EA020062B1 - Solid dosage form having an anorectic effect (variants) - Google Patents

Abstract

The invention relates to the pharmaceutical industry and medicine and can be used in the creation and administration of solid dosage forms for the treatment and/or prophylaxis of obesity. The present invention addresses the problem of creating an effective solid dosage form containing sibutramine hydrochloride monohydrate and having an anorectic effect. The problem of interest is solved by the inclusion of additional mineral substances in the solid dosage form and also by the use of carbon-13 and nitrogen-15 isotopes. The technical results of the invention are a greater therapeutic effect (a reduction in body weight or a decrease in the rate of weight gain) in the treatment and/or prophylaxis of obesity with no decrease in the duration of the effect or increase in the concentration of sibutramine hydrochloride monohydrate, and a more rapid onset of said therapeutic effect.

Description

The invention relates to the field of pharmaceutical industry and medicine and can be used to create and use solid dosage forms for the treatment and / or prevention of obesity.

Background of the Related Art

In industrialized countries, obesity is a significant and serious aspect of public health. This problem affected all segments of the population, regardless of social and professional affiliation, age, place of residence and gender. In Western Europe, up to 25% of people are overweight or obese. In the United States, overweight is recorded in 60% of the population, and 27% are obese, which causes premature death of about 300 thousand Americans a year (Ljp: // ^ tute.teb11pk8.gi/ag11s1.eir? 81b = 2155).

Therefore, an important problem of modern medicine is the creation of new drugs for the treatment of obesity.

One of the directions for solving this problem is the creation of solid dosage forms based on sibutramine, salts of sibutramine or their analogues.

It is known that sibutramine (or a salt of sibutramine) can be used to prevent and / or treat obesity, depression, Parkinson's disease (see CB 2098602, ZhO 88/06444). Sibutramine can also be used to reduce insulin resistance and increase sugar resistance, as well as to prevent or treat diseases such as gout, hyperuricemia, hyperlipemia, osteoarthritis, anxiety, sleep disorder, sexual dysfunction, chronic fatigue syndrome (CP 2290924, I8 6174925, I8 6162831, I8 6355685, I8 6376551, etc.).

The pharmacological effect of sibutramine (or salt of sibutramine) can be described as follows. Sibutramine has an anorexigenic effect, reduces appetite and the amount of food consumed, enhances the feeling of fullness, increases thermogenesis, and blocks the formation of fats.

Externally, the therapeutic effect of the use of sibutramine is manifested as follows: suppressing appetite, reducing body weight or reducing the rate of increase in body weight.

Studies have shown that the effect of sibutramine (pure sibutramine) with a weight of M and the effect of the salt of sibutramine (which was formed by sibutramine with a weight of M) are identical.

Let us explain the above. The action of sibutramine weighing 8.36 mg is identical to the action of a salt of sibutramine (sibutramine hydrochloride monohydrate) weighing 10 mg. Sibutramine hydrochloride monohydrate weighing 10 mg contains 8.36 mg of pure sibutramine.

We describe in more detail the pharmacological action of sibutramine hydrochloride monohydrate (salt of sibutramine).

The authors conducted experiments on animals - male rats weighing 330-340 g (suffering from obesity) and male rats weighing 230-250 g (suffering from exhaustion) using sibutramine hydrochloride monohydrate, which showed a significant decrease in body weight and a decrease in the rate of increase in body weight in animals of these weight categories.

Studies have confirmed a decrease in the synthesis of fatty acids and cholesterol (by about 10-15%) in the liver after oral administration of sibutramine hydrochloride monohydrate to an animal. The dose of sibutramine hydrochloride monohydrate was 0.0003 mg of sibutramine salt per 1 g of animal body weight. With this dose of sibutramine hydrochloride monohydrate, the appetite in animals was suppressed by 3035% during the day. The evaluation was carried out by comparing the amount of food eaten in rats receiving sibutramine hydrochloride monohydrate and rats from the control group not taking sibutramine hydrochloride monohydrate over a certain period of time. In experiments in animals, there was no desire to eat more after the end of the action of sibutramine hydrochloride monohydrate. It was also found that the greatest therapeutic effect in rats was observed when taking sibutramine hydrochloride monohydrate 1 hour before a meal. The effectiveness of sibutramine hydrochloride monohydrate also turned out to be dependent on the dosage of the drug. Increasing the dose to 0.0004 mg of sibutramine hydrochloride monohydrate per 1 g of animal body weight led to a slight increase in the therapeutic effect.

Observations of people taking sibutramine hydrochloride monohydrate (daily dose of 15 mg) showed that they reduced their weight by an average of 5-6 kg in 2 months.

The present invention claims four variants of a solid dosage form.

An analogue to each variant of the solid dosage form is a solid dosage form for the treatment or prevention of obesity, including crystalline hemihydrate of sibutramine methanesulfonate (see patent KP 2290924, published January 10, 2007). A component of the preparation of sibutramine methanesulfonate hemihydrate is sibutramine.

The analogue has a slight increase in the therapeutic effect (suppression of appetite) can be achieved by increasing the concentration of sibutramine methanesulfonate hemihydrate.

Another analogue to each variant of the solid dosage form claimed in the invention is a solid dosage form having anorexigenic effect, containing sibutramine hydrochloride monohydrate, mineral substances (ICR: // teF.gi/Eos/a2003.j1t).

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In the analogue, the active substance of sibutramine hydrochloride monohydrate is placed in capsules with a dosage of 10 or 15 mg. Accordingly, 8.36 and 12.54 mg of sibutramine are in the capsules.

Excipients: microcrystalline cellulose, calcium stearate.

The capsule is made using dyes (titanium dye, dioxide, azorubine dye, patent blue dye), gelatin.

In an analogue, minerals are used: calcium, magnesium, titanium, sodium (in the dye azorubine).

Signs of an analogue that coincide with the characteristics of each variant solid dosage form claimed in the invention are as follows:

... a solid dosage form having anorexigenic effect, containing sibutramine hydrochloride monohydrate, minerals: calcium, sodium, and the solid dosage form is made in the form of a capsule.

The disadvantages of the analogue are as follows:

the impossibility of increasing the therapeutic effect (reducing body weight or reducing the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity. The analogue has two types of capsules with 10 and 15 mg of sibutramine hydrochloride monohydrate. An increase in concentration causes a slight increase in the therapeutic effect;

relatively long time of the onset of the therapeutic effect (about 1 h).

The solid dosage form with sibutramine hydrochloride monohydrate can also be made in the form of a tablet (yyr: // etobo-tedap.pagob.gi/10.y1t1). The composition of the tablet, in addition to the above additional substances, may include chalk (calcium, magnesium).

The solid dosage form with sibutramine hydrochloride monohydrate may additionally include magnesium oxide, potato starch, aerosil, calcium stearate, povidone, basic magnesium carbonate, titanium dioxide, talc and other substances.

Further in the description (to simplify the description and ordering of terms) sibutramine hydrochloride monohydrate will be called as the main active substance. All other substances in the solid dosage form (microcrystalline cellulose, calcium stearate, dyes, gelatin, chalk, minerals, etc.) will be called pharmaceutically acceptable additional substances.

In addition, there is an analogue with minerals (patent VI 2156087, published September 20, 2000). The patent describes a dietary supplement (BAA) for food, including potassium (4-380 mg / l), magnesium (1-510 mg / l), iron (1-2100 mg / l), zinc (1-1240 mg / k) and an additional 29 different minerals and drugs. The patent claims that the dietary supplement has various medicinal properties. The dietary supplement described in the patent by known technologies can be made in the form of a solid dosage form.

However, sibutramine is absent in the dietary supplement and the dietary supplement does not have anorexigenic effect.

Other analogues with minerals. A known method for the prevention and treatment of pathologies caused by an increased and / or low content of physiologically necessary macro- and microelements in the human body, including laboratory analysis of human substrates, the identification of excess and / or deficiency of macro- and microelements and the selection of medicines (patent VI 2238749, published 10/27/2004).

So, with an excess of nickel in the human body, plants are selected:

Aralia Manchurian (root) - 20.0 g;

marsh rosemary (aerial parts) - 20.0 g;

three-leaf watch (leaf) - 40.0 g and another 17 plants containing biological nickel antagonists, mainly iron, calcium, magnesium, cobalt, manganese, zinc, copper, with a biological accumulation coefficient above 1.0 and contributing to the neutralization and removal of nickel from organism.

With an excess of lithium in the human body, plants are selected:

Schisandra chinensis (leaf) - 40.0 g;

May birch (leaf) - 20.0 g;

and 11 more plants containing biological lithium antagonists, mainly iron, sodium, potassium, iodine, with a biological accumulation coefficient above 1.0 and contributing to the neutralization and elimination of lithium from the body.

There is also known a method for the prevention and treatment of pathologies caused by an increased or decreased content in the human body of physiologically necessary or potentially toxic macro- and microelements (patent VI 2263511, published 10.11.2005). In the method, when there is an excess of macro- and micronutrients in the body, phyto-collections from medicinal plants are used as medicines, which help to neutralize and remove from the body an excess of these macro- or micronutrients and containing the maximum concentration of antagonists of the detected excess macro- or microelements. So, with an excess of aluminum, plants are used that contain the maximum concentration of its antagonists such as iron, boron, silicon, phosphorus, magnesium, calcium; at from

- 2 020062 the cobalt booth - its antagonists: manganese, iron, nickel. Herbal marshmallow (root), warty birch (leaf) or drooping birch (leaf), three-leafed watch (leaf), and other medicinal plants are included in the phytosport.

In the above two patents, the content of minerals in plants has not been investigated or indicated. It is known that the amount of mineral substances in a particular plant depends on their content in the soil and on the mineral nutrition of plants and can range from 0.00001 to 0.7% by weight of a dry plant.

In the invention, the authors enrich the solid dosage form based on sibutramine with mineral substances at a content exceeding one or two orders of magnitude (or more) the content of mineral substances in all medicinal plants, including those described in patents KI 2263511 and 2238749.

In the process of conducting research, the effect of small concentrations of mineral substances on the achievement of technical results was verified. It has been established, as will be indicated below, that the mineral substances in the concentrations in which they are found in the studied plants and phytochemicals do not affect the achievement of the indicated technical results.

In addition, the authors conducted a mineral analysis of various plants, including medicinal plants, and phyto-collections for the content of mineral substances.

Investigated: hops (cones), chamomile (flowers), flea plantain (leaf), shepherd’s bag (aerial part), common dandelion (root and leaf), marshmallow (root), birch (leaf), field horsetail (root) , odorous celery (herb), calendula officinalis (flowers), wormwood (herb), etc.

The studied plants contain minerals: potassium, calcium, magnesium, iron, manganese, copper, zinc, cobalt, etc. It has been established that the content by weight of potassium, calcium, magnesium in plants is high: 0.0001-0.7%. So, calcium contains 0.01-0.1%, potassium - 0.003-0.7%, magnesium - 0.0001-0.01%.

The content by weight of iron, manganese, copper, zinc, cobalt, chromium is low: 0.00003-0.0001%. The molybdenum content is 0.00001%.

When developing an application for an invention, the authors conducted studies to determine the content of minerals in Reduxine and Goldline capsules of various manufacturers: Ozone LLC, Russia, Ranbaxi Laboratory Limited Industrial, India.

The concentration of mineral substances was determined by the atomic absorption method for determining the content of sodium, potassium, calcium, magnesium, iron, manganese, copper, zinc, lead, cadmium, cobalt, nickel, chromium and other minerals. [Guidance on methods for monitoring the quality and safety of dietary supplements. - M .: Federal Center for Sanitary Inspection of the Ministry of Health of Russia, 2004. - 240 p., P.1.3.2.1].

The mineral composition of Reduxin and Goldline capsules of various manufacturers is given in table. 1. No other minerals were found in capsules.

In the table. 1 and in the description, the dimension mg / kg denotes the content of an element (in particular, a mineral substance) in milligrams per kilogram of solid dosage form (in 1 kg of solid dosage form).

The prototype of each variant of the solid dosage form claimed in the invention is a solid dosage form with anorexigenic effect, containing sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg: sibutramine hydrochloride monohydrate G10 ³ - 655 10 ³ sodium 0.15 - 100000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0

The above features of the prototype coincide with the features of each variant of the claimed invention.

In this case, the solid dosage form is made in the form of a capsule or tablet (see publication on the Internet, Solid dosage form based on sibutramine or sibutramine monohydrate hydrochloride with anorexigenic effect, 1Bp: // | sGopb.gi / gi / 51a1 / 2-agis1s5 / 37-5 | L1gatt).

The disadvantages of the prototype are as follows:

the impossibility of increasing the therapeutic effect (reducing body weight or reducing the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity. An increase in concentration causes a slight increase in the therapeutic effect;

relatively long time of the onset of the therapeutic effect (about 1 h).

In the invention, the disadvantages of the prototype are eliminated by introducing into the tablet a strictly defined amount of additional mineral substances. The options for the partial replacement of ¹² C carbon isotopes by ¹³ C carbon isotopes and the substitution of ¹⁴ Ν nitrogen isotopes by ¹⁵ азота nitrogen isotopes are also considered.

