KR20080109044A - Lactate and calcium containing pharmaceutical composition and uses thereof - Google Patents

Abstract

The invention relates to a pharmaceutical composition containing 250 to 5000 millimoles per liter of lactate or lactic acid, 0.5 to 1.99 millimoles per liter of calcium and optionally 2 to 10 millimoles per liter of potassium. The invention also relates to pharmaceutical uses of this composition. ® KIPO & WIPO 2009

Description

Lactate and calcium containing pharmaceutical composition and its use {LACTATE AND CALCIUM CONTAINING PHARMACEUTICAL COMPOSITION AND USES THEREOF}

The present invention relates to lactate and calcium containing pharmaceutical compositions, methods of making the pharmaceutical compositions as well as various medical and therapeutic uses of the compositions. In particular, the present invention relates to pharmaceutical compositions and their treatment in the treatment of diseases and conditions such as postoperative treatment, hypotensive cardiovascular disease, brain diseases, organ dysfunction, obesity, acute hemodynamic difficulties due to medical and surgery, sepsis shock or obesity It is about a use. In one particular aspect, the present invention also relates to the use of lactate hypertonic solution for the treatment of brain disease.

Lactic acid itself or its anionic form, lactate anion or salt thereof has been found to have a fairly wide range of uses in the pharmaceutical field. Traditionally, the lactate anion is used as a buffer in dialysis compositions (see, eg, Chung et al. Perit. Dial. Int. 2000, 20 Suppl. 5: S57-67 or US Pat. No. 6,610,206). See). Lactate also contains human blood and isotonic aqueous solution (130 mmol / l Na ⁺ , 5.4 mmol / l K ⁺ , 1.85 mmol / l Ca ²⁺ , 27 mmol / l lactate and 112 mmol / l Cl ⁻ ) And one of the Ringer lactates used as a physiological saline solution for intravenous infusion in hypovolemia. Lactate is also disclosed in U.S. Pat. have. According to this patent, solutions containing 0.01 to 2400 mmol / l L-lactate are suitable for oral, oral, dialysis and irrigation therapy. Specific examples of diseases that can be treated according to the above US patents are acidosis, dehydration, blood electrolyte deficiency, shock, malnutrition and uremia.

More recently, the lactate anion has also been the subject of study in patients undergoing cardiac surgery. In this study, the metabolic and hemodynamic effects of 1M lactate solution (consisting of 90 g of lactate per liter and 23 g of sodium) were investigated in postoperative patients who underwent scheduled coronary artery bypass graft (CABG) (Mustafa, I. and Leverve, XM Shock, 18, 306-310, 2002). The authors conclude from the study that the lactate solution is safe and well tolerated in patients undergoing this type of surgery.

WO 98/08500 discloses hypertonic compositions containing L-arginine as an active ingredient other than crystalline, especially for the treatment of traumatic brain injury. Among other compounds such as sodium chloride or sodium acetate, sodium lactate is disclosed in WO 98/08500 as a potential crystalline / buffer.

Finally, WO 2004/096204 discloses compositions containing 250 to 2400 millimoles of lactic acid or lactate per liter, 2 to 10 millimoles of potassium per liter and optionally 2 to 5 millimoles of calcium per liter. According to WO 2004/096204, the composition can be used for various therapeutic purposes, for example, treatment of elevated intracranial blood pressure (ICP) or brain edema that can be caused by traumatic brain injury, acute hemodynamics caused by multiple traumas. It can be used for therapeutic indications such as treatment of difficulty, shock or post-surgical situations.

However, despite these promising developments, lactate containing compositions that are easy to manufacture, easy to use and suitable for a wide variety of therapeutic applications will still be desirable. Accordingly, it is an object of the present invention to provide such a composition.

This object is in particular solved by a pharmaceutical composition which is characterized by the respective independent claims of the claims. Such compositions are pharmaceutical compositions containing 250 to 5000 millimolar of lactic acid or lactate per liter, and 0.5 to 1.99 mmol of calcium per liter.

The present invention relates to the use of hypertonic lactate and calcium-containing compositions (compositions comprising lactate at concentrations as disclosed herein as active ingredients) for a very wide range of uses and treatment of hypoglycemia and postoperative treatment, for example coronary arteries. It is based on the finding that it has high efficacy in the treatment of patients who have undergone bypass graft (CABG) or percutaneous coronary angioplasty (PTCA). The combination of metabolic lactate anions with calcium ions in the concentration ranges disclosed herein, eg, 0.5-1.99 mmol, has been found to strongly increase the hemodynamic function of the patient. For example, the presence of lactate and calcium together significantly increases heart contraction (due to contractile effects). In addition, the combination allows for tension relaxation in the general circulation of pulmonary angiogenesis (decreases vascular resistance), thereby significantly increasing cardiac output even in patients with heart failure, for example. In addition, clinical studies indicate that administration of the compositions of the present invention as a postoperative treatment improves neurocognitive function or condition, for example in patients undergoing cardiac surgery. The compositions disclosed herein also have a significant ischemic / antioxidative effect and can therefore be used to improve the recovery of sick patients after ischemic reperfusion injury. In this regard, it should be noted that the compositions of the present invention also have a significant volume effect (bodily fluid replenishment), making the compositions attractive agents for patients in need of infusion for example for resuscitation.

