Injecting ceramic-based implants for filling of crinkles, skin cavity and cicatrices and method for production thereof
SUBSTANCE: described are implants based on biodegradable thixotropic compound with pseudo-plastic properties and implant injected under skin or into skin in fibrous tissue. Containing microparticles of at least one biocompatible ceramic compound in suspension, in at least one liquid carrier containing at least one compound based hyaluronic acid and at least one biodegradable thixotropic compound with pseudo-plastic properties. Also disclosed is kit for preparation such implants directly before application, as well as implant production and using for filling of crinkles, and/or skin cavity, and/or cicatrices.
EFFECT: implants of simplified injection.
14 cl, 4 ex
The technical field to which the invention relates.
The present invention relates to implants that can be injected subcutaneously or intradermally in fibrous tissue intended for use in human or an animal in a restorative or cosmetic surgery or aesthetic dermatology to fill wrinkles, wrinkles, skin depressions and scars, including dermal defects that appear as a result of treatment, which may lead to the development of lipodystrophy, often expressed in lipoatrophy entity.
The level of technology
Until today used a certain number of means. Each tool has its advantages and disadvantages.
- Easy to use by injection were silicone oil, which is now banned. However, after injection was observed migration of the silicone droplets in the tissues beneath the point of injection, under the action of its own weight. Improperly used or used in too large quantities of silicone was the cause of siliconomas and even persistent allergic reactions. Silicone is not biodegradable substance.
- Teflon paste is a suspension of particles of polytetrafluoroethylene (diameter from 10 to 100 μm) in glycerol. In many cases, this tool was dangerous and caused chronic zeros the haunted infection, and for most patients it had to be removed from the skin and subcutaneous tissue several months after injection. It was also proved that the smallest particles of polytetrafluoroethylene hit in the liver.
In the last ten years was widely used collagen suspension. Very long collagen occupied a leading position in this field of application, as it was practically the only means permitted for distribution in the market in order to treat aging skin. Approximately 3% of patients were reported cases of allergic reactions. Most patients resorption of collagen in average is 3-5 months, which requires multiple injections per year in order to achieve a certain efficiency. Finally, it should be noted that collagen is of animal origin.
Biological sampling from the patient. The idea was interesting, but clinical experience has shown the futility of reimplantation of fat cells, which was absorbed and disappear within a few weeks. Another solution was to add a plasma in collagen gelatin of animal origin (from cattle and pigs). The results were not impressive, and the tool is of animal origin.
Hyaluronic acid used in most pharmaceutical forms is whether the majority of medical devices used in the form of a gel of sodium hyaluronate. It is widely used, because of the ease of injection and security applications, and is a good alternative due to its biocompatibility and lack of toxicity. In addition, these gels of sodium hyaluronate are widely used in eye surgery. However, their ability to Express bioresorption (typically comprising from 4 to 6 months) may disappoint some users in filling wrinkles or skin depressions, as the injection must be repeated through a small and regular intervals.
- Bioplastic materials that are polymerized microparticles (diameter from 70 to 140 μm), dispergirovannykh in polyvinylpyrrolidone. Were cases of rejection reactions.
The beads of polymethylmethacrylate (emission spectra obtained for pure) in diameter from 20 to 40 microns in suspension or solution of gelatin, or in a solution of collagen, or in a solution of hyaluronic acid. Emission spectra obtained for pure is not byroslawsky material, although widely used in the field of ophthalmology in the form of an intraocular implant. In the field of aesthetic dermatology yet sufficient experience to determine the effects of intradermal implantation after five or six years after the introduction of the implant. In addition, when the medium was a solution of collagen (stomach the CSOs origin) was registered 3% of cases of allergies.
Microparticles of polylactic acid (PLA) is a polymorphic species and diameter from 40 to 63 μm in suspension in sodium carmellose. The product, marketed under the name Newfill®has a good perspective, as it provides long-term effectiveness of the treatment while limiting the number of sessions injection. Used polymer is L-PLA 100 (100% levogyrate crystalline form PLA), which has an extremely slow kinetics of resorption (over 5 years). However, concerns about resistance of PLA crystals in the tissues, which in some cases may cause a chronic inflammatory response with repeated injections.
