WO2010082326A1 - Ozone/oxyglutathione ocular perfusion liquid and washing liquid and method of producing the same - Google Patents

Abstract

The purpose of this object is to provide a novel and useful ozone/oxyglutathione ocular perfusion liquid and washing liquid wherein ozone is dissolved in an oxyglutathione ocular perfusion liquid and washing liquid, and an example of a method of producing the same. Although drugs for intraocular and extraocular perfusion should be aseptic, the mere addition of an antibiotic results in problems such as promoting the appearance or proliferation of a resistant strain, achieving only a narrow antibacterial spectrum or requiring a troublesome procedure for treating a waste liquid after using. In contrast thereto, ozone is free from the troublesas described above because of being capable of autolyzing to harmless oxygen.

Description

Ozone / oxyglutathione eye perfusion / cleaning solution and method for producing the same

The present invention relates to an oxyglutathione eye perfusion / cleaning solution and a method for producing the same.

In ophthalmic surgery such as cataract surgery, vitreous surgery, glaucoma surgery, etc., as shown in Patent Document 1, oxyglutathione (oxiglutatione) having corneal endothelium protecting action is effective for intraocular and extraocular perfusion and washing. There is a formulation as an ingredient, and is marketed under the trade name “BS SPLUS (registered trademark)” (BSSPLUS, Alcon Laboratories, Inc.). This preparation contains potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glucose, sodium bicarbonate, sodium hydrogen phosphate hydrate, pH adjuster, etc. as additives, and oxyglutathione Dissolved in isotonic buffer close to aqueous humor composition. In addition, there is one having a similar composition and marketed under the trade name “Opeguard Neo Kit (registered trademark)” (Senju Pharmaceutical Co., Ltd.).
In this preparation, oxyglutathione, which is an active ingredient, cannot be stably stored for a long period of time at a neutral pH suitable for intraocular and extraocular perfusion and washing. In addition, it is mixed with the diluting solution at the time of use, and is so-called two-component.

JP-A-5-310580

By the way, it has been reported that if bacteria enter the eye during surgery, postoperative endophthalmitis occurs frequently and serious damage such as blindness remains. In order to prevent bacteria from invading, antibiotics are instilled as a preoperative aseptic technique, and antibiotics are instilled during surgery. Antibiotics are also added to the drugs for intraocular and extraocular perfusion to ensure sterility and to eliminate the invading bacteria.

However, according to a report in the 1990s (Takahisa Koga, et al .: Frequency and prevention of endophthalmitis after cataract surgery. Ophthalmic surgery, 11: 175-178, 1998) Endophthalmitis after cataract surgery occurs at a frequency of 0.06 to 0.2%, and it is considered that one eye is still present in 500 to 1700 eyes.
This is because the countermeasures are based on the use of antibiotics. On the contrary, the development and growth of resistant bacteria are promoted, and each antibiotic has a unique antibacterial spectrum and works against all bacteria. It doesn't seem to be unrelated to the survival of bacteria.
In addition, when an antibiotic is added to a drug for intraocular and extraocular perfusion, waste liquid treatment after use becomes troublesome.
Therefore, in order to solve the above-mentioned problems, the present invention provides an oxyglutathione eye perfusion / cleaning solution that can ensure sterility without adding antibiotics as an prevention of endophthalmitis, and an example thereof. It aims at providing a suitable manufacturing method.

The inventor has focused on ozone having a strong bactericidal action. Ozone water production methods and equipment have already been established on the commercial level, but oxyglutathione eye perfusion / cleaning solution contains impurities such as oxyglutathione, so-called water impurities. It was predicted that it would be difficult to dissolve ozone in glutathione eye perfusion and washing solution. However, surprisingly, ozone was dissolved in the oxyglutathione eye perfusion / cleaning solution relatively smoothly, and the present invention was proposed.

