FR3068233A1 - INTRA-ARTERIAL MEDICAL DEVICE AND APPLICATIONS - Google Patents

Abstract

The invention relates to an intra-arterial medical device comprising an active ingredient selected from bisphosphonates and its applications in the treatment of atherosclerosis.

Description

The invention relates to an intra-arterial medical device comprising an active principle, and its applications, in particular in the prevention and treatment of certain cardiovascular diseases, and in particular atheroma or atherosclerosis.

The atheroma which can affect all the arteries is a process of progressive thickening and invasion of the arterial lumen leading to its narrowing, called stenosis, and which can lead to its obstruction, called thrombosis, and then cause a defect. blood supply to the organ to be supplied with oxygenated blood. This phenomenon results from a deposit by accumulation of different elements, namely fatty substances, derivatives or blood constituents, but also minerals of which the majority is calcium. It is now established that arterial calcifications are present from the early stages of the disease and strongly influence the mechanical behavior of the atheroma plaque.

An artery consists of three tunics, the intima which is in direct contact with the blood circulation, the media which gives elasticity to the artery and the weed at the periphery. In the atheroma process, two types of calcification are distinguished according to their location in the artery.

The first calcifications are localized at the level of the intima and are very closely associated with atherosclerosis since 90% of atherosclerotic plaques carry calcification. This type of calcification will occasionally introduce rigid mineral elements into a predominantly lipidic and therefore soft lesion. This situation generates a mechanical imbalance of the plaque favoring its rupture and consequently, the risks of thrombosis, tearing of the wall of the artery or arterial dissection, and emboli.

The second calcifications, also known as Mônckeberg sclerosis, are located at the level of the media. They are particularly associated with advanced age, diabetes and chronic renal failure. They cause the arterial wall to stiffen. At the aortic level, they favor the occurrence of arterial hypertension and left ventricular insufficiency and at the level of the vessels of smaller caliber, they generate a insufficiency of the irrigated organ by alteration of the distal vascularization.

Often these two types of calcification coexist.

The populations affected by these pathologies are people over 55 years of age from Western countries in whom a prevalence of obliterating arterial disease of the lower limbs (AOMI) of 10 to 20% is observed, but also patients with chronic renal failure on dialysis. It has also been found that patients with osteoporosis or demineralizing inflammatory arthropathy develop more arterial calcifications than the general population. Certain rare genetic diseases, such as the disease called ACDC (Arterial Calcification due to Deficiency in CD73) due to a mutation in the NT5E gene coding for the protein CD73, are characterized by the development of massive arterial calcifications. Patients with this mutation develop major calcified arterial lesions in the lower limbs, starting at their thirties.

AOMI represents a real public health problem. Indeed, the vascular mortality associated with this pathology is major with 18 to 30% of deaths at 5 years. In a patient with critical ischemia, the risk of mortality at one year is 25% and the risk of amputation 30%.

These calcifications also have a major clinical impact. In open surgery, their presence in large quantities can make it difficult, if not impossible, to bypass the lower limbs. In endovascular surgery, their presence increases the difficulties of crossing lesions and increases the risk of complications such as perforation of vessels or dissection, as well as the risk of technical failure. By modifying the mechanical characteristics of the vessels, calcifications also promote the occurrence of stent fractures.

The most common endovascular treatment for atherosclerotic plaques is angioplasty with or without a stent. It involves introducing a balloon or balloon into an artery, inflating it to dilate the area of the atheromatous artery, and leaving a stent in place, if necessary. This treatment is generally combined with medical treatment with an antiplatelet agent to thin the blood, and / or with a lipid-lowering agent to lower cholesterolemia and / or with an antihypertensive agent. To date, there is no specific treatment for arterial calcifications, research efforts being concentrated on the lipid component of atheroma plaque and on the problem of restenosis after stenting.

The invention provides an effective solution by the local treatment of calcium plaques and which can be implemented simply, whatever the patient's condition, and having no side effects.

