KR20030007686A - Pharmaceutical composition comprising a free-radical scavenging sedative agent and a metal ion chelating agent - Google Patents

Abstract

The present invention relates to the use of certain sterile sedative pharmaceutical compositions, in particular with pharmaceutically acceptable diluents or carriers, for the treatment of critically ill patients and for improving survival in critically ill patients, and for the manufacture of a medicament for improving the survival of such patients. Pharmaceutical compositions containing free radical scavenging sedatives (e.g., propofol) and metal ion chelating agents (e.g., edetate), in particular propofol dissolved in water-immiscible solvents, are emulsified with water and surfactants It relates to the use of such a composition which is stabilized in use and further contains an oil-in-water emulsion containing a metal ion chelating agent (eg disodium edetate).

Description

PHARMACEUTICAL COMPOSITION COMPRISING A FREE-RADICAL SCAVENGING SEDATIVE AGENT AND A METAL ION CHELATING AGENT}

Despite advances in emergency care medications, the survival rate of critically ill patients is still low, highly variable and the general mortality ranges from 10% to 40%. Beyond improvements in the development and treatment of antibiotics (e.g., newer resuscitation technologies such as ventilation and fluid administration), despite years of medical research involving a number of drugs and treatments, There was almost no effect on survival. Thus, there is a large unmet medical need to improve the survival of critically ill patients.

Propofol is an intravenous sedative and can be used, for example, for induction, maintenance and sedation of general anesthesia in an intensive care unit. Propofol is a very successful anesthetic and is marketed under the trademark 'Diprivan' for use in human treatment and under the trademark 'Rapinovet' for veterinary use.

After identifying the anesthesia properties of propofol, British Patent Application 13739/74 was filed, which was issued to British Patent No. 1,472,793. Corresponding patents have been granted in the United States (USP 4,056,635, USP 4,452,817 and USP 4,798,846) and in many other areas.

The discovery that accidental exogenous microbial contamination due to non-sterile handling of Diprivan's agent may cause 'clusters' of post-operative infections is a suitable additive (additives are 'contact contamination' Development of modified formulations containing one log increase (i.e., 10-fold) can delay the growth of conventional microorganisms within 24 hours following exogenous contamination). The development of modified edetate-containing formulations of propofol in particular has led to the application and licensing of British Patent No. 2,298,789. Corresponding patents are granted, for example, in the United States (USP 5,714,520; USP 5,731,355; USP 5,731,356; USP 5,908,869) and elsewhere. Commercially available modifiers of 'Dipriban' contain 0.005% disodium edetate.

To meet FDA regulations, the US conducted a clinical trial program between 1993 and 1998 using a modified formulation of 'Dipriban'. His purpose was to examine how the addition of 0.005% disodium edetate to 'diprivan' had an effect on its pharmacodynamics, efficacy and safety profile. No difference in pharmacodynamics or efficacy was expected. However, it has been assumed that this can lead to differences in serum calcium and magnesium concentrations, and possibly renal function. Thus, these safety parameters have become the primary measure in clinical trial programs.

The program, including 10 separate clinical trials, confirmed that the addition of disodium edetate (0.005% w / v) did not affect the efficacy or pharmacodynamics of 'Diprivan'. With regard to safety, no clinically significant effects on calcium or magnesium levels were observed, and no impairment of calcium or magnesium homeostasis due to short or long term use of modified formulations after their introduction was reported. Indeed, the overall adverse event profile of the modified 'Diprivan' did not appear to be clinically different from the adverse profile of the 'Diprivan'. The only significant effect is the greater excretion of zinc in the urine of intensive care unit (ICU) patients receiving modified formulations for long-term sedation compared to patients receiving standard sedatives. Although the clinical significance of these findings is unclear, the prescribing information has been changed to consider using zinc supplementation when administering 'diprivan' modified with prolonged infusion in patients with predisposition to zinc deficiency.

The nature and pattern of adverse events reported spontaneously at all 'Diffriban' uses were also monitored, and although the exact number could not be determined, the pattern of adverse effects reported after the introduction of the modified formulation was associated with a population of infections associated with accidental exogenous microbial contamination. It is similar to the pattern before its introduction except for the decrease in. No new or unexpected side effects were seen, suggesting that the addition of disodium edetate does not affect the safety profile of 'diprivan'. In particular, there was no increase in the number of reports that could be due to the toxicity of disodium edetate, such as signs of hypocalcemia or kidney damage.

The raw data obtained from the clinical trial program was not previously publicly available. In addition, as noted above, the primary endpoint of these tests was to observe whether there were any (clinically) significant inappropriate changes in the adverse event profile by the modified 'diprivan' formulations.

We could report that the data from our four clinical trials suggest improved survival in certain critical patients. In addition, more specific survival / result analysis (not previously required) of the data obtained from these clinical trials was performed. We report for the first time new results obtained from this particular specific assay in the present invention. Medical progress is often made through this new analysis of medical data. In other words, the conclusions and applications of the assays of the present invention represent novel and surprising results that have not been described previously.

Briefly, we have not previously noticed 2,6-diisopropylphenol (propofol) when administered in the present invention with a surprisingly modified formulation 'diprivan', ie a formulation containing 0.005% disodium edetate. It has been shown to have properties that were not effective and effective in significantly improving survival in certain critical patients. Observation of these new traits, for example, provides the opportunity to treat selected patient populations in intensive care units (ICUs) with specific propofol-containing agents, thereby reaching a markedly improved survival advantage over surrogate sedatives / anesthetics. to provide. The results reported in the present invention are the first to show that 2,6-diisopropylphenol (propofol) in a modified formulation 'Diprivan' has the real advantage of improving survival in critically ill patients and for the treatment of such patients Present a new therapeutic course.