According to the present invention, ozone / oxyglutathione ocular perfusion / cleaning solution can be provided as an initial solution of ozone to a concentration of 1 to 4 ppm at which a sufficient bactericidal effect is expected at room temperature for ocular perfusion / cleaning solution.
The above-mentioned ozone / oxyglutathione eye perfusion / cleaning liquid is a combination of two liquids to produce an oxyglutathione eye perfusion / cleaning liquid, while supplying oxygen gas as a raw material gas to the ozone gas generation unit to generate ozone gas, as described above It can be manufactured by blowing ozone gas into the liquid to dissolve ozone. The ozone concentration of the produced ozone / oxyglutathione eye perfusion / cleaning liquid is measured by the ultraviolet absorption method conventionally used after the liquid is once discharged out of the apparatus, so that the composition of the liquid does not change.

◎ Ozone destroys bacterial cell membranes due to its strong oxidizing power, and eventually destroys the cells themselves, lysing without losing its original shape. Therefore, it is thought that resistant bacteria do not appear. In addition, the bactericidal spectrum ranges from viruses to general bacteria. Furthermore, if the oxidizing power is exhausted, it will become harmless oxygen, and since it has a short half-life in the first place, there is no worry of residual. Therefore, the ozone / oxyglutathione ocular perfusion / cleaning solution in which ozone is dissolved can ensure sterility and does not require special waste liquid treatment.

It is a block diagram of the manufacturing apparatus which implement | achieves the manufacturing method of the ozone oxyglutathione eye perfusion and washing | cleaning liquid which concerns on embodiment of this invention. It is a manufacturing flowchart at the time of using the manufacturing apparatus of FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Ozone / oxyglutathione production apparatus 2 ... Oxygen cylinder for medical use 5 ... Bag (oxyglutathione accommodation)
6, 16 ... Sterile extension tube made of silicon 8 ... Air supply valve 9 ... Ozone gas generating part 10 ... Processing tank (ozone dissolving part / gas-liquid separating part)
DESCRIPTION OF SYMBOLS 11 ... Ejector 12 ... Exhaust ozone treatment part 17 ... Pinch valve 18 ... Hand piece 19 ... Ozone concentration meter

[Ozone / Oxyglutathione Eye Perfusion / Cleaning Solution]
The ozone / oxyglutathione eye perfusion / cleaning solution according to the present invention is obtained by dissolving ozone in an oxyglutathione eye perfusion / cleaning solution.

The oxyglutathione eye perfusion / cleaning solution is a two-component solution composed of an oxyglutathione solution which is an active ingredient and a diluting solution, and is combined when used.
In the present invention, the above-mentioned commercially available products can be used as the oxyglutathione eye perfusion / cleaning solution.

The ozone / oxyglutathione eye perfusion / cleaning solution of the present invention is dissolved in the above-described oxyglutathione eye perfusion / cleaning solution at an initial dissolved concentration of 1 to 4 ppm at room temperature.
To date, hand-washing devices using ozone water have been developed, and hospitals have already used this type of hand-washing device to perform hand-washing before surgery. In view of safety and safety, it is recommended that the dissolved concentration of ozone be 4 ppm. However, in the present invention, the use is an ophthalmic perfusion / cleaning solution, and the bactericidal effect is presumed to be sufficiently obtained if the dissolved concentration of ozone is 1 ppm or more. Therefore, 1 to 4 ppm at room temperature, which is a normal use environment. We are aiming to produce ozone dissolved at the initial dissolved concentration.

[Preferred production method of ozone / oxyglutathione eye perfusion / cleaning solution]
Oxyglutathione eye perfusion / cleaning liquid is prepared by combining the two liquids, while oxygen gas is supplied as a raw material gas to the ozone gas generating part to generate ozone gas by discharge, and ozone gas is blown into the liquid described above, and the fineness by ozone gas is generated. Ozone is physically dissolved in water by gas-liquid contact between bubbles and water, and dissolved.
In consideration of the use as an eye perfusion / cleaning solution, it is preferable to use oxygen gas, usually high-purity oxygen gas supplied from a medical oxygen cylinder, instead of dry air gas as the source gas. In addition, when high-purity oxygen gas is used, nitrogen gas that acts as a catalyst in ozone generation is relatively lost, so that it is difficult to generate ozone. More preferably, the oxygen concentration is high and the oxygen concentration is about 98%. It is preferable to use a gas.

