WO1999045936A1 - Supercritical conditioned gas mixture containing co2, no and optionally a neutral gas - Google Patents

Abstract

The invention concerns a conditioned NO/CO2 mixture containing at least nitric oxide (NO) and carbon dioxide (CO2), characterised in that it is in supercritical state. Preferably, said NO/CO2 mixture pressure is higher than about 73.10<5> Pa at 304.21 K. The invention also concerns a pressurised container, such as a gas cylinder, containing such a supercritical NO/CO2 mixture and a method for expanding such NO/CO2 mixture to ensure a constant concentration in NO while the gas cylinder is being emptied.

Description

CONDITIONED SUPERCRITICAL GAS MIXTURE CONTAINING C02, NO AND POSSIBLY NEUTRAL GAS

The object of the present invention relates to a conditioned gas mixture containing carbon dioxide (C0 ₂ ), nitrogen monoxide (NO) and optionally at least one neutral gas, such as nitrogen (N ₂ ), a process for the preparation of such a mixture in conditioned form at a pressure greater than 30.10 5 Pa, preferably greater than 70.105 Pa.

Laparoscopy, also called laparoscopy, is a medical technique used not only for diagnostic purposes, but also for therapeutic or surgical treatment.

Thus, this technique is more and more used during gynecological surgical intervention, in particular during an operation of puncture of an ovarian cyst or an operation of tubal ligation. In addition, this technique is also used in digestive surgery.

The growing and constant development of this laparoscopy technique is linked in particular to technical progress made in the field of medical imaging and, in parallel, in the field of associated medical equipment, such as scalpels, forceps ...

Usually, a laparoscopic operation uses an insufflator intended to inflate the abdominal wall of the patient by injecting a gas or a gaseous mixture through said wall and then to maintain the intra-abdominal pressure by injection at 2

rapid flow and low pressure of said gas or gas mixture, for the time necessary for carrying out the medical procedure.

The quantity or volume of gas or gas mixture injected into the patient's body depends in particular on gas leaks through the orifice through which the surgeon or the like operates, on the intra-abdominal pressure and on the duration of the intervention. medical.

In general, the gas used for this purpose is carbon dioxide (CO ₂ ).

However, it has been observed that the insufflation of C02 inside the patient's body, since it increases the intra-abdominal pressure, causes a decrease in the blood flow of the abdominal organs, in particular the kidneys and the intestines. , i.e. hypoperfusion of these organs.

However, this hypoperfusion can be attenuated, or even eliminated, by adding a small amount of nitrogen monoxide (NO) to the CO ₂ , as described in document WO-A-9715312.

In addition, documents US-A-5670177 and O-A-9715311 describe the use of a gas mixture containing carbon dioxide and nitrogen monoxide to manufacture a gaseous medicament for combating ischemia.

Currently, gas mixtures containing NO and C0 ₂ , which can be used for medical purposes, also contain nitrogen (N ₂ ) in trace amounts.

For example, such NO / N ₂ / CO ₂ mixtures can be produced by premixing approximately 4% NO in nitrogen, then adding the appropriate amount of CO ₂ , so as to obtain a final mixture containing approximately 20 ppm NO (part per million by volume), less than 1% nitrogen and the rest being C0 ₂ ; this final mixture is generally packaged in gas cylinders or the like. However, the known mixtures of. type NO / C0, possibly containing trace nitrogen, have a major drawback, namely that they do not allow their packaging in a container, for example in a bottle, at a pressure greater than 30 × 10 ⁵ Pa.

Indeed, when the pressure of such NO / "C0 ₂ mixtures is increased beyond 30.10 Pa, the CO ₂ is in two-phase liquid / vapor equilibrium and the distribution of NO in the two phases then depends on its solubility, which varies according to the pressure and temperature conditions of the mixture.

It follows that during the emptying of the pressurized container containing the NO / C0 mixture, for example a gas cylinder, the concentration of the constituents of the liquid and gaseous phases tends to fluctuate. Thus, measurements of the solubility of NO in C0 ₂ give variations in the NO content in the gas phase at equilibrium of 4% at 15 ° C and 54.10 ⁵ Pa and by 14% at 15 ° C and at 66.10 ⁵ Pa.

