HK1147439B - Dye solution - Google Patents

Description

Field of invention

The invention relates to a water-based biocompatible preparation for selective staining of the internal limiting membrane (ILM) and/or the epiretinal membrane (EMR) in the human or animal eye and a kit containing the water-based biocompatible preparation according to the invention.

Background to the invention

Eye diseases such as cataracts, glaucoma, age-related macular degeneration and diabetic retinopathy, as well as retinal changes and retinal detachments are increasing, due to, among other things, longer life expectancy. Treatment of these and other eye diseases is often indicated by vitrectomy, which must ensure that the retina is damaged as little as possible. A precautionary measure is to remove the intraocular membrane (ILM) and any intraocular membranes from the retina as described above in order to prevent the infection of the retina by the retrieved membranes.

For example, US 7.014.991 describes a process for staining ocular structures in the human eye, where the staining is done by injecting the dye indigo disulphate into the appropriate tissue.

Other dyes, such as Brilliant Blue G, Brilliant Blue R, Patent Blue V, or Methylene Blue have also been proposed for use in the eye. EP 1553 984 describes triphenylmethane dyes, e.g. BBR and Patent Blue V for staining of membranes to be removed from the eye. Ünlü et al. (2000), J. Cataract Refract. Surg. describes Enzian Blue for selective staining of the anterior chamber of the eye.

During vitrectomy or surgery, the eye cavity is rinsed with a dye solution. One problem with the previously known dye solutions is that the dye solution is distributed, diluted and rinsed out by the dye solution. This has several disadvantages.

To overcome this disadvantage, it has already been proposed to add a thickener to the dye solution, such as hyaluronic acid, which increases the viscosity of the dye solution. The increase in viscosity is intended to reduce the penetration of the dye into the washing solution due to reduced mobility, i.e. steric barrier, and to allow it to reach closer to the dyeing membrane. However, the high viscosity of the dye solution means that the dye can now penetrate poorly from this to the membrane, so that the need for dye solution is higher than the amount necessary to only heat the membrane. WO 03/05257 ICG describes a polyvinyl alcohol or a pyrrolidine dye.

The invention was therefore intended to provide a preparation that can selectively stain membranes, in particular those to be removed, such as the membrana limitans interna (ILM) and/or the epiretinal membranes (ERM), in the human or animal eye, which is easily applied, travels to the membrane immediately after application and distributes itself without over-staining the rinsing solution, and is not cytotoxic and is well tolerated.

This task is solved by a preparation as defined in the claims, in particular claim 1.

The sub-claim includes beneficial educational background.

Detailed description of the invention

Surprisingly, a preparation containing at least brilliant blue G as a dye was found to allow effective and selective staining of ILM and/or ERM when the density of the preparation is set in a range from 1.01 g/cm3 to 1.5 g/cm3, preferably 1.01 g/cm3 to 1.3 g/cm3.

It has been found that a dye solution with an increased density compared to water when injected into the eye cavity during a surgical procedure sinks, avoiding rapid mixing with the rinse solution, and spreads and stains the membrane after the rinse, thus avoiding that the dye is washed away too quickly with the rinse solution and also that the dye clouds the field of vision.

The preparation of the invention is based on water as a solvent, whereby other solvents may be incorporated in smaller proportions if they are homogeneous with water and biologically compatible. The use of single and multiple alcohols, as used in the medical field, is considered. If another solvent is used, it is particularly preferable to use a glycol or glycerin. Mixtures of the above-mentioned solvents are also considered. If a solvent is added to water, it should be used in a proportion not exceeding 20%, preferably not exceeding 10% by weight.

In addition to water as solvent and the dye, which is described below, the preparation of the invention contains as an essential component a density adjusting agent. The density adjusting agent must be biologically compatible, must not be toxic and must be homogeneously miscible with water, if necessary after the addition of a small amount of a solubility mediator such as alcohol, so that a clear transparent solution is obtained. It must also be compatible with the dye, i.e. must not significantly affect the solubility of the dye. When the preparation is discontinued, the osmolarity must also be taken into account in order not to cause any damage to the tissue by osmosis. The osmolarity should be in a range of 280-330 L/L, with a moisture content of 300 L/L.