That is, pharmaceutical compositions containing free radical scavenging sedatives (eg, propofol) and metal ion chelating agents (eg, edetate) may be valuable as treatments to improve survival in certain critical patients.

Studies comparing the use of propofol in ICUs with other sedatives (eg Midazolam) focused on goals such as cost, weaning and nutrition. This study did not reveal any benefit in survival or mortality associated with the use of any particular sedative. One report analyzing 18 trials comparing midazolam and propofol (without EDTA) in ICU sedation showed similar mortality rates for propofol and midazolam (Intensive Care Medicine, 1999, 25 1999-Suppl 1 pp S158 Abs.-12 ^th Annual Congress of European Society of Intensive Care Medicine, Berlin, 3-6 Oct. 1999). Previous studies have not shown the survival benefits of modified 'Drifevan' over other sedatives.

Given the specific complexity of the processes involved in death and multiple organ dysfunction / insufficiency, the effectiveness of the modified 'dipriban' in reacting to the complex actions involved in death is truly surprising.

The present invention relates to methods of treating and improving survival for critically ill patients and to the use of certain sterile sedative pharmaceutical compositions for the manufacture of a medicament for improving the survival of such patients.

Accordingly, the present invention provides a method for improving survival in critically ill patients, including administering a pharmaceutical composition containing a free-radical scavenging sedative and a metal ion chelating agent together with a pharmaceutically acceptable diluent or carrier.

The invention also relates to a pharmaceutical composition described and claimed in British Patent No. 2,298,789, which includes improving the survival in critically ill patients, including administering a pharmaceutical composition containing a free-radical scavenging sedative and a metal ion chelating agent. Provide a method.

In particular, the present invention is a sterile agent for parenteral administration containing propofol dissolved in a water-immiscible solvent, emulsified by water, stabilized using a surfactant, and further containing an oil-in-water emulsion containing a metal ion chelating agent. Provided are methods for improving survival in critically ill patients, including administering a pharmaceutical composition.

Even more particularly, the present invention provides a sterile agent for parenteral administration containing propofol dissolved in a water-immiscible solvent, emulsified with water and stabilized with a surfactant, and further containing an oil-in-water emulsion containing edetate. Provided are methods for improving survival in critically ill patients, including administering a pharmaceutical composition.

The present invention also provides a pharmaceutical composition for use as a medicament containing free-radical removal sedatives and metal ion chelating agents together with pharmaceutically acceptable diluents or carriers and improving survival in critically ill patients.

The present invention also provides a pharmaceutical composition for use as a medicament containing free-radical removal sedatives and metal ion chelating agents and described and claimed in British Patent No. 2,298,789, which improves survival in critically ill patients. .

In particular, the present invention provides propofol dissolved in a water-immiscible solvent, emulsified with water and stabilized with a surfactant, further containing an oil-in-water emulsion containing a metal ion chelating agent, which provides survival in critically ill patients. Provided are sterile pharmaceutical compositions for parenteral administration for use as a medicament for improving.

Even more particularly, the present invention provides that propofol dissolved in a water-immiscible solvent is emulsified with water and stabilized with a surfactant, further containing an oil-in-water emulsion containing edetate, which provides survival in critically ill patients. Provided are sterile pharmaceutical compositions for parenteral administration for use as a medicament for improving.

The invention also provides the use of a pharmaceutical composition containing a free-radical removal sedative and a metal ion chelating agent together with a pharmaceutically acceptable diluent or carrier for the manufacture of a medicament for improving survival in critically ill patients.

The present invention also provides a use of a pharmaceutical composition containing free-radical removal sedatives and metal ion chelating agents and for the manufacture of a medicament for improving survival in critically ill patients, as described and claimed in British Patent No. 2,298,789. to provide.

In particular, the present invention is a sterile agent for parenteral administration containing propofol dissolved in a water-immiscible solvent, emulsified by water, stabilized using a surfactant, and further containing an oil-in-water emulsion containing a metal ion chelating agent. The use of the pharmaceutical composition for the manufacture of a medicament for improving survival in critically ill patients is provided.

Even more particularly, the present invention provides a sterile agent for parenteral administration containing propofol dissolved in a water-immiscible solvent, emulsified with water and stabilized with a surfactant, and further containing an oil-in-water emulsion containing edetate. Use of the pharmaceutical composition for the manufacture of a medicament for improving survival in critically ill patients is provided.

In addition, the present invention provides substantially the methods and uses described herein with reference to experiments and results.

The methods and uses of the invention relate to use in warm blooded animals, such as humans, in sedation.

'Improvement in survival' and 'improving survival' mean that a critical patient is still alive at clinically significant time, such as 7 days post sedation. An additional clinically significant time is 28 days after sedation. The time after sedation can be determined from the point at which sedation begins (as in a clinical trial program) or from the point at which sedation is stopped. These terms also suggest that a critical patient is indicative of a decrease or absence in a problem associated with the condition and / or does not require additional mechanical aeration, and / or is unlikely to die by a physician, and / or Also included are cases considered to have improved viability.

