MX2008008679A - Coronary stent that releases medicamentuous composition to prevent and treat restenosis and fabrication process - Google Patents

Abstract

A stent is described that releases medicamentous composition to prevent and treat restenosis and the fabrication process that comprehends between 10,0 to 500,0 Ug/cm2 of the surface of the stent coated with rapamycin (sirolismus) or analogous and between 0,01 to 20,0 Ug/mm2 of the surfaceof the stent coated with paclitaxel or analogous.

Description

CORONARY EXPANSIBLE ENDOPROTESIS THAT RELEASES A MEDICINAL COMPOSITION FOR PREVENTION AND TREATMENT OF REESTENOSIS FIELD OF THE INVENTION This invention relates to an expandable stent for coronary artery that has a drug composition for the prevention and treatment of restenosis. More specifically, it comprises a coronary artery stent that releases a drug composition that includes a synergistic combination of rapamycin or its analogues, and paclitaxel or its analogues and that inhibits cell proliferation and, consequently, restenosis.

BACKGROUND According to the health authorities, half of the deaths registered worldwide are the result of coronary heart disease. Faced with the seriousness of the problem, scientists from around the world devote a large proportion of their time to the formulation of drugs and more effective methods to deal with these diseases.

The introduction of stent implants in the coronary arteries has been the second largest step in the treatment of percutaneous coronary artery disease obstructive since the introduction of balloon angioplasty. The stent implant almost completely inhibits the abrupt closure of vessels and has significantly reduced late restenosis with the elimination of acute vascular retraction of the vessel and, in particular, the chronic negative remodeling of the vessel.

The first stents were rudimentary, which caused problems in the correct implant, and a high rate of subacute thrombotic occlusions. Since then the technology of the stents has improved significantly, resulting in more flexible stents, with a lower profile and, therefore, easier placement. Today, stenting is a safe and predictable procedure. The need for emergency rescue surgeries has been significantly reduced, allowing percutaneous treatment of a wide variety of obstructive coronary lesions.

However, focal or diffuse hyperplasia of the neointima can occur within the stent, which causes clinically significant obstructions in 15% to 20% of cases. Post-implant obstruction occurs due to the appearance of excessive scars throughout the stent structure. This metallic mesh causes a serious trauma in the coronary tissue and a strong immunological reaction in the bodies of some patients. The result is the renewal of thinning of the vessel.

A method of managing the occurrence of stent thrombosis and late restenosis in the stent could be an increase in blood compatibility and stent tissue through stent coatings that could be passive or active. Passive coatings such as those of polymers or inorganic coatings offer a biologically inert barrier between the surface of the stent, the wall of the blood vessel and the circulating blood, in an attempt to decrease anti-inflammatory responses and prevent thrombosis in the stent. Hyperplasia of the neointima. Active coatings are biologically active because they contain drugs (heparin, paclitaxel or rapamycin) that are released in certain doses to prevent the occurrence of thrombosis or restenosis.

Rapamycin or sirolimus is a powerful antiproliferative agent that acts in the G1-S phase of the cell cycle. It also has antibiotic, fungicide and immunosuppressant activities. As an antiproliferative agent, it has been used in coronary stents providing a significant reduction in the rates of neointima hyperproliferation in the stents, ie reobstruction after stent implantation as a result of the disordered and excessive proliferation of endothelial and smooth muscle cells. inside the stent.

Paclitaxel is a cellular antiproliferative agent that acts at the end of the cell cycle in the G2-M phase. Developed as an antineoplastic drug, it is now used in coronary stents due to the effectiveness in reducing the rates of restenosis in stents.

Patent WO03037397 describes a composition impregnated in a stent comprising at least one bioabsorbable polymer such as for example polyester and a therapeutic substance such as for example sirolimus, actinomycin-d and paclitaxel.

The patent US2004432226 describes a stent impregnated with a drug with anti-restenotic characteristics chosen from the group including alcerán, cytoxan, leucerán, cis-platino, bicnu, adriamycin, doxorubicin, cerubidine, idamicin, mitracín, mutamicín, fluorouracil, methotrexate, toguanina, toxotere, etoposide, vincristine, irinotecan, hicampatin, matulan, vumon, hexalin, hydroxyurea, gemzar, oncovin, etofophos, tacrolimus (fc506) and the following rapamycin analogues: sdz-rad, cci-779, 7-epi-rapamycin, 7 -epi-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy, 2-demethyl and proline.

