KR100263443B1 - Biodegradable implant precursor - Google Patents

Abstract

PURPOSE: A kit for forming a biodegradable implant precursor is provided to control a placement of a polymer solution for forming an implant precursor easily in an implanted site. CONSTITUTION: The kit for forming a biodegradable implant precursor comprises a device for forming the implant precursor in vitro comprising (i) a part for maintaining a polymer solution while forming the implant precursor, (ii) a part for compressing a polymer solution while forming the implant precursor, and (iii) a part for hinge-connecting the maintaining part to the compressing part; at least one spacer part(8,9) for keeping a space between the maintaining part and the compressing part; a vial containing a polymer mixture composed of a bio-compoundable, biodegradable, water-coagulant thermoplastic polymer and a pharmaceutically acceptable water-miscible organic solvent; and a vial containing an aqueous medium source.

Description

Biodegradable Implant Precursor Kit {Biodegradable Implant Precursor}

Infection of the gum tissue by plaque bacteria during periodontal disease causes the ligaments attaching to the gums and teeth to contract, demineralize the bone tissue that supports the root and to form periodontal pockets in the gum tissue adjacent to the teeth. Successful periodontal restoration is known to occur in gum epithelial cells, gum fibroblasts or osteoblasts when the periodontal ligament cells are left to implant the root surface. Surgery alone, however, does not restore the damaged periodontal.

Implant technology has been developed to promote periodontal restoration and to achieve periodontal restoration. For example, Millipore Filters and Gore-TexMembrane microporous membranes have been developed for use in periodontal tissue regeneration. The periodontal flap is typically incised and a microporous membrane surgically inserted to cover the surface of the root and physically block the epithelial cells from moving along the root surface.

These membranes have several drawbacks. In addition to the variable results, a second surgery is required to remove the membrane after tissue regeneration is achieved since the membrane is not biologically degraded. In addition, there is a high degree of infection associated with the use of these membranes.

In order to rule out surgical removal of the implant, microfibrillary collagen, polylactic acid and polygalactin (bicyclyl Membranes made of biologically absorbent materials such as meshes were used. Fitting and positioning these membranes at the site of implantation is cumbersome and time consuming, and the therapeutic effects of these membranes cannot be ascertained. In addition, the degradation time of the membrane composed of collagen is variable, and the risk of adverse immune response to such heterologous protein material is inappropriate in the body.

Thus, liquid systems containing biodegradable polymers have been developed, in which case the liquid is injected into the implant and solidified at that location to form a biodegradable implant with a solid microporous matrix. Implants do not require surgical removal. However, it is difficult to control the transfer and suppression of the liquid system within a specific zone within the implantation site, and the liquid may spread to other zones than the implantation site.

Accordingly, there is a need for an article that facilitates control of placement at the implantation site of the liquid polymer solution to form the implant. There is also a need to develop precursors for solid grafts that solidify in place and are neither complete liquids nor completely solids to form solid microporous implants. There is also a need for precursors to solid grafts that can be applied to tissue defects in animals and can be molded in place to conform to tissue defects. What is also required is the development of in vivo and ex vivo forming means for making implant precursors having such properties.

These and other objects are in accordance with the present invention comprising an apparatus for forming an ex vivo biodegradable implant precursor which, when implanted in an animal such as a human or other mammal, is cured at that location and becomes a solid transplant with a microporous matrix. Achieved by a kit for forming a biodegradable implant precursor ex vivo.

The implant precursor (IMPLANT PRECURSOR) is a two-part structure consisting of an outer bag (OUTER SAC) with liquid contents. Implants precursors consist of biocompatible, biodegradable and / or biocorrosive, water-coagulating thermoplastic polymers or copolymers that are insoluble in pharmaceutically acceptable water-soluble organic solvents and aqueous media. The two-part structure of the implant precursor is formed by contacting a portion of the aqueous coagulant polymer solution with water or other aqueous media to disperse the solvent into the aqueous media. This causes the polymer to solidify on the surface of a portion of the polymer solution adjacent to the aqueous medium to form an outer bag having a constant viscosity, from gelatinous to waxy, while the solution inside the bag (i.e. the bag contents) remains liquid. do. The bag contents of the implant precursor may change from viscous to a slight viscous form.

The implant precursor can be applied to the site of implantation of an animal, such as a void, defect, incision or hard or soft tissue. Once located at the implant site, the implant precursor forms a solid microporous implant by dispersion of the organic solvent into the surrounding tissue fluid and further coagulation of the polymer. The resulting matrix of the implant preferably has a highly porous inner nose portion and a bilayer pore structure in which an outer layer or epidermis with relatively few pores is formed. Pores are formed in the solid matrix of the implant by dispersing the solvent from the composition into the surrounding tissue fluid. Optionally, the implant precursor may include separate pore forming agents such as sucrose, sodium chloride, cellulose based polymers, and the like, which can create pores in the polymer matrix of the solid implant.

The resulting solid graft is biodegradable, bioabsorbable and / or biocorrosive and is gradually absorbed into surrounding tissue fluids such as serum, lymph, cerebrospinal fluid (CSF), saliva, etc., and is capable of enzymatic, chemical or cytogasification. Through the decomposition. In general, the implant will be absorbed over about 2-3 years, preferably within about 1-9 months, more preferably within about 60-80 days. Implants may also be used, for example, for selective enhancement of cell growth and tissue regeneration and for the transport of biologically active substances to animals.

Implants precursors may also include bioactive agents such as anti-inflammatory agents, antiviral agents, antimicrobials, growth factors and hormones useful for treating and preventing infections at the site of transplantation. Implants obtained from in situ coagulation of the implant precursors may also serve as a system for transporting the bioactive agent to the animal. Release rate modifiers may also be included in the implant precursor to control the rate of degradation of the implant matrix and / or the rate of in vivo release of the bioactive agent from the implant matrix. Suitable materials for inclusion as release rate regulators include dimethyl citrate, triethyl citrate, ethyl heptanoate, glycerin, hexanediol and the like.

The implant precursor is (a) coating a surface of a suitable support substrate with an effective amount of an aqueous medium to form a layer, (b) water-coagulating such as polylactide, polycaprolactone, polyglycolide or copolymers thereof Distributing an effective amount of a liquid polymer solution made of a biodegradable thermoplastic polymer and a water-soluble pharmaceutically acceptable organic solvent such as N-methyl-2-pyrrolidone to the aqueous layer, and (c) dispensing an effective amount of the aqueous medium of the polymer solution. It may be formed in vivo or ex vivo by adding to the surface and (d) leaving the polymer adjacent to the aqueous medium to solidify to form an implant precursor having an outer pocket containing the liquid contents. The thickness of the implant precursor is preferably controlled by compressing the mass of polymer that solidifies between two solid flat surfaces such as, for example, glass plates, porous plastics. An aqueous medium is added to the surface of the support substrate and the surface of the polymer solution in small but effective amounts to initiate coagulation of the polymer to form the outer pocket of the implant precursor.

Implant progenitors may also be formed in vivo by dispensing the polymer solution into soft or hard tissue or other support substrates of the animal body. Precursors may also be formed ex vivo by decomposing the polymer solution into a support substrate made of glass, porous plastic, sintered stainless steel, porcelain, bone and other similar materials.

In the modification method of forming the implant precursor, a certain amount of the liquid polymer solution is added to the surface of the support substrate to form a line (line) that outlines a boundary around a certain zone. Implant precursors can then be formed within the boundaries of the border zone. If the borderline is formed in tissue defects in vivo, the implant precursor may be prepared outside the body and applied to the defect within the boundaries of the borderline.

Optionally, a support layer may be applied to the tissue surface to provide an adhesive substrate for securing the implant precursor to the surface of the tissue defect. Materials useful for forming the adhesive support layer include, for example, the liquid polymer solution, water-soluble materials such as gelatin, and the like. The support layer may be in the form of a bead, film or film having a thickness as desired.

