RU2802063C1 - Feed supplement in tablet form for cats with chronic kidney insufficiency - Google Patents

Abstract

FIELD: veterinary medicine.

SUBSTANCE: invention can be used to treat chronic renal failure in cats. The feed additive is made in the form of a tablet and contains taurine, chitosan and calcium carbonate as biologically active compounds, as excipients — lactose and calcium stearate at a certain ratio of components.

EFFECT: use of the invention will provide a detoxifying effect, binding excess phosphates, reducing the level of urea and creatinine in the blood serum. The tablet is attractive to animals due to the smell of milk.

1 cl, 2 tbl

Description

The field of technology. Feed supplement in the form of a tablet for cats with chronic renal failure belongs to the field of veterinary medicine and can be used for the treatment and prevention of chronic renal failure in cats.

Chronic renal failure (CRF) in cats is a pathological condition characterized by a violation of the renal regulation of the body's chemical homeostasis, with partial or complete impairment of the formation and excretion of urine due to a decrease in glomerular filtration [1].

CRF in cats is one of the most common diseases along with oncological diseases and pathologies of the cardiovascular system [5].

Regardless of age, CRF is diagnosed in cats in 2–20% of cases [12] and in 30–40% of cases in cats older than 10 years. CRF is the most common cause of death in cats older than 5 years (over 13% of cases) [20]. However, there are cases of the disease in young felines, which can often be triggered by factors such as bacterial or combined infections of the urinary tract, birth defects, long-term exposure to toxins, or several factors in combination [1].

Identification of pathologies of the urinary system, in which a complex symptom complex occurs, including pain and uremic syndrome, due to a long latent period, is difficult and is characterized by scarcity and non-specific clinical manifestations, in this regard, treatment is often started late [5], when the changes are already irreversible character [1].

A combination of azotemia (increased serum creatinine and/or urea levels) and inadequately low specific gravity of urine is usually used to diagnose CRF in clinical practice [20]. The gold standard for assessing kidney function is the glomerular filtration rate (GFR) [15]. However, traditional methods for measuring GFR, such as renal clearance or multiple-sample plasma clearance methods, are generally impractical for clinical use [19].

A decrease in GFR can be detected by measuring the specific gravity of urine, and damage to the glomeruli by diagnosing proteinuria [14]. Plasma creatinine and urea levels are negatively correlated with GFR [20]. Creatinine is a breakdown product of creatinine phosphate in mammalian muscles, is produced at a constant rate and excreted from the body in the urine without being reabsorbed in the kidneys [15], therefore, the determination of serum creatinine concentration characterizes the ability of the kidney to filter and the health of the kidneys. Significantly elevated plasma creatinine concentration indicates an increase in the pathological process, which can lead to severe complications in cats suffering from CRF [22].

Urea is a protein breakdown product and is normally excreted by the kidneys. A number of recent experimental data indicate that urea is toxic at concentrations characteristic of CRF, causing molecular changes associated with insulin resistance, free radical formation, apoptosis, and disruption of the protective intestinal barrier. Urea is a source of formation of cyanates, ammonia, and carbamylated compounds [26].

The level of phosphorus can also serve as a marker of GFR. Phosphorus supplied with food is absorbed from the gastrointestinal tract and freely filtered in the renal glomeruli. If in healthy animals the intake of phosphorus with food remains constant, then the level of phosphorus in the blood remains constant [13]. At the same time, it has been shown that a diet high in highly available phosphorus can have an adverse effect on renal function parameters, even in healthy cats [18]. In animals with renal insufficiency, a decrease in GFR leads to phosphorus retention, hyperphosphatemia [13], and progression of CRF [21].

Hyperphosphatemia is a negative prognostic factor in cats with CKD [18] and is one of the most important factors of endogenous intoxication [2].

Thus, inadequately high levels of urea, creatinine and phosphorus in the blood can serve as markers of CRF [9]. Dietary phosphorus restriction is most effective in prolonging the survival time of cats with CKD [14]. But the most effective is a complex effect, including dietary nutrition and the use of phosphate binders [2, 23].

The level of technology. Phosphate binders that reduce serum phosphate levels include: calcium preparations (calcium carbonate and calcium acetate); sevelamer hydrochloride (Renagel) and sevelamer carbonate (Renvela); aluminum hydroxide (Almagel Neo) and lanthanum carbonate (Fosrenol) [9].