- The use of CMC (derived cellulose) may, on the one hand, cause allergic reactions, and, on the other hand, the body is missing an enzyme system capable of decomposing cellulose. In addition, the need to prepare immediately before use and vigorous stirring for homogenization before use, poor molding product limit its use and alienate many users. After two years, in some cases the appearance of granulomas, and cystic nodules, most of which require removal.
Disclosure of inventions
The present invention which is the elimination of the disadvantages of the known products, available on the market, and in particular such as the use of products of animal origin, in particular, from the cattle, the need for regular injections (every few months), allergic reactions, difficulty of implementation of the injection.
In this regard, in one embodiment, the implementation of the present invention use biodegradable thixotropic connection with pseudoplastic-type properties used in the injected implant in accordance with the present invention, to stabilize the suspension and, in particular, to facilitate the injection of any material, biodegradable or not, facilitate the manufacture of the above-mentioned implant and injection molding of the above-mentioned implant using thin needles typically has a size of 25-30, preferably used for dermatological and/or aesthetic purposes.
In another embodiment of the invention uses resorbed ceramic compound selected because of its safety and is already used for medical purposes, in particular in the field of implant bone tissue.
Known patents and/or patent applications, of which we can mention the patent EP-B1-0627899, which describes the composition of the injected implant containing biocompatible ceramic matrix presets is existing in a liquid pharmaceutically acceptable carrier, selected from the group of biocompatible organic polymers in the buffer the aquatic environment, spreading from the injection site into the fabric, and mixtures thereof, in which a ceramic matrix contains particles with a size distribution in the range from 50 μm to 250 μm. The implant according to this patent is designed to be filled fibrous cavities mainly near the bone or hard tissue. If it is mentioned that the described implant can be injected into the soft tissue through needles larger than 20, more preferably 22, together with this (and in contrast) indicates that it is preferable that the injection, which should contribute to the growth of tissues, should be carried out using needles size 20 and less than and close to the bone or cartilage for treatment of the nose or treatment of sphincter. On the other hand, specifies that the size of the ceramic material constituting from 50 μm to 250 μm, preferably from 100 μm to 200 μm, should allow injection by using thin needles. When the amount is more than 50 μm, as indicated, the ceramic particles will be unduly subjected to phagocytosis. When the amount is more than 200 μm, as indicated, is difficult for the injection of particles. In the example implementation, injected and analyzed implants containing hydroxyapatite (ON) in a mixture of collagen. All of them are characterized by the beginning of the om calcification. None of the examples do not only use ceramics. Indeed, in the introductory part of the patent specifies that the collagen acts on filling under the skin surface, while the ceramic particles are used for the regeneration of the nearby bone and cartilage. However, as mentioned above, the presence of collagen is undesirable.
Also known documents, registered in the name of William G. Hubbard, a it WO-A-93/15721, and in the name of Bioform Inc., namely, WO-A-01/12247 and EP-A-1080698. They describe biocompatible and permanent, that is not resorbed (not absorbed), materials containing a matrix of ceramic particles to increase the amount of soft tissue (or "soft tissue" in English terminology). The said particles have a spherical shape and size adjustable, typically from 35 to 150 μm, however, this size may be less than 35 μm, preferably from 10 to 35 μm. In documents WO-A-93/15721 and WO-A-01/12247 preferred ceramic material is hydroxyapatite or NAR, but for this purpose you can also use the tricalcium phosphate. The bearer of these particles is biocompatible and resorbed idcompany material containing polysaccharide. In the document WO-A-93/15721 among the possible polysaccharides indicated carboxymethylcellulose (CMC) sodium and glycerin, the most preferred is a combination of them. The document WO-A-01/12247 among the possible polysaccharides indicated hyaluronic acid, but above all, carboxymethylcellulose (CMC) sodium and glycerin, the most preferred is a combination of them. The main difference of these implants from implant in accordance with the present invention is a permanent implant of the prior art.
