HK1025268B - Implant for subcutaneous or intradermal injection - Google Patents

Description

The invention relates to an implant for injection by subcutaneous or intradermal means, intended for use in humans in reconstructive or plastic surgery and cosmetic dermatology, for the filling of wrinkles, fine lines, skin depressions, acne scars and other scars, and in dentistry for the filling of gums.

The implant shall consist of bioresorbable microspheres or microparticles suspended in a gel, the microspheres or microparticles being composed of at least one polymer selected from lactic acid polymers, glycolic acid polymers and coglycolic lactic acid polymers.

To date, a number of products have been used for this purpose, each with its own advantages and disadvantages.

Silicone gel (or silicone oil) is easy to use, however, after injection, silicone droplets have been found to migrate into tissues below the injection point, by simple gravity. Silicone is frequently the cause of chronic inflammation, granuloma formation, and even late allergic reactions.

Teflon paste is a suspension of polytetrafluoroethylene particles (10-100 μm in diameter) in glycerin. This product has in many cases caused severe and chronic serous infections, and had to be removed after a few months from the dermal and subdermal tissues of most patients.

Collagen suspensions have been used extensively in the last ten years, but the results have been rather disappointing as collagen is absorbed in 1 to 3 months, and allergic reactions have been reported in about 2% of patients.

Biological samples from the patient himself: the idea was interesting, but clinical experience has shown that the reimplantation of fat cells fails, and they are absorbed and disappear in a matter of weeks.

Another method involved adding patient plasma to a collagen gelatin of bovine and porcine origin.

Hyaluronate gels were a good alternative due to their bio-compatibility and non-toxicity. They are also widely used in eye surgery. However, their rapid bio-absorption (up to 2 months) makes them ineffective for use in plastic surgery.

Bioplastics are polymerized silicone particles (diameter 70-140 μm) dispersed in polyvinylpyrrolidone.

The microspheres of polymethyl methacrylate (PMMA) with a diameter of 20 to 40 μm are suspended either in a gelatin solution or in a collagen solution. PMMA is not biodegradable, but there is no backward look at what this implant gives after 5 or 6 years.

WO 96 33751 describes a biphasic injectable composition consisting of insoluble fragments of a hydrogel of hyaluronic acid or one of its highly cross-linked salts.

WO 93 13755 describes a collagen-based injectable composition, comprising microcapsules of atelocollagen or a mixture of atelocollagen and a polysaccharide, and states that heterologous, i.e. bovine collagen, is the material with the highest performance in terms of biocompatibility and in vivo stability.

EP 711 548 describes bioabsorbable microdispersions comprising, on the one hand, a carrier fluid which is a liquid polymer and, on the other hand, a specific particulate material selected from various solid homopolymers formed from ε-caprolactone, p-dioxanone or trimethylene carbonate units and from various solid copolymers formed from ε-caprolactone and other units, or trimethylene carbonate and other units.

The purpose of the invention is to remedy the disadvantages of known products.

The invention uses microspheres or microparticles made of a neutral polymer, selected from the polymers of lactic acid, glycolic acid and coglycolic acid, chosen for its safety and already widely used by the pharmaceutical industry either orally or parenterally.

The implant according to the invention combines the convenience of use without prior manipulation, the syringe-like nature of the product, the absorbability in a controlled time of the polymer as well as the vector gel, the absence of allergenicity of the product, which makes any prior testing unnecessary.

The microspheres or microparticles must have a controlled bio-resorbability with a resorbability time of 1 to 3 years. This means that the polymer will degrade after injection in situ into low molecular weight compounds that will be eliminated from the body by natural processes. In no case does an insoluble implant seem desirable. It is always a foreign body placed in a living tissue.

The microspheres or microparticles are suspended in a gel. They must be larger than 5 μm in diameter, preferably larger than 20 μm, in order not to be absorbed by macrophages. They must be smaller than 150 μm in diameter, preferably smaller than 40 μm, in order to be injected with a fine needle and not to form granular clumps under the finger.

A family of polymers essentially meets the previous definition: polylactic acids (PLA), polyglycolides (PGA) and their copolymers (PLAGA).

In view of the many studies already carried out and the good knowledge of the products, in particular in the manufacture of microspheres and resorbability, it seems advantageous to use a mixture of polylactic acid (PLA) and polylactic-co-glycolic acid (PLAGA).

Many tests have also shown that a polymer consisting of a poly-L-lactic acid (crystalline), a poly-D-lactic acid (amorphous), or a mixture of these two acids is preferably preferred. Its molecular weight, calculated by viscosimetry, is advantageously between 70000 and 175,000 Daltons, and preferably between 120000 and 170000 Daltons, an intrinsic viscosity of 3 and 4 dl/g, and preferably between 3.35 and 3.65 dl/g, a specific rotation of -150 and -160°, a melting point of 178.0 to 190.1°C, a melting point of 85.0 to 90.0 J/g, a volume percentage of solvent residues < 0.01%, and a percentage by weight of the monohydrous resin (PUCH-PRA) is available in the BIO-basic chemical (BIO-PRA) product.

