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INVENTION
Russian Federation Patent RU2214283

Implant for subcutaneous or intradermal

Implant for subcutaneous or intradermal

Name of the inventor: AZIYUS Jerome (FR); Thess Atem (FR); GUSHE Frank (FR); LAGLENN Benedict (FR); Laugier-LAGLENN Elizabeth (FR)
The name of the patentee: Pharmaceuticals AVENTIS HOLDINGS INC. (US)
Patent Attorney: Natalia Lebedeva G.
Address for correspondence: 129010, Moscow, ul. Boris Spassky, 25, p.3, Ltd. "Gorodissky and Partners", pat.pov. N.G.Lebedevoy
Starting date of the patent: 1998.06.12

The invention relates to medicine, namely to plastic or reconstructive surgery and aesthetic dermatology. An implant for subcutaneous or intradermal administration to a human by injection consists of biologically degradable microspheres or microparticles in suspension in a gel, wherein said microspheres or microparticles are composed of at least one polymer selected from polymers of lactic acid polymers, glycolic acid and copolymers of lactic acid glycolic acid. The implant may be prepared as a lyophilizate capable of adding water for injection to recover injectable implant. The implant has resorbability within 1-3 years, does not cause allergic reactions.

DESCRIPTION OF THE INVENTION

The invention relates to an implant for subcutaneous or intradermal administration, intended for use in plastic or reconstructive surgery and in the human aesthetic dermatology, to fill wrinkles, fine lines, skin depressions, acne scars and other scars, but also to fill in odontostomatology gums.

Up to now, to this end a certain number of products were used. Each product has advantages and disadvantages.

Easily used is silicone gel (or silicone oil). However it found that migration is observed after the injection of silicone droplets in the tissue located under the injection point, by simple gravity. Silicone is often the cause of chronic inflammation, the formation of granulomas, and even of late allergic reactions. Silicone is not subjected to biological degradation and is often found in the liver.

Teflon paste is a suspension of polytetrafluoroethylene particles (diameter: 10-100 microns) in glycerine. In many cases, this product provokes serious, severe and chronic infections, and most patients require its recovery after a few months of the skin and subcutaneous tissue. and it has been proven that small polytetrafluoroethylene particles can be detected in the liver.

In the last ten years is very widely used collagen suspension. However, the results are rather unsatisfactory in the sense that the collagen is resorbed in 1-3 months. and about 2% of patients allergic reactions noted. Finally, it should be noted that collagen is bovine collagen.

With regard to the biological sample of the patient, the idea is certainly interesting, but clinical trial showed reimplantation failure of fat cells, which are absorbed and disappear within a few weeks.

Another system is the addition of patient plasma in collagen gelatin of bovine and porcine origin. The results are even more unsatisfactory and the product is of animal origin.

Hyaluronate gels are a good alternative, because of their biocompatibility and lack of toxicity. Furthermore, they are widely used in ophthalmic surgery. However, their rapid biological resorbability (maximum 2 months) makes them ineffective for use in plastic surgery.

Bioplastics are polymerized silicone particles (70-140 microns diameter) dispersed in polyvinylpyrrolidone. The product may be recovered, considering the chronic inflammation and rejection reactions that provokes it.

Known microspheres of polymethylmethacrylate (PMMA) with a diameter of 20-40 micrometers as a suspension or solution of gelatin or collagen in solution. PMMA does not undergo biodegradation, but the lack of time necessary to get to know that the implant gives after 5 or 6 years. Furthermore, the vector is collagen of bovine origin solution with allergy problems, which are known to him.

The aim of the invention is to eliminate the drawbacks of known products.

According to the invention the microspheres or microparticles formed neutral polymer selected because of its safety and already widely used in the pharmaceutical industry, where it is administered either orally or parenterally.

The implant invention combines the ease of use without any prior manipulation, the possibility of introducing a syringe product resorbability, for a controlled time of the polymer gel as the vector, no allergenicity of the product, which eliminates the need for a preliminary test.

The microspheres or microparticles should have a controlled biological resorbability providing resorbable time from 1 to 3 years. This means that the polymer in situ after injection degraded to low molecular weight compounds are removed from the body by natural processes. In no case nerezorbiruyuschiysya implant is not desirable. It is always about the foreign body, introduced into living tissue.

The microspheres or microparticles suspended in a gel. They should have a diameter greater than 5 microns and preferably greater than 20 microns, they are not absorbed to macrophages. They should have a diameter of less than 150 microns, and preferably less than 40 microns, on the one hand, they can be administered by injection via a thin needle, and, on the other hand, does not create a granulosa finger clusters.

Essentially two classes of polymers meet the above definition: polycaprolactones (especially poly- caprolactone) as well as polylactides (lactic acid polymers or PLA), polyglycolides (glycolic acid polymers or PGA) and their copolymers (copolymers of lactic acid with glycolic acid or PLAGA).

Whereas many studies already carried out and widely known products, in terms of manufacturing and resorbable microspheres, it appears preferable to use a mixture of the lactic acid polymer (PLA) with a copolymer of lactic acid with glycolic acid (PLAGA). The proportions of each of these two acids allow to determine residual activity of the product.