In a presently preferred embodiment of the invention, the concentration of lactic acid or lactate anion is in the range of about 350 to about 250 millimoles, or about 400 to about 1500 millimoles, or 500 to about 1500 millimoles per liter. In another preferred embodiment, the concentration of lactic acid or lactate anion is in the range of about 800 to about 1200 millimoles per liter. In some embodiments, concentrations of about 500 or about 1000 mmol of the lactic acid or lactate per liter have been found to be particularly suitable. In this regard it is noted that the term "about" as used herein with respect to the lactate concentration typically means a deviation of ± 10 to ± 50 millimoles / liter.

However, depending on the specific application and also the severity and the individual of the condition to be treated, any suitable lactate concentration may be selected within the range of 250 to 5000 mmol / l. Thus, any lactate concentration within this range, such as 350, 500, 800, 2200, 3500, or 4800 millimolar lactate, may be present in other compositions of any concentration, such as 2 to 2, in the composition of the present invention. Any potassium concentration in the range of 10 mmol, or calcium concentrations within the ranges disclosed herein can be used.

In this respect, it should also be noted that the term "lactate" encompasses both enantiomeric forms, D-lactate as well as L-lactate (preferably L-lactate). However, mixtures of L- and D-lactates can also be used in the present invention so long as the D-lactate is present in an amount that does not have an adverse or even toxic effect on the patient to be treated. The term “lactic acid” thus also includes D-lactic acid and L-lactic acid and further includes lactic acid in polymer or oligomeric form, for example polylactic acid (polylactate). Moreover, derivatives of lactic acid, such as esters of lactic acid, are also within the meaning of the term "lactic acid". Examples of such esters are, to mention a few, esters of lactates with polyols such as methyl lactate, ethyl lactate, or glycerol. Moreover, the use of lactic acid, lactic acid derivatives such as esters thereof, and mixtures of lactates is also within the scope of the present invention, ie the pharmaceutical compositions may contain lactic acid, polylactic acid and lactate salts.

In order to achieve the electrical neutrality of the compositions of the invention (especially once the composition is present as a fluid), when lactate is used, cations such as ammonium, dimethylammonium, diethylammonium, sodium or such cations Mixtures of these are also present in the composition. Preferably, sodium is used in some embodiments as counterion for the lactate anion, ie the concentration of sodium in this case is equal to the selected lactate concentration. For this reason, sodium lactate is the preferred compound used in the preparation of the composition of the present invention. If lactic acid is used, no other cations (except protons or H ₃ O ⁺ resulting from dissociation of lactic acid) need to be present to achieve electrical neutrality. However, in some cases, when lactic acid is used as the active ingredient in the present invention, there may be physiologically useful cations as described below in addition to the lactic acid.

In some embodiments, the calcium concentration in the compositions of the present invention ranges from about 1.2 to about 1.75 millimoles per liter, from about 1.3 to about 1.6 millimoles per liter, or from about 1.3 to about 1.7 millimoles per liter. In one embodiment the calcium concentration is exactly or approximately 1.36 mmol per liter. The term "about" in this context typically means a deviation of ± 0.1 or ± 0.2 millimoles per liter when used in the present invention with respect to calcium concentration.

In addition, the composition may also contain potassium. The presence of potassium has been found to be particularly useful for preventing hypokalemia, which can be caused by treatment with hypertonic sodium lactate alone. In some embodiments of the compositions of the present invention, the potassium concentration is in the range of 2 to 10 millimoles per liter, or 2.5 to 6 millimolar potassium per liter. In some embodiments, potassium concentrations of about 3.5 mmol or about 4 mmol / L are presently preferred. In this regard it is noted that the term "about" typically means a deviation of ± 0.1 to ± 0.2 mmol / liter when used in the present invention with respect to potassium concentration.

In addition to the components described above, the compositions according to the invention comprise one or more anions for providing electrical neutrality to calcium and optionally also potassium which may be present in the compositions of the invention. All pharmaceutically acceptable anions can be used for this purpose. Examples of such anions are, to mention a few, inorganic and organic anions such as chloride, iodide, phosphate, sulfate, citrate, or malonate. In some embodiments, the composition comprises chloride as a counter ion that is negatively charged for both potassium and calcium cations.

According to the above, the composition of the present invention is preferably used as an aqueous solution.

In one particular embodiment, the compositions of the present invention contain the aforementioned components in the following concentrations:

Approximately 1000 millimeters / liter of lactate,

About 4 mmol / liter potassium (K),

About 1.36 mmol / liter of calcium (Ca), and

About 1000 mmol / liter sodium (Na).

When chloride is used as counterion for both potassium and calcium, the chloride concentration is therefore about 6.72 mol / l.

In another specific embodiment, the compositions of the present invention contain the aforementioned ingredients in the following concentrations:

Approximately 500 millimoles / liter of lactate,

About 4 mmol / liter potassium (K),

About 1.36 mmol / liter of calcium (Ca), and

About 500 mmol / liter sodium (Na).

When chloride is used as counterion for both potassium and calcium in this embodiment, the chloride concentration is therefore about 6.72 mol / l.

In another specific embodiment, the following concentrations are used in the composition:

Approximately 500 millimoles / liter of lactate,

About 3.5 to 4.2 mmol / liter potassium (K),

About 1.2 to 1.4 millimoles per liter of calcium (Ca), and

500 mmol / liter sodium (Na).

When chloride is used as counterion for both potassium and calcium in this embodiment, the chloride concentration is therefore about 4.9 to 6.8 mol / l.

Yet another example of a preferred embodiment of the present invention is a composition having the following concentrations:

Approximately 750 millimoles / liter of lactate,

About 3.5 to 4.2 mmol / liter potassium (K),

About 1.2 to 1.4 millimoles per liter of calcium (Ca), and

750 mmol / liter sodium (Na).

