Biopharmaceutics factors affecting Modified release products Dr. Jwan Mohammed

Biopharmaceutics factors affecting MR dosage forms An ideal extended-release (ER) drug product should demonstrate; complete bioavailability, minimal fluctuations in drug concentration at steady state, reproducibility of release characteristics independent of food, and minimal (diurnal) day time variation. Unfortunately its not easy to manufacture such an ideal product

The ER oral drug products remain in the gastrointestinal (GI) tract longer than conventional (immediate-release) drug products. Thus, drug release from an ER drug product is more subject to be affected by the anatomy and physiology of the GI tract, GI transit, pH, and its contents such as food compared to an immediate-release oral drug product.

The physiologic characteristics of the GI tract, including variations in pH, blood flow, GI motility, presence of food, enzymes and bacteria, etc, affect the local action of the extended-release drug product within the GI tract and may affect the drug release rate from the product.

Biologic consideration of GIT The most important factors affecting the biopharmaceutics of the MR products in the GIT are: pH food Transit time Amount of fluid present

1. Effect of pH Stomach has a low pH thus it is acidic Gastro resistant coated dosage forms are designed to resist acidic pH Some patients can have higher pH due to age, disease, or ethnic (race) origin. This can lead to dosage form disintegration and dissolution in the stomach resulting in premature drug release and /or dose dumping The solubility of some drugs are pH dependent, therefore; their solubility is different at different sites of the GIT

In the small intestine the pH increases due to the secretion of bicarbonate This is often used as a trigger for the delivery of drug in the small intestinal by the gastro resistant coating (enteric coating) The pH is gradually increased to reach 7 at the ileo-caecal junction In the colon the pH slightly drops because of the secretion of short chain fatty acids by the bacteria in colon but the pH rises again at distal areas. In some people the pH does not rise to 7, so if a polymer is used that dissolve at pH 7, for those people the drug will not be dissolved

2. Effect of Food Ingestion of food can affect the transit time for the drug in any part of GIT In the presence of food, the stomach is in the digestive phase; in the absence of food, the stomach is in the interdigestive phase. Fatty material, nutrients, and osmolality may further extend the time of the drug staying in the stomach.

The drug release rates from some extended-release drug products are affected by mechanism of drug release, viscosity, pH and food. Dissolution of drugs in the stomach may also be affected by the presence or absence of food. When food and nutrients are present, the stomach pH may change from 1 to 2 by stomach acid (usually HCl) secretion to about 3–5 because of the food and nutrients neutralization. If the pH of stomach is high enough it may lead to tablet coating erosion and tablet dissolution in stomach for an enteric coated tablet

The rate of drug release of various ER formulations can be affected by the composition of the coadministered meal. This effect may result in both “positive” and “negative” effect Positive food effects usually come with drug release speeding up from ER formulation, which may cause high risk for patients The solubilization effect by bile micelles in the presence of food may have a positive effect on drug absorption

Negative food effects may take effect at an opposite direction by increasing the viscosity in the upper GI tract, delay the absorption rate, and prolong the passage time of ER drug product in GI tract. A longer time of retention in the stomach may expose the drug to stronger agitation in the acid environment.

3. Transit time The time that a dosage form spends in the stomach, small intestine and colon can be critical for some MR drugs During the digestive phase, food particles or solids larger than 2 mm are retained in the stomach, whereas smaller particles are emptied through the pyloric sphincter at a first-order rate depending on the content and size of the meals. During the interdigestive phase, the stomach rests for a period of up to 30–40 minutes, coordinated with an equal resting period in the small intestine. In fasting state (interdigestive phase) the stomach will empty a MR dosage form within 1-2 hours

MR dosage forms prepared as a single unit that does not disintegrate in stomach can be trapped in stomach if given in the digestive phase of stomach until it is emptied with food. With most single-unit dosage forms, there is a risk of erratic performance due to variable stomach emptying and GI transit time.

Multiple unit systems e. g Multiple unit systems e.g. pellets or granules filled into a hard capsule shell may have more advantages Selection of a pellet or bead dosage form may minimize the risk of erratic stomach emptying, because pellets are usually scattered soon after ingestion.

The small intestine is the site of absorption for most drugs The transit time through the small intestine normally is 3-4 hrs but it can be highly variable (from 0.5 to 9 hrs has been recorded). It should be considered that for a MR dosage form which releases the drug very slowly the drug may remain in the site of absorption only for a short time. colon has a very variable transit time (1-72 hrs) If a MR dosage form did not disintegrate in stomach or small intestine it will reach the colon and their effect will depend on the degree of absorption of the drug in the colon Presence of bacteria affect the absorption of drug in the colon

4. Fluid present in the GIT Fluid levels can be highly variable in the stomach, small intestine and colon. In the stomach there may be around 100 ml of total fluid, in the small intestine there is around 50-100 ml of free fluid (not bound with digested material and thus free to dissolve the drug). The colonic fluid can be viscous with around 10 ml of free fluid available. For the MR formulations the amount of free fluid available is important for drug release to occur. Less free fluid is available as the dosage form travels down the gut.

The composition of the fluid can also affect the drug release such as; ions, fats, enzymes, and salts. Presence of fat may slow down the release from a swelling matrix system (a swelling matrix requires water to hydrate and leading to swelling of the matrix and then releases the drug), this means that achieving the required blood level of the drug may require more time compared to when fat is not present in the GIT fluid. Sugars can sometimes disrupt the controlled-release gels.

Biopharmaceutics characteristics of a drug The important biopharmaceutics properties of a drug to be used as a controlled delivery system are as follow: 1. molecular weight of drug: the rate of absorption of drug is inversely proportional to the molecular weight of the drug. Drugs that have low molecular weight their absorption is faster and complete, these drugs are good candidates for controlled delivery formulations. Drugs with large molecular size and higher molecular weight such as peptides and proteins are poor candidates for oral controlled release systems.

2. drug solubility: Drugs that their solubility is not dependent on pH and have good aqueous solubility are good candidates for controlled release system, e.g. pentoxyfylline Drugs with poor solubility or pH dependent solubility are not suitable for controlled delivery system, e.g. phenytoin.

3. Mechanism and site of absorption: Generally drugs from first and second biopharmaceutical class (highly soluble high permeable and low soluble and high permeable) can be prepared as MR formulations. Drugs that are absorbed by active transport and those absorbed through a window (absorbed only through a specific area of the GIT) are not suitable to be formulated as a controlled delivery system

Biopharmaceutical classification system Good candidates for MR formulations bad candidates for MR formulations Reducing solubility

Is it suitable to prepare a potent drug or a drug with a narrow therapeutic index as an extended release dosage form?