RU2847065C2 - Method for improving the filtering function of kidneys in subject - Google Patents

Abstract

FIELD: chemistry; medicine; pharmaceutics.

SUBSTANCE: present invention relates to a method for improving the filtering function of the kidneys in a subject, comprising administering a pharmaceutical composition to the subject daily for 6 months, wherein said composition contains poloxamer-188 as a pharmacologically active substance and an auxiliary substance, which is a water-salt solution, where salt in water-salt solution is selected from sodium chloride in amount of 0.3–0.9 wt. % from potassium chloride in amount of 0.03–0.04 wt. % from magnesium chloride in amount of 0.01–0.02 wt. %, wherein a single daily dose of poloxamer-188 is 8.6 to 90.0 mg/kg of the subject's body weight, wherein said pharmaceutical composition is presented in the form of a solution for oral administration, and wherein said subject is a human.

EFFECT: present invention provides substantially reduced side effects as compared to the closest analogue.

1 cl, 1 tbl, 3 ex

Description

The invention relates to the field of medicine and veterinary science, in particular to a method for improving the filtering function of the kidneys in a subject.

Kidney disease is currently not only a medical problem worldwide, but also a public health issue. Unfortunately, it is reaching epidemic proportions. It is believed that approximately 10% of the world's population suffers from kidney disease. The kidneys perform such vital functions as detoxification; removal of excess fluid; production of the hormone erythropoietin, which is necessary for maintaining normal hemoglobin levels; and maintenance of blood pressure. Their primary function is filtration. In kidney disease, this function is impaired, resulting in the accumulation of metabolic waste products, such as urea and creatinine, in the blood. It should be noted that the underlying cause of impaired renal filtration function is a variety of factors, such as congenital malformations, hypothermia, overflow of the bladder, chronic fatigue, metabolic disorders, sudden weight loss, obesity, chemotherapy, excessive alcohol consumption, xanthine oxidase deficiency, etc., and a wide range of diseases, including diabetes mellitus and arterial hypertension.

The prior art includes the medicinal product "Lespefril," manufactured by VIFITECH CJSC (Russian Federation). It contains Lespedeza bicolor shoots, 95% ethyl alcohol, purified water, and anise oil (registration number in the State Register of Medicines of the Russian Federation LS-000571), selected as the closest analogue. This medicinal product increases glomerular filtration, reduces azotemia (promotes the elimination of urea, creatinine, and uric acid from the body), and increases diuresis.

Among the disadvantages of this drug, it should be noted that sodium is removed from the body when it is administered, which can lead to hyponatremia.

The present invention is based on the task of developing a pharmaceutical composition for improving the filtering function of the kidneys, the high-quality composition of which will ensure the achievement of a technical result consisting in a significant reduction in the side effects arising from its use in comparison with the closest analogue.

The stated problem is solved in that a method for improving the filtering function of the kidneys in a subject has been developed, which comprises administering a pharmaceutical composition to the subject daily for 6 months, wherein said composition contains poloxamer-188 as a pharmacologically active substance and an auxiliary substance which is an aqueous-salt solution, wherein the salt in the aqueous-salt solution is selected from sodium chloride in an amount of 0.3-0.9 wt. %, from potassium chloride in an amount of 0.03-0.04 wt. %, from magnesium chloride in an amount of 0.01-0.02 wt. %, wherein a single daily dose of poloxamer-188 is from 8.6 to 90.0 mg/kg of the subject's body weight, wherein said pharmaceutical composition is presented in the form of a solution for oral administration, and wherein said subject is a human.

Taking into account the fact that poloxamer-188 binds to damaged cell membranes in areas with reduced lipid density, and also promotes stability and restores membrane barrier function, the authors of the present invention proposed the use of a pharmaceutical composition containing poloxamer-188 for the purpose of improving the filtering function of the kidneys in a subject.

