Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08H—DERIVATIVES OF NATURAL MACROMOLECULAR COMPOUNDS
  • C08H1/00—Macromolecular products derived from proteins
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08H—DERIVATIVES OF NATURAL MACROMOLECULAR COMPOUNDS
  • C08H1/00—Macromolecular products derived from proteins
  • C08H1/06—Macromolecular products derived from proteins derived from horn, hoofs, hair, skin or leather
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F289/00—Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds not provided for in groups C08F251/00 - C08F287/00
• • G—PHYSICS
  • G02—OPTICS
  • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
  • G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
  • G02B1/04—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of organic materials, e.g. plastics
  • G02B1/041—Lenses
  • G02B1/043—Contact lenses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea

Definitions

• This invention relates to a biocompatible polymer containing the copolymerization product of a mixture of hydrophobic and hydrophilic acrylic and/or allelic monomers, and telo-collagen preliminarily purified from glucoproteins and proteoglucanes.
• the material is useful for the production of soft intraocular lenses, refractive intraocular contact lenses, and standard contact lenses useful for example, in correcting aphekia, myopia and hypermetropia.
• Polyenic water-solvent ionic monomers may be used in order to produce a water-solvent layer.
• this decreases the resistance of such copolymers against swelling.
• the system of polyenic copolymers, based upon acrylamid or acrylic acid with HEMA has a tendency towards excessive swelling beyond all bounds. This happens because pure homopolymers, polyacrylamide or polyacrylic acid, contained in this system, dissolve in water. Therefore, it is an advantage to produce a polymer which would be able to form such a vital water-solvent layer, and would not affect the polymer resistance against swelling.
• An object of the present invention is to provide a biocompatible optically transparent polymeric material based on telo-collagen.
• a further object of the present invention is to provide a biocompatible polymer containing the copolymerization product of a mixture of hydrophobic and hydrophilic acrylic and/or allelic type-monomers and telo-collagen.
• An object of the present invention is to provide a method of making a biocompatible, optically transparent, polymeric material based on collagen.
• a further object of the present invention is to provide a method of making a biocompatible polymer containing the copolymerization product of a mixture of hydrophobic and hydrophilic acrylic and/or allelic type-monomers and telo-collagen.
• the present invention is directed to methods of making a biocompatible polymeric material based on collagen for use in the produclion of deformable lenses.
• the present invention is also directed to an deformable lens comprised of the present optically transparent, biocompatible, polymeric material.
• the present invention is further directed to methods for making deformable lenses.
• the present invention is also directed to methods for correcting aphekia (absence of the lens of the eye), myopia or hypermetropia in a patient by surgically implanting in the eye of the patient, the present deformable lens.
• the biocompatible polymeric material according to the present invention is made as a copolymerization product of a mixture of hydrophobic and hydrophilic acrylic and/or allelic monomers graft polymerized with telo-collagen.
• one or more hydrophobic acrylic and/or allelic monomers are mixed with one or more hydrophilic acrylic and/or allelic monomers, and the resultant solution is then mixed with telo-collagen dissolved in one or more hydrophilic acrylic and/or allelic monomers.
• the resulting material is then irradiated to form the present biocompatible optically transparent polymeric material.
• the telo-collagen used in the present invention is essentially type IV collagen obtained from pig's eye sclera or cornea.
• the collagen is a naturally stable polyenic, which comprises hydrophobic, hydroxylic and polarized amino-acids (Matsumura, T., Relationship Between Amino-Acid Composition and Differentiation of Collagen, L t. J. Biochem. 5(75,1:265-274 (1972), and Traub W., and Piez K.A., The Chemistry and Structure of Collagen, Advances in Protein Chem 25:243-352, (1971). It is not advisable to use a modified collagen in the system according to the present invention since this collagen biodegrades with time (U.S. Patent No. 4,978,352, December 18, 1990).
• the resulting biocompatible polymeric material is an elastic biopolymer, based upon the mixture of the hydrophobic and hydrophilic monomers and telo-collagen.
• the product of the hydrophobic and hydrophilic monomer copolymerization exhibits an elevated hydrolytic stability and a much higher index of refraction, if compared with a polymer which is based upon hydrophilic monomers alone.