The apparatus for forming the implant precursor ex vivo is preferably a two-part assembly comprising support means for maintaining the polymer solution on a surface such as a porous plate or block during formation of the implant precursor and means for pressing the polymer solution during formation of the implant precursor. Do. The support means and the crimping means are preferably connected together by a hinge connecting means located along one side of the support means and the crimping means so that the crimping means can be rotated and positioned in the polymer solution on the support means. The support means and / or the pressing means are preferably made of a porous material such as porous plastics, sintered stainless steel, porcelain and other similar materials which are absorbent to water. The aqueous medium is applied as a layer to the surface of the support means, the polymer solution is applied to the aqueous layer, and the second aqueous layer is applied to the polymer solution. Two or more spacers, such as washers, are preferably disposed on the surface of the support means to form a constant zone therebetween, and the implant precursor is preferably formed in the zone between the spacers. It is then preferable to place the pressing means on a support having a spacer to solidify the polymer solution interposed therebetween and to squeeze the solidified polymer mass. The support and compression means of the device are held in a sandwich arrangement until the outer pocket of the implant precursor is formed.

The implant precursor obtained by separating the support and compression means is then removed from the device, trimmed to the desired position and placed on the implant site.

The kit according to the invention comprises a certain amount of the above-described polymer solution in a precursor forming device, one or more barrier means, one or more vials or other vessels, and an amount of phosphate buffered saline in one or more vials or other similar vessels. Kits according to the present invention may include tweezers or other similar means for picking up the formed implant precursor; Calibrated tweezers or other similar means for measuring the dimensions of tissue defects and / or implant precursors; Lattice molds or other similar means for measuring the dimensions of an implant precursor; Surgical scalpels, razors, or other similar means for trimming the implant precursor to a desired size; And / or cotton pads or other similar means for absorbing the aqueous medium from the surface of the implant precursor.

Implant progenitors may be used, for example, to enhance cell growth and tissue regeneration, wound and organ repair, nerve regeneration, soft and hard tissue regeneration, and the like.

The implant precursors described above are applied and left to tissue defects to coagulate with implants having a solid microporous matrix.

As used herein, the term “graft site” refers to a site where an implant precursor is formed or applied to hard tissue such as bone or soft tissue such as muscle or fat. Examples of transplant sites include tissue defects such as tissue regeneration sites; Void spaces such as periodontal pockets, surgical incisions or other formed pockets or cavities; Congenital sinuses such as oral, vaginal, rectal or nasal, and blindness of the eye; And other sites where the implant precursor may be located to form a solid implant.

'Biodegradable' means that the polymer and / or polymer matrix of the implant is decomposed over time by enzyme action, hydrolysis and / or other similar mechanisms in the human body, and is referred to as 'biocorrosive' Means that the implant matrix is corroded or degraded for a long time due to at least partly contact with substances found in surrounding tissue fluids and cellular action, and the term 'bioabsorbability' means that the polymer matrix is Decomposed and absorbed in the human body means.

Since the implant precursor does not flow like a liquid, it is easy to manipulate and deploy the liquid polymer system to form the implant in the selected zone of the tissue defect without freely flowing the polymer solution out of the zone of the implant. The implant precursor provides a system for forming an implant having a predetermined thickness, size, and shape. Unlike solid implants, implant precursors are easy to manipulate and may be molded within the defect site because they solidify. Advantageously, the moldability of the implant precursor allows the precursor to conform to cracks, cracks, holes, etc. at the tissue junction site. In addition, the surface of the implant precursor is sticky to the touch and tends to be properly maintained when applied to tissue bonds. Implant precursors consist of a biodegradable, water-solidified thermoplastic polymer and a water-soluble, non-toxic organic solvent.

When implanted into the body of an animal, the organic solvent of the implant precursor is dispersed into the surrounding tissue fluid and the polymer coagulates to form a solid microporous implant. The resulting solid implants have a variety of uses, such as barrier systems to enhance cell growth and tissue regeneration, and the transport of biologically active agents such as drugs.

Polymer solution

Biodegradable, such as polylactide, polycaprolactone, polyglycolide or copolymers thereof, as described in US Pat. No. 4938763 (July 3, 1990), which is incorporated by reference, for preparing implant precursors. A liquid polymer solution is prepared which is composed of a water-soluble, non-toxic organic solvent such as thermoplastic polymer which is water-coagulating and N-methylpyrrolidone. The polymer solution may optionally include a pore former.

Polymers or copolymers are virtually insoluble in water and body fluids and are biodegradable and / or biocorrosive in the body of an animal. The implant precursor and the resulting solid implant are biocompatible in that the polymer, solvent and polymer matrix do not cause actual tissue irritation or necrosis at the implant site.

Thermoplastic Polymer

Thermoplastic polymers useful in liquid polymer solutions for forming implant precursors include biodegradable, bioabsorbable, and pharmaceutical compatible polymers that soften when exposed to heat but return to their original state when cooled. The thermoplastic polymer may be dissolved in an aqueous carrier or solvent to form a solution. In addition, the thermoplastic polymer may solidify or solidify to form an outer bag having a constant viscosity from gelatin type to wax type, and the dispersion of the solvent component from the polymer solution and the polymer coagulate upon contact with the aqueous medium to form a solid microporous matrix. Can be formed.

In general, thermoplastic polymers suitable for use in the polymer solution include those having the above properties. Examples include polylactide, polyglycolide, polycaprolactone, polyanhydride, polyamide, polyurethane, polyesteramide, polyorthoester, polydioxanone, polyacetal, polyketal, polycarbonate, polyphosphazene , Polyhydroxybutyrate, polyhydroxy valerate, polyalkylene oxalate, polyalkylene succinate, poly (maleic acid), poly (amino acid), poly (methyl vinyl ether), poly (maleic anhydride), chitin, Chitosan and copolymers, tetrapolymers or mixtures thereof. Polylactide, polycaprolactone, polyglycolide and copolymers thereof are very preferred thermoplastic polymers.

The thermoplastic polymer is mixed with a suitable organic solvent to form a solution. The solubility or miscibility of the polymer in the individual solvent can vary depending on factors such as the crystallinity, hydrophilicity, hydrogen bonding capacity and molecular weight of the polymer. Thus, the molecular weight and concentration of the polymer in the solvent are adjusted to achieve the desired solubility. Highly preferred thermoplastic polymers are those having low crystallinity, low hydrogen bonding, low solubility in water and high solubility in organic solvents.

Solvent

Suitable solvents for use in thermoplastic polymer solutions are biocompatibility, pharmaceutical acceptability, miscibility with polymer components and water, and aqueous media such as tissue fluids surrounding the implanted site, such as serum, lymph, cerebrospinal fluid (CSF) and saliva, for example. Are things that can spread into it. The solvent preferably has a Hilderbrand (HLB) solubility ratio of about 9-13 (cal / cm 3) ^1/2 . The polarity of the solvent must be effective to provide at least about 10% solubility in water and to dissolve the polymer component.

Useful solvents for liquid polymer solutions include, for example, alkyl esters such as N-methyl-2-pyrrolidone, 2-pyrrolidone, C ₂ -C ₆ alkanols, propylene glycol, acetone, methyl acetate, ethyl acetate, ethyl lactate, Alkyl ketones such as methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, dialkylamides such as dimethyl sulfone, cyclic alkylamides such as tetrahydrofuran, caprolactam, decylmethyl sulfoxide, oleic acid, propylene carbonate, NN-diethyl-m- Aromatic amides such as toluamide, 1-dodecylazacycloheptan-2-one and the like. Preferred solvents are N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate and propylene carbonate.

