Stuart R. Gallant, MD, PhD

The focus of today’s post is oral drug release—immediate, delayed, and extended.  Many technologies exist for controlling drug release—the focus of this post is on the interaction of gastrointestinal anatomy and oral dosage forms to understand how drug release can be manipulated.

Bioavailability

Bioavailability is typically depicted as a concentration of the drug in systemic circulation versus time.  The typical shapes of the bioavailability curve for an intravenously administered and an orally administered drug are depicted above.  For an orally administered medication to become bioavailable, it must experience a multistep process of delivery:

1. Dissolution:  The tablet or capsule must be transformed from its manufactured form which is taken by the patient into its dissolved form in the gut.  The rate of dissolution will be affected by the coating of the dosage form, the particle size distribution and solubility of the prodrug or active, formulation agents such as buffers and surfactants which may enhance solubility, as well as the food contents and secretions of the gut.
2. Transport:  The dissolved prodrug or active must move across the intestinal wall and enter venous circulation.
3. Circulation:  Once the drug enters venous circulation, it must pass the liver, often a site of significant degradation.  Once the drug enters systemic circulation it is distributed throughout the body, eventually reaching its target.

Chemical Equivalence:  A drug product has the same active ingredient in the same amount, compared to reference product; formulation may differ. Bioequivalence:  A drug delivers the same concentration of the active ingredient to the plasma and tissues, compared to reference product. Delayed Release:  A dosage form which releases portions of the drug over time. Extended Release:  A dosage form which lengthens the time of bioavailability, allowing less frequent dosing.

Gastrointestinal Anatomy

The gastrointestinal tract is a food processing digestion, absorption, and disposal system.  Narrating the journey of food and medicine through the GI system, the significant stages are:

• Mouth:  Food is masticated and combined with saliva which contains salivary amylase to begin breakdown of starches.  In the mouth, orally disintegrating tablets break down immediately, and chewable tablets are broken into small fragments.
• Stomach:  Food and liquids are brought quickly to the stomach which is a muscular organ capable of mixing its contents to encourage digestion.  The parietal cells of the stomach secrete hydrochloric acid to aid digestion.  Although acid secretion increases in response to food consumption, the buffering power of food in the stomach actually raises stomach pH in the fed state (pH 4.3 to pH 5.4), compared to the fasting state (pH 1 to pH 3).  The combination of mastication, salivary amylases, acid hydrolysis, and the mixing action of the stomach reduces the size of food particles to less than 2 mm before they are released into the small intestine.

• Small intestine:  The small intestine is characterized by its great length (3 to 5 meters) and modest diameter, providing a larger surface area for adsorption.  The contents of the stomach (chyme) pass through the pyloric sphincter into the duodenum, the first segment of the small intestine.  Within the duodenum, two important inputs to the intestinal contents occur:
  • The liver contributes bile which contains bile salts, cholesterol, fatty acids, and lecithin, as well as bilirubin.  The bile salts form micelles with dietary fat in the chyme, increasing solubility and enhancing intestinal absorption.
  • The pancreas contributes trypsinogen, chymotrypsinogen, elastase, carboxypeptidase, pancreatic lipase, nucleases and amylase, as well as bicarbonate.  The source of the bicarbonate is the parietal cells of the stomach—it stoichiometrically balances the hydrochloric acid in the chyme, raising the pH of the contents of the small intestine closer to neutrality.

• Large intestine:  The large intestine begins at the cecum (shown in red in the figure above) and forms an inverted U-shape across the anterior abdomen, ending at the rectum.  The large intestine has lower length (about 1.5 to slightly less than 2 meters) and greater diameter, compared to the small intestine, resulting in the longest residence time of any segment of the gastrointestinal tract.  A major activity of the large intestine is removal of water to produce a compact stool.  Within the large intestine, drug absorption is relatively unpredictable because:  1) drug may become sequestered within the stool and 2) the high bacterial counts in the colon can lead to degradation of the drug.

Representative pH values in fasting and fed state, as well as residence times are provided in the table below [1]:

	Fasting pH	Fasting Residence Time (hr)	Fed pH	Fed Residence Time (hr)
Stomach	1-3	0.5-0.7	4.3-5.4	1
Duodenum	6	0.5	5.4	0.5
Jejunum	6-7	1.7	5.4-5.6	1.7
Ileum	6.6-7.4	1.3	6.6-7.4	1.3
Cecum	6.4	4.5	6.4	4.5
Colon	6.8	13.5	6.8	13.5

One significant observation is that the transit time from mouth to the entrance of the large intestine is about 4.5 hours in fed or fasting state.  Any dosage form which has not made its contents available for absorption within that time window faces the more unpredictable absorption of the large intestine.

