DESC:TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to an implant and more particularly, a surface modified implant or a part thereof.
BACKGROUND OF THE INVENTION
[0002] Cardiovascular diseases, including arthrosclerosis, results from arterial narrowing due to the accumulation of fatty deposits on the arterial wall, which restricts blood flow through a vessel. Percutaneous transluminal angioplasty, referred to commonly as angioplasty, helps to enlarge the lumen of the affected artery by radial hydraulic expansion. However, in some instances, the vessel restenosis chronically or closes down acutely, negating the positive effects of angioplasty procedure. In a kind of vascular injury induced by atherosclerosis, vascular smooth muscle cells in the artery wall undergo hyper proliferation. It invades and spreads into an inner vessel lining, making these vessels susceptible to a complete blockage when a local blood clotting occurs, thus leading to a death of tissue. Under such cases of severe atherosclerosis, medical device or end prostheses, commonly referred to as "stents" are proposed for mechanically keeping the vessel open after completion of the angioplasty procedure. This coronary stent is used to open blockages in an artery of a human body. The Stent is elongated tubular metallic structures, with either solid or lattice-like walls, and also may either be expandable or self-expanding balloon. With the stent in place, restenosis may or may not be inhibited, but the degree of blockage is reduced due to a structural strength of the stent opposing the inward force of any restenosis, thus maintaining the patency of the vessel. Thus, this stent device, also referred as prosthesis device, ultimately helps to repair, replace or correct a damaged blood vessel. This prosthesis device helps to rectify a variety of defects including stenosis of the vessel, thrombosis, occlusion, or an aneurysm.
[0003] The stents deployed in conditions of arthrosclerosis or other diseased states demands that the stent material be appropriately biocompatible, hemocompatible as well as mechanically durable. This necessitates the use of metals including titanium (Ti), 316L stainless steel (SS — medical grade), Nitinol (an alloy of Nickel and Titanium) and Cobalt-Chromium (Co-Cr), for vascular stenting applications.
[0004] Coronary angioplasty - also known as percutaneous transluminal coronary angioplasty (PTCA) – was first introduced in the late 1970s as a minimally-invasive means of reopening coronary arteries that had become narrowed with plaque, so restricting blood flow. The procedure involves a balloon being inserted via a catheter into a peripheral artery and guided to the blocked coronary artery, where it is inflated to compress the plaque against the artery wall to re-establish blood flow, before being removed. However, it soon became apparent that balloon angioplasty had its limitations: in a relatively small number of cases the process weakens the artery wall to such an extent that although it is successfully dilated, it collapses once the balloon is deflated (‘elastic recoil’), leading to the need for emergency bypass graft surgery (CABG). But a much greater problem is restenosis- the phenomenon whereby the artery begins to re-narrow as a result of the body’s healing response to the trauma of angioplasty: the equivalent of scar tissue forming over an injury. This has been observed in between 30 and 40 percent of all procedures within the first year. Bare-metal stents (BMS) were introduced in the mid-1990s with the aim of overcoming the deficiencies of balloon angioplasty. Essentially expandable mesh cylinders, they are mounted on a balloon and open out once inside the coronary artery to line the wall. Subsequent refinement to earlier designs offer improved flexibility, making it easier to deliver to the narrowed artery. Yet although BMS certainly overcame the problems of artery wall collapse by propping it open once the balloon is deflated, the challenge of restenosis was found to persist, although not to the same degree as with balloon angioplasty: in between 20and 30 percent of cases the treated artery was found to re-narrow within six months of stent insertion, leading to the need for a repeat procedure. Insertion of a BMS can cause an additional problem: although the stent is eventually incorporated into the artery wall as tissue forms over it (‘endothelialization’), beforehand there is a risk that the blood clots due to the presence of a ‘foreign body’, forming a potentially life-threatening blockage (thrombus) to the artery. For this reason, patients given a BMS are advised to take a combination of anti-clotting drugs for at least three to six months after initial insertion. Drug-eluting stents (DES) were developed to specifically address the problems of restenosis encountered with BMS. They consist of a BMS coated with a polymer which gradually releases a drug to inhibit the cell proliferation that causes restenosis. By the time all the drug has been released by the polymer - a period of between six and nine months – the main risk of restenosis has been minimized.
