WO1994013717A1

WO1994013717A1 - A method for the production of a soft contact lens

Info

Publication number: WO1994013717A1
Application number: PCT/CA1992/000529
Authority: WO
Inventors: Anatoliy Mihailovich Sokolyuk; Natalia Vladimirovna Kokosha; Zoya Rudolfovna Ulberg; Fyodor Danilovich Ovcharenko
Original assignee: 958075 Ontario Inc. Carrying On Business As Eurocan Ventures
Priority date: 1992-12-04
Filing date: 1992-12-04
Publication date: 1994-06-23
Also published as: AU3078992A

Abstract

According to this method of obtaining a solid contact lens, an acrylamide and N,N'-methylene-bis-acrylamide are first purified and then used to prepare solutions of 310-750 g/l acrylamide, 0.5-9.0 g/l N,N'-methylene-bis-acrylamide, 0.1-3.0 g/l N,N,N'N'-tetramethylethylenediamine, and 0.1-4.0 g/l ammonium persulphate. These solutions are mixed and placed in the form to carry out simultaneous polymerization and cross-linking, over a period sufficient for the production of a hydrogel material in the shape of a soft contact lens. After the lens is retrieved from the form, it is saturated with water until equilibrium state.

Description

A METHOD FOR THE PRODUCTION OF A SOFT CONTACT LENS

The present invention relates to the sphere of obtaining medical materials from cross-linked polymeric hydrogele; specifically, to a method of obtaining a soft contact lens , which can be used in medical practice.

U.S. Patent 4,430,458 describes a cross-linked hydrogel polymeric material intended for contact lenses. The process of obtaining contact lenses from the hydrogel material containing at least 65% by weight of water includes polymerization in the form of mixed monomers:

(1) 20 to 40 mole % of an amide of acrylic or methacrylic acid;

(2) 25 to 55 mole % of an N-vinyl lactam of the U-vinyl pyrxolidone type;

(3) 5 to 20 mole % of an hydroxyalkyl ester of acrylic or methacrylic acid;

(4) 1 to 10 mole % of acrylic or methacrylic acid;

(5) at least about 5 up to about 10 mole % of a poly- merizable hydrophobic vinyl monomer which is at least one monomer selected from the group consisting of vinyl aromatic hydrocarbons of the styrene type and hydrophobic esτer of acrylic or methacrylic acid.

aexe the initiator is, for example, methyl ethyl keτone peroxide, and the cross-linking agent, for example, ethylene glycol dimethacrylate.

The process of polymerization in the form continues for 48 hours at 60°-100°; the linking of the polymer is initiated by exposure to light. As a result a hard contact lense is received. It is then cut and immersed in an aqueous medium for 4 days. After saturation it contains 65-70% by weight of water.

However, the above process of obtaining cross-linked hydrogel material is time and work-consuming, apart from tne fact that the water content after saturation is insignificant (65-75%) .

It is common knowledge that , in order to ensure the cornea normal functioning conditions w hen wearing durable soft contact lenses , the latter must have high oxygen per meability; there also must be normal ion exchange between the biologic tissue and the environment, which is characterized by the diffusion coefficient. Studies show that the latter drops in polymeric hydrogels with the increasing of the density of linkage of the polymeric hydrogel, and that this coefficient depends on the amount of water bound by the system.

It is, therefore, obviously important to raise the water content in the cross-linked polymeric gels that are used for soft contact lenses. There do exist cross-linked polymeric gels with high water-contents that are used for various medical and biological purposes. For example, U.S. 4,388,428 describes a collagen-based polymeric hydrogel. Here polymerization involves cross-linking agents, including N,N'-dimethyl acrylamide. The hydrogel thus obtained has, according to the patent, 90-95% by weight of water and high oxygen peiroeability.

But even so, increasing water content in the polymeric hydrogel simultaneously reduces its physical-mechanical indices. In other words, the hydrogel is harder to use for soft contact lenses and other medical products.

The same is true of the polyacrylamide gel obtained using the GB 21,145,788 technique.