• telo-collagen molecules 320.000D
• their size up to 1000A
• the disorientalion of molecules in space the refraction index 1.47
• the refraction index of the hydrogel base substance, the aqueous number is equal to 1.336, which is substantially different from the refractive index of collagen 1.47, resulting in opacification of the gel, if a suspension of collagen in aqueous monomer is made.
• telo-collagen containing telo-peptide is the basic element of interaction among collagen molecules. This produces a stable gel in the mixture of hydrophobic and hydrophilic monomers, and this gel neither precipitates nor coagulates.
• I. is intensity of incident light
• w light diffusion angle
• C concentration of particles per volume unit
• ⁇ length of incident light wave
• N, refraction index of particles
• V volume of particles.
• a preferred hydrophilic acrylic monomer for use in the present invention is 2- hydroxyethyl melhacrylate (HEM A), and a preferred hydrophobic monomer for use in the present invention is 4-metharyloxy-2-hydroxybenzophenone.
• the telo-collagen is preferably produced from pig's eye sclera or cornea.
• telo-collagen is intended for the purposes of this inventio a naturally stable polyenic, that contains hydrophobic, hydroxylic and polarized amino-acid (Matsumura, T., Relationship Between Amino-Acid Composition and Differentiation of Collage Lut. J. Biochem 3(15):265-214 (1972).
• the present telo-collagen is essentially type IV telo-collagen preferably made from pig' eye sclera or cornea, and has a viscosity of greater than or equal to lOOOcPs.
• the present tel collagen retains the telo-peptides and has a refractive index of about 1.44 to 1.48.
• Biocompatible polymeric material By the terminology “biocompatible polymeri material” is intended a material which is made by combining or mixing one or more hydrophobi monomers (acrylic and/or allelic monomers), and one or more hydrophilic monomers (acryli and/or allelic monomers), and graft-copolymerizing the resultant mixture with a telo-collagen/hydrophilic monomer/acid solution.
• Monomer By the term “monomer” denotes the molecular unit that by repetition, constitutes a large structure or polymer.
• organic acid an acid made up of molecules containing organic radicals.
• Such acids include for example, formic acid (H-COOH), acetic acid (CH 3 COOH) and citric acid (C 6 H g O 7 ), all of which contain the ionizable -COOH group.
• Acrylic By the term “acrylic” is intended synthetic plastic resins derived from acrylic acids.
• Optically transparent is intended the property of a polymeric material to allow the passage of light at or above the threshold of visual sensation (i.e., the minimum amount of light intensity invoking a visual sensation).
• the present biocompatible polymeric material including COLLAMER has a refractive index i the range of 1.44 to 1.48, more preferably 1.45 to 1.47, and most preferably 1.45 to 1.46.
• Th best mode of the present invention is the biocompatible polymeric material COLLAMER.
• polymerization is intended a process in which monomer combine to form polymers. Such polymerization can include “addition polymerization” wher monomers combine and no other products are produced, and “condensation polymerization” where a by-product (e.g. ater) is also formed.
• additional polymerization wher monomers combine and no other products are produced
• condensation polymerization where a by-product (e.g. ater) is also formed.
• suitable polymerization processes ca be readily selected and employed for the production of the present biocompatible polymeri material by those of ordinary skill in the art to which the present invention pertains.
• Polyene By the term “polyene” is intended a chemical compound having a series o conjugated (alternating) double bonds, e.g., the carotenoids.
• Refractive index is intended a measurement o the degree of refraction in translucent/transparent substances, especially the ocular media.
• the “refractive index” is measured as the relative velocity of light in another medium (such as th
• the present polymeric material as compared to the velocity of light in air.
• the refractive index(n) is 1.52
• n 1.33.
• Tensile Strength By the terminology “tensile strength” is intended the maximal stress or load that a material is capable of sustaining expressed in kPa.
• the present biocompatible polymeric material including COLLAMER has a tensile strength in the range of about 391-1778 kPa, preferably 591-1578 kPa, more preferably 791-1378 kPa, and most preferably in the range of from 991 kPa to 1178 kPa.
• the present material "COLLAMER” has a tensile strength of preferably 1085 ⁇ . 493 kPa.
• the tensile strength of a polymeric material can be readily determined using known methods, by those of ordinary skill in the art.
