FR2679772A1 - Emboli made of non-absorbable particles coated with haemostatic material - Google Patents

Abstract

Particulate product, comprising a particulate carrier made of a biomaterial, which cannot be absorbed in the biological fluids, coated with at least one haemostatic or thrombogenic material.

Description

 The present invention relates to the medical and surgical field, more specifically the field of interventional radiology.

 For about ten years, embolization has taken an increasing place in the therapeutic arsenal, on a preoperative, palliative basis or as the only treatment for surgical or medical conditions. Embolization involves obliterating vessels, especially arteries, endovascularly. It is done at the same time as arteriography. This technique allows effective intervention today in the areas of cervicocephalus, thoracic, abdominal, retro-peritoneal, pelvic or limbs. A particularly interesting application is the treatment of severe hemorrhages. By way of bibliographic reference in the field of the invention, mention may be made of the work "Interventional radiology and ultrasound" by R.

DUVAUX - FERIER in collaboration with A. RAMEE and GUIBERT,
Axone editions.

 For short-term embolization, especially in the pre-operative phase, it has been proposed to use collagen in the form of dura mater cut into fragments or in the form of collagen powder. Although absorbable, collagen can still clog vessels for several days.

 For the long term, either small steel spirals ("coils") or various synthetic materials in the form of spheres are used.

 Many radiologists are reluctant to use this technique because animal testing has revealed certain physiological defects due to the use of these spirals. Furthermore, the establishment of the spirals is not easy. As for materials in the form of spheres, rigorous calibration is not easy to obtain. The implementation of the spheres is difficult by suspension in physiological saline, or in a collagen-physiological saline mixture.

 The present invention relates to emboli whose original structure overcomes the drawbacks of the prior art.

 It generally relates to a particulate product comprising a particulate support made of biomaterial, not absorbable in biological fluids, coated with at least one hemostatic or thrombogenic material.

 The particulate support can be of any kind and shape, provided that it is constituted by a biomaterial which is not absorbable in biological fluids. This support can therefore be organic or inorganic in nature, and it must be compatible with biological tissues, in particular with veins and arteries. Preference is given to polymers which may in particular be chosen from the following polymers: polypropylene, polyethylene, polyamide, silicone, fluorinated polymers, such as polyvinylidene fluoride, polyurethane, polyester, unplasticized polyvinyl chloride, alone , as a mixture or as copolymers.

The support is presented in the form of particles whose particle size is suitable for the specific application envisaged. In general, the particle size is on the order of about 50 µm to about 1.2 mm. In particular, emboli with a particle size of 100-200 μm are used for cerebral neuradiology. To close the other arteries, the following grain size ranges are used depending on their location and diameter:
200 Hm - 400 Hm
or 400 pm - 800 pm
or 1 - 1.2 mm
The geometric shape of the support particles is not an essential characteristic of the invention, the only condition being that they must be able to be transported to the place of application in the human or animal body. However, it has been found in practice that very good results are obtained with particles of generally spherical shape.

 According to the invention, the above-mentioned particles, advantageously the polymer spheres, are coated with at least one hemostatic or thrombogenic material, such as collagen, oxycellulose, modified celluloses or gelatin. Collagen of any origin can be used, for example bovine collagen. The coating material is of the type generally used in hemostatic dressings. The thickness of the coating must be sufficient so that the embolus obtained has the ability to have an apparent density lower than the non-absorbable particle which it covers. Therefore and also because the coating according to the invention is hydrophilic, the embolus absorbing physiological saline can be easily put in place. The coating layer has on the other hand, the ability to cause a microthrombus in situ which binds the emboli together and which ensures the holding in place of the embolization. In general, thicknesses greater than 5 micrometers, in particular from 50 to 150 micrometers approximately, have been found to be suitable.

 For the manufacture of the product of the invention, it may be sufficient to bring together and intimately mix the support particles, optionally ground to the desired particle size, with the hemostatic material, such as collagen. Depending on the nature of the support, bringing the support particles into contact with the hemostatic material makes it possible to achieve satisfactory coating of the particles with said material.

 In a very simple embodiment, the surface of the particles is partially dissolved in non-absorbable biomaterial and the hemostatic-thrombogenic material is coated, which is then used in the form of finely ground powder.

 In the case where the surface of the particles cannot be solvated to fix the coating, an adhesion agent or adhesive made of biomaterial is used, for example an adhesive of polyvinylidene fluoride (PVDF) dissolved in dimethylacetamide (DMA ) or polyvinyl chloride (PVC) dissolved in cyclohexanone to coat polyethylene (PE) beads with powdered collagen. These indications and the examples below will be sufficient for those skilled in the art to achieve the fixing of the coating of hemostatic material on the support particles according to the particular nature thereof.

 The advantage of the non-absorbable particle-hemostatic coating combination is ease of placement through a catheter since the density of the emboli is close to the density of the physiological saline.

