Analysis of the design of regulated release drug delivery systems for oral drugs

Modified release drug is a technology or method that modifies the delivery of a therapeutic drug by physically, chemically, or biologically modifying the therapeutic drug components to obtain a page-dependent blood concentration as determined by clinical pharmacology experiments. Oral regulated release formulations include: extended - release (ER) and delayed - release (DR) products.

Modulated release drug delivery systems can achieve specific clinical objectives that cannot be achieved with conventional formulations by modulating the absorption of the drug or altering the site of release.

The therapeutic benefits of properly designed modulated release formulations include

Improved drug efficacy and reduced toxic side effects;

Ease of use and improved patient compliance with drug administration;

Optimization of performance;

Screening for new active drugs or developing new clinical indications.

Modified release drug is a technology or method that can modify the delivery of a therapeutic drug by physically, chemically, or biologically modifying the therapeutic drug components to obtain paged blood concentrations as determined by clinical pharmacology experiments. Oral regulated release formulations include: extended - release (ER) and delayed - release (DR) products. Delayed-release formulations are capable of releasing the drug continuously over a period of administration, thus reducing the frequency of administration compared to common dosage forms, such as solutions or immediate-release formulations.

Oral regulated release drug formulations are designed to vary the rate of drug input (dissolution and absorption) in the gastrointestinal tract in order to obtain a predetermined blood concentration profile.

PART .01

Common oral regulated release formulations for drug release

① Delayed - release ): e.g. enteric coated;

② fixed-point or timed release ( site - specific or timed release ): such as colonic drug delivery

(iii) extended - release: e.g. zero, primary, secondary release, etc;

④ by programmed release ( programmed release ): such as pulsatile, delayed, extended release, etc.

Figure 1. Examples of oral regulated release profiles

Here we present a few examples of medication-regulated release products that have achieved clinical and commercial success:

(i) Procardia XL is a nifedipine zero-stage release tablet that not only reduces the three-times-a-day dosing regimen to once-a-day, but also significantly improves the efficacy to safety ratio;

② Asaco and Lialda TM are mesalazine delayed-release tablets that release mesalazine in the ileum or the end of the colon for the treatment of ulcerative colitis.

Let's take a look at what are the common oral delayed release drug delivery systems

Table 1: Common oral sustained release drug delivery systems on the market

	Skeleton type	Reservoir type	Permeation pump type
Drug delivery systems	Hydrophilic skeleton	Membrane Control	Primary permeation pumps
	Turbidity/diffusion control Swelling / dissolution control Hydrophobic skeleton	Constant Velocity Release Non-constant release Membrane - skeleton combination type	Microporous permeation pumps Multi-layer permeation pumps (e.g. Push-pull®, Push-stick®)
Common dosage forms	Large film Multi-unit small piece Multi-layer tablets Press-coated tablets	Multi-unit coated micro-pills Multi-unit Coated Small Tablets Large Coated Tablets	Coated Large Tablets Coated multi-layer tablets

 

1Skeleton type formulation

In skeletal formulations, the active drug (e.g., in the form of pins, amorphous, and, in a few cases, molecular dispersions) is homogeneously mixed with rate-controlling materials and other inert ingredients. The drug is released by diffusion or dissolution in skeletal formulations. According to the characteristics of rate-controlling materials, skeleton-type formulations can be divided into the following two categories: a. Hydrophilic; b. Hydrophilic type; b. hydrophobic type.

From the application point of view, the former type of skeleton type formulation in which the controlled release material consists of water-insoluble and/or water-absorbing swellable material, and the latter type consists of water-insoluble and low swellable material.

a Hydrophilic skeletal formulations

Polymer-based drug delivery systems, in which the drug release involves two competing mechanisms, Fickian diffusion release and free diffusion release. The main rate-controlling material is a hydrophilic polymer, which swells rapidly upon absorption of water and forms a gel layer on the formulation surface. Diffusion through the viscous gel layer is not the only route of drug release, but relaxation of the polymer chains leading to skeletal dissolution contributes to the overall release of the drug. Which release mode plays a major role in drug release is determined by the nature of the particular drug and the composition of the backbone.

b Hydrophobic skeletal formulations

were the first formulations used in clinical practice to modulate release. However, hydrophobic skeletal formulations are not suitable as carriers for insoluble drugs because the drug concentration gradient in the skeleton is too low to allow the drug to be released within the expected gastrointestinal transit time.

Figure 2. Hydrophilic and hydrophobic skeleton systems and respective release steps

2 Reservoir-type polymeric formulations

A typical reservoir-type formulation is prepared by coating a tablet core containing a solid drug or a highly concentrated drug solution with a controlled-release material. In this dosage form, the only structure that can effectively limit the release of the drug is the polymeric coating that encases the drug reservoir.

Common regulated-release reservoir-type ro-admin formulations include polymer-coated micro-pills or tablets, capsules containing various contents (microparticles, microspheres, or nanoparticles), and other common formulations. Polymeric coating films typically include a hydrophilic or additive composition (e.g., a second polymeric material, surfactant, or plasticizer, etc.) that is porous and provides a predetermined resistance to diffusion of the drug from the reservoir to the external solvent. This resistance varies depending on the thickness of the membrane, and the properties of the membrane and the soluble material in a given environment. In practice, the mechanism of drug release from the coating dosage form can be summarized as follows:

(i) drug transport through the capillary meshwork filled with the dissolution medium (K = 1)

②Drug transport through the hydrated solubilized membrane layer

③ drug release through cracks, micropores, etc. on the coating membrane (K = 1)

Preferred reservoir-type formulations often consist of many coating units, such as micropills, microspheres, and mini-tabs.