When chloride is used as counterion for both potassium and calcium, the chloride concentration is therefore about 4.9 to 6.8 mol / l.

Yet another preferred embodiment of the present invention is a composition having the following concentrations:

504 millimoles / liter of lactate,

4.02 mmol / liter potassium (K),

1.36 mmol / liter calcium (Ca),

504 mmol / liter sodium (Na).

6.74 mmol / liter chloride (used as counter ions for K and Ca).

The composition may further contain other components, for example additional physiologically suitable cations such as magnesium or zinc. Magnesium may be present at a concentration of about 3 or about 4 mmol / liter. The composition may also contain phosphate in addition to or separate from such physiologically suitable cations. The phosphate may be added in any suitable form, for example as monohydrogen or dihydrogen phosphate. Examples of suitable phosphate salts are NaH ₂ PO ₄ and Na ₂ HPO ₄ . If present, the phosphate is typically used at concentrations of up to 5 mmol / liter. A further compound that may also be added to the compositions of the present invention at a concentration of about 5 mmol / liter or less is ATP. ATP can be used in the form of its magnesium salt.

Other suitable additives that may be included in the composition are agents that exert an osmotic effect (osmolite and osmotic agent) and thus can further increase the osmotic effect of the compositions of the present invention. Examples of such osmolite and osmotic agents include, but are not limited to, carbohydrate compounds, gelatin, alginates, polyvinyl-pyrrolidone, serum proteins such as albumin or mixtures thereof. Examples of suitable carbohydrate compounds include pectin, sorbitol, xylitol, dextrose, polydextrose, condensed glucose, modified and unmodified starches such as hydroxyethyl starch (HES), pentamethyl starch (penta starch), carboxymethyl starch Or mixtures of these carbohydrate compounds. These carbohydrates can usually be present at concentrations up to about 10% (w / v). For example, a typical concentration of hydroxyethyl starch is 6% (w / v). When another osmagent, for example gelatin, is selected as an additive, it is typically present in an amount up to about 3.5% or 4%.

As already mentioned, the compositions of the present invention can be used for a wide variety of therapeutic uses. For example, hypoglycemia (used in the conventional sense of the present invention refers to a physical condition with reduced plasma volume), heart disease, brain disease, organ dysfunction, obesity, and acute hemodynamic difficulties due to medical and surgery It can be used for the treatment of a disease or a disease selected from among. The composition can also be used for resuscitation and also for post-operative / surgical treatment of patients.

One embodiment of the postoperative treatment relates to the use of the composition of the present invention for the treatment or prevention of edema. Edema may be caused or associated with any kind of treatment of a patient who has undergone cardiac surgery, kidney surgery, cosmetic surgery, or orthopedic surgery, for example, to name just a few. Edema to be treated or prevented may also be separate from postoperative treatment and may include burn wounds (or another disease in which blood loss occurs due to ejection of body fluids and proteins), trauma, such as traumatic brain injury, or organ failure, It should be noted that for example it may be associated with or caused by a disease such as (congestive) heart failure or chronic venous insufficiency.

Another embodiment of postoperative treatment relates to the use of the present compositions for postoperative treatment (eg, resuscitation) of a patient who has undergone cardiac surgery. The cardiac surgery is typically an invasive cardiac surgery such as open heart surgery. Examples of cardiac surgery in which a patient can be treated with a composition disclosed herein after surgery include, but are not limited to, non-selective coronary artery bypass graft (CABG) or percutaneous coronary angioplasty (PTCA) (also known as angioplasty or balloon angioplasty). There is.

The term "CABG" in the present invention refers to a surgical procedure that takes healthy blood vessels from another part of the patient's body (usually inside the leg or chest wall) and uses them to make a detour around a blocked coronary artery. Used. In the process, one end of the blood vessel is implanted (attached) to the lower right side of the containment, while the other end is implanted over the left side of the containment. As a result, blood can flow back to the heart muscle. The term CABG also includes multiple bypasses such as double bypass surgery (performing two transplants), triple bypass surgery, or quadruple bypass surgery.

The term " PTCA " is also used herein in the conventional sense to refer to a surgical procedure that first inserts a catheter and directs it to the blocked area of a diseased artery and then penetrates the first catheter with a second catheter with a small balloon at the end. Used. Once the balloon tip reaches the containment area, the balloon is inflated. This reduces plaque formation, expanding the artery for blood circulation. Finally, the balloon is deaerated and removed from PTCA.

According to the above, the compositions of the present invention can be used as an agent in an intensive care unit (ICU) in emergency situations (for example for the treatment of increased intracranial pressure as discussed in detail below), as well as for obese or hyperphysical patients. It can be used as an oral supplement.

One therapeutic use of interest is the use of a pharmaceutical composition of the invention for the treatment of brain diseases. Also in this case, only lactate and / or lactic acid and calcium need to be present in the composition of the present invention. Examples of such brain diseases are traumatic brain injury, cerebral ischemia or non-traumatic brain injury, metabolic diseases associated with brain donor failure and complications associated with surgery.

In one embodiment, the traumatic brain injury is closed or open head injury (CCT). Surprisingly, the pharmaceutical compositions of the present invention can significantly reduce the increase in intracranial pressure (ICP) caused by the traumatic brain injury, as well as the standard osmotic approach to lowering the increased ICP. It has been found to surpass efficiency.

In addition, the compositions of the present invention can also be administered to patients suffering from non-traumatic brain injury, such as seizures or cynicism, or to patients with metabolic diseases associated with brain dysfunction, such as liver or hypoglycemic coma. The compositions of the present invention are also useful for the treatment of any (intracellular) brain edema caused by traumatic or non-traumatic brain injury (disease) due to its strong osmotic effect, and thus the edema is reduced or prevented.

