There are several methods that are known for the delivery of a pharmaceutical composition for the treatment of various medical conditions. The therapeutic agent in a pharmaceutical composition may be delivered to a human or veterinary patient by various routes of administration such as but not limited to subcutaneous, topical, oral, intraperitoneal, intradermal, intravenous, intranasal, rectal, intramuscular, and within the pleural cavity.
One of the methods of administration of a drug is by introducing an implantable medical device containing the desired drug/therapeutic agent in a formulation, partly or completely into/onto the respective site such as but not limited to esophagus, trachea, colon, biliary tract, urinary tract, vascular system or other locations within a human or veterinary patient wherein the medical device may be a stent, catheter, balloon, dental implants, orthopedic implants, etc.
Exposure, however, to a medical device which is implanted or inserted into the body of a patient can cause the body tissue to exhibit adverse physiological reactions. For instance, the insertion or implantation of certain catheters or stents can lead to the formation of emboli or clots in blood vessels. For example, when a medical device is introduced into and manipulated through the vascular system, the blood vessel walls can be disturbed or injured. Clot formation or thrombosis, and/or cell proliferation often results at the injured site, causing stenosis (i.e., closure) of the blood vessel. Additionally, if the medical device is left within the patient for an abnormal period of time, thrombus may form on the device itself with subsequent cell proliferation, again causing restenosis.
Drug-Eluting Stents (DES) are made to resist stenosis or cell proliferation by coating them with therapeutic agents which elute at the target site at a desired rate and desired dose to achieve desired drug concentration in the vessel wall tissue. The rate of release of therapeutic agent in surrounding blood stream and on the surrounding tissue is very important to get desired clinical result, at the same time controlling adverse effects. To control the release rate, the therapeutic agents are coated on stents along with other components like polymers which are biodegradable/bioabsorbable or non-biodegradable/non-bioabsorbable.
Treatment of damaged vascular tissue, thrombosis and restenosis, sees the need for administering therapeutic substances to the treatment site. For example, anticoagulants, antiplatelets and cytostatic/cytotoxic agents are commonly used to prevent thrombosis of the coronary lumen, to inhibit development of restenosis, and to reduce post-angioplasty proliferation of the vascular tissue. In order to provide an efficacious concentration of therapeutic substances to the treated site (site of pathology) by systemic administration of such medication produces adverse or toxic side effects for the patient. Such problem is overcome by way of local delivery wherein smaller levels of medication, as compared to systemic dosages, are delivered to the site of pathology. Local delivery produces fewer side effects and achieves more effective results. Of the techniques applied for local delivery of the drugs, most common is through the use of medicated stents or drug eluting stents.
Recently, various types of drug-coated stents have been used for the localized delivery of biologically active materials to the wall of a body lumen to prevent restenosis. The biologically active materials used as part of the stent coating typically have one or more therapeutic activities such as but not limited to antithrombotic activity, antiproliferative activity, anti-inflammatory activity, vasodilatory activity, or lipid-lowering activity. Generally, biologically active materials are adhered to the stent surface in admixture with a carrier polymer.
A method involving the use of a polymeric carrier along with the therapeutic agent/s coated onto the body of the stent is disclosed in U.S. Pat. No. 5,464,650, U.S. Pat. No. 5,605,696, U.S. Pat. No. 5,865,814, and U.S. Pat. No. 5,700,286. U.S. Pat. No. 5,843,172 and U.S. Pat. No. 6,240,616, report a medicated prosthesis, such as a stent, deployed in a human vessel. The metallic stent in consideration has a plurality of pores in the metal which are loaded with medication. When the stent is implanted into the vasculature of a patient, the medication in the stent dissipates into the tissue of the vasculature close to the stent. The stent may be formed from a porous metal in the form of a wire, tube, or metal sheet. Porous metal is formed by sintering metal particles. In some cases, sintering the particles or fibres is done in several layers.
In another recent prior art, U.S. Pat. No. 5,972,027, expandable intraluminal stents made of a powdered metal or polymer are provided as well as their method of manufacture. These stents are characterized by a desired porosity, with a drug compressed into the pores of the stent. The stents are formed by subjecting one or more powdered materials in a die cavity to a pressure treatment followed by a heat treatment. The material may be cast directly in a stent-like form or cast into sheets or tubes from which the inventive stents are produced. The so-formed porous metal or polymer stent is then loaded with one or more drugs.
U.S. Pat. No. 6,379,381 discloses an implantable stent capable of being loaded with substances. In one example, the prosthesis is a cylindrical-shaped body having depots or pores formed thereon. The depots can be formed at pre-selected locations on the body of the stent and can have a pre-selected depth, size, and shape. The depots can have various shapes including a cylindrical or a conical shape. Such depots are formed as laser trench. Laser fabrication and physical/chemical etching techniques well known to one of ordinary skill in the art have been used. Substances such as therapeutic substances, polymeric materials, polymeric materials containing therapeutic substances, radioactive isotopes, and radio-opaque materials can be deposited into the depots.
The US patent application no. 2006/0085062 discloses an endolumenal stent system for promoting endothelialization of vascular injury sites, comprising: an endolumenal stent; a porous surface on the endolumenal stent having a plurality of pores; and a composite material located within each of the pores and comprising a bioerodable polymer in combination with a therapeutically effective amount of a bioactive agent.