[0005] Drug-eluting stents in current clinical use were approved by EU Authorities and FDA after clinical trials showed they were statistically superior to bare-metal stents for the treatment of native coronary artery narrowing, having lower rates of major adverse cardiac events (usually defined as a composite clinical endpoint of death + myocardial infarction + repeat intervention because of restenosis).
[0006] Stents are indicated to improve the diameter of the coronary artery lumen, when narrowing causes ischemia (reduced oxygen delivery to the muscle supplied by that artery). The drug helps in inhibiting neo intimal proliferation and controls the excessive cell growth post stent implantation in the coronary artery.
[0007] Implant with multiple coating is disclosed in a patent reference EP1 933 893B1. However, effective binding capacity of the coating is a concern in this particular patent reference.
[0008] Drug Delivery stent comprising drug-receiving zones in a form of pores passing through its wall and reinforcements has been disclosed in a patent reference DE10200387A1.
[0009] The above-described deficiencies of existing system are merely intended to provide an overview of some of the problems of conventional systems, and are not intended to be exhaustive. Other problems with conventional systems and corresponding benefits of the various non-limiting embodiments described herein may become further apparent upon review of the following description.
SUMMARY OF THE INVENTION
[00010] The following presents a simplified summary of the objects of the invention in order to provide a basic understanding of some aspects of the invention. These objects are not an extensive overview of the present invention. It is not intended to identify the key/critical elements of the invention or to delineate the scope of the invention. Its sole purpose is to present some concept of the invention in a simplified form as a prelude to a more detailed description of the invention presented later.
[00011] The present invention relates to a polymer free drug eluting coronary stent system. The surface modified implant or a part thereof, comprising a first drug is an anti-proliferative drug, and a second drug is a non-polymeric lipophilic agent, wherein the release of the first drug is controlled by the second drug, and wherein the first and second drugs are sprayed on the surface modified implant or a part thereof.
[00012] In an embodiment, the first and the second drug are sprayed along with a shellac on the medical implant.
[00013] In an embodiment, a non-polymeric solution of the first drug, the second drug and a shellac sprayed over the surface modified implant.
[00014] In an embodiment, the first drug is Everolimus and the second drug is Probucol.
[00015] In an embodiment, the implant is made up of a metal. In particular, the drugs are coated on a Cobalt Chromium stent.
[00016] In an embodiment, a pre-specified concentration of shellac improves release of the drugs.
[00017] In an embodiment, the pre-specified concentration of shellac provides efficient spray coating integrity of the drugs with the implants.
[00018] In an embodiment, burst of the drugs is sustained to be released up to a time span of 30 days.
[00019] In an embodiment, the Stent is coated with Everolimus in a polymer free drug delivery matrix of lipophilic carrier Probucol.
[00020] Other aspects, advantages, and silent features of the invention will become apparent to those skilled in the art from the following detailed description, which, taken in conjunction with the annexed drawings, discloses exemplary embodiments of the invention.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[00021] The above and other aspects, features, and advantages of certain exemplary embodiments of the present invention will be more apparent from the following description taken in conjunction with the accompanying drawings in which:
Figure 1 illustrates a unique combination drug, in an embodiment of the present invention; and
Figure 2 illustrates a manufacturing process, in accordance with an embodiment of the present invention.
Persons skilled in the art will appreciate that elements in the figures are illustrated for simplicity and clarity and may have not been drawn to scale. For example, the dimensions of some of the elements in the figure may be exaggerated relative to other elements to help to improve understanding of various exemplary embodiments of the present disclosure. Throughout the drawings, it should be noted that like reference numbers are used to depict the same or similar elements, features, and structures.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[00022] The following description with reference to the accompanying drawings is provided to assist in a comprehensive understanding of exemplary embodiments of the invention. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary.