A patient group that benefits from the present invention is a 'critical patient', a patient who does not administer a sedative for chronic disease, ie, a 'critical patient', for example, has an acute attack, injury or trauma. For example, a patient in need of sedation following surgery (medical or emergency) following surgery, medical treatment or trauma. In particular, critically acute patients in ICUs are included. Patients with about 70% or more likely mortality (eg due to original disease conditions such as severe renal failure) are unlikely to benefit from the present invention. Likewise, the benefits of the present invention will also have a mortality of about 5% or less and will have little effect on endogenously suitably healthy patients. Accordingly, the present invention provides, in one embodiment, a potential treatment for certain patients at risk of developing multiple organ failure / dysfunction. In another embodiment, the uses and methods of the present invention are provided for surgical patients in need of selective and / or emergency surgery followed by sedation. In a further embodiment, uses and methods of the present invention are provided for critically ill patients with an APACHE II score of 24 or less, preferably 19 or less. Preferably, the uses and methods of the present invention are provided for patients early in the course of their critical disease (ie, when the systemic inflammatory response is not fully activated).

The inventors believe that the effect described herein is due to the combined use of free-radical removal sedatives and metal ion chelating agents. Each of these components may be simultaneously (in the case of 'Dipriban' with the results reported herein, ie as formulated in one formulation), separately (eg, via separate infusion lines), or sequentially As long as the elongation is maintained and the appropriate metal ion chelating agent dose and concentration must be maintained in vivo at the same time. Appropriate levels of metal ion chelating agents are a function of a number of factors, including patients, their overall condition and metal ion homeostasis, and whether any additional metal ion supplements are being administered to the patient. In one embodiment, the metal ion chelation properties and concentrations are those obtained from disodium edetate in a modified formulation of 'diprivan' used in the appended experiments and results.

The components can be administered continuously or by intermittent bolus injection by infusion (either together or separately as co-infusion). For example, propofol formulations that do not contain a metal ion chelating agent can be administered with independent administration of the metal ion chelating agent.

While not wishing to be bound by theory, the inventors believe that the effects described herein are beneficial synergies due to the reduction in physiological stress caused by the use of free radical sedative sedatives, and acute stresses due to the use of metal ion chelating agents. It is believed that it can derive from the beneficial effects on the reaction. Beneficial synergy is believed to cause lower levels of stress-related agents and / or antioxidant effects.

The benefits reported in the present invention are believed to result, in part, from the free radical scavenging / antioxidative effect of the sedative propofol. That is, formulations containing other free radical scavenging / antioxidant sedatives may also show advantages. Free radical sedative sedative means a sedative that also has the ability to remove free radicals in vivo (along with the ability to react to free radical mediated oxidative stress responses). Apart from propofol, other such ingredients may include barbiturates such as, for example, phenobarbital. Free radical scavenging sedatives are preferably substantially lipophilic.

The advantage is also that a metal ion chelator that chelates a (trace) metal ion partially involved in the oxidative process, such as a divalent metal ion involved in an enzyme free radical mechanism that causes cell death and cell death. It is believed to originate from. Such metal ions include calcium, iron, zinc and copper. The metal ion chelating agent is preferably hydrophilic in nature. The benefit can be observed by appropriate inhibition of calcium influx induced apoptosis (Ca channel blockers such as nifedipine may also be useful in this respect) and / or enhanced hypozemia and / or iron serum level reduction. Certain combinations of (lipophilic) free radical removal / antioxidant sedatives and (hydrophilic) metal ion chelating agents are believed to be important in achieving a balanced reaction to oxidative stress. The lipid component of an oil-in-water emulsion used as a pharmaceutically acceptable carrier may also provide part of the beneficial synergy. The relative concentrations of the components may vary, provided that sedation and appropriate metal ion chelating agent capacity and concentration are maintained. The addition of other antioxidants (eg vitamin E) may also have additional beneficial effects.

For certain advantages, attention should be paid to the following factors:

1. To ensure maximum benefit is observed, the time to sedation should preferably be as soon as possible after the injury (generally within 1 to 2 hours), but the time may vary depending on the individual patient and the nature of the injury.

2. The duration of treatment should be as long as deemed necessary by the attending physician. The duration of treatment that allows the benefit to be observed may be longer than that normally required or used in routine practice for mechanical aeration. Thus, treatment can continue if a therapeutic effect is expected or observed. The beneficial effect can be demonstrated by, for example, improvement or maintenance in the standard physiological measures, such as normalization of organ function and / or blood pressure, body temperature and / or immune function (usually when a decrease is expected). Treatment will typically be 24 hours or longer.

3. The depth of sedation can be mild, moderate or intense, depending on the specific patient and the extent of their disease. Sub-sedative doses may be usefully administered in certain patients.

4. The dose of ingredients should be sufficient to achieve the desired level of sedation and to obtain the appropriate metal ion chelating agent dose. A dose of disodium edetate in the range of 5 × 10 ⁻⁵ g / hr to about 0.05 g / hr, based on a 'dipriban' dosage level in the range of 0.3-8.0 mg / kg / hr, is suitable for certain advantages. Based on these values, equivalent doses of other metal ion chelating agents can be calculated.