Injected implants in accordance with the present invention allows to eliminate the disadvantages of the known solutions. In particular, they allow you to fill in wrinkles, wrinkles, scars and/or skin depressions using a simple and effective product that is capable of almost total bioresorption.
First and foremost object of the present invention is the manner in which the implant can be injected subcutaneously or intradermally into fibrous tissue, preferably at least one biodegradable thixotropic connection with pseudoplastic-type properties, preferably, at least one bioresorbable thixotropic connection with pseudoplastic-type properties, and more preferably at least one thixotropic connection with pseudoplastic-type properties based on xanthene resin.
Such biodegradable thixotropic connection with pseudoplastic-type properties used in the injected implant in accordance with this izobreteny is m, allows you to stabilize the suspension and greatly facilitate the injection of any material, biodegradable or nonbiodegradable, simplifies the manufacture of the above-mentioned implant and injection molding of the above-mentioned implant using thin needles typically has a size of 25-30, preferably used for dermatological and/or aesthetic purposes.
The second object of the present invention is an implant that can be injected subcutaneously or intradermally in fibrous tissue containing at least one biodegradable thixotropic connection with pseudoplastic-type properties, preferably, at least one bioresorbables thixotropic connection with pseudoplastic-type properties, and more preferably at least one thixotropic connection with pseudoplastic-type properties based on xanthene resin.
In particular, the present invention relates to a variant the execution of the said implant is an implant that can be injected subcutaneously or intradermally, containing microparticles of at least one biocompatible ceramic compounds in suspension in at least one liquid carrier, with the said implant is characterized by the fact that these microparticles are biodegradable, preferably bioresorbability, and have a size of from 10 to 8 μm, preferably from 10 to 50 μm, more preferably from 10 to 45 μm, and most preferably from 15 to 40 microns. These ceramic compound contains at least one element selected from the group comprising tricalcium phosphate (βTCP) and biphasic products (HRV), includes DRUG and βTCP in varying proportions, with preferably the mentioned element is βTCP, and the fact that the said liquid medium contains at least one connection based on hyaluronic acid and at least one biodegradable thixotropic connection with pseudoplastic-type properties, preferably at least one bioresorbables thixotropic connection with pseudoplastic-type properties, and more preferably, at least one thixotropic connection with pseudoplastic-type properties based on xanthene resin.
Under the "implant" in accordance with the present invention should be understood as intended for implantation of the composition, and the composition, which has already been implanted in the body of man or animal. Under "liquid media" in accordance with the present invention should be understood the connection that transports ceramic compound which is in liquid form. The term "liquid" means in this case that the same gel, for example, visco-plastic gel. Under the "gel" in the framework of the present invention should be understood three-dimensional physical structure, having a viscosity, rheological (viscoplasticity) and thixotropic (mistakemate) properties. This gel means having at least one thixotropic connection with pseudoplastic-type properties. Under "fibrous tissue" in the framework of the present invention should be understood subcutaneous space mainly of a fibrous nature, which can be filled with fibers. The term "subcutaneous" in the framework of the present invention should be understood as "hypodermic"that is "under the skin layer. The term "intradermal" in the framework of the present invention should be understood "thicker skin". Under "suspension" in the framework of the present invention should be understood condition powder, dispersed in a liquid not dissolving in said liquid.
By "biodegradable" or "decomposition" in the framework of the present invention should be understood decay in the biological environment of the material, resulting cellular, enzymatic, bacterial or viral activity. Biodegradation corresponds to the loss of physical properties. Under the "bioresorbable" or "resorption" in the framework of the present invention should be understood biodegradation, which is oversheets complete disappearance of the material, the products of biodegradation are excreted by the kidney or metabolic means.
The implant in accordance with the present invention in the preferred embodiment, or in another embodiment, contains at least one biodegradable thixotropic connection with pseudoplastic-type properties, preferably, at least one bioresorbables thixotropic connection with pseudoplastic-type properties, and more preferably at least one thixotropic connection with pseudoplastic-type properties based on xanthene resin. For example, this connection is cantoral 180®produced by CPKELCO Inc.
