Three Examples of Multiparticulates Enabling Performance a Matrix Tablet Can’t 

For Modified (Controlled) Release Oral Solid Dosage Forms

In modified release oral solid dosage forms, matrix tablets dominate the field. They’re usually cheaper to develop, less expensive to manufacture, and easier to transfer. However, in certain situations, a multiparticulate formulation is better, or may even be the only way to achieve the controlled release performance you’re looking for.

This blog looks at three such cases.

For more on choosing between matrix and multiparticulate for modified release oral solid dosage forms, read Pros and Cons of Matrix vs. Multiparticulate Formulations.

What patient benefits might we be looking for?

Generally, in switching from immediate release to modified or controlled release formulations, the goal is to achieve either a therapeutic or patient compliance benefit. Possibilities include:

Therapeutic benefits might be:

• More reliable effect/blood levels
• Prolonged action
• Fewer side effects (by lowering Cmax or slowing release to limit local irritation)
• Drug release closer to site of action
• Limited food effect
• Better bioavailability

Patient compliance advantages:

• Less frequent dosing
• Greater convenience (fewer pills to take)
• Better adherence to prescribed dosing schedule

Think of it in terms of more consistent effect/more consistent blood levels or tuning the dissolution profile to meet a pharmacokinetic and pharmacodynamic need for the therapy. The result may be reduced side effects, delayed onset of action, or alteration in the rate at which the drug enters the system, influenced by metabolism and absorption. Furthermore, you may be able to reduce food effect and improve bioavailability as you encourage better patient compliance by reducing dosage frequency.

Either matrix or multiparticulate dosage forms can provide some or all of these benefits. In the following scenarios, though, multiparticulate dosage forms can enable performance that is difficult or even impossible to achieve with matrix tablets.

Example 1: Esophageal Transit and Gastric Emptying Behavior

When you take a tablet or a capsule, put it in your mouth, and swallow it, it travels down your esophagus into your stomach, and then after some period of time in the stomach, it releases into your small intestine.

This last step is gastric emptying and it controls the timing of the pH environment that the dosage form experiences during its journey. Once the dosage form makes it through the esophagus and enters the stomach, it is exposed to liquid and the dissolution process can begin — at a low pH.

But how consistent are these processes from patient to patient? Here are a few things we know about the swallowing and esophageal transit component:

• It’s typically quick.
• However, one study of 56 seemingly healthy elderly subjects (average age 83) showed that 84% of them had difficulty swallowing and/or abnormal transit through the esophagus.
• Uncoated tablets, in particular, can stick in the esophagus.
• Delays in esophageal transit will change the time lag between when you take the product and when it actually starts dissolving.
• Variation occurs from patient to patient, from one patient population to another, and with different dosage types.

The next consideration after the product has reached the stomach is gastric emptying — a key event in the drug release process:

• The environment rapidly transitions from low pH acid to a higher pH — around 4.5 to 5 in the duodenum, then gradually continues to rise as the product transits down the GI tract.
• Speed of emptying is influenced by the presence of food, its composition (especially fat content) and particle size.
  • Gastric retention time and gastric emptying when a drug is taken on an empty stomach are far different than when the drug is taken with food.
  • Small particles generally pass through the pyloric sphincter into the duodenum more easily and more consistently.
• Other factors, such as patient-to-patient variability, physical activity, posture, and time of day can also play a role.

Multiparticulate vs. Matrix Tablets in Terms of Gastric Emptying
Matrix	Multiparticulate
Can be retained in stomach	Small particles exit stomach more gradually and consistently
More likely to result in local irritation	Better if local irritation is a concern
Transit affected by food — a high fat meal can lead to retention for 10 hours or more	Less food effect — more timely, consistent release
More patient-to-patient variability	Less patient-to-patient variability
Appropriate if release, solubility, and absorption do not rely on or vary with pH	Possibly a better choice if pH does affect release, solubility, or absorption

Patient to patient, dissolution, solubility, and absorption are often more consistent with a multiparticulate than with a matrix tablet. Does this matter? It depends.

If gastric emptying directly affects the plasma profile because of pH effect on mechanism of release, drug solubility, or drug absorption, multiparticulates may exhibit less patient-to-patient variability.

Example 2: Achieving Complex, Multiphase Release Profiles

Multiparticulates can also be advantageous for formulating complex release profiles. It’s easy to change the dose by altering fill weight, and you can combine different particle populations to achieve the desired PK profile. For example, you might blend immediate release (IR) and sustained release (SR) pellet populations into a capsule for a burst effect followed by a sustain. You might achieve 20% release of your drug immediately, followed by 80% of the dose over a sustained period of time.