'Pharmaceutical compositions containing free-radical scavenging agents and metal ion chelating agents' include compositions containing both components (so simultaneous administration of each component is allowed), and also each individual component separately or sequentially Included are systems that can be administered. Thus, a further feature of the present invention is a pharmaceutical composition containing a free-radical removal sedative such as barbiturate, and a metal ion chelating agent together with a pharmaceutically acceptable diluent or carrier. Preferred pharmaceutically acceptable diluents or carriers are oil-in-water emulsions using water-immiscible solvents (see other sections of this specification for further details).

Other additives may also be present in pharmaceutical compositions in which free radical scavenging sedatives (eg, propofol) and metal chelating agents (eg, edetate) are present in a composition suitable for administration (“combinations with other therapeutic agents”). See below for details). Suitable pharmaceutical compositions containing propofol for use in the present invention are described in British Patent Nos. 2,298,789 and US Pat. No. 5,714,520, the contents of which are incorporated herein by reference, and corresponding applications in other regions. It is described in the patent and claimed.

'Oil-in-oil emulsion' refers to a separate two-phase system that is in equilibrium and is, in fact, entirely dynamic and stable thermodynamically.

The term 'edate' includes polyaminos such as metal ion chelation / isolators such as 'edate' (ethylenediaminetetraacetic acid-EDTA), diethylenetriaminepentaacetic acid (DTPA) and EGTA, and derivatives thereof Carboxylate chelators are included. For example, the disodium derivative of edetate is known as disodium edetate. In general, suitable metal ion chelating agents are their salts having a lower affinity for the free acid form than calcium and their derivatives described in particular in British Patent 2,298,789. Particularly preferred metal ion chelating agent is disodium edetate. Desferoxime is a further suitable metal ion chelating agent.

In propofol compositions containing edetate, generally the metal ion chelating agent may be present in the composition at a molar concentration (relative to the metal ion chelating agent free acid) in the range of 3 × 10 ⁻⁵ to 9 × 10 ⁻⁴ . Preferably, the metal ion chelating agent free acid is in the range of 3 × 10 ^-5 to 7.5 × 10 ^-4 , for example in the range of 5 × 10 ^-5 to 5 × 10 ^-4 , more preferably 1.5 × 10 ^-4 to 3.0 It is present in the x10 ^-4 range, most preferably about 1.5 x 10 ^-4 . In particular, the metal ion chelating agent free acid is present in the range of about 0.0005% to 0.1% w / v. The 0.005% concentration of disodium edetate used in the modified 'Dipriban' was chosen to prevent significant growth of microorganisms for at least 24 hours in case of accidental exogenous contamination (see UK Patent No. 2,298,789). Corresponding information from a patent is incorporated herein by reference). Depending on the nature of the metal ion chelating agent chosen, the benefits of the present invention may be obtained using concentrations lower than 0.005%.

Propofol compositions suitable for use according to the invention generally contain 0.1 to 5% by weight of propofol. Preferably, the composition contains 1-2 wt% propofol, in particular about 1% or about 2% propofol. Propofol alone can be emulsified with water using a surfactant, but propofol is preferably dissolved in a water-immiscible solvent prior to emulsification. The water-immiscible solvent is suitably present in an amount up to 30% by weight of the composition, more suitably 5-25%, preferably 10-20%, in particular about 10%.

A wide range of water-immiscible solvents can be used in compositions suitable for use in the present invention. Generally, water-immiscible solvents are vegetable oils such as soybean oil, safflower oil, cottonseed oil, corn oil, sunflower oil, peanut oil, castor oil or olive oil. Preferably the vegetable oil is soybean oil. Alternatively, the water-immiscible solvent is an ester of a medium or long chain fatty acid, for example mono-, di- or triglycerides; Or chemically modified or prepared, such as ethyl oleate, isopropyl myristate, isopropyl palmitate, glycerol esters or polyoxyl cured castor oil. As a further alternative, the water-immiscible solvent can be marine oil, such as cod liver oil or another fish-derived oil. Suitable solvents also include fractionated oils, such as fractionated coconut oil or modified soybean oil. In addition, compositions suitable for use in the present invention may contain a mixture of two or more of the above water-immiscible solvents.

Propofol, used alone or dissolved in a water-immiscible solvent, is emulsified using a surfactant. Suitable surfactants include synthetic nonionic surfactants such as ethoxylated ethers and esters and polypropylene-polyethylene block copolymers, and naturally occurring phosphatides such as phosphatides such as eggs and soybean phosphatides. And modified or artificially engineered phosphatides (eg, prepared by physical fractionation and / or chromatography), or mixtures thereof. Preferred surfactants are egg and soy phosphatide.

Compositions suitable for use in the present invention are suitably formulated to a physiologically neutral pH, generally in the range of 6.0-8.5, using alkalis, such as sodium hydroxide, as needed.

Compositions suitable for use in the present invention may be made isotonic with blood by incorporating a suitable tonicity modifier, for example glycerol.

Compositions suitable for use in the present invention are generally sterile preparations and are prepared, for example, according to conventional manufacturing techniques using aseptic preparation or termination sterilization by autoclaving. Further details on the preparation of a composition suitable for use in the present invention are included in the patents mentioned at the beginning of this specification and incorporated herein by reference.

Compositions suitable for use in the present invention are useful as anesthetics, including sedation and induction and maintenance of general anesthesia, which properties may be useful in improving survival in critically ill patients in accordance with the present invention. Propofol is suitable for both induction and maintenance of general anesthesia, sedation to supplement local analgesia, sedation of aspirated patients undergoing intensive care, and conscious sedation for conscious sedation for surgery and diagnostic procedures in intensive care. It is a functional anesthetic. Propofol can be administered by single or repeated intravenous bolus injection, or by continuous infusion. It is removed and metabolized very quickly from the bloodstream. Thus, the depth of sedation is easily controlled, and the recovery of the patient at the time of discontinuation of the drug is usually fast and the patient often progresses much clearer than after administration of other anesthetics.

