RU2795624C1 - Composition for the treatment of biotin-deficient conditions in children, as well as a method of treatment using such a composition - Google Patents

Abstract

FIELD: medicine and pharmaceuticals.

SUBSTANCE: group of inventions can be used to treat biotin-deficient conditions in children of the first year of life and older. A composition for the treatment of biotin-deficient conditions in children of the first year of life and older is proposed, containing biotin, vitamins B1, B2, B3, B5, B6, B9, a filler, which is a mixture of dextrose and maltodextrin in a ratio of 1:1 by weight, with the following the ratio of components in grams per 1,000 g of the following mixture: Biotin — 2.5–10; B3-Nicotinamide — 0.488; B5-Calcium pantothenate — 0.12; B6-pyridoxine hydrochloride — 0.05; B1-Thiamin mononitrate — 0.04; B2-Riboflavin — 0.045; B9-Folic acid — 0.0106; filler — the rest. A method for treating biotin-deficient conditions in children of the first year of life and older includes adding the specified composition to a food product suitable for children of the first year of life and older, and a single dose of biotin of 2.5–20 mg, and the daily dose reaching 100 mg/day.

EFFECT: invention makes it possible to effectively and safely treat biotin-deficient conditions in children of the first year of life and older, and the indicated agent has a high solubility, which makes it possible to add it to breast milk substitutes and complementary foods.

3 cl, 3 ex

Description

The claimed invention relates to compositions for conditions in children, including the first year of life, as well as to a method for the treatment of biotin-deficient conditions.

Biotinidase deficiency is a hereditary autosomal recessive disease from the group of organic acidurias, which is based on a biotin-deficient state. It is known that biotinidase is an enzyme involved in the metabolism of biotin, a water-soluble vitamin of group B, which is a cofactor in the synthesis of fatty acids, the breakdown of amino acids and gluconeogenesis. Biotin functions as a coenzyme for four carboxylases. Biotinidase is found in the cells of the liver, kidneys, and in the blood serum.

The disease is caused by a deep or partial absence of the biotinidase enzyme and is characterized by a wide range of clinical manifestations, which include neurological symptoms, skin manifestations, changes in the organs of vision and hearing, and immunity disorders. The average age of the onset of the disease is 3-6 months, in rare cases it manifests even after 10 years.

Early diagnosis is critical, as early initiation of biotin treatment in the neonatal period provides an opportunity to prevent the formation of severe clinical manifestations and mental retardation. With a partial deficiency of biotinidase and no treatment, severe damage to the brain and immunity develops, with a deep deficiency of the enzyme, the risk of death is high. The use of specific therapy with biotin at a dose of 10-30 mg/day in this pathology leads to the relief of seizures, regression of neurological disorders, hair growth, restoration of acid-base balance and a decrease in the level of organic acids in the urine.

In the prior art, nutritional supplements based on biotin and B vitamins are known, in particular, a vitamin supplement is known containing an effective amount of vitamin B1, an effective amount of vitamin B2, an effective amount of nicotinic acid, an effective amount of vitamin B6, an effective amount of biotin and an effective amount of pantothenic acid; and (2) where the mass ratio of biotin to vitamin B1 is from 1:20 to 1:25; where the mass ratio of biotin to vitamin B2 is from 1:25 to 1:30; where the mass ratio of biotin to nicotinic acid is from 1:310 to 1:330; where the mass ratio of biotin to vitamin B6 is from 1:30 to 1:35; where the mass ratio of biotin to pantothenic acid is from 1:110 to 1:130; and (b) where the person has increased activity [patent for the invention of the Russian Federation No. 2 665 635, C2].

The disadvantage of this supplement is the possibility of its use in adults, starting from the age of 18 years. Its use for specific nutrition, as well as for children, is unacceptable due to the fact that the supplement contains unacceptable components.