Mixtures of solvents that provide varying solubility in the polymer component may be used to increase the solidification rate of the polymer, which exhibits a slower solidification rate. For example, the polymer may be a good solvent (i.e., a solvent that provides a high degree of solubility) and a poor solvent (i.e., a solvent that provides a low degree of solubility) or a nonsolvent (i.e., a solvent in which the polymer does not dissolve) with respect to the polymer component. It may also be mixed with a coagulation solvent system consisting of a mixture of). The solvent mixture preferably contains an effective amount of good solvent and poor solvent or nonsolvent in the mixture so that the polymer remains soluble when the polymer is in solution but solidifies upon dispersion or diffusion of the solvent into the surrounding tissue fluid at the implantation site.

In general, the concentration of the polymer in the liquid polymer composition will achieve rapid and effective dispersion of the solvent and solidification of the polymer. This concentration is approximately saturation from about 0.01 g of polymer per ml of solvent, preferably from about 0.1 g per ml of saturation.

Upon contact with an aqueous medium such as water, serum, body fluids such as lymph, and the like, the solvent diffuses from the polymer solution into the aqueous medium. This causes the polymer to solidify adjacent to the aqueous medium at the surface of the polymer solution to form a two-part structure consisting of an outer bag with liquid contents. The liquid content of the implant precursor may range from viscous to sticky. The outer bag can range from viscous gelatin form to moldable wax form. The resulting implant precursor may then be applied to the site of implantation. Upon implantation, the solvent from the implant precursor is dispersed into the surrounding tissue fluid to form an implant with a solid polymer matrix.

The implant precursor solidifies in place within about 0.5-4 hours after implantation, preferably within about 1-3 hours, more preferably within about 2 hours, to become a solid matrix.

Pore forming and pore forming agent

When placed at the implant site of the animal, the implant precursor solidifies to form a solid microporous matrix structure. The matrix preferably consists of a microporous inner core portion and an outer microporous epidermis. The pores of the inner core portion are preferably formed uniformly, and the epidermis of the solid implant is virtually nonporous relative to the porous nature of the core. The outer epidermal portion of the implant preferably has pores with a diameter that is significantly smaller in size than the pores of the inner core portion.

The pores may be formed in the matrix of the implant by several means. Dissipation, diffusion, or dispersion of the solvent from the polymer matrix to be solidified into the adjacent tissue fluid may produce pores including pore channels in the polymer matrix. Dispersion of the solvent from the solidified mass forms pores in the solid implant. The pore size of the solid implant ranges from about 1-1000 microns and the pore size of the epidermal layer is preferably about 3-500 microns. Solid microporous implants have a porosity of about 5-95%.

Optionally, pore formers may be included in the polymer solution to create additional pores in the polymer matrix. The pore forming agent may be a pharmaceutically acceptable organic or inorganic water soluble material that is soluble in water and body fluids and that disperses from the solidified polymer matrix and / or solid matrix of the implant into the surrounding body fluid at the site of implantation. Porous matrices formed by mixing pore formers have similar pore structures in size.

The pore former is preferably soluble or dispersible in an organic solvent to form a homogeneous mixture with the polymer as a dispersion or suspension or as a solution. The pore former may also be a water immiscible material that quickly decomposes into a water soluble material. The pore former is preferably mixed with the thermoplastic polymer and the solvent in the mixture before the matrix is formed. Suitable pore-formers that can be used in the polymer composition include, for example, sugars such as sucrose and dextrose, salts such as sodium chloride and sodium carbonate, hydroxylpropyl cellulose, carboxymethylcellulose, polyethylene glycol, and polymers such as polyvinylpyrrolidone. Solid crystals, such as salts or sugars, which provide a constant pore size are preferred.

When the implant precursor is applied to the site of implantation, the solvent and / or pore former is dissipated into the surrounding body fluids. This causes microporous channels to form in the polymer matrix to be solidified. Optionally, the pore-forming agent may be dispersed from the matrix into the surrounding tissue fluid at a rate slower than that of the solvent, or may be released from the matrix for a long time by biodegradation or bioerosion of the matrix. The pore-forming agent is a implant matrix that coagulates within a short time after implantation to form a matrix having porosity and pore structure effective for performing the special purpose of the implant, such as a barrier system for tissue regeneration and a matrix for sustained release of the drug. Preferably dispersed from.

The porosity of the solid implant matrix can be varied by the concentration of water soluble or water miscible components such as solvents and / or pore formers in the polymer composition. For example, high concentrations of water soluble materials in thermoplastic compositions can produce polymer matrices with high porosity. The concentration of pore former for the polymer in the composition may be altered to achieve different degrees of pore formation or porosity in the matrix. Generally, the polymer composition will comprise about 0.01-1 g of pore former per gram of polymer.

The size or diameter of the pores formed in the matrix of the solid implant may vary depending on the size and / or distribution of the pore forming agent in the polymer matrix. For example, pore formers that are relatively insoluble in the polymer mixture may optionally be included in the polymer composition depending on the particle size to produce pores having a diameter corresponding to the size of the pore former. Pore forming agents that are soluble in the polymer mixture may be used to alter the pore size and porosity of the implant matrix by the distribution and / or aggregation pattern of the pore forming agent in the polymer mixture and the solid polymer matrix to be solidified.

When the implant is used to promote guided tissue regeneration, the diameter of the pores in the matrix is preferably effective to inhibit epithelial cell growth and to promote the growth of connective tissue cells into the polymer matrix of the implant. It is also desirable that the size of the pores and porosity of the matrix of the implant facilitate the diffusion of other growth promoters, such as nutrients and growth factors, into the cells grown into the matrix. The degree of porosity of the matrix is desirable to provide an implant that is capable of maintaining structural integrity for a desired period of time without being damaged or broken during use.

In order to provide an implant effective for bone cell regrowth and tissue regeneration, the diameter of the pores of the implant is preferably about 3-500 microns, preferably about 3-200 microns, more preferably about 75-150 microns . The matrix preferably has a porosity of about 5-95%, preferably about 25-85%, to provide optimal internal growth and optimal structural integrity of the cells and tissues into the matrix.

The pore diameter and distribution in the polymer matrix of the solid implant can also be determined by scanning microscopy, for example by irradiation of the cross section of the polymer matrix. The porosity of the polymer matrix may be measured according to suitable methods known in the art, such as, for example, mercury injection porosity measurements, specific gravity or density comparisons and calculations from scanning electron micrographs. In addition, the porosity may be calculated according to the percentage of water soluble materials included in the polymer composition. For example, a polymer composition containing about 30% polymer and about 70% solvent and / or other water soluble components will result in an implant having a polymer matrix of about 70% porosity.

Bioactive agent

Optionally, the polymer solution may include the bioactive agent alone or in a mixed state such that the implant precursor and the implant provide a delivery system of the bioactive agent to adjacent or remote tissues and organs of the animal. Implants Precursors and bioactive agents that can be used alone or in combination with the implants can provide a local or systemic biological, physiological or therapeutic effect, for example, on the body of an animal, including a mammal, There are drugs or other suitable biological, physiological or pharmaceutical actives that can be released from the matrix into adjacent or surrounding tissue fluid.

The bioactive agent may be soluble in the polymer solution to form a homogeneous mixture or may be insoluble in the polymer solution to form a suspension or dispersion. Upon implantation, the bioactive agent is mixed into the implant matrix. Since the matrix degrades over long periods of time, the bioactive agent is preferably released from the matrix into adjacent tissue fluid at a controlled rate. The release of the bioactive agent from the matrix may be altered by, for example, the solubility of the bioactive agent in the aqueous medium, the distribution of the active agent in the matrix, the size, shape, porosity, solubility and biodegradability of the implant matrix.