Numerous experiments and fed to the preference of the polymer which is a polymer of L-lactic acid (crystalline) polymer of D-lactic acid (amorphous) polymers, or a mixture of these two acids. Its molecular weight calculated by viscometry, is preferably from 70,000 to 175,000 daltons and preferably from 120,000 to 170,000 Daltons, the intrinsic viscosity is 4.3 dl / g, and preferably from 3.35 to 3.65 dl / g, a specific rotation is from to -150 o -160 o, the melting temperature of 178,0-190,1 o C, the heat of fusion of 85,0-90,0 J / g, the amount of residual solvents below 0.01%, and the proportion of residual monomer (lactic acid) is less than 0.1%. Such a product is commercially available from PURAC BIOCHEM in Gorinchem (Netherlands).

Biodegradable synthetic polymers are resorbed for about fifteen years, exploring under the direction of Michel VERT, head of scientific research at CNRS The first clinical application of PLA launched in 1981 for various indications in facial traumatology. lactic acid polymers now used systematically biologically resorbed within surgical implants. The use of PLA in medicine today is diverse and extensive (surgery on the bones, maxillofacial surgery, pharmacological formulations with controlled release: implants, microspheres, nanospheres, vaccines).

Destruction of lactic acid polymers and / or glycolic acid in a biological medium occurs exclusively chemical mechanism of nonspecific hydrolysis. This hydrolysis products are then transformed into the metabolic process, and then removed from the human body. Chemical hydrolysis of the polymer is complete; it occurs the quicker, the better pronounced amorphous character of the polymer and the lower molecular weight. Thus, the time can be adjusted resorbable by acting on the composition of the mixture and / or the molecular weight of the polymer or polymers. The biocompatibility of PLA and PLAGA polymers makes them an excellent basis for cell growth and tissue regeneration.

The microspheres or microparticles incorporated into the gel. This gel is used as a vector to maintain the microspheres or microparticles in the form of a homogeneous suspension resorbed in about 2 months, which corresponds to the time required for creating fibrosis around the microspheres or microparticles. It mainly consists of water to prepare a preparation for injection and gelling agent allowed for injection: cellulose derivatives, particularly carboxymethyl cellulose (CMC), at a concentration of 0,1-7,5 wt. %, And preferably 0.1-5.0 wt.%. and may be resorted to the use of hydroxypropyl methylcellulose (HPMC), which is commonly used for intraocular injection within cataract operations. and it is possible to use a synthetic hyaluronic acid, applied for intraocular injections and subcutaneous injections. And you can use lactic acid esters, caproic acid esters, etc.

Getting a good dispersion of the microspheres or microparticles and the homogeneity of the gel provided by the use of a surfactant selected for its safety and its permitted use subcutaneously or intradermally. Use polyoxyethylene (it is sold under the name Tween 80) or pluronic acid.

The product may be in a pre-filled syringe of sterile, ready for use and equipped with a needle, or in vials of sterile suspension. It may be in the vial containing the lyophilisate, to which is attached an ampoule of sterile water (water for preparing a preparation for injection) or in a pre-filled syringe with two compartments, one of which contains a lyophilisate of microspheres or microparticles, and the other contains water to make preparation for injection.

The implant does not require allergy tests. It contains no animal product.

Protocol in case of obtaining implant ready to use suspension of microspheres described below.

A. Preparation of microspheres of polylactic acid. Used the classic method or a solvent evaporation method called controlled precipitation or any other way to obtain microspheres of the desired size.

B. Preparation of a gel with a viscosity sufficient to maintain the microspheres in suspension. This change in viscosity depending on the amount and size distribution of microspheres dispersed in the gel microspheres. This amount is 50-300 g / l, and preferably 60-200 g / l.

B. Distribution of the gel into syringes or into vials in a controlled atmosphere (class 10 4).

D. Sterilization of vials or syringes or use of a process making the end product suitable for administration by subcutaneous injection.

The following protocol describes obtaining microparticles lyophilized PLA, in the case of polymer L, D polymer or mixtures thereof:

A. PLA Krioizmelchenie under nitrogen gas passed through a filter with a pore size of 0.22 microns, at a temperature below -80 o C for sifting on a sieve with a hole size of 100 micron light.

B. Screening of the microparticles through a stainless steel sieve with a hole size of 100 micron light.

B. Preparation environment for lyophilization, comprising dissolving with stirring CMC (gelling agent), apyrogenic mannitol (cryoprotective agent) and polysorbate (surfactant) in water for preparing a preparation for injection, filtering the resulting solution through a filter having a pore size of 0.22 um under nitrogen passed through a filter with a pore size of 0.22 .mu.m, and sterilization in an autoclave for 20 minutes at 121,5 o C.

G. Distribution of the microparticles 100 mg per vial of 4 ml nominal capacity.

D. Distribution environment for lyophilization by 1,05 ± 0,05 g vials containing microparticles have a lactic acid polymer.