The GB 21,145,786 method is designed to produce poly- acrylamide gel for medical and biological purposes and boils down to this: A,B and C initial solutions are prepared for polymerization. The A solution is prepared by dissolving 5 ml of H,N,N',N'-tetramethylethylenediamine in 995 ml of distilled water. The B solution is obtained by dissolving 7.35 g M,N'-methylene-bis-acrylamide in 350 ml distilled water heated to 60°C, filtering the solution, adding 280 g acrylamide and then up to 1,000 ml distilled water. The C solution is prepared by dissolving 1.4 g ammonium persulphate in 1,000 ml distilled water.

The solutions thus prepared are mixed: 2 parts of B solution, 4 parts of C solution, and 1 part of A solution, so as to receive a reaction mix.

This reaction mix is then placed in the form for polymerization. It can consist of two parallel plates, or a reac tor whose inner surface repeats the form of the contact less. After the polymerization of the reaction mix, which lasts for 3 - 15 min, a cross-linked polyacrylamide gel is received, which can be used as an artificial medium for microorganisms, also as soft contact lenses and artificial lenses of the eye.

The cross-linked polyacrylamide gel thus obtained contains (in percent by weight of mass):

polyacrylamide - 3.0 - 28.0

sodium ohloride solution - 72,0 - 97.0.

However, such a polyacrylamide gel proves moat effective when used as an artificial medium-for growing-microorganisms. Its use as soft-durable contact lenses is less-preferable, in that it shows-low physical-mechanical characteristics.

There is yet another method of obtaining a durable soft contact lense from a. cross-linked polyacrylamide gel with a high water content (up to 97%). It is described in S. U. A

959.313.

According to this method, the first step is to prepare initial solutions for polymerization with the following con- oβntration (g/l):

aorylamide - 100-300

N,N'-methylene-bis-acrylamide - 10 - 150

N,N,N',N'-tetramethylenediamine - 5 - 100

Said solutions are mixed in various volumetric ratios. The most optimal ratio: N,N,N' ,N'-tetramethylenediamine (mix: acrylamide solution and N.N'-methylene-bis-acrylamide = 1:2). Other ratios are possible, too, but within the.1:15 limits.

The mix thus obtained, together with ammonium persulphate, 0.5-07 ml in toto, is placed in the form. Polymeriza- tion in closed volume, lasts between 2 and 15 min, at +20°C.

The contact lense thus obtained is retrieved from the form and rinsed in 10-15 ml distilled water or sterile 0.85ft sodium chloride solution for 20-30 min, with solution 1 being changed three times.

Soft contact lenses produced according to the above method possess sufficiently high physical-mechanical characteristics only when sufficiently thick, which hinders their adjustment to the eye apple. Besides, the thicker the lens, the lower its diffusive performance. Here and further on, under diffusive qualities we understand the ability of the material of the soft contact lens to excercise free transportation of K⁺, Na⁺, Ca⁺⁺ions and oxygen which ensure the normal funotion- ing of the cornea when wearing durable oontact lenaes.

The present invention is aimed at increasing the physical-chemical and diffusive qualities of a soft contact lens with a high water content (up to 97%) and lower thickness.

This goal is attained by our technique, whereby in the process of obtaining a soft-contact lens acrylamide and H,N'mβthylene-bis-ecrylamide are cleansed by reoryatalization before preparing solutions of the said acrylamide and N,N'-methylenebis-acrylamide, as well as N,N',N',N'-tetramethylenediamine and ammonium persulphate in an acceptable solvent with the follow- lag concentration:

acrylamide - 310.0 - 750.0 g/l

N.N'-methylene-bis acrylamide - 0.5 - 9.0 g/l

N,N,N' ,N'-tetramethylethylenediamine - 0.1 -3.0 g/l ammonium persulphate - 0.1 - 4.0 g/l.

The solutions thus obtained are mixed and placed in the form for polymerization, and simultaneously for crosslinking, over a period required to receive a hydrogel material in the shape of a soft contact lens. The latter is then retrieved from the form and immersed until balanced saturation.