In a preferred embodiment of an implant in accordance with the present invention microparticles of ceramic compounds, as a rule, are resorbed (or almost resorbed after implantation in fibrous tissue in the period from 2 to 36 months, preferably from 3 to 24 months and more preferably from 4 to 18 months. In this case we are talking about resorbed ceramic material. Of course, that the carrier liquid is chosen so, that he himself was also biodegradable and preferably bioresorbables, and is also compatible with resorption of the ceramic compounds. In all cases, as a rule, in the accordance with the present invention avoid the use of native animal such as bovine collagen.
The size of the microparticles is an average size, measured by sieving (usually by suction through a sieve or vibration sieve in accordance with the standards AFNOR) or by laser granulometry. The percentage errors of the approximate and usually is about 10% at screening, and about 2% by laser granulometry. Preferably, the particles generally have a size in the range of 10 to 80 μm, preferably from 10 to 50 μm. More preferably the particulates have a size of from 10 to 45 μm, and more preferably from 15 to 40 microns.
In the framework of the present invention, the microparticles can be of any shape. According to a variant of execution of the microparticles essentially can be in the form of beads. Under the "particles" in the context of the present invention should be understood microparticles, containing or not containing a coating of biocompatible excipient known to specialists in this field.
Thus, in accordance with the present invention resorbed ceramic microparticles are inorganic and non-metallic material, usually having passed through the processing by annealing at high temperature and under pressure (sintering). The basic structure of ceramic materials is two-phase: vitreous phase (Matri is a) and the crystalline phase (crystalline needles). Traditional ceramic materials are burnt clay, porcelain, faience, glass, etc. New ceramic materials are preferred in accordance with the present invention, have the General properties, such as high corrosion resistance, mechanical properties for dense ceramic materials and ionic electrical properties for industrial applications. There are different collections of ceramic materials, depending on their composition, from which you can specify the calcium phosphates, which are bioactive ceramic materials.
The objective of the implant can be injected into the body of the implant is the formation of the fabric of new collagen fibers, which is usually called the Genesis of the new collagen and which is responsible for filling in wrinkles or skin depressions. It is necessary to start the mechanism, i.e. the synthesis of new collagen fibers, however, the implant should not remain in the body of the ingot for a long time. Indeed, any foreign body implanted in the body, causes nonspecific inflammatory response to a foreign body, so the period of his stay in the body should be medium. The choice of ceramic compounds with defined above for a period of resorption preferably should allow to combine maximum efficiency with a minimum of R is taken.
Indeed, as a rule, it is not desirable to use any preservision implant. So, preferably in accordance with the present invention a ceramic compound, which represents the mineral phase, which is almost completely decomposes or dissolves after subcutaneous or intradermal injection, and then almost completely removed from the body by natural processes.
In addition, the implant in accordance with the present invention preferably should meet the requirements of ease of use, resorption in a controlled period of time as the media, and ceramic compounds, lack of allergenicity of the product (due to the absence of compounds of animal origin) and does not require any preliminary tests.
According to the invention, a ceramic compound, usually has a specific surface area of 0.5 m2/g to 100 m2/g, preferably from 2 m2/g to 27 m2/, As a rule, the specific surface area measured by the BET method.
The present invention also concerns the injected implant, in which the microparticles are present in the liquid medium at the ratio of weight/volume, is strictly greater than 0% and smaller than 15%, preferably comprising from 2% to 12%.
In accordance with the present invention, the ceramic is e connection as a rule, contains at least one element selected from the group comprising tricalcium phosphate (βTCP) and biphasic products (HRV)containing hydroxyapatite (NAR) and βTCP in varying proportions, preferably this element is βTCP, provided that these particles are biorenewable, preferably bioresorbability. Thus, microparticles of a DRUG excluded from the present invention.