Examples of cardiovascular diseases or heart diseases that can be treated by the compositions of the present invention include, to mention a few, complications of myocardial ischemia, heart failure, cardiac and vascular complications of diabetes, acute infarction, ischemic reperfusion injury, or atherosclerosis. .

Since the composition generally exerts an ischemic effect, the composition can also be used for the treatment of patients suffering from malfunction of any organ. Examples of specific organ failures that can be treated include, but are not limited to, kidney failure, liver failure, or heart failure. It is also possible to treat psychogenic shock caused by heart failure, for example with the compositions of the present invention.

The compositions of the present invention have also been found to be useful in the treatment of any form of acute hemodynamic difficulties. The acute stress can be caused, for example, by multiple traumas, postoperative conditions, septic shock, respiratory illness, or acute respiratory distress syndrome.

In accordance with the above, the compositions disclosed herein are usually administered as a fluid. To this end, any suitable mode of fluid administration to the patient can be used. Preferably, the composition is administered parenterally (eg by intravenous, intramuscular or subcutaneous administration) by infusion or injection. For intravenous administration, the compositions of the invention can be provided, for example, as continuous infusion, bolus infusion or bolus injection. A typical daily maximum dose of lactate is about 4.5 to about 7.5 millimoles per kilogram body weight per day or about 4.5 to about 10 millimoles per kilogram body weight per day or 0.315 to 0.525 moles lactate per day or 0.315 moles for a 70 kg body weight. To 0.700 molar lactate / day. Any amount deemed suitable for the patient may be administered in any suitable dosage. For example, when using a composition containing about 500 mM lactate, it corresponds to an amount of 5 millimoles / kg or less (corresponding to 10 ml / kg body weight or 70 ml total volume of 0.5 m lactate solution for a 70 kg body weight patient). Can be injected continuously for up to 12 hours. Such dosing regimens may be selected for postoperative treatment of, for example, patients after cardiac surgery. On the other hand, when using a solution of 2500 mmol / liter lactate concentration, the amount of 5 mmol lactate / kg body weight can be administered by continuous infusion within about 2.4 hours (total injection volume is 70 kg body weight patient For 140 ml). If desired, the amount of 5 mmol lactate / kg body weight may also be administered by bolus injection using a solution of a concentration of 5000 mmol / liter lactate. In this case, for example, five bolus injections of each 14 ml of such lactate solution can be given to the patient over a period of 12 hours. When polylactate is used in the compositions of the present invention, oral administration is the preferred route.

The invention also relates to a process for the preparation of a pharmaceutical composition containing 250 to 5000 millimoles of lactic acid or lactate per liter, 0.5 to 1.99 millimoles of calcium per liter and optionally, if present, also 2 to 10 millimoles of potassium per liter. The method comprises in one preferred embodiment providing each amount of sodium lactate or lactic acid, calcium chloride and optionally potassium chloride and dissolving the compounds in a pharmaceutically acceptable solvent. In this regard, it is noted that the components necessary for the preparation of the liquid composition of the invention, for example sodium lactate, lactic acid, calcium chloride and potassium chloride, can also be mixed as a solid, and then the mixture is only administered to a patient in need thereof. Before being dissolved in a pharmaceutically acceptable solvent. Accordingly, pharmaceutical compositions comprising lactate or lactic acid and calcium (and optionally also any additional ingredients such as potassium or magnesium or osmolysates) in solid form are also within the scope of the present invention. Under some circumstances, for example when the storage room is limited, it may even be advantageous to prepare a solid mixture of the components of the composition of the present invention and to prepare its liquid form only when necessary.

In principle, all suitable combinations of compounds which give a composition with the desired content can be used in the preparation of the composition of the invention. For example, the composition can be prepared from lactic acid, sodium lactate, calcium chloride (x 2 H ₂ O), and optionally potassium chloride. On the one hand, mixtures of calcium lactate, sodium lactate, and optionally sodium chloride, can also be used in the preparation of the compositions of the invention.

The solvent may be any suitable pharmaceutically acceptable solvent, such as water, or water and an organic solvent, such as ethanol, as long as it can dissolve the solid component, in particular in the amounts specified, in the composition. It may be a mixture. Typically, the solvent is deionized, primary or secondary distilled or microfiltered water, the purity of which is acceptable for pharmaceutical use. The fluid composition prepared as above may be further treated, for example, by heat sterilization or sterile filtration before administration to the patient. An example of a preferred solvent / pharmaceutical carrier used in the preparation of the compositions of the present invention is sterile injectable water (WFI) as classified by the US Pharmacopoeia (USP).

The invention is further illustrated by the accompanying drawings and the following non-limiting examples.

Efficacy and Safety of Hypertonic Lactate Solution as Fluid Resuscitation Compared with Modified Ringer Lactate in Patients After CABG (Coronary Artery Bypass Graft)

A randomized open-label study was conducted to investigate the efficacy of the hypertonic lactate calcium containing solution (HL) of the present invention on Ringer lactate (RL) as bodily fluid resuscitation to maintain hemodynamic stability in patients after CABG. It was performed to evaluate the stability. The composition of Ringer lactate used is provided below.

Patients were included in the study after CABG aged 18 to 75 who needed fluid resuscitation in the intensive care unit (ICU). 230 patients were enrolled for this purpose: 208 patients were analyzed, 109 patients in the HL group and 99 patients in the RL group; Twenty two patients were withdrawn due to protocol violations, with 6 patients in the HL group and 16 patients in the RL group. The demographic and baseline characteristics of these patients are summarized in Table 1.