This solution consists of an intra-arterial medical device comprising an active principle which will destroy the calcium plaque. According to the invention, the active principle is chosen from bisphosphonates and bisphosphonate salts.

By intra-arterial device is meant any device intended to be implanted in an artery, to remain there or not, including any device which can be absorbed in part or in whole.

Biphosphonates are compounds which correspond to the following formula I:

O

RI 1 X X / \ X ori Λ U UH ρζ R2 1 OH O (D

in which RI represents hydrogen, a hydroxyl group or a halogen and R2 represents a hydroxyl group, a halogen or a carbon group having on the order of 1 to 10 carbon atoms, saturated or unsaturated, linear, cyclic and / or branched, which can comprise at least one heteroatom chosen from nitrogen, oxygen, sulfur, phosphorus and halogens.

In the definition above, the choice of RI and R2 is made so that they contribute to an affinity of the bisphosphonate for calcium.

This definition includes, in particular, etidronic acid, chlodronic acid, tiludronic acid, pamidronic acid, alendronic acid, risedronic acid, ibandronic acid, zoledronic acid.

The bisphophonate salts are advantageously chosen from metal and in particular disodium salts of bisphosphonates, and in particular of any of the abovementioned acids.

Some bisphosphonates are known as a drug, they are administered orally or parenterally. Thus, etidronate, alendronate, risedronate are prescribed in the treatment of osteoporosis. Etidronate is also indicated for the treatment of Paget's disease, as well as for the prevention of bone loss in patients requiring prolonged corticosteroid therapy. Others, such as pamidronate or zoledronate are used to treat hypercalcemia.

According to an implementation of the invention, the device also comprises at least one other active principle. As an example, it is paclitaxel.

From a pathophysiological point of view, the formation of arterial calcifications does not result from a passive mechanism but on the contrary responds to a highly regulated phenomenon, not yet fully understood, and which has many similarities with the regulation of bone tissue. It has been observed in patients with chronic renal failure, a simultaneous progression of bone mineral loss and the development of arterial calcifications, as the renal function declines.

This regulatory mechanism is probably one of the essential factors responsible for the limited effectiveness of bisphophonates administered systemically for the treatment of hypercalcemia. This limit is perfectly illustrated by the example of a rare genetic disease, Generalized Arterial Calcification of Infancy (GACI). This disease leads to the death, a few days after birth, of affected children, due to infarction, multivisceral failures and aortic dissections, resulting from massive calcifications of the coronary arteries and the proximal aorta. For the sake of compassion, etidronate has been administered to certain children with encouraging results, these attempts having enabled child survival and the almost complete regression of calcifications. However, this success was acquired at the cost of bone deformations not compatible with normal life.

The invention provides a treatment for calcium plaques, based on bisphosphonates, which does not have the aforementioned drawbacks of the treatments administered systemically. The authors discovered that a local delivery on the most significant atheromatous lesions, of a bisphosphonate in high dose, allows to punctually destroy these lesions thanks, on the one hand, to a physicochemical process during which the bisphosphonate fixed on the calcium components of these lesions and, on the other hand, to a biological process, during which the bisphosphonate-calcium component complex thus formed is phagocytosed by the cells of the arterial wall of the smooth muscle and macrophage type. Interestingly, the solution of the invention overcomes the regulatory phenomenon described above which could have caused undesirable effects on bone metabolism.

The device of the invention advantageously comprises a bisphosphonate chosen from etidronic acid, chlodronic acid, tiludronic acid, pamidronic acid, alendronic acid, risedronic acid, ibandronic acid, acid zoledronic, or chosen from the salts of any of these acids, or any mixture of these acids and / or these salts. These bisphosphonates are effectively known in oral or parenteral administration, and therefore have no contraindication in local intraarterial administration according to the invention. In a preferred implementation of the invention, the active principle is etidronate disodium.