Therefore, water-compatible liquids with a density above the water density are considered. A useful means of increasing the density is heavy water, D2O, which allows the density to be adjusted to the desired range. Heavy water is characterized by excellent tolerability. It is tolerated by eukaryotes at up to 20% water concentration and does not cause irritation in the area of application. It is miscible with water at any concentration, does not tend to precipitate or separate and has no detectable differences in solubility with water.The desired density value of 1.01 g/cm3 to 1.5 g/cm3, preferably 1.01 g/cm3 to 1.3 g/cm3, is reached. The appropriate amount, which also depends on the other ingredients, can be found by simple experiments or calculations. If heavy water is the density setting agent, it is preferably used in a quantity of 5-20%. The preparation with heavy water is also very simple and can be easily made by mixing due to the good miscibility of the two components.

Polysaccharides are suitable for increasing density and are readily available. They are also toxicologically safe and biologically compatible. Polysaccharides are molecules composed of more than two, preferably more than 5, especially preferably more than 10 sucride units. Although mono- and disaccharides can generally increase density, according to the invention, only non-reducing disaccharides are used to increase density. The use of monosaccharides and reducing disaccharides may lead to undesirable effects, so they may not be neutral.

Other means of adjusting the density are neutral polymers such as polyether, polyvinyl alcohol, polyester, polyacrylic acid copolymer, polyvinylpyrrolidone.

Combinations of the above means are also well suited to adjust the density of the preparation of the invention, e.g. a combination of heavy water and one or more polysaccharides.

The amount of heavy water and/or other or other densitisers shall be chosen so that the density of the finished preparation is within the required range of 1,01 g/cm3 to 1,5 g/cm3, preferably 1,01 g/cm3 to 1,3 g/cm3, and the density of the preparation may be determined by any common method generally known to the professional.

It has been shown that increasing the density to 1.01 g/cm3 already produces the desired effect, i.e. that the dye solution, after application, rapidly sinks down into the eye socket and can then spread on the membrane. This allows selective dyeing of the membrane without deteriorating the operator's vision. A density difference of less than 0.01 g/cm3 in relation to water is no longer sufficient to cause the dye preparation to drop specifically. The drop then occurs as slowly as in the preparation of the state of the art and leads to the problems listed above.

Another important aspect of the preparation according to the invention is the use of brilliant blue G as a dye. Compounds that can specifically and specifically stain the ILM and/or EMR so that the membrane is visually different from the retina can be used as a dye. The dye must also be soluble in water or in the mixture of water and another solvent. It must not be toxic, especially cytotoxic or cell damaging, nor cause damage to the retina or toxic effects due to light reactions such as ICG or trypanosome. It should also have a good blue staining ability to maintain a low amount of dye.

Colouring matters of the group of triphenylmethane dyes such as Brilliant Blue G, Brilliant Blue R, Brilliant Blue FCF, Patent Blue V, Bromphenol Blue, Lysamine Green SF, Lysamine Green G, Fast Green, Methyl Green, Brilliant Green, Commassie Violet R 200, Rosanillin, of the group of azo dyes or diazo dyes such as Orange G, Ponceau 2R, Chromotrope 6 R, Ponceau 6 R, Tartrazine, Azophloxin, Ponceau B, Evans Blue, Chicago Blue, of the group of coding dyes such as 3,3'-dioxyethylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedioxylanedi

Of the three-phenylmethane dyes, Coomassie Violet R 200 and Chicago Blue could be used in particular preference. Of the brilliant blue dyes, Brilliant Blue G is preferred because of its particularly good staining ability. It can be used in a concentration of less than 0.3 g/l. This concentration already results in sufficient selective staining of ILM and/or EMR. Other suitable dyes include Lissamine Green SF, Lissodododide Green, Gillian Gyanto, Laxanthine, Azidine, Chloropropane, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine, iodine,

To further enhance the beneficial properties of the preparation of the invention, an additive to reduce viscosity may be added to the preparation, which, due to its higher density, sinks more rapidly, but is even less distributed in the washing solution, as it accumulates on the membrane until it is close to the membrane due to the increased viscosity. However, an effect already achieved by the application of the additive must be increased in a suitable way, so that the viscosity of the preparation is not so greatly increased that it is easily released into the membrane, which can lead to a more stable and dangerous condition, which can lead to the formation of dangerous substances such as the toxicity of the liquid. This is a problem which can be solved by the use of a more stable method of preparation.