• Hypermetropia By the term “hypermetropia” (h.) is intended farsightedness/longsightedness, i.e., long or far sight which is an optical condition in which only convergent rays can be brought to focus on the retina. Such conditions include: (1) absolute h.— that cannot be overcome by an effort of accommodation; (2) axial h.— h. that is due to shortening of the anteroposterior diameter of the globe of the eye; (3) curvature h.— h. which is due to the decreased refraction of the anterior diameter of the globe of the eye; (4) manifest.— h. that can be compensated by accommodation; (5) facultative h. ⁇ manifest h.; (6) latent h.— the difference
• Myopia By the term “myopia” (m) is intended “shortsightedness; nearsighledness; near or short sight; that optical condition in which only rays a finite distance from the eye focus on
• Such conditions include: (1) axial tn.-m. due to elongation of the globe of the eye; (2) curvature.— m. due to refractive errors resulting from excessive corneal curvature; (3) degenerative.— pathologic m.; (4) index m.- . arising from increased refractivity of the lens, as in nuclear sclerosis; (5) malignant.-palhologic m.; (6) night.— m. occurring in a normally emmetropic eye because long light rays focus in front of the retina; (7) pathologic— degenerative or malignant., progressive, marked by fundus changes, posterior staphyloma and subnormal corrected acuity; (8) prematurity m.,. ⁇ m.
• Hydrophilic allelic monomer is intended for the pu ⁇ oses of the present invention any monomer containing an allyl group which monomer is soluble in water.
• Hydrophilic acrylic monomer By the terminology “hydrophilic acrylic monomer” is intended any monomer containing an acrylic group which monomer is soluble in water.
• HEMA is a hydrophilic acrylic monomer because it is soluble in water even though it contains both hydrophilic groups and hydrophobic groups.
• Hydrophobic allelic monomer is intended for the pu ⁇ oses of the present invention, any monomer containing an allyl group, which monomer is not soluble in water.
• Hydrophobic acrylic monomer is intended for the pu ⁇ oses of the present invention, any monomer containing an acrylic group, which monomer is not soluble in water.
• Deformable lens is intended any type of deformable lens, for example, for correcting hypermetropia or myopia, where the lens comprises the present material.
• deformable lens includes those disclosed in U.S. Patent Application Serial Nos. 08/318,991 - 14 -
• Such lense include: intraocular lenses for implantation into a patient's eye, for example, into the anterio chamber, in tlie bag or in the sulcas; refractive intraocular lenses for implantation into a patient' eye, for example, into the anterior chamber or in the sulcas; and standard soft contact lenses.
• Implant By the term “implant” is intended the surgical method of introducing th
• hydrophilic monomers and hydrophobic monomers must be selected such tha the hydrophobic monomer(s) is soluble in the hydrophilic monomer(s).
• the hydrophili monomer acts as a solvent for the hydrophobic monomer.
• Suitable monomers can be readil selected by those of ordinary skill in the art to which the present invention pertains.
• Suitable hydrophobic monomers include:
• hydrophilic monomers include:
• HEMA 2-hydroxyethyl methacrylate
• the hydrophilic monomer is mixed wilh an acid, in particular formic acid.
• the weight ratio of hydrophilic monomer to acid is preferably in the range of about 5: 1 to about 50: 1 , preferably 14:1 to 20: 1 , and most preferably, 14: 1.
• This solution is preferably filtered through a 0.2 microfilter.
• an acidic telo-collagen solution is prepared by mixing telo-collagen with organic acid (preferably formic acid).
• the solution is preferably 2 % by weight telo-collagen in 1 M formic acid.
• the solutions resulting from steps 1 and 2 are then mixed together.
• the resultant solution is preferably mixed from about 10 minutes to 60 minutes, most preferably 20 minutes at a temperature of 15-30°C.
• the ratio of telo-collagen to hydrophilic monomer is about 1:2 to about 1:7, preferably 1:3 to 1:6, and most preferably 1:4.
• the hydrophobic monomer and hydrophilic monomer are mixed together in a weight ratio of about 10: 1 to 1: 1, preferably 8:l ' to 3:1, and most preferably 5: 1.
• the monomers are mixed wilii stirring for about 30 to 90 minutes, preferably 60 minutes at 70 to 95°C, preferably 80-95°C, and most preferably 80-92°C.
• the resulting solution is preferably filtered through a 0.2 micron filler.