Dose levels suitable for improving survival in critically ill patients in accordance with the present invention are generally within the ranges commonly used for sedation. Dose levels in the range of 0.3-8.0 mg / kg / hr may be used for adults in the case of 'diprivan', but this may be optimized to achieve the desired effect in a particular patient according to conventional techniques in the art. have. For sub- to moderate sedation, continuous infusions of about 0.3-4.0 mg / kg / hr are generally used. For further information on administration, see US 5,714,520, which is incorporated herein by reference.

In use, the propofol composition of the present invention may be administered for longer periods than is used for simple sedation, ie the patient may remain under sedation until effective treatment is deemed to have been provided. Artificial aeration requires sedation, and the propofol formulations of the present invention can be used for this purpose. At the same time, the propofol formulations of the present invention can improve viability by mechanisms independent of artificial aeration.

Combinations with Other Therapies

Further features of the present invention provide pharmaceutical compositions for parenteral administration containing free radical sedative sedatives (eg, propofol) suitable for use in the present invention, which compositions are for example therapeutic or pharmaceutical Oil-in-water emulsions containing a chemical component, wherein the component is emulsified alone or in a water-immiscible solvent, emulsified with water and free radical scavengers (e.g. propofol) and stabilized with a surfactant And a metal ion chelating agent.

Suitable therapeutic or pharmaceutical ingredients are those that can be administered parenterally in an oil-in-water emulsion. In general, these components (they can be administered separately, sequentially or simultaneously from the propofol composition) are lipophilic compounds, for example antifungal, anesthetic, antibacterial, anticancer, antifungal, antioxidant, components that act on the central nervous system. , For example diazepam, steroids, barbiturates and vitamin preparations. The most useful ingredients are ingredients that may have additional advantages in the treatment or prevention of multiple organ dysfunction and death and their causes, such as antibacterial agents, NSAIDs, vitamin E, fluid therapy and vasofunctional amines. Maintenance treatment of organ dysfunction may include artificial aeration and dialysis.

Accordingly, the present invention provides for the use of a pharmaceutical composition for parenteral administration containing a free radical sedative sedative (eg, propofol) for the manufacture of a medicament for improving survival in critically ill patients, the composition comprising Oil-in-water emulsions containing, for example, therapeutic or pharmaceutical ingredients, wherein the ingredients are emulsified either alone or in water-miscible solvents with water and free radical removal sedatives (e.g. propofol). And stabilized with a surfactant), and further contains an amount of a metal ion chelating agent. Also provided are methods for improving survival in critically ill patients, including the use of such compositions. In particular, this feature of the present invention relates to such oil-in-water emulsions that are generally administered to patients in need over one or more days.

References herein to representative and preferred propofol compositions and methods for their preparation for use in the present invention apply mutatis mutandis to oil-in-water emulsions containing other therapeutic or pharmaceutical ingredients.

Experiment and result

Data from four clinical trials suggesting improved survival in certain critical patients is summarized in Table 1.

The program included four studies of adult ICU alignment. Three of these tests compared the modified formulation 'Diprivan' to the 1% original formulation 'Diprivan'. These were trial 53 (surgical ICU patient (SICU)), trial 54 (medical ICU patient (MICU)) and trial 60 (patients with renal failure). The fourth trial, Test 69, compared the modified formulation 'Dipriban' against standard sedatives (SSAs without EDTA) in medical, traumatic and surgical ICU patients.

ICU Survival Data for Original and Modified Formulation 'Diprivan' Number of trial treatment patients 7-day follow-up death rate% survival rate p-value 28-day follow-up deaths% survival% p-value 53 Modifiers 59 Original 6354 Modifiers 42 Original 4360 Modifiers 18 Original 1969 Modifiers 106 SSA 104 0 0 100 0.0068 13 879 21 79 0.459 13 30 704 22 78 1.0004 21 7918 17 83 0.30324 23 77 1 2 98 0.00411 17 8319 45 55 1.00019 44 565 28 72 0.7287 37 6333 31 69 0.76835 34 66

Follow-up was timed from the end of ICU sedation.

Analysis of mortality from these trials was not the primary measure.

Trial 53 in surgical patients was followed by a 7-day follow-up, especially in patients receiving modified formulation 'Diprivan' (0/59 patients) compared to patients receiving the original 'Diprivan' (8/63 patients). There was a statistically significant lower (p = 0.006) mortality in the city. There was also a significantly lower mortality in the modified formulation group at 28-day.

In other trials, the mortality benefit may be less obvious for several reasons, although perhaps not statistically significant. For example, these reasons include a small number of patients, severe illnesses (eg, severe renal failure), and therefore patients that do not seem to be effective by the present invention, or duration of treatment that is too short to observe the benefits. Can be. In addition, in trial 53, patients were administered propofol preparations early in the course of each patient's disease (ie immediately after surgery), while in other trials, they were administered later in the course of the disease. That is, a greater consequent benefit may be provided when the modified formulation 'diprivan' is initially administered in the course of a critical disease (ie, when the systemic inflammatory response is not fully activated).