Polymer solutions, implant precursors and implants comprise bioactive agents in an amount effective to provide the animal with the desired level of biological, physiological, pharmacological and / or therapeutic effect. In general, there is no upper limit on the amount of bioactive agent included in the polymer solution. The only limitation is the physical limitation for advantageous applications. That is, the bioactive agent should not be present in high concentrations that are too high to inject solution or dispersion viscosity. The lower limit of the amount of bioactive agent mixed into the polymer solution will depend on the time required for the activity and treatment of the bioactive agent.

The bioactive agent may also stimulate biological or physiological activity on the animal. For example, bioactive agents may act to enhance cell growth and tissue regeneration, act as a birth control, and cause neurostimulation or bone growth.

Examples of useful bioactive agents include substances that can promote the growth and survival of cells and tissues or increase the function of cells or their metabolic precursors, such as nerve growth promoters such as gangliosides, nerve growth factors, and the like; Hard or soft tissue growth promoters such as fibronectin (FN), human growth hormone (HGH), protein growth factor interleukin-1 (IL-1), and the like; Bone growth promoters such as hydroxyapatite, tricalcium phosphate and the like; And antiviral agents such as vidarabine or acyclovir, antibacterial agents such as penicillin or tetracycline, and substances useful for preventing infection at implanted sites such as antiparasitic agents such as quinacrine or chloroquinine.

Suitable bioactive agents also include anti-inflammatory agents such as hydrocortisone, prednisone, and the like; Antibacterial agents such as penicillin, cephalosporin, bacitracin and the like; Insect repellents such as quinacrine, chloroquinine and the like; Antifungal agents such as nystatin, gentamicin and the like; Antiviral agents such as acyclovir, ribaribin, interferon and the like; Anti-tumor agents such as methotrexate, 5-fluorouracil, adriamycin, tumor specific antibodies conjugated to toxins, tumor necrosis factors, and the like; Analgesics such as salicylic acid, acetaminophen, ibprofen, flurbiprofen, morphine and the like; Local anesthetics such as lidocaine, bupivacaine, benzocaine and the like; Waxy such as hepatitis, influenza, measles, rubella, tetanus, polio, rabies and the like; Central nervous system agents such as sedatives, B-adrenergic agonists, dopamine and the like; Growth factors such as colony stimulating factor, platelet induced growth factor, fibroblast growth factor, transforming growth factor B, human growth hormone, bone morphogenic protein, insulin type growth factor and the like; Hormones such as progesterone, follicle stimulating hormone, insulin, somatotropin and the like; Antihistamines such as diphenhydramine, chlorphencramine, and the like; Cardiovascular agents such as digitalis, nitroglycerin, papaverine, streptokinase, and the like; Cimetidine, hydrochloride; Anti-ulcer agents such as isopropamide, iodide and the like; Bronchodilators, such as metaprotenal sulfate, aminophylline, and the like; Vasodilators such as deophylline, niacin, minoxidil and the like; And other similar materials. Another example of a bioactive agent is as described in US patent application Ser. No. 07 / 783,512, filed Oct. 28, 1991.

Thus, the implants formed may function as a delivery system for drugs and other bioactive agents to tissues adjacent to or away from the implant. The bioactive agent is preferably mixed with the polymer matrix and released into the surrounding tissue fluid and associated body tissue or organ.

Release control of bioactive agent

The release rate of the bioactive agent and / or the degradation rate of the implant in vivo can be controlled by altering the form and molecular weight of the polymer, including the release rate control agent and / or altering the formulation and concentration of the components constituting the polymer solution.

The release rate of the bioactive agent from the implant matrix can be controlled by altering the molecular weight of the polymer contained in the polymer solution. For the implant matrix formed via the liquid polymer solution, it was found that the release rate of the bioactive agent follows the 'U' curve as the molecular weight of the polymer increases. That is, the release rate of the bioactive agent decreases as the molecular weight of the polymer increases, passes through the lowest point, and then increases again. As a result, the polymer solution can be formulated in the optimum polymer molecular weight range such that the bioactive agent is released over a selected time. For example, in order to achieve a relatively rapid release of the bioactive agent from the implant matrix, the polymer molecular weight at either of the lowest points for the particular polymer will be used in the polymer solution. For the release of bioactive agents over a relatively long time, the polymer molecular weight at the lowest point for a particular polymer is preferred.

For polymer systems, the typical minimum release rate of the bioactive agent from the solid implant matrix occurs at an intrinsic viscosity (I.V. deciliter / g) of about 0.2, but may vary depending on the composition of the polymer solution. In order to achieve sustained release of the bioactive agent from the implant matrix, it is desirable to adjust the polymer's molecular weight to at least about 0.1 intrinsic viscosity (I.V.) or to a molecular weight of about 2000 by gel permeation chromatography. Typically, the acceptable sustained release rate is about 0.8 I.V. Or a molecular weight of about 100,000 or less. More preferably, the molecular weight is adjusted to fall within the range of about 0.1-0.5 I.V. for effective sustained release. The desired molecular weight range for poly (DL-lactide) or lactide-co-glycolide systems is about 0.1-0.5 I.V. If the molecular weight of a particular polymer is selected from these parameters and the release of the bioactive agent is too slow or too fast, the release rate can be changed simply by measuring several experimental points along the U curve for the polymer and adjusting the molecular weight.

The molecular weight of the polymer can be altered by various methods known in the art. Typically, the choice of method is determined by the type of polymer solution to be composed. For example, when a biodegradable thermoplastic polymer is used by hydrolysis, the molecular weight can be changed, for example by controlled hydrolysis in a steam autoclave. Typically, the degree of polymerization can be controlled, for example, by varying the number and form of reactive groups and the reaction time.

Further description of controlling the release rate of the bioactive agent from the implant matrix by changing the polymer composition of the polymer solution is described in US patent application Ser. No. 07 / 776,816, filed Oct. 15, 1991.

Emission control

The polymer solution may also include a release rate modifier to provide controlled sustained release of the bioactive agent from the solid implant matrix. Release rate modifiers are believed to alter the release rate of the bioactive agent from the implant matrix by altering the hydrophobicity of the polymer implant.

The use of release rate modifiers may be in the range of magnitudes of folds (eg, 1-10-100), preferably up to a 10-fold change, compared to release of the bioactive agent from a solid matrix without release rate modifiers. It may also reduce or increase the release of. For example, naltrexone and doxycycline are virtually completely released from the polymer matrix composed of poly (DL-lactide) within about 2-3 days ex vivo. By the addition of release rate modifiers such as ethyl heptanoate hydrophobic to the polymer solution and formation of the implant matrix by interaction of the polymer solution with the aqueous medium, the release rate of naltrexone or doxycycline is achieved in about 7 days with complete release of the drug. May be delayed to cause When a large amount of release rate controlling agent is mixed into the polymer solution, the release period can be increased up to about 14 days. Other hydrophilic rate modifiers, such as polyethylene glycol, may increase the release of the bioactive agent. With the appropriate choice of polymer molecular weight and an effective amount of release rate control agent, the release rate and extent of release of the bioactive agent from the implant matrix may vary from relatively high speed to relatively low speed, for example.

Useful release rate modifiers include, for example, organic materials that are water soluble, miscible with water, or water insoluble (ie, incompatible with water), with water insoluble materials being preferred. Release rate modifiers are preferred for organic compounds that increase the flexibility and the ability of the polymer molecules to substitute second molecules between the polymer molecules as complement molecules for bonding and slide past each other. Such organic compounds preferably contain hydrophobic and hydrophilic zones for carrying out the bond of the second atom. The release rate control agent is preferably compatible with the mixture of solvent and the polymer used to prepare the polymer solution. Release rate modifiers are also preferably pharmaceutically acceptable materials.