The first clinical uses of PLA began in 1981 for various indications in facial trauma. The use of lactic acid polymers has become systematic in the context of bio-absorbable surgical implants. The medical applications of PLA are now diverse and extensive (bone surgery, maxillofacial surgery, controlled-release pharmacological formulations : implants, microspheres, nanospheres, vaccines).

The degradation of lactic acid and/or glycolic acid polymers in the biological environment is done exclusively by a non-specific chemical hydrolysis mechanism. The products of this hydrolysis are then metabolized and eliminated by the human body. The chemical hydrolysis of the polymer is complete; it occurs all the more rapidly as its amorphous character is pronounced and its molecular mass is low. Thus, the time of solubility can be regulated by acting on the composition of the mixture and/or on the molecular mass of the polymer (s). The biocompatibility of the polymers PLA and PLAGA makes them excellent supports for cell growth and tissue regeneration.

The microspheres or microparticles are contained in a gel. This gel, used as a vector to keep the microspheres or microparticles in a homogeneous suspension, is soluble in about 2 months, which corresponds to the time required for the formation of fibroses around the microspheres or microparticles. It consists mainly of water for injection preparation and a gelling agent authorised for injection: cellulose derivatives, and more specifically carboxymethylcellulose (CMC) at a weight concentration of 0.1 to 7.5%, and preferably 0.1 to 5.0% .

The proper dispersion of the microspheres or microparticles and the homogeneity of the gel shall be ensured by the use of a surfactant, chosen for its safety and authorized for subcutaneous and intra-dermal use, using polyoxyethylene sorbitol monooleate (marketed as Tween 80) or pluronic acid.

The product may be presented in sterile pre-filled syringes ready for use, with a needle, or in vials of sterile suspension. It may also be presented in a vial containing a freeze-dried product accompanied by a vial of sterile water (water for injection) or in a pre-filled syringe with two compartments, one containing the freeze-dried product of microspheres or microparticles and the other containing water for injection.

The implant does not require allergen testing, and it contains no animal products.

The manufacturing protocol for the implant is described below in the case of a ready-to-use microsphere suspension. A. Preparation of microspheres of lactic acid polymer. The conventional technique of evaporation of solvent, or the so-called controlled precipitation technique, or any other technique used to obtain microspheres of the desired calibre is used.B. Preparation of a gel of sufficient viscosity to keep the microspheres suspended. This viscosity will be adjusted according to the particle size of the microspheres and the proportion of microspheres dispersed in the gel. This proportion will be 50 to 300 g/l, and preferably 60 to 200 g/l.C. Distribution of the gel into syringes or vials, under controlled atmosphere (cilis 104).D. Sterilization of the vials, or use of a process whereby the finished product is made ready for injection by means of a syringe.

The manufacturing protocol for freeze-dried PLA microparticles, whether L-polymer, D-polymer or a mixture thereof, is described below. A. Cryo-crushing of PLA under 0.22 μm filtered nitrogen gas at a temperature below -80°C on a 100 μm.B screening grid. Sifting of microparticles on 100 μm.C stainless steel sieves. Preparation of the freeze-drying medium including agitation of CMC (gelling agent), apyrogen mannitol (cryoprotective agent) and polysorbate (surfactant) in water for injection, filtration at 0.22 μm of the solution obtained under nitrogen gas filtered at 0,Distribution of microparticles at a rate of 100 mg per vial of nominal capacity 4 ml.E. Distribution of the freeze-drying medium at a rate of 1.05 ± 0.05 g in vials already containing the polylactic acid microparticles.F. Dispersion of microparticles in the freeze-drying medium by an ultrasonic dispersion system to obtain a homogeneous suspension.G. Preclosure of the vials with caps (specific for freeze-drying), rapid freezing below -70°C, storage of the frozen vials at -40°C, and automatic freezing and freezing of the vials.H. Encapsulation and mirage of vials, prior to sterilization by irradiation γ.

Of course, it is possible to combine the above methods, for example to obtain a ready-to-use microparticle suspension or a micro-sphere freeze-dried product, where the microparticles or microspheres are made up of any of the above polymers and mixtures thereof.

The following paragraphs are added:

2 g of PLA is dissolved in 20 ml of organic solvent (ethyl acetate). This solution is dispersed in 100 ml of water containing 5 g of polyoxyethylene sorbitan monooleate. A moderate stirring in the vortex is maintained until the solvent evaporates and microspheres of medium diameter 40 μm are formed. The formed microspheres are recovered by sedimentation, filtration and drying. They are then included in a gel consisting of water and CMC (0.5% by mass).

The following paragraphs shall apply:

The solution is dissolved in 100 ml of water containing 5 g of polyoxyethylene sorbitan monooleate. A moderate stirring is maintained in the vortex until the solvent evaporates and microspheres of medium diameter 80 μm are formed. The formed microspheres are recovered by sedimentation, filtration and drying. They are then included in a gel consisting of water and CMC (0.5% by mass).

