Delayed-release

Conventionally, drugs release their pharmaceutical active ingredient within minutes of ingestion. Pills and capsules which contain pellets may also release their contents after a time lag. This drug delivery system is called a delayed-released system. It is also named enteric-coated formulation.

Enteric-coated dosage forms, such as coated tablets, sugar-coated tablets, soft and hard gelatin capsules, granulates, or pellets, have their firm place in the medical field.

Delayed-release capsules which contain pellets release the drug at a time later than immediately after administration (i.e. there is a significant lag time between a patient taking a medicine and the drug releasing from the dosage form)(1).

Delayed drug release is commonly achieved via enteric coating of dosage forms such as tablets, capsules, and multiparticulates. Typically, enteric coatings are pH activated, wherein they are insoluble at low pH but dissolved readily at higher pH (e.g., pH 5–7).

Advantages of delayed-release pellets

First, the main function of an enteric coating is to protect the underlying dosage form and drug substance, enabling it to remain intact in the gastric environment and instead dissolve and undergo drug release in the small intestine. Second, such strategies are used to prevent gastric mucosa irritation caused by certain drugs (e.g., non-steroidal anti-inflammatory drugs; NSAIDs), or to avoid the degradation of acid-labile drugs in GI fluid, such as enzymes or peptides. Protection can be easily and readily provided with the application of polymeric coatings that are inherently insoluble at acidic pH values.

Also, enteric coatings can also be applied for the local treatment of intestinal diseases.

Site-specific targeting is a type of delayed release that aims to target specific regions of the gastrointestinal tract, e.g. the small intestine or colon. Medicines used to treat inflammatory bowel diseases (e.g., budesonide) also use delayed-release coatings using polymers to enable targeting in specific regions in the GI tract.

Disadvantages of delayed-release formulation

Several studies have shown that enteric-coated products designed to release in the proximal small intestine do not disintegrate rapidly after emptying from the stomach. Indeed, it was shown in vivo that such products can take up to 2 h to disintegrate in the human small intestine. Drug release will then occur in the distal small intestine causing a delayed response to medication, and potentially reducing the bioavailability of those drugs with an absorption window in the upper small intestine (2)

Enteric-coated drugs should be taken 1 hour before or 2 hours after a meal. This administration point can be hard for patients to follow(3).

Extended-release pellets

The oral route of drug administration is the most straightforward and popular option for patients. More than 70% of all medicines are delivered orally due to the ease of administration which thereby improves patient adherence. Oral medicines are also generally cheaper to develop than those for other routes of administration. One of these dosage forms is a pellet which finally be filled in capsules.

Most medicines administered by the oral route provide what is known as ‘immediate-release’ drug delivery or ‘conventional’ drug delivery. A common example is the use of paracetamol (acetaminophen) for treating a headache; the tablet or capsule disintegrates quickly in the stomach fluids which releases the drug to provide a rapid onset of therapeutic effect following dissolution and absorption in the gastrointestinal tract. However, there are some situations in which this rapid onset is not desirable and a modification of the drug release pattern (or profile) is necessary to slow it down or to extend the drug’s effects (e.g. for instance over 24 hours). These advanced oral drug delivery formulations are often referred to as oral modified-release drug delivery systems. Modified-release drug delivery refers to the manipulation or modification of drug release from a solid oral dosage form (e.g. tablet, pellet, or capsule) with the specific aim of delivering drugs at:

1. desired rates;
2. predefined time points; or
3. specific sites in the gastrointestinal tract.

Modified-release drug delivery is a broad term that covers a variety of different approaches, one of them extended-release dosage form. Extended-released dosage forms allow a reduction in dosing frequency compared with when the drug is present in an immediate-release dosage form (i.e. drug plasma levels are sustained for longer periods). These are also known as prolonged-release or sustained-release dosage forms and are also referred to as controlled-release dosage forms.

What do modified-release pellets mean for the patient?

Keeping the drug in the therapeutic range

Maintaining drug levels overnight

Chronotherapy

Reducing side effects

Improving patient adherence

Treatment of local areas in the gastrointestinal tract

What do modified-release drug pellets mean for healthcare professionals and the pharmaceutical industry?

Provides physician, pharmacist, and patient choice

Product life extension

Cost savings for healthcare providers

Before an extended-release pellet is developed, the suitability of the drug in question should be considered. The solubility of a drug in aqueous media and its ability to permeate the intestine are key considerations when one is assessing whether a drug may be suitable for modified release.

There are three potential rate-limiting steps in the bioavailability of a drug from a dosage form:

1. release from the dosage form (release of pellets from capsule);
2. dissolution of the drug; and
3. absorption through the gastrointestinal mucosa.

High-solubility and high-permeability drugs are most suitable for extended-release delivery. For drugs with low solubility (<1 mg/mL), the low rate of dissolution can already give some inherent sustained-release behavior of the pure drug molecule, and the dissolution of drug particles in the gastrointestinal tract can be the rate-limiting step. After drug release and dissolution have occurred, absorption comes next. Drugs with low permeability are unlikely to be suitable for extended-release preparations. This is because they are already rate-limited in their absorption. Other considerations as to the suitability of a drug for extended-release include how quickly a drug is eliminated once it is in the bloodstream. The most suitable drugs may have relatively short elimination half-lives (t1/2 ¼ 4 hours to 6 hours)(1).

