Formulation scientists tasked with developing oral formulations often face many challenges such as drug instability in the acidic and alkaline environments of the gastrointestinal (GI) tract and unsatisfactory absorption variations of compounds with poor physicochemical properties such as low solubility or low permeability. The primary function of the GI tract is to digest and absorb nutrients and water while at the same time impede the entry of potentially noxious luminal contents such as harmful pathogens and toxins. This function is accomplished by the establishment of intestinal barriers formed by a continuous sheet of polarized columnar epithelial cells that separate the external luminal environment from the internal environment of the body and exhibit selective absorption (1-3). Oral formulations must, therefore, be able to withstand the hostile acidic environment of the stomach and the high enzymatic activity in the small intestine, circumvent the inherently impermeable intestinal epithelial barrier and the binding capacities of the resident mucus and luminal contents, escape the efflux system that pumps substances back into the lumen, and evade first pass metabolism by the liver (3). Pharmaceutical Technology spoke with Anshul Gupte, PhD, senior formulation scientist, and Michael DeHart, PhD, development scientist, from the CDMO Metrics, about the strategies used to enhance oral absorption and the challenges in developing oral formulations for poorly permeable drugs.
PharmTech: What factors influence drug absorption in the GI tract?
Metrics: Characteristics of the drug that influence absorption include particle size, solubility, lipophilicity, stability, ionization state (pKa), and polymorphism. Sometimes these characteristics work against each other to improve absorption. For example, a drug that is more lipophilic may increase permeability, but may result in lower solubility, thereby, decreasing the overall absorption. To overcome deficiencies of absorption due to drug properties, the dosage form may help improve absorption by altering the disintegration and dissolution time, increasing residence time in the intestine, and providing delayed release in the lower intestine instead of the stomach.
The absorption of the drug through the GI tract is governed by either a simple passive diffusion or active transport with the aid of transporters located in the GI tract. For most drugs, passive diffusion is the mode of transport. The amount of drug absorbed is dictated by the gradient created across the membranes in the stomach and the small intestine as well as the chemical structure of the drug molecule itself such as the size and degree of ionization. Size and absorption usually have an inverse relationship. Most drugs are weak acid or bases, therefore, the pH of the stomach and the intestinal tract affects the degree of ionization of the drug, which directly affects the solubility of the drug in the GI tract. The stomach has a pH of between 1 and 2 while the intestine has a pH ranging from 4 to 8. With this environment, the intestine provides a wide pH range for drugs to exist in their ionized state, which increases their solubility compared to the more lipid-soluble, un-ionized state.
Most of the absorption takes place in the intestine mainly because the intestine offers much greater surface area for drug uptake. The residence time of the drug in the stomach may vary depending on the time for gastric emptying. The latter is affected by food uptake, other drugs, and other factors. Due to the acidic nature of the stomach mucosa and the presence of enzymes such as pepsin, drugs may be degraded before they are absorbed. The presence of fatty foods can also lead to increased gastric emptying time, which can lead to degradation or reduced absorption of some drugs.
Lipinski’s rule of five has been used as a preclinical tool to assess the bioavailability of a drug. According to Lipinski’s rule of five, the molecular weight of the drug has to be below 500 Da for it to be a good candidate for oral absorption. Additionally, Lipinski’s rule of five states that the drug molecule should have less than five hydrogen-bond donors and not less than 10 hydrogen-bond acceptors. The log P for the drug should ideally be less than 5. A balance between the polarity and lipophilicity of the drug is necessary so that the drug has sufficient solubility in the gastric media as well as permeability through the gastric mucosa.
To optimize drug absorption, pharmaceutical scientists employ formulation strategies such as salt formation to increase drug solubility, micronization or particle size reduction to increase surface area, inclusion of surfactants and emulsion system to alter wetting and dispersibility, and addition of buffer systems that alter the microenvironment pH. Spray drying and conversion of the drug into its amorphous, and thus, more soluble form is well established. In the case of a moderately or highly permeable drug, the disintegration and subsequent dissolution from the formulation are critical rate-limiting steps. In the case of an immediate-release formulation, the disintegration of the dosage form is the critical step for the drug to be in solution and subsequently absorbed. The dissolution of the formulation in the fed and fasted gastric media and intestinal media is usually studied in vitro to establish a relationship for the drug in vivo. Additionally, the drug could be formulated into sustained-release, delayed-release dosage forms.