Conventionally, pure water or ultrapure water has been used as water, because the amount of impurities in ozone water is reduced and the dissolved state of ozone is stabilized. On the other hand, oxyglutathione ocular perfusion / cleaning solution contains more impurities than pure water or ultrapure water, and ozone seems to be difficult to dissolve, but electrolyte ions such as potassium ions and magnesium ions Surprisingly, it is physically absorbed in water stably as microbubbles.

[Manufacturing equipment]
The manufacturing apparatus 1 by the so-called aeration method in which the above-described ozone gas is blown and the surrounding configuration will be described with reference to FIG.
First, the oxygen gas supply means and the oxyglutathione eye perfusion / cleaning liquid supply means will be described.
Reference numeral 2 denotes a medical oxygen cylinder, reference numeral 3 denotes a pressure reducing valve, and reference numeral 4 denotes a flow rate regulator. An oxygen gas supply means constituted by these is connected to the manufacturing apparatus 1 through a gas pipe. Therefore, the oxygen gas accumulated in the medical oxygen cylinder 2 is depressurized by the pressure reducing valve 3 and supplied to the supply destination at a predetermined flow rate by the flow rate regulator 4.
Reference numeral 5 denotes a bag containing the processing liquid. The bag 5 contains an oxyglutathione eye perfusion / cleaning solution in which two solutions are combined. One end of a sterilization extension tube 6 made of silicon is connected to the bottom of the bag 5 to constitute an oxyglutathione eye perfusion / cleaning liquid supply means.

In the manufacturing apparatus 1, reference numeral 7 denotes a pressure switch, reference numeral 8 denotes an air supply valve, reference numeral 9 denotes an ozone gas generator, and reference numeral 11 denotes an ejector, which are inserted into the gas pipe from the upstream side. .
In the pressure switch 7, an appropriate pressure is set in consideration of the ozone gas generation capability in the ozone gas generation unit 9 and the raw solution, in this case, the dissolution efficiency of ozone gas blown into the oxyglutathione eye perfusion / cleaning solution. When the pressure is reached, a notification signal to that effect is transmitted to the control unit, and the control unit is configured to operate the ozone gas generation unit 9.
The ozone generator 9 converts oxygen into ozone by silent discharge, and is equipped with a discharge unit.

The code | symbol 10 shows the processing tank as an ozone dissolution part and a gas-liquid separation part. The material constituting the treatment tank 10 is required to have ozone resistance and heat resistance corresponding to autoclave sterilization. For example, PFA (= tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer), PTFE ( = Polytetrafluoroethylene (tetrafluoroethylene). The former is more suitable for actual use because it is further excellent in hardness and workability.
Considering only ozone resistance and heat resistance, titanium and stainless steel such as SUS316L are also candidates as metal materials, but there is a risk of spilling of fine debris generated during metal elution and processing. Therefore, it is not preferable. Similarly, glass materials such as quartz and Pyrex (registered trademark) are also candidates, but they are not preferable because they may be damaged at the time of desorption.

Since the treatment tank 10 exerts a gas-liquid separation action, even if an appropriate amount of oxyglutathione eye perfusion / cleaning liquid is filled and accommodated, the escape space where gas separated into the upper part of the tank, mainly ozone gas, can flow out. Is designed to ensure that For example, when 500 mL is filled, it is preferable that a clearance space with a height of 50 mm or more is secured upward.
The other end of the above-described silicon sterilization extension tube 6 is connected to the upper portion of the treatment tank 10, and the oxyglutathione eye perfusion / cleaning solution is supplied into the tank through the tube 6. A gas pipe is connected to the lower side of the side so that ozone gas fed from the gas pipe via the ejector 11 is blown into the oxyglutathione eye perfusion / cleaning liquid in the tank as fine bubbles. It has become.