The device can be in any suitable form enabling the above active ingredient to be delivered locally to / in an atheromatous plate or on / in a calcium plate. The technologies of balloons and stents well known to those skilled in the art are perfectly suitable for implementing the invention.

In the prevention of restenosis which intervenes quickly after the placement of a stent, stents or balloons are used comprising an antiproliferative active principle which prevents the proliferation and cell migration phenomena which cause restenosis. However, this technology has never been used for the local treatment of the calcium component of the atheroma according to the invention which can be supplemented by the physical action of the stent or balloon. The invention furthermore includes any device comprising, in addition to one or more bisphosphonates, an antiproliferative active principle for preventing restenosis in the treated artery, such as paclitaxel.

The active principle according to the invention is fixed by any method of connection to the device. Obviously, an optimal fixation will be sought, making it possible to bring the active principle to the site to be treated in the artery and to release it in contact with the lesion. The effect of the active ingredient on an active balloon mainly results from the efficiency of its transport and distribution to the arterial wall during the inflation time of the balloon against the wall. Ideally, the greatest amount of active ingredient possible should be transferred during the 30-60 seconds that the inflation of the balloon lasts and during which it is in contact with the wall. Thus, the device advantageously comprises a matrix in which said active principle is incorporated and from which it can be released in contact with an arterial wall. By incorporation into the matrix, it is understood any fixation such as by adsorption, by absorption, by more or less fragile physicochemical bond, direct or indirect involving for example coupling, by encapsulation.

Lipophilic components naturally having a greater propensity to cross the hydrophobic barrier of the endothelial cell layer of the vessels, the matrix is preferably chosen from lipophilic polymers and phospholipids.

Given the cellular biological phenomenon described above in which the bisphosphonate-calcium component complex is phagocytosed, a preferred matrix is of phospholipid nature, and better still constituted by liposomes, in particular nanoliposomes. Bisphosphonates effectively have the capacity to associate with liposoluble molecules to form complexes which are particularly suitable for the technology of the invention.

The device can also comprise any excipient conventionally used by the manufacturers of active balloons and stents. It is judiciously chosen in order to be able to retain the active principle on the balloon during navigation of the balloon in the arterial network to the lesion site, then to allow the homogeneous and effective transfer of the active principle towards the arterial wall. Examples of such excipients are iopromide, urea, butyryl-trihexyl-citrate, polysorbates, sorbitol, dextrans, hydrogels, polyethylene glycol.

Advantageously, the concentration of active principle (s) on the device ranges from 3 to 9 pg / mm ² . When the device comprises a matrix, the weight ratio of the active ingredient (s) to the matrix is at least 0.1 and / or at most 0.5.

The invention also relates to a method of manufacturing a device of the invention. It comprises the step of coating a device without the active principle, but preferably of a matrix in which the bisphosphonate active principle is distributed, everywhere means in particular by micropipettage or by spraying (spray-coating). As said previously, this technology is known to a person skilled in the art who may refer in particular to that applied to the manufacture of balloons activated with paclitaxel.

For the preparation of bisphosphonate liposomes, those skilled in the art may also refer to the article by D. Gutman et al, Journal of Controlled Release 161 (2012) 619-627 describing the preparation of alendronate liposomes. The liposome-biphosphonate matrix can be produced in the form of a film, then extruded and deposited on a balloon. The active principle weight ratio is of the order of 1: 3 to 1: 5. The size of the particles is determined so as to allow the internalization of the particles by the monocyte-macrophages and to allow the particles to be easily sterilized. It is preferably between 80 and 200 nm. The negative charge of the particles also promotes their absorption by the arterial wall.

In addition to its ability to locally destroy atheromatous plaques, a device according to the present invention has a double effect, as explained below.