• the solutions from steps 3 and 4 are mixed together in a weight ratio in the range of about 1 : 1 to 50: 1 , preferably 2: 1 to 5 : 1 , and most preferably 3:1.
• the solution is preferably mixed 20 minutes with no heating at a temperature of 25-40°C.
• Mixing is preferably performed with a homogenizer.
• the resulting material from Step 5 is then preferably degassed (i.e., using centrifugation or other means well-known to those of ordinary skill in the art to which the present invention applies).
• the resulting material from Step 6 is irradiated to form a final product that can be dried, and stored, (i.e., stored in a desiccator due to its hydroscopic nature).
• the material from Step 6 can also be stored in a refrigerator, for example at 5°C to 10°C, prior to irradiation.
• a turbo-type mixer such as a homogenizer, is preferably employed for mixing the solutions of at least Steps 3 and 5, and the mixing times set forth above are based on using a turbo-type mixer.
• the present polymeric material is made by mixing the hydrophobic monomer in two stages to increase the solution viscosity, where in stage one the telo-collagen complex and a mixture of formic acid with 2-hydroxyelhyl-methacrylate are used as a stabilizer of ultra-colloidal stale solution and in stage two a hydrophobic blend of at least one monomer is introduced into the gel produced.
• a 1M acid solution preferably 1M formic acid is prepared.
• the quantity of acid solution required for dissolution of the swollen tissue is calculated using a ratio of swollen collagen tissue: (sclera or cornea) acid solution of about 40:0.5 to 55:2, preferably about 45:1 to about 52: 1.5, most preferably about 50: 1.
• the swollen tissue is then dispensed in a homogenizer for about 10 to 20 minutes, preferably about 15 minutes at 2 to 10 RPM, preferably 4-5 RPM, at room temperature.
• the produced solution is then filtered through a funnel glass filter with a pore size of 100-150 microns, the filtrate is then filtered througli a second funnel glass filter with a pore size of 75-100 microns.
• the produced homogenic solution is then transferred into a container.
• the hydrophilic monomer preferably HEMA is mixed with the hydrophobic monomer, preferably MHBPH in a weight ralio of about 5: 1 and healed for one hour at 80°C to 92°C with stirring (e.g., using a stirrer hot plate).
• the heated solution is then filtered through 5.0 micron filter.
• HEMA is mixed with an organic acid (preferably formic acid), preferably in a weight ratio of about 14: 1. This mixture is added to the collagen solution produced (A) in a weight ratio of HEMA solution:collagen solution of about 1:3, and mixed for about 20 minutes at room temperature. The mixing is preferably performed using a homogenizer at a rate of 6000 RPM.
• the HEMA MHBPH solution of B.(l) is then mixed in small portions with the HEMA telo-collagen solution of B.(2).
• the mixing is preferably performed in a homogenizer for 10 minutes at room temperature.
• the following equation can be used to aid in the selection of the appropriate concentration of monomer necessary to result in the present polymeric material having an index of refraction in the present desired range (1.44 to 1.48, preferably 1.45 to 1.47, and most preferably 1.45 to 1.46).
• the monomer of copolymerization with telo-collagen complex is selected such that:
• N p refractive index of dry polymer
• N c refractive index of telo-collagen (about 1.45 to 1.46)
• Nj refractive index of i-monomer
• n number of monomers
• i monomer number
• hydrophobic and hydrophilic monomers must be selected such that the hydrophilic monomer is a solvent for the hydrophobic monomer, i.e., the hydrophobic monomer is soluble in the hydrophilic monomer.
• the mixture was then slored in a refrigerator al a lemperalure of 5°C, and was thereafter dispersed in a homogenizer for 15 minutes at 4-5 RPM at room lemperalure.
• the produced solution was then fillered through a funnel glass filler with a pore size of 100-150 microns. Thereafter, the filtrate was fillered through a funnel glass filter with a pore size of 75-100 microns. The final homogenic solution was then transferred into a 250ml container.
• HEMA HEMA 527.4g was mixed with 106.2g of MHBPH and healed for one hour at 80°C using a stirrer hot plale. The healed solution was fillered through an Aero 50-5.0 micron filter. 2. 1 15.6g of HEMA was then mixed with 99.4g of formic acid in a hermetic glass container with a Teflon lid. lOOg portions of tlie IIEMA/acid solution were added into 333g of lelo-collagen solution and mixed for 20 minutes at room lemperalure. The mixing was performed in a homogenizer at a rate of 6000 RPM.