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SUMMARY OF THE INVENTION

The following definitions are used in the description.

Solid dosage forms are tablets, capsules, powders (including sachets, capsules), granules. Capsules belong to an independent class of solid dosage forms.

Tablets - solid dosage form (1Bp: // | sGopb.gi / gi / 51a1 / 2-agTs1e5 / 33-de1s11). Tablets are made by compressing drugs. Tablets are of various shapes, in particular in the form of cylinders, balls, flattened balls. Tablets are prescribed for oral administration. In some cases, tablets are used for the preparation of solutions, including injection, as well as for subcutaneous implantation (Esperal).

Powders - solid dosage form with the property of flowability. Powders can be placed in bags, containers. Often powders are located in capsules. Capsules are coatings for metered-dose powdered drugs used internally.

There are powders for external (as powders) and internal use. When taken with water, mineral water, milk, etc.

Pill is a solid dosage form, which is a dosage medicine in the form of a ball.

Granules - a solid dosage form in the form of grains (grains) of a round, cylindrical or other shape.

Capsules are a solid dosage form. Capsules (in shells) contain liquid, pasty or powdery medicines (formulations). Medicines are placed in a capsule for various reasons: unpleasant taste and / or smell of the drug, instability in the acidic environment of the stomach, irritating effect on the mucous membranes, etc. (Lyp: //v.1p1etGah.yu/agys1e/4415).

Anorexigenic action - an action that reduces appetite (enhances the feeling of fullness). Anorexigenic drugs are used in the treatment of obesity. The mechanism of action of anorexigenic drugs is associated with the influence of these drugs on the central nervous system. They stimulate the center of saturation and inhibit the center of hunger, located in the hypothalamic region of the brain. Anorexigenic drugs have the ability to stimulate the transmission of nerve impulses in adrenergic and dopaminergic synapses.

Thermogenesis - the generation of heat by the body to maintain a constant body temperature and ensure the functioning of all its systems, from the functioning of intracellular processes, and up to ensuring blood circulation, digestion of food, the ability to move, etc.

People prone to fullness have a slow metabolism, their thermogenesis system is deregulated. This is expressed, in particular, in the chilliness of the body. Instead of generating heat from food, the body stores the incoming energy in the form of adipose tissue.

Shelf life - the period during which the solid dosage form retains its properties to the extent that ensures its intended use.

Starch (SBN ₁₀ O ₅ ) _p - polysaccharides of amylose and amylopectin, of which alpha-glucose is a monomer. Starch, synthesized by different plants in chloroplasts, under the influence of light during photosynthesis, slightly differs in the structure of grains, the degree of polymerization of molecules, the structure of polymer chains and physicochemical properties.

Aerosil - colloidal silicon dioxide (81О ₂ ), a light micronized powder with pronounced adsorption properties. Technical name - pyrogenic silicon dioxide.

Magnesium oxide is a chemical compound with the formula MdO, colorless crystals, insoluble in water.

Calcium stearate is a mixture of calcium salts of stearic and a mixture of stearic and synthetic fatty acids, obtained by the reaction of neutralization of acids with calcium hydroxide. It is used as a plasticizer and is described by the empirical formula С ₃₆ Н ₇₀ О ₄ Са.

Magnesium carbonate - magnesium carbonate, MdCO ₃ , magnesium salt of carbonic acid.

Titanium oxide (titanium dioxide, titanium dioxide) T1O ₂ is an amphoteric tetravalent titanium oxide. Used in food coloring E171.

Talc - Md ₃ 81 ₄ About ₁₀ (OH) ₂ - crystalline substance. It is a crumbly powder of white (occasionally green) color.

Tropeolin - a coloring matter, is described by the formula No. 8O ₃ -C ₆ H ₄ -H: G.

Tartrazine is a synthetic azo dye, is described by the formula C ₄₆ N _U M | No. 1 ₃ O ₉ 8 ₂ .

Karmaziin - C ₂₀ H ₁₂ H ₂ Ma ₂ O ₇ 8 ₂ is a food additive that belongs to the group of dyes.

Patented blue dye (food additive E131) - azo dye of synthetic origin, having a dark bluish-violet color. The dye is obtained by synthesis from coal tar. Molecular formula of the dye: C ₅₄ H ₆₂ Ca ₄ O _{1 4} 8 ₄ .

Gelatin contains about 50% carbon, 6.6% hydrogen, 18.3% nitrogen and 25% oxygen. Contains a small amount of phosphate lime and sulfur.

Lime is a material obtained by calcining carbonate rocks (limestone, chalk), consisting mainly of CaO and MdO.

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Sibutramine is a substance with anorexigenic effect.

Sibutramine has the chemical name 1- (4-chlorophenyl) -Y, M-dimethyl-alpha- (2-methylpropyl) cyclobutanemethanamine.

The most commonly used isomer mixture is (±) -1- (4-chlorophenyl) -Y, M-dimethyl-alpha- (2-methylpropyl) cyclobutanemethanamine.

The formulas of sibutramine isomers are as follows:

Sibutramine can form a salt (part of the salt).

In this case, it is said, for example, that sibutramine is in the form of hydrochloride. The name of this substance is as follows: sibutramine hydrochloride monohydrate.

Sibutramine hydrochloride monohydrate has the chemical name monohydrate (±) -1- (4-chlorophenyl) -Y, M-dimethyl-alpha- (2-methylpropyl) cyclobutanemethanammonium chloride.

The formulas of the isomers of sibutramine hydrochloride monohydrate are as follows:

Sibutramine can form other salts (be part of other salts). For example, they say that sibutramine can be in the form of acetate.

The name of this substance is as follows: 1- (4-chlorophenyl) -Y, M-dimethyl-alpha- (2-methylpropyl) cyclobutanemethanammonium acetate.

Other chemical name: cyclobutanemethanamine (as acetate):

(±) -1- (4-chlorophenyl) -Y, M-dimethyl-alpha- (2-methylpropyl) -

In the substance 1- (4-chlorophenyl) -Y, M-dimethyl-alpha- (2-methylpropyl) cyclobutanemethanammonium, 82% subitramine acetate.

In addition, sibutramine can be in solid dosage form as subutramine acetate, subutramine formate, subutramine sulfate, etc.

The present invention is the creation of an effective solid dosage form using sibutramine hydrochloride monohydrate with anorexigenic effect.

In the description claimed four variants of the invention.

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In the first embodiment of the invention, the problem is solved due to the fact that the solid dosage form having anorexigenic effect contains sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate PO ³ - 655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 - 128.0 cobalt 0.0003 - 5.0

In the particular case, the solid dosage form may be in the form of a tablet or in the form of a capsule.

The first embodiment of the invention differs from the prototype in the following set of features: it contains minerals in the following ratio of components in mg / kg:

potassium 0.13-15000.0 iron 0.01 -128.0 cobalt 0.0003 - 5.0

In the second embodiment of the invention, the problem is solved due to the fact that the solid dosage form having anorexigenic effect contains sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate G10 ³ - 65 5 10 ³ sodium 0.15 - 100000.0 potassium 0.13 - 15000.0

calcium 0.16-40500.0 magnesium 15.0-61050.0

iron 0.01 -128.0 cobalt 0.0003 - 5.0 and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total carbon in the solid dosage form is from 0.003 to 0.75.

In the particular case, the solid dosage form may be in the form of a tablet or in the form of a capsule.

The second embodiment of the invention differs from the prototype in the following combination of features: it contains minerals in the following ratio of components in mg / kg:

potassium 0.13-15000.0 iron 0.01 - 128.0 cobalt 0.0003 - 5.0 and the solid dosage form is made in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total carbon in the solid dosage form is from 0.003 to 0.75.

In the third embodiment of the invention, the problem is solved due to the fact that the solid dosage form having anorexigenic effect, contains sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate PO ³ -655 10 ' sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 - 128.0 cobalt 0.0003 - 5.0

- 6 020062 and the solid dosage form is made in such a way that it contains nitrogen isotopes ¹⁵ Ν and the ratio of the amount of nitrogen isotopes ¹ ^ to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.

In the particular case, the solid dosage form may be in the form of a tablet or in the form of a capsule.

The third embodiment of the invention differs from the prototype in the following combination of features: it contains minerals in the following ratio of components in mg / kg:

potassium 0.13-15000.0 iron 0.01 - 128.0 cobalt 0.0003 - 5.0 and the solid dosage form is made in such a way that it contains ¹ ^ nitrogen isotopes and the ratio of ¹ ^ nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.

In the fourth embodiment of the invention, the problem is solved due to the fact that the solid dosage form having anorexigenic effect, contains sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate G10 ³ - 65 5 10 ³ sodium 0.15 - 100000.0 potassium 0.13 - 15000.0

calcium 0.16 - 40500.0 magnesium 15.0-61050.0

iron 0.01 - 128.0 cobalt 0.0003 - 5.0 and the solid dosage form is made in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total carbon in the solid dosage form is from 0.003 to 0.75; and ¹ ^ nitrogen isotopes and the ratio of the amount of ¹ ^ nitrogen isotopes to the total amount of nitrogen in solid dosage form is from 0.0001 to 0.1375.

In the particular case, the solid dosage form may be in the form of a tablet or in the form of a capsule.

The fourth embodiment of the invention differs from the prototype in the following set of features: it contains minerals in the following ratio of components in mg / kg:

potassium 0.13-15000.0 iron 0.01 - 128.0 cobalt 0.0003 - 5.0 and the solid dosage form is made in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total carbon in the solid dosage form is from 0.003 to 0.75; and nitrogen isotopes ¹⁵ Ν and the ratio of the number of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is from 0.0001 to 0.1375.

The technical results of each of the four variants of the invention are:

an increase in the therapeutic effect (decrease in body weight or a decrease in the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity;

reduction of the onset of the therapeutic effect of the use of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity.

In the particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can be set in narrower ranges of values in mg / kg:

sodium 0.15 - 50700.0 potassium 0.13 - 7000.0 calcium 0.16 - 23050.0 magnesium 0.15 - 25800.0 iron 0.01 - 110.0 cobalt 0.0003 - 4.1

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In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 0.15 - 15000.0 potassium 0.13 - 1300.0 calcium 0.16 - 12050.0 magnesium 0.15 - 18600.0 iron 0.01 - 98.5 cobalt 0.0003 - 3.0

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 0.15 - 1700.0 potassium 0.13 - 570.0 calcium 0.16 - 3700 magnesium 0.15 - 6500 iron 0.01 - 57.0 cobalt 0.0003 - 2.5

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 0.15 - 250.0 potassium 0.13 - 85.0 calcium 0.16 - 500.0 magnesium 0.15 - 1000.0 iron 0.01 - 15.8 cobalt 0.0003 - 1.5

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 0.15 - 100.0 potassium 0.13 - 25.0 calcium 0.16 - 250.0 magnesium 0.15 - 550.0 iron 0.01 - 5.0 cobalt 0.0003 - 1.0

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 1.0 - 50700.0 potassium 0.3 - 7000.0 calcium 0.5 - 23050.0 magnesium 0.7 - 25800.0 iron 0.05 - 110.0 cobalt 0.001 - 4.1

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

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sodium 1.0 - 15000.0 potassium 0.3 - 1300.0 calcium 0.5 - 12050.0 magnesium 0.7 - 18600.0 iron 0.05 - 98.5 cobalt 0.001 - 3.0

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 1.0 - 1700.0 potassium 0.3 - 570.0 calcium 0.5 - 3700 magnesium 0.7 - 6500 iron 0.05 - 57.0 cobalt 0.001 - 2.5

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 1.0 - 250.0 potassium 0.3 - 85.0 calcium 0.5 - 500.0 magnesium 0.7 - 1000.0 iron 0.05 - 15.8 cobalt 0.001 - 1.5

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 1.0 - 100.0 potassium 0.3 - 25.0 calcium 0.5 - 250.0 magnesium 0.7 - 550.0 iron 0.05 - 5.0 cobalt 0.001 - 1.0

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 5.0 - 50700.0 potassium 1.3 - 7000.0 calcium 12.5 - 23050.0 magnesium 5.75 - 25800.0 iron 0.1 - 110.0 cobalt 0.025 - 4.1

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

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sodium 5.0 - 15000.0 potassium 1.3 - 1300.0 calcium 12.5 - 12050.0 magnesium 5.75 - 18600.0 iron 0.1 - 98.5 cobalt 0.025 - 3.0

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 5.0 - 1700.0 potassium 1.3 - 570.0 calcium 12.5 - 3700 magnesium 5.75 - 6500 iron 0.1 - 57.0 cobalt 0.025 - 2.5

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 5.0 - 250.0 potassium 1.3 - 85.0 calcium 12.5 - 500.0 magnesium 5.75 - 1000.0 iron 0.1 - 15.8 cobalt 0.025 - 1.5

In another particular case of the implementation of the first, second, third and fourth variants of the invention, the content of mineral substances in solid dosage form can also be set in narrower ranges of values in mg / kg:

sodium 5.0 - 100.0 potassium 1.3 - 25.0 calcium 12.5 - 250.0 magnesium 5.75 - 550.0 iron 0.1 - 5.0 cobalt 0.025 - 1.0

The narrower ranges of mineral values given above can be selected for different groups of patients (children, pregnant women, etc.).