Patent WO2004110302 describes a method for reducing the level of restenosis by placing a stent with continuous administration of a dose of an anti-restenotic agent, such as paclitaxel.

CA2269310 discloses a method for delivering rapamycin locally, in a stent body or mixed or limited to a coating of a polymer applied in a stent to prevent restenosis.

US2003176915 describes a stent containing rapamycin mixed or limited to a polymer coating to prevent restenosis.

US2005085902 describes a method of treatment for cardiovascular disease by implanting a stent that releases rapamycin.

Patent US200410030379 describes an implantable medical device with an active agent that includes rapamycin, tacrolimus, everolimus and paclitaxel.

Patent WO2005018702 describes a medical device that includes two or more active agents or more layers of polymers where the second active agent is chosen from several active agents such as for example rapamycin, paclitaxel, everolimus, docetaxel or their combination.

Patent US20050163818 describes an implantable medical device where the bioactive agent is chosen from several active agents such as for example paclitaxel, sirolimus, rapamycin, everolimus and docetaxel.

Patent US20040254634 describes a device in which the active agent is selected from the group consisting of rapamycin, everolimus, paclitaxel, docetaxel, among others.

Thus, the use of endostents (expandable endoprostheses) impregnated medications constitutes the most significant advance in the change of interventional cardiology. The technical literature presents coronary stents impregnated with rapamycin and the like, and / or paclitaxel and analogues that caused the reduction in rates of restenosis from 25 to 30% in stents without impregnation of drugs at 7-8% in drug-impregnated stents.

Although the technical literature describes coronary stents that although partially solve the problem of neointima hyperproliferation within the stent by releasing a drug composition that includes a first active agent chosen from rapamycin and analogues and a second active agent chosen from paclitaxel or analogues, a synergistic combination effective in inhibiting cell proliferation is provided by means of a specific concentration of the active agents of the formulation.

Thus, the open literature does not describe or suggest a coronary stent that releases a drug composition for the prevention and treatment of restenosis that includes the combination of rapamycin or analogs and paclitaxel or the like in a concentration that generates a dramatic consequence in the effectiveness of the formulation that acts in different phases of the cell cycle, such as for example a coronary stent that releases a medicated composition that is described and claimed in this application.

In general, this invention relates to a stent (expandable stent) that releases a drug composition for the prevention and treatment of restenosis comprising from 18.0 to 1200.0 micrograms / stent of rapamycin or the like and from 10.0 to 400.0 micrograms / stent of paclitaxel or analogs where the combination of these two active agents in established concentrations generates a dramatic consequence in the effectiveness of the formulation.

One of the concentrations of the invention comprises a coronary stent impregnated with the two active cellular antiproliferative agents that act in different phases of the cell cycle.

DETAILED DESCRIPTION OF THE INVENTION The technical literature describes that rapamycin or analogues specifically acts on the G1-S phase of the cell cycle while paclitaxel or analogs inhibit the cell cycle by acting on the G2-M phase of the cell cycle.

The combination of these two active agents, rapamycin or analogs and paclitaxel or analogs in the concentrations established in this invention generated a dramatic consequence in the effectiveness of the formulation.

The coronary stent that releases a drug composition for the prevention and treatment of restenosis, subject matter of this invention, comprises from 18.0 to 1200.0 micrograms / stent of rapamycin or the like and from 10.0 to 400.0 micrograms / stent of paclitaxel or the like.

The ranges established in this medicinal composition, the subject matter of this invention, take into consideration the different diameters and extensions of the coronary stents.

The active agents rapamycin analogs are chosen from biolimus, everolimus, tacrolimus, zotarolimus and pimecrolimus Paclitaxel analogues are chosen from docetaxel.

The tests carried out in pigs demonstrated the effectiveness of the combination of rapamycin or analogs and paclitaxel or analogues in the concentrations established in this invention, in the coating of coronary stents for the prevention of restenosis.