Propofol and EDTA administration in these trials are summarized below (ZD # 1 = modified formulation; DIP = original formulation).

Propofol Injection Rate (mcg / ㎏ / min) Exam number Treatment group N Average range 53 ZD # 1DIP 5962 31.6432.18 2.37-79.314.5-72.85 54 ZD # 1DIP 4240 40.2734.51 2.84-105.266.43-123.67 60 ZD # 1DIP 1819 7.8912.62 1.99-17.090.86-45.91 69 ZD # 1 106 36.0 3.3-154.3 General ZD # 1DIP 0.86-154.31.99-123.67

EDTA injection rate (ng / ㎏ / min) Exam number Treatment group N Average range 53 ZD # 1 59 158.18 11.86-396.54 54 ZD # 1 42 201.33 14.18-526.31 60 ZD # 1 18 39.47 9.93-85.44 69 ZD # 1 106 179.8 16.7-771.3 General ZD # 1 9.93-771.3

In test 53, the average total dose of EDTA administered was 39.1 ± 82.91 mg.

Period of sedation (hrs) Exam number Treatment group N Average range 53 ZD # 1DIP 5963 41.5143.74 2.0-308.50.92-503.25 54 ZD # 1DIP 4240 111.3195.57 7.83-362.4212.25-483.77 60 ZD # 1DIP 1819 74.0769.58 4.0-265.4223.0-122.33 69 ZD # 1 106 149.1 6.7-645.0 General ZD # 1DIP 2.0-645.00.92-503.25

Survival analysis of trials 53, 54 and 60

In each of the three trials patients were randomly administered 1% propofol in the aqueous emulsion, ie, the original 'Diprivan' (control) or propofol-EDTA, ie the modified formulation 'Diprivan' (therapeutic group). All tests were conducted in accordance with the provisions governing informed consent and were approved by the jury. All patients provided had written informed consent prior to enrolling in the trial.

Patients who had a history of hypersensitivity to the test drug or any of its components in all three trials, or had participated in another study drug trial within 30 days of the study entry, were excluded from the participation.

Exam 53

SICU patients 17 years of age or older and hemodynamically stable and expected to require intubation and mechanical aeration for at least 2 days were suitable for inclusion in the trial. If patients were unable to respond to the stimulus due to prolonged paralysis due to trauma or neuromuscular blockade, they were unfit for the test.

Exam 54

Appropriate patients were admitted to the ICU with pulmonary insufficiency or adult respiratory distress syndrome (ARDS) as one of their main diagnoses or complications, and were 13 years of age expected to be hemodynamically stable and require at least 48 hours of sedation and mechanical ventilation. Or more men and women.

Exam 60

Suitable patients were 17 years of age or older, expected to be hemodynamically stable and require intubation and mechanical aeration for ≥ 24 hours, obtain appropriate levels of postoperative analgesia (SICU patients only) Patients with SICU or MICU with function (estimated creatinine clearance ≦ 40 ml / min). Criteria for exclusion include the inability to respond to stimuli due to head injury and paralysis.

Patients received either propofol or propofol-EDTA randomly. Sedation was initiated by continuous infusion at an initial rate of 5 μg / kg / min, and then adjusted until the patient achieved the required level of sedation. The sedative dose could be adjusted to change the level of sedation over a short period of time, and the level of sedation could also be changed by the investigator if different levels of sedation are thought to be more appropriate for the patient.

If possible, the test drug continued to be administered to the patient until extubation was expected. During the weaning period, either propofol or propofol-EDTA could provide mild sedation. If the patient meets the appropriate criteria for extubation at the end of removal of mechanical aeration, the test drug is discontinued and the patient is exhaled.

In all trials, standard non-sedative medications that were considered necessary and were not expected to interfere with the test drug or affect test measurements were administered at the investigator's discretion. Intestinal nutrition was a preferred form of nutritional maintenance, but parenteral nutrition was also allowed.

Only morphine sulfate and fentanyl were allowed for analgesic in SICU and MICU patients. In patients with renal failure, appropriate analgesics were given postoperatively before the start of propofol or propofol-EDTA infusion. During sedation, patients were administered fentanyl by epidural or intravenous infusion for analgesia. For patients receiving lipid infusions for nutritional supplementation, the amount of lipids administered simultaneously was reduced to compensate for the amount of lipids injected as part of propofol and propofol-EDTA formulations.

Demographic variables and treatment descriptors were compared to assess the comparability of the Propofol and Propofol-EDTA groups. Chi-square analysis was used for category variables (gender), while the Wilcoxon test (using normal approximation and continuity correction of 0.5) was used for continuous variables (e.g. Age, body weight, APACHE II score, total propofol dose, mean propofol infusion rate and duration of infusion). Gender, age, weight, and severity of the disease indicated by the APACHE II scores were not significantly different between the propofol and propofol-EDTA groups.

Median total propofol dose, median infusion period and mean infusion rate did not differ significantly between groups. In addition, none of the measured experimental values were significantly different between the propofol and propofol-EDTA groups. Serum ionized calcium and magnesium, intact PTH, 1,25-dihydroxyvitamin D, sodium, potassium and phosphate levels, and renal function (as assessed by BUN and serum creatinine levels) in both groups were similar. Blood pressure and heart rate were similar between the propofol and propofol-EDTA groups.