 The hemostatic-thrombogenic coating material being strongly fixed to the surface of the particles cannot be entrained in vessels beyond the desired embolization site.

 Another advantage of the emboli according to the invention is the fact that the coating material placed by the endovascular route creates a microthrombus at the desired location for embolization.

 The entanglement of the emboli with fibrin keeps the emboli in place. As the support material for the particles is not absorbable, embolization is therefore theoretically final. However, it is known that if the vessels are blocked, new vessels form around the stenosis where the vessels become free after a few months by exclusion of emboli.

 The invention will be further illustrated, without being in any way limited, by the examples which follow.

EXAMPLE 1
Granules of PVDF (Solvay Company - FDA approval) are ground at-180 C in a cryogenic mill. The granular mass obtained is then screened by a series of superimposed stainless steel screens. 500 mg of PVDF grains with a particle size of 315-400 microns are then triturated in a 1 ml solvent mixture
H2O and 6 ml DMA (= dimethylacetamide). 500 mg of native collagen, or slightly cross-linked by a thermal process, are then added and the whole is left for 3 h at 50 C. Then spread in a Petri dish and dried for 14 h at 37 C. crushes and sieves.

Two different particle sizes are obtained:
- approximately 320 mg of coated grains of> 400 and <630 microns and,
- approximately 200 mg of coated grains of> 315 and <400 microns.

 It is observed that the first fraction has a coating of approximately 100 microns of collagen.

 The collagen layer of the second fraction is much thinner, around 400 microns.

 The emboli thus obtained are packaged in containers, sterilized by radiation or with ethylene oxide, and ready for use.

 The practitioner suspends these emboli in physiological saline and injects them through a catheter for embolization.

EXAMPLE 2
100 mg of PE grains with a particle size of 100-200 microns, crushed by a cryogenic mill are crushed in a biomaterial adhesive consisting of PVC without plasticizer, dissolved in cyclohexanone at approximately 20%.

 Then, one coats with collagen and one proceeds as in Example 1: one dries, crushes, sieves and one obtains grains of PE coated, of a diameter of approximately 250-300 microns.

EXAMPLE 3
Polyamide (PA-6) beads with a diameter of 0.8 mm are treated with 80% formic acid for 6 minutes. Decanted, coated with collagen powder, washed, dried, crushed, sieved. PA beads coated with collagen are thus obtained with a diameter of 0.9 to 1.0 mm.

EXAMPLE 4
200 mg of polypropylene beads with a diameter of 0.6 mm are kneaded in a dimethylacetamide adhesive containing approximately 6% of polyvinylidene fluoride. 100 mg of powdered oxycellulose is added as used for hemostatic dressings. It is triturated, dried, crushed, sieved and we obtain polypropylene grains coated with oxycellulose with a particle size of 630 to 800 microns.

 The coating layer is hydrophilic and, moreover, it has thrombogenic properties.

Claims (10)

 1. Particulate product comprising a particulate support made of biomaterial, not absorbable in biological fluids, coated with at least one hemostatic or thrombogenic material.  2. Product according to claim I, characterized in that the support is chosen from the following polymers: polypropylene, polyethylene, polyamide, silicone, fluorinated polymers, such as polyvinylidene fluoride, polyurethane, polyester, unplasticized polyvinyl chloride , alone, as a mixture or as copolymers.  3. Product according to one of claims 1 or 2, characterized in that its particle size is from 50 pm to 1200 pm approximately, in particular from 300 to 700 pm approximately.  4. Product according to any one of claims 1 to 3, characterized in that the support particles are of generally spherical shape.  5. Product according to any one of claims 1 to 4, characterized in that the hemostatic or thrombogenic material is of the type generally used in hemostatic dressings, in particular collagen, such as bovine collagen, oxycellulose , modified celluloses or gelatin.  6. Product according to any one of claims 1 to 5, characterized in that it comprises polyvinylidene fluoride (PVDF) particles coated with bovine collagen.  7. Product according to any one of claims 1 to 6, characterized in that the thickness of the coating material is greater than 5 micrometers, in particular about 50 to 150 micrometers.  8. Method for obtaining the product according to any one of claims 1 to 7, characterized in that the surface of the particles is partially dissolved in non-absorbable biomaterial and the hemostatic-thrombogenic material is coated, which is then used as a finely ground powder.  9. A method for obtaining the product according to any one of claims 1 to 7, characterized in that an adhesive or adhesion agent in biomaterial is used to fix the coating on the support particles, for example a polyvinylidene fluoride (PVDF) adhesive dissolved in dimethylacetamide (DMA) or polyvinyl chloride (PVC) dissolved in cyclohexanone to coat polyethylene (PE) beads.  10. Application of the particulate product according to any one of claims 1 to 7 as an embolus for the embolization of vessels in medicine, surgery or radiology.