This provides:

an increase in the therapeutic effect (decrease in body weight or a decrease in the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity;

reduction of the onset of the therapeutic effect.

In the particular case of the implementation of the first, second, third and fourth variants of the invention, the content of sibutramine hydrochloride monohydrate in solid dosage form can be set in a narrower range of values.

The solid dosage form, hydrochloride monohydrate having 1 -10 ³ -655-10 ³ mg / kg.

The solid dosage form, hydrochloride monohydrate having 1 -10 ³ -350-10 ³ mg / kg.

The solid dosage form, hydrochloride monohydrate having 1 -10 ³ -250-10 ³ mg / kg.

The solid dosage form, hydrochloride monohydrate having 1 -10 ³ -150-10 ³ mg / kg.

A solid dosage form having anorexigenic anorexigenic anorexigenic anorexigenic anorexigenic effect, action, action, action, action, contains contains contains contains sibutramine sibutramine sibutramine sibutramine sibutramine

- 10 020062 anorexigenic anorexigenic anorexigenic anorexigenic action, action, action, action, contains contains contains sibutramine sibutramine sibutramine sibutramine hydrochloride monohydrate 1 -10 ³ -105-10 ³ mg / kg.

The solid dosage form having one hydrochloride monohydrate -95-10 -10 ^{3 3} mg / kg.

The solid dosage form having one hydrochloride monohydrate -55-10 -10 ^{3 3} mg / kg.

Solid dosage form having a hydrochloride monohydrate 25-10 ³ -655-10 ³ mg / kg

Solid dosage form having a hydrochloride monohydrate 25-10 ³ -105-10 ³ mg / kg

In the particular case of the implementation of the second and fourth variants of the invention, the content of carbon isotopes ¹³ C in solid dosage form can be set in a narrower range of values. Described this may be so.

The solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total carbon in the solid dosage form is from 0.003 to 0.55.

The solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of the ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.25.

The solid dosage form is made in such a way that it contains ¹³ C carbon isotopes and the ratio of the ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.1.

The solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.05.

The solid dosage form is made in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total carbon in the solid dosage form is from 0.003 to 0.025.

The solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of the ¹³ C carbon isotopes to the total carbon in the solid dosage form is from 0.003 to 0.015.

In the particular case of the implementation of the third and fourth variants of the invention, the content of nitrogen isotopes ¹⁵ N in solid dosage form can be set in a narrower range of values. Described this may be so.

The solid dosage form is designed in such a way that it contains ¹⁵ N nitrogen isotopes and the ratio of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1.

The solid dosage form is designed in such a way that it contains ¹⁵ N nitrogen isotopes and the ratio of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.09.

The solid dosage form is designed in such a way that it contains ¹⁵ N nitrogen isotopes and the ratio of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.05.

The solid dosage form is designed in such a way that it contains ¹⁵ N nitrogen isotopes and the ratio of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.03.

The solid dosage form is made in such a way that it contains ¹⁵ N nitrogen isotopes and the ratio of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.015.

The solid dosage form is designed in such a way that it contains ¹⁵ N nitrogen isotopes and the ratio of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.0137.

In order to increase the content of carbon and nitrogen in solid dosage form, it is advisable to increase the content of pharmaceutically acceptable carbon-containing and nitrogen-containing auxiliary substances.

As indicated above (to simplify the description and ordering of terms), we call sibutramine hydrochloride monohydrate as the main active substance. All other substances in the solid dosage form will be called pharmaceutically acceptable additional substances.

Pharmaceutically acceptable additional substances may be:

a pharmaceutically acceptable excipient;

a pharmaceutically acceptable carbonaceous excipient;

a pharmaceutically acceptable carbonaceous adjuvant;

- 11 020062 pharmaceutically acceptable carbon-containing additional substances with mineral substances;

a pharmaceutically acceptable nitrogen-containing excipient;

pharmaceutically acceptable nitrogen-containing additional substance;

pharmaceutically acceptable nitrogen-containing additional substances with mineral substances;

cellulose;

microcrystalline cellulose;

calcium stearate;

metal oxides (in particular magnesium oxide; titanium dioxide);

aerosil;

povidone;

magnesium basic carbonate;

talc;

mineral substances (in particular, sodium, calcium, etc.);

pharmaceutically acceptable dye or pharmaceutically acceptable dyes; dye azorubine;

patented blue dye;

gelatin and others

If the substance is a pharmaceutically unacceptable substance for the solid dosage form in question, then such a substance is not used in the dosage form.

In the particular case of the implementation of the first embodiment of the invention, the solid dosage form having anorexigenic effect can be made in the form of a tablet or capsule containing sibutramine hydrochloride monohydrate, pharmaceutically acceptable salts of mineral substances or pharmaceutically acceptable additional substances, while at least part of the pharmaceutically acceptable additional substances contain minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate pharmaceutically acceptable additional substances the rest while the content of mineral substances in solid dosage form in mg / kg:

10 ³ -655 10 ³

sodium 0.15-100000.0 potassium 0.13 -15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0

In the particular case of the implementation of the first embodiment of the invention, the solid dosage form having anorexigenic effect can be made in the form of a tablet or capsule containing sibutramine hydrochloride monohydrate, pharmaceutically acceptable salts of mineral substances or pharmaceutically acceptable additional substances, while at least part of the pharmaceutically acceptable additional substances contain pharmaceutically acceptable salts of minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate pharmaceutically acceptable additional substances the rest while the content of mineral substances in solid dosage form in mg / kg:

G1O ³ -655 1O ³

sodium 0.15-100000.0 potassium 0.13 -15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0

As indicated above, mineral substances in solid dosage form may be present in pharmaceutically acceptable salts.

In addition, minerals in solid dosage form can be present in pharmaceutically acceptable oxides, as well as in various pharmaceutically acceptable complex compounds.

- 12 020062

In the particular case of the second embodiment of the invention, the solid dosage form having anorexigenic effect can be in the form of a tablet or capsule containing sibutramine hydrochloride monohydrate, pharmaceutically acceptable salts of mineral substances or pharmaceutically acceptable additional substances, with at least a portion of pharmaceutically acceptable additional substances contain minerals in the following ratio of components in mg / kg:

with sibutras on hydrochloride monohydrate G10 ³ - 65 5 10 ³ pharmaceutically acceptable additional substances; the rest is the content of mineral substances in solid dosage form in mg / kg:

sodium 0.15-100000.0 potassium 0.13 -15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75.

In the particular case of the second embodiment of the invention, the solid dosage form having anorexigenic effect can be in the form of a tablet or capsule containing sibutramine hydrochloride monohydrate, pharmaceutically acceptable salts of mineral substances or pharmaceutically acceptable additional substances, with at least a portion of pharmaceutically acceptable additional substances contain pharmaceutically acceptable salts of minerals in the following ratio of components in mg / kg:

with sibutras on hydrochloride monohydrate G10 ³ - 65 5 10 ³ pharmaceutically acceptable additional substances; the rest is the content of mineral substances in solid dosage form in mg / kg:

sodium 0.15-100000.0 potassium 0.13 -15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0

And the solid dosage form is made in such a way that it contains ¹³ C carbon isotopes and the ratio of the ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75.

As indicated above, mineral substances in solid dosage form may be present in pharmaceutically acceptable salts.

In addition, minerals in solid dosage form can be present in pharmaceutically acceptable oxides, as well as in various pharmaceutically acceptable complex compounds.

In the particular case of the implementation of the third embodiment of the invention, the solid dosage form having anorexigenic effect can be made in the form of a tablet or capsule containing sibutramine hydrochloride monohydrate, pharmaceutically acceptable salts of mineral substances or pharmaceutically acceptable additional substances, while at least part of the pharmaceutically acceptable additional substances contain minerals in the following ratio of components in mg / kg:

with sibutras on hydrochloride monohydrate G10 ³ - 65 5 10 ³ pharmaceutically acceptable additional substances; the rest is the content of mineral substances in solid dosage form in mg / kg:

- 13 020062

sodium 0.15-100000.0 potassium 0.13 -15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0

And the solid dosage form is made in such a way that it contains nitrogen isotopes ¹⁵ N and the ratio of the number of nitrogen isotopes ¹⁵ N to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.

In the particular case of the implementation of the third embodiment of the invention, the solid dosage form having anorexigenic effect can be made in the form of a tablet or capsule containing sibutramine hydrochloride monohydrate, pharmaceutically acceptable salts of mineral substances or pharmaceutically acceptable additional substances, while at least part of the pharmaceutically acceptable additional substances contain pharmaceutically acceptable salts of minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate pharmaceutically acceptable additional substances the rest while the content of mineral substances in solid dosage form in mg / kg:

ΓΙΟ ³ - 655 ΊΟ ³

sodium 0.15-100000.0 potassium 0.13 -15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0

And the solid dosage form is made in such a way that it contains nitrogen isotopes ¹⁵ N and the ratio of the number of nitrogen isotopes ¹⁵ N to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.

As indicated above, mineral substances in solid dosage form may be present in pharmaceutically acceptable salts.

In addition, minerals in solid dosage form can be present in pharmaceutically acceptable oxides, as well as in various pharmaceutically acceptable complex compounds.

In the particular case of the fourth embodiment of the invention, the solid dosage form having anorexigenic effect can be in the form of a tablet or capsule containing sibutramine hydrochloride monohydrate, pharmaceutically acceptable salts of mineral substances or pharmaceutically acceptable additional substances, with at least a portion of pharmaceutically acceptable additional substances contain minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate pharmaceutically acceptable additional substances the rest while the content of mineral substances in solid dosage form in mg / kg:

ΓΙΟ ³ -655 10 ³

sodium 0.15-100000.0 potassium 0.13 -15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 -128.0 cobalt 0.0003 - 5.0

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75; and nitrogen isotopes ¹⁵ N and the ratio of the number of nitrogen isotopes ¹⁵ N to the total amount of nitrogen in solid dosage form is from 0.0001 to 0.1375.

In the particular case of the implementation of the fourth embodiment of the invention, the solid dosage form having anorexigenic effect can be made in the form of a tablet or capsule containing

14 020062 sibutramine hydrochloride monohydrate, pharmaceutically acceptable salts of mineral substances or pharmaceutically acceptable additional substances, while at least part of the pharmaceutically acceptable additional substances contain pharmaceutically acceptable salts of mineral substances in the following ratio of components in mg / kg:

with sibutras on hydrochloride monohydrate G10 ³ - 65 5 10 ³ pharmaceutically acceptable additional substances; the rest is the content of mineral substances in solid dosage form in mg / kg:

sodium 0.15-100000.0 potassium 0.13 -15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75; and nitrogen isotopes ¹⁵ Ν and the ratio of the number of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is from 0.0001 to 0.1375.

As indicated above, mineral substances in solid dosage form may be present in pharmaceutically acceptable salts.

In addition, minerals in solid dosage form can be present in pharmaceutically acceptable oxides, as well as in various pharmaceutically acceptable complex compounds.

Mineral substances (Eg, Ζη, etc.) in solid dosage form can be contained in pharmaceutically acceptable oxides, pharmaceutically acceptable salts, for example succinates, chlorides, carbonates or sulfates, as well as in various pharmaceutically acceptable complex compounds.

In the particular case of the invention, the solid dosage form can be made in such a way that tropeolin and / or tartrazine and / or calcium stearate and / or magnesium carbonate are used as a pharmaceutically acceptable carbon-containing additional substance.

The dimension mg / kg, related to the elements of the solid dosage form, means their content (in mg) in 1 kg of solid dosage form.

A solid dosage form in the form of a tablet may contain a shell. The shell can be made using the following substances: Opadry II white, talc, titanium dioxide, polyvinyl alcohol or other pharmaceutically acceptable substances.

The technical results of the invention are:

an increase in the therapeutic effect (reduction in body weight or a decrease in the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity. Strengthening the effects of sibutramine hydrochloride monohydrate;

reducing the time of the onset of the therapeutic effect of using sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity, which can significantly expand the possibilities of using the claimed solid dosage forms. It will take less time from the moment you take the solid dosage form with sibutramine hydrochloride monohydrate to the time you start eating. This is important when taking the medicine in the morning before breakfast.

The developed solid dosage form can be used in the treatment of the same diseases for the treatment of which the drug Reduxin, G oldline and their analogues are used.

An additional technical result may be an increase in the shelf life of the claimed solid dosage forms with sibutramine hydrochloride monohydrate, compared with the prototype, at temperatures of 26-30 ° C and above, which was established experimentally.

The prototype (as well as the analogues of Reduxin and Goldline) retained the stability of properties at a temperature of 26 ° C for 2.7 years, at a temperature of 27 ° C for 2 years, at a temperature of 30 ° C for 1.5 years.