Survival was summarized by counting the number of surviving patients and calculating descriptive statistics on the survival of deceased patients. Product-limit (Kaplan-Meier) estimates of the survival function were calculated for both propofol and propofol-EDTA groups within each test group (SICU, MICU and renal failure patients). The log-rank test and Wilcoxon test were also used to compare survival curves between the two groups within each test group.

1 shows survival curves by treatment group (propofol or propofol-EDTA), test group (SICU, MICU or renal failure) and baseline APACHE II score (<15, 15-24, or> 24).

FIG. 2 shows estimates of survival based on models incorporating test groups, baseline APACHE II scores, and effects of treatment effects. For patients with an APACHE II score of 11, the model predicts an improvement in survival for SICU patients administered Propofol-EDTA (FIG. 2A). In patients with an APACHE II score of 21, overall survival is expected to be worse than in patients with an APACHE II score of 11. The use of modified formulation 'Diprivan' is expected to improve survival in both SICU and renal failure patients (FIG. 2B). For patients with an APACHE II score of 30, the model predicts that the modified formulation 'Diprivan' will significantly improve survival in SICU patients (FIG. 2C).

Cox proportional hazards regression analysis was used to model the effect of predictors of survival. The model predicts survival time T based on survival function S (t) = Pr (T> t), where the risk is h (t) >> Pr (t <T, t + dt | T> t) / dt. The actual risk model is log h (t) = log h ₀ (t) + bx, where no baseline risk is defined.

The null model was a model categorized by patient population (ie, a model that allows different baseline risk functions for patients in the SICU, MICU, and renal failure groups without the limitation that these three risks are proportional). The APACHE II score, and treatment parameters (propofol alone versus propofol-EDTA) were added to the Young model with different slopes and sections for each of the three tests. The therapeutic effect differed between the three trials. Other factors that significantly affected survival included age, sex, height, weight, serum albumin levels, total propofol dose, mean propofol infusion rate, median infusion duration, SAPS II, patient type (medical vs. surgery), And gradual addition of medical career (malicious vs. other). Statistical calculations were performed using SAS for Window version 6.12.

3 summarizes the results of the Cox proportional hazard model. The linear predictor on the y-axis is to the extent that mortality is expected to increase with each predictor. The x-axis reflects the broad impact of the APACHE II score on survival. In the SICU test group, the addition of EDTA yielded an effect corresponding to decreasing the APACHE II score from 38 to 10. The effect produced by using modified formulation 'Dipriban' in patients with renal failure was dependent on the APACHE II score. Survival in patients with an APACHE II score <25 is expected to be improved by a modified formulation 'Diprivan' and in patients with an APACHE II score> 30 is expected to be poor.

The results of this analysis suggest that the modified formulation 'Dipriban' significantly improves survival in critically operative patients, and its effect on survival in patients with renal failure is variable so that survival in patients with an APACHE II score of <24 Although improved, patients with an APACHE II score> 24 show lower survival rates.

In this test, we found no evidence of EDTA-induced kidney toxicity as assessed by BUN and creatinine levels.

The main finding in this trial is the improved survival seen in patients with SICU who are receiving a modified formulation, Diprivan, compared to patients receiving the original, Diprivan.

The mortality rate for the SICU propofol group was close to the predicted value, while the ratio for the SICU propofol-EDTA (modified formulation 'diprivan') group was lower than expected, which suggests a beneficial therapeutic effect. will be.

It is unclear why MICU and severe renal failure patients did not realize the benefits equivalent to the modified formulation 'Dipriban' seen in SICU patients. In SICU patients, the critical disease was more acutely expressed, and treatment with the modified agent 'diprivan' started faster after a more severe attack than with a MICU patient. There is a possibility of causing the therapeutic benefit to progress further in MICU and renal failure patients than in SICU patients. MICU and renal failure patients have also been shown to have more severe and longer duration of illness prior to admission to the ICU. It also appears that the malnutrition was greater in these patients. Moreover, MICU patients had a basic deficiency of trace minerals compared to SICU patients, and renal patients with large APACHE II scores could have more advanced kidney disease.

The results of this test suggest that the modified formulation 'Diprivan' may have a beneficial therapeutic effect in selected groups of critically ill patients, and the maximum effect on survival is seen in SICU patients. The benefit of the modified formulation 'Diprivan' in SICU patients was large enough to suggest that the modified formulation 'Diprivan' could represent a potential new treatment for the treatment of critically ill patients with systemic inflammatory syndrome. .

Summary of Drawings

1: Survival curve by treatment group (A), test group (B) and APACHE II score (C) : ZD = modified formulation; Defibvan = Original

FIG. 2: Estimates of survival based on models incorporating effects of treatment on test group and APACHE II scores of 11 (A), 21 (B) and 30 (C).

SICU-non EDTA = SICU patient receiving propofol;

SICU-EDTA = SICU patient receiving propofol-EDTA;

Renal Failure-Non EDTA = Renal Failure Patients Receiving Propofol;

Renal failure-EDTA = renal failure patient receiving propofol-EDTA;

MICU = MICU patients receiving propofol or propofol-EDTA (all MICU patients are grouped together).

Figure 3: Results of Cox Proportional Risk Model

Linear predictors on the y-axis are to the extent that mortality is expected to increase with each predictor. The broad impact of the APACHE II score on survival in all groups is evident.