Hydroxyapatite (NAR) of General formula CA10(PO4)6(OH)2is closest to the crystals of biological Apatite. Generally, the atomic ratio CA/P (1,67) is less than the atomic ratio in the bone. Tricalcium phosphate (βTCP) has the formula CA3(PO4)2. The ratio of CA/P, as a rule, is 1.5. Two-phase products (HRV) join NAR and βTCP with varying degrees of respect. It should be noted that these products requires consideration of many variables contributing to their biological behavior: elementary composition, the nature of mineral phases, micro - and macroporosity, the presence of impurities.
In the most preferred implementation of the present invention, the ceramic compound is bioactive and therefore has the property chemical exchange with living tissues. By "biological activity" within this is of subramania should understand the property, providing specific chemical reactions in the area of interface between implant and tissue-receptor. It depends on the chemical and physico-chemical properties of the material and the opposite bioinertness (property biocompatible, but inert materials). After implantation, injection connection, as a rule, is a region of the extracellular dissolution and decomposition of the cell of origin, depending on the chemical structure (βTCP, HRV), physical structure (pores) and environmental material. Biological fluid, including liquid medium filling the micropores of the ceramic compounds, calcium fortified.
Decomposition, which preferably is the resorption of the implant in accordance with the present invention, as a rule, should not be too quick to let go of nonspecific inflammatory response to a foreign body, responsible for the synthesis of new collagen fibers. NAR is very little soluble, and the degree of its decomposition, as a rule, is very low in vivo, but varies with pH. βTCP is much more soluble and, as a rule, has a fairly high degree of decomposition in vivo. Two-phase products have properties that vary depending on the relationship between NAR and βTCP. Thus, most always the result of implantation depends on the kinetics of colonization and resorption, which is usually caused by chemical and physico-chemical characteristics of the injected implant in accordance with the present invention; preferably these criteria are monitored, due to the nature of the implant in accordance with the present invention.
For example, ceramic particles are particles Biosorb®sold as particles βTCP SBM.
Typically, the carrier liquid has a limited bioresorption ability, component, usually from about one to four months.
Preferably the liquid carrier of the implant is biocompatible gel, preferably bioresorbables gel.
In a preferred implementation of the present invention carrier liquid is such that the connection on the basis of hyaluronic acid mainly contain hyaluronic acid. The phrase "based on" in the framework of the present invention should be understood that at least the main part of the above-mentioned connection is hyaluronic acid, cross stitched or no, or one of its salts or one of its polysaccharide derivatives.
In a preferred implementation of the present invention mentioned the connection on the basis of hyaluronic acid hyaluronic acid with a molecular weight higher than the surrounding one million daltons, preferably in the range of one million to five million daltons.
The liquid medium may also optionally contain at least one element selected from the group comprising cellulose derivatives such as CMC (carboxymethylcellulose), a receiver array (hypromellose), HPC (hydroxypropylcellulose) and other glucosaminoglycans, in addition to hyaluronic acid.
The implant in accordance with the present invention has the form of microparticles, if necessary, the shape of the beads in suspension in the liquid medium carrying the said microparticles. These particles should have a diameter exceeding 10 μm, in order to avoid rapid or instant phagocytosis by macrophages. They should have a diameter less than 45 microns, so that they can be injected using a very fine needle (usually ranging in size from 25 to 30). Preferably, according to the invention, the carrier liquid is chosen so that it had its own viscosity sufficient for injection through a needle ranging in size from 25 to 30, for example, from 1500 to 4000 m3/kg at 25°and to maintain the homogeneity of the mineral phase, which is a ceramic compound in suspension in the liquid phase, which is the carrier liquid.