Example dissolution modeling of a multiparticulate containing 20% immediate release particles and 80% sustained release particles to achieve an extended release effect.

You can also achieve this profile with a matrix tablet by putting an immediate release coating of drug on the outside of the SR tablet, but you may be limited by the dose amount. With a high ratio of IR to SR, the coating becomes prohibitively thick. Similarly, if you have a high dosage strength, the coating on the outside of the tablet becomes prohibitively thick for processing. The multiparticulate formulation is considerably easier.

One illustration of this is Naprelan^®, which was a naproxen sodium, once-a-day product developed by Elan. This was a multiparticulate tablet: Pellets were created that sustained the release of the naproxen. They were then compacted into a tablet that disintegrated in the stomach. The goal was to maintain consistent blood levels and achieve constant analgesia over 24 hours while reducing the incidence of gastric ulcers by reducing exposure frequency of the stomach to the naproxen. Instead of being exposed twice a day, the stomach was only exposed once a day.

Plasma level profiles of twice-a-day naproxen and once-a-day multiparticulate Naprelan^®. Naprelan exhibits a more consistent level and only one peak exposure, reducing stomach irritation.

Example 3: Another Complex Multiphase Release Profile

In this multiparticulate, to mimic BID dosing, we combine an IR particle population with a delayed release (DR) population that effects a four to five-hour delay. With 50% of the dose as an IR and the other 50% as a DR, the result is a pulsatile release profile that is equivalent to taking two capsules five or six hours apart.

Dissolution modeling of a twice-a-day pulsatile release profile formulated by combining IR and DR particles 50:50 in a multiparticulate.

Achieving this profile with a tablet could be possible with a monolithic matrix with an IR coating, but it would only be practical at a very low dose. The IR dose incorporated into the coating would be limited by processing considerations.

In contrast, with a multiparticulate, a biphasic release profile is easy to achieve. You make immediate release beads and coat some of them as a delayed release version. Then, you can easily modulate the dose by altering the proportion of each bead type filled in the capsule.

Pulsatile release is useful if the peak-to-trough ratio influences efficacy because of:

• Tolerance effects
• Input rate effects
• Metabolism
• Absorption

Ritalin LA^® is biphasic on purpose to better mimic BID IR dosing and minimize tolerance.

An example of this kind of formulation is Ritalin LA, in which half of the dose is an immediate release formulation and the other half releases about five hours later. This is important for methylphenidate because this drug is subject to a tolerance effect. If you sustain the blood levels, efficacy decreases over time. However, if you allow that first immediate release dose to drop off a little and then provide a second pulse, efficacy is maintained.

For other drugs, preserving the semblance of BID dosing is an important consideration for metabolism or absorption. If there’s a metabolic pathway in the GI tract that changes with input rate, a DR formulation will achieve a similar effect to an IR. In contrast, an SR formulation with a slower release rate may produce different ratios of potentially active metabolites in the bloodstream, creating a formulation that is not bioequivalent to the original product.

Pilot PK Studies Guide the Formulation of Multiparticulates With Complex Release Profiles

When you’re trying to hit a specific PK profile, either for bioequivalence or for therapeutic reasons, a pilot PK study is invaluable. First, you make a few or several different basic pellet prototypes, such as an IR version, a slow sustained release version, and a delayed release version. Then you dose these into subjects to obtain PK results for each of your components.

As the above examples demonstrate, this data can be used to model the result of mixing your prototypes. Varying the fractional populations is a quick way to produce different dosage strengths or dissolution profiles from the same sets of pellets, for clinical research purposes. By working with your pharmacokineticist, you can be reasonably certain that if you actually make that dosage form, you’re going to see the predicted pharmacokinetic blood profiles.

With tablets, on the other hand, this modeling is more difficult to do. Every time you want to change the proportions in the formulation, you need to reformulate the whole dosage form to be sure of still achieving your target dissolution profile. Having made these changes to the formulation and the process, the product’s in vivo behavior is less predictable.

When You Do Need to Work With Multiparticulates, Societal™ CDMO Can Help

Matrix tablets have many advantages, but sometimes they aren’t the right choice to achieve your goals.

If your drug is prone to cause local irritation, a multiparticulate will help spread that dosage across the GI tract. For a drug that is very prone to food effect and exhibits high subject-to-subject PK variability with pH affecting API release, solubility, or absorption, a multiparticulate may also be your best option.

Further, multiparticulates enable you to make quick changes to the dosage strength or the dissolution profile. For this reason, they are easier to iterate for clinical studies just by mixing and matching the same sets of pellets.

While matrix tablets are often the best choice, there are compelling reasons to work with multiparticulates. Societal experts have the experience to help.