From there, the quantity of NO / C0 ₂ mixture that can be introduced into a bottle is limited, which presents a potential danger for a patient undergoing surgical intervention requiring the use of such a N0 / C0 ₂ mixture and significant discomfort for the surgical team performing the procedure, since during the said operation it is necessary to have recourse to several bottles, which can cause a temporary stoppage, not acceptable from the point of view of patient safety , the supply thereof with said gas mixture or require more complex implementation systems and more manipulations, which increases all the more risks for the patient and the overall costs of the operation. The object of the present invention is therefore to provide a conditioned gas mixture containing at least C0 ₂ and NO at a pressure greater than 30.10 Pa, preferably greater than 70.10 Pa, which makes it possible to considerably increase the quantity of gaseous mixture can be packaged in the same bottle and overcomes the above problems and drawbacks.

In particular, the N0 / C0 ₂ gas mixture according to the invention has the particularity of guaranteeing a constant concentration of NO of the N0 / C0 mixture, throughout the duration of emptying of the pressurized container containing it.

The invention then relates to a conditioned NO / C0 ₂ mixture containing at least nitrogen monoxide (NO) and carbon dioxide (C0), characterized in that it is in the supercritical state.

The critical point of a compound, commonly called point C, is the point at which the liquid-vapor equilibrium curve of said compound ends. At point C, there is therefore a monophasic intermediate state between the liquid state and the gaseous state of said compound which is called critical state or if we move away significantly from point C, the supercritical state, which corresponds at temperatures and pressures higher than those of C. Depending on the case, the process of the invention comprises one or more of the following characteristics:

- Its pressure is greater than approximately 73.10 5 Pa at 304.21 K, preferably greater than or equal to 80.10 Pa; - Its pressure is at most 200.10 ⁵ Pa at 293 K, preferably at most 150.10 Pa;

- It further comprises at least one constituent chosen from nitrogen, argon, xenon, krypton and helium; - the NO concentration is between 10 ppb and 200 ppm, preferably between 500 ppb and 100 ppm; - It contains at least 30% of C0 ₂ , preferably from 40% to 80% of C0 ₂ .

The invention also relates to a pressure vessel containing a supercritical NO / CO ₂ mixture. Preferably, the container is chosen from gas bottles having a capacity of 1 to 50 1, preferably from 5 to 20 1.

According to another aspect, the invention relates to a method for relaxing a NO / C0 mixture conditioned according to the invention, contained in a pressurized container, in which a relaxation of said mixture is carried out containing at least NO and C0 ₂ by emptying said container and controlling at least one of the parameters chosen by the pressure, temperature and flow rate of the N0 / C0 ₂ mixture, so as to obtain a gaseous mixture containing NO and C0 ₂ substantially without formation of liquid phase .

Preferably, an N0 / C0 ₂ mixture is recovered containing at least NO and C0 ₂ , said N0 / C0 ₂ mixture having a constant NO concentration during the emptying time of said container.

Advantageously, the flow rate of the N0 / C0 ₂ mixture is between 0 and 25 l.min-, preferably between 1 and 10 l.min

Furthermore, the invention also relates to the use of a NO / C0 ₂ supercritical mixture according to one of claims 1 to 6 for the manufacture of a gaseous medicament intended to be used in laparoscopy and / or to combat against regional hypoperfusion or systemic hemodynamic changes.

The invention further relates to a method of therapeutic treatment of the human or animal body or a method of diagnosis of the human or animal body using a gas mixture containing nitrogen monoxide, carbon dioxide, optionally a neutral gas. , such as nitrogen or helium obtained by expansion of a NO / C0 ₂ supercritical mixture according to the invention.

The invention will now be described in more detail using examples given by way of illustration but not limiting of the invention. In order to test the validity of the preparation process according to the invention, a supercritical mixture containing CO ₂ , NO and a neutral gas, in this case argon, was produced in 5 and 20 liter bottles. The NO / CO / Ar ternary mixture obtained is at a pressure of approximately 130 × 10 ⁵ Pa at 20 ° C.

The NO, CO ₂ and argon contents of said mixture are indicated in the table below.

Then, the bottles were emptied for an emptying time of 2 hours 30 minutes (test 1) and approximately 10 hours (test 2).