E. dispersing the microparticles in a medium for the lyophilization using ultrasound dispersion system in order to obtain a homogeneous suspension.

J. Preliminary clogging vials using caps with stanchions (specific for lyophilization), rapid freezing to a temperature below -70 o C, storage of the frozen vials at a temperature below -40 o C and finally lyophilization vials and automatic blockage.

Z. capping and testing lumen bottles prior to sterilization by irradiation U.

Of course, it is possible to combine the above methods work, for example, for ready-mixed microparticle suspension or lyophilizate microspheres, wherein the microspheres or microparticles are formed by any of the aforementioned polymers, and mixtures thereof.

example 1

2 g of PLA are dissolved in 20 ml of organic solvent (ethyl acetate). This solution was dispersed in 100 ml of water containing 5 g of polyoxyethylene sorbitan monooleate. Moderate stirring is Vortex maintained until evaporation of the solvent and formation of microspheres having a mean diameter of 40 microns. The microspheres formed are recovered by sedimentation, filtration and drying. They are then included in a gel consisting of water and CMC (0,5 wt.%). After moderate stirring, the distribution is carried out.

example 2

2 g of PLA are dissolved in 20 ml of organic solvent (dichloromethylene). This solution was dispersed in 100 ml of water containing 5 g of polyoxyethylene sorbitan monooleate. Moderate stirring is Vortex maintained until evaporation of the solvent and formation of microspheres having a mean diameter of 80 microns. The microspheres formed are recovered by sedimentation, filtration and drying. They are then included in a gel consisting of water and CMC (0,5 wt.%). After moderate stirring, the distribution is carried out.

example 3

2 g of PLA are dissolved in 20 ml of organic solvent (chloroform). This solution was dispersed in 100 ml of water containing 5 g of polyoxyethylene sorbitan monooleate. Moderate stirring is Vortex maintained until evaporation of the solvent and formation of microspheres having a mean diameter of 50 microns. The microspheres formed are recovered by sedimentation, filtration and drying. They are then included in a gel consisting of water and HPMC (1 wt.%). After moderate stirring, the distribution is carried out.

example 4

Carried krioizmelchenie 600 g lactic acid polymer to a final particle size of 20 to 100 microns, with a median of 40 microns. These microparticles are dispensed into 100 mg per vial.

6.5 kg of medium prepared for lyophilization by dissolving 97.5 g of CMC sodium salt, 276.25 g of apyrogenic mannitol and 6.5 g of polysorbate 80 in a sufficient amount to 6.5 liters of water to prepare an injection preparation. The medium was dispensed at 1 g per vial.

With products of examples 1-4 carried out experiments on animals (hairless mice and New Zealand rabbits). The results are identical, and for the first two months, beginning with the eighth day after injection, observing the appearance of giant cells surrounding a mesh polylactic acid crystals, and then create their transformation by fibrosis, which restores the subcutaneous tissue.

CLAIM

1. Injectable implant for subcutaneous or intradermal administration to a human by injection, consisting of biologically degradable microspheres or microparticles in suspension in a gel, in that the said microspheres or microparticles are composed of at least one polymer selected from polymers of lactic acid polymers glycolic acid and lactic acid-glycolic acid copolymers.

2. An implant according to claim 1, characterized in that the content of the microspheres or microparticles in the gel is 50-300 g / l, preferably 60-200 g / l.

3. An implant according to claim 1 or 2, characterized in that the microspheres or microparticles have a mean diameter of 5-150 microns, preferably 20-40 microns.

4. An implant according to any one of claims 1-3, characterized in that the microspheres or microparticles are biodegradable over a period of 1-3 years.

5. An implant according to any one of claims 1-4, wherein said polymer is a polylactic acid chosen from poly-L-lactic acid, poly-D-lactic acid and mixtures thereof.

6. The implant of claim 5, wherein the polylactic acid has a molecular weight of 70000-175000 Daltons, preferably 120000-170000 Daltons, internal viscosity of 3.4 dl / g, preferably 3.35-3.65 dl / g, percent residual monomer content of less than 0.1%, and the percentage of residual solvents below 0.01%.

7. Implant according to any of claims 1 to 6, characterized in that the gel includes a gelling agent mainly carboxymethylcellulose (CMC) or hydroxypropylmethylcellulose (HPMC) at a concentration of 0,1-7,5 wt.%, Preferably 0.1 -5.0 wt.%.

8. An implant according to any one of claims 1-7, used in reconstructive or cosmetic surgery and aesthetic dermatology for filling wrinkles, fine lines, skin cracks and scars from acne or other scars, and in dentistry for filling the gums.

9. The lyophilizate obtained by freeze-drying injectable implant according to any one of claims 1-7 and capable of recovering to an implant for subcutaneous injection or intradermal administration by adding water for injection.

10. The lyophilisate according to claim 9, used in plastic or reconstructive surgery and in the human aesthetic dermatology for filling wrinkles, fine lines, skin cracks and scars from acne or other scars, and in dentistry for filling the gums.

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Publication date 01.04.2007gg