PharmTech: What strategies are used to increase oral absorption of poorly permeable drugs?
Metrics: Creating an esterified prodrug is the most common way of increasing permeability for a highly soluble drug. Prodrugs are reversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug. Common functional groups that are employed for prodrug formation are amine, hydroxyl, sulfhydryl, and carboxyl moieties. A few examples of the drug/esterified prodrugs are acyclovir/valacyclovir and melagatran/ximelagatran. Esterification of these drugs eliminates an ionized functional group and increases the lipophilicity of the drug molecule. When developing prodrugs, the pharmaceutical scientist must be careful that the increased permeability due to increased lipophilicity doesn’t result in reduced solubility, whichcould offset any increase in absorption due to increased permeability.
Another approach is to use polymers that, in general, mask the inherent hydrophilic nature of the API and hence, lead to enhanced absorption. Liposomes, nanoparticles, and microspheres are all polymer-based delivery systems that generally incorporate a hydrophilic compound inside a lipid membrane. Mucoadhesive polymers can be used to increase the residence time in the GI tract. Specific molecular weights and combinations of polyethylene oxide, for example, have been shown to exhibit excellent adhesive characteristics in vivo.
Other methods include the formation of bile salt complexes or using cyclodextrin inclusion complexes, which allows poorly soluble drugs to be combined with cyclodextrins, thereby, creating a soluble complex. Developing self-emulsifying drug-delivery systems (SMEDDS) is another strategy to increase oral absorption of a poorly soluble drug. These systems are typically administered as soft gelatin capsules. The drug is dissolved in the oil phase, and through careful selection of surfactants, SMEDDS are able to promote GI absorption by inhibiting bile secretion. In addition, the surface area of cells exposed to certain surfactants is increased.
PharmTech: What are the challenges when developing oral formulations for poorly permeable drugs?
Metrics: One challenge is that a drug would be soluble in the gastric media, but would not get absorbed along the GI tract and is subsequently eliminated from the body. One must consider the permeability change over the entire length of GI tract. Another factor to consider is whether the drug is a substrate for the active transport system in the gastric mucosa. The strategy of creating SMEDDS can be undertaken by those companies that possess soft gelatin capsule technology. In some cases, there may be benefit of a delayed-release formulation.
The two biggest hurdles in formulation development for a poorly permeable drug are cost and time. Using newer technologies or equipment that have not been fully tested and validated as a commercial option poses a risk. Therefore, proven methodologies such as the addition of functional excipients, particle size reduction, modified-release tablets, or enteric coatings may offer the most practical option to increasing permeability.
PharmTech: What are some recent advances in oral absorption enhancement strategies?
Metrics: Spray drying to generate amorphous material to increase bioavailability is becoming more prevalent. Spray drying is a fast process where the drug molecule and a stabilizer, usually a polymer, can generate a wide range of particle sizes to improve solubility (BCS II and IV) or permeability (BCS III and IV). The spray-dried amorphous material generated from spray drying can then be processed into tablets or capsules with specific release profiles. Other techniques that generate amorphous material to improve absorption are hot-melt extrusion, freeze drying, and supercritical fluid drying. Each of these techniques has their own advantages and disadvantages.
A more recent advancement in increasing oral absorption is the advent of chronotherapeutics. Chronotherapy uses the body’s natural, circadian rhythms to improve absorption of drugs. For example, blood flow, active versus resting state, and gastric mobility are a few things that change throughout the course of the day that could influence drug absorption. To effectively target the circadian rhythms of the body, several techniques have been developed to offer pulsatile drug release. To achieve the pulsatile-release profile, tablets are generally formulated with multiple layers that contain a combination of immediate-release, extended-release, and delayed-release matrixes. The one-step drug coating (OSDrC) Optidose technology, a proprietary technology of Catalent, can manufacture multiple layer tablets and a tablet-in-tablets with multiple core placement to achieve almost any desired pulsatile-release profile. In a similar fashion, capsules containing beads with various polymer coatings can effectively deliver a drug using the body’s circadian rhythms.
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3. T.Y. Ma and J.M. Anderson, “Tight Junctions and the Intestinal Barrier,” in Physiology of the Gastrointestinal Tract, L.R. Johnson, Ed. (Academic Press, Burlington, MA, 4th ed., 2006) pp 1559-1594.