Eligible patients require fluid resuscitation in the intensive care unit (ICU) at the maximum dose of 10 ml / kg body weight or Ringer lactate over 30 ml / kg body weight over the first 12 hours after CABG. Provided in doses. In the HL group of the study, hydroxyethyl starch (HES) could be administered when more sap was needed and a maximum volume of hypertonic lactate solution was reached.

Patients who underwent concurrent surgery requiring an aortic balloon pump or who had severe arrhythmia (VT, AF rapid response, heart blockage), severe hemodynamic balance, severe bleeding or reoperation were excluded. Patients with hypernatremia (Na> 155 mmol / L), severe liver failure (SGOT and SGPT> 2 x normal), or severe renal failure (creatinine> 2 mg%) were also excluded.

The hypertonic lactate solution according to the invention used in this test was a solution having an osmolality value of 1020 mOsm / L in a clear colorless glass bottle and having the following composition:

ingredient Volume / 1000 ml Concentration (mmol / l) Sodium lactate solution (50% w / v) 113 g (equivalent to 56.5 g) 504 Potassium chloride 0.30 g 4.02 Calcium Chloride x 2H ₂ O 0.20 g 1.36 Water for injection To 1000 ml

The hypertonic lactate solution was administered at a maximum volume of 10 ml / kg body weight through the central vein over the first 12 hours.

An instant Ringer lactate solution in a plastic bottle of the following composition was used as a comparison:

ingredient Volume / 1000 ml Concentration (mmol / l) Sodium lactate 3.1 g 25.4 Sodium chloride 6.0 g 102 Potassium chloride 0.30 g 4.02 Calcium chloride 0.20 g 1.80 Water for injection To 1000 ml

The Ringer lactate was administered at a maximum dose of 30 ml / kg body weight intravenously over the first 12 hours.

An instant hydroxyethyl starch (HES) solution of the following composition in a plastic bottle was used when the maximum volume of hypertonic sodium lactate was reached:

ingredient Volume / 1000 ml Concentration (mmol / l) O- (2-hydroxyethyl) -amylopectin hydrolyzate HES MW 200,000 60 g Sodium lactate (50% w / v) 4.48% Sodium chloride 6.0 g 102 Potassium chloride 0.30 g 4.02 Calcium Chloride x 2H ₂ O 0.22 g 1.50 Water for injection To 1000 ml

The efficacy of the solution used in the study was evaluated by:

Hemodynamic status (heart index (CI), mean arterial pressure (MAP), pulmonary vascular resistance index (PVRI), systemic vascular resistance index (SVRI), central venous pressure CVP, pulmonary capillary wedge pressure (PCWP), heart rate ( HR)

2. Fluid balance (urine drainage; total fluid loss, including urine, sewage, and bleeding; hypertonic lactate solution or total fluid infusion, including modified Ringer lactate, blood products, and other fluids).

3. Reduced pollutant ion channel drug use.

The safety was evaluated by the following: 1. Laboratory parameters hemoglobin, hematocrit, sodium, potassium, chloride, calcium, magnesium, lactate, and blood gas analysis (pH, PO ₂ , PCO ₂ , bicarbonate). 2. Any clinical signs that the investigator considers important.

Statistical method: When the comparative differences between the HL and RL groups were found by unpaired Student's t-test or chi-square test or by two-way ANOVA for repeated measurements, then significant differences were found between the two groups ( post hoc) Analysis (Statview).

Detailed description of the research facility

After surgery, patients were observed in the ICU. During the period immediately following this surgery, patients were prepared with Ringer lactate or hypertonic lactate solution according to the group assigned to the patient to maintain PCWP 12-15 mmHg and / or CVP 8-12 mmHg. The therapeutic agent is administered according to body weight, hypertonic lactate solution is given in the HL group at a maximum dose of 10 ml / kg BW up to 12 hours after CABG and Ringer lactate is given to the RL group for a similar period of up to 30 ml / kg BW. Provided in doses. When the maximum dose of the hypertonic lactate solution was reached, infusion of HES was allowed if maintenance of fluid therapy was needed.

Post-operative care was standardized: mean arterial pressure was maintained at 60-90 mmHg with dopamine or norepinephrine and milnon or nitroglycerin (NTG) as needed. Hemoglobin concentrations were maintained around 10 mg / dL by transfusion as needed. Cardiac index and other hemodynamic parameters were maintained by contractile promoters, vasodilators and / or humoral resuscitation, taking into account the patient's overall hemodynamic balance and the special effect (s) of the drugs. For example, norepinephrine was given when target PCWP and CVP were reached in the presence of low systemic vascular resistance (SVR) but the CI was still below 2.5 l / min / m 2. However, when the SVR was high, it provided melonon; Dobutamine was given when the SVR was normal.

Hemodynamic parameters including heart rate (HR), systolic, diastolic and mean arterial pressure (MAP), cardiac output, vascular resistance, central venous pressure (CVP), and pulmonary capillary wedge (PCWP) when the patient arrives at the ICU. Evaluated and monitored every hour and at 12 hours immediately thereafter. Parameters such as cardiac index (CI), systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI) were subsequently calculated using the standard formula. In this regard, it is noted that due to the nature of patient management in the ICU where stabilization of the patient is most important, it was not possible to obtain hemodynamic parameters immediately upon arrival at the ICU and prior to any transfusion administration as a baseline value. The earliest measurements could be made at 1 hour of arrival. Within the 1 hour, some of the patients already needed to provide fluids (51 in the HL group and 48 in the RL group), so that the measurement of T1 (time) in the patients could be considered as baseline There was no. In the remaining patients (58 in the HL group and 51 in the RL group), T1 could be considered as the baseline value as disclosed in Table 2b.