We aucceeded in solving the problem of raising the physical-mechanical properties of the soft contact lens, while reducing its thickness and simultaneously increasing its oxygen-ion permeability by applying reagent solutions in the above proportions and previously ridding the aorylamide and N,N'-methylene-bis-acrylamide of the remnants of acrylic acid. As it turned out (and it will be demonstrated further on herein), even a trace of acrylic acid can produce negative effects on the properties of the soft contact lens. At the same time, other forms of micropollution practically leave the said reagents uneffeoted.

Specifically, this will be demonstrated in regard to monomers with varying contents of the main agent -acrylamide - from 98.6% Beanal (Hungary), Aldrich (U.S.) to 99.9% Electran (U.K.); and N,N'-methylene-bis-acrylamide - from 96.8% Reanal (Hungary), Fluka Chemica (Switzerland) to 99.9% Electran (U.K.). The content of acrylic acid in the said monomers was Λ/ 0.02ft.

It appears feasible to prepare solutions for soft con- tact lenses with high prognostic and sufficiently nigh diffusive propertiea with these concentrations:

acrylamide - 310.0 - 550.0 g/l

N,N^,-methylene-bis-acrylamide - 4.5 - 9.0 g/l

N,N,N',N'-tetramethylethylenediamine - 0.1 - 1.0 g/l ammonium persulphate - 2.0 -4.0 g/l.

The following concentration^s/are possible for producing soft contact lenses with the highest diffusive properties and sufficient elasticity indices:

acrylamide - 700 - 750 g/l

N,N'-methylene-bis-acrylamide - 0.5 -3.0 g/l

N,N,N',N'-tetramethylethylenediamine - 2.0 - 3.0 g/l ammonium persulphate - 0.1 - 10 g/l.

She method of obtaining polyacrylamide gel is implemented as follows.

At first the monomers - acrylamide and N,N'-methylene- bis-acrylamlde - are cleansed of all traces of acrylic acid.

Acrylamide used: C₃H₅NO, mol.weight 71.08 - white crystaline powder, odorless; melting temperature 84.5±0.3°C. Density:

1.122 g/cm³; dissolvability: 25°C (215.5 g per 100 g water);

dissolves in methanol, ethanol, acetone, chloroform, benzol.

It is possible to use acrylamide of Reanal manufacture (Hungary), also Aldrich (U.S.); content of basic agent: 98.6%; acrylic acid: 0.02%; acrylamide made by Electran (U.K.) - basic agent: 99.9%t; acrylic acid: 0.02ft. N,N'-methylene-bis-acrylamide used: C₇H₁₀N₂O₃, mol. mass 154,16, white crystalline odorless powder; melting temperature: 185°C; water dissolvability: 20°C (3g per 100 g water). It is possible to use N.N'-methylene-bis-acrylamide made by Reanal (Hungary), Fluca Chemica (Switzerland) - basic agent: 96.8ft; acrylic acid: 0.02%; that produced by

Electran (U.K.) - basic agent: 99.9%; acrylic acid: 0.02%.

The aforementioned monomers are cleansed of the traces of acrylic acid, for example, by recrystalization.

Acrylamide recrystalization'is performed as follows: 70 g acrylamide is dissolved in 1 liter of chloroform at 50-60°C, then the mix is filtered while etill hot. The filtrate is cooled in a refrigerator to -15-20°C. The falling out crystals are tnen filtered off and rinsed on the filter with cold chloroform. After drying out the crystals their melting tem- perature is determined.

The content of the basic agent increases to 99.9% when using acrylamide made by Reanal (Hungary) or Aldrich (U.S.). Ko traces of acrylic acid are detected. If acrylamide of

Electran (U.K.) manufacture is applied, the basic agent's content rises to 99.95%, with no traces of acrylic acid.

N,N'-metnylene-bis-acrylamide is recrystalized in acetone. To do so, 36 g N,N'-methylene-bis-acrylamide is dissolved in one liter of acetone, boiled with reverse refrigeration, let through a filter, then cooled till a temperature below zero, whereupon the fallen out- crystals are filtered off and the melting temperature determined.

The content of the basic substance is higher wnen using N.N'-methylene-bis-acrylamide made by Reanal (Hungary), Fluca Chemica (Switzerland), and registers up to 98%. No traces of acrylic acid are detected. When using N,N'-methylene-bis-acry- lamide of Electran (U.K.) manufature, the content of the basic agent reaches 99.94%.