[00023] Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness.
[00024] The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purpose only and not for the purpose of limiting the invention as defined by the appended claims and their equivalents.
[00025] It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
[00026] By the term “substantially” it is meant that the recited characteristic, parameter, or value need not be achieved exactly, but that deviations or variations, including for example, tolerances, measurement error, measurement accuracy limitations and other factors known to those of skill in the art, may occur in amounts that do not preclude the effect the characteristic was intended to provide.
[00027] Features that are described and/or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and/or in combination with or instead of the features of the other embodiments.
[00028] It should be emphasized that the term “comprises/comprising” when used in this specification is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
[00029] The present invention discloses a surface modified medical implant coated with an anti-proliferative drug in a non-polymeric drug matrix. The surface modification of the implant acts as a reservoir for a non-polymeric drug coating matrix and thereby, prolongs the drug release from the surface modified implant over the time. The non-polymeric matrix comprises a lipophilic agent Probucol which thereby controls the drug release from the surface modified implant. The non-polymeric matrix also comprising a resin which maintains the coating integrity of the non-polymeric drug matrix over the surface modified implant.
[00030] The non-polymeric drug matrix provides the burst drug release during the first week and then sustain the drug release up to 30 days.
[00031] Figure 1 illustrates a polymer free drug eluting coronary stent system. A first drug is an anti-proliferative drug, and a second drug is a non-polymeric and a highly lipophilic agent acting as a drug carrier. The release of the first drug is controlled by the second drug, and the first and the second drugs are sprayed along with a shellac on the modified surface of the implant. The first drug is Everolimus and the second drug is Probucol. The stent is a Cobalt Chromium metallic platform mounted. The drug delivery system comprises of an Everolimus drug applied in a polymer free drug delivery matrix consisting of a Probucol (matrix builder) and a Shellac resin.
[00032] In an embodiment, the platform stent system of Polymer Free Everolimus eluting coronary stent system is a laser cut Cobalt Chromium (L605) stent. In another embodiment, the stent is constructed of circumferential strut rings that are connected to each other with visible links.
[00033] The surface of stent is modified by sand blasting process to make it porous. The surface has a small porous hole which acts as a reservoir when a drug formulation is coated on the stent. The Pores then allow drug to be released into the tissue over a period. This makes the adhesion of formulation easier and drug delivery more effective.
[00034] In a further preferred embodiment of the invention imperfections such as e.g., burrs are removed before at least a portion of the surface of the stent is roughened. This has the advantage that the surface can be roughened more uniform which leads to better flow dynamics. Thus, less turbulences can occur on the surface which results in a reduction of restenosis.
[00035] According to the invention the surface is modified or roughened to a predetermined extent by sandblasting. Moreover, sandblasting results in an improvement of the fatigue behavior. Further the durability of the stent and the surface bonding can be improved. The rough surface also provides an increased surface area for an attachment of a drug or therapeutic agent. Further a stent with a thinner wall with higher radial force and therefore less material can be achieved which also leads to a decrease of restenosis. With sandblasting the surface can be better controlled and produced and further a more uniform and trauma less surface can be achieved.
[00036] Furthermore, the use of corundum for sandblasting results in a surface which is technically different from a normal sandblasted surface. It has the advantage that less energy must be used and/or less time for this finishing sandblasting than for a sandblasting process to remove burrs. Further the sandblasted surface has less depth regarding the "cavities". Furthermore, the chemical behavior of such a stent is different from commonly known electropolished stents. The surface chemistry is different due to the incorporation of sand particles into the surface. An immediately passivated surface leads to more chemically stable passive layers than surfaces which have been passivated in equilibrium.