As viscosity regulating biocompatible agents, i.e. agents that adjust viscosity, one or more of the following groups may be used: polyether, polyvinyl alcohol, polyester, polyacrylic acid copolymer, polyvinyl pyrrolidone, and other polymers, multi-value alcohols such as glycerin, propylene glycol, butylene glycol, water-soluble cellulose derivatives such as methyl cellulose, xanthan gum, starch, hyaluronic acid and their respective derivatives, chondroitin sulphate and sodium sulphate. As viscosity regulators, those that not only increase viscosity but also the diets produced at the same time may also be used. In this case, it is important to note that both of these substances are readily regulated.

Surprisingly, butylene glycol was found to be a viscosity-regulating agent, which leads to good dispersion. An addition of butylene glycol can therefore cause the applied preparation to sink downwards and, once it has reached the membrane, spread there and rapidly stain the membrane. This is explained, without being based on a theory, by the fact that butylene glycol has a membrane-affecting affinity and, due to its lipophilic groups, adsorbs the dye.

The viscosity of the preparation according to the invention is preferably set so that the viscosity of the shell at 25 °C and a shear rate of 10 s-1 is in the range of 1 to 500 mPa. Preferably, the viscosity of the shell at 25 °C and a shear rate of 10 s-1 is set to a range of 50 to 275 mPa. The viscosity can be set by the viscosity regulators mentioned above. If the viscosity is in the range of 1 to 500 mPa under the specified measurement conditions, the effects obtained with the preparation according to the invention are significantly enhanced.without significant washing of the dye with the rinse solution. The dye is therefore only released at the site of application by capillary effects on the membrane, which then stains. If the viscosity is less than 1 mPa under the specified measurement conditions, the effect of rapid deposition of the preparation of the invention cannot be further enhanced. It is possible that at least part of the dye will be worn out before the membrane is stained with the rinse solution and thus no longer available for staining the membrane.The viscosity of the preparation is so high that the dye cannot be optimally released from the droplets that are formed. This significantly reduces the ability of the dye to diffuse, resulting in a rapid, homogeneous colouring of the membrane. The membrane is not optimally moistened with the dye and therefore does not colour as clearly. A particularly good colouring result is achieved when the dynamic viscosity is at 25 °C and a shear rate of 10 s-1 in a range of 50 to 275 mPa.

It has been found that problems may occur when dye solutions are given into the eye, and when the dye solution is given with the usual syringes, the pressure created during the injection becomes too high and the dye can get behind the retina.

The problem is solved by using syringes in which the needle diameter, the ratio of cylinder diameter to canopy diameter and the aspect ratio are adjusted to avoid damage. In the present invention, syringes with a very small needle diameter are preferred to keep the damage to the eye as low as possible. The cylinder diameter is adjusted to the needle diameter to avoid the occurrence of a venturi effect to a large extent. In other words, the length of the syringe intended to be administered must also be as small as possible, so that the diameter of the needle diameter to canopy diameter is 0.1 to 0.2 to 0.2 to 0.1 to 0.1 to 0.1 to 0.2 inches. In addition, the preferred aspect ratio should be between 1 to 1 inches, with a ratio of 1 to 1 inches, and in particular between 1 to 1 inches.

A further subject matter of the invention is therefore a kit comprising a syringe containing a cylinder and a cannula containing a dye preparation according to the invention for selective staining of the membrana limitans interna and/or of epiretinal membranes in the human or animal eye, with a ratio of cylinder diameter to cannula diameter in the range of 10 - 2 to 1-2, preferably 20:1 to 4:1, preferably 8:1. The ratio of cylinder length to cylinder diameter in the range of 15 to 5 to 16:1 is preferred. The kit thus features a syringe whose cylinder diameter is equal to the diameter of the cannula. It has been found that the ratio of a small canister to a larger canister is proportional to the size of the canister, so that no one can achieve a more uniform rate of preparation in the same canister.