SICU-non EDTA = SICU patient receiving propofol;

SICU-EDTA = SICU patient receiving propofol-EDTA;

Renal Failure-Non EDTA = Renal Failure Patients Receiving Propofol;

Renal failure-EDTA = renal failure patient receiving propofol-EDTA;

MICU = MICU patients receiving propofol or propofol-EDTA (all MICU patients are grouped together).

Clinical trial

The benefits described herein can be demonstrated in a prospective study where mortality is the primary endpoint and a modified formulation 'diprivan' is compared with the original formulation 'diprivan', for example.

Trial treatment is an intravenous infusion of propofol starting at a rate of 5 μg / kg / min and titrated to obtain a depth of sedation that is deemed appropriate by the investigator. A modified formulation 'Diprivan' at% concentration is used. Note that the benefit is also believed to focus on 2% concentrations, where the amount of disodium edetate is half the amount at the equivalent propofol dose of 1% concentration.

The test was performed for each cancer (80% probability and for 28-day mortality in 17.5% of the original 'Diprivan' arm and 28% of the modified formulation 'Diprivan' arm). to provide a p <0.05 significance level.

Exam summary

To compare 28-day mortality in adult surgical ICU patients sedated by the original 'diprivan' versus the modified formulation 'diprivan', the original 'diprivan' versus the modified formulation 'diprivan' Multicentre randomized comparisons of mortality in adult surgical ICU patients (at least 18 years of age and requiring sedation for endotracheal intubation for at least 24 hours) were performed. Patients with head injuries or patients with established doses of sedation with medications other than dipriban in the period immediately preceding consideration of the trial are excluded.

The primary endpoint is 28 days from the onset of sedation (after surgery) regardless of the severity-adjusted 28-day mortality rate, ie sedation mortality and duration of sedation (minimum duration of treatment is 24 hours). It is within death. Thus, primary endpoints include patients who died on day 27 after sedation for 1 day and then began sedation and patients who died on day 27 after sedation for 10 days and then started sedation.

Secondary endpoints include 7- and 28-day sequential assessment of tracheal insufficiency following the onset of sedation and time on aeration.

Data recorded include patient demographics, past medical history, medication (with restrictions on co-administration without EDTA), reasons for surgery, type of anesthetic (with restrictions on surgical anesthetics without EDTA), SAPS II and SOFA at baseline and 7- and 28-day, duration of sedation (and aeration) and total dose and side effects of propofol.

Claims (16)

A pharmaceutical composition for use as a medicament comprising a free-radical scavenging sedative and a metal ion chelating agent in combination with a pharmaceutically acceptable diluent or carrier for improving survival in critically ill patients. Propofol dissolved in a water-immiscible solvent is emulsified by water and stabilized using a surfactant, further comprising an oil-in-water emulsion containing a metal ion chelating agent and used as a medicament to improve survival in critically ill patients Sterile pharmaceutical compositions for parenteral administration for A sterile pharmaceutical composition according to claim 1 or 2, wherein the metal ion chelating agent is edetate and is used for use as a medicament to improve survival in critically ill patients, Use of a sterile pharmaceutical composition containing free-radical removal sedatives and metal ion chelating agents for the manufacture of a medicament that improves survival in critically ill patients. 5. Use of a sterile pharmaceutical composition according to claim 4 containing a free-radical removal sedative and a metal ion chelating agent together with a pharmaceutically acceptable diluent or carrier for the manufacture of a medicament for improving survival in a critically ill patient. 6. The oil-in-water emulsion of claim 4 or 5, wherein the composition is propofol dissolved in a water-immiscible solvent, emulsified with water and stabilized using a surfactant, and further comprising an oil-in-water emulsion comprising a metal ion chelating agent. , For the manufacture of a medicament that improves survival in critically ill patients. Use according to any of claims 4 to 6, wherein the metal ion chelating agent is edetate. 8. A sterile pharmaceutical composition according to any one of claims 4 to 7, wherein the sterile pharmaceutical composition comprises (a) 1 weight percent propofol, (b) 10 weight percent soybean oil, (c) 1.2 weight percent egg phosphatide, (d) 2.25 weight percent glycerol, (e) sodium hydroxide, (f) water and (g) 0.005 weight percent disodium edetate. 8. A sterile pharmaceutical composition according to any one of claims 4 to 7, wherein the sterile pharmaceutical composition comprises (a) 2% by weight propofol, (b) 10% by weight soybean oil, (c) 1.2% by weight egg phosphatide, (d) Use in the form of an oil-in-water emulsion containing 2.25 wt% glycerol, (e) sodium hydroxide, (f) water and (g) 0.005 wt% disodium edetate. Use according to any one of claims 4 to 9, wherein the critical patient is a surgical patient. A method of improving survival in a critical patient, comprising administering to a critical patient an effective amount of a pharmaceutical composition comprising a free-radical removal sedative and a metal ion chelating agent. The method of claim 11, comprising administering a pharmaceutical composition comprising a free-radical removal sedative and a metal ion chelating agent together with a pharmaceutically acceptable diluent or carrier. 13. A pharmaceutical according to claim 11 or 12, wherein propofol dissolved in a water-immiscible solvent is emulsified with water and stabilized using a surfactant, further comprising an oil-in-water emulsion comprising a metal ion chelating agent. A method comprising administering a composition. The method according to any one of claims 11 to 13, wherein the metal ion chelating agent is edetate. The method of claim 11, wherein the pharmaceutical composition is defined in claim 8 or 9. The method of claim 11, wherein the critical patient is a surgical patient.