There was an approx. 40–50-fold increase in oral bioavailability compared with crystalline or amorphous powders in rats, and its inter-individual variation was reduced significantly. So far, a number of application studies have been conducted or are ongoing for SMSD to improve biopharmaceutical properties of pharmaceutical substances and/or nutraceuticals.

Fig. 2. Schematic Presentation of Self-micellizing Solid Dispersion

In our previous studies on itraconazole, itraconazole-loaded SMSD employing Soluplus® showed improved and consistent dissolution behavior in biorelevant dissolution media, resulting in stable oral absorption even under hypochlorhydric50) and fed/fasted conditions.8) Thus, a Soluplus®-based SMSD system has the potential to facilitate stable dissolution and consistent oral absorption of poorly soluble drugs even under variable GI conditions owing to the non-ionic property and high solubilization effect of Soluplus®. When the SMSD approach was applied to celecoxib, an SMSD formulation of celecoxib could be micellized in aqueous media with a mean diameter of 153 nm, and it showed fast dissolution behavior even under acidic conditions.51) In propantheline-pretreated rats with impaired gastric motility, orally-dosed crystalline celecoxib showed a prolonged mean absorption time (MAT), and AUC0–4 was reduced to as low as 12% compared with that in normal rats. Interestingly, an SMSD formulation of celecoxib could suppress the delay and decrease of absorption in propantheline-treated rats. Herein, SMSD could increase the bioavailability of drugs while reducing the inconsistency of oral absorption under various pathophysiological conditions, and further investigation of its efficacy, safety and reasonable manufacturing might accelerate the clinical application of SMSD.

5. CONCLUSION

Absorption of orally-taken drugs can be complex and influenced by various physicochemical and biopharmaceutical characteristics of the drugs and GI physiology-related factors. Marked attention has been focused to establish new oral dosage forms with improved and stable pharmacokinetic behavior. Better understanding of these factors and the alterations in GI physiology is required to ensure the safe and effective use of oral medications. Research interests in the detailed mechanisms on alteration of oral absorption would lead to further breakthroughs in several areas of both formulation design and pharmacokinetic prediction, and these activities might overcome several limitations and potential problems of oral dosage forms. Also, alliances between formulators and physiologists might continue to be a cornerstone of product development in future years, hopefully providing biorelevant in vitro tests as a useful tool for formulation analysis, reliable physiologically-based pharmacokinetic models for pharmacokinetic prediction, and eventually new oral dosage forms with stable efficacy and high-level safety.

Acknowledgments

I would like to express my sincere appreciation to collaborators, Professors Wei Wu (Fudan University), Robert K. Prud’homme (Princeton University), and Hak-Kim Chan (University of Sydney), for fruitful discussions and encouragement throughout the work. I truly thank past and present staff and students and ex-colleagues at Pfizer Global Research and Development and ILS Inc.

Conflict of Interest

The author declares no conflict of interest.

Notes

This review of the author’s work was written by the author upon receiving the 2023 Pharmaceutical Society of Japan Award for Divisional Scientific Promotion.

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