Several other relevant biological parameters can be derived from arteries (PaO ₂ , PaCO ₂ , pH and bicarbonate) or veins (Na ⁺ , K ⁺ , Cl ⁻ , when patients enter the ICU and at 6 and 12 hours thereafter. Ca ⁺⁺ , Na ⁺ , Mg ⁺⁺ , lactate) using blood taken from the joules. Hemoglobin (Hb) and hematocrit (Ht) were also measured at these times. Total urine and bleeding were measured hourly.

Efficacy Result

Hemodynamic effect

There was no significant difference in baseline hemodynamic parameters except for PVRI (p <0.05). Changes in all hemodynamic parameters of the patient's total cohort were observed immediately after surgery in the ICU as follows: MAP, SVRI, PVRI, CVP, and PCWP were significantly reduced (p <0.0001) after CI HR increased significantly (p <0.0001). Clinical aims for contractile / angibrolytic administration as well as humoral resuscitation have been reached in both RL and HL groups. Similar cardiac filling pressures (CVP and PCWP) (Tables 7 and 8) and arterial pressure (Tables 2a, b, c, where Table 2b) showed significant differences in all observed hemodynamic parameters within the two groups. This indicates that the baseline values for all hemodynamic parameters are the same in the HL and RL groups) and despite the HR (Table 3), the CI was significantly higher in the HL group compared to the RL (p). = 0.018) (Table 4). Since calcium concentrations were similar in both the composition of the present invention and Ringer's lactate, the increase in cardiac index was due to the (unexpected) "synergistic effect" of hypertonic lactate concentration and calcium concentration used in the solution of the present invention. It must be.

Since several patients in the HL group received HES infusion as opposed to the RL group, the hemodynamic status of the subgroups of patients following HES infusion was analyzed. From the comparison between HES + and HES-, CVP (Table 14) and PCWP (Table 15) are different and both variables are significantly lower in the HES + group compared to HES- because of the baseline (p = 0.006 and p = 0.025, respectively). This is clear. This is in the group of patients (HES +) where the cardiac filling pressure seems to need to provide more fluid after reaching the maximum allowable load of hypertonic lactate solution, compared to the significantly lower MAP of the group. Although lower (both of these groups were within acceptable ranges), hemodynamic status, as assessed by CI (Table 11) and HR (Table 10), indicates the same in these two groups. Thus, the patients were given more fluids as HES, mainly because of low CVP and PCWP, not because of inadequate heart function. Moreover, the discovery of similar PVRI (Table 13) indicates that the lower resistance observed in the HL group is the result of hypertonic lactate solution injection rather than the use of HES, regardless of the additional injection of HES.

Fluid balance

Parameters involved in fluid balance in RL and HL: urine drainage, total fluid loss (urine, sewage and bleeding), total fluid infusion (ringer lactate or hypertonic lactate solution, blood products and HES in use), and total body fluid Balance (total fluid infusion + total fluid loss). Urine excretion (Table 16) and total fluid loss (Table 17) over the first 12 hours after the surgery were not significantly different in both groups (p> 0.05), whereas total fluid infusion (Table 18) showed almost no HL. Half (1319.70 ± 71.30 vs. 2430.35 ± 122.61 ml / 12 hours for HL and RL, p <0.0001, respectively), which was significantly lower in HL compared to RL (p <0.0001), resulting in a significant negative fluid balance. (-793.40 ± 71.37 mL / 12 hours, p <0.0001 vs 0), compared to the fluid balance of 0 observed in the RL group (+ 42.71 ± 114.73 mL / 12 hours, NS vs 0). Thus, despite a similar hemodynamic status and diuretic effect, but much lower fluid infusion rate and substantial negative fluid balance, a higher cardiac index was reached in the HL group compared to RL, demonstrating another benefit of the compositions of the present invention. .

As already mentioned, the HL group is not homogeneous because some patients received an additional infusion of HES while others did not. Therefore, it was analyzed whether the fluid balance parameters according to the subgroups were associated with HES infusion. Total discharge (Table 21) was the same regardless of HES infusion (p> 0.05) and urine discharge (Table 22) was significantly higher in HES +, but slightly higher than in HES- group (p = 0.040). Total fluid infusion (Table 23) was significantly higher in HES + compared to HES- (1578.77 + 75.09 vs. 764.57 + 91.32 mL / 12 hours, p <0.0001, respectively). As a result, the humoral balance (Table 24) was less negative in HES + compared to HES- (−646.65 + 83.62 vs. −1107.86 + 116.07 mL / 12 hours, p <0.05, respectively).

Accompanying drug use

Careful standardization of postoperative care was maintained to maintain an average arterial pressure of 60 to 90 mmHg with dopamine or norepinephrine and milnonone as needed. No patient needed adrenaline administration. Comparison between the HL and RL groups showed no significant difference in the number of patients given dobutamine, nitroglycerin and norepinephrine, respectively. However, Milnon was used significantly less frequently in the HL group than in the RL group (28 vs 39%, p = 0.05). Thus, the compositions of the present invention can also be used to reduce administration of contractile stimulating drugs, such as milnon, in postoperative treatment of a patient.