Also known from the prior art is a pharmaceutical composition for the prevention and treatment of polyneuropathy in the form of a solid dosage form, including Biotin as an active agent, and Metocel K100 LV, Metocel K4M, microcrystalline cellulose, copovidone, colloidal silicon dioxide and a pharmaceutically acceptable salt of stearic acid as excipients. acid, with the following content, wt. %:

Biotin 40-60 Metocel K100 LV 14-21 Metocel K4M 5-10 Microcrystalline cellulose 7-18 Copovidone 1.5-3 colloidal silicon dioxide 0.4-1 Pharmaceutically acceptable salt stearic acid 0.6-1

It should be noted that today there is not a single composition that would contain a therapeutic dose of biotin and be suitable for use in children, including the first year of life.

Thus, the problem of treating biotin-deficient conditions in children, including children of the first year of life, is very acute and has not yet been resolved.

The task set by the applicants was to create a product that can be used to feed young children, including the first year of life, for the treatment of biotin-deficient conditions, while such a product must be safe for children to eat, and must have a high solubility. It was also an object of the invention to develop a method for the treatment of children with biotin-deficient conditions using the obtained product.

The technical result obtained in the implementation of the invention is the safety and efficacy for children of the first year of life and older of the agent for the treatment of biotin-deficient conditions, while such an agent has a high solubility, which allows such an agent to be added to breast milk substitutes and complementary foods.

The technical result is achieved by creating a composition for the treatment of biotin-deficient conditions in children of the first year of life and older, where the composition contains biotin, vitamins B1, B2, B3, B5, B6, B9, a filler, which is a mixture of dextrose and maltodextrin in a ratio of 1: 1 by weight, with the following ratio of components in grams per 1000 g of the mixture:

Biotin 2.5 - 10 B3-Nicotinamide 0.488 B5-Calcium pantothenate 0.12 B6-pyridoxine hydrochloride 0.05 B1-Thiamin mononitrate 0.04 B2-Riboflavin 0.045 B9-Folic acid 0.0106 Filler rest

wherein the composition is formed in the form of a dry powder mixture.

In this case, the composition can be packaged with sachets weighing 2 g, where each sachet contains in mg:

Biotin 5 - 20 B3-Nicotinamide 0.976 B5-Calcium pantothenate 0.24 B6-pyridoxine hydrochloride 0.1 B1-Thiamin mononitrate 0.08 B2-Riboflavin 0.09 B9-Folic acid 0.0212 Filler rest

The technical result is also achieved by creating a method for the treatment of biotin-deficient conditions in children of the first year of life and older, where the composition according to claim 1 is added to a food product suitable for children of the first year of life and older, and a single dose of biotin is from 2.5 up to 20 mg, and the daily dose reaches up to 100 mg / day. For children up to a year, a single dose can be 2.5 mg, which is obtained by completely dissolving the sachet in a 1 ml liquid, followed by dividing this volume into 2 parts.

The finished composition has a high solubility, for the possibility of using both in a concentrated solution (1 ml) and for dissolving it in a food product.

The composition contains from 250 to 1000 mg of biotin per 100 g of product to effectively compensate for biotinidase deficiency.

A single dosage of biotin for a patient ranges from 2.5 to 20 mg, while the daily dose can reach 100 mg / day.

Vitamins of group B in the product have an additional general therapeutic effect. The amount of biotin is contained in a verified dosage to correct the deficiency, and the remaining B vitamins come in an amount of 10% of the daily requirement for additional enrichment of the diet.

As a filler, a mixture of dextrose and maltodextrin is used in a ratio of 1:1 by weight.

Treatment of biotinidase deficiency should be started as early as possible to prevent the development of neurological disorders. The composition of the product is formulated for use in children of the first year of life and for older children.

The composition is adapted for joint use with breast milk substitutes, complementary foods and other food products in which it dissolves / mixes easily. The inventive composition is easy to mix into any food product, where it will completely dissolve, and also will not cause a significant change in the BJU of the product in which it will be mixed. This will allow doctors or parents to control the concentration of biotin in the diet.

The product is obtained by simple mixing of the components in the indicated quantitative ratios until a mass uniformity of 99% is achieved. The mixing time depends on the type of mixer used. Next, the product is packaged.