Calcium-containing phosphate binders are well tolerated, quite effective and have low cost. However, one should take into account the threat of hypercalcemia, which can cause calcification of tissues and blood vessels [17].

Almagel Neo effectively controls the level of phosphorus in the blood and is often used in veterinary practice. The disadvantages of the drug include the possibility of aluminum poisoning [9].

Phosphate-binding compounds that do not contain calcium and aluminum - sevelamer hydrochloride and sevelamer carbonate are effective phosphate-binding agents, in addition, the drugs also reduce the level of low-density lipoprotein cholesterol, but require high doses, causing dyspepsia, and have a high cost. [9, 17].

The pharmacological action of lanthanum carbonate (Fosrenol) is due to the formation of an insoluble complex - lanthanum phosphate with a decrease in the concentration of phosphates [9]. However, the drug taken with food has an unpleasant taste and is quite expensive [17].

More recently, a novel iron-based phosphate binder, sucroferric oxyhydroxide (SO), has been reported to be effective in lowering serum phosphate levels with minimal gastrointestinal side effects. Currently, studies of its pharmacological activity are being carried out [17].

To date, it is known about the existence of a combined composition for the treatment of progressive kidney disease [EP 2818176, 2014]. The invention relates to the treatment of progressive kidney diseases, including chronic renal failure in domestic animals and is a mixture in the following ratio, wt. %: ACE oligopeptides - 2.0; the sum of polysaccharides extracted from Astragalus membranaceus (Fabaceae) - 10.0; calcium carbonate - 3.75; magnesium carbonate - 1.0; chitosan - 1.0; hydrophilic silicon dioxide - 1.0; butylhydroxytoluene - 0.02; liver powder - 10.0; polyoxyethylene monooleate - 0.5; migliol - up to 100.0. At the same time, ACE oligopeptides are a hydrolyzate of scallop extract peptides, which inhibit the activity of angiotensin-converting enzyme, dilate blood vessels, thereby exhibiting moderate antihypertensive properties. Astragalus membranous polysaccharides suppress the overexpression of profibrotic factors (eg TGF-β1), reduce the infiltration of inflammatory cells (eg macrophages) and the expression of pro-inflammatory cytokines (IL-2, IL-6, TNF-α). A mixture of calcium carbonate and magnesium carbonate is used by the authors as a phosphate binder. Chitosan - as a compound that binds uremic toxins. Hydrophilic silicon dioxide (Aerosil 200) is used as a gel-forming component, butylhydroxytoluene - as an antioxidant, liver powder - as a flavoring agent; miglyol - as a filler [EP 2818176, 2014].

The disadvantage of the invention can be considered that the proposed composition is a viscous gel-like liquid that must be administered to cats per os, which may be accompanied by profuse salivation, possibly vomiting and, accordingly, inaccurate dosing of the proposed composition.

The closest to the invention are Ipakitine®, (Vetoquinol, France) and Renal (Candioli, Italy). Both feed additives are a powder that must be added to the feed, contain calcium carbonate and chitosan as pharmacologically active substances. Renal contains potassium citrate, which binds calcium in the urine and alkalizes it.

The disadvantages of the use of Renal include the limitation of its use in the late stage of renal failure, due to the high level of serum potassium [9].

In addition, both additives must be used with food, but, as is known, in CRF in cats, both at the initial and conservative stages of the disease, there is a decrease in appetite, intermittent vomiting, vomiting of food [6].

Both feed additives are expensive and may become scarce.

To date, no domestic analogues of the invention have been found in the available literature.

The objective of the invention is to expand the range of domestic veterinary feed additives to eliminate the manifestation of CRF, reduce the risk of disease progression and prolong the life of cats with this pathology by developing a domestic feed additive in the form of tablets, the effectiveness of which is due to the composition, ease of use and dosing accuracy.

Disclosure of the essence of the invention. The proposed feed supplement for cats with CRF contains chitosan, calcium carbonate and taurine as biologically active compounds, calcium stearate and lactose as excipients in the following ratio, wt. %: taurine - 15.5%; chitosan - 24.8%; calcium carbonate - 31%; calcium stearate - 1%; lactose rest.

