MX2008009020A - Pharmaceutical compounds that contain nanoparticles useful for treating restenotic lesions - Google Patents

Abstract

Pharmaceutical compounds that contain nanoparticles useful for treating restenotic lesions are herein described containing nanoparticles of rapamycin (sirolimus) or analogues and/or nanoparticles of paclitaxel or analogues alone or together, mentioned nanoparticles with or without cationic coating.

Description

PHARMACEUTICAL COMPOUNDS CONTAINING USEFUL NANOPARTICLES FOR THE TREATMENT OF REASSENESSAL LESIONS FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions containing nanoparticles useful for the treatment of restenotic lesions. More specifically, it comprises pharmaceutical compounds containing nanoparticles, nanocapsules, liposomes or nanotubes and one or more cellular antiproliferative agents with or without a cationic coating for the treatment of restenotic lesions.

BACKGROUND OF THE INVENTION The development of restenosis can be observed angiographically and is defined as a reduction of the coronary luminal diameter that occurs after the dilation of an obstruction.

To prevent vessel closure, tubular metal devices known as stents (expandable stent) are implanted. This technique greatly reduces the problem of restenosis, but does not prevent it from existing. The blood flow at the end is damaged due to a blockage of the coronary artery after the stent has been implanted due to the excessive and disorganized proliferation of endothelial fat cells and muscle cells within the stent.

Thus, restenosis occurs in approximately 25% of cases of stent implants without drug coating, this rate can be raised to 50%, in accordance with the clinical and angiographic characteristics of the obstructive lesion and coronary arteries to be treated by the patient.

Redenal studies have shown that the rate of restenosis can be significantly reduced by implanting stents coated with drugs capable of inhibiting neointima proliferation for a few weeks.

Although these stents reduce restenosis to 8%, which is the smallest rate ever achieved by a coronary device in the coronary artery, restenosis persists and constitutes a serious problem and for which it is difficult to find a solution. In addition, the high cost of the drug-coated stent limits its regular use in most countries.

Several techniques were used to treat restenosis within the stent, such as balloon balloon catheter angioplasty, cutting balloon, directional atherectomy, and laser. All these techniques represent high costs, high high complexity and do not present better results than the balloon catheter, which is the simplest and cheapest option.

Brachytherapy with beta and gamma radiation has also been widely studied as a technique for the treatment of restenotic lesions. The initial results were promising, but a loss of the initial result was observed over time, which gives this technique a palliative effect.

Other negative aspects of this technique are the very high costs and its logistics, because there is a need for a specialist in brachytherapy during the procedure and radioactive sources for short periods as well as protection and isolation of areas in case of using gamma radiation. Therefore, currently, brachytherapy is a technique almost extinct.

The use of the stent coated with antiproliferative medicine constitutes the best therapeutic strategy nowadays to treat restenotic lesions with a recurrence rate between 14 and 22% - However, the high cost and results not as satisfactory as those presented with the use of this drug-coated stent in the treatment of new lesions, without treatment injuries, limit the wide use of this therapeutic strategy.

The administration of rapamycin orally was also studied and presented a rate of restenosis of approximately 22% with the use of high doses. The costs are reasonable, but the results are not so satisfactory.

Rapamycin or sirolimus is a potent cellular antiproliferative agent that acts in the G1-S phase of the cell cycle. It also has antibiotic, fungicide and immunosuppressive properties.

As a cellular antiproliferative agent, it has been used in coronary stents, providing a significant reduction in rates of neointima hyperproliferation within the stent called restenosis. This cellular antiproliferative effect was demonstrated in several in vitro studies and in animals and humans.

The literature of the technique presents products and methods, which, although they reduce the rate of new restenosis within the stent, do not present satisfactory medium and long-term results. Thus, there is a need for the development of a method that presents better results such as the local infusion of nanoparticles containing one or more cellular antiproliferative drugs with or without cationic coating.

Thus, the literature of the art neither discloses nor suggests medicated compounds containing nanoparticles at least one active cellular antiproliferative agent such as for example rapamycin (sirolimus) or analogs and paclitaxel or the like, with or without a cationic coating for the treatment of restenotic lesions. These compounds are described and claimed in the present application.

In general, the present invention relates to medicinal compounds containing nanoparticles useful for the treatment of restenotic lesions, and comprises rapamycin nanoparticles (sirolimus) or analogs and / or paclitaxel nanoparticles or the like, alone or together with the aforementioned nanoparticles, with or without cationic coating.

Nanoparticles containing one or more cellular antiproliferative agents for local infusion for the treatment of restenotic lesions within the stent are a feature of the invention.

A method of administering rapamycin or analogues and / or paclitaxel and the like, alone or together that constitutes a lower cost of the procedure compared to other techniques for the treatment of restenosis is a feature of the invention.

A simple execution method is a feature of the invention.

