Control of drug release by transient modification of local microenvironments

This is a continuation of U.S. application Ser. No. 11/339,062, filed Jan. 25, 2006, which claims benefit of U.S. Provisional Application No. 60/646,913, filed Jan. 25, 2005, and U.S. Provisional Application No. 60/760,129, filed Jan. 18, 2006. All of these applications are incorporated herein by reference.

This invention is generally in the field of (micro)containment/controlled release or exposure devices, and more particularly to implantable medical devices for the storage and controlled exposure or release of contents located in reservoirs in these devices, and applications therefor.

Undesirably, some drugs have limited solubility or undergo gelation at physiological pH. Certain phase changes of drugs can impede release from highly concentrated dosages. Such phase changes can be particularly problematic when controlling drug delivery in microenvironments. Examples of controlled delivery of drugs or other chemicals to microenvironments from implantable medical devices having microreservoirs is described in U.S. Pat. No. 5,797,898, No. 6,527,762, and No. 6,491,666, and U.S. Patent Application Publication No. 2004/0247671, all of which are incorporated by reference herein. In particular, certain types of drug formulations, such as concentrated lyophilized dosages and concentrated organic solvent solutions, tend to gel at the reservoir opening when exposed to physiological fluid and block, impede, or otherwise interfere with the release of drug from the implantable medical devices. For certain drugs this gelation is due to its limited solubility at physiological pH. For example, teriparatide, which is hPTH(1-34), has a limited solubility at physiological pH. Thus, when teriparatide is released from a drug delivery device and contacts physiological fluid, there is the potential for a precipitate or gel to form and adversely affect the drug\'s release.

It would be desirable to eliminate or compensate for unwanted gelation, aggregation, or precipitation of drugs or otherwise increase the delivery rate of the drugs so that drug release from reservoirs or other microcontainment devices is unimpeded and can properly controlled. In many instances, solid dosage forms are desired for their stability. It would further be desirable to improve delivery of drug formulations, particularly protein drugs, from implanted medical devices, particularly where the drug is stored in the devices as a solid or in concentrated, rather than dilute, solutions. It would also be desirable to decrease the time required for substantially all of a dose of a drug formulation to be released from a drug delivery device, where the drug is one requiring rapid delivery.

Methods, formulations, and devices are provided for enhancing drug delivery from a medical device. In one aspect, a method is provided for increasing the rate or quantity of a drug formulation released from an implantable drug delivery device, which method comprises the step of providing a release-modifying agent within or proximate to the implantable drug delivery device, in a manner effective to inhibit gelation, aggregation, or precipitation of the drug formulation being released from the device. The drug formulation and the release-modifying agent may be stored together in at least one reservoir in the implantable drug deliver device. Alternatively, the release-modifying agent may be stored in one or more reservoirs separate from the drug formulation.

The release-modifying agent may operate by altering a chemical or physical property of the physiological environment within or proximate to a reservoir from which the drug formulation is released from the device, or it may operate by altering a chemical or physical property of the drug formulation. For instance, the release-modifying agent may enhance release of the drug formulation from the device to the physiological environment, having a first pH, in which the device is implanted by imparting a second pH to at least a portion of the physiological environment within or proximate to the device where the drug formulation is stored and/or released, the second pH being less than or greater than the first pH. In other examples, the release-modifying agent may enhance release of the drug formulation to the physiological environment by (i) altering the hydrophobic or hydrophilic nature of the physiological environment within or proximate to said at least one reservoir having the drug formulation, (ii) binding to hydrophobic or hydrophilic domains of the drug formulation, or (iii) inhibiting oxidation of the drug formulation in the physiological environment.

In one embodiment, the drug formulation comprises an amino acid, a peptide, or a protein. In one example, the drug formulation comprises human parathyroid hormone or an analog thereof. In other examples, the drug formulation comprises a leutenizing hormone-releasing hormone, a gonadotropin-releasing hormone, a natriuretic peptide, exenatide, pramlintide, a tumor necrosis factor (TNF) inhibitor, an analog thereof, or a combination thereof.