[00037] When blasting the surface, the resulting lattice imperfections (e.g. vacancy, dislocation) and further possible phase transitions lead to an increased surface energy and thus to a surface which is chemically more reactive. This can lead to a faster chemical running and/or to additional chemical reactions than in the equilibrium.
[00038] In a further preferred embodiment, the stent is annealed after the surface has been roughened or modified to a predetermined extent to make him more flexible
[00039] According to the invention, the term "coated”, or "coating" means that the implant or part thereof has a layer (either at its surface or below another coating) comprising the given material or the given materials. In general, the thickness of the coating will be in the range of 5 to 15 µm, although the skilled person will appreciate that also other thicknesses could be used.
[00040] In an embodiment, the Stent delivery system is a semi-compliant PTCA balloon catheter. The Stent delivery system is a rapid exchange catheter composed of a proximal single-lumen shaft, a dual lumen distal shaft and a balloon close to the catheter tip. The proximal shaft consists of a stainless steel PTFE coated tube with a proximal end luer-lock connector (hub) for balloon inflation.
[00041] The first drug is Everolimus. In an embodiment, the first drug is used for inhibition of cellular growth at the same time it has anti-inflammatory properties which helps in addressing any adverse response in the coronary artery to any substance or material. In another embodiment, the first drug is delivered through a Polymer Free Drug Delivery matrix to create a formulation which is coated on the stents. The first drug is also known for anti-Inflammatory and anti-Proliferative properties and therefore, controls cells proliferation after stent implantation.
[00042] The second drug is Probucol. The second drug is used as a matrix builder and provides controlled release of drug from the Polymer Free Everolimus Eluting Coronary Stent System. The Polymer Free drug delivery matrix consisting of Probucol with Shellac Resin is used in the medical device. The lipophilic agent (Probucol) retards the drug release leaving a Bare Metal Stent at the end of elution. The second drug acting as a lipophilic agent release from the stent and in turn also control releases the anti-restenotic drug (Everolimus, the first drug). The matrix builder has a high lipophilic profile and enables a rapid absorption by the tissue and minimizing systemic exposure.
[00043] Wax Free shellac is used in the Polymer Free Everolimus Eluting Coronary Stent System as a component which is highly biocompatible. It is used to control the drug loss and drug release from the device. This also supports the Drug release and is a kind of natural polymer. The shellac resin provides the strength to the coating. A pre-specified concentration of shellac provides efficient spray coating integrity of the drugs with the implants
[00044] An ethanol is used as solvent in the drug coating process. The Polymer free drug formulation is prepared in the ethanol which evaporates after the coating process.
[00045] Figure 2 illustrates a manufacturing process for the surface modified implant or a part. In an aspect of preparing the surface modified implant, the first drug and the second drug, along with shellac resin are coated over the surface modified implant.
[00046] Shellac is a brittle or flaky secretion of the lac insect Coccus lacca, found in the forests of Assam and Thailand. When purified, the chemical takes the form of yellow/brown pellets, this possibly providing the basis for the "Wing Source Story." Shellac is a natural polymer and is chemically like synthetic polymers, thus it is considered a natural plastic.
[00047] It can be molded by heat and pressure methods. It is soluble in alkaline solutions such as ammonia, sodium borate, sodium carbonate, and sodium hydroxide, and also in various organic solvents. When dissolved in alcohol, typically blends containing ethanol and methanol, shellac yields a coating of superior durability and hardness and is available in numerous grades. Shellac refined for industrial purposes may either retains its natural wax content or is refined wax-free by filtration. Orange shellac is bleached with sodium hypochlorite solution to form white shellac and is produced in wax-containing and wax-free form.
[00048] Shellac comprises, as main constituents, aleuritic acid and shellolic acid. However, the term "shellac" also comprises analogues and derivatives of shellac as discussed above which may comprise analogues and derivatives of these acids.