During the emptying of the bottle of test 1, the emptying rate is variable and is done with stops, while in test 2, the emptying rate is substantially constant. During tests 1 and 2, the content of nitrogen monoxide (NO) is measured continuously by chemiluminescence analyzers of the COSMA type or, as the case may be, of the ECO PHYSICS type.

BOARD

NO / C0 ₂ / AR mixture Duration Flow Variation of the

NO test C02 Argon NO content (ppm) () () drain drain during drain

1 22 50.2 ~ 49.8 2 h 30 variable NO

2 21 50.2 - 49.8 10 h 6 1 / min NO

As it appears in the preceding table, the two tests carried out show the stability of the value of NO content of the mixture produced by the process of 7

the invention, during the entire bottle emptying operation.

In fact, during all this time, no variation in the NO content was noted. More specifically, the content of C0 ₂ at the start and end of emptying during test No. 2 did not change and remained substantially constant at 50%.

In addition, a gas chromatographic analysis (MTI) carried out at the end of the drain does not reveal the presence of any particular impurity, such as CO, N ₂ 0 or

CnHm, within the detection limits of the analyzer

(<1 ppm).

It follows that the ternary gas mixture NO / C0 ₂ / neutral gas according to the invention is applicable to the medical field.

The single figure shows, by way of example, the liquid / vapor curve of a ternary N0 / C0 / N ₂ mixture containing approximately 70% of C0 ₂ , approximately 30% of N ₂ and 20 ppm of NO, as a function of the temperature and pressure of the mixture.

On this curve, the temperature (in K) is represented on the abscissa and the pressure (in bars) is given on the ordinate.

For such a mixture, the critical point or point C corresponds to a pressure of approximately 110.10 Pa and to a temperature of approximately 287 K.

The supercritical mixtures NO / 70% CO ₂ /30% N ₂ according to the invention are therefore defined by a pressure and a temperature greater than or equal to those of point C.

Claims

 8 1. NO / C0 conditioned mixture containing at least nitrogen monoxide (NO) and carbon dioxide (C0 ₂ ), characterized in that it is in the supercritical state. 2. NO / CO ₂ mixture according to claim 1, characterized in that its pressure is greater than approximately 73.10 Pa at 304.21 K, preferably greater than or equal to 80.10 ⁵ Pa. 3. NO / C0 ₂ mixture according to one of claims 1 or 2, characterized in that its pressure is at most 200.10 Pa at 293 K, preferably at most 150.10 ⁵ Pa. 4. NO / C0 ₂ mixture according to one of claims 1 to 3, characterized in that it further comprises at least one constituent chosen from nitrogen, argon, xenon, krypton and helium. 5. NO / C0 ₂ mixture according to one of claims 1 to 4, characterized in that the NO concentration is between 10 ppb and 200 ppm, preferably between 500 ppb and 100 ppm. 6. NO / C0 ₂ mixture according to one of claims 1 to 5, characterized in that it contains at least 30% of C0 ₂ , preferably from 40% to 80% of C0 ₂ . 7. Pressure vessel containing a supercritical NO / CO mixture according to one of claims 1 to 6. 8. Pressure vessel according to claim 7, characterized in that it is chosen from gas cylinders having a capacity of 1 to 50 1, preferably from 5 to 20 1. 9. Method for relaxing an NO mixture / C0 ₂ in the supercritical state according to one of claims 1 to 6, contained in a pressurized container according to one of claims 7 or 8, in which one operates an expansion of said mixture containing at least NO and C0 ₂ by emptying said container and controlling at least one of the parameters chosen by the pressure, the temperature and 9 the flow rate of the NO / CO ₂ mixture, so as to obtain a gaseous mixture containing NO and CO ₂ substantially without formation of the liquid phase. 10. The expansion method according to claim 9, characterized in that a NO / CO ₂ mixture containing at least NO and C0 ₂ is recovered, said NO / C0 ₂ mixture having a constant NO concentration over time. emptying said container. 11. Expansion method according to one of claims 9 or 10, characterized in that the flow rate of the NO / C0 mixture is between 0 and 25 l.min, preferably between 1 and 10 l.min 12. Use of a NO / C0 ₂ supercritical mixture according to one of claims 1 to 6 for the manufacture of a gaseous medicament intended to be used in laparoscopy and / or for combating regional hypoperfusion or modifications systemic dynamics.