The preferred packaging option is sachets, individual sachets of 2 g of the product. A single dose contains in mg:

Biotin 5 - 20 Nicotinamide 0.976 Calcium pantothenate 0.24 Pyridoxine hydrochloride 0.1 Thiamine mononitrate 0.08 Riboflavin 0.09 Folic acid 0.0212 Filler rest

The patient, depending on the severity of the course of the disease, is prescribed a therapeutic dose. Biotinidase deficiency can be partial, biotinidase activity is at least 0.5 nmol/min/ml (10-30% of the average normal activity in blood serum) or total, biotinidase activity is less than 0.5 nmol/min/ml (less than 10% of normal serum activity). Depending on the diagnosis, a starting dose of 2.5 mg / day or 10 mg / day is used. the starting dose can be adjusted twice with an interval of 2 weeks based on the indicators of the level of acylcarnitines (C ₅ OH) in the blood and the levels of urine organic acids (3-hydroxyisovaleric, 2-oxoglutaric) in the patient's urine.

Before use, the composition is completely dissolved in the product prepared for consumption. The effectiveness of the prescribed treatment is determined by the dynamics of indicators of acylcarnitines (C5OH) in the blood and the levels of organic acids in the urine (3-hydroxyisovaleric, 2-oxoglutaric) in the urine relative to the initial level at the time of diagnosis. It also takes into account the absence of negative dynamics in the level of development and neurological status in the process of taking the product. The composition can be used both independently and in combination with concomitant drug therapy.

The claimed technical result is achieved due to the totality of the features of the invention under consideration and is confirmed by examples.

Example 1

Patient F., a boy, was born at term at 39 weeks, weighing 2800 g, body length 48 cm. The Apgar score at 1 and 5 minutes was 8 and 8 points, respectively. Two days before admission to the hospital, the parents noted an increase in lethargy, the appearance of "drowsiness" in the child, the boy almost completely lost his appetite. On the third day of illness, the parents turned to a neurologist.

According to a biochemical blood test, the child showed an excess of ammonium levels by 2.5 times, a 2-fold drop in alkaline phosphatase activity against the background of a sharply reduced (3-fold) level of phosphorus, and no signs of kidney dysfunction were detected. Blood for aminoaciduria: revealed an increase in the concentration of 3-hydroxy-isovaleryl-2-methyl-3-hydroxybutyrylcarnitine (deficiency of biotinidase). Blood to determine the activity of biotinidase: activity 0.66 nmol / min / ml (normal 4.40-12).

From the date of the final diagnosis (on the 8th day), in the treatment of the child, in agreement with the specialist of the center of orphan diseases, the claimed composition was prescribed in dosages recommended for patients with biotinidase deficiency, in this case 2.5 mg / day. By the day the final diagnosis was established, the child remained lethargic, muscle tone was sharply reduced, the level of consciousness was assessed as stunning, the child was fed only through a gastric tube.

A complete correction of the acid-base balance in the child occurred only after the specific treatment started. If normalization of blood pH occurred already on the 2nd day of treatment (pH 7.36), then the level of lactate on the day of prescription of the claimed product was 4.6 mmol/L. The concentration of lactate in the blood on the 2nd day of specific treatment decreased by 2 times and already on the 3rd day of treatment with the claimed product returned to physiological values. In parallel, there was a restoration of muscle tone and strength in the child, a decrease in drowsiness, and the appearance of appetite. On the 4th day of specific treatment, the child was transferred to the pediatric department in a stable condition, and on the 7th day he was discharged home under the supervision of specialists with a recommendation of a daily dosage of 5 mg/day.

Example 2

Patient X., a boy, was born at term at 41 weeks, weighing 3200 g, body length 52 cm. The Apgar score at 1 and 5 minutes was 8 and 9 points, respectively. Two days before admission to the hospital, the child's parents applied to the children's polyclinic with complaints about the baby having difficulty breathing, after the first visit to the polyclinic, the parents noted an increase in lethargy, the appearance of "drowsiness" in the child, the boy almost completely lost his appetite. On the third day of illness, the parents turned to a neurologist. On examination, the specialist noted that the child was in a state of coma, hypothermia. In this connection, the child was urgently sent to the hospital, the intensive care unit with a referral diagnosis: "Neuroinfection of unknown etiology."