Thus purified, the monomers of acrylamide and N,N'-methy- lene-bis-acrylamide can be stored for a month and used to prepare solutions.

After the above purifying procedures, the monomers of acrylamide and N,N'-methylene-bis-acrylamide are used for the preparation of solutions, the solvent being a sodium chloride solution or any other acceptable solvent - for example, distilled water.

An acrylamide solution has a concentration of 310-750 g/l, and that of N.N'-methylene-bis-acrylamide 0.5-9.0 g/l.

To prepare the polymerizing mix solutions of N,N,N',N'- tetramethylethylenediamine and ammonium persulphate are pre- pared. N,N,N',N'-tetramethylethylenediamine used: C₆H₁₆H₂.

molecular weight: 116.21; colorless liquid of 0.7Bg/cm³density.

Content of the basic agent: 98.2%. Manufacturer: Reanal (Hungary).

Ammonium persulphate :/NH₄/₂S₂O₈ - molecular mass 228.19; colorless plate-like crystals; density 1.982 g/cm³ ; decomposition temperature: 120°C; dissolvability: 15.5°C (74.8 g per 100 g water).

Content of the basic agent: 98ft.

Manufacturer: Reanal (Hungary).

A solution of N,N,N' ,N'-tetramethylethylenediamine has a concentration of 0.1 - 3.0 g/l, and that of ammonium persul- phate 0.1 -4.0g/l .

The above solutions are used to prepare the polymerizing mix.

The ratio of N,N,N',N'-tetramethylethylenediamine and the mix of acrylamide and N,N'-methylene-bis-acrylamide in the polymerizing mix is used in such a way as to ensure that the ratio between N,N,H',N'-tetramethylethylenediamine and the mix of acrylamide -and N,N'-methylene-bis-acrylamide range from 1:6 to 1:25. Ammonium persulphate is added to the polymerizing mix as an initiator.

An amount of 0.5-0.7 ml polymerizing mix ia placed in the form of, for example, soft contact lens, after which the polymerization is carried out in closed volume, at 20-30°C, over a period of 45-60 min.

After polymerization the cross-linked polyacrylamide gel in the form of a soft contact lens is rinsed in 10-15 ml distilled water or sterile sodium chloride solution for 20-30 min (changing solution three times). Then the lens is immersed for 24 till saturated. It can contain 87-98ft by weight of water.

Soft contact lenses thus obtained have been used in me- dical practice. Patients treated at AQUALAN, Ltd. (Ukraine) wore continuously soft contact lenses produced following the above procedures for as many as three months and snowed good corrective results. Some patients wore lenses continuously for 13-16 months and took them off only because the lenses failed to provide adequate correction due to pollution by protein.

In soft contact lenses thickness, relative elongation, elasticity, refraction coefficient, water content, ion diffusion (Na⁺,K⁺,Ca⁺⁺⁾, and that of oxygen, were determined. The thickness was determined with the help of an ordinary micrometer.

The elasticity and relative elongation were tested using a Weiler-Rebinder modification at 9.6 cm/min clasp stretching, at 20±3 °C. Refraction coefficient was determined using an ordinary refractometer, at 20±3°C.

Water content was determined by weighing saturated lenses and those dried to constant weight.

Dioptrics of the soft contact lenses were determined using an ordinary dioptometer.

The ion diffusion (K⁺, Na⁺, Ca⁺⁺⁾ and oxygen diffusion coefficients were determined by comparing the concentration of corresponding ions on both sides of the membrane - in this case the soft contact lens, produced following the above procedures.

Example 1.

A soft contact lens was obtained using the method and techniques described above herein.

An acrylamid and N.N'-methylene-bis-acrylamide were first purified by way of recrystalization.

To receive a soft contact lens, a solution of 310 g/l acrylamide, a solution of N,N^,-methylene-bis-acrylamide 9,0 g/l , a solution of 0.1 g/l N,N,N',N'-tetramethylethylenedia- mine, and a solution of 4.0 g/l ammonium persulphate were used.