It limits the occurrence of restenosis:

Following endovascular treatment of an atheromatous lesion, monocyte-macrophage type cells accumulate at the treated site due to the initiation of an inflammatory mechanism. Their effect, through phagocytosis and the secretion of mediators of inflammation, is to protect the organism from external aggression. However, their accumulation in excess can have a deleterious effect and maintain or even aggravate the effects of inflammation. This is what happens when there is a post-angioplasty restenosis and placement of a stent. The biphosphonates which are analogues of pyrophosphates, once delivered to the site of the angioplasty will be phagocytosed by cells of the monocyte macrophage type and accumulate at the intracellular level, causing apoptosis of these cells. This depletion of monocyte-macrophages will have a beneficial inhibitory effect on the occurrence of restenosis.

It also makes it possible to prevent the development of subsequent calcifications:

By attaching to the crystals, biphosphonates prevent their aggregation and growth. At high doses, their effect is to prevent the development of calcifications and reversion effects have been observed in vivo and in vitro.

The invention has the advantage of implementing a known technology for the purposes of treatment, but also of prevention, of atheroma, but which had never been envisaged in the context of this disease. The use of bisphophonate leads to effective treatment and prevention, doubled by effects as described above, complementary and unexpected. To date, no molecule or mechanical treatment has shown any significant effect on arterial calcifications. However, it has been shown that infra-popliteal lesions, which are extremely present in diabetic and renal failure patients, have characteristics different from atheromatous lesions in other territories. These lesions are distinguished by their calcified character, leading to a "stone" of the vessel, its occlusion and clinically at a high risk of major amputation (leg and thigh).

The invention also relates to a method of therapeutic treatment using a device of the invention as described above. This method aims in particular at least partial disappearance of atheromas or intra-arterial calcium plaques, for the treatment of atherosclerosis, but also the preventive treatment of such plaques.

The method of placing the active balloon or active stent with biphosphonates uses the technologies currently used in current clinical practice, which are well known and practiced by those skilled in the art. It is recalled below.

By percutaneous approach, a typically femoral arterial puncture will be performed in an anterograde manner (it is pricked down ie in the direction of flow). A guide is introduced into the artery, breadcrumb that guarantees to be in the light. Then an introducer will make it possible to stabilize this arterial access and its internal lumen is large enough to accept the passage of material of larger caliber like balloon and stent. The lesion to be treated is identified by arteriography: injection of radiopaque product and acquisition of this injection by a radiology device such as an image intensifier used in the operating room. Once the lesion has been identified, the balloon or stent is brought into contact with this lesion according to the technical choice of the operator and the lesion is treated. A control arteriography allows to judge the final quality of the gesture. The patient is then treated with a drug of the anti-platelet aggregating type as is the case for the placement of a conventional stent or after angioplasty.

Claims (10)

1. Intra-arterial medical device comprising an active principle chosen from bisphosphonates. 2. Device according to claim 1, characterized in that the active principle is chosen from etidronic acid, chlodronic acid, tiludronic acid, pamidronic acid, alendronic acid, risedronic acid, ibandronic acid, zoledronic acid, the salts of any of these acids, and mixtures of these acids and / or these salts. 3. Device according to claim 2, characterized in that the active principle is etidronate disodium. 4. Device according to any one of the preceding claims, characterized in that it comprises at least one other active principle, for example paclitaxel. 5. Device according to any one of the preceding claims, characterized in that it is chosen from balloons and stents. 6. Device according to any one of the preceding claims, characterized in that it comprises a matrix in which said active principle is incorporated and from which it can be released in contact with an arterial wall. 7. Device according to claim 6, characterized in that the matrix is chosen from lipophilic polymers, phospholipids. 8. Device according to claim 7, characterized in that the matrix is chosen by the liposomes. 9. Device according to any one of the preceding claims, characterized in that the concentration of active principle ranges from 3 to 9 pg / mm ² . 10. Device according to any one of the preceding claims, characterized in that the weight ratio of the active ingredient (s) to the matrix is at least 0.1 and / or at most 0.5.