Poloxamers are known to be block copolymers of polyoxyethylene and polyoxypropylene, used not only as excipients but also as medicinal agents with beneficial biological properties. Poloxamer is most widely used as an emulsifier for intravenous perfluorocarbon-based emulsions, as well as a stabilizer that provides clarity to elixirs and syrups. Furthermore, poloxamer is used as a wetting agent in eye drops, ointments, and gels, and as a binding agent in tablets. Poloxamers are also used to treat pathological hydrophobic interactions in blood and other biological fluids, as they improve blood flow and reduce the adhesion of macromolecules and cells. It should be noted that there are several types of commercial poloxamers, which are known under different trade names and differ from each other in molecular weight, the number of polyoxyethylene (POE) and polyoxypropylene (POP) blocks in the molecule.

Table 1 presents the characteristics of the indicated commercial poloxamers-188.

Table 1 – Characteristics of commercial poloxamers-188.

Poloxamer classification according to USP (United States Pharmacopoeia) Molecular weight, Da Amount of oxypropylene blocks, % Some examples of trade names of poloxamers Poloxamer 188 7680-95101 16.3-20.1 Pluronic F68, Lutrol 68, Kolliphor188 (manufacturer BASF), Synperonic PE/F68 (manufacturer CRODA)

Note: 1 – Information from the United States Pharmacopeia.

Poloxamer-188 also contains molecules of sizes both smaller than 4500 Da and larger than 13000 Da (M. Emanuele and B. Balasubramaniam, Differential Effects of Commercial-Grade and Purified Poloxamer 188 on Renal Function, Drugs in R D. 2014 Jun; 14(2): 73-83).

Poloxamer-188 is a nonionic amphiphilic copolymer consisting of a central chain of hydrophobic polyoxypropylene flanked at both ends by hydrophilic polyoxyethylene. Its average molecular weight is approximately 8500 kDa. Furthermore, poloxamer-188 is known to be low-toxic and has no side effects when administered to a subject.

The term "improving the renal filtration function of a subject" as used herein refers to an improvement in certain indicators of renal function in a subject, namely, an increase in the subject's daily urine output, a decrease in the subject's blood creatinine and urea levels, and an increase in the subject's glomerular filtration rate. It should be noted that these indicators vary depending on the subject's gender and age.

The term "24-hour urine output" as used in this document refers to the volume of urine excreted by a subject in 24 hours.

The term "glomerular filtration rate" in this document refers to the volume of blood plasma cleared from the glomerular capillaries of the kidney into Bowman's capsule per unit of time.

The term "creatinine level" in this document refers to the quantitative content of creatinine in blood plasma. Creatinine is the end product of creatine breakdown, which plays an important role in energy metabolism in muscle and other tissues. Normally, creatinine is freely filtered by the renal glomeruli and then, without reabsorption or additional secretion in the tubules, is almost completely excreted in urine. Thus, an increase in serum creatinine concentration is a consequence of decreased renal filtration and is a key marker of kidney disease.

Another key marker worth noting is urea levels, an increase in which in the serum indicates impaired glomerular filtration and suggests kidney disease. Urea is one of the end products of protein metabolism and contains nitrogen. It is produced in the liver, transported by the blood to the kidneys, where it is filtered through the glomeruli, and then excreted in the urine (approximately 85% of urea is excreted from the body through blood filtration in the kidneys). Rapid protein breakdown and kidney damage rapidly increase urea levels in the blood.

In a preferred embodiment, the pharmaceutical composition is presented in the form of a solution for oral administration.

Formulations of the pharmaceutical compositions according to the present invention suitable for oral administration can be presented as aqueous solutions using an appropriate solvent. Preferred solvents are water for injection or purified water. Additionally, aqueous formulations may include metal salts such as sodium chloride, potassium chloride, and magnesium chloride, as well as the following additional components: glucose, ascorbic acid, and inosine.

The quantitative content of additional components in the said composition is 0.3-0.9 wt.% for sodium chloride, 0.03-0.04 wt.% for potassium chloride, 0.01-0.02 wt.% for magnesium chloride, 0.5-10 wt.% for glucose, 0.1-1.0 wt.% for ascorbic acid and 0.1-1.0 wt.% for inosine.

Solutions containing poloxamer-188 may be packaged in containers such as vials.

The pharmaceutical compositions of the present invention may be formulated by any method known in the pharmaceutical art.

In a preferred embodiment, the single daily dose of poloxamer-188 is from 8.6 to 90.0 mg/kg of subject body weight.

Also in a preferred embodiment of the claimed invention, the pharmaceutical composition is administered to a subject that is a mammal.