Taurine is a beta-amino acid essential for cats. Taurine is present in all organs and tissues of cats, including the nervous system and muscles. If most mammals are characterized by the formation of taurine in the body, then in cats the process of formation of taurine is absent, but the amino acid itself is vital. Taurine does not accumulate in the body of a cat, so its intake should be regular [7].

A sufficient concentration of taurine in the body of cats is of particular importance in chronic renal failure, since the amino acid has membrane-protective properties, normalizes the exchange of calcium and potassium ions in cells, reduces the level of urea and creatinine, reducing uremic intoxication, leading to the death of the animal [4].

In the glomerulus, where inflammatory cytokines induce leukocyte migration, T-cell activation, fibrosis, sclerosis, and scarring in CKD, the role of taurine as an antioxidant becomes paramount. Taurine has an effect on reactive oxygen species that activate podocytes and increase protein excretion [16]. Taurine promotes natriuresis and diuresis through osmoregulatory activity in the kidneys [25]. Therefore, taurine deficiency is associated, among other things, with kidney dysfunction [24].

Chitosan is a deacetylated derivative of chitin, a natural polymer of 2-acedamido-2-deoxy-β-D-glucose found in crustacean shells, insects, and fungi [10].

Chitosan is an aminopolysaccharide (2-amino-2-deoxy-β-D-glucan) [3].

There is evidence that chitosan, by binding indoxyl, prevents the formation of indoxyl sulfate, a uremic toxin, reducing its content in the experiment by 38.5%, while the amount of phosphates decreases by 17.8% [11, 27].

Calcium carbonate - phosphate binder, is used in the invention as a compound that binds excess phosphates into an insoluble complex - calcium phosphate, which is excreted from the animal's body by evacuation with feces, reducing or eliminating the phenomenon of hyperphosphatemia in an animal with CRF.

Lactose or milk sugar is used in the proposed composition as an inert filler that provides the tablets with optimal solubility, tableting powder - fluidity, compressibility and ability to bind biological substances. Of all the grades of lactose, anhydrous has the best compressibility, which makes it possible to use the direct compression process to obtain tablets, eliminating additional technological steps, including the need for moisture. The key parameter is also the ability of lactose to provide high uniformity of dosing of biologically active substances that are part of the tablet mixture. In addition, lactose gives the tablets the taste and smell of milk.

Calcium stearate is added to the proposed composition in a minimum amount as a lubricant.

The average weight of the tablets was determined using an analytical balance (VSL 60/0.1A, Russia), disintegration was determined using a semi-automatic disintegration tester (OLpharmPRO D-2) complete with 2 baskets of 6 tablets and a built-in automatic basket lifter; using a tablet friability tester (ERWEKA TAR 120), quantitative determination of taurine and calcium carbonate - using an automatic titrator (ATP-02). Specification for feed additive for cats with CRF in the form of tablets in accordance with OFS.1.4.1.0015.15 "Pills" are presented in Table 1.

Table 1
Specification for food additive for cats with chronic renal failure in the form of tablets Defined indicator Method of determination Result Description visual Elongated tablets, with a flat surface, without chamfers and notches, beige, inclusions are allowed, with a slight smell of milk Authenticity Qualitative response:
- To 0.5 g of crushed tablets add 10 ml of purified water, shake and filter. To the obtained filtrate add 1 ml of 0.1 M sodium hydroxide solution and 0.06 ml of 1% phenolphthalein solution;
- The precipitate from the filter is transferred to a test tube and 0.5 ml of diluted hydrochloric acid is added;
- 2-3 drops of ammonium oxalate solution are added to 2-3 drops of the resulting solution. - a raspberry color appears, disappearing when 1 ml of formaldehyde solution, previously neutralized by phenolphthalein (taurine), is added to the solution;
- gas bubbles are released (carbonate ion);
a white crystalline precipitate precipitates, insoluble in acetic acid, soluble in hydrochloric acid (calcium cation). Average weight, g Gravimetric 0.32 g Deviations from the average mass Gravimetric No more than ±5% disintegration rotating basket No more than 15 min. Abrasion resistance Tablet friability tester Not less than 97% quantitation
- taurine - potentiometric titration (formal titration);
- titrimetric determination (complexometry) - taurine (0.046-0.054 g/tab.); - calcium carbonate
(0.095 - 0.105 g/tab.)