The Commission has

2 g of PLA is dissolved in 20 ml of organic solvent (chlorophyll) and dispersed in 100 ml of water containing 5 g of polyoxyethylene sorbitan monooleate. A moderate stirring in the vortex is maintained until the solvent evaporates and microspheres of medium diameter 50 μm are formed. The formed microspheres are recovered by sedimentation, filtration and drying.

The Commission shall adopt implementing acts.

600 g of polylactic acid is cryo-grinded to a final particle size of 20-100 μm with a median of 40 μm. These microparticles are broken down at 100 mg per vial.

6.5 kg of freeze-drying medium is obtained by dissolving 97.5 g of sodium CMC, 276.25 g of apyrogen mannitol and 6.5 g of polysorbate 80 in 6.5 litres of water for injection, divided by 1 g per vial.

Animal tests (hairless mice and New Zealand rabbits) were carried out with the products of examples 1 to 4. The results are identical and during the first two months and on the eighth day after the injection, the appearance of giant cells surrounding the polylactic acid crystals in a network is observed and then their transformation by creating fibrosis that reconstitutes the subcutaneous tissue.

Claims (14)

1. Injectable implant for human administration consisting of bioresorbable microspheres or microparticles in suspension in a gel, said microspheres or microparticles consisting of at least one polymer chosen from the lactic acid polymers, the glycolic acid polymers and the lactic co-glycolic acid polymers.
2. Implant according to claim 1, characterized in that the proportion of microspheres or microparticles in the gel is from 50 to 300 g/l, preferably 60 to 200 g/l.
3. Implant according to anyone of claims 1 and 2, characterized in that the microspheres or microparticles have a mean diameter of from 5 to 150 µm, preferably from 20 to 40 µm.
4. Implant according to anyone of claims 1 to 3, characterized in that the microspheres or microparticles are bioresorbable within a period of 1 to 3 years.
5. Implant according to anyone of claims 1 to 4, characterized in that said polymer is a polylactic acid chosen from poly-L-lactic acid, poly-D-lactic acid and mixtures thereof.
6. Implant according to claim 5, characterized in that the polylactic acid has a molecular weight of 70 000 to 175 000 Dalton, preferably 120 000 to 170 000 Dalton, an intrinsic, viscosity of 3 to 4 dl/g, preferably 3.35 to 3.65 dl/g, a percentage by weight of residual monomer below 0.1% and a percentage by volume of residual solvents below 0.01%.
7. Implant according to anyone of claims 1 to 6, characterized in that the gel includes mainly, as gelling agent, carboxymethylcellulose (CMC) or hydroxypropylmethylcellulose (HPMC) at a concentration by weight of 0.1 to 7.5%, preferably from 0.1 to 5.0%.
8. Freeze-dried product obtained by freeze-drying a product according to anyone of claims 1 to 7, and capable of reconstituting an injectable implant by addition of water for injection.
9. Prefilled sterile syringe provided with a needle, containing an injectable implant according to anyone of claims 1 to 7.
10. Vial of sterile suspension, containing an injectable implant according to anyone of claims 1 to 7.
11. Vial containing a freeze-dried product according to claim 8 accompanied by an ampule of water for injection.
12. Prefilled syringe comprising two compartments, one compartment containing the freeze-dried product according to claim 8, the other compartment comprising water for injection.
13. Process for the manufacture of an implant according to anyone of claims 1 to 7 in the form of a suspension of microspheres or microparticles, said process comprising the following steps:

    - preparation of microspheres or microparticles of polymer by solvent evaporation or controlled precipitation or any other technique which makes it possible to obtain microspheres or microparticles of the desired size,

    - preparation of a gel of sufficient viscosity to maintain the microspheres or microparticles in suspension,

    - distribution of the gel into syringes or into vials in a controlled atmosphere (class 10⁴),

    - sterilization of the vials or syringes or use of a process which makes the finished product suitable for injection by the subcutaneous route.
14. Process for the manufacture of an implant according to anyone of claims 1 to 7 in the form of freeze-dried polymer microspheres or microparticles, said process comprising the following steps :

    - cryogrinding of the polymer under gaseous nitrogen filtered at 0.22 µm, at a temperature of less than -80°C, on a 100 µm screening grid,

    - sieving of the microparticles or microspheres on a 100 µm stainless steel grid,

    - preparation of the freeze-drying medium including the dissolution, with stirring, of the carboxymethylcellulose, apyrogenic mannitol and polysorbate in water for injection, filtration at 0.22 µm of the solution obtained under gaseous nitrogen filtered at 0.22 µm, and sterilization in an autoclave for 20 minutes at 121.5°C,

    - distribution of the microparticles or microspheres at a rate of 100 mg per vial of 4 ml nominal capacity,

    - distribution of the freeze-drying medium, at a rate of 1.05 ±0.05 g into the vials already containing the polymer microparticles or microspheres,

    - dispersion of the microparticles or microspheres in the freeze-drying medium by an ultrasound dispersion system in order to obtain a homogeneous suspension,

    - prestoppering of the vials using pillar stoppers, rapid freezing below - 70°C, storage of the frozen vials below - 40°C, then freeze-drying and automatic stoppering of the vials,

    - fitting of capsules and examination of the vials, before sterilization by γ irradiation.