3 Osmotic pump type controlled release formulations

Osmotic pump type controlled release formulations are similar to reservoir type formulations but contain a permeation enhancer which absorbs more water from the surrounding medium to allow it to pass through the semi-permeable membrane. This dosage form is also referred to as a primary (single chamber) osmotic pump. The release of the active substance in this formulation is controlled by the semi-permeable membrane, through which water can pass freely. The drug is released from the small pores in the formulation using the osmotic pressure generated within the formulation as the driving force. The size of the release pores should have a little range to prevent too rapid release of the drug, and at the same time the hydrostatic pressure within the system can be reduced, and the hydrostatic pressure can reduce the osmotic pressure can also change the volume of the formulation.

Two common types of osmotic pump type formulations used in the development of oral formulations are single-chamber primary osmotic pump formulations and dual-chamber osmotic pumps (e.g., Push - Pul® and Push - Stick®)).

Figure 3. Diagram of different types of osmotic pumps

PART .02

Other oral regulated release formulations

1 Enteral drug release

Enteral release refers to the delayed release of a drug until the drug formulation passes through the stomach into the gastrointestinal tract. A range of prescription processes have been successfully used to delay drug release, including single or multi-unit coated formulations, capsule formulations, or osmotic pumps. The earliest physicochemical method used to delay drug release was to coat the formulation with an enteric coating, which is capable of acting as a barrier layer to control the localized release of the drug in the digestive system.

Enteric coating materials that can more than prevent the release of drugs in the stomach are mostly acidic polymers and are therefore stable or insoluble under acidic conditions. Once the formulation reaches the small intestine, the enteric coating is able to dissolve rapidly under gastrointestinal pH conditions, as shown in Figure 4. For example, aspirin, a drug that is irritating to the stomach, is a formulation coated with an enteric coating, and the drug is released only when it reaches the small intestine.

Figure 4. Examples of different types of delayed drug release systems and their release processes

2 Colonic drug release

Colon-targeted drug delivery systems in the gastrointestinal tract have attracted attention and have significant therapeutic advantages for certain drugs, such as effective treatment of localized lesions in the colon (e.g., ulcerative colitis, irritable bowel syndrome) by reducing the incidence of systemic drug side effects and lowering the dose administered. Colonic delivery systems are essentially time-delayed delivery formulations, which release drugs immediately or slowly at the colonic site.

For optimal colonic delivery formulations, the active drug is not released in the more upper environment of the gastrointestinal tract until the drug is released at the site closest to the colon. Given the unique drug release environment of the colon (pH, transit time, pressure, or microorganisms), various methods and techniques are used to study colon-located drug delivery formulations. These include the use of pH-sensitive or slow-dissolving polymer-coated formulations, swelling or osmotic pump delayed-release formulations, and the use of drug carriers that are more degradable by the colonic flora.

3 Pulsatile drug release

Pulsatile release is, in general, a mode of drug delivery in which a portion of the total drug load is released suddenly at a specified time, followed by a period of no or little drug release (stagnation period), with alternating release and non-release processes. Oral pulsatile release formulations are formulations that are administered orally followed by a certain pattern of violent release of the drug.

In the field of regulated release formulations, these non-single release and multiple drug delivery formulations release patterns have been recognized and shown to have specific clinical benefits that may lead to:

(i) optimization of chronotherapy;

(ii) simulation of endocrine physiological models;

(iii) optimal therapeutic regimens for receptor-producing drugs, where constant drug concentrations lead to receptor downregulation.

4 Biphasic drug release

In non-single extended release formulations, the biphasic release model is most often applied to avoid maintaining constant blood concentrations. The conventional rationale for this design includes:

(i) Rapid onset of action of the formulation by adding an immediate-release component to the extended-release formulation;

(ii) For chronotherapy drugs, the combination of a delayed-release component in the extended-release formulation to optimize the dosing schedule;

(iii) generating blood concentration fluctuations and avoiding or attenuating the apparent grantability due to continuous exposure of the drug to the receptor site;

4 Overcome problems related to nonlinear pharmacokinetic first-pass effects, specific pharmacokinetics or pharmacodynamics that can lead to reduced bioavailability or altered drug-to-metabolite ratios.

For example, some of the biphasic drug release formulations currently available on the market are verapamil, diltiazem, nifedipine, and lidilim.

PART .03

Summary

Utilizing modulated release technologies is the most critical factor in achieving the desired clinical outcomes, including determining the clinical rationale and understanding the drug properties. The successful design of a commercially viable modulated release formulation depends on the physicochemical, biopharmaceutical, pharmacokinetic, and biological properties of the drug candidate and is not dependent on a specific release technique. However, there is no one-size-fits-all release technology, and different release technologies are often available for compounds with properties suitable for the preparation of regulated release formulations. Therefore, it is more important to choose a release technique based on technical conditions, practical conditions, exploitability and commercial value.

References

[1] Qiu , Y (2007). Design and Evaluation of Oral Modified - Release Dosage Forms Based on Drug Property and Delivery Technology .

[2] Eichel , H . J , Massmann , B . D & Cobb , Jr ., J . E . Delayed , sustained － released diltiazem pharmaceutical preparation . US Patent 5529790.

[3］Pharmacological theory and practice in the development of solid oral dosage forms

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