Introduction:
Controlled drug delivery is one that delivers the drug at a predetermined rate, locally or systemically, for a specified period of time.
The rationale for the controlled release dosage form can be summarized as below:
To provide a location-specific action within the GIT.
To avoid an undesirable local action within the GIT.
To provide a programmed drug delivery pattern.
To increase the rate and extent of absorption/bioavailability.
To extend the duration of the drug's action.
Approaches to design formulations.
Based on the mechanism of drug-release and carrier used, the modified-release dosage form can be classified into the following six categories;
Diffusion based system.
Reservoir type.
Matrix type.
Dissolution based system.
Reservoir type.
Matrix type.
Methods using Ion-exchange.
Methods using osmotic pressure.
pH-independent formulations.
Altered-density formulations.
Dissolution Controlled-release Formulations:
Controlled release preparations of drugs could be made by decreasing their rate of dissolution.
The approaches to achieve this include,
preparation of appropriate salts or derivatives,
coating the drug with a slowly dissolving material,
incorporating it into a tablet with a slowly dissolving carrier.
Dissolution-controlled systems can be made in several different ways:
By alternating layers of drug with rate controlling coats, a pulsed delivery can be achieved. If the outer layer is a quickly releasing bolus of drug, initial levels of the drug in the body can be quickly established with pulsed intervals following.
An alternative method is to administer the drug as a group of beads that have coatings of different thicknesses. Since the beads have different coating thicknesses, their release will occur progressively. Those with the thinnest layers will provide the initial dose. The maintenance of drug levels at later times will be achieved from those with thicker coatings. This is the principle of spansule technology or microencapsulation.
The dissolution process at a steady state is described by Noyes Whitney equation:
where,
dC/dt = Dissolution rate
D = Diffusion coefficient of the drug through pores
h = Thickness of the diffusion layer
A = Surface area of the exposed solid
Cs = Saturated solubility of the drug
C = Concentration of drug in the bulk solution
Based on the technical refinement, it is classified as:
Matrix type
Encapsulation type
Matrix Type
Matrix dissolution devices are prepared by compressing the drug with a slowly dissolving carrier into a tablet.
Controlled dissolution by:
Altering porosity of tablet
Decreasing its wettability
Dissolving at a slower rate
The drug release is determined by the dissolution of the polymer used.
Examples: Dimetane extencaps, Dimetapp extents.
Encapsulation Type
The drug particles are coated or encapsulated by the microencapsulation technique. The pellets are filled in hard gelatin capsules, popularly called ‘spansules’.
Once the coating material dissolves, the entire drug inside the microcapsule is immediately available for dissolution and absorption.
Here the drug release is determined by dissolution rate and thickness of polymer membrane, which may range from 1 to 200 µ.
The dissolution rate of the coat depends on the stability and thickness of the coating.
Examples:
Ornade spansules.
Chlortrimeton repetabs.
Diffusion based systems:
Diffusion systems are characterized by the release rate of a drug being dependent on its diffusion through an inert membrane barrier.
Usually, this barrier is an insoluble polymer.
In general, two types of diffusional systems are recognized.
reservoir devices
matrix devices.
The released drug from a reservoir device follows Fick’s first law of diffusion.
Where,
J = flux, amount/area-time
D = Diffusion coefficient of the drug in the polymer, area/time
dc/dx = Change in concentration with respect to polymer distance
Reservoir Devices:
Reservoir devices are characterized by a core of the drug, the reservoir, surrounded by a polymeric membrane.
The nature of the membrane determines the rate of release of drugs from the system.
The advantages of reservoir diffusional systems are, zero-order delivery is possible and the release rate will vary with polymer type.
The disadvantages of reservoir diffusional systems are, a system must be physically planted, it is difficult to deliver high-molecular-weight compounds, and rupture can result in dangerous dose dumping.
Matrix Devices:
Drugs are uniformly distributed throughout a polymer matrix in a matrix device.
In this model, the drug first dissolves and then diffuses out of the matrix in the outer layer that is exposed to the bathing solution.
The interaction between the bathing solution and the solid drug moves toward the interior as this process continues.
For this system to be diffusion controlled, it is obvious that the rate of drug particle dissolution within the matrix must be much faster than the rate of drug dissolution leaving the matrix.