The resulting feed additive in the form of tablets meets the requirements of the specification.

Implementation of the invention. Determination of the biological activity of the proposed feed additive for cats with CRF in the form of tablets was carried out on the basis of the Dzerzhinsk veterinary hospital (400107, Volgograd region, Volgograd, Karl Liebknecht street, 6).

The study included 40 cats of different sexes aged 5 to 10 years with a body weight of 2.5-6.5 kg, who were diagnosed with chronic renal failure of the III degree according to IRIS (creatinine content ranged from 251 to 440 µmol/ l, according to the International Renal Interest Society, IRIS) based on the results of a clinical examination, anamnesis, general urinalysis and biochemical analysis of blood serum.

Urine sampling was carried out by cystocentesis.

Urinalysis was performed using Combiscreen 11SUS test strips; sediment microscopy - according to generally accepted methods in veterinary medicine (Vinnikov N.T., 2003). Urine density was determined using a hydrometer with a scale range of 1.001 to 1.050 µg, as well as an Interkus VUR3 refractometer. Determination of inorganic phosphorus was carried out according to the method of Bell - Briggs - Yudilevich. Protein in urine was determined spectrophotometrically by the Lowry method. Creatinine level was measured according to the method based on its reaction with sodium picrate (Yaffe method). The concentration of urea was determined by the formation of a red complex in the presence of thiosemicarbazide and iron (III) cations (a set of reagents - "Urea 450" PLAVA-Lachema). Biochemical studies of blood serum and clinical urine tests were performed on the day of admission of patients - on the 1st day of admission and then on days 7, 14, and 30 (Table 2). Statistical processing of the obtained data was carried out using the Statistica 6 program.

The dynamics of biochemical parameters in experimental animals against the background of the use of the proposed feed additive in the form of tablets was studied in a comparative aspect with the most commonly used additive in cats with CRF - Ipakitine. For this purpose, all selected animals were randomly divided into two groups. The first group of animals received during feeding the supplement Ipaquitine, in the form of a powder, which was added to wet food in the amount of 1 g of powder per 5 kg of animal weight. The proposed tool in the form of tablets was received by animals of the second group at a dose of 1 tablet per 5 kg of animal weight during meals.

The use of feed additives was started after stopping the exacerbation of chronic renal failure through symptomatic, pathogenetic and replacement therapy, carried out for 7 days. At the same time, all experimental animals were transferred to Hill's k/d medicated food.

As a result of the studies, it was found that upon admission to the clinic, the specific gravity of urine in all patients included in the study was below 1.030.

table 2
Comparative assessment of the dynamics of biochemical parameters in cats with chronic renal failure when using complex feed additives Defined indicator Reference values Days of observation feed additive Ipaquitine Suggested Composition Urea, mmol/l 3.5-12 1 18.1±1.5 17.4±0.3 7 16.3±0.9 15.3±0.5 14 12.2±0.6 12.2±0.8 21 11.9±0.5 11.7±0.6 thirty 11.8±0.4 10.2±0.8 Creatinine, µmol/l 44-160 1 370.4±8.6 373.2±10.9 7 314.2±6.5 316.3±8.2 14 262.8±5.3 264.8±6.1 21 258.4±8.4 249.4±6.3 thirty 236.1±5.2 163.1±4.8 Phosphorus, mmol/l 0.9-2.5 1 2.6±0.1 2.6±0.1 7 2.4±0.2 2.4±0.2 14 2.1±0.2 2.1±0.1 21 1.8±0.2 1.7±0.3 thirty 1.5±0.1 1.4±0.2 Total protein, g/l 57-79 1 75.6±1.9 75.6±1.9 7 75.4±1.2 75.2±1.2 14 73.2±1.6 72.2±1.1 21 70.1±1.9 67.1±2.3 thirty 70.3±2.5 68.2±0.8 Albumin, g/l 24-39 1 26.5±0.3 26.3±0.8 7 26.3±1.8 27.4±1.2 14 24.2±1.4 23.2±0.6 21 26.4±1.3 28.1±0.3 thirty 28.6±1.2 34.3±0.8 Calcium mmol/l 1.9-2.6 1 1.9±0.2 2.2±0.2 7 1.9±0.2 1.9±0.2 14 2.1±0.1 1.9±0.1 21 2.1±0.2 2.1±0.2 thirty 2.5±0.2 2.2±0.2 Potassium, mmol/l 3.5-5.3 1 3.1±0.1 3.1±0.1 7 2.9±0.4 3.3±0.1 14 3.0±0.1 4.2±0.2 21 3.1±0.2 4.6±0.1 thirty 3.1±0.2 4.4±0.1 Sodium, mmol/l 142-158 1 171.3±10.9 171.3±10.9 7 172.2±9.6 168.2±6.4 14 172.6±1.8 152.6±4.8 21 170.4±1.9 153.4±5.3 thirty 168.3±10.1 148.3±5.1