The ratio between N.N,N',N'-tetramethylethylenediamine and the mix of acrylamide and N,N'-methylene-bis-acrylamide was 1:6. The time of polymerization: 60 min. Temperature: +25°C. The soft contact lens thus obtained was -3D.

In this contact lens, elasticity, water content, relative elongation, refraction coeeficient, and that of Na⁺,

K⁺, Ca⁺⁺ and oxygen were determined.

The results are provided in Table 1.

Example 2.

Acrylamide and N,N'-methylene-bis-acrylamide were first purified by means of recrystalization. To receive a soft contact lens, a solution of 750 g/l acrylamide, that of 0.5 g/l N.N'-methylene-bis-acrylamide, 3.0 g/l N,N,N',N'-tetramethylethylenediamine, and 0.1 g/l ammonium persulphate were used.

The ratio between the solution N,N,N',N'-tetramethyl- ethylenediamine and the mix of acrylamide and N.N'-methylene- bis- was 1:11.

Time of polymerization: 45 min; temperature: 25°C.

The soft contact lense obtained was -10 D.

The βoft contact lens's thickness, relative elongation, tensile strength, water content, refraotion and the coefficient of ion (a⁺, K⁺, Ca⁺⁺) and oxygen diffusion.

The results are provided in Table 1.

Example 3.

A βoft contact lens was produced using the method and techniques described above herein.

Acrylamide and N,N'-bis-acrylamide were first purified by means recrystalization.

To receive a soft contact lens, solutions of 520 g/l acrylamide, 5.0 g/l N,N'-methylene-bis-acrylamide, N,N,N',N'tetramethylethylenediamine (1.0 g/l), and 2.0 g/l ammonium persulphate were used.

The ratio between the solution N,N,N',N'-tetramethyl- ethylenediamine to the mix of initial solutions (acrylamide and N,N'-bis-acrylamids) was 1:7.

Time of polymerization: 50 min. Temperature: 25°C.

The soft contact lens thus obtained registered +6 D.

This soft contact lens was tested for thickness, relative elongation, elasticity, refraction coefficient, water content, and the coefficients of ion (Ha⁺, K⁺, Ca⁺⁺) and oxygen diffusion.

The results are provided in Table 1.

Example 4 (comparative).

Acrylamide and N,N'-bis-acrylamide were first purified by means of recrystalization.

To receive a soft contact lens, solutions of 300 g/l acrylamide, 9.0 g/l N,N'-bis-acrylamide, 0.1 g/l N,N,N',N'- tetrame thrlethylenediamine, and 4.0 g/l ammonium persulphate were used.

The ratio between the solution of N,N,N',N'-tetramethyl- ethylenediamine and the mix of the solutions of acrylamide and N,N'-bis-acrylaide was 1:5.

Time of polymerization: 40 min. Temperature: 25°C.

The soft contact lens thus obtained was +5 D.

The soft contact lens was also tested for thickness, relative elongation, elasticity, water content, refraction coefficient and the coefficients of ion (Na⁺, K⁺, Ca⁺⁺) and oxygen diffusion.

The results are provided in Table 1.

Example 5 (comparative)

A soft contact lens was obtained using the method and techniques deβcribed abover herein.

Acrylamide and N,N'-bis acrylamide were first purified by means of recrystalization.

To receive a soft contact lens, solutions of 760 g/l acrylamide, 10.0 g/l N,N'-bis-acrylamide, 4.0 g/l N.N,N'.N'- tetramethylethylenediamine, and 5.0 g/l ammonium persulphate were used.

The ratio between the solution N,N,N',N'-tetramethy¬- ethylenediamine and the mix of solutions of acrylamide and N,N'-bis-acrylamide was 1:12.

Time of polymerization; 45 min. Temperature: 25°C.

The soft contact lens thus obtained registered -9.5 D.

The soft contact lens was also tested for thickness, relative elongation, elasticity, water content and refraction coefficient, as well as for the coefficients of ion (Na⁺, K⁺, Ca⁺⁺) and oxygen diffusion.

The reβults are provided in Table 1.

Example 6 (comparative)

Acrylamide and N.N'-bis-acrylamide were first purified by means of recrystalization.