Reference numeral 12 denotes an exhaust ozone treatment unit. The exhaust ozone treatment unit 12 is provided with a catalyst such as manganese oxide or palladium oxide that oxidizes ozone and returns it to oxygen. In addition, a heater that is appropriately operated is provided in order to activate the catalyst. Since the undissolved ozone gas flows into the exhausted ozone treatment unit 12 from the ozone gas discharge pipe extending from the upper part of the treatment tank 10, ozone is decomposed into harmless oxygen and then released into the atmosphere. It has become.
Reference numeral 13 denotes a water level sensor. The water level sensor 13 detects whether an appropriate amount of oxyglutathione eye perfusion / cleaning liquid is contained in the treatment tank 10.
Reference numeral 15 denotes a gas-liquid separation partition. The gas-liquid separation partition 15 partitions the vicinity of the bottom inside the processing tank 10 to form a space in which undissolved ozone gas does not flow.

Reference numeral 16 denotes a sterilization extension tube made of silicon, and an extraction portion on one end side of the tube 16 enters a space surrounded by the gas-liquid separation partition wall 15 in the processing tank 10. A pinch valve 17 is inserted into the tube 16 on the upstream side. The pinch valve 17 has a structure in which a flexible tube is crushed from the outside to block the supply line, and contamination from the outside is prevented. A handpiece 18 is attached to the tip that extends out of the apparatus.
Reference numeral 19 denotes an ozone concentration meter. The ozone concentration meter 19 receives the ozone / oxyglutathione eye perfusion / cleaning liquid discharged from the tube 16 to the outside of the apparatus and measures the dissolved ozone concentration. The ozone concentration meter 19 guides the ozone / oxyglutathione eye perfusion / cleaning liquid once out of the apparatus to a quartz glass tube, and measures the dissolved ozone concentration based on the relative ratio of the ultraviolet absorption of ozone. Since the ozone concentration meter 19 is not inserted in the middle of the tube 16 which is a supply line of ozone / oxyglutathione eye perfusion / cleaning solution, the ozone / oxyglutathione eye perfusion / washing solution supplied from the tube 16 is always stabilized. Therefore, it is not affected by the ozone decomposition accompanying the measurement of dissolved ozone concentration at a small flow rate.

In addition, the processing tank 10 can be removed from surrounding supply means and the like. The processing tank 10 is sterilized by an autoclave before use, and is then mounted to form the configuration shown in FIG.

Next, operation | movement of the manufacturing apparatus 1 is demonstrated according to the flowchart of FIG.
First, the whole amount of oxyglutathione eye perfusion / cleaning solution is transferred into the treatment tank 10 through the above-mentioned supply means.
On the other hand, the power switch (not shown) of the manufacturing apparatus 1 is turned on, and the states of the water level sensor 13 and the pressure switch 7 are detected.
When the state of the water level sensor 13 and the pressure switch 7 is normal, the air supply valve 8 is opened, the compressed oxygen gas is supplied into the apparatus, and the ozone gas generating unit 9 is activated at the same time. Start generating.

Then, the pinch valve 17 is opened and closed at an appropriate interval, and the ozone / oxyglutathione eye perfusion / cleaning solution is passed through the ozone concentration meter 19 to measure the dissolved ozone concentration. The desired concentration range is set to 1.5 ppm (above) to 2.0 ppm (below), and when the measurement result is less than 1.5 ppm, the ozone gas generator 9 is kept in the ON state to dissolve ozone. Prompt. On the other hand, when the measurement result is 2.1 ppm or more, the ozone gas generation unit 9 is turned off. When the measurement result is 1.5 ppm (or higher) to 2.0 ppm (or lower), the preparation is completed, that is, an ozone / oxyglutathione solution having an effective ozone dissolved concentration range is accommodated in the treatment tank 10. It is notified by lighting a ready lamp (not shown in FIG. 1) that the cage is ready for use, and prompts the operator to press the ozone / START switch (not shown in FIG. 1).