The kit or syringe preferably uses a 19 to 27 gauge, preferably 23 or 25 gauge, needle. 19 to 27 gauge needles are suitable for injection into the eye. Their outlet is small enough not to cause significant damage at the injection site, but still large enough to apply the invention to the eye at a sufficient speed. If the syringe cylinder is adjusted accordingly in diameter, pressure buildup inside the syringe or needle that will cause the injection to be too tightly pressed into the eye is avoided.In a preferred embodiment, such a cannula is used together with a syringe with a cylinder diameter of 3 to 10 mm. 23 or 25 gauge cannulas are particularly preferred when the dynamic viscosity of the preparation is 25 °C and a shear rate of 10-1 in a range of 1 to 500 mPa.that a sufficiently large quantity of the preparation of the invention can be deposited at the site of application at a sufficiently rapid rate without causing the preparation to explode from the cannula by pressure clogging, thus preventing the preparation from being injected behind the desired site of application, thus achieving optimal membrane staining.

The preparations of the invention described above and the syringes provided for their administration allow the colouring of membranes in the eye, ILM and/or ERM, in a specific way. Depending on the dye used, it is possible to colour either one type of membrane only, i.e. ILM or ERM only, or both. In one embodiment, the preparation of the invention can be used to cause a negative colouration of the eosin membrane in order to remove it. In this embodiment, a solution of the dye Brillant Blue G is used, which selectively colours the ILM but not the ERM. In this way, the uncoloured (MIL) membrane can be distinguished from the coloured (MIL) membrane and can therefore be removed.

The invention is further explained by the following examples, which describe, but are not limited to, solutions of dyes with increased density and their manufacture.

Example 1

0,025 g of brilliant blue G, 5 g of sucrose, 0,19 g of disodium hydrogen phosphate, 0,03 g of sodium dihydrogen phosphate and 0,82 g of sodium chloride are weighed precisely and filled with distilled water per 100 g. The raw materials are treated in a glass bottle for 1 h at a maximum temperature of 60 °C, producing a homogeneous solution with a concentration of dye 0,25 g/L and a density of 1,023 g/cm3.

Example 2

0,025 g of brilliant blue G, 5 g of trehalose, 0,19 g of disodium hydrogen phosphate, 0,03 g of sodium dihydrogen phosphate and 0,82 g of sodium chloride are weighed precisely and filled with distilled water per 100 g. The raw materials are treated in a glass bottle for 1 h at a maximum temperature of 60 °C, producing a homogeneous solution with a concentration of dye 0,25 g/L and a density of 1,023 g/cm3.

Example 3

0,025 g brilliant blue G, 0,19 g disodium hydrogen phosphate, 0,03 g sodium dihydrogen phosphate and 0,82 g sodium chloride are weighed precisely and filled to 100 g with a mixture of distilled water and D2O. The raw materials are treated in a glass bottle for 1 hour at a maximum temperature of 60 °C to obtain a homogeneous solution with a concentration of dye 0,25 g/L and a density of 1,018 g/cm3.

Example 4 Colouring matter + glycerol

0,025 g Brilliant Blue G, 0,19 g disodium hydrogen phosphate, 0,03 g sodium dihydrogen phosphate and 0,82 g sodium chloride are weighed precisely and filled with a mixture of distilled water and 10% glycerol.

Example 5

The method described in examples 1 to 4 produces a dye solution with the following composition: Other

Substanz	Einwaage soll ist in g	Einwaage ist in g
Polyvinylpyyrolidon	6	6,0067
Brilliant Blau G	0,0125	0,0125
0,095	0,0950
0,015	0,0159
NaCl	0,41	0,4100
Wasser	auf 50 g	auf 50 g

A homogeneous solution with a density of 1.028 g/cm3 and a viscosity of 7.38 mPa was obtained.

