1. Field of the Invention
The present invention relates to a method of controlled release of an active ingredient or agent, microstructures for the controlled release of an active ingredient or agent, and compositions containing such microstructures. In particular, the present method relates to the use of submicron diameter hollow cylinders (tubules) which contain an active agent within the inner hole or lumen of the tubule for the controlled release of the active agent. The tubules may be self-assembled from lipids or peptides or other self-assembly molecules and may be coated with electroplated metal or ceramics. Alternatively, the tubules may be constructed of an inorganic material such as a metal or ceramic.
2. Discussion of the Background
As man constructs artifacts, nature, in the form of weather, microbes and marine life, works to break the artifact down and return it to nature. Since before recorded history, man has applied coatings to artifacts to both beautify and protect the artifact.
Coatings incorporating materials which are aimed at destroying or diverting microbes and marine life are known. The most common coatings are paints used on land based structures of all types and marine coatings used on seaside and seaborne artifacts such as pilings, ship hulls, towers and other structures.
Biological fouling of surfaces such as ship hulls exposed to seawater is a problem which has existed since man first put to the sea. The diversity of fouling organisms and the environments in which they live create complex problems which any useful antifouling coating must overcome. Because these organisms add weight and hydrodynamic drag when they attach to vessels, effective hull fouling control is necessary to minimize fuel consumption, maintain operational speed and maneuverability, and preserve the hull from corrosion.
The schemes to defeat the attachment of drag producing organisms to ships and other man made artifacts almost matches the diversity of the organisms themselves. Any useful biocidal system must be effective against organisms which range from slime-forming bacteria and algae to shell-forming invertebrates with minimal damage to the remainder of the environment.
By definition, biocidal agents are highly toxic to the target species and to other animals and plants as well. The use of highly toxic and environmentally persistent antifoulants such as lead, mercury, arsenic, and cadmium compounds has been discontinued because of environmental degradation. In addition, the highly effective tributyltin compounds have also been banned from use by several state and federal agencies as well as foreign governments because of the detrimental overall impact.
Although in use in one form or another for over a thousand years, the predominant toxicant in use today is copper in the form of copper sulfate, copper hydroxide, cuprous oxide, copper napthenate or copper metal in powder or sheet form. Too great a concentration of copper can also be harmful to the environment. Paints and coatings in use today contain up to 70% by weight of cuprous oxide and release to the environment far more than the minimum effective amount of copper. Of course, the rate of copper release declines exponentially as the coating ages because exposure of the paint to the environment leaches active toxins until the paint is no longer effective.
Although now the toxin of choice, copper is an environmental hazard which is toxic to invertebrate and vertebrate marine organisms which include many economically valuable species such as oysters and clams, fish and seaweed. The release of copper to the environment must be carefully controlled. In addition, if large quantities are inhaled or ingested during hull repainting, copper oxide can be a hazard for dockyard workers. In contained waters which are frequented by large ocean-going vessels, such as the Suez Canal, the water quality has deteriorated because of high levels of copper. Paints which release high levels of copper may soon be restricted by environmental regulation.
Many inventors have tried to find a way of balancing the beneficial against the detrimental effects of releasing copper or other agents to prevent microbial or marine fouler action adjacent a treated surface. U.S. Pat. No. 4,098,610 describes a biocidal glass additive for marine paints which slowly releases copper. U.S. Pat. No. 4,129,610 describes a water soluble coating for ships which slowly releases copper. Another slow toxin release scheme is described by Foscante et al. in U.S. Pat. No. 4,385,134, in which a polymer is used as the slow release agent. Other marine anti-fouling paints and coatings are described in U.S. Pat. Nos. 4,480,011; 4,594,365; 4,602,011. U.S. Pat. No. 4,531,975 describes a marine coating which uses hollow glass bead microspheres or balloons to thicken and change the coating's density.
The mechanisms and history of antifouling paints as well as a discussion of the problems with ablative or erodible type dispensing coatings can be found in Foscante et al. U.S. Pat. No. 4,670,481. Foscante describes a paint incorporating tributyltin.
A deficiency of soft ablative paints and in some of the harder leaching paints is rapid mechanical erosion caused by flowing seawater. Often erosion of the coating in the bow, skegs, struts, and keel sections of the ship is more rapid than that in large flat surfaces. Paint is removed quickly from those areas, and the underlying hull is exposed to the ravages of marine fouling agents.
Coatings or paints which incorporate particles of copper or similar materials have the added problem that erosion of the ablative coating surrounding the particle can result in the sudden release of the particle and loss of its benefits. Thus without rational control of the leaching of toxicant from the coating, premature release of large amounts of the biocide in a dropped particle pollutes the environment and reduces the long term performance of marine antifouling paint.
Other problems are present when secondary or auxiliary toxins are used. Secondary toxin materials cannot be effective in promoting extended service lifetimes of conventional coatings unless these highly soluble materials can be protected from rapid leaching and chemical breakdown. Regardless of the myriad schemes developed to release copper and other toxins slowly, the problems of controlled slow release have not been solved.
The need for slow release of biocidal and pesticidal agents is not restricted to a marine environment. In many land environments, mold and other microbial and insect pests attack houses, vehicles and other land based artifacts. Copper and other toxic materials are incorporated into paints coatings and roofing material to suppress or destroy pest activity. U.S. Pat. Nos. 3,894,877; 3,888,683; 3,888,682; and 3,888,176 are all directed at incorporating algaicidal materials into roofing products. Land based artifacts suffer ablative wear similar to sea borne artifacts. A constant exposure of fresh toxic material is needed to protect the coated surface from microbial or pest infestation.