While the polymer provides the drug-coated stent with several important functions, the use of the polymer also burdens the stent with certain disadvantages. Often, coating the biologically active material with a polymer can result in drug entrapment within the polymer coating so that the biologically active material diffuses from the stent to the area to be treated too slowly and/or at too low a concentration. Moreover, conventional coating methods typically use a continuous phase coating such as a liquid carrier polymer phase to dispose the biologically active material on the stent. Such methods often result in disposing an excess amount of polymer on the stent surface. The presence of excess polymer is generally considered to be detrimental to tissue recovery, and a bare metal stent is believed to promote better vascular healing than a stent having a polymer finish.
Further, these polymers cause inflammation to the arterial wall leading to in-stent restenosis (ISR). Other distinct factors that cause ISR include neointimal hyperplasia and other well known cardiovascular complexities. Substantial research is being carried out to eliminate the negative/adverse effects of vascular stenting by eliminating the use of polymeric material for therapeutic coating of the stents.
Obstacles often encountered with the use of a polymeric coating include difficulties in coating a complicated geometrical structure, poor adhesion of the polymeric coating to the surface of a stent, and biocompatibility of the polymer.
US patent application no. 2003/0064965 discloses a medical device which comprises: a plurality of particles, which are supported within the matrix of a macrostructure, dispersed on the surface of the medical device, each particle comprising a therapeutic drug or a combination of therapeutic drugs having anti-proliferative activity in the cardiovascular system, wherein the particles are selected from the group consisting of liposomes, microparticles, nanoparticles, and drug aggregates, and wherein the medical device is contacted with a tissue or circulation such that the drug is released from the particle into the surrounding tissue or blood circulation in less than 5 minutes after the contacting step. The macrostructure is selected from the group consisting of fibrin gels, hydrogels and glucose and the particles are supported within the matrix of a macrostructure. This formulation is specifically suitable for medical devices like balloon catheters which remain in the body for short time. This formulation can not be used where sustained release is required over a long period of time varying from a few days to 60 days.
US patent application No. 2008255509A1 describes a coated medical device for rapid delivery of a therapeutic agent to a tissue in seconds or minutes. The coating contains a therapeutic agent, at least one of an oil, a fatty acid, and a lipid, and an additive. The additive has a hydrophilic part and a drug affinity part which is one of the hydrophobic part which has affinity to therapeutic agent by hydrogen bonding or van der Waals interactions. This formulation is specifically suitable for medical devices like balloon catheters which remain in the body for a short time during which the drug should be delivered to the target site like a tissue. This formulation can not be used where sustained release of therapeutic agent is required over a long period of time.
Disadvantages associated with the aforementioned methods are (1) quite a lot of the drug is lost in the blood; (2) only a fraction of the drug is able to reach the target cell/tissue, which necessitates incorporation of high drug dose on the medical devices e.g. stent to achieve efficacious drug dose in the target tissue; (3) very fast release of therapeutic agent; (4) a narrow range of release kinetics and (5) a part of the drug and delivery vehicle residing for a long time or permanently on the stent surface after implantation causes inflammation, delayed healing and incomplete endothelialization which in turn results into acute, sub-acute and late thrombosis. In some cases, the entire quantity of drug and/or the vehicle is not released.
Non polymeric compositions for coating a medical device are described in patents/patent applications. Patent applications US20080206305A1, US20080109017A1 and US20080113001A1 describe a barrier device having one or more barrier components in plurality of tiers that exhibit modulated healing properties, anti-inflammatory properties, non-inflammatory properties, therapeutic properties, and/or adhesion-limiting properties. The barrier component can be a non-polymeric cross-linked gel (comprising molecules covalently cross-linked into a three-dimensional network) derived at least in part from a fatty acid compound or a biocompatible oil (naturally occurring oil, such as fish oil, cod liver oil, cranberry oil, or other oils having desired characteristics which may be partially hydrogenated to get a wax to allow the oil to adhere to a device for a longer period of time) and may include a therapeutic agent. The barrier component, though non-polymeric, is a cross-linked gel.
Application No. WO2007011385A2 describes a method of curing to form a gel, comprising a non-polymeric substance and determining an amount of cross-linking desired within the substance as a result of curing by applying heat at a selected temperature for a selected time period to achieve desired amount of cross-linking to form the gel.
Patent application US20060083768A1 describes method of increasing the viscosity of an oil-based composition comprising at least one fatty acid (and salts); and combining the oil-based composition with one or more therapeutic agents in an amount sufficient to increase viscosity of the oil based composition. The method comprises (optionally) the step of mixing the therapeutic agents with a solvent prior to combining the therapeutic agent with the oil-based composition. The viscosity increases from about 5 cPs to about 150,000 cPs. The release of the therapeutic agents is extended by the increased viscosity of the oil-based composition which prevents the removal of the coating from a medical device in vivo.
Patent application No. US 2005/0251245 describes methods of forming pores on a surface. The porous portion is attached to or integrated into the main structure of the medical device such as stent. The method of forming pores is mainly chemical where a voltage application to aid the chemical etching is mentioned. The etching method is described in general for metals specifically for stainless steel. The surface is prepared for doping the elution material on the porous surface. However, it does not reveal parameters for forming desired pore structure. Method of doping the surface is not revealed.
Patent application Nos. US20080181928A1 and WO2008077248A1 describe depositing a porous layer of ceramics and other materials on medical device by electrochemical deposition, electrophoretic deposition (EPD), sol gel processes, aero-sol gel processes, biomimetic (BM) processes, spraying, and dipping. A coating is applied on this surface where coating comprises a dry film comprising lipid bilayer and pharmaceutically effective agent/s wherein the coating is free of a polymer. The lipid bilayer comprises lipid/s capable of forming a liposome encapsulating the pharmaceutically effective agent when exposed to an aqueous solution.