Useful release rate modifiers include, for example, fatty acids, triglycerides, other similar hydrophobic compounds, organic solvents, plastic compounds and hydrophobic compounds. Suitable release rate regulators are, for example, 2-ethoxyethyl acetate, methyl acetate, ethyl acetate, diethyl phthalate, dimethyl phthalate, dibutyl phthalate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate Esters of mono-, di- and tricarboxylic acids such as acetyl tributyl citrate, acetyl triethyl citrate, glycerol triacetate and di (n-butyl) secatetate and the like; Polyhydroxy alcohols such as propylene glycol, polyethylene glycol, glycerin and sorbitol; fatty acid; Triesters of glycerol such as triglycerides, epoxidized soybean oil and other epoxidized vegetable oils; Sterols such as cholesterol; Alcohols such as C ₆ -C ₁₂ alkanols and 2-ethoxyethanol. Release rate modifiers may be used alone or in combination with other such drugs. Suitable mixtures of release rate regulators are, for example, glycerin / propylene glycol, sorbitol / glycerine, ethylene oxide / propylene oxide, butylene glycol / adipic acid. Preferred release rate modifiers are dimethyl citrate, triethyl citrate, ethyl heptanoate, glycerin and hexanediol.

The amount of release rate control agent included in the polymer solution will vary depending on the desired release rate of the bioactive agent from the implant matrix. The polymer solution preferably contains about 0.5-15%, preferably about 5-10% release rate modifier.

Further description of the release rate control or rate control is described in US patent application Ser. No. 07 / 776,818, filed Oct. 15, 1991.

Other factors for controlling the release rate

The release rate of the bioactive agent from the implant matrix can also be controlled by changing the concentration of the polymer in the polymer solution. For example, the thinner the polymer concentration, the faster the bioactive agent is released from the implant matrix. For example, for systems containing a polymer concentration of about 5% flurbiprofen and about 55% poly (DL-lactide), about 11.4% per day and about 23% cumulative release per day May be provided. For a polymer concentration of about 45%, the cumulative release rate is about 23% per day and about 40% per day.

This effect can be used as desired with other means to more effectively control the release of the bioactive agent from the implant matrix. For example, by controlling the concentration of the polymer and / or bioactive agent with control of the molecular weight and amount of the release rate modifier, a wide range of release rates can be achieved.

The release rate of the bioactive agent from the implant matrix can also be altered by adding additives such as pore formers as mentioned.

Formation of Transplant Progenitors

Multiple methods can be used to form the implant precursor. In general, implant precursors are formed by dispensing a liquid polymer solution onto the surface of a support substrate. The aqueous medium is placed in contact with the polymer solution and then the solvent is diffused from the polymer solution and the aqueous medium is diffused into the solution. This causes the polymer adjacent to the aqueous medium to solidify, thereby forming the outer pocket of the implant precursor.

Suitable support substrates include, for example, hard or soft tissues of animals or in vitro materials such as glass, stainless steel, porcelain, solid plastics or porous plastics. These ex vivo materials may optionally have adhesion layers of different materials, such as nylon filters, or coatings or surface treatments or additives that allow the support substrate to absorb the aqueous medium. The aqueous medium can be blood, saliva or other body fluids when the substrate is in an animal. Aqueous media that can be used in vivo or ex vivo are water and saline solutions. Other aqueous media may be used if the aqueous media cause coagulation of the polymer solution and are therapeutically acceptable.

The aqueous medium may be present on the surface of the support substrate or within the support substrate prior to dispensing the polymer solution or the aqueous medium may be applied to the top and around the polymer solution after the polymer solution is in place. Solidification of the bottom of the polymer solution requires the movement of the aqueous medium underneath the polymer solution.

The amount of aqueous medium used and the time the polymer solution is in contact with the aqueous medium depends on the composition of the polymer solution and the aqueous medium, the nature of the support substrate, the geometry of the device, the amount and dimensions of the polymer solution, and the viscosity desired for the implant precursor. Depends For constant coagulation of the implant precursor, the viscosity of the implant precursor can change from gelatin form to a fairly rigid form that maintains moldable form and shape by increasing the time the polymer solution is in contact with the aqueous medium. After the implant precursor is formed, the aqueous medium may be removed by tilting the support substrate and / or the implant precursor to allow the aqueous layer to drain or by wiping the aqueous layer with an absorbent material such as cotton, gauze pad or sponge. Alternatively, the implant precursor may be trimmed to the desired size and shape and then placed at the implant site. The implant precursor is trimmed within about 1-60 minutes, preferably 1-10 minutes, of the end of the coagulation process and transplanted into the animal. If the implant precursor is not implanted or placed out of contact with the aqueous medium, the implant precursor will soften and return to full liquid phase. This process is caused by the interaction between the outer bag layer and the liquid contents. Redistribution of the solvent and the aqueous medium to the implant precursor destroys the outer pockets formed during the coagulation process, forming a continuous liquid phase.

The dimensions of the implant precursor can be controlled in a number of ways. The thickness of the implant precursor is about 300-1500 μm, preferably about 600-1200 μm. The desired length and width depend on the dimensions of the animal's implantation site. In a preferred method, the thickness is adjusted during the solidification process and the length and width are adjusted in the next finishing step. The polymer solution is distributed to the flat support substrate, and the second flat portion of the support substrate is placed on top of the polymer solution to press the polymer solution thinly until the desired spacing between the support substrates is obtained. This spacing can be defined by spacers or other means for holding the support substrate portions separately. Aqueous media may be present during or after this process. Coagulation of the polymer solution in this confined space results in a sheet of implant precursor material having a uniform thickness of the central and edge portions. The implant precursor is then cut from the center portion of the sheet using a razor blade, surgical scalpel or other means. This finishing step allows control of the length, width and shape of the implant precursor.

Another method of controlling the dimensions of the implant precursor involves dispensing the polymer solution into a support substrate whose desired zone (ie, width, length) is defined by some type of barrier. These can be adjusted as described above or by pulling a flat article such as a spatula or similar means across the surface of the solidified polymer mass. The polymer solution may also be dispensed into recesses or voids in a precast die or mold, or similar device, having dimensions of the implant precursor (ie, width, length, depth or thickness). An additional amount of polymer solution may be added to the surface or edge of the solidified polymer mass to adjust the dimensions.

Various devices may be used to form the implant precursor. One such device that can be used in vivo or ex vivo is a 'tweezers wiper'. The tweezers wiper is constructed by attaching a plate or wire loop with holes to one blade of the tweezers at right angles to the tweezers blade so that when the tweezers blade is unfolded, the second blade sweeps the surface of the plate or wire loop. do. The plate or wire loop is placed in a tissue or ex vivo support substrate such that the hole in the plate or the interior of the wire loop defines a zone for the implant precursor. The polymer solution is then dispensed into this specification and leveled by passing a second blade of tweezers over the polymer solution to level it. An aqueous medium is then added to allow solidification. Alternatively, the aqueous medium is added before the leveling process. Once the implant precursor has sufficiently solidified, the 'pinsen wiper' is separated from the substrate. The resulting implant precursor is then left in place in vivo.

In another embodiment, the implant precursor may be formed in vivo or ex vivo by forming a border on the surface of the support substrate to contain the polymer solution in a defined zone. In order to form a boundary to the support substrate, a certain amount of water or other aqueous medium is added to the surface of the support substrate as a coating, the polymer solution is distributed as a line to the water layer to form a defined zone, and then a certain amount of water is added to the polymer solution. It is added to the surface to cause the surface of the polymer solution to solidify. The resulting border is a two part tubular structure formed by an outer bag with liquid contents. The implant precursor may be formed within the boundaries of the boundary by dispensing an amount of polymer solution to the aqueous layer coated on the support substrate within the boundary zone and adding the aqueous medium to the polymer layer to form a two-part structure of the implant precursor. When the border is formed on the surface of the tissue defect in vivo, the exogenous precursor formed ex vivo may also be applied to the defect in the zone formed by the border. Since the polymer further solidifies to form a solid graft matrix so that the solidified masses conform to the contours of the tissue defect and the graft site, it is desirable to process the graft precursor and its associated boundaries manually by hand. When treating periodontal bone tissue by this method, it is desirable to apply a boundary line to the root and ligament tissue of the bone defect site.

