The present invention relates generally to the enhancing retention of substances in biological target site, and more particularly to applying a chemical barrier for prolonging agent residence time in a biological tissue.
The medical and veterinary fields have long used agents to treat, diagnose and prevent countless medical conditions. The substances are used to alter the body""s function at the molecular level. The types of agents that are administered to biological systems include natural and synthetic drugs, biological agents, therapeutic radiation, and the like.
There are many complications that accompany the use of agents. The efficacy of chemical treatment depends on several variables including (1) the mechanism of chemical reaction, (2) penetration of the chemical into a target site, (3) amount of chemical that is delivered, (4) proficiency of delivery, and (5) residence time of the chemical at the target site.
The composition of the chemical is one factor that impacts these variables. Enormous efforts are placed on devising new and improved compounds. In particular, chemicals are formulated for providing optimal reaction mechanisms and penetration.
The agent""s route of administration and travel to the treatment site further influence the variables to efficacy. Traditional routes of administration include intravenous, oral, inhalational, topical, transdermal, subcutaneous, intramuscular, buccal, intra-arterial, intrathecal and rectal.
Methods of directly administering an agent are of special interest. Such local applications reduce the distance through which the agent must travel between the site of administration and the intended target place. As a result the chemical has a higher bioavailability at the target site. Unlike systemic delivery, local delivery of chemical can be made at high concentrations without causing systemic toxicity issues. Where the agent must extensively travel through the body to reach the target tissue, the agent may be metabolized in the gut, portal blood or liver prior to entry into other systemic circulation. Moreover, an agent flowing through the circulation to reach its proposed destination may be retained by blood plasma proteins instead of binding to its intended tissue protein. Direct routes are also useful for reducing potential undesirable effects, producing high local concentrations of agent at the treatment site, and continuously attending to chronic conditions.
In order to enhance chemical performance, medical devices are constructed and medical procedures devised to facilitate contacting the agent with its target site. For example, many devices and methods have been designed to increase agent penetration, the amount of agent delivered and the efficiency of chemical function.
Special routes of administration are available for dispensing agents directly to a target tissue. The agents may be attached to a carrier that is implanted near the target site, e.g. drug delivery stents. Other local agent delivery devices include microporous balloon catheters, ultrasound-enhanced delivery through microporous balloons, intra-vascular injection catheters, iontophoresis, etc. Intra-vascular, intraoperative or intrathecal catheters may also be surgically inserted near the target organ for delivery of agents. In an exemplary case, gene therapy agents are presented to the heart through a catheter that is percutaneously introduced, such as through the femoral artery, and guided upstream into the left ventricle and epicardium for agent introduction into the pericardial space. In such procedures, access to the pericardium may also be gained intra-vascular or through a thoracotomy.
Once an agent is administered, the chemicals progress throughout the body to and from the target site via the bloodstream, diffusion and active transport systems. Most fluids move freely through the circulatory system and pass to various areas of the body through capillaries. There are some natural barriers that restrict movement of molecules throughout the body, such as the blood-brain barrier for hindering the passage of selective chemicals to the brain. Most capillaries, however, have vessel walls with cells arranged in a manner that allow molecules as large as 20,000-30,000 Daltons to pass under pressure through the vessel wall.
After an agent reaches its intended treatment site, it is typically absorbed by blood vessels and washed away with circulating blood flow. Agents are then usually excreted from the body by transfer via the circulation to the kidneys, liver, gastrointestinal tract, lungs, salivary glands and sweat glands.
However, frequently an agent is only effective while it is in contact with the target site, e.g. bound to a receptor. Mechanisms that resist removal of an agent by circulating blood flow permit the agent to create a more dramatic outcome at the treatment site. Prolonged agent retention times at the target location enhance many treatments, especially those requiring long-term administration of agent. Moreover, since less agent is quickly washed away with these methods of increasing agent retention, a smaller amount of agent is required. Hence, the cost of the agent is reduced. Furthermore, the lower dosage of agent may decrease side effects that sometimes occur with larger amounts.
Many medical conditions benefit from prolonged agent residence time at the target site, such as cardiac conditions. Coronary heart disease is the most common disease and cause of death in civilized, western countries. In the treatment of atheroslerotic coronary disease, percutaneous transluminal coronary angioplasty (PTCA) may be performed to reduce obstructions in a vessel. PTCA involves the introduction of a catheter with a small dilating balloon at its tip. The catheter is snaked through the arteries, often in the arm or leg, to a site where the vessel has narrowed. The balloon is inflated to increase the cross-sectional area of the vessel.
Although PTCA treatment has a high success rate in widening the vessel, often the vessel re-narrows or re-closes post dilation, referred to as xe2x80x9crestenosis.xe2x80x9d In restenosis, proliferation of smooth muscle cells does not initiate until a long time (48-72 hours) after the PTCA procedure is performed. Treatment of restenosis includes delivery of anti-proliferation drugs to the site of the diseased vessel wall following PTCA and during the same surgery. Yet, the drug treatment is only mildly effective because the bloodstream removes the drug from the tissue quicker than the time it takes for the onset of restenosis. The drug is encouraged to diffuse out of the area of higher agent concentration in the vessel walls to the site of lower concentration in the internal lumen of the vessel. The flowing blood maintains this lower agent concentration inside of the vessel. In this manner, the agent is readily washed away from the target site and agent has a limited residence time in the tissue.