According to clinical and laboratory examinations, the child showed no signs of an infectious process (the level of leukocytes in the blood is normal, C-reactive protein 0.03 mg/l and procalcitonin 0.08 ng/ml are not elevated). However, according to the acid-base and electrolyte analysis, the child was diagnosed with severe metabolic acidosis at the time of admission: pH 6.873, BE -24.7, lactate 6.8 mmol/l. Also, at the time of admission, the child was diagnosed with moderate anemia (Hb 111 g/l), hypocoagulation (PTI 14%, APTT 65.1 seconds, fibrinogen 1.72 g/l). According to a biochemical blood test, the child showed an excess of ammonium levels by 2.5 times, a 2-fold drop in alkaline phosphatase activity against the background of a sharply reduced (3-fold) level of phosphorus, and no signs of kidney dysfunction were detected.

From the date of the final diagnosis (on the 8th day), in the treatment of the child, in agreement with the specialist of the center of orphan diseases, the claimed composition was prescribed in dosages recommended for patients with biotinidase deficiency, in this case 10 mg / day. Prior to the appointment of specific treatment, the level of wakefulness remained at the level of stupor for a long time, and mechanical ventilation was completed only on the 5th day of treatment. By the day the final diagnosis was established, the child remained lethargic, muscle tone was sharply reduced, the level of consciousness was assessed as stunning, most of the time the child needed additional oxygen supplementation due to the persistence of secondary respiratory failure, the child was fed only through a gastric tube.

A complete correction of the acid-base balance in the child occurred only after the specific treatment started. If normalization of blood pH occurred already on the 2nd day of treatment (pH 7.34), then the level of lactate on the day of prescription of the claimed product was 6.6 mmol/l. The concentration of lactate in the blood on the 2nd day of specific treatment decreased by 2 times and already on the 3rd day of treatment with the claimed product returned to physiological values. In parallel, there was a restoration of muscle tone and strength in the child, a decrease in drowsiness, relief of respiratory failure, and the appearance of appetite. On the 4th day of specific treatment, the child was transferred to the pediatric department in a stable condition, and on the 7th day he was discharged home under the supervision of specialists while maintaining a daily dosage of 10 mg/day.

Example 3

Patient K.A., a 2.5-month-old boy, was urgently delivered to the Department of Psychoneurology due to repeated seizures, loss of psychomotor skills, atopic dermatitis, persistent conjunctivitis with mucopurulent discharge from the eyes.

From the anamnesis: the onset of the disease at the age of 2 months, when, against the background of full health during wakefulness, generalized myoclonic seizures occurred for the first time, involving all major muscle groups, lasting up to 1 minute, with a frequency of 1 time per day; post-attack arousal was noted. During the week, there was an increase in seizures up to 2-3 times a day, the addition of complex partial seizures (with turning the head to the left / right, adversion of the eyes), lasting up to 1 min, with a frequency of 1-2 times a day. Due to the increase in generalized myoclonic and the appearance of complex partial seizures up to 6-8 times a day, the patient was hospitalized in the department of psychoneurology, where he was first prescribed antiepileptic therapy (convulex up to 75 mg/kg/day) with a slight positive effect (reduction of seizures on 25%).

From the anamnesis of life it is known that the boy was born at 39 weeks. Apgar score 7/8 points. Birth weight 3520 g, height 51 cm. There were no neurological disorders during the stay in the maternity hospital.

Somatic status at admission: a serious condition for the underlying disease. Sopor. The child refuses to eat. The skin is pale, dry, large-lamellar peeling all over the body. total alopecia. Peripheral lymph nodes are not enlarged. Visible mucous membranes of normal color, clean. The conjunctiva of the eyes is edematous, hyperemic. There are no catarrhal phenomena. Breathing stridor. In the lungs, breathing is hard, carried out in all fields, there are no wheezing. The borders of the heart are within the normal range. Heart sounds are loud, rhythmic. The abdomen is soft and painless.