The preparations made according to the invention maintained their stability at a temperature of 26 ° C for 3.5 years, at a temperature of 27 ° C for 3 years, at a temperature of 30 ° C for 2.5 years.

Currently, an increase in the onset of the therapeutic effect is provided by the dosage of the drug and the time of its effect;

the introduction into the dosage form of an auxiliary ingredient - an accelerator of the speed of exposure (a special case of a regulator of the speed of exposure);

proactive (preventive) use of the drug.

- 15 020062

Here are some examples.

It is known that the drug Reduxin must be administered 1 hour before the onset of action.

A known dosage form (application KI 94015245, published 12/27/1995), in which a 5-10% solution of hyaluronic acid is used as a regulator of the speed of exposure.

Known pacemaker drug (patent KI 2068697, published 10.11.1996), containing the poison of green toad, chlorobutane dihydrate, sodium chloride and water. To increase the onset of the pacemaker effect (while maintaining the duration of action) provided by the specified poison, up to 95% ethyl alcohol is introduced into the drug. Alcohol due to osmotic phenomena causes pain and local negative reaction, which accelerates the effect of the drug.

Biologically active additives are known which, when introduced together with the active principle, increase the pharmacological activity of therapeutic drugs by optimizing the rate of assimilation of the active principle. So, polyvinylpyrrolidone and sorbic acid are additionally introduced into the antitumor agent (AS USSR No. 1683190, publ. 20.04.1995). These components increase the antitumor activity of the active principle.

In the invention, a reduction in the time of the onset of the therapeutic effect (increase in the speed of the onset of the therapeutic effect) is achieved while maintaining the duration of action without increasing the concentration of the main active substance due to the introduction of mineral substances into the solid dosage form, as well as ¹³ C and ¹⁵ из isotopes.

Below is the well-known information about minerals.

Minerals are subdivided into macro- and microelements.

Macronutrients include calcium, phosphorus, magnesium, potassium, sodium, chlorine and sulfur.

Trace elements iron, copper, manganese, zinc, cobalt, iodine, fluorine, chromium, molybdenum, vanadium, nickel, strontium, silicon, selenium are recognized as essential for human and animal life.

It is known that macronutrients regulate water-salt metabolism, maintain osmotic pressure in cells and intercellular fluids, which is necessary for the movement of nutrients and drugs between them. Blood formation processes occur with the participation of iron, copper, manganese, calcium and other mineral substances (elements). Minerals (trace elements) activate the action of enzymes, hormones, participate in all types of metabolism.

Minerals in solid dosage form are found in pharmaceutically acceptable oxides, pharmaceutically acceptable salts, for example succinates, chlorides, carbonates or sulfates, as well as in various pharmaceutically acceptable complex compounds.

Minerals have an antimicrobial effect by inactivating the enzymes necessary for the functioning of microorganisms. Enzyme inactivation occurs through the interaction of metal ions with sulfhydryl groups of enzymes.

Metals have a pronounced local effect on the mucous membranes. At the concentrations of mineral substances considered in the application, the local action of these substances may be astringent or irritating.

The mechanism of local action of metals is due to their ability to react with tissue proteins. As a result of this interaction, proteins coagulate and form albuminates with metal ions. Moreover, if partial coagulation of proteins occurs only in the surface layers of tissues, an astringent or irritating effect is observed that is reversible.

The studies carried out during the development of the application for the invention showed that mineral substances (a strictly defined list of mineral substances in strictly limited ranges) included in the solid dosage form with sibutramine hydrochloride monohydrate increase (enhance) its therapeutic effect, i.e. enhance the therapeutic effect of the use of the main active substance.

For all variants of solid dosage forms considered in the invention, the rational ranges of the values of the content of mineral substances are as follows in mg / kg:

sodium 0.15-100000.0 potassium 0.13 -15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0

When developing the invention, the achievement of technical results was established:

an increase in the therapeutic effect (decrease in body weight or a decrease in the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity;

reduction of the onset of the therapeutic effect;

- 16 020062 increasing the stability of the solid dosage form with sibutramine hydrochloride monohydrate over the shelf life at temperatures of 26-30 ° C and above is ensured by the introduction of certain minerals (a certain combination of minerals) in a solid quantity strictly defined for each mineral in the solid dosage form. As a result of the research, a weight range in solid dosage form was established for each mineral.

The use of less than indicated in the range, the amount of mineral substance does not lead to the achievement of technical results. The use of a larger amount of a mineral substance than indicated in the range not only does not lead to the achievement of technical results, but in some cases worsens the therapeutic effect of the action of sibutramine hydrochloride monohydrate. It was found that with an increase in the concentration of mineral substances in solid dosage form (above the stated ranges), they suppress the effect of sibutramine hydrochloride monohydrate, i.e. the therapeutic effect of sibutramine hydrochloride monohydrate disappears.

Additional increase therapeutic effect, reduce the time onset of therapeutic effect without increasing the concentration of the main active ingredient in a solid dosage form provided by the partial replacement of a solid dosage form of carbon isotope ¹² C in carbon isotopes ¹³ C and partial substitution of isotopes for ¹⁴ Ν isotopes ¹⁵ Ν.

List of figures, drawings and other materials

In FIG. 1 shows the graphs of weight gain of rats depending on the solid dosage form.

In FIG. 2 shows weight gain charts for obese rats taken with the solid dosage form.

In FIG. Figure 3 shows the scheme of a cavitation reactor for isotopic enrichment of various mixtures.

In FIG. 4 shows a cross section of a cavitation reactor.

In FIG. 5 is a diagram of an isotope enrichment facility.

In FIG. 6 shows graphs of the dependence of the weight of the eaten food by rats depending on the time of administration of the solid dosage form.

Information confirming the possibility of carrying out the invention

The invention is illustrated by the examples below.

Example 1 - a method of introducing minerals into water (into a solution).

Example 2 - a method of obtaining a solid dosage form and verification of stability.

Example 3 - tests of solid dosage forms for general toxicity.

Example 4 illustrates the action of the prototype.

Examples 5-8 illustrate the effect of the claimed solid dosage forms.

Example 1

The introduction of mineral substances into the solution (into water) was carried out according to the method described in the Guide to methods for monitoring the quality and safety of biologically active food additives. - M .: Federal Center for Sanitary Inspection of the Ministry of Health of Russia, 2004, - 240 p.

It should be noted that there are other ways of introducing mineral substances into the solution.

Solutions were prepared from pure metals using pharmaceutically acceptable solvents to ensure storage stability of the solutions.

To conduct in-depth studies when developing an application for the invention, metal concentrations in each of the four variants of the invention were provided in the following ranges in mg / kg:

sodium 0.05 - 140,000 potassium 0.05 - 20,000 calcium 0.05 - 67000 magnesium 0.05 - 95,000 iron 0.008 - 300.0 cobalt 0.00006 - 19.0

The concentration of metals in solutions was controlled by the atomic absorption method for determining the contents of sodium, potassium, calcium, magnesium, iron, manganese, copper, zinc, lead, cadmium, cobalt, nickel, and chromium. [Guidance on methods for monitoring the quality and safety of dietary supplements. - M .: Federal Center for State Sanitary and Epidemiological Supervision of the Ministry of Health of Russia, 2004, - 240 p., Clause 1.3.2.1].

After the introduction of mineral substances into the solvent, solid dosage forms were prepared on its basis by known methods.

- 17 020062

Example 2

The claimed solid dosage form (capsule) was prepared as follows. The solvent with minerals was mixed with the main active ingredient (sibutramine hydrochloride monohydrate), if necessary, with pharmaceutically acceptable (s) additional (s) substance (s).

As pharmaceutically acceptable additional substances used, in particular, microcrystalline cellulose, calcium stearate.

If necessary, the resulting solution was processed in a reactor for the purpose of isotope enrichment. The isotope enrichment method will be described below. After that, the resulting composition was dried to obtain a powder. Then the powder was placed in capsules with a specific dosage. Capsules were made using gelatin, dyes (titanium dye dye; azorubine dye, patented blue dye).

The claimed solid dosage form (tablet) is made by compressing a tableted mixture - the main active ingredient (sibutramine hydrochloride monohydrate) and pharmaceutically acceptable additional substances.

To give additional properties, the desired shape and weight, pharmaceutically acceptable additional substances were introduced into the tablet, in particular mineral substances, potato starch, aerosil, sugar, a pharmaceutically acceptable excipient, in particular talc, etc.

Excipients affect the rate of release, the rate and completeness of absorption of the main active ingredient and other pharmaceutically acceptable additional substances.

If necessary, before tableting (at the stage of work with the solution), the resulting solution was processed in the reactor for the purpose of isotope enrichment. The isotope enrichment method will be described below.

The control showed the qualitative performance of solid dosage forms in the form of capsules and in the form of tablets.

Similarly, other solid dosage forms with minerals described in the patent were obtained.

Conducted stability studies have shown that the solid dosage forms thus obtained are stable and retain their initial values when stored for 4 years at temperatures up to 25 ° C.

In addition, it provides increased shelf life of the claimed solid dosage forms with sibutramine hydrochloride monohydrate, compared with the prototype, at temperatures of 26-30 ° C and above.

As mentioned above, the solid dosage forms made according to the invention maintained their stability at a temperature of 26 ° C for 3.5 years, at a temperature of 27 ° C for 3 years, at a temperature of 30 ° C for 2.5 years.

Example 3

Tests for general toxicity were carried out by oral administration of a solution obtained from a solid dosage form based on sibutramine hydrochloride monohydrate and minerals to rats. In solid dosage form, 75% of the carbon isotopes of ¹³ C and 13.75% of nitrogen isotopes of ¹⁵ обеспеч were provided.

For studies of the concentration of mineral substances in solid dosage form selected in mg / kg:

sodium 0.05 - 140,000 potassium 0.05 - 20,000 calcium 0.05 - 67000 magnesium 0.05 - 95,000 iron 0.008 - 300.0 cobalt 0.00006 - 19.0

LI ₅₀ is approximately 3800 mg / kg of rat weight. The tests carried out allow us to attribute the claimed solid dosage forms in the applicable doses (0.0001-4% or less from LI ₅₀ ) to non-toxic substances.

With prolonged use of a solid dosage form based on sibutramine hydrochloride monohydrate and minerals in rats, no changes in the organs and tissues of the body were detected.

LI ₅₀ - the average dose of a substance based on sibutramine hydrochloride monohydrate and minerals, causing the death of half of the individuals of the test group.

- 18 020062

Example 4

The effectiveness of the prototype is illustrated in FIG. one.

Curve 36 is the upper bound for weight gain in rats (with an initial weight of 330-340 g), obese depending on the time of feeding. Feeding conditions - the constant availability of food, attractive to rats, rich in fats.

Sibutramine hydrochloride monohydrate was not used.

Curve 35 is the lower bound for weight gain in rats (with an initial weight of 230-250 g) suffering from malnutrition depending on the time of feeding. Feeding conditions - the constant availability of food, attractive to rats, rich in fats.

Sibutramine hydrochloride monohydrate was not used.

Dependence of weight gain in rats (with an initial weight of 330-340 g), obese depending on the time of feeding, passes through region 34, near curve 36.

Sibutramine hydrochloride monohydrate was not used.

Dependence of weight gain in rats (with an initial weight of 230-250 g) suffering from depletion depending on the feeding time passes through region 34, near curve 35.

Sibutramine hydrochloride monohydrate was not used.

Curve 38 is the upper bound for weight gain in rats (with an initial weight of 330-340 g), obese depending on the time of feeding. Feeding conditions - the constant availability of food, attractive to rats, rich in fats.

In the experiments, the prototype was used with sibutramine hydrochloride monohydrate at a dose of 0.0003 mg / g, 1 hour before the start of feeding.

Curve 39 is the lower bound of weight gain in rats (with an initial weight of 230-250 g) suffering from malnutrition depending on the time of feeding.

Feeding conditions - the constant availability of food, attractive to rats, rich in fats and animal proteins.

In the experiments, the prototype was used with sibutramine hydrochloride monohydrate at a dose of 0.0003 mg / g, 1 hour before the start of feeding, once a day.

All experimental dependences of weight gain in rats with an initial weight of 230-250 g and 330-340 g depending on the feeding time pass through region 37.

In the experiments, the prototype was used with sibutramine hydrochloride monohydrate at a dose of 0.0003 mg / g, 1 hour before the start of feeding.

An increase in the dose of sibutramine hydrochloride monohydrate in the prototype from 0.0003 to 0.0004 mg / g shifts the curves of weight gain in rats from feeding time down to curve 35. Further increase in the dose of sibutramine hydrochloride monohydrate over 0.0004 mg / g did not increase the effect.

In FIG. 1 shows a region 40 bounded by curves 39 and 41, through which the curves of weight gain versus time pass in rats taking solid dosage forms with sibutramine hydrochloride monohydrate, minerals enriched with ¹³ C carbon isotopes and nitrogen isotopes N.