In this case, the mammal is preferably a human or "human companion animal." The term "human companion animal" means any domestic animal, including, but not limited to, cats, dogs, rabbits, guinea pigs, ferrets, hamsters, mice, horses, cows, goats, and pigs. Preferred mammals include humans, dogs, cats, and rabbits.

Preferably, the pharmaceutical composition is administered to the mammal daily for 6 months.

Below are examples of improvements in kidney filtering function in humans using a pharmaceutical composition containing poloxamer-188. Poloxamer-188 brands such as Kolliphor P188 were used.

Example 1

Patient A., a 9-year-old boy, was diagnosed with left renal hypoplasia, left renal scarring, left reflux nephropathy, and vicarious hypertrophy of the right kidney. Daily diuresis was 600 ml, with the normal range being 900-1200 ml, significantly below normal. Oral treatment with a poloxamer-188 (Kolliphor P188) saline solution was prescribed at a dose of 90.0 mg/kg once daily for 6 months. After administration of the above-mentioned pharmaceutical composition, daily diuresis increased to 1000 ml, which is normal for this indicator.

Example 2

Patient H., a 69-year-old woman, was diagnosed with chronic pyelonephritis. The glomerular filtration rate and blood creatinine levels were analyzed. The analysis revealed the following: the glomerular filtration rate was 53 ml/min with a normal value of > 60 ml/min, which is significantly below the norm, and the blood creatinine level was 95 μmol/l with a norm of 58-110 μmol/l for women over 60 years of age, which is the norm for this indicator. Oral treatment with poloxamer-188 (Kolliphor P188) saline solution was prescribed at a dosage of 8.6 mg/kg once daily for 6 months. After using the above-mentioned pharmaceutical composition, the glomerular filtration rate was 79 ml/min, and the creatinine level was 69 μmol/l, which is the norm for these indicators.

Example 3

Patient R., a 67-year-old man. Diagnosis: chronic renal failure. An analysis was performed for glomerular filtration rate, creatinine and urea levels in the blood. The analysis revealed the following: glomerular filtration rate was 38 ml/min with the normal value > 60 ml/min, which is significantly below the norm, the blood creatinine level was 159 ml/min 1.73 m2 with the normal value of 58-110 ml/min 1.73 m2, which is significantly above the norm, the blood urea level was 10.6 mmol/l with the normal value of 3.2-7.1 mmol/l. Oral treatment with a water-salt solution of poloxamer-188 (Kolliphor P188) was prescribed at a dosage of 22.86 mg/kg once a day for 6 months. After using the above pharmaceutical composition, the glomerular filtration rate was 77 ml/min, the level of creatinine and urea in the blood was 89 ml/min, 1.73 m sq. and 6.5 mmol/l, respectively, which is the norm for the indicated indicators.

The study revealed a positive effect of the pharmaceutical composition containing poloxamer-188 on the filtering function of the kidneys after oral administration to the subject, in addition, no side effects were detected.

The present invention is illustrated by the above examples, which are in no way intended to limit the subject matter of the present invention. The duration of treatment with a pharmaceutical composition containing poloxamer-188 is 1-6 months, with each single daily dose of the pharmaceutical composition containing poloxamer-188 in a range of 8.6 to 90.0 mg/kg of subject body weight.

Thus, a pharmaceutical composition has been developed to improve the filtering function of the kidneys, the high-quality composition of which ensures the achievement of a technical result consisting in a significant reduction in the side effects resulting from its use in comparison with the closest analogue.

Claims (1)

A method for improving the filtering function of the kidneys in a subject, comprising administering a pharmaceutical composition to the subject daily for 6 months, wherein said composition contains poloxamer-188 as a pharmacologically active substance and an excipient which is an aqueous-salt solution, wherein the salt in the aqueous-salt solution is selected from sodium chloride in an amount of 0.3-0.9 wt. %, from potassium chloride in an amount of 0.03-0.04 wt. %, from magnesium chloride in an amount of 0.01-0.02 wt. %, wherein a single daily dose of poloxamer-188 is from 8.6 to 90.0 mg/kg of the subject's body weight, wherein said pharmaceutical composition is presented in the form of a solution for oral administration, and wherein said subject is a human.