To receive a soft contact lens, solutions of 500 g/l acrylamide, 0.4 g/l N,N'-bis-acrylamide, 0.05 g/l N,N,N',N'- tetramethylethylenediamine, and 0.06 g/l ammonium persulphate.

The ratio between the solution N,N,N',N'-tetramethylethylenediamine and the mix of solutions of acrylamide and N,N'-bisacrylamide was 1:7.

Time of polymerization: 45 min. Temperature: 25°C.

The soft contact lens thus obtained registered 0.0 D.

The soft contact lens was also tested for thickness, relative elongation, elasticity, water content, refraction coefficient, as well as for the coefficients of ion (Na⁺, K⁺, Ca⁺⁺) and oxygen diffusion.

The results are provided in Table 1.

Example 7 (comparative)

A soft contact lens was produced using the method and techniques described above herein(see Example 1).

Acrylamide and N,N'-bis-acrylamide were used without : prior recrystalization and contained up to 0.02% by weight of acrylic acid.

The soft contact lens thus obtained was tested for thickness, relative elongation, elasticity, water content, ion (Na⁺, K⁺, Ca⁺⁺) and oxygen diffusion coefficients.

The results are shown in Table 1.

Example 8 (comparative)

A soft contact lense was received using the method and techniques described in Example 2.

Acrylamide and N,N'-bis-acrylamide were used without prior recrystalization and contained up to 0.02% by weight of acrylic acid.

The soft contact lens thus obtained was tested for thickness, relative elongation, elasticity, water content, coefficients of ion (Na⁺, K⁺, Ca⁺⁺) and oxygen diffusion.

The results are summed/

in Table 1.

Example 9 (comparative)

A soft contact lens was produced using the method and techniques described in Example 3.

The soft contact lens thus obtained was tested for thickness, relative elongation, elasticity, water content. ion (Ha⁺, K⁺, Ca⁺⁺) and oxygen diffusion coefficients.

The results are provided in Table 1.

Table 1 shows that the method and techniques of obtaining soft contact lenses, as laid down in the preaent invention (Example 1 - 3), unlike the conventional method (SU,A, 959,313) produces soft contact lenses of lesser thickness but with higher physical-mechanical and diffusive properties, which makes it possible to use them as soft durable contact lenses worn continuously over considerable periods. At the same time, comparative analysis (Example 4-9) testifies to the significance of all the parameters contained in the formula of the present invention, in that they distinguish the present method from all the other known methods and techniques.

Needless to say that the examples cited herein are but a few possibilities of realizing the present invention. There are other variants that actually do not exceed the limits set by the formula of the present invention.

Claims

We therefore claim patent rights to:

1. A method of obtaining a soft contact lens, whereby acrylamide and N,N'-methylene-bis-acrylamide are first purified by way of recrystalization, after which solutions of the said acrylamide and N,N'-methylene-bis-acrylamide are prepared, as well as solutions N,N,N',N'-tetramethylethylenediamine and ammonium persulphate, using an acceptable solvent, with a concentration of: acrylamide - 310.0-750 g/l, N,N'-methylene-bis-acrylamide - 0.5-9.0 g/l, N,N,N'N'-tetramethylethylenediamine - 0.1-3.0 g/l, and ammonium persulphate 0.1-4.0 g/l. These solutions are then mixed and placed in the form to perform polymerization and simultaneously crosslink the agents. This process lasts for a period of time sufficient to receive a hydrogel material in the shape of a soft contact lens. After retrieving it from the foam, the soft contact lens is immered in water until balanced saturation.

2. A process, as per Claim 1, of preparing solutions of 310.0-550.0 g/l acrylamide, 4.5-90 g/l N,N'-methylene-bis- acrylamide, 0.1-1.0 g/l N,N,N',N'-tetramethyethylenediamine, and 2.0-4.0 g/l ammonium persulphate.

3. A process, as per Claim 1, of preparing solutions of 700-750 g/l acrylamide, 0.5-3.0 g/l N,N'-methylene-bis- acrylamide, 2.0-3.0 g/l N,N,N',N' -tetramethylethylenediamine, and 0.1-1.0 g/l ammonium persulphate.