Example 5 illustrates the effect of the claimed solid dosage forms with minerals and the content of sibutramine hydrochloride monohydrate 1 g / kg

In the table. 2 shows the mineral compositions of solid dosage forms without the use of carbon isotopes ¹³ C and nitrogen isotopes Ά

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 1 and 6 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

In FIG. 2 shows an enlarged fragment of FIG. one.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 7 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 5 does not differ from the action of the solid dosage form with serial number 4. Therefore, its use is impractical.

Admission to rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 43 (near the upper boundary).

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through area 44 (near the upper border).

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through area 45 (near the upper border).

- 19 020062

In the table. 3 shows the mineral compositions of solid dosage forms using ¹³ C carbon isotopes. The ratio of ¹³ C carbon isotopes to total carbon in solid dosage forms is 0.003.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 8 and 13 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 14 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 12 does not differ from the action of the solid dosage form with serial number 11. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 43 (between the upper boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 44 (between the upper boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 45 (between the upper boundary and the center of the region).

In the table. 4 shows the mineral compositions of solid dosage forms using isotopes of nitrogen ¹⁵ S. The ratio of the amount of nitrogen isotopes ¹⁵ N to the total amount of nitrogen in solid dosage form is 0.0001.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 15 and 20 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 21 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 19 does not differ from the action of the solid dosage form with serial number 18. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 43 (between the upper boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 44 (between the upper boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 45 (between the upper boundary and the center of the region).

In the table. 5 shows the mineral compositions of solid dosage forms using ¹³ C carbon isotopes and ¹⁵ N nitrogen isotopes. The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.003. The ratio of the amount of nitrogen isotopes ¹⁵ N to the total amount of nitrogen in solid dosage form is 0.0001.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 22 and 27 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 28 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 26 does not differ from the action of the solid dosage form with serial number 25. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 43 (through the center of the region).

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 44 (through the center of the region).

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 45 (through the center of the region).

- 20 020062

In the table. 6 shows the mineral compositions of solid dosage forms using ¹³ C carbon isotopes. The ratio of ¹³ C carbon isotopes to the total carbon in solid dosage form is 0.75.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 29 and 34 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 35 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 33 does not differ from the action of the solid dosage form with serial number 32. Therefore, its use is impractical.

Admission to rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 43 (between the lower boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 44 (between the lower boundary and the center of the region).

Admission to rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 45 (between the lower boundary and the center of the region).

In the table. 7 shows the mineral compositions of solid dosage forms using isotopes of nitrogen ¹⁵ S. The ratio of the amount of nitrogen isotopes ¹⁵ N to the total amount of nitrogen in solid dosage form is 0.1375.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 36 and 41 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 42 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 40 does not differ from the action of the solid dosage form with serial number 39. Therefore, its use is impractical.

Admission to rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 43 (between the lower boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 44 (between the lower boundary and the center of the region).

Admission to rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 45 (between the lower boundary and the center of the region).

In the table. Figure 8 shows the mineral compositions of solid dosage forms using ¹³ C carbon isotopes and ¹⁵ N nitrogen isotopes. The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.75. The ratio of the amount of nitrogen isotopes ¹⁵ N to the total amount of nitrogen in solid dosage form is 0.1375.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 43 and 48 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 49 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 47 does not differ from the action of the solid dosage form with serial number 46. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 43 (near the lower boundary of the region).

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 44 (near the lower boundary of the region).

Reception rats with an initial weight of 330-340 g of a solid dosage form with a serial number ensures the passage of the curve of the dependence of weight gain on time through region 45 (near the lower boundary of the region).

- 21 020062

Example 5 confirms an increase in the therapeutic effect, namely, a decrease in body weight, a decrease in the rate of increase in body weight, while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate during treatment, as well as in the prevention of obesity.

Example 6 illustrates the effect of the claimed solid dosage forms with minerals and a sibutramine hydrochloride monohydrate content of 33 g / kg.

In the table. 9 shows the mineral compositions of solid dosage forms without the use of carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 11 and 61 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

In FIG. 2 shows an enlarged fragment of FIG. one.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 71 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 51 does not differ from the action of the solid dosage form with serial number 41. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 21 provides the passage of the curve of the dependence of weight gain on time through region 43 (near the upper border).

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 31 provides the passage of the curve of the dependence of weight gain on time through region 44 (near the upper border).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 41 provides the passage of the curve of the dependence of weight gain on time through area 45 (near the upper border).

In the table. 10 shows the mineral compositions of solid dosage forms using ¹³ C carbon isotopes. The ratio of ¹³ C carbon isotopes to total carbon in solid dosage forms is 0.003.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 81 and 131 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 141 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 121 does not differ from the action of the solid dosage form with serial number 111. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 91 provides the passage of the curve of the dependence of weight gain on time through region 43 (between the upper boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 101 provides the passage of the curve of the dependence of weight gain on time through region 44 (between the upper boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 111 provides the passage of the curve of the dependence of weight gain on time through region 45 (between the upper boundary and the center of the region).

In the table. 11 shows the mineral compositions of solid dosage forms using nitrogen isotopes ¹⁵ Ν. The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.0001.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 151 and 201 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 211 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 191 does not differ from the action of the solid dosage form with serial number 181. Therefore, its use is inappropriate.

Admission to rats with an initial weight of 330-340 g of solid dosage form with serial number

161 provides the passage of the curve of the dependence of weight gain on time through region 43 (between the upper boundary and the center of the region).

Admission to rats with an initial weight of 330-340 g of solid dosage form with serial number

171 provides the passage of the curve of the dependence of weight gain on time through region 44 (between the upper boundary and the center of the region).

- 22 020062

Admission to rats with an initial weight of 330-340 g of solid dosage form with serial number

181 provides the passage of the curve of the dependence of weight gain on time through region 45 (between the upper boundary and the center of the region).

In the table. 12 shows the mineral compositions of solid dosage forms using carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν. The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.003. The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.0001.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 221 and 271 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 281 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 261 does not differ from the action of the solid dosage form with serial number 251. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 231 provides the passage of the curve of the dependence of weight gain on time through region 43 (through the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 241 provides the passage of the curve of the dependence of weight gain on time through region 44 (through the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 251 provides the passage of the curve of the dependence of weight gain on time through region 45 (through the center of the region).

In the table. 13 shows the mineral compositions of solid dosage forms using ¹³ C carbon isotopes. The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.75.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 291 and 341 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 351 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 331 does not differ from the action of the solid dosage form with serial number 321. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 301 ensures the passage of the curve of the dependence of weight gain on time through region 43 (between the lower boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 311 provides the passage of the curve of the dependence of weight gain on time through region 44 (between the lower boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 321 provides the passage of the curve of the dependence of weight gain on time through region 45 (between the lower boundary and the center of the region).

In the table. 14 shows the mineral compositions of solid dosage forms using nitrogen isotopes ¹⁵ Ν. The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.1375.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 361 and 411 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 421 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 401 does not differ from the action of the solid dosage form with serial number 391. Therefore, its use is impractical.

Admission to rats with an initial weight of 330-340 g of solid dosage form with serial number

371 provides the passage of the curve of the dependence of weight gain on time through the region 43 (between the lower boundary and the center of the region).

Admission to rats with an initial weight of 330-340 g of solid dosage form with serial number

381 provides the passage of the curve of the dependence of weight gain on time through region 44 (between the lower boundary and the center of the region).

- 23 020062

Admission to rats with an initial weight of 330-340 g of solid dosage form with serial number

391 provides the passage of the curve of the dependence of weight gain on time through the region 45 (between the lower boundary and the center of the region).

In the table. 15 shows the mineral compositions of solid dosage forms using ¹³ C carbon isotopes and ¹⁵ азота nitrogen isotopes. The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.75. The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.1375.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 431 and 481 provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 491 provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 471 does not differ from the action of the solid dosage form with serial number 461. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 441 provides the passage of the curve of the dependence of weight gain on time through region 43 (near the lower boundary of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 451 provides the passage of the curve of the dependence of weight gain on time through region 44 (near the lower boundary of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 461 provides the passage of the curve of the dependence of weight gain on time through region 45 (near the lower boundary of the region).

Example 6 confirms the increase in the therapeutic effect, namely, a decrease in body weight, a decrease in the rate of increase in body weight, while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate during treatment, as well as in the prevention of obesity.

Example 7 illustrates the effect of the claimed solid dosage forms with minerals and a sibutramine hydrochloride monohydrate content of 655 g / kg.

In the table. 16 shows the mineral compositions of solid dosage forms without the use of carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 1ίί and 6ίί provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

In FIG. 2 shows an enlarged fragment of FIG. one.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 7ίί provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 5ίί does not differ from the action of the solid dosage form with serial number 4ίί. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 2ίί provides the passage of the curve of the dependence of weight gain on time through area 43 (near the upper border).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 3ίί provides the passage of the curve of the dependence of weight gain on time through area 44 (near the upper border).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 4ίί provides the passage of the curve of the dependence of weight gain on time through area 45 (near the upper border).

In the table. 17 shows the mineral compositions of solid dosage forms using ¹³ C carbon isotopes. The ratio of ¹³ C carbon isotopes to total carbon in solid dosage forms is 0.003.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 8ίί and 13ίί provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 14ίί provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 12ίί does not differ from the action of the solid dosage form with serial number 11ίί. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 9 номером provides the passage of the curve of the dependence of weight gain on time through region 43 (between

- 24 020062 the upper boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 10ίί provides the passage of the curve of the dependence of weight gain on time through region 44 (between the upper boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 11ίί provides the passage of the curve of the dependence of weight gain on time through region 45 (between the upper boundary and the center of the region).

In the table. 18 shows the mineral compositions of solid dosage forms using isotopes of nitrogen ¹⁵ Ν. The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.0001.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 15ίί and 20ίί provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 21ίί provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 19ίί does not differ from the action of the solid dosage form with serial number 18ίί. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 16ίί provides the passage of the curve of the dependence of weight gain on time through region 43 (between the upper boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 17ίί provides the passage of the curve of the dependence of weight gain on time through region 44 (between the upper boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 18ίί provides the passage of the curve of the dependence of weight gain on time through region 45 (between the upper boundary and the center of the region).

In the table. 19 shows the mineral compositions of solid dosage forms using carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν. The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.003. The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.0001.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 22ίί and 27ίί provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 28ίί provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 26ίί does not differ from the action of the solid dosage form with serial number 25ίί. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 23ίί provides the passage of the curve of the dependence of weight gain on time through region 43 (through the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 24ίί provides the passage of the curve of the dependence of weight gain on time through region 44 (through the center of the region).

Admission to rats with an initial weight of 330-340 g of solid dosage form with serial number 25ίί ensures the passage of the curve of the dependence of weight gain on time through region 45 (through the center of the region).

In the table. 20 shows the mineral compositions of solid dosage forms using ¹³ C carbon isotopes. The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.75.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 29ίί and 34ίί provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 35ίί provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 33ίί does not differ from the action of the solid dosage form with serial number 32ίί. Therefore, its use is impractical.

Admission to rats with an initial weight of 330-340 g of solid dosage form with serial number

30ίί provides the passage of the curve of the dependence of weight gain on time through region 43 (between the lower boundary and the center of the region).

- 25 020062

Admission to rats with an initial weight of 330-340 g of solid dosage form with serial number

31ίί provides the passage of the curve of the dependence of weight gain on time through region 44 (between the lower boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 32ίί provides the passage of the curve of the dependence of weight gain on time through region 45 (between the lower boundary and the center of the region).

In the table. 21 shows the mineral compositions of solid dosage forms using isotopes of nitrogen ¹⁵ Ν. The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.1375.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 36ίί and 41ίί provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 42ίί provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 40ίί does not differ from the action of the solid dosage form with serial number 39ίί. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 37ίί provides the passage of the curve of the dependence of weight gain on time through region 43 (between the lower boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 38ίί provides the passage of the curve of the dependence of weight gain on time through region 44 (between the lower boundary and the center of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 39ίί provides the passage of the curve of the dependence of weight gain on time through region 45 (between the lower boundary and the center of the region).

In the table. 22 shows the mineral compositions of solid dosage forms using carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ ов. The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.75. The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.1375.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial numbers 43ίί and 48ίί provides the passage of the curve of the dependence of weight gain on time through region 42 (see Fig. 2). This is not better than the prototype.

Reception rats with an initial weight of 330-340 g of solid dosage forms with serial number 49ίί provides the passage of the curve of the dependence of weight gain on time over curve 38 (see Fig. 2). This is worse than the prototype.

The action of the solid dosage form with serial number 47ίί does not differ from the action of the solid dosage form with serial number 46ίί. Therefore, its use is impractical.

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 44ίί provides the passage of the curve of the dependence of weight gain on time through region 43 (near the lower boundary of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 45ίί provides the passage of the curve of the dependence of weight gain on time through region 44 (near the lower boundary of the region).

Reception rats with an initial weight of 330-340 g of solid dosage form with serial number 46ίί provides the passage of the curve of the dependence of weight gain on time through region 45 (near the lower boundary of the region).