Variations in Gastrointestinal Behavior

A wide range of conditions can result in variation in the behavior of the gastrointestinal tract:

• 40% of elderly in developed countries consume a proton pump inhibitor (PPI) [2].  Many cystic fibrosis patients consume a PPI, as well.  Raising gastric pH can affect the release of some drugs.  PPIs also alter the microbial population of the gut [3].
• Approximately one quarter million people receive bariatric surgery every year in the US.  Restrictive procedures (sleeve gastrectomy, vertical banded gastroplasty, adjustable gastric banding, and gastric stapling) reduce food ingestion.  Malabsorptive procedures (jejunoileal bypass and jejunocolic bypass) reduce the absorption of food, and potentially drugs.  A study of these types of procedures showed generally reduced drug absorption [4].
• Some diseases have substantial effects on the gut (Crohn’s disease, ulcerative colitis, celiac disease, inflammatory bowel disease, irritable bowel syndrome, and others).
• Elderly patients may have reduced interest in eating due to changes in how the perceive taste and changes in satiety.  This can lead to a “tea and toast” diet which can affect the behavior of the gut.

In considering how both normal and disease-related variation in gut behavior may affect drug absorption, consideration should always be given to syndromes which are more prevalent in the patient population which will be receiving the drug.  For instance, if the target population is cystic fibrosis patients, it should be expected that many of these patients will consume a PPI and that the pH profile of their gut, along with the microbial population, will be different, compared to the population without cystic fibrosis.

Capsules

One of the easiest ways to control release of a drug is through encapsulation.  The drug product can be formulated using widely available blending and granulation equipment, prior to capsule filling.  Hard gelatin capsules release more than 50% of their contents within 10 minutes [5].  Release is somewhat more rapid under acid pH conditions, than near neutrality:

In general, hard gelatin capsules release most of their contents to the stomach.  Some alternative capsule products include:

• Capsugel VRcaps Plus:  Gelatin products are safe and effective; however some manufacturers prefer to remove animal source materials.  VRcaps Plus are an immediate release product similar to hard gelatin, but they constructed of HPMC which is a non-animal source material. 
• Capsugel DRcaps:  DRcaps have a delayed release of approximately 50 minutes independent of pH.  Given that the residence time of the stomach is approximately 1 hour, in most cases the capsule should have passed into the small intestine prior to releasing its contents.  In a Lonza white paper, the subjects consumed a light breakfast 30 minutes prior to receiving a test capsule [6].  Subsequent imaging showed release of the test material in the small intestine.

Coatings

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and other conditions by inhibition of COX-1 and COX-2.  Diclofenac is a BSC class II drug (high permeability, low solubility) with an onset of action of 30 min and an elimination half-life of 1-2 hours.  Diclofenac drug product is available in a number of forms, including enteric coated tablet, topical gel, suppository, and injectable (IM and IV) forms.  Enteric coating prevents contact of diclofenac with the mucosa of the stomach, reducing the risk of stomach irritation.

Numerous enteric coatings are commercially available [7]:

Product	Form	Polymer
Eudragit L30D	Latex dispersion	Poly (MA-EA)
Eudragit L100-55	Spray-dried latex	Poly (MA-EA)
HP-F	Micronized dry powder	HPMCP
Sureteric	Formulated, dry powder system	PVAP
Acryl-Eze	Formulated, dry powder system	Poly (MA-EA)
Aquarius Control ENA	Formulated, dry powder system	Poly (MA-EA)
Aquateric	Spray-dried pseudo latex	CAP
Aquacoat ECD	Pseudo latex dispersion	CAP
Aquasolve	Micronized, dry powder	HPMCAS
CAP	Dry powder	CAP
CAT	Dry powder	CAT

The strategy of enteric coating is a “delayed release” strategy with the goal of releasing the active into the small intestine, avoiding stomach irritation.  In testing this dosage form, USP requires a 2-hour soak in 0.1 N HCl to simulate the stomach environment, followed by phosphate pH 6.8 buffer at 37° C.  The following data was collected on diclofenac tablets coated with Aquarius Control ENA enteric coating [8]:

As can be seen in the figure, not much happens during the 2-hour soak in 0.1 N HCl.  There is a modest weight gain (data not shown), as some of the solution intrudes into the tablets.  After the change of pH at 120 minutes, rapid dissolution begins.  The thinner coating (3% by weight) releases the drug more rapidly, but even the heavier coating (10% by weight) releases essentially all of its diclofenac within 60 minutes.  Recall that the transit time for the small intestine is 3.5 hours, so plenty of time remains for adsorption after the coating is dissolved.