Bio Erodible and Combination of Diffusion and Dissolution Systems:
These systems can combine the diffusion and dissolution of both the matrix material and the drug.
Drugs not only can diffuse out of the dosage form, as with some previously described matrix systems, but the matrix itself undergoes a dissolution process.
The complexity of the system varies from the fact that, as the polymer dissolves, the diffusional path length for the drug may change.
Typically, this results in a moving boundary diffusion system.
Zero-order release can occur only if surface erosion occurs and the surface area does not change over time.
The bioerodible matrix in such a system has the inherent benefit of preventing ghost matrix formation and eliminating the need for implant site removal.
The disadvantages of this system include the difficulty in controlling kinetics due to multiple release processes, as well as the potential toxicity of degraded polymers.
Another bioerodible system technique is to chemically bond the drug to the polymer.
In most cases, the drug is released from the polymer via hydrolysis or an enzymatic reaction.
A swelling-controlled matrix is a third type that uses a combination of diffusion and dissolution.
In this system, the drug is dissolved in the polymer, but instead of an insoluble or eroding polymer, as in previous systems, the polymer swells. This allows water to enter, causing the drug to dissolve and diffuse out of the swollen matrix.
The release rate in these systems is highly dependent on the polymer swelling rate, drug solubility, and the amount of soluble fraction in the matrix.
Because polymer swelling must occur prior to drug release, this system typically minimizes burst effects.
Osmotically controlled systems:
The driving force in these systems is osmotic pressure, which produces a controlled release of the drug.
Consider a semi-permeable membrane that allows water through but not drugs. A tablet containing a drug core is surrounded by such a membrane, and when exposed to water or any other body fluid, water will flow into the tablet due to the osmotic pressure difference.
These systems generally appear in two different forms.
The first contains the drug as a solid core, along with an electrolyte that is dissolved by the incoming water. The electrolyte provides a high osmotic pressure difference.
The second system contains the drug in solution within the device behind an impermeable membrane. The electrolyte surrounds the bag.
Both systems have single or multiple holes bored through the membrane to allow drug release.
In the first case, high osmotic pressure can only be relieved by pumping a drug-containing solution out of the hole. Similarly, in the second example, the high osmotic pressure compresses the inner membrane, allowing the drug to escape through the hole.
One of the benefits of osmotically controlled devices is that a zero-order release is possible.
Different drugs do not require reformulation, and drug release is unaffected by the system's environment.
The disadvantages of these systems include the fact that they can be much more expensive than conventional tablets and that their quality control is more extensive.
Ion-Exchange Systems:
Ion-exchange systems generally use resins composed of water-insoluble, cross-linked polymers.
These polymers contain salt-forming functional groups in repeating positions on the polymer chain.
The drug is bound to the resin and released by exchanging with appropriately charged ions in contact with the ion-exchange groups.
Resin+ − Drug− + X− → resin+ − X− + Drug−
Conversely,
Resin− − Drug+ + Y+ → Resin− − Y+ + Drug+
Where, X− and Y+ are ions in the GI tract.
The free drug then diffuses out of the resin.
The resin is combined with the drug solution to create the drug-resin complex, either by repeatedly exposing the resin to the drug in a chromatography column or by allowing it to remain in the solution for an extended period of time.
The amount of crosslinking agent used to prepare the resin affects the resin's rigidity, diffusional path length, and area of diffusion, all of which affect how quickly drugs diffuse out of it.
This system is beneficial for drugs that are highly susceptible to enzymatic degradation because it provides a protective mechanism by temporarily altering the substrate.
The limitation of this approach to controlled release is that the release rate is proportional to the concentration of ions present in the area of administration.
The release rate of the drug can be impacted by variations in diet, water intake, and individual intestinal content even though the ionic concentration of the GI tract is relatively constant within bounds.
An improvement in this system is to coat the ion-exchange resin with a hydrophobic rate-limiting polymer, such as ethyl cellulose or waxes. These systems rely on the polymer coat to govern the rate of drug availability.
Commonly asked questions.
Discuss different approaches to controlled drug release system formulations.
Write a note on diffusion controlled drug delivery systems.
Write a note on dissolution controlled drug delivery systems.
Write a note on Ion exchange based controlled drug delivery systems.