Sixteen commercially available coronary stents 3.0 x 18 mm were used in the study: (a) three of them were coated with a reabsorbable polymer and rapamycin at a dose of from 18.0 to 1200.0 micrograms / stent; (b) three of them were coated with a resorbable polymer and paclitaxel at a dose of from 10.0 to 400.0 micrograms / stent; (c) three of them were coated with a resorbable polymer, rapamycin or the like at a dose of from 18.0 to 1200.0 micrograms / stent and paclitaxel or the like in a dose of from 10.0 to 400.0 micrograms / stent; (d) three of them were coated with any active agent without polymer; (e) three of them were coated with a resorbable polymer, rapamycin at a dose of 5.0 to 18.0 micrograms / stent and paclitaxel at a dose of 5.0 to 10.0 micrograms / stent; and (f) three of them were coated with a resorbable polymer, rapamycin at a dose of from 1200.0 to 3000.0 micrograms / stent and paclitaxel at a dose of from 400.0 to 2000.0 micrograms / stent.

Eight pigs with a left anterior descending artery and a circumflex artery with an approximate diameter of 2.75 mm were submitted to the implantation of the aforementioned stents by means of fluoroscopy. The stents were implanted in the amount of one stent per coronary artery to give a total of 2 stents per 1 pig in random combinations. The use of two stents with the same coating in the same pig was not allowed. At the end of the procedure an angiography and intravascular ultrasound control was done to analyze the expansion and the position of the stent, as well as to evaluate the minimum luminal diameter and the minimum luminal area.

In 90 days the pigs were studied again by means of coronary angiography and with intravascular ultrasound to evaluate the intra-stent restenosis and the neointima proliferation. The results of the late loss (LL) and stenosis diameter (SD) for each stent were calculated, the average of these results for each stent group was calculated as follows. shows in Table 1.

TABLE I: Results of late loss and stenosis diameter in coronary stents.

The results obtained demonstrate the superiority of coronary stents coated with a polymer and an active agent in relation to uncoated stents, which are already known in the state of the art. However, they also show the best results of the combination of the two active agents, rapamycin or analogs and paclitaxel or analogues, in the concentrations established in this invention, as demonstrated in point c, with respect to the isolated use of rapamycin or of paclitaxel in the coronary stents coating as shown in points a and b.

In situations of coronary stents coating with formulations comprising rapamycin in a dose of 5.0 to 18.0 micrograms / stent and paclitaxel in a dose of 5.0 to 10.0 micrograms / stent, no significant effect was seen in the inhibition of cell proliferation, as shown in point e.

In the situations of the coronary stents coating with formulations comprising rapamycin in a dose of from 1200.0 to 3000.0 micrograms / stent and paclitaxel in a dose of from 400.0 to 2000.0 micrograms / stent, a toxic effect and an inflammatory reaction exacerbated with a consequent increase in neointima hyperplasia, as shown in point f.

Thus, the coronary stent that releases a drug composition comprising rapamycin or analogs between 18.0 and 1200.0 micrograms / stent and paclitaxel or analogs between 10.0 and 400.0 micrograms / stent showed a dramatic reduction in neointima proliferation, which highlights the effectiveness of the formulation that acts synergistically in different phases of the cell cycle.

Claims (1)

1. CLAIMS CORONARY STENT THAT RELEASES A MEDICINAL COMPOSITION FOR THE PREVENTION AND TREATMENT OF REESTENOSIS, characterized by comprising from 18.0 to 1200.0 micrograms / stent of rapamycin or the like and from 10.0 to 400.0 micrograms / stent of paclitaxel or the like. THE CORONARY STENT THAT RELEASES A MEDICINAL COMPOSITION FOR THE PREVENTION AND TREATMENT OF REESTENOSIS according to claim 1, characterized in that the rapamycin analogues are chosen from biolimus, everolimus, tacrolimus, zotarolimus or pimecrolimus. THE CORONARY STENT THAT RELEASES A MEDICINAL COMPOSITION FOR THE PREVENTION AND TREATMENT OF REESTENOSIS according to Claim 1, characterized in that the paclitaxel analogues are chosen from docetaxel.