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Sandra Conway

Technology Lead
5 min read

Making the Medicine Go Down: Specialized Oral Solids Delivery Technologies

The oral administration of drugs in tablet or capsule form is still the most common practice for taking medicines today and oral solids accounts for a large proportion of drugs in the development pipeline. Most oral solid formulations are designed to release the drug immediately after swallowing for rapid absorption into the bloodstream. However, some products have been developed to release the drug in a specific way following ingestion and provide a “controlled-release” of the drug products. In this article, Sandra Conway, Technical Lead at Pfizer CentreOne discusses some of the drug development technologies that provide a more specialized approach to oral dose delivery.

Why controlled release?

Controlled-release products are considered by drug developers for the following reasons:

  • To provide improved pharmacokinetic profiles compared with the immediate release product (i.e. steady state plasma concentration resulting in reduced adverse events)

  • Reduced dosing frequency for improved patient convenience and/or compliance and improvement in overall efficacy. Controlled-release products are often adopted for drugs with short half-lives which are used to treat chronic conditions

Many marketed controlled-release products are hydrogel-based tablets or capsules containing coated beads, which can be produced using conventional pharmaceutical manufacturing equipment. However, to achieve particularly demanding drug release criteria it is sometimes necessary to adopt more sophisticated pharmaceutics, such as the use of osmotic pumps, which require more complex manufacturing strategies. 

Osmotic pump technologies

Osmotic pump tablets are coated with a semi-permeable membrane which is breached in one location by a laser-drilled port. Water permeates through the membrane, dissolving excipients in the core and thus raising the internal pressure. The raised pressure in the core causes the contents to be forced through the laser-drilled port at a constant rate.

The benefits of osmotic pump technologies for controlled drug release are:

  • Zero-order drug release (i.e. drug is released at the same rate over a given period of time).

  • The drug release rate is independent of the gastric pH

  • The release rate from the delivery system is not affected by the presence of food (i.e. no food effect)

  • High degree of in-vitro/in-vivo correlation with these kind of delivery systems

  • Single daily dose is achievable

Pfizer CentreOne has two osmotic pump technologies within its Gastro-Intestinal Therapeutics Systems (GITS) portfolio. The Swellable Core Technology (SCT) consists of a round, bilayer core. One layer which contains the drug and a second layer which swells as water diffuses into the core, applying pressure on the drug-containing layer and thus extruding the drug through the laser-drilled port (Figure 1).

The Extrudable Core System (ECS) consists of a single-layer core containing both the drug and a polymeric viscosity enhancer. As water permeates the semi-permeable membrane the polymer hydrates and swells. The internal osmotic pressure increases and the viscous, drug-containing fluid is pushed through the laser-drilled port (Figure 2). The modified oval shape of the tablet helps control the release rate of the drug.

 

Figure 1. Schematic illustrating the working principle for the SCT. As water permeates the membrane the swellable layer expands, applying pressure on the drug-containing layer and hence forcing the drug through the port.

 

Figure 2. Schematic illustrating the working principle for the ECS. As water permeates the membrane the internal pressure (P) forces the drug-containing fluid through the port.

 

The single-layer design of the ECS allows higher drug loading compared with the SCT technology and the modified oval shape of the tablets make them easier to swallow compared with round SCT tablets. Single-layer ECS cores are also easier to manufacture compared with bilayer SCT tablets. The advantage of SCT tablets is that they deliver a more complete delivery of the unit dose from the tablet compared with ECS tablets.   

For both the SCT and ECS osmotic pump tablet technologies, control of drug release depends upon the presence of a semi-permeable film with a laser-drilled port. The semi-permeable membrane is typically composed of a water-insoluble cellulosic polymer incorporating a water-soluble pore-forming agent. The permeability and thickness of the film are critical for achieving the required drug release rate. Film-coating of the tablet cores is therefore a critical process, particularly the intra-tablet coat uniformity to ensure coat integrity. Process analytical technologies (PAT) are employed to determine the process endpoint for coating and ensure the correct film thickness is achieved. A cross-section image of a coated tablet is shown in Figure 3.

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Figure 3. Cross-section of osmotic pump tablet showing semi-permeable film coat

The size of the port in the membrane is also critical for controlling drug release. Therefore, the laser-drilling process requires tight control. Vision systems are used for 100 per cent inspection of all laser-drilled tablets to ensure the presence, correct  location and size of the port for all tablets produced.

Osmotic pump technologies have become popular for controlled drug delivery purposes and there are now many marketed products which utilise this approach. Some examples of commercially available osmotic pump products are given in Table 1 below.

 

Product Drug substance Dose (mg) Indication Manufacturer
Glucotrol® XL Glipizide 5, 10 Diabetes Pfizer
Minipress® XL Prazosin 2.5, 5 Hypertension Pfizer
Cardura® XL Doxazosin Mesylate 4, 8 Hypertension Pfizer
Procardia® XL Nifedipine 30, 60, 90 Hypertension Pfizer

Table 1. Commercially available SCT-type products

Conclusion

Controlled release technologies provide versatile platforms for oral drug delivery. It is now possible to tailor drug release to match complex administration criteria in a single dosage form.

Osmotic pump technologies have become particularly popular due to their consistency of performance. In particular, the degree of correlation between in vitro versus in vivo performance is usually better with these osmotic controlled released forms than other conventional dosage forms. This is primarily due to the insensitivity of the release rate to food, pH and position in the GI tract.

There are now many marketed products that use this principle, for instance, they are used extensively for administration of hypertension drugs – providing accurate control of dose delivery and management of pharmacokinetics. They also offer the opportunity for extending the time between dosing intervals and thereby make life easier for patients on long-term medication, especially important for patients on multiple medications.

The use of controlled-release technologies in drug development will therefore certainly grow in popularity to meet patient needs.