The experiments showed that the partial replacement in the solid dosage form of carbon isotopes of ¹² C with carbon isotopes of ¹³ C can increase the therapeutic effect by 5% or more.

The experiments also showed that partial replacement in solid dosage form of nitrogen isotopes ¹⁴ Ν with nitrogen isotopes ¹⁵ Ν can increase the therapeutic effect by 3-5% or more.

Example 7 confirms an increase in the therapeutic effect, namely, a decrease in body weight, a decrease in the rate of increase in body weight, while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate during treatment, as well as in the prevention of obesity.

Example 8 illustrates the reduction in the time of the onset of the therapeutic effect under the action of the claimed solid dosage forms with minerals and sibutramine hydrochloride monohydrate, see FIG. 6.

The dose (daily dose) of sibutramine hydrochloride monohydrate was 0.0003 mg / g, administered orally in the form of a capsule or tablet.

In FIG. Figure 6 shows a graph of the dependence of the weight of feed C (g) eaten by two rats with an initial weight of 335 and 243 g per day, versus time άί (h), where L is the time interval between the time of the start of feeding the rats and the time of taking the solid dosage form.

- 26 020062

The time interval άΐ is determined by the formula άΐ = Tnk - Tpr, where Tnk is the time of the beginning of feeding (h);

TPR - the time of taking the solid dosage form (h), when the conditions are met Tnk> Tpr.

In the experiments, άΐ was varied in the range from 0 to 2.5 hours.

In the graph of FIG. 6, the following is presented.

Curve 46 - the dependence of the weight of the feed C (g) eaten by a rat with an initial weight of 335 g, versus time άΐ when used for treatment of the prototype.

A minimum of food eaten per day was observed at άΐ = 1 h.

The maximum was observed at άΐ = 0 h.

Curve 50 - dependence of the weight of feed C (g) eaten by a rat with an initial weight of 243 g, versus time άΐ when used for treatment of the prototype.

A minimum of food eaten per day was observed at άΐ = 1 h.

The maximum was observed at άΐ = 0 h.

The use of the claimed solid dosage forms for treatment shifts the minimum of food eaten per day from άΐ = 1 hour to άΐ = 0.5-0.6 hours

There is a reduction in the time of the onset of the therapeutic effect, which can significantly expand the possibilities of using solid dosage forms.

Curve 47 shows the dependence of the weight of food C (g) eaten by a rat with an initial weight of 335 g versus time άΐ when used for treatment of solid dosage forms 2, 2ί, 2ίί, 9, 9ί, 9ίί, 16, 161, 16ίί.

Curve 49 shows the dependence of the weight of food C (g) eaten by a rat with an initial weight of 335 g versus time άΐ when using solid dosage forms 32, 32ί, 32i, 39, 39ί, 39ίί, 46, 46ί, 46ίί for treatment.

All other claimed solid dosage forms provide for the passage of the curves of dependence of C on άΐ in region 48.

Curve 51 shows the dependence of the weight of food C (g) eaten by a rat with an initial weight of 243 g versus time άΐ when used for treatment of solid dosage forms 2, 2ΐ, 2ίί, 9, 9ί, 9ίί, 16, 161, 16ίί.

Curve 53 shows the dependence of the weight of food C (g) eaten by a rat with an initial weight of 243 g versus time άΐ when using solid dosage forms 32, 32ί, 32i, 39, 39ί, 39ίί, 46, 46ί, 46ίί for treatment.

All other claimed solid dosage forms provide the passage of the curves of dependence of C from άΐ in the region 52.

Analyzing the results of using minerals used in conjunction with sibutramine hydrochloride monohydrate, we can draw the following conclusion.

The combined use of mineral substances in the claimed ranges and sibutramine hydrochloride monohydrate in the claimed ranges plays an important role in the conversion of fat into muscle fuel.

In addition, it was found that the joint use of mineral substances in the claimed ranges and sibutramine hydrochloride monohydrate in the claimed ranges activates the metabolism processes, regulates the absorption of glucose by the cells of the body and helps to maintain a normal physiological level of glucose in the blood, maintains a stable level of sugar in the blood, and promotes the utilization of insulin.

An analysis of the research results showed that the joint use of minerals in the claimed ranges, sibutramine hydrochloride monohydrate in the claimed ranges, as well as the use of ¹³ C carbon isotopes in the declared ranges and ¹⁵ азота nitrogen isotopes in the declared ranges enhances the effect of sibutramine hydrochloride monohydrate.

Analysis of the experimental results showed that for the first embodiment of the invention it is advisable to use solid dosage forms No. 2-4, 2ί-4ί and 2ίί-4ίί.

For the second embodiment of the invention, it is advisable to use solid dosage forms No. 9-11, 9ί-11ί, 9ίί-11ίί, 30-32, 301-321, 30y-32i.

For the third embodiment of the invention, it is advisable to use solid dosage forms No. 16-18, 16ί-18ί, 16ΐΐ-18ΐΐ, 37-39, 371-391, 37ίί-39ίί.

For the fourth embodiment of the invention, it is advisable to use solid dosage forms No. 23-25, 23ί-25ί, 23ίί-25ίί, 44-46, 441-461, 44ίί-46ίί.

Thus, the application is described and technical results are confirmed when using solid dosage forms of all the claimed options. When using the claimed options solid dosage forms will be achieved.

an increase in the therapeutic effect (decrease in body weight or a decrease in the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity;

reduction of the onset of the therapeutic effect.

When developing an application for an invention, studies of the first, second, third and fourth variants of the claimed solid dosage form with an expanded mineral content

- 27 020062 substances. Additionally, to the composition of mineral substances in the solid dosage form indicated in the claims, the following were used in mg / kg:

copper - 0.0001 - 20.0.

This also ensures the achievement of the claimed technical results.

When developing an application for an invention, studies of the first, second, third and fourth variants of the claimed solid dosage form with an expanded content of mineral substances were carried out. Additionally, to the composition of mineral substances in the solid dosage form indicated in the claims, the following were used in mg / kg:

chrome - 0.0005 - 6.9.

This also ensures the achievement of the claimed technical results.

When developing an application for an invention, studies of the first, second, third and fourth variants of the claimed solid dosage form with an expanded content of mineral substances were carried out. Additionally, to the composition of mineral substances in the solid dosage form indicated in the claims, the following were used in mg / kg:

molybdenum - 0 0001 - 5.9.

This also ensures the achievement of the claimed technical results.

When developing an application for an invention, studies of the first, second, third and fourth variants of the claimed solid dosage form with an expanded content of mineral substances were carried out. Additionally, to the composition of mineral substances in the solid dosage form indicated in the claims, the following were used in mg / kg:

copper 0.0001 -20.0 chrome 0.0005 - 6.9

This also ensures the achievement of the claimed technical results.

When developing an application for an invention, studies of the first, second, third and fourth variants of the claimed solid dosage form with an expanded content of mineral substances were carried out. Additionally, to the composition of mineral substances in the solid dosage form indicated in the claims, the following were used in mg / kg:

chrome 0.0005-6.9 molybdenum 0 0001 - 5.9

This also ensures the achievement of the claimed technical results.

When developing an application for an invention, studies of the first, second, third and fourth variants of the claimed solid dosage form with an expanded content of mineral substances were carried out. Additionally, to the composition of mineral substances in the solid dosage form indicated in the claims, the following were used in mg / kg:

copper 0.0001 - 20.0 molybdenum 0 0001 -5.9

This also ensures the achievement of the claimed technical results.

When developing an application for an invention, studies of the first, second, third and fourth variants of the claimed solid dosage form with an expanded content of mineral substances were carried out. Additionally, to the composition of minerals indicated in the claims, in solid dosage form was used in mg / kg;

copper 0.0001 -20.0 chrome 0.0005 - 6.9 molybdenum 0 0001 - 5.9

This also ensures the achievement of the claimed technical results.

Studies of the first variant of a solid dosage form with an expanded content of mineral substances were also conducted. In a formalized form, the studied solid dosage form can be described as follows.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

- 28 020062

sibutramine hydrochloride monohydrate 1 10 ³ - 655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 - 128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 - 20.0 chromium 0.0005 - 6.9 molybdenum 0 0001 5.9

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ - 655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01-128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0 molybdenum 0 0001 6.9

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ - 655 1 0 ³ sodium 0.15-100000.0 potassium 0.13 -15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01 - 128.0 manganese 0.003 -50.8 zinc 0.001 - 320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0 molybdenum 0 0001 5.9

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

- 29 020062

sibutramine hydrochloride monohydrate PO ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 chromium 0.0005 - 6.9 molybdenum 0 0001 - 5.9

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13-15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate ³ -65 510 ³ G10 sodium 0.15-100000.0 potassium 0.13 -15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01-128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 molybdenum 0 0001 - 5.9

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ -65510 ' sodium 0.15-100000.0 potassium 0.13-15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01 - 128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0

- 30 020062

When using the first variant of a solid dosage form with an expanded content of minerals, it was found:

an increase in the therapeutic effect (decrease in body weight or a decrease in the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity;

reduction of the onset of the therapeutic effect.

Studies of the second variant of a solid dosage form with an expanded content of mineral substances were also conducted. In a formalized form, the studied solid dosage form can be described as follows.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ - 655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01 - 128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0 chromium 0.0005 - 6.9 molybdenum 0 0001 - 5.9

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate G10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 - 128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0 chromium 0.0005 - 6.9

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

- 31 020062

sibutramine hydrochloride monohydrate 1 10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 -128.0 manganese 0.003 -50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0 molybdenum 0 0001 - 5.9

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ - 655 1 0 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01-128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 chromium 0.0005-6.9 molybdenum 0 0001 - 5.9

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 - 128.0 manganese 0.003 -50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

- 32 020062

sibutramine hydrochloride monohydrate 1 10 ³ - 655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01-128.0 manganese 0.003 -50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 molybdenum 0 0001 - 5.9

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01 - 128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75.

When using the second variant of a solid dosage form with an expanded content of minerals, it was found:

an increase in the therapeutic effect (decrease in body weight or a decrease in the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity;

reduction of the onset of the therapeutic effect.

Studies of the third variant of a solid dosage form with an expanded content of mineral substances were also conducted. In a formalized form, the studied solid dosage form can be described as follows.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 - 128.0 manganese 0.003 -50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0 chromium 0.0005 -6.9 molybdenum 0 0001 - 5.9

- 33 020062 and the solid dosage form is designed in such a way that it contains ¹⁵ N nitrogen isotopes and the ratio of the number of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate PO ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01-128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003-5.0 copper 0.0001 -20.0 chromium 0.0005 -6.9

and the solid dosage form is made in such a way that it contains ¹⁵ N nitrogen isotopes and the ratio of the number of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01 - 128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0 molybdenum 0 0001 - 5.9

and the solid dosage form is made in such a way that it contains ¹⁵ N nitrogen isotopes and the ratio of the number of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ - 655 1 0 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01 - 128.0 manganese 0.003 -50.8 zinc 0.001-320.0 cobalt 0.0003 - 5.0 chromium 0.0005 - 6.9 molybdenum 0 0001 - 5.9

and the solid dosage form is made in such a way that it contains ¹⁵ N nitrogen isotopes and the ratio of the number of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.

- 34 020062

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 manganese 0.003 -50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0

and the solid dosage form is made in such a way that it contains nitrogen isotopes ¹⁵ Ν and the ratio of the number of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01-128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 molybdenum 0 0001 - 5.9

and the solid dosage form is made in such a way that it contains nitrogen isotopes ¹⁵ Ν and the ratio of the number of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate G10 ³ - 655 1 0 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 - 128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0

and the solid dosage form is made in such a way that it contains nitrogen isotopes ¹⁵ Ν and the ratio of the number of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in the solid dosage form is from 0.0001 to 0.1375.

When using the third variant of a solid dosage form with an expanded content of minerals, it was found:

an increase in the therapeutic effect (decrease in body weight or a decrease in the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity;

reduction of the onset of the therapeutic effect.

Studies of the fourth variant of a solid dosage form with an expanded content of mineral substances were also conducted. Formulated test solid dosage form

- 35 020062 can be described as follows.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01-128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0 chromium 0.0005-6.9 molybdenum 0 0001 - 5.9

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75;

¹⁵ N nitrogen isotopes and the ratio of the number of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in solid dosage form is from 0.0001 to 0.1375.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate I 10 ³ - 655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 manganese 0.003 - 50.8 zinc 0.001 - 320.0 cobalt 0.0003 - 5.0 copper 0.0001 - 20.0 chromium 0.0005 -6.9

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75;

¹⁵ N nitrogen isotopes and the ratio of the number of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in solid dosage form is from 0.0001 to 0.1375.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate G10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 - 128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0 molybdenum 0 0001 - 5.9

- 36 020062 and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total carbon in the solid dosage form is from 0.003 to 0.75;

¹⁵ N nitrogen isotopes and the ratio of the number of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in solid dosage form is from 0.0001 to 0.1375.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ - 65 5 1 0 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01 - 128.0 manganese 0.003 - 50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 chromium 0.0005 -6.9 molybdenum 0 0001 - 5.9

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75;

¹⁵ N nitrogen isotopes and the ratio of the number of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in solid dosage form is from 0.0001 to 0.1375.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ - 65 5 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 manganese 0.003 -50.8 zinc 0.001-320.0 cobalt 0.0003 - 5.0 copper 0.0001 -20.0

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75;

¹⁵ N nitrogen isotopes and the ratio of the number of ¹⁵ N nitrogen isotopes to the total amount of nitrogen in solid dosage form is from 0.0001 to 0.1375.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

- 37 020062

sibutramine hydrochloride monohydrate G10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0 - 61050.0 iron 0.01 - 128.0 manganese 0.003 -50.8 zinc 0.001 -320.0 cobalt 0.0003 - 5.0 molybdenum 0 0001 - 5.9

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75;

nitrogen isotopes ¹⁵ Ν and the ratio of the number of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is from 0.0001 to 0.1375.