Immediate release

Since the last several decades conventional dosage forms like capsules, solids, pills, powders, solutions, emulsions, suspension aerosols, and pellets which are filled in capsules are used in the various treatments of acute or chronic disease.

Today this formulation can be considered as a/the primary pharmaceutical product is mostly

seen in the overall market. The tablet is the most popular among all dosage forms existing today because of the convenience of self-administration, compactness, and easy manufacturing.

More than 70% of all medicines are delivered orally due to the ease of administration which
thereby improves patient adherence. Oral medicines are also generally cheaper to develop than
those for other routes of administration.

Pellets like most medicines administered by the oral route provide what is known as ‘immediate-release’ drug delivery or ‘conventional’ drug delivery. Most drugs are immediate-released formulations and conventional therapy is often required. Immediate drug release dosage forms disintegrate rapidly after administration and release its active pharmaceutical ingredient.

Drugs administered orally as a solid need to dissolve before they can be absorbed. Tablets and capsules dissolve within minutes of ingestion. After dissolution in gastrointestinal fluids, drug

molecules enter the bloodstream via absorption through the intestinal mucous membrane. In this drug delivery system, drugs can exert their medical effect in a short period. absorption of the contained medication is commonly complete in 2-3 hours and is associated with the peaking of blood levels of the drug. The blood level of the drug gradually drops as the drug is metabolized and eliminated. When the concentration of the drug in the blood is lower than a certain concentration, the next dose is needed.

Advantages of the immediate-release formulation
1. Rapid onset of action
2. Easy manufacturing
3. They are cheaper.
4. Easy administration
5. Better drug dosing
Disadvantages of the immediate-release formulation
1. Dose dumping (unintended release of a large amount of drug)
2. Multiple doses should be taken daily
3. Rapid absorption of a drug results in rapid rise of the blood levels of the drug and hence
adverse effects related to the high levels

Sustained-Release pellets

Pharmaceutical products may release their contents within minutes of ingestion; these are immediate-release formulations. Pills and capsules that include pellets that finally be filled in capsules may also release their contents after a time lag, or a little at a time, or in some other predetermined way; these are time-release formulations. Lately, many drugs have been time-release formulated to reduce their local adverse effects in the gastrointestinal tract, to reduce adverse effects associated with peak blood levels, or to artificially extend their half-life.

Most drugs are immediate-release formulations; the tablet or capsule dissolves within minutes of ingestion. Absorption of the contained medication is commonly complete in 2-3 hours and is associated with peaking of blood levels of the drug. The blood drug levels thereafter gradually drop as the drug is metabolized and eliminated. Sometimes, there may be reasons why physicians may want to slow down this sequence of events, and this becomes possible through the use of time-release formulations. Importantly, whereas the arguments for the time-release formulation appear reasonable in each case, the evidence does not necessarily exist for the posited advantage(s) of each marketed formulation. If rapid absorption of a drug results in a rapid rise in blood levels of the drug and hence adverse effects related to the high levels, the risk can be reduced by formulating the drug as a sustained-release or extended-release formulation. In such a formulation, the release of the drug and hence its absorption will be slow. This will result in a lower peak blood level and hence a lower risk of associated adverse effects.

If blood levels of a drug remain high for a long time, the experience of associated adverse effects is prolonged. This risk is reduced when the absorption of the drug is slowed and when peak blood levels are consequently blunted, such as through the use of sustained-release drug pellets.

If a drug has a short half-life, there will be a rapid fall in the blood level of the drug as the drug is metabolized and eliminated. This fall in blood level may be associated with a loss of efficacy of the medication, or even with symptoms of drug withdrawal. So, the drug will need to be administered at frequent intervals for uniform blood levels to be maintained. Sustained-release pellets in capsules with short half-lives obviate the need for repeated intraday dosing by allowing the administration of a larger dose per dosing occasion.

ADVANTAGES OF TIME-RELEASE PELLETS

These include a reduction in GI adverse effects, a reduction in adverse effects associated with peak blood levels, and an extension of the effective half-life of the drug.

Sustained-release dosing is also associated with relatively uniform blood levels of the drug across the course of the day; peaks and troughs in blood levels, noticeable with immediate-release dosing, are diminished. The advantage of blunted peaks is that the risk of adverse effects, associated with the peaks, is diminished. The advantage of shallower troughs is that the risk of loss of efficacy (or the appearance of withdrawal symptoms), associated with a fall in blood levels, is minimized. When adverse effects are fewer, compliance is improved.

DISADVANTAGES OF TIME-RELEASE PELLETS

Time-release pellets are associated with certain disadvantages. As a result of the gradual release, in most patients, the tablet reaches the colon before complete dissolution. Absorption from the colon is not as good as that from the small intestine. As a consequence, particularly with once-daily formulations, small quantities of medication are excreted unabsorbed in the form of pellets in the feces. The cost of therapy with time-release formulations is therefore slightly higher not only because of the cost of the formulation but also because of the need for the extra dose. Patients who overdose with time-release formulations may experience delayed or prolonged toxicity. This may be seen, for example, with sustained-release lithium and sustained-release clomipramine.

However, sustained-release and extended-released pellets are nearly identical but some clinical trials have been conducted to show the difference between sustained and extended-released dosage forms in release profile and efficacy in release profile and efficacy (1).