• the HEM ⁇ /MHBPH solution was then added in small portions to the HEMA telo-collagen solution.
• the mixing was performed in a homogenizer for 10 minutes at room temperature.
• Step B(3) was then poured into the glass vials and centrifuged for 15 minutes to remove air.
• the vials were then irradiated at 5Kgray to polymerize and cross-link the present material.
• pig's eye sclera was used. 300g of 2-hydroxyelhyl melhacrylate was mixed with 16g of formic acid. 50g of telo-collagen was filtered purified from sclera using alkaline hydrolysis with 200g NaOH and 200g of Na,SO « in 2.5 liters of water, and filtered through a 100 micron filter. The telo-collagen was mixed wilh 2-hydroxyelhyl melhacrylate and the formic acid solution containing 2-hydroxyelhyl melhacrylale. 20g of 4-methacryIoxy-2- hydroxybenzophenone (MHBPH) dissolved in HEMA was then added. This mixture was radiated wilh gamma radiation in the range of 3.5-5.0 Kgray to polymerize and cross-link all the components.
• MMBPH 4-methacryIoxy-2- hydroxybenzophenone
• Hydrophobic monomers were used in Ihis system lo reduce the abso ⁇ lion of water and swelling of the polymerized material when introduced into the aqueous media of the eye.
• the hydrophobic monomer was chosen so that the refraclive index of the resultant polymer increased to be approximately equal lo the refraclive index of telo-collagen.
• HEMA 2-hydroxyethyl melhacrylate
• Example 2 The same procedure in Example 2 can be utilized, except the following monomers can be subsliluled:
• the pu ⁇ ose of this lest was to determine the lensile properties of the present collamer material. This includes tensile strength, Young's modulus, and percent elongation at failure. The data collected was used to construct standards for inspection. The tensile test is similar lo the silicone lensile test. The sample geometry is different but the stress fundamentals remain the same.
• A Hydrated cross sectional area of specimen, square meters, (m 2 ).
• the Inslron was set up and calibrated according to ESOP #202.
• the testing fixtures were brought together so the centerlines were aligned and there was approximately 8 mm between the posts. This was designated zero and the fixtures returned to this position every time after the
• the chart recorder was set at zero load and deflection before every test.
• the chart recorder recorded kilograms-force load and jaw separation. Load is used to determine the ultimate tensile strength (see formula 1, Test Data Section), the stress at which the sample fails.
• the sample was not set up lo test elongation using a standard gage length but a formula in the
• the performance of the specimen proved Ihe material to be elastic and wilh the stress increasing at a linear rale until failure.
• the linear increase can be one of two things: (1) it is possible the specimens have stress risers on the inside diameter. Stress risers would be caused by the milling process, because ⁇ il doesn't have the surface finish of the lalhe-turned outer diameter; this may not allow the material (o neck down during the plastic deformation stage of
• the present material showed COLLAMER good resistance to tear propagation, which would happen at any stress risers.
• the cross sectional area of the failed part was flat, which was indicative of elastic failure.
• the combined data from the present COLLAMER samples gave an average tensile slrenglh of 1084.6 kilopascals (kPa), and an average elongation of 324.9 percent (%).
• the tolerance for average tensile slrenglh was calculated as ⁇ _ 3 limes the standard deviation, giving an upper tolerance of 1578 kPa (229 psi) and a lower tolerance of 591 kPa (86 psi).
• the tolerance for the elongation is calculated in the same manner. The upper tolerance is 395 % elongation and the lower tolerance is calculated as 255 % elongation. See Appendix 3 for the calculations.
• the tensile slrenglh standard is 1085 ⁇ 493 kPa (157 ⁇ 71 psi) and the elongation is 325% ⁇ 70.
• Young's modulus standard is 189 ⁇ 25 kPa (27 ⁇ 11 psi).

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• 1996
  • 1996-06-07 AU AU61701/96A patent/AU718546B2/en not_active Expired
  • 1996-06-07 KR KR1019970708642A patent/KR19990022163A/ko not_active Application Discontinuation
  • 1996-06-07 WO PCT/US1996/010013 patent/WO1996040818A1/en not_active Application Discontinuation
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