A solid dosage form with anorexigenic effect, contains sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ -655 10 ' sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 manganese 0.003 - 50.8 zinc 0.001 - 320.0 cobalt 0.0003 - 5.0

and the solid dosage form is designed in such a way that it contains ¹³ C carbon isotopes and the ratio of ¹³ C carbon isotopes to the total amount of carbon in the solid dosage form is from 0.003 to 0.75;

nitrogen isotopes N and the ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is from 0.0001 to 0.1375.

When using the fourth variant of a solid dosage form with an expanded content of minerals, it was found:

an increase in the therapeutic effect (decrease in body weight or a decrease in the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity;

reduction of the onset of the therapeutic effect.

In experiments, liquid dosage forms based on sibutramine hydrochloride monohydrate, minerals, and ¹³ C and ¹⁵ из isotopes were also investigated. Their effectiveness is comparable with the effectiveness of solid dosage forms.

At present, ¹³ C carbon isotopes in the world are widely used in biochemistry and medicine for diagnostics. The invention presents the results of our own studies on the effect of carbon ¹³ C isotopes on the effectiveness of solid dosage forms based on sibutramine hydrochloride monohydrate.

It has been experimentally established to increase the stability of the claimed solid dosage forms over the shelf life by replacing (from 0.3 to 75%) carbon isotopes of ¹² C with carbon isotopes of ¹³ C. It has been established that carbon isotopes of ¹³ C in the dosage form slow down the reactions occurring in the dosage form, form stronger covalent bonds than carbon isotopes ¹² C.

Carbon isotopes ¹³ C increase the resistance of molecules to the oxidative effects of radicals.

Carbon isotopes ¹³ C are not toxic. The experiments show that feeding rats with foods enriched with 75% carbon ¹³ C, does not lead to side effects and the deterioration of their health.

In the process of experimental verification of the claimed solid dosage forms enriched in carbon ¹³ C isotopes, it was found that they have increased stability, they are not toxic and,

- 38 020062 in addition, have an anti-inflammatory effect compared with the solid dosage form, in which there are no ¹³ C.

Methods for the production of a stable highly enriched non-radioactive isotope ¹³ С (carbon13) are widely used in Russian and world industry. Well-developed methods for producing the carbon-13 isotope by gas diffusion through porous septa, vapor diffusion, thermal diffusion, as well as by distillation, isotope exchange, centrifugation, electrolysis, genetic engineering, etc. A brief description of these methods is given in [Isotope Separation. Physical Encyclopedia. 1Shr: //Shs.asa4st1s.gi/Shs.p Shepsde11u51S5/1071/Izotopov].

At the Moscow State Academy of Fine Chemical Technology. M.V. Lomonosov practiced modern nanotechnology for the production and incorporation of atoms of stable carbon isotopes ¹³ C into molecules of various structures. The Academy receives molecules of isotope-labeled compounds with various levels of isotope enrichment - from fractions of a percent to 100% of the isotopes in a substance. The work is in the interests of medical diagnosis. In [Nanotechnology and the inclusion of dei atoms 13 13 18 18 of terium H, carbon C, nitrogen N and oxygen O in the molecules of amino acids and proteins. L1p: //8at11b.yi/o/o1ed_te_t/syositep18apY8eytd8o1deto8shto1yokitep1upap1ebpo1odat kisiseyi1ea1oto \\ '<1e) 1ep] a211g1G.51i1p1 | 165 references to foreign sources of information on the isotopic enrichment of various substances are given.

In turn, the authors actively participated in the work on the isotopic enrichment of hydrocarbons, as well as reagents for the production of various drugs. The reagents were enriched with ¹³ C carbon isotope (replacing ¹² C carbon isotopes with ¹³ C carbon isotopes) in a cavitation reactor designed by Professor V. I. Kormilitsyn. (Moscow Energy Institute - Technical University).

The reactor was manufactured according to the method described in [R.F. Ganiev, V.I. Kormilitsyn, L.I. Ukrainian. Wave technology for the preparation of alternative fuels and the efficiency of their combustion. - M.: Scientific and Publishing Center Regular and chaotic dynamics, 2008. - 116 p.]. The flow velocity in the reactor along the channel length varied from 10 to 50 m / s.

In FIG. 3 is a diagram cavitation reactor for isotopic enrichment of various mixtures, in particular, the reagents for the preparation of solid dosage forms on the basis of sibutramine hydrochloride monohydrate enriched carbon isotope ¹³ C. The reactor is located in a plant which comprises 6NK 6x1-pump, which provides a maximum flow rate of 90 m ³ / h, head 125 m with an electric motor power of 75 kW, a rotational speed of an electric motor rotor and a pump wheel of 2950 rpm. Additionally, the installation contains tanks for reagents and measuring instruments.

In experiments, the electric motor power was reduced to 11 and 1.5 kW with reduced consumption.

The installation diagram is shown in FIG. 5.

The cavitation reactor 1 (see Fig. 3) is made in the form of a flat Laval nozzle with cavitation bodies 2–9 in channel 10.

In FIG. 4 shows a cross section of a cavitation reactor. The reactor channel in the area of cavitation bodies is divided into several channels. For example, cavitation bodies 5 and 6 divide the channel into smaller channels 13, 14 and 15. Outside, the channel is limited by walls 16 and 17, as well as two covers 11 and 12.

In FIG. 3, arrows 18 show the direction of movement of the reagent at the inlet to the reactor, arrow 19 shows the direction of movement of the reagent at the outlet of the reactor.

In the wall 16, channels 24 and 25 are made for supplying carbon dioxide and nitrogen to the cavitation zones.

Installation works as follows. The hydrocarbon reagent from the tank 28 (see Fig. 5) is pumped through the reactor 27 through the pump 27 and enters the tank 28. The pressure drop across the reactor is controlled by pressure gauges 29 and 30. The temperature of the reactant is monitored by thermometer 31. The reagent is heated in the tank by a heater 32.

When the reactor is operating, the hydrocarbon reagent moves along the cavitator channel in direction 18. When flowing around cavitation bodies, the stream is divided into several streams. Beyond the cavitation bodies, cavitation areas arise. In particular, behind the bodies (if you look in the direction of movement of the reagent) cavitation 2, 3, and 4 are cavitation zones 20, 21, 22, and 23. Upon entering the cavitation region, the reagent boils, cavitation bubbles appear, and cavitation bubbles collapse when leaving the cavitation region . Moreover, in the area (in place) of the collapse of the cavitation bubble, an increase in pressure is observed to several thousand atmospheres and an increase in temperature to 1000 ° C and above. Through channels 24 and 25, carbon dioxide is supplied to the stream so that the gas enters the cavitation zone.

The gas-vapor mixture obtained in the reactor together with the liquid reagent enters the tank 28. Next, the gas-vapor mixture is fed through a pipe 33 to a separator with a porous partition, where the gas-vapor mixtures with ¹³ C and ¹² C are separated. After which the mixture is transferred to a liquid state.

In the experiments, the reactor worked from several hours to several days. A direct dependence of the degree of enrichment of the vapor-gas mixture and the reagent with the ¹³ C isotope ^{on the} operating time of the cavitation reactor is established.

The amount of ¹³ C carbon isotopes was controlled by high resolution mass spectroscopy.

- 39 020062

As a result of the experiments, the reagent was enriched in the ¹³ C carbon isotope from 0.3 to 75%.

Thus, solutions (reagents) were obtained, and solid dosage forms based on sibutramine hydrochloride monohydrate with a content of ¹³ C isotopes from 0.3 to 75% of all carbon in solid dosage form were obtained from solutions.

Solid dosage forms were enriched with nitrogen isotopes ¹⁵ Ν in a manner similar to the above method. When the reagent was enriched, reactor gas 1 (see Fig. 3) was supplied with nitrogen gas ¹⁴ Ν through channels 24 and 25.

In the claimed solid dosage forms, the active substance is sibutramine hydrochloride monohydrate. The content of sibutramine hydrochloride monohydrate is from 1-10 ³ to 655-10 ³ mg / kg.

In the research process, a solid dosage form was created in the form of a tablet with the possibility of separation into parts.

In a formalized form, a tablet, which can be divided into parts, is described as follows.

A solid dosage form made in the form of a tablet contains the main active substance and a pharmaceutically acceptable additional substance, and the tablet is made with the possibility of separation into parts to obtain two parts for which the conditions are met:

K = (01 + (32) / (3 = 0.9 + 1.0;

B = | 01 - 02 I / O = 0 + 0.1, where K is an indicator characterized in that when dividing, two main parts are obtained, and they can also receive more than two parts, however, at the same time, two of the received parts are the largest in size;

B is an indicator characterized by the fact that upon separation two parts are obtained, the weight of which can differ by no more than 10%;

- the weight of the first part of the solid dosage form after separation of the solid dosage form;

- the weight of the second part of the solid dosage form after separation of the solid dosage form;

- the weight of the solid dosage form before separation.

In addition, work was carried out to create a solid dosage form with the possibility of dividing it into parts and obtaining two parts with different indicators. So, a certain indicator (for example, the content of a mineral substance, the content of sibutramine hydrochloride monohydrate, etc.) in the first part of the solid dosage form differs from the corresponding indicator in the second part of the solid dosage form.

Another example. A solid dosage form was prepared with the possibility of dividing into parts and obtaining two parts for which the content of sibutramine hydrochloride monohydrate in the first part of the solid dosage form differs from the content of sibutramine hydrochloride monohydrate in the second part of the solid dosage form by 0.01-10%.

A solid dosage form made with the possibility of separation into parts with different indicators is called a hybrid solid dosage form. A solid dosage form made with the possibility of separation, for example, into two parts, was made by pressing two prefabricated half-tablets.

This embodiment of the solid dosage form expands the possibilities of using the dosage form.

Hybrid solid dosage forms can be described in various ways. Below are a few formal descriptions of these dosage forms, which may be special cases for each of the claimed variants of the invention.

A solid dosage form having an anorexigenic effect, made in the form of a tablet, contains sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ - 655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0

- 40 020062 and the tablet is made with the possibility of separation into parts to obtain two parts for which the conditions are met:

K = (O1 + 02) / 6- 0.9 + 1.0;

B = | C1-02 | / O = 0 + 0.1, where K is an indicator characterized by the fact that upon separation they receive two main parts, and can also receive more than two parts, however, two of the obtained parts are the largest in size;

B is an indicator characterized by the fact that upon separation two parts are obtained, the weight of which can differ by no more than 10%;

- the weight of the first part of the solid dosage form after separation of the solid dosage form;

- the weight of the second part of the solid dosage form after separation of the solid dosage form;

- the weight of the solid dosage form before separation, and the content of sibutramine hydrochloride monohydrate in the first part of the solid dosage form is different from the content of sibutramine hydrochloride monohydrate in the second part of the solid dosage form.

Moreover, the difference is from 0.01 to 10%.

The difference can be from 0.01 to 5%.

The difference can be from 0.001 to 5%.

The difference can be from 0.1 to 5%.

The difference can be from 0.01 to 1%.

The difference can be from 0.001 to 0.1%.

The difference can be from 1 to 50%.

The difference can be from 1 to 70%.

A solid dosage form having an anorexigenic effect, made in the form of a tablet, contains sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate 1 10 ³ - 655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0

and the tablet is made with the possibility of separation into parts to obtain two parts for which the conditions are met:

K = (O1 + 02) / O = 0.9 + 1.0;

B = | O1-02 | / O = 0 + 0.1, where K is an indicator characterized by the fact that during the separation two main parts are obtained, and they can also receive more than two parts, however, two of the obtained parts are the largest in size;

B is an indicator characterized by the fact that upon separation two parts are obtained, the weight of which can differ by no more than 10%;

- the weight of the first part of the solid dosage form after separation of the solid dosage form;

- the weight of the second part of the solid dosage form after separation of the solid dosage form;

- the weight of the solid dosage form before its separation, while the sodium content in the first part of the solid dosage form is chosen so that it differs from the sodium content in the second part of the solid dosage form.

Moreover, the difference is from 0.001 to 10%.

The difference can be from 0.001 to 70%.