Data of laboratory and instrumental methods of examination upon admission:

• in clinical analyzes of blood and urine in the dynamics of deviations from the norm were not revealed;

• in the biochemical blood test, the level of alkaline phosphatase was increased - 1001 U / l (norm up to 727), total protein was reduced - 43.0 g / l (norm 54-87) due to albumin - 27 g / l (norm 38-51);

• indicators of the acid-base state of the blood: upon admission, pronounced metabolic acidosis: pH of capillary blood 7.22 (norm 7.37-7.45), ABE - 15.6 mmol/l (norm 0 ± 2.3), pCO2 27 .6 mmHg Art. (norm 32-45), pO2 71.9 mm Hg. Art. (norm 83-108), HCO3 - 10.9 mmol/l (norm 22.2-27.9);

• blood for lactate content: lactate concentration is increased - 4.8 (normal 0.9-1.8);

• blood for aminoaciduria: an increase in the concentration of 3-hydroxy-isovaleryl-2-methyl-3-hydroxybutyrylcarnitine (deficiency of biotinidase) was detected;

• blood for determination of biotinidase activity: activity 0.26 nmol/min/ml (normal 4.40-12).

Treatment: within 2 weeks without significant effect, therapy with dexazone, convulex up to 75 mg/kg/day, Elkar was carried out, to which the claimed composition was additionally prescribed in a total dose of 10 mg of biotin per day. In the treatment, sachets of 2 g were used for the first time with a composition of 5 mg of biotin, which was used twice during the day during feeding. Subsequently, after 2 weeks of observation, the dose was increased to 30 mg per day. In this case, twice a sachet of 2 g with a dose of 5 mg of biotin and one sachet of 2 g with a dose of 20 mg of biotin were used.

On the second day of the application of pathogenetic therapy with the claimed composition, the convulsions were completely stopped. After that, a gradual decrease in the dose of convulex was started. The child began to master age-appropriate motor skills, indicators of his mental development improved.

Dynamic observation after 6 months at the age of 8.5 months against the background of ongoing pathogenetic therapy showed positive dynamics: convulsions did not recur, the child is active, receives therapy in the form of the claimed product at a dose of biotin 30 mg/day.

As stated above, the claimed product is characterized by high solubility. A sachet weighing 2 g is completely dissolved in a liquid volume of 1 ml. This degree of dissolution allows dividing the volume of 1 ml into two parts for adding to the food product for children under 1 year old when prescribing a single dose of 2.5 mg.

The claimed composition is absolutely safe. Its use in children did not cause any diagnosed side effects.

Claims (6)

1. Composition for the treatment of biotin-deficient conditions in children of the first year of life and older, characterized in that it contains biotin, vitamins B1, B2, B3, B5, B6, B9, filler, which is a mixture of dextrose and maltodextrin in a ratio of 1:1 by weight, with the following ratio of components in grams per 1000 g of the mixture: Biotin 2.5-10 B3-Nicotinamide 0.488 B5-Calcium pantothenate 0.12 B6-pyridoxine hydrochloride 0.05 B1-Thiamin mononitrate 0.04 B2-Riboflavin 0.045 B9-Folic acid 0.0106 Filler rest wherein the composition is formed in the form of a dry powder mixture. 2. The composition according to claim 1, characterized in that it is packaged with a sachet weighing 2 g, where each sachet contains, mg: Biotin 5–20 Nicotinamide 0.976 Calcium pantothenate 0.24 Pyridoxine hydrochloride 0.1 Thiamine mononitrate 0.08 Riboflavin 0.09 Folic acid 0.0212 Filler rest 3. A method for the treatment of biotin-deficient conditions in children of the first year of life and older, characterized in that the composition according to claim 1 is added to a food product suitable for children of the first year of life and older, and a single dose of biotin is 2.5-20 mg, and the daily dose reaches up to 100 mg / day.