[00049] A pre-specified concentration of shellac provides efficient spray coating integrity of the drugs with the implants. In an embodiment, the pre-specified concentration of shellac is in a range of 1.14mg/100ml to 1.16mg/100ml. The pre-specified concentration of shellac provides efficient spray coating integrity of the drugs with the implants. Shellac resin improves the release of the drug during the first week followed by a sustain release of drugs over a period of 30 days as well as a better coating integrity is also accomplished by use of the shellac.
[00050] The first and the second drugs are sprayed along with a shellac on the modified surface of the implant. In an embodiment, the first drug is Everolimus, and the second drug is Probucol. The spray solutions are prepared in ethanol as a solvent.
[00051] A drug release analysis referred herein as determination of drug release from the stent over a period, herein for example 6 days. The drug is released from the coated stent from the surface of the stent over the time. The sample kept in the simulated conditions and sampling from the solution is performed on regular intervals and checked for the drug content present in the solution by High performance liquid chromatography (HPLC).
[00052] Chromatography is a technique to separate mixture of substances into their components based on their molecular structure and molecular composition. This involves a stationary phase (a solid, or a liquid supported on a solid) and a mobile phase (a liquid or a gas). The mobile phase flow through the stationary phase and carries the components with weaker interactions. These differences in rates cause the separation of various components.
[00053] High performance liquid chromatography (HPLC) is basically a highly improved form of a column liquid chromatography having a basic principle of separation from a sample into its constituent parts because of the difference in the relative affinities of different molecules for the mobile phase and the stationary phase during the separation.
[00054] In an exemplary embodiment, the below table 1 shows the composition of the drugs per 100 ml of with the shellac concentration of 0.14% over the stents.
[00055] Figure 3 represents the graphical representation of table 1 and table 2. The shellac concentration is 0.14%. A black dash line represents the total amount of released drug in 6 days and remaining drug for different samples of stents, for example RD-1, RD-2 and RD-3. A blue dash line represents drug release for different samples, for example RD-1, RD-2 and RD-3 after or on 6 days. An orange dash line represents drug content over the stent for different samples, for example RD-1, RD-2 and RD-3 after or on 6 days. Below Table 1 provides the experimental data of the stents, for example RD-1, RD-2 and RD-3 coated with the drug when the shellac concentration is 0.14%. Drug release data is collected every day and till 6 days. Figure 3 which represents graphical representation shows that when the shellac concentration is 0.14%, the sample RD-1 releases 22.09% of the initial drug present at the stents on or after 6 days. Similarly, RD-2 releases 22.63% and RD-3 release 22.00%.

[00056] Experiments 1: 0.14% Shellac
[00057] Experiments 2: 0.16% Shellac
[00058] Experiments 3: 0.18% Shellac
[00059] Figure 4 represents the graphical representation of table 3 and table 4. Experiment 2 is conducted with the shellac concentration of 0.16%. As like above experiment 1, a black dash line represents the total amount of released drug in 6 days and remaining drug for different samples of stents, for example RD-1, RD-2 and RD-3. A blue dash line represents drug release for different samples, for example RD-1, RD-2 and RD-3 after or on 6 days. An orange dash line represents drug content over the stent for different samples, for example RD-1, RD-2 and RD-3 after or on 6 days. In the above Table 2 provides the experimental data of the stents, for example RD-1, RD-2 and RD-3 coated with the drug when the shellac concentration is 0.14%. Drug release data is collected every day and till 6 days. Figure 4 which represents graphical representation which shows that when the shellac concentration is 0.14%, the sample RD-1 releases 19.37% of the initial drug present at the stents on or after 6 days. Similarly, RD-2 releases 19.61% and RD-3 release 19.21%.