The attack of wood and laminated wood products, such as plywood, represents a particularly important case of biological degradation of man-made objects. Specifically, larva of insects, such as carpenter ants, termites, powder post beetles, and wood boring bees, are known to attack wood and the resins which bind the individual sheets of wood in a section of plywood together ("Application of fenitrothion microcapsule for insect-proof plywood panel" M. Kawashima, T. Ohtsubo, S. Tsuda, T. Itoh, and K. Tsugi, Proceedings of the 7th International Symposium on Microencapsulation and Controlled Release, p. 88.) resulting in a weakening of the plywood. Further, insects such as termites and carpenter ants are well known to eat wood. The reduction in strength of the wood and plywood arising from the attack of such pests can jeopardize the structural integrity of a building and cause great economic loss.
Conventionally, plywood and lumber are pressure treated with agents such as creosote, cooper sulfate, arsenical compounds, organotin compounds. However, such conventional treatments are not satisfactory, because heavy metal compounds, arsenical compounds, creosote and organotins cause environmental degradation, are a health hazard to persons who handle and use woods, and are toxic in large amounts. Thus, it is desirable to provide methods and compositions for the slow, controlled release of agents which will afford protection to such wood products.
Another situation, where the slow, controlled release of a biologically active agent is desirable is the application of pesticides to agricultural crops. Such pesticides include not only insecticides and fungicides, but also selective herbicides for the control of weeds. Conventional methods for the controlled release of pesticides and herbicides include microencapsulation. However, such methods provide only a modest increase in the time of effectiveness (from 1-2 days to 5-7 days).
The slow, controlled release of pesticides is also important for the protection of animals, such as pets and farm animals. Thus, flea and tick collars are designed to release pesticides such as 2-chloro-1-(2,4,5-trichlorophenyl)vinyl dimethyl phosphate at a slow and controlled rate. However, conventional flea and tick collars have effective lifetimes which are only on the order of months, and the release of the agent is not linear with time. Thus, many animal owners are reminded that it is time to change an animal's collar, by discovering that the animal is infested with fleas or ticks.
In addition to providing methods and compositions for the slow, controlled release of pesticides, microbicides, herbicides, fungicides, insecticides, and bactericides, the slow, controlled release of beneficial agents such as fertilizers, trace nutrients, vitamins, hormones and the like is also desirable. Specific applications, include the application of fertilizers to agricultural crops, house plants and garden plants, shrubs, and trees. Conventional techniques for the controlled release of such agents suffer from the same draw backs as described above, e.g., short increase in the time of effectiveness and/or nonlinear release with time.
It is known that materials may be incorporated and released in a linear manner, or on demand. Many types of encapsulation in spherical particles, or in solid rods have been well established (D. Wise, Biopolymeric Controlled Release Systems, Vol. II, CRC Press, Boca Raton, (1984).
As described in U.S. Pat. No. 3,318,697, it is known to metal coat lipid and wax globules. For pharmaceutical and other purposes, it is known to incorporate materials inside a waxy globule or a liposome.
It is further known that polymerizable phospholipids form hollow cylindrical structures which are commonly referred to as tubules. These are described in U.S. Pat. Nos. 4,877,501 and 4,990,291. The efficient synthesis of these compounds is fully described in U.S. Pat. No. 4,867,917 entitled "Method for Synthesis of Diacetylenic Compounds". The methods necessary to coat these microstructures with a range of metals is fully described in U.S. Pat. No. 4,911,981 entitled "Metal Clad Lipid Microstructures".
These tubules are hollow tube-shaped microstructures fabricated by self organization of polymerizable diacetylenic phospholipid molecules. Morphologically, tubules are analogous to soda straws with diameters of approximately 0.05 to 0.7 .mu.m and lengths from 1 to 1,000 .mu.m. The tubule diameter, the length and the number of bilayers comprising the wall are all controllable parameters which are controlled by the fabrication methods employed.
The preparation of tubules is also discussed in an article by Schnur et al., "Lipid-based Tubule Microstructures", Thin Solid. Films, 152, pp. 181-206, (1987) and the articles cited therein. That same article, in which one of the inventors is a co-author, also describes metal coating tubules and using them as microvials to entrap, transport and deliver polymeric reagents to a desired site. However, there is no suggestion of using such tubules for controlled release of an active agent.
Burke et al, ("Entrapment of 6-Carboxyfluorescein within Cylindrical Phospholipid Microstructures", Thomas G. Burke, Alok Singh, Paul Yager, Annals of the New York Academy of Sciences, Biological Approaches to the Controlled Delivery of Drugs, Ed. R. L. Juliano, 507, 330-333 (1987)) disclose the entrapment of the hydrophilic fluorophore, 6-carboxyfluorescein, in the lumens of such tubules. The movement of liposomes within the tubule is reported. Again, there is no suggestion of utilizing such tubules for the slow, controlled release of an active agent.
Each of the ablative or erodible materials of the prior art tend to dispense particles of material to the environment which causes an uneven and sometimes overly high concentrations of the toxic material. In addition, the agent to be dispensed often reduces or weakens the integrity of the coating. Thus, there remains a need for methods and compositions for the slow, controlled release of active agents.
USPTO Backgrounds
USPTO Backgrounds