Example 6

The method described in examples 1 to 4 produces a dye solution with the following composition: Other

Substanz	Einwaage soll ist in g	Einwaage ist in g
Methylcellulose E 10 M (2 wt.%)	25	24,9986
Brilliant Blau G	0,0125	0,0125
0,095	0,0956
0,015	0,0151
NaCl	0,41	0,4099
Wasser	auf 50 g	auf 50 g

A homogeneous solution with a density of 1.007 g/cm3 and a viscosity of 142.79 mPa was obtained.

The dye solutions produced in examples 1 to 6 were used to stain the membrana limitans interna in the human or animal eye. All six solutions were found to be very well applied and to have immediately evaporated after application and stained the ILM. The staining was even more intense with the same amount of dye than with a Briliant Blue G solution applied for comparison, as known from DE 10255601.

Claims (15)

1. A water-based, biocompatible preparation for the selective staining of the internal limiting membrane (ILM) and/or of epiretinal membranes (ERM) in the human or animal eye, containing at least Brilliant Blue G as dye, wherein the preparation has a density in the range of 1.01 g/cm³ to 1.5 g/cm³.
2. The preparation according to claim 1, additionally containing a dye selected from the group consisting of azo dyes, cyanine dyes and/or natural dyes or mixtures thereof.
3. The preparation according to claim 1 or 2, wherein the preparation has a density in the range of 1.01 g/cm³ to 1.3 g/cm³.
4. The preparation according to one of claims 1 to 3, characterised in that the concentration of the Brilliant Blue G in the finished preparation is up to 0.3 g/l, preferably 0.25 g/l.
5. The preparation according to one of the preceding claims for use as a dye for a negative representation of epiretinal membranes.
6. The preparation according to one of the preceding claims, characterised in that, as an agent that adjusts the density of the preparation, it contains heavy water, a polymer selected from polyethers, polyvinyl alcohol, polyesters, polyacrylic acid copolymers, polyvinyl pyrrolidone, a polysaccharide selected from hydroxyethyl starch or dextran, or mixtures thereof.
7. The preparation according to one of claims 1 to 5, characterised in that, as an agent that adjusts the density of the preparation, it contains a polyether.
8. The preparation according to one of the preceding claims, characterised in that it additionally contains at least one viscosity-adjusting agent, selected from: polyethers, polyvinyl alcohol, polyesters, polyacrylic acid copolymers, polyvinyl pyrrolidone, and other polymers, polyhydric alcohols such as glycerol, ethylene glycol, propylene glycol, butylene glycol, cellulose, xanthan gum, starch, hyaluronic acid and the respective derivatives thereof, chondroitin sulfate and sodium sulfate.
9. The preparation according to one of claims 1 to 8, characterised in that the preparation has a dynamic viscosity in the range of 1 to 500 mPas, preferably in a range of 50 to 275 mPas, at 25°C and a shear rate of 10 s^-1.
10. The preparation according to claims 1 to 9, characterised in that the osmolarity of the solutions produced is in the range of 280-330 mosmol/l, preferably 300 mosmol/l.
11. A kit comprising a syringe with barrel and cannula and a water-based preparation according to one of claims 1 to 10 for the selective staining of the internal limiting membrane (ILM) and/or of epiretinal membranes (ERM) in the human or animal eye, wherein the ratio of barrel diameter to cannula diameter is from 10 to 2 : 1 to 0.2, preferably 20 : 1 to 4 : 1.
12. The kit according to claim 11, characterised in that the ratio of barrel length to barrel diameter is in a range of 15 to 5 : 1.
13. The kit according to claim 11 or 12, characterised in that the syringe has a cannula with 19 to 27 gauge, preferably 23 or 25 gauge.
14. The kit according to claim 13, characterised in that the syringe has a barrel diameter of 3 to 10 mm.
15. The preparation according to one of claims 1 to 10 or the kit according to one of claims 11 to 14 for use in surgical treatment on the eye, comprising the selective staining of the internal limiting membrane (ILM) and/or of epiretinal membranes (ERM) in the human or animal eye.