When the START switch is pressed, the pinch valve 17 is opened, and ozone / oxyglutathione eye perfusion / cleaning solution is supplied from the handpiece 18 to the patient's eye. Therefore, the ozone / oxyglutathione eye perfusion / cleaning solution can disinfect the eyes of the patient to whom it is supplied, while maintaining itself in a sterile state.
In addition, the operation time is an average of 10 minutes and an interval of 10 minutes, and an average of 150 mL is used in 10 minutes. Therefore, it takes up to 1 hour to use up 500 mL. Ozone self-decomposes over time and the dissolved ozone concentration decreases. However, when the dissolved ozone concentration falls below the lower limit of the effective concentration range, the ozone generator 9 operates again and starts generating ozone. Therefore, the ozone dissolved concentration is maintained in the effective concentration range as long as the manufacturing apparatus 1 is operated.

Using 500 mL of the product name “BSS Plus (registered trademark)” (BSS PLUS, Alcon Laboratories, Inc.), an ozone / oxyglutathione eye perfusion / cleaning solution was manufactured using the manufacturing apparatus configured as shown in FIG. An ozone / oxyglutathione eye perfusion / cleaning solution having an ozone dissolved concentration of 1.9 ppm was obtained. When this ozone / oxyglutathione eye perfusion / cleaning solution was analyzed, no change in composition was observed with the oxyglutathione eye perfusion / washing solution used as a raw material solution.
The ozone / oxyglutathione eye perfusion / cleaning solution was filled into a nominal 500 mL wide-mouth light-shielding medium, left open in an ambient atmosphere at room temperature of 25 ° C., and the concentration was measured every 10 minutes. Later, 1.35 ppm, 0.98 ppm after 20 minutes, and 0.71 ppm after 30 minutes were obtained. That is, it was confirmed that the half-life was about 20 minutes.

The embodiment of the present invention has been described in detail above. However, the specific configuration is not limited to this embodiment, and the present invention can be changed even if there is a design change without departing from the gist of the present invention. included.
For example, the manufacturing apparatus described above is merely an example, and any device that can dissolve ozone without changing the composition of the oxyglutathione eye perfusion / cleaning solution may be used even if the configuration is different.

The ozone / oxyglutathione eye perfusion / cleaning solution of the present invention has no sterilization, but has sufficient sterility. Therefore, it can be said that the drug is highly safe from the patient side. On the other hand, from the viewpoint of medical personnel, it can be manufactured on the spot using commercially available oxyglutathione eye perfusion / cleaning solution, which is convenient. In addition, even when bacteria are mixed when preparing the oxyglutathione eye perfusion / cleaning solution by combining the two solutions, they are sterilized by the sterilization action of the dissolved ozone.

Claims (4)

Ozone / oxyglutathione eye perfusion / cleaning solution, wherein ozone is dissolved in oxyglutathione eye perfusion / washing solution containing oxyglutathione as an active ingredient. The ophthalmic / oxyglutathione eye perfusion / cleaning solution according to claim 1, wherein the initial dissolved concentration of ozone is 1 to 4 ppm. 3. The method for producing an ozone / oxyglutathione eye perfusion / cleaning liquid according to claim 1 or 2, wherein oxygen gas is supplied as a raw material gas to the ozone gas generating section to generate ozone gas, and this ozone gas is blown into the oxyglutathione eye perfusion / cleaning liquid. The manufacturing method characterized by making it melt | dissolve in. In the method for producing ozone / oxyglutathione eye perfusion / cleaning liquid according to claim 3, the ozone / oxyglutathione eye perfusion / cleaning liquid produced is discharged from the apparatus, and the dissolved ozone concentration is measured by a voltage change equation. The manufacturing method characterized by continuing to operate the ozone gas generating unit until the dissolved ozone concentration is reached.

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