[00060] Figure 5 represents the graphical representation of table 5 and table 6. Experiment 3 is conducted with the shellac concentration of 0.18%. As like above experiments 1 & 2, a black dash line represents the total amount of released drug in 6 days and remaining drug for different samples of stents, for example RD-1, RD-2 and RD-3. A blue dash line represents drug release for different samples, for example RD-1, RD-2 and RD-3 after or on 6 days. An orange dash line represents drug content over the stent for different samples, for example RD-1, RD-2 and RD-3 after or on 6 days. In the above Table 2 provides the experimental data of the stents, for example RD-1, RD-2 and RD-3 coated with the drug when the shellac concentration is 0.14%. Drug release data is collected every day and till 6 days. Figure 4 which represents graphical representation which shows that when the shellac concentration is 0.14%, the sample RD-1 releases 16.02% of the initial drug present at the stents on or after 6 days. Similarly, RD-2 releases 16.35% and RD-3 release 17.99%.
[00061] As summary, with shellac concentration of 0.14%, release of drugs is 22.24% (withing 6 days), 69.38% remaining drug over the stents, and total drug release + remaining drug over the stents are 91.62%
[00062] With shellac concentration of 0.16%, release of drugs is 19.40% (within 6 days), 68.43% remaining drug over the stents, and total drug release and remaining drug over the stents are 87.83%.
[00063] With shellac concentration of 0.18%, release of drug is 16.79% (within 6 days), 66.06% remaining drug over the stents, and total drug release and remaining drug over stents are 82.60%.
[00064] Figure 6 represents the graphical representation of the release of drugs at concentration of shellac 0.14%, 0.16% and 0.18%. The conclusion stands that the shellac with 0.14% has a better release than all the higher concentration. Thus, it is desired to have a concentration of 0.14% of shellac coated on the stents or lower.
[00065] While few embodiments of the present invention have been described above, it is to be understood that the invention is not limited to the above embodiments and modifications may be appropriately made thereto within the spirit and scope of the invention.
[00066] While considerable emphasis has been placed herein on the particular features of this invention, it will be appreciated that various modifications can be made, and that many changes can be made in the preferred embodiments without departing from the principles of the invention. These and other modifications in the nature of the invention or the preferred embodiments will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.
,CLAIMS:We claim:
1. A surface modified implant or a part thereof, comprising:
a first drug is an anti-proliferative drug, and
a second drug is a non-polymeric lipophilic agent,
wherein the release of the first drug is controlled by the second drug, and
wherein the first and second drugs are sprayed on the surface modified implant or a part thereof.
2. The surface modified implant as claimed in claim 1, further comprising:
a first solution of the first drug and the second drug, and
a second solution comprising the first drug and a shellac,
wherein the first solution is sprayed coated over the surface modified implant and sequentially spraying the second solution over the surface modified implant.
3. The surface modified implant as claimed in claim 1, further comprising:
a third non-polymeric solution of the first drug, the second drug and a shellac sprayed coated over the surface modified implant.
4. The surface modified implant as claimed in claim 1, wherein the first drug is Everolimus and the second drug is Probucol.
5. The surface modified implant as claimed in claim 1, wherein the implant is made up of a metal.
6. The surface modified implant as claimed in claim 1, wherein the implant is valve, a dental implant, a stent or an orthopedic implant system.
7. The surface modified implant as claimed in claim 2, wherein the first, the second, or the third solutions are prepared in ethanol as a solvent.
8. The surface modified implant as claimed in claim 2, wherein a pre-specified concentration of shellac improves release of the drugs.
9. The surface modified implant as claimed in claim 8, wherein the pre-specified concentration of shellac is 0.14 % or lower.
10. The surface modified implant as claimed in claim 8, wherein the pre-specified concentration of shellac is 0.14%.
11. The surface modified implant as claimed in claim 2, wherein a pre-specified concentration of shellac provides efficient spray coating integrity of the drugs with the implants.
12. The surface modified implant as claimed in claim 11, wherein the pre-specified concentration of shellac is 0.14% or lower.
13. The surface modified implant as claimed in claim 2 and 3, wherein burst of the drugs is sustained to be released up to a time span of 6 or more days.
Dated this 21 April 2023
----------DIGITALLY SIGNED--------- APPLICANT Translumina Therapeutics LLP