Implant precursor forming device

A preferred method of preparing the implant precursor ex vivo is by the use of a device as shown in FIG. However, various shapes, sizes, and arrangements of the implant precursor forming apparatus can be adjusted as needed.

FIG. 1 shows a preferred device design showing the closure during the solidification process, the device being held together by a hinge 3 at one end and a latch mechanism 4 and 5 at the other end. It consists of the case which consists of (1) (2). Each upper and lower portion comprises a porous hydrophilic plastic sheet 6, 7. When the case is closed, the two porous hydrophilic plastic sheets 6, 7 are held apart by the spacers 8, 9 as shown in FIG. This device is used by opening the case to fill the pores of the porous hydrophilic plastic sheet 6, 7 with an aqueous medium. The polymer solution is dispensed into the porous hydrophilic plastic sheet at the bottom of the case and the case closed as shown in FIG. Spacers 8 and 9 control the thickness of the implant precursor by defining the interval at which the polymer solution is maintained during the solidification process. Once the desired coagulation process has elapsed, the case is opened to trim the implant precursor and then transplant.

FIG. 2 shows in detail the preferred embodiment of the device design shown in FIG. 1, which comprises one part not shown in FIG. This is the finishing grating 10 which is part of the lower part 2 of the case. The case consists of upper and lower parts (1) (2) joined by a hinge (3) formed by snapping two upper and lower parts of the case together. The case consists of gamma-ray resistant polypropylene. Other case materials that are able to withstand sterilization by contact with the polymer solution and gamma-irradiation and can be used that are quite rigid can be used. The latch mechanism (4) (5) allows the opening and closing of the case and as part of the upper and lower portions (1) (2) that are easily snapped together at regular intervals to keep the case tightly closed during the solidification process. Consists of. The porous hydrophilic plastic sheet (6) (7) allows the aqueous medium to fill the pores of the sheet, and then the hydrophilic properties required to exchange the aqueous medium with the solvent between the polymer solution and the aqueous medium in the pores during the solidification process. It is a flat, rigid sheet with porosity. The porosity of the sheet is one factor controlling the rate of solidification. The porous plastic may comprise a mixture of hydrophobic polymers mixed or treated with an inherently hydrophilic polymer or a surfactant or other agent that increases hydrophilicity. The material used in the preferred embodiment is polyethylene mixed with a surfactant. The spacers 8 and 9 are rectangular of gamma-ray resistant polypropylene. The finishing grating 10 is the flat part of the lower part 2 of the case. After the coagulation process, the implant precursor is placed in the finishing grid and trimmed to the desired shape, length and width using a surgical scalpel, razor blade or other similar means. The finishing grating has a shape of 1 mm 2 and assists in finishing to a predetermined dimension. This shape may exist as part of the case itself, may be printed on the case, or may be printed on a label attached to the case. In a preferred embodiment, the shape is printed on a transparent label attached to the underside of the lower part 2. The shape is visible through the transparent label to the slightly blurred lower portion 2 and to the transparent label material. Labeling and printing on the underside of the case precludes the possibility of physical or chemical interaction of the label or print with the implant precursor.

The dimensions of the device depend on the desired dimensions of the implant precursor. In order to produce implant precursors having a length and width of about 20 mm or less and a thickness of approximately 675 μm, the following approximate dimensions are suitable. The spacers 8 and 9 are 675 mu m thick, 0.5 cm wide, and 2.5 cm long. The porous plastic sheet is 4.5 cm long, 3.0 cm wide, and 0.3 cm thick. The finishing grid 10 is 3.5 cm wide and 3.5 cm long. The upper and lower portions 1, 2 of the case are approximately 7.5 cm in width and 5 cm in length, and the pores of the porous plastic sheet 6, 7 are 30 cm in depth. For proper thickness control, the case must be designed such that the spacers 8 and 9 are closed so that they remain firmly between the porous plastic sheets 6 and 7 so that solidification occurs at an interval corresponding to the thickness of the spacer.

Adhesive floor

To increase the adhesion of the implant precursor to the site of implantation, an adhesive layer may be applied to the surface of the tissue, and then the formed implant precursor is placed on the support layer. The adhesive layer assists in supporting the position of the implant precursor when the implant precursor solidifies at the implant site and becomes a solid matrix. The adhesive layer consists of a bioabsorbable, biodegradable and / or bioerodible material that can adhere to the surface of the tissue defect and the surface of the implant precursor. The adhesive layer may be formed, for example, by applying a small but effective amount of the liquid polymer solution to the surface of the tissue defect in the form of beads or as a coating.

Ground floor

To maintain the structure and morphology of the implant precursor or to form the implant precursor directly in vivo, a support layer can be applied to the surface of the tissue, and then the polymer solution or formed implant precursor is placed on the support layer. . Suitable materials for use in forming the support layer include, for example, substances in the blood such as blood clots or other body fluids, water soluble polymers such as gelatin or polyvinylpyrrolidone, and the like.

The support layer for coagulation may be formed, for example, by puncturing the tissue with a needle to allow a small but effective amount of blood to flow and then to stand to coagulate. The formed implant precursor, or the liquid polymer solution itself, may be added to the surface of the support layer at the implant site.

In another embodiment, granules or small pieces of biodegradable porous material, such as polylactic acid, cellulose oxide or gelatin, may be used to fill tissue defects or voids, and then the formed implant precursors may be added to the granular support material. Alternatively, the polymer solution may be dispensed into the support layer to form the implant precursor.

Another useful support layer is a solid matrix having a porous bubble structure. Such matrices may be provided, for example, by mixing air into the polymer solution to provide bubble viscosity, and by allowing the mixture to stand to coagulate into a matrix having relatively large pores and / or cavities.

Bubbles may be mixed into the polymer solution, for example by vigorously stirring the polymer solution and injecting air into the polymer solution using a syringe and other similar means. It is preferable to add an aqueous medium to the surface of the foamed mixture to allow the polymer to solidify to form a matrix with large cavities.

Large pores may also be provided to the solid support matrix by mixing the polymer solution with a gas former, such as a mixture of citric acid and sodium carbonate or sodium bicarbonate. When contacted with an aqueous medium, the gas former reacts to form gas bubbles, such as carbon dioxide, in the polymer matrix that solidify.

If voids are desired between the tissue defect and the solid graft, the support layer is preferably formed of a water soluble and / or highly resorbable material. For example, the support layer is a Johnson & Johnson Co. Needle and commercially available from eopjyon Needle Co. surge jisel ^TM gel or foam-like ^TM oxidized cellulose or gelatin material; Water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol and hydroxypropyl cellulose; And water soluble materials that will dissolve in a few days, such as other materials. The water soluble support layer is preferably dissolved within about 1-14 days, preferably about 2-4 days after implantation of the implant precursor.

If it is desired to promote tissue internal growth from the graft into the stroma, the support layer is preferably composed of a porous material having a relatively long degradation rate. Suitable materials include polylactic acid materials such as Drilllock ^™, commercially available from THM biomedical incorporation typically applied to molar extraction sites to inhibit dry sockets, such as Interpor 200, commercially available from Interpo International. Hydroxyapatite material. Advantageously, a support layer made of a porous material, such as polylactic acid or hydroxyapatite, allows blood to penetrate and coagulate within the matrix providing the nutrients to promote tissue internal growth. Internal tissue growth into the support matrix eventually degrades the support layer.