Microgranules

Another approach is creation of an “extended release” form.  Diltiazem is a calcium channel blocker used to treat hypertension, angina, certain hear arrhythmias, and other conditions.  Diltiazem is a BSC class I drug (high permeability, high solubility) with a short plasma half-life (3 to 7 hours) and reduced bioavailability due to significant first-pass hepatic clearance.

Sanofi improved the pharmacokinetic properties of diltiazem using coated microbeads [9].  The drug product consisted of 400 to 1400 micron diameter granules consisting of inert grain substrate coated with diltiazem and a binder (polyvinyl pyrrolidone).  The granules were surrounded by a microporous membrane consisting of a film forming polymer (ethylcellulose), a plasticizing agent (castor oil), and a filling material (talc, kaolin, silica, metal silicate, or metal oxide).  For convenience, the microbeads are filled into capsules.  For diltiazem to be absorbed, fluid from the gastrointestinal tract must dissolve diltiazem in situ within the microbeads, then the diltiazem molecules must diffuse out of the microporous membrane surrounding the microgranules.  Once outside of the microbeads, diltiazem is free to be absorbed across the intestinal membrane.

This approach extends bioavailability curve of diltiazem as seen in the figure below [10]:

With ordinary diltiazem, the majority of the area under the curve occurs before 10 hours.  It would be expected that a patient receiving this medication daily would experience peaks and valleys in anti-hypertensive effect of the drug.  In contrast, the microgranular form stretches out the effect over a longer period of time.  One can imagine that the effect would be uniform around the clock, once several doses had been taken and a steady state was achieved.

Since the transit time through the stomach and small intestine is 4.5 hours, it stands to reason that a significant amount of the diltiazem absorption happens from the colon.  Although it was mentioned above that colonic absorption can be inconsistent and unpredictable, in this case colonic absorption seems to work quite well.

Other Considerations

As with all oral formulations, the standard considerations apply to immediate, delayed, and extended-release products:

• BCS class:  Both permeability and solubility affect the pharmacokinetics of immediate, delayed, and extended-release products.
• Particle size distribution:  All solid drug products exist as aggregates of drug substance with excipients.  Larger aggregates tend to dissolve more slowly than smaller aggregates.  Processes that control particle size distribution, such as milling, can enhance absorption.
• Excipients:  Excipients can enhance absorption by drawing water into the drug product matrix (through hydrophilicity) and by enhancing solubility (through buffering and through solvation as by detergents).
• Pro-drugs:  The time for conversion to active species can play an important role in pharmacokinetics.

[1] Shargel, L. and Yu, A.B.C.  Applied Biopharmaceutics & Pharmacokinetics, McGraw Hill, 7^th Edition.

[2] Zirk-Sadowski, J., et al.  “Proton-Pump Inhibitors and Long-Term Risk of Community-Acquired Pneumonia in Older Adults,” J Am Geriatr Soc . 66(7):1332-1338 (2018).

[3] Freedberg, D.E., et al.  “The impact of proton pump inhibitors on the human gastrointestinal microbiome,” Clin Lab Med. 34(4): 771–785 (2014).

[4] Alawan, A.A., et al.  “Drug absorption in bariatric surgery patients: A narrative review,” Review Health Sci Rep 26;5(3):e605 (2022).

[5] Gray, V.A., et al.  “Use of Enzymes in the Dissolution Testing of Gelatin Capsules and Gelatin-Coated Tablets—Revisions to Dissolution <711> and Disintegration and Dissolution of Dietary Supplements <2040>,” Dissolution Technologies, Nov, 6-19 (2014).

[6] Lonza White Paper, “DRcaps Capsules Achieve Delayed Release Properties for Nutritional Ingredients in Human Clinical Study”.

[7] Qiu, Y., et al.  Developing Solid Oral Dosage Forms, 2^nd Edition.

[8] Ashland White Paper, “Delayed-release Diclofenac Sodium Tablets:  Scaling Up the Coating Process.”

[9] Desmolin, H.  “Microbeads of diltiazem, a process for their manufacture and a sustained-release pharmaceutical composition containing them,” Canadian Patent CA1336326C.

[10] Thiercelin, J.F., et al.  “Development and Pharmacokinetics of a New Sustained-Release Formulation of Diltiazem,” Journal of Cardiovascular Pharmacology, 16, S31-S37 (1990).

Disclaimer:  PharmaTopo^TM provides commentary on topics related to drugs.  The content on this website does not constitute technical, medical, legal, or financial advice.  Consult an appropriately skilled professional, such as an engineer, doctor, lawyer, or investment counselor, prior to undertaking any action related to the topics discussed on PharmaTopo.com.