Current approaches to increase chemical retention times involve manipulating the agent prior to its introduction into a biological system. Typically, functional molecules are pre-attached to the agent to alter the physical structure of the agent in a manner that hinders absorption of the agent after it is delivered into the blood stream. In one such technique, a polyanionic sulfate group is bound to a drug in order to impart negative charges. The negatively charged drug repels from the negatively charged walls of a capillary and resists absorption onto the vessel wall. Thus, the agent is retained within the peripheral circulation.
Some retention systems attempt to provide for gradual release of an agent from a delivery source. Prior to administering, an agent may be coupled to a carrier that slows the release of the agent at the target site. One exemplary system binds a drug to an ionic carrier for administering to the eye. Tear fluid gradually dissolves the carrier to release the drug. Other systems include microcapsules that encapsulate the drug. The shell is biodegradable, such as by hydrolysis, to slowly release the drug.
In other methods, a drug is pre-incorporated into a solid polymeric material that is inserted into a vessel. Once the material reaches the target site, the material is reconfigured to form a support structure on the vessel surface. For example, the solid material may be heated to melt the material, molded to the shape of the internal vessel surface and then re-solidified. A problem with this system is that the manipulation of the material once it is in the vessel, such as by heating, may disrupt the agent and vessel.
There are many problems with these current systems that require the agent be structurally manipulated prior to entry into the body. A significant drawback to the use of pre-altered agents is that modification of each chemical agent is complicated and expensive. Retention mechanisms and attachment structures must be tailored for each agent of interest. The resulting change in molecular structure of the agent composition may compromise chemical action. Furthermore, pre-attachment of a delivery component to the agent results in an increased size of the agent composition. This altering of the agent may hinder penetration or delivery of the chemical.
Moreover, carrier systems do not lengthen the time that agent molecules contact a target site, but rather provide a constant supply of agent to a site. Thus, these systems require large amounts of agent in order to lengthen the effect. These carrier systems are also limited by the amount of agent that may be administered in the vehicle.
In view of these limitations with current systems, there is a need for a platform for prolonging chemical residence time that may be applied universally across a variety of agents. Furthermore, a system is desired which lengthens agent effect by extending the time in which agent molecules contact a site, rather than increases the agent dosage. The mechanism should not hinder chemical reaction, penetration or delivery and cause minimal damage to the tissue. In particular, an approach for hindering reabsorption of an agent by the bloodstream without manipulating the agent prior to administering would be advantageous.
An agent retention system and process is provided for prolonging the residence time of an agent in, on or near a tissue. In general, the system increases agent effectiveness at a treatment site by extending the time in which agent molecules contact the site, rather than increasing the agent dosage. The tissue that benefits from the retention system may be any biological tissue having at least one surface. For example, the tissue may be a vessel, organ, tumor cells, or the like.
A biodegradable barrier that is separate from the agent is utilized in the present invention the barrier has a binding member to couple the barrier to a tissue surface. The barrier may be a biodegradable molecule that is biocompatible with the target tissue. For example, the barrier may be a poly(anino acid), such as poly-L-lysine. The binding member permits attachment of the barrier to the tissue surface by a variety of binding mechanisms, such as ionic binding, covalent binding, electrostatic interactions, hydrogen bonding, and the like. For example, the barrier""s binding member may be a cationic ion for binding to an anionic member of the tissue surface. In one embodiment of the barrier, a charged binding member is included for adhering to an oppositely charged member on an interior vessel surface and a passive platelet inhibitor.
In one embodiment of the agent retention method according to the present invention, a pre-treatment agent is contacted with the tissue, followed by contact with the barrier to the tissue surface. A sufficient amount of the barrier is allowed to adhere to the tissue surface to hinder diffusion of the agent through the tissue surface as compared to diffusion of the agent without the presence of the barrier.
In some cases, the barrier is contacted with a tissue surface prior to introduction of a post-treatment agent. In this embodiment, the post-treatment agent is contacted with the barrier and the agent attaches to the barrier. The agent is retained at the tissue for a prolonged period of time as compared to the retention of the agent without the presence of the barrier.
In still other configurations, the retention system is applied to a tissue having an inner tissue wall and tissue surface. The agent and biodegradable barrier are administered to a patient in a time-varied manner. A sufficient amount of the barrier""s binding member is allowed to couple the barrier to the tissue surface to hinder diffusion of the agent through the tissue surface.
The barrier composition may be formulated by admixing a barrier having a binding member and a delivery carrier. The barrier component is present in an amount sufficient to couple to the tissue surface and to permit transport of the agent from the tissue surface at a lower rate than agent transport in the absence of the barrier composition.
The retention system may comprise the barrier and a conduit, e.g. a catheter, having at least one opening for administering the agent and barrier. The barrier, agent and optionally the conduit may also be included in a system for increasing agent residence time in a tissue.
The benefits of the agent retention system are direct in that the system may be universally applied across a variety of agents. With the present retention system, any pre-treatment agents may be retained for longer in the tissue. Agent need not be reformulated with the barrier or even compatible with the barrier. In one embodiment, the approach hinders reabsorption of an agent by the bloodstream without needing to manipulate the agent prior to administration into a patient.
The mechanism for agent retention according to the present invention does not hinder chemical reaction, penetration or delivery of the agent. The process further may result in only minimal damage to the tissue.
Other features and advantages of these and other embodiments are discussed in detail below.