Kits for Forming Implant Precursors

Kit for forming the implant precursor in vitro in accordance with the present invention comprises (i) a precursor forming device as described above, which is a two-part device hinged along one side; (ii) one or more spacer means such as washers, rods, blocks, etc. to maintain a gap or space between two halves of the device; (Iii) one or more vials or other similar means containing the polymer solution described above; And (iv) one or more vials or other similar means containing an aqueous medium such as water and phosphate buffered saline. The kit may comprise tweezers or other similar means for lifting and holding the formed implant precursor; Devices such as calibrated tweezers for measuring the dimensions of tissue defects and / or implant precursors; Lattice molds and other similar means for measuring the size of the implant precursor, surgical scalpels, razor blades or other similar means for finishing and size the implant precursor; And / or cotton pads or other similar means for removing the aqueous medium from the surface of the implant precursor.

Use of Implant Precursors

Implant precursors may be used to treat various tissue defects. The implant precursor can also be applied to implant sites in animals, such as voids, defects, surgical incisions, etc., of soft or hard tissue by known surgical techniques.

Once placed in the implant site, the implant precursor solidifies into a solid, formable matrix within about 0.5-4 hours, preferably within about 0.75-3 hours, more preferably within about 1-2 hours.

For example, implant precursors can be used in methods for treating bone tissue defects such as arm or leg bone fractures, tooth defects, and the like. When the bone tissue is surgically separated from adjacent soft tissue to expose the defect and the implant precursor is placed in the bone defect, the implant precursor cures at that location to become a solid implant.

Implant progenitors may also be used as barrier systems for guided tissue regeneration. The implant precursor may be formed outside the body of the animal and then administered to a site of implantation, such as tissue having pores such as periodontal pockets, soft tissue defects, surgical incisions, bone defects. Once the implant precursor is administered to the tissue regeneration site, the implant precursor solidifies to form a solid microporous matrix that provides a surface on which cells can grow. In order to increase the regeneration of hard tissues such as bone tissue, it is desirable to provide a support for new cell growth that replaces the matrix as the solid implant matrix is gradually absorbed or corroded by body fluids.

One example of using an implant precursor as a barrier system is the treatment of periodontal disease. For such treatment, the gum tissue placed on the root is surgically incised from the root and bone to form a gingival envelope or pocket, and an implant precursor is placed in the pocket and bone. After placement, the tissue is sutured to seal the pocket and the implant precursor is left to cure to form a solid microporous implant.

The implant precursor may be engineered at the site of implantation to match the contour of the tissue defect. For example, in a periodontal defect, the gum tissue flap may be pushed onto the solidified implant matrix disposed in the exposed root and bone, thereby applying pressure to the surface of the tissue that lies on the solidified matrix. The matrix to be solidified is malleable and such manipulations result in the implant being in a form that conforms to tissue defects on the one hand and to the contours of the tissue on the other hand. The tissue may be shrunk to match the profile (ie, shape) of the implant matrix, and optionally, additional amounts of polymer solution may be added to reinforce the matrix and fill in the rugged portions as needed. If the implant precursor is too large, a portion of the matrix to be solidified may be cut along the edge of the tissue, for example directly above the gum line of the gum tissue pocket. The tissue may then be properly anchored onto the implant matrix, such as by suturing the tissue at either end of the pocket to properly retain the implant and tissue.

To aid adhesion of the implant precursor to the surface of the tissue defect, a bead or coating of the polymer solution described above may be applied on the defect to provide a sticky surface. The implant precursor or liquid polymer solution may then be applied to the surface of the bead or coating.

Implant precursors may also be used to attach the skin grafts to the underlying tissue of the wound. Such use of implant precursors helps to facilitate the prevention and treatment of seroma or hematoma formation. The implant precursor preferably includes topical antibiotics.

Implant precursors may also be used to augment the sutures of surgical incisions, such as incisions through the sternum, for example, for stabilizing the sternum and facilitating healing. In such use, the implant precursor is applied to both sides of the sternum prior to suturing the sternum with metalwires and / or sutures. The implant precursor preferably comprises growth factors and / or antibiotics.

The implant precursor advantageously provides a means for attaching the implant article to tissue covered with a mucus layer, such as, for example, gum tissue. The implant precursor also allows the liquid polymer solution to be applied to the implant site without the free flow of the liquid polymer solution into the band other than the zone identified for treatment. For example, in the treatment of periodontal defects, the use of the implant precursor of the present invention can avoid the accumulation of polymer solution into the space between the periodontal zone where the ligament cells are located and the root. In addition, the implant precursor of the present invention allows the barrier implant to better align to the tissue defect site than other devices that are used in the air.

The microporous polymer matrix of the implant can be biodegradable, biocorrosive and / or bioabsorbed within the implantation site of the animal. The molecular weight of certain polymers and polymers may vary depending on the desired period of time (eg, days or weeks to years) for retaining the solid polymer matrix in the implantation site. When implants are used to enhance cell growth and tissue regeneration, it is desirable that the polymer matrix can be degraded at an rate effective to enable replacement of the matrix by cell growth from adjacent cells or tissues.

The composition of the liquid polymer solution for the preparation of the implant precursor and the administration of the implant precursor and the polymer solution in vivo ultimately depend on the judgment and prescription of a physician who takes care of the patient's health, such as a doctor or dentist. The choice of specific composition of ingredients is made by a health care professional. Solid implants derived from bioactive agent-free implant precursors can function as structures for promoting cell growth and tissue regeneration. Implants with bioactive agents not only function in that capacity, but also deliver the properties of the bioactive agent.

The amount and concentration of ingredients in the implant precursor administered to a patient may generally be effective to achieve the intended task. If such a task is to fill the void gap, an effective amount of the component and an implant precursor having a suitable size will be administered to achieve this task. For administration of the bioactive agent, the amount and release rate will be in accordance with the manufacturer's recommendation of the bioactive agent. Generally, the concentration of bioactive agent in a liquid polymer solution is about 0.01-400 mg per gram of polymer solution.

When explaining the present invention by a preferred embodiment as follows. However, the present invention may be modified in various ways without departing from the spirit and scope of the present invention.

Example 1

Ex vivo formation of implant precursors with porous polyethylene substrates.

A polymer mixture was prepared consisting of about 37% poly (DL-lactide) (DL-PLA) and about 63% N-methyl-2-pyrrolidone (NMP). DL-PLA has a molecular weight of about 65000 Daltons. (Intrinsic viscosity of about 0.50 dL / g in chloroform) A polypropylene vessel was filled with the polymer mixture, each vessel containing about 0.8 g of the polymer mixture. These filled containers were then sterilized by exposure to gamma irradiation at a level of 25-35KGy, resulting in a final molecular weight of DL-PLA of about 38,000 Daltons. (Intrinsic viscosity in chloroform is about 0.34 dL / g)

The apparatus shown schematically in FIG. 2 was used to form the implant precursor from the liquid polymer mixture. The porous polyethylene substrate on each side of the case was saturated with about 2.5 mL of sterile saline. Two polypropylene spacers were placed in the porous polyethylene substrate in the lower half of the case (closest to the finishing grid), parallel to the hinge of the case and parallel to the edge of the porous polyethylene substrate. The vessel filled with the polymer mixture was opened and its contents (approximately 0.6 g) discharged to the center of the porous polyethylene substrate between the spacers. The case was closed, latched and opened again 6 minutes later. Partially hard articles were removed from the porous polyethylene substrate and placed in the attached finishing zone, then trimmed using sterile razor blades and sorted according to size.

Visual inspection of the implant precursor revealed that it was opaque, semi-rigid and flexible. The implant precursor had a two-part structure consisting of a gelatinous outer layer and a more liquid central core. Chemical analysis showed that the implant precursor contained about 58% NMP.

Example 2

Ex vivo formation of implant precursors.