Special analysis to assess the effect on the cardiac index

As with other hemodynamic parameters, measurements of cardiac index (CI) were performed hourly starting at 1 hour in the ICU (T1, T2, etc.). In 98 patients (48 patients in the RL group, and 50 patients in the HL group), fluids were administered in the ICU within the first hour, so baseline data could not be obtained prior to fluid administration in the patients in this group. The other 109 patients (51 were given RL and 58 were given HL) were given fluids after 1 hour and measurements at T1 could be considered as baseline values. The presence of baseline values is particularly important for determining the magnitude of the increase in cardiac index by fluid administration.

It is clear from Table 25 that the two groups have the same baseline value. This observation implies that randomization (including large groups of patients) in the study is valid and supports the conclusions of efficacy and safety parameters disclosed elsewhere in this report. In this group, cardiac index measurements at subsequent times are shown in Table 26. Two-way analysis (Anova) gave a value of 0.447 while repeated measurements gave a value as shown in Table 27 with repeated measurements. Binary Anova for repeated measurements showed a p value rather than a significance level, but it was evident that patients receiving HL from unilateral Anova analysis always had a consistent tendency to have higher CI relative to RL. At 12 hours, the difference reaches a statistically significant level (p = 0.06). Compared to the overall analysis of 208 patients shown above, the decrease in the statistical significance is the effect of smaller sample size due to partitioning. Table 28 shows an increase in cardiac index relative to baseline values in the HL group, while Table 29 shows the same for the RL group. Both groups showed an increase in statistical significance for each baseline value, but the increase in the HL group (0.3 to 0.8) was higher than the RL group (0.14 to 0.53). The difference in cardiac index improvement between the HL and RL groups was then analyzed by unilateral Anova, giving statistically significant values (p = 0.05 at 12 hours) as shown in Table 30.

The results of this efficacy can be summarized as follows:

a) Hemodynamic function (MAP, HR, CVP, PCWP) was maintained at comparable levels between the two groups, while urine output was found to be similar between the two groups. This indicated that similar tissue perfusion in the HL group could be maintained at the same level as the RL group despite much lower transfusion infusion in the HL group (P <0.0001). This effect has been demonstrated to be independent of HES administration. With lower vascular resistance compared to the RL group, and also without a drop in MAP, the trend towards higher increases in CI in the HL group demonstrates a contractile promoting effect.

b) Patients in HL group showed higher CI (p = 0.0179) compared to RL group. The effect was also shown to be independent of HES administration.

c) Companion drug use: The number of patients receiving milnon in the HL group was significantly lower than in the RL group (28% versus 39%, p <0.05). The small number of patients who have been given Milinone is an advantage not only in terms of cost but also in terms of gain.

d) Separate analyzes of CIs performed on patients receiving fluid administration (HL or RL) after more than 1 hour in the ICU, and therefore at CI (1 hour), could be used as baseline values (HL group = 58, and RL group = 51 patients), the cardiac index increase (0.79 ± 0.62) in the HL group at 12 hours was found to be higher than RL (0.53 ± 0.62) (p = 0.05). The baseline for CI in these groups is similar, and the increase in CI observed in the group without a baseline at 1 hour is already significant (2.47 ± 0.71 vs. 2.11 ± 0.61; p = 0.007) in the HL group This indicates that the effect of increasing the CI of is immediately occurring.

Based on the above efficacy results with comparable hemodynamic parameters and tissue perfusion, and lower vascular resistance, patients in the HL group had higher cardiac index and lower total fluid infusion. The latter is also worth mentioning because the lower infusion infusion significantly reduces the risk of postoperative edema. In addition, separate studies ongoing for a group of patients provided that postoperative treatment of patients undergoing cardiac surgery improved neurocognitive function within about 6 months after the surgery compared to patients receiving the aforementioned Ringer lactate. Seems to indicate.

Patient Demographics and Baseline Features

Number of patients / age, age / sex ratio / pump on / pump off / aortic cross clamping, min / weight / height / no graft / bleeding / dosing time, time at ICU

Footnote) *: pump-on patient

**: delay between arrival of the ICU and the time of resuscitation fluid administration

Baseline value of hemodynamic parameters (prior to fluid administration)

Significant differences were observed in all observed hemodynamic parameters, implying that the baseline values of all hemodynamic parameters were the same in the HL and RL groups.

parameter

Mean arterial pressure / variance analysis in HL and RL groups

Heart rate in HL and RL groups

 Cardiac Index in HL and RL Groups

 Systemic Vascular Resistance Index in HL and RL Groups

Pulmonary vascular resistance index in HL and RL groups

 Central venous pressure in HL and RL groups

 Pulmonary capillary wedge pressure in the HL and RL groups

Average arterial pressure in the HES + and HES- groups

 Heart rate in HES + and HES- groups

 Cardiac Index in HES + and HES- Groups

 Systemic Vascular Resistance Index in HES + and HES- Groups

 Pulmonary vascular resistance index in the HES + and HES- groups

Central venous pressure in HES + and HES- groups

Pulmonary capillary wedge pressure in the HES + and HES- groups

Hourly urine drainage from HL and RL groups

Footnote) T1: First measurement after randomized treatment and after ICU

T2: 1 hour after T1

Cumulative total fluid loss in HL and RL groups

 Cumulative total infusion in HL and RL groups

Cumulative fluid balance in HL and RL groups

 Hourly urine drainage from HES + and HES- groups

Footnote) T1: First measurement after randomized treatment and after ICU

T2: 1 hour after T1

 Cumulative total fluid loss in HES + and HES- groups

Cumulative total infusion in HES + and HES- groups

 Cumulative fluid balance in HES + and HES- groups

Use of accompanying drugs

Shrink Drug Use / Dobutamine / Millionone / Norepinephrine / Vasodilation Drug Use