The release-modifying agent may be selected from cosolvents, viscosity modifiers, chaotropic agents, polymers, salts, polymeric salts, surfactants, acids, bases, polymeric acids, polymeric bases, and combinations thereof. In one embodiment, the release-modifying agent comprises at least one non-volatile, monoprotic or polyprotic organic acid. In another embodiment, the release-modifying agent comprises at least one non-volatile, mono- or poly-functional base. A preferred release-modifying agent comprises citric acid.

In one embodiment, the implantable drug delivery device comprises one or more discrete microreservoirs. In one embodiment, the drug formulation is stored in and released from a plurality of discrete reservoirs provided in an array on a surface of the implantable drug deliver device. In one embodiment, the volume of each reservoir is between 1 nL and 500 μL.

In another aspect, an implantable medical device is provided for the storage and controlled release of a drug formulation. In one embodiment, the device comprises: a body portion; at least one reservoir located in at least one surface of the body portion and having at least one release opening; at least one drug formulation, which comprises at least one drug, disposed within the at least one reservoir; and a release-modifying agent disposed within the at least one of the reservoirs or within one or more second reservoirs. In one embodiment, the device may further include at least one reservoir cap closing off the release opening; and activation means for selectively disintegrating the reservoir cap to permit release of the drug formulation from the at least one reservoir. Preferably, the activation means for selectively disintegrating the reservoir cap comprises electrical circuits, a power source, and a controller for disintegrating the reservoir caps by electrothermal ablation.

In one embodiment, the drug formulation and the release-modifying agent are both stored in the same at least one reservoir. In one variation, the drug formulation comprises a solid matrix that has pores or interstices. In another variation, the device further includes one or more excipient materials, wherein the release-modifying agent and the one or more excipients materials are located in the pores or interstices of the solid matrix. One or more of the excipient materials may be in solid form. In one embodiment, the one or more excipient materials may include a polyethylene glycol or another polymeric material. The release-modifying agent may be located in the pores or interstices of the solid matrix. The release-modifying agent may enhance release of the drug formulation into a physiological liquid by increasing the capillary action of the physiological liquid through the matrix solid or by causing the solid matrix to be crystalline. In one particular variation, the release-modifying agent may be provided in the at least one reservoir in the form of one or more first layers and the drug formulation is provided in the at least one reservoir in the form of one or more second layers adjacent to and/or interspersed with the one or more first layers. In another embodiment, the drug formulation and the release-modifying agent are in the form of a molten solution or suspension.

In another embodiment, the release-modifying agent is stored in the one or more second reservoirs, separate from the drug formulation.

In some embodiments, the release-modifying agent enhances release of the drug formulation from said at least one reservoir to the physiological environment by inhibiting gelation, aggregation, or precipitation of the drug formulation. In one embodiment, the physiological environment has a first pH, and wherein the release-modifying agent enhances release of the drug formulation from said at least one reservoir to the physiological environment by imparting a second pH to at least a portion of the physiological environment within or proximate to the at least one reservoir having the drug formulation, the second pH being less than or greater than the first pH. In other embodiments, the release-modifying agent enhances release of the drug formulation from said at least one reservoir to the physiological environment by (i) altering the hydrophobic or hydrophilic nature of the physiological environment within or proximate to said at least one reservoir having the drug formulation, (ii) binding to hydrophobic or hydrophilic domains of the drug formulation, or (iii) inhibiting oxidation of the drug formulation in the physiological environment.

In one embodiment, the at least one reservoir further includes a polyethylene glycol or another back-fill material.

In another embodiment, the drug formulation is sealed in the at least one reservoir at a reduced pressure, relative to ambient pressure, or with an inert gas, or both at a reduced pressure and with an inert gas.

In a preferred embodiment, the at least one reservoir is a microreservoir. In another embodiment, the device has a plurality of discrete reservoirs provided in an array on a surface of the body portion and containing the drug formulation. In various embodiments, the body portion is in the form of a chip, a disk, a tube, or a sphere. The body portion may be made of silicon, a metal, a polymer, a ceramic, or a combination thereof.