Several types of polymer based controlled release systems and a wide range of applications thereof have been presented in the literature. In most systems the mechanism controlling the release rate is based on diffusion, chemical reaction or solvent activation.
Diffusion controlled systems can typically be divided into reservoir, matrix and hybrid devices.
Reservoir drug delivery devices have a polymer membrane encasing the active agent. The active agent can be in the solid or in the liquid state, and the membrane can be microporous or non-porous. Upon activation, the active substance diffuses through the membrane at a controllable rate. As long as the drug core can be maintained in a saturated solid or suspension state, the release rate of the drug will be constant versus time until exhaustion of the active substance excess.
The saturated state would be difficult to maintain for drugs having low fluid solubility. Further, although the requirements for constant release would be met, the release will generally not be constant in the initial and end period. When the system is placed in a release medium, it takes a certain time for the system to reach a steady state and either a lag time or an initial burst is observed. If the membrane does not contain drug molecules at the time of placement, an induction period will be needed to saturate the membrane. Burst release is often observed in reservoir systems stored for some time prior to use. During storage the agent saturates the entire membrane. When placed in a release medium, the agent that has diffused to the surface of the membrane is released immediately, causing a burst effect. Also dose dumping due to minor flaws in the coating can lead to burst release even prior to patient administration.
Toward the end of the release period the concentration of the dissolved drug in the core will decrease below the saturation point and as a result the release rate will decrease.
In the matrix system the drug is dissolved or dispersed in a polymer matrix. The release rate is often proportional to the square root of elapsed time. The release behavior of these systems is dependent on the physical properties of the drug, drug load, particle size, solubility of the drug in the polymer and diffusivity in the polymer matrix. In addition, the shape of the device, surface area and the path length of diffusion are also important parameters. With these systems the release rate will decrease with time as a result of increasing path length for the drug solutes to diffuse from the center of the device to the surface. One proposed method to improve the consistency of release is to use systems with uneven initial drug distributions, with higher loading concentrations towards the center of the device (Lee, Polymer 25 (1984), pp. 973-978).
In a hybrid system, another type of matrix device, the active substance is homogeneously dispersed in the polymer matrix, which is covered by a rate limiting membrane. Drug release is controlled by both the polymer membrane and the matrix. Drug dissolves first into the core polymer, dissolved drug travels by diffusion towards the inner surface of the membrane, dissolves in the membrane, diffuses through the membrane to the outer surface of the membrane and dissociates finally into the surrounding media. The release rate can be accurately adjusted with this system, but initial burst can take place and toward the end of the release period the release rate commonly decreases.
Burst release may be the optimal mechanism of delivery in rare instances, but is often problematic because it is unpredictable and, even when the burst is desired, the amount of burst cannot be significantly controlled. The initial high release rates may lead to drug concentrations near or above the toxic level in vivo. Any drug released during the burst stage may also be metabolized and excreted without being effectively utilized. Even if no harm is done during the burst release, this amount of drug is essentially wasted, and the ineffective drug usage may have therapeutic and economic effects.
Methods to prevent or minimize the burst effect in a wide range of polymer/drug systems have been described and include for example surface extraction of the active agent prior to in vivo usage, using double-walled microspheres with layers made of different inert or erodible polymers, and modifying the surfaces of the drug-loaded matrix via an outer layer of polymer coating [see for example Xiao Huang and Christopher S Brazel Journal of Controlled Release, 73, (2-3), 2001, 121-136]. Unfortunately, many of the methods involve additional costly steps, which are not necessarily suitable for pharmaceuticals and in any case result in reduced drug loading percentages or the introduction of additional materials.
The traditional way to adjust the release rate of a drug substance in a polymer based delivery system has been to change different parameters, such as the area of the device, the thickness of the membrane; the drug load in the core, the core and membrane material, end capping the device or incorporating fillers into the polymer composition of the membrane. By increasing the loading of filler, steric hindrance or diffusion path increase to slow down the release of the active substance. For an ideal delivery system the predetermined release rate should also remain as constant as possible during the whole life-span of the device. This would be important to maintain the daily dosage of the drug in a therapeutically effective window long enough, and still lower the total amount of drug administered to the patient. It would also enable reasonably low drug load in the device so that the disposal of the device after the treatment period would be less problematic and would satisfy environmental requirements.
U.S. Pat. No. 5,660,848 discloses an implantable drug delivery device comprising a matrix core, an outer layer, and an intermediate layer between the core and the outer layer. The intermediate layer is made of porous polymeric material, preferably cellulose or regenerated cellulose. WO 03/017971 discloses an embodiment wherein a drug delivery system comprises a core and two elastomer membrane layers of different thickness for controlling the release rate of active agents. The elastomer membrane is preferably a siloxane-based elastomer, such as poly(dimethylsiloxane) (PDMS) or poly(ethylene oxide)-PDMS. In US 2005/0214251, drug formulations for sublingual and subcutaneous administration of insulin are disclosed. In one embodiment the formulation may be in the form of a film comprising a bottom layer and a top layer which surround a core layer containing the active agent.