Ceramic connection in accordance with the present invention can be obtained Liu is a diversified known specialist way. There are two types of ways, depending on whether the ceramic compound of synthetic or natural (biological). Getting on the first type of method used for ceramic compounds of synthetic origin, are described below. Basic products obtained by chemical synthesis in the form of a powder. Formation for use by subcutaneous or intradermal injection (porosity and shape) requires various operations after firing at a temperature generally below 900°C. Thus, the powder can be sealed under pressure, then heated to a temperature typically in the range of 1100 to 1500°that results in at least partial sintering of the components of the powder. Is melting the above-mentioned components, then the agglomeration of micro-crystals formed upon cooling and remaining in the United state. Internode these microcrystals determine microporosity, i.e., the size of microparticles, at least partially, average size, typically less than 5 microns. Microporosity simultaneously depends on pressure and temperature. Adding to the powder, for example, naphthalene balls preferably can create macroporosity, that is, the size of the microparticles, at least partially, typically exceeding 100 microns. The diameter of the macropores is determined is by the diameter mentioned balls, which they are sublimated at a high temperature.
As for the second type of method used to obtain ceramic compounds of natural origin, it is generally similar to the first type of receipt, that is using the same heat treatment, but on the basis of already existing porous biological structures, often phosphocalcic (corals, bones). Mentioned heat treatment destroys organic elements and leads to ceramization postchallenge basis.
Determination of physico-chemical characteristics of ceramic compounds in accordance with this invention, generally known to the specialist. It can be done by elementary analysis, for example, by quantifying [calcium (CA), phosphorus (P) and trace element(s)], determine whether it is possible audience of heavy elements (pollution) and/or determine the ratio Sa/R. It can also be implemented, in addition to elemental analysis or separately, by using the diffraction of x-rays, for example, in the determination of mineral phases (NAR, βTCP), by determining the degree of crystallinity (size, shape crystals) and/or detection of crystal defects. It can also be implemented, in addition to elemental analysis and/iLike x-ray diffraction or separately, using infrared spectrometry, for example, by defining functional groups (carbonates, the presence of water, organic compounds, ionic substitution, etc.)by structure determination (determination of the surface condition, micro - and macro porosity).
The present invention concerns also a method of obtaining injectable implant in accordance with the present invention, containing the following steps:
- at the preliminary stage get biocompatible ceramic compound as defined above microparticles;
on another stage, regardless of previous preliminary step, get a solution of a liquid medium containing at least one connection based on hyaluronic acid and at least one biodegradable thixotropic connection with pseudoplastic-type properties;
after this ceramic compound obtained in the preliminary stage, injected into the carrier liquid, obtained at different stages during the final stage with the purpose of obtaining a mostly homogeneous suspension, usually by using the homogenization type mixer.
By "liquid media" in the context of the present invention should be understood mixture of a liquid medium, it is possible, in a solvent, preferably in an aqueous solvent.
The injected implant is in accordance with the present invention can be used in ready to use form in a pre-filled syringe, in ready to use form in a pre-filled vial or in the form of dried substances that require pre-cooking prior to use.
The present invention concerns also set for the preliminary preparation of the implant in accordance with the present invention, containing at least one biocompatible ceramic compound and at least one carrier liquid.
Set in accordance with the present invention typically contains in the first part of the ceramic compound and in the second part of the carrier, and allows the application to prepare injectable implant in accordance with the present invention immediately prior to use.
The present invention relates to the use of the injected implant in accordance with the invention, designed to fill wrinkles and/or wrinkles and/or skin depressions and/or scars, containing subcutaneous injection of the implant. It applies to both the human body and an animal body. Thus, this use relates primarily to the field of reconstructive or plastic surgery or to the field of aesthetic dermatology.
The implementation of the invention
These examples and included in our products various connections:p> βTCP
They were selected due to resorption capacity, viscosity and stabilizing properties in suspensions.
Examples of compositions (%, weight/volume):
|Sodium hyaluronate||2%||Sodium hyaluronate||2,2%|
|Xanthan gum||0,5%||Xanthan gum||0,5%|
|Sodium hyaluronate||2,2%||Sodium hyaluronate||2,2%|
|Xanthan gum||0,6%||Xanthan gum||0,6%|
|Sodium hyaluronate||1,8%||Sodium hyaluronate||1,8%|
|Xanthan gum||1%||Xanthan gum||1%|
|Sodium hyaluronate||1,6%||Sodium hyaluronate||1,6%|
|Xanthan gum||0,8%||Xanthan gum||0,8%|