DETAILED DESCRIPTION OF THE INVENTION The nanoparticles useful for the treatment of restenotic lesions, the object of the present invention, comprise nanoparticles of rapamycin (sirolimus) or analogs or nanoparticles of paclitaxel or the like, alone or together, said nanoparticles with or without cationic coating.

The cationic coating aims to increase adhesion, penetration and diffusion of nanoparticles that contain at least one medicine cellular antiproliferative in tissue responsible for neointima hyperplasia since the cells have negative electrical charge and the nanoparticles have charge positive.

Optionally, nanocapsules, liposomes or nanotubes are used.

The solution with nanoparticles of rapamycin or analogs is instilled in a dose comprising intervals of 10 to 500 Ug / cm2 of the surface of the stent and preferably 80 to 240 Ug / cm2 of the surface of the stent.

The rapamycin analogues (sirolimus) are: Biolimus, Everolimus, Zotarolimus and Mitomycin.

The paclitaxel analogs comprise docetaxel.

The method consists in the infusion of rapamycin nanoparticles or analogs and / or paclitaxel or analogues alone or together, into the wall of the coronary artery through a specific catheter for local infusion of the medicine. This procedure should be done after dilating the stent with a conventional balloon catheter.

The local infusion of nanoparticles containing one or more cellular antiproliferative agents constitutes a therapeutic strategy, technically of the same technical execution, potentially efficient and economically viable for the treatment of restenotic lesions within the stent.

To evaluate the results obtained from these compounds in the treatment of restenotic lesions, a study was carried out on pigs in the following manner: Two solutions of nanoparticles containing rapamycin were prepared in a bioabsorbable polymer. A solution with and without cationic coating.

Twelve commercially available stents with measurements of 3.0 x 16.0 mm were implanted with high pressure in the anterior descending coronary artery (2.75 mm in diameter) in six pigs, where two stents were implanted in the coronary artery, one in the transition of the next third and another in the middle third.

In 30 days all pigs were studied with cineangiocoronary angiography and intercoronary ultrasound, which showed evident restenosis (obstruction greater than 50%) in all previously implanted stents. Next, angioplasty with a conventional balloon catheter measuring 3.0 x 16.0 mm in all stents followed by local infusion of rapamycin nanoparticles without cationic coating with a medicine infusion catheter in four stents and coated nanoparticles was carried out. cationic in the other four.

In 60 days, all pigs were studied with coronary angiography and coronary ultrasound, which showed stenosis with an average area of 63% in stents treated only with conventional angioplasty, 20% in stents treated with rapamycin nanoparticles without cationic coating, and 18 % in stents treated with rapamycin nanoparticles with cationic coating.

The results obtained have demonstrated the satisfactory local effect of the local infusion of rapamycin nanoparticles with or without cationic coating in the prevention of recurrent episodes of restenosis after the treatment of restenosis within the stent. There are no significant differences in the use of rapamycin nanoparticles with cationic coating in relation to rapamycin particles without cationic coating, but there is a small advantage that favors nanoparticles with cationic coating.

Claims (6)

CLAIMS:

1. PHARMACEUTICAL COMPOSITIONS CONTAINING USEFUL NANOPARTICLES FOR THE TREATMENT OF REESTENOTIC LESIONS characterized by comprising nanoparticles of rapamycin (sirolimus) or analogues and / or paclitaxel nanoparticles or analogues alone or together, said nanoparticles with cationic coating.

2. PHARMACEUTICAL COMPOSITIONS CONTAINING USEFUL NANOPARTICLES FOR THE TREATMENT OF REASSENSEAL LESIONS characterized by comprising nanoparticles of rapamycin (sirolimus) or analogues and / or paclitaxel nanoparticles or analogues alone or together, said nanoparticles without cationic coating.

3. PHARMACEUTICAL COMPOSITIONS CONTAINING USEFUL NANOPARTICLES FOR THE TREATMENT OF REASSENTIONAL LESIONS according to Claims 1 and 2, characterized by the optional use of nanocapsules, liposomes, nanotubes.

4. PHARMACEUTICAL COMPOSITIONS CONTAINING USEFUL NANOPARTICLES FOR THE TREATMENT OF REASSENTICAL LESIONS according to Claims 1 and 2, characterized in that the rapamycin analogues are chosen from Biolimus, Everolimus, Zotarolimus and Mitomicin.

5. PHARMACEUTICAL COMPOSITIONS CONTAINING USEFUL NANOPARTICLES FOR THE TREATMENT OF REASSENTICAL LESIONS according to Claims 1 and 2, characterized in that the paclitaxel analog comprises docetaxel.

6. PHARMACEUTICAL COMPOSITIONS CONTAINING USEFUL NANOPARTICLES FOR THE TREATMENT OF REASSENTICAL LESIONS characterized by comprising the infusion of rapamycin nanoparticles or analogues and / or paclitaxel or analogues alone or together, into the wall of the coronary artery through a specific catheter for local infusion of Medicine.