Thus, the conducted studies have shown significant changes in the filtration capacity of the kidneys when using both feed additives in cats with III degree of CRF. If, upon admission of patients to the hospital, all cats showed signs of polydipsia, lack of appetite, apathy, and after 30 days of using feed additives, their condition improved significantly. It should be noted that in the second group, the animals behaved more actively than the patients of the first group, the appetite and condition of the coat differed significantly compared to the cats of the first group, in which, despite the general improvement, there was no significant change in the desire to consume food, the hair remained dull.

An analysis of the dynamics of biochemical blood parameters indicates an almost identical normalization of the determined parameters. A decrease in azotemia was observed in both groups, with minor differences.

However, the concentration of creatinine in the blood serum of patients of the second group after 30 days of application of the proposed composition in the form of tablets decreased by 2.3 times (56.3%), almost approaching the norm. In the group of animals treated with Ipakitin - 1.6 times (36.3%) and by the time the experiment was completed it exceeded the maximum value of the norm by 47.5%, having decreased from the initial value by more than 1.5 times.

The level of urea in both groups had almost the same dynamics and decreased in the second group by 1.7 times, in the first group of animals - more than 1.5 times.

In both groups, a stable amount of total protein and albumin was also observed.

Almost equally in both groups, the content of free phosphorus decreased - almost 2 times, compared with the initial values.

Significant differences between the indicators in the experimental groups were observed in the concentrations of sodium and potassium. So, if in the second group of animals the sodium concentration decreased from 171.3±10.9 mmol/l to a concentration of 148.3±5.1 mmol/l, and the potassium concentration increased from the values of the minimum normal limits to 4.4±0 ,1 mmol/l, then in the first group of animals the concentration of both potassium and sodium remained at the same level both at the beginning and at the end of the experiment, which may be due to the pharmacological activity of taurine.

The calcium concentration had a constant tendency to increase in the animals of the first group, while in the second group this indicator remained stable throughout the experiment.

Thus, both feed additives effectively eliminate hyperphosphatemia, normalizing the condition of animals. However, in the group of animals treated with Ipakitine, a persistent decrease in appetite was observed (by about 15% -20% of the norm recommended by the manufacturer), in the second group - a gradual uniform increase in feed intake. In addition, the uniformity and completeness of dosing of the proposed composition was of great importance due to the fact that the animals received the drug in tablets, regardless of the amount of food consumed. The advantage of the proposed feed additive is also associated with the presence of taurine in it, which normalized the concentration of potassium, sodium and calcium, in contrast to Ipakitine, when used in animals, a gradual increase in calcium concentration was observed at stable low levels of potassium in the blood.

The technical result consists in the creation of a domestic feed additive for the prototype of which Ipakitine can be taken, but with a different form, convenient for use, ensuring dosing accuracy and the introduction of taurine, an essential amino acid, the deficiency of which in cats can cause kidney degeneration [8].

The results obtained in the course of the conducted studies indicate that the invention can be used as a specific feed additive for cats with CRF to reduce or eliminate the manifestations of pathology and prolong their life.

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Claims (1)

Feed additive in the form of a tablet for cats with chronic renal failure, characterized in that it contains taurine, chitosan and calcium carbonate as biologically active substances, and lactose and calcium stearate as excipients in the following ratio of components, wt.%: taurine - 15.5%; chitosan - 24.8%; calcium carbonate - 31%; calcium stearate - 1%; lactose rest.