Implant precursors were formed as in Example 1 above but the case was kept closed for 8 minutes. This article was more rigid than the article from Example 1 above.

Example 3

Ex vivo formation of implant precursors.

Implant precursors were formed as in Example 1 above but the case was kept closed for 4 minutes. This article was less rigid than the article from Example 1 above.

Example 4

In Vitro Formation of Transplant Precursor with Free Substrate.

Two spacers with a thickness of approximately 430 μm were constructed by bonding two sets of three glass microscope cover slides together. They were placed on one glass microscope slide that lies in the space between them. Approximately 0.3 g of the same polymer mixture as in Example 1 was dispensed on a microscope slide between spacers using a syringe. Water was sprayed three times on the polymer mixture using an atomizer. After 30 seconds, water spray was repeated. After another 30 seconds, another microscope slide was sprayed with water and then pressed onto the solidified polymer mass and spacer. The solidified polymer mass was sprayed three times with water and then left to cure for 60 seconds. Then three water sprays and 60 seconds of curing were repeated. The glass microscope slide and the solidified polymer mass were then placed on a 1 mm 2 grating, and then the polymer mass was trimmed to the desired size and shape using a sterile razor blade. The cut section was then sprayed three times with water and left to cure for 60 seconds to cure. The gauze pad was then used to remove excess water. Opaque and flexible implant precursors were then prepared for transplantation.

Example 5

Ex vivo formation of implant precursors with free substrates.

A 2-inch by 3-inch microscope slide with a 20-mm by 20-mm graph on the bottom was placed on a 2-inch by 3-inch by 1 / 4-inch Gray-Lite # 14 black background glass. A 1 inch diameter 750 micron stainless steel washer was placed on top of the microscope slide. Washers were placed on the left and right sides of the graph engraved on the bottom. The polymer mixture prepared as described in Example 1 was covered and flattened on the surface of the microscope slide to remove bubbles or non-uniform zones. Sterile isotonic saline was carefully dropped in the middle of the liquid polymer layer and flowed laterally to cover the entire film. The brine was left for 1 minute to remain in contact with the polymer mixture, at which time the outer surface or skin became opaque. The excess brine was then carefully removed by air spray or sponge, and more polymer mixture and brine were added to repeat the whole process to solidify the polymer. After the second layer had solidified for 1 minute, a standard 1 inch x 3 inch glass microscope slide moistened with saline solution was placed in the polymer mixture and pressed to the height of the stainless steel washer (750 μm). In addition, saline was added to the sides of the standard glass microscope slides to soak the underside of the slides. The pressed material was left to cure for at least 10 minutes. Standard microscope slides and washers were then removed and the implant precursor film was cut to the dimension of the periodontal defect using a single razor blade.

Example 6

Application of Implant Precursor to Periodontal Defects.

The first molars of the lower jaw of a 65-year-old man were selected for treatment because of long-lasting pocket depths and branching problems. During surgery, the entire thickness periodontal flap was lifted, the defects were peeled off, the roots were scraped off, and the dimensions of the defects were measured. A custom barrier membrane of the implant precursor prepared according to Example 5 was applied to the periodontal defect to cover the edge of the bone by 2-3 mm approaching the level of the coronal lesion. The precursor material was attached directly to the teeth and bones without requiring proper closure. The buckle flap was in situ on the defect and the implant precursor and sutured to the tongue tongue tissue. Periodontal treatment was applied to the surgical band and systemic antibiotic treatment was performed for 7 days. After a week, the fully formed barrier was placed in place. At 1 month, the barrier was also present but was replaced by the mouth from the tooth surface due to the formation of granulation tissue between the barrier and the root surface. At 6 months of examination, the barrier was no longer apparent and the epithelium grew in the first zone of granulation tissue. At the time of clinical probe measurement, the periodontal pocket depth decreased from 5mm to 2mm, and the adhesion level of tissue to teeth increased from 7mm to 4mm. In addition, the horizontal branch depth was reduced from 5 mm to 3 mm. All clinical measurements showed good tissue regeneration at the site of the defect.

Example 7

Treatment with the use of implant precursors with a backing layer.

The polymer mixture may also be prepared as described in Example 1. The femur of anesthetized male rats may be incised surgically to form defects. Granules of Sergecell ^™ oxidized cellulose may be applied to the defect to stop bleeding and fill the defect. The implant precursor prepared as described in Example 1 may also be applied to the surface of a SugiCell ^™ support layer. The tissue is then returned to its proper closure. The implant precursor further solidifies to become a solid barrier matrix.

Example 8

Treatment of forming an implant precursor on a support layer in vivo.

The femoral bone of the anesthetized male rat may be incised surgically to form a defect, or granules of EG Cell ^TM oxidized cellulose may be applied to the defect to stop bleeding and fill the defect. The polymer mixture prepared according to Example 1 may then be applied directly to the surface of the Sugicell ^™ support layer. Moisture from the tissue defects partially solidifies the liquid polymer, resulting in the formation of the same implant precursor as described in Example 1. The soft tissue is then returned to its proper closure. The implant precursor thus formed becomes more coagulated with the solid barrier matrix.

Example 9

Treatment with Implant Precursors Including Bioactive Agents.

The polymer mixture may also be prepared as described in Example 1. 5% by weight of doxycycline hydrate can also be added to this mixture. Implant articles may then also be prepared in vivo from the drug / polymer mixture as described in Example 1. The implant article may be placed in the periodontal defect as described in Example 6. Doxycycline is distributed from the breakdown of solid barrier implants to prevent bacterial infection.

Example 10

In vivo formation of implant precursors in bone.

The polymer mixture may be prepared as described above in Example 1.

The femoral bone of anesthetized male rats may be surgically incised to form a film with a thin layer of phosphate buffered saline (PBS) solution. The polymer mixture (about 1-3 ml) may be dispensed from a syringe or eye drop onto the surface of bone tissue covered with water. The buffer (about 1-3 mL) may be partitioned into the layers of the polymer mixture. After 2-5 minutes, the polymer mixture solidifies to form a gelatinous outer layer with the liquid contents of the implant precursor.

The implant precursor may be covered with the tissue and the tissue properly closed. Implant precursors gradually solidify into a solid matrix. After 5-10 days, the graft site may be reopened and the graft article mass naturally replaced by internal growth of the bone tissue.

.

1 is a perspective view of an example of an implant precursor forming apparatus.

2 is a perspective view of the implant precursor forming apparatus of FIG. 1 showing the arrangement of a series of spacers.

3 is a side view of the implant precursor forming device of FIG. 2 showing the placement of the aqueous layer and polymer solution layer in the zone between the spacers.

4 is a side view of the implant precursor forming device of FIG. 3 showing the precursor forming device in a closed position during formation of the implant precursor.

.

.

Claims (2)

(a) support means for retaining the polymer solution during formation of the graft precursor, (ii) means for compressing the polymer solution during formation of the graft precursor, and (iii) hinged support means to the compression means. A hinge connecting means positioned along an edge of one of the support means and the crimping means, and the crimping means can be rotated to be positioned with the polymer solution of the support means to form the implant precursor in vitro. Device for making; (b) at least one spacer means for maintaining a gap between the support means and the crimping means and the crimping means when the crimping means is rotated to the support means; (c) a vial containing a polymer mixture consisting of a biocompatible, biodegradable, water-solidifying thermoplastic polymer and a pharmaceutically acceptable water miscible organic solvent; And (d) a vial containing an aqueous medium source. The method of claim 1, further comprising: (e) means for lifting and holding the formed implant precursor; (f) means for measuring the dimensions of the tissue defect or implant precursor; (g) grating means for measuring the dimensions of the graft precursor; (h) means for cleaving the graft precursor; Or (i) at least one of means for removing the aqueous medium from the surface of the graft precursor.