 Cardiac index baseline value (1 to CI) before fluid administration

Group Statistics / Sap / Mean / Standard Deviation / Standard Error Mean

Cardiac Index in Patients with Baseline Values

 Unilateral ANOVA for Cardiac Index in Patients with Baseline ANOVA

Sum / Mean Square of In-Group / In-Group / Sum / Square

 Increment of CI against baseline value in HL group, paired sample test

95% confidence interval of pair / mean / standard deviation / standard error mean / difference / child / parent

Increment of CI against baseline value in HL group, paired sample test

 Increase in Cardiac Index vs. Baseline Value Unilateral Anova for SPSS ANOVA

 Hemodynamic parameters

parameter/

Footnote) T1: First measurement after randomized treatment and after ICU

T2: 1 hour after T1

Data is mean ± SEM. Statistical comparison: binary ANOVA for repeated measures: significantly different from RL (p <0.05); Student's t-test: significantly different from b RL (p <0.05)

Hemodynamic parameters

Claims (34)

A pharmaceutical composition containing 250 to 5000 millimoles per liter of lactic acid or lactate, and 0.5 to 1.99 millimoles per liter of calcium. The method of claim 1, The composition of the lactic acid or lactate is in the range of 400 to 2400 mmol / liter. The method according to claim 1 or 2, Wherein the concentration of lactic acid or lactate is in the range of 800-1200 mmol / liter. The method according to any one of claims 1 to 3, Wherein the concentration of lactic acid or lactate is about 500 mmol / liter or about 1000 mmol / liter. The method according to any one of claims 1 to 4, Sodium (Na) is used as a counter ion for the lactate. The method according to any one of claims 1 to 5, A composition further containing potassium. The method of claim 6, The potassium concentration is in the range of 2-10 mmol / liter. The method of claim 7, wherein The potassium concentration is in the range of 2.5 to 6 mmol / liter. The method according to any one of claims 1 to 8, The calcium concentration is in the range of 1.2 to 1.7 mmol / liter. The method of claim 9, The calcium concentration is in the range of 1.3-1.5 mmol / liter. The method according to any one of claims 1 to 10, Chloride (Cl) is present as a counter ion for potassium and calcium. The method according to any one of claims 1 to 11, The composition wherein the lactate is L-lactate. The method according to any one of claims 1 to 12, A composition that is an aqueous solution. The method according to any one of claims 7 to 13, Approximately 1000 millimeters / liter of lactate, About 4 mmol / liter potassium (K), About 1.36 mmol / liter of calcium (Ca), and About 1000 mmol / liter of sodium (Na) A composition having a concentration of The method according to any one of claims 7 to 13, Approximately 500 millimoles / liter of lactate, About 4 mmol / liter potassium (K), About 1.36 mmol / liter of calcium (Ca), and About 500 mmol / liter of sodium (Na) A composition having a concentration of The method according to any one of claims 1 to 15, A composition further comprising an osmolyte selected from the group consisting of carbohydrate compounds, gelatin, alginates, polyvinyl-pyrrolidone, serum proteins and mixtures thereof. The method of claim 16, Wherein said carbohydrate compound is pectin, dextrose, polydextrose, hydroxyethyl starch, pentamethyl starch, carboxymethyl starch, condensed glucose, sorbitol, xylitol or mixtures thereof. First in the treatment or prevention of a disease or condition selected from the group consisting of hypoglycemia, postoperative treatment of patients, cardiovascular disease, brain disease, organ failure, obesity, resuscitation, edema and acute hemodynamic difficulties due to medical and surgical procedures Use of the pharmaceutical composition of claim 17. The method of claim 18, The postoperative treatment of the patient is the treatment or prevention or treatment of edema of the patient who has undergone cardiac surgery. The method of claim 19, Said cardiac surgery is coronary artery bypass graft (CABG) or percutaneous coronary angioplasty (PTCA). The method of claim 18, And wherein said brain disease is selected from the group consisting of traumatic brain injury, cerebral ischemia or non-traumatic brain injury, metabolic diseases associated with brain dysfunction and complications associated with surgery. The method of claim 21, And said traumatic brain injury is a closed or open head injury. The method of claim 22 or 23, Use of the increased skull internal pressure caused by said traumatic head injury. The method of claim 21, The non-traumatic head injury is seizure or cold-lesion. The method of claim 21, The metabolic disease associated with brain dysfunction is liver or hypoglycemic coma. The method according to any one of claims 18 and 21 to 25, Use of the brain edema caused by the brain disease is reduced or prevented. The method of claim 18, And the cardiovascular disease is selected from the group consisting of myocardial ischemia, cardiac dysfunction, cardiac and vascular complications of diabetes, acute infarction, ischemic reperfusion injury, and atherosclerosis. The method of claim 18, The organ failure is liver failure or heart failure. The method of claim 27, Use of the heart failure to cause psychogenic shock. The method of claim 18, And wherein said acute hemodynamic difficulties are caused by multiple traumas, post-surgical conditions, septic shock, respiratory illness, or acute respiratory distress syndrome. The method according to any one of claims 18 to 30, Use of the composition is administered by infusion or injection. A process for preparing a pharmaceutical composition containing 250 to 5000 millimoles per liter of lactic acid or lactate, and 0.5 to 1.99 millimoles per liter of calcium, Providing respective amounts of lactic acid or potassium lactate and calcium chloride and dissolving the compounds in a pharmaceutically acceptable solvent. The method of claim 32, And providing each amount of potassium chloride to provide a potassium concentration of 2 to 10 mmol. 34. The method of claim 32 or 33, The solvent is deionized or distilled water.