The difference can be from 0.01 to 5%.

The difference can be from 0.001 to 5%.

The difference can be from 0.1 to 5%.

The difference can be from 0.01 to 1%.

The difference can be from 0.001 to 0.1%.

- 41 020062

The difference can be from 1 to 50%.

The difference can be from 1 to 70%.

A solid dosage form having an anorexigenic effect, made in the form of a tablet, contains sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate PO ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15,000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 -128.0 cobalt 0.0003 - 5.0

and the tablet is made with the possibility of separation into parts to obtain two parts for which the conditions are met:

K = (O1 + 02) / O = 0.9 + 1.0;

1_ = I 01 - 02 | / 0 = 04) .1, where K is an indicator characterized by the fact that upon separation they receive two main parts, and can also receive more than two parts, however, two of the received parts are the largest in size ;

B is an indicator characterized by the fact that upon separation two parts are obtained, the weight of which can differ by no more than 10%;

C1 is the weight of the first part of the solid dosage form after separation of the solid dosage form;

- the weight of the second part of the solid dosage form after separation of the solid dosage form;

- the weight of the solid dosage form before its separation, while the calcium content in the first part of the solid dosage form is chosen so that it differs from the calcium content in the second part of the solid dosage form.

Moreover, the difference is from 0.001 to 10%.

The difference can be from 0.001 to 70%.

The difference can be from 0.01 to 5%.

The difference can be from 0.001 to 5%.

The difference can be from 0.1 to 5%.

The difference can be from 0.01 to 1%.

The difference can be from 0.001 to 0.1%.

The difference can be from 1 to 50%.

The difference can be from 1 to 70%.

A solid dosage form having an anorexigenic effect, made in the form of a tablet, contains sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg:

sibutramine hydrochloride monohydrate PO ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15,000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 -128.0 cobalt 0.0003 - 5.0

and the tablet is made with the possibility of separation into parts to obtain two parts for which the conditions are met:

K = (01+ 02) / O = 0.9 = 1.0;

B = | O1 - 02 | / O = 0 = 0.1, where K is an indicator characterized by the fact that upon separation they receive two main parts, and can also receive more than two parts, however, two of the obtained parts are the largest in size;

- 42 020062

B is an indicator characterized by the fact that upon separation two parts are obtained, the weight of which can differ by no more than 10%;

- the weight of the first part of the solid dosage form after separation of the solid dosage form;

- the weight of the second part of the solid dosage form after separation of the solid dosage form;

- the weight of the solid dosage form before its separation, while the magnesium content in the first part of the solid dosage form is chosen so that it differs from the magnesium content in the second part of the solid dosage form.

Moreover, the difference is from 0.001 to 10%.

The difference can be from 0.001 to 70%.

The difference can be from 0.01 to 5%.

The difference can be from 0.001 to 5%.

The difference can be from 0.1 to 5%.

The difference can be from 0.01 to 1%.

The difference can be from 0.001 to 0.1%.

The difference can be from 1 to 50%.

The difference can be from 1 to 70%.

Thus, the implementation of the claimed solid dosage forms provides: an increase in the therapeutic effect (decrease in body weight or decrease in the rate of increase in body weight) while maintaining the duration of action without increasing the concentration of sibutramine hydrochloride monohydrate in the treatment and / or prevention of obesity;

reducing the time of the onset of the therapeutic effect, which can significantly expand the possibilities of using solid dosage forms.

Table 1

The mineral composition of Reduxin and Goldline capsules of various manufacturers

Mineral substance Reduxin. Mineral content (in milligrams) per kilogram of solid dosage form (mg / kg) Goldline. Mineral content (in milligrams) per kilogram of solid dosage form (mg / kg) sodium, mg / kg 77.1 13.7 *) calcium, mg / kg 6.3 127.8 magnesium, mg / kg 414.8 24.5

*) The average value after studies of 10 capsules of Reduxin (sibutramine hydrochloride monohydrate 15 mg) from 10 different packages and 10 capsules of Goldline (sibutramine hydrochloride monohydrate 15 mg) from 10 different packages. The scatter of values ranged from 1 to 10%.

table 2

Solid dosage form with sibutramine and minerals

Minerals The serial number of the solid dosage form with 1 gram of salt of sibutramine (sibutramine hydrochloride monohydrate) and minerals, mg / kg one 2 3 4 5 6 7 sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

- 43 020062

Table 3

Solid dosage form with sibutramine, minerals and carbon isotopes ¹³ C.

The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.003

Minerals The serial number of the solid dosage form with 1 gram of salt of sibutramine (sibutramine hydrochloride monohydrate), carbon isotopes ¹³ C and minerals, mg / kg 8 nine 10 eleven 12 thirteen 14 sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

Table 4 Solid dosage form with sibutramine, minerals and nitrogen isotopes ¹⁵ Ν.

The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.0001

Minerals The serial number of the solid dosage form with 1 gram of salt of sibutramine (sibutramine hydrochloride monohydrate), nitrogen isotopes ¹⁵ Ν and minerals, mg / kg fifteen sixteen 17 eighteen nineteen twenty 21 sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

- 44 020062

Table 5

Solid dosage form with sibutramine, minerals, ¹³ C carbon isotopes and ¹⁵ азота nitrogen isotopes.

The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.003.

The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.0001

Minerals The serial number of the solid dosage form with 1 gram of salt of sibutramine (sibutramine hydrochloride monohydrate), carbon isotopes ^{| 3} C, nitrogen isotopes ^<3 Ν and minerals, mg / kg 22 23 24 25 26 27 28 sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

Table 6

Solid dosage form with sibutramine, minerals and carbon isotopes ¹³ C.

The ratio of the number of carbon isotopes ¹³ C to the total amount of carbon in solid dosage form is 0.75

Minerals The serial number of the solid dosage form with 1 gram of salt of sibutramine (sibutramine hydrochloride monohydrate), carbon isotopes ¹³ C and minerals, mg / kg 29th thirty 31 32 33 34 35 sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

- 45 020062

Table 7

Solid dosage form with sibutramine, minerals and isotopes of nitrogen ¹⁵ Ν.

The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.1375

Minerals The serial number of the solid dosage form with 1 gram of salt of sibutramine (sibutramine hydrochloride monohydrate), nitrogen isotopes ^Ι5 Ν and minerals, mg / kg 36 37 38 39 40 41 42 sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

Table 8 Solid dosage form with sibutramine, minerals, carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν.

The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.75.

The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.1375

Mine * real substance The serial number of the solid dosage form with 1 gram of salt of sibutramine (sibutramine hydrochloride monohydrate), carbon isotopes ¹³ C, nitrogen isotopes ^Ι5 Ν and minerals, mg / kg 43 44 45 46 47 48 49 sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

- 46 020062

Table 9

Solid dosage form with sibutramine and minerals

Minerals The serial number of the solid dosage form with 33 grams of salt of sibutramine (sibutramine hydrochloride monohydrate) and minerals, mg / kg 1 ϊ 2ΐ 3 ί 4ϊ 5Ϊ 6 ϊ 7ϊ sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

Table 10 Solid dosage form with sibutramine, minerals and carbon isotopes ¹³ C.

The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.003

Minerals The serial number of the solid dosage form with 33 grams of salt of sibutramine (sibutramine hydrochloride monohydrate), carbon isotopes ^{| 3} C and minerals, mg / kg 81 9ί 10 ϊ 11 ΐ 12 1 13ί 14ί sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

- 47 020062

Table 11 Solid dosage form with sibutramine, minerals and nitrogen isotopes ¹⁵ Ν.

The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.0001

Minerals The serial number of the solid dosage form with 33 grams of salt of sibutramine (sibutramine hydrochloride monohydrate), nitrogen isotopes ¹⁵ Ν and minerals, mg / kg 15 ϊ 161 171 181 191 20 ϊ 21 ί sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

Table 12 Solid dosage form with sibutramine, minerals, carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν.

The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.003.

The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.0001

Minerals The serial number of the solid dosage form with 33 grams of sibutramine salt (sibutramine hydrochloride monohydrate), carbon isotopes ^{| 3} C, nitrogen isotopes ¹⁵ Ν and minerals, mg / kg 22 1 23 Ϊ 24Ϊ 25ί 26Ϊ 27 ί 28 ϊ sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

- 48 020062

Table 13

Solid dosage form with sibutramine, minerals and carbon isotopes ¹³ C.

The ratio of the number of carbon isotopes ¹³ C to the total amount of carbon in solid dosage form is 0.75

Minerals The serial number of the solid dosage form with 33 grams of sibutramine salt (sibutramine hydrochloride monohydrate), carbon isotopes ^|} C and minerals, mg / kg 29ί 30 ί 31 ϊ 32 ί 33 ί 34 ί 35 ί sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

Table 14 Solid dosage form with sibutramine, minerals and nitrogen isotopes ¹⁵ N.

The ratio of the amount of nitrogen isotopes ¹⁵ N to the total amount of nitrogen in solid dosage form is 0.1375

Minerals The serial number of the solid dosage form with 33 grams of sibutramine salt (sibutramine hydrochloride monohydrate), ^Ι5 Ν nitrogen isotopes and minerals, mg / kg 361 37 ΐ 38ί 39ί 401 41 ί 42 ί sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

- 49 020062

Table 15

Solid dosage form with sibutramine, minerals, ¹³ C carbon isotopes and ¹⁵ азота nitrogen isotopes.

The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.75.

The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.1375

Mine ral substances The serial number of the solid dosage form with 33 grams of sibutramine salt (sibutramine hydrochloride monohydrate), ¹³ C carbon isotopes, ^Ι5 Ν nitrogen isotopes and minerals, mg / kg 43 ί 44ί 45 ϊ 46ί 47 ϊ 48ί 49 ί sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

Table 16 Solid dosage form with sibutramine and minerals

Minerals The serial number of the solid dosage form with 655 grams of salt of sibutramine (sibutramine hydrochloride monohydrate) and minerals, mg / kg 1 P 211 3 ί ί 4I 5ϋ 6 ί ί 7ϋ sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

- 50 020062

Table 17

Solid dosage form with sibutramine, minerals and carbon isotopes ¹³ C.

The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.003

Minerals The serial number of the solid dosage form with 655 grams of salt of sibutramine (sibutramine hydrochloride monohydrate), carbon isotopes ¹³ C and minerals, mg / kg 8I 9 ί ί 10 ί ί 11 And 12 ίί 13 ίί 14 ϋ sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

Table 18 Solid dosage form with sibutramine, minerals and nitrogen isotopes ¹⁵ Ν.

The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.0001

Minerals The serial number of the solid dosage form with 655 grams of sibutramine salt (sibutramine hydrochloride monohydrate), ¹⁵ Ν nitrogen isotopes and minerals, mg / kg 15 ίί 16 ί ί 17 ϋ 18 ί ί 19 ί ί 20 ίί 21 ίί sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

- 51 020062

Table 19

Solid dosage form with sibutramine, minerals, ¹³ C carbon isotopes and ¹⁵ N nitrogen isotopes.

The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.003.

The ratio of the amount of nitrogen isotopes ¹⁵ N to the total amount of nitrogen in solid dosage form is 0.0001

Mine real substance The serial number of the solid dosage form with 655 grams of sibutramine salt (sibutramine hydrochloride monohydrate), ¹³ C carbon isotopes, ¹⁵ из nitrogen isotopes and minerals, mg / kg 22nd 23 And 24 and 25 ϋ 26 ϊ ί 27 ϋ 28 And sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

Table 20 Solid dosage form with sibutramine, minerals and carbon isotopes ¹³ C.

The ratio of the number of carbon isotopes ¹³ C to the total amount of carbon in solid dosage form is 0.75

Minerals The serial number of the solid dosage form with 655 grams of salt of sibutramine (sibutramine hydrochloride monohydrate), carbon isotopes ^{| 3} C and minerals, mg / kg 29 ϋ ZON 31st 32nd 33rd 34th 35th sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

- 52 020062

Table 21 Solid dosage form with sibutramine, minerals and nitrogen isotopes ¹⁵ Ν.

The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.1375

Mine real substance The serial number of the solid dosage form with 655 grams of sibutramine salt (sibutramine hydrochloride monohydrate), ^Ι3 Ν nitrogen isotopes and minerals, mg / kg 36 And 37 ίί 38 ίί 39 ϋ 40 and 1 41 ϋ 42 ίί sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

Table 22 Solid dosage form with sibutramine, minerals, carbon isotopes ¹³ C and nitrogen isotopes ¹⁵ Ν.

The ratio of ¹³ C carbon isotopes to total carbon in solid dosage form is 0.75.

The ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form is 0.1375

Minerals The serial number of the solid dosage form with 655 grams of sibutramine salt (sibutramine hydrochloride monohydrate), carbon isotopes ^{| 3} C, nitrogen isotopes ^{, 5} Ν and minerals, mg / kg 4311 44 And 45 ίί 46 ί ί 47 ίί 48 ίί 49 ίί sodium 0.05 0.15 77.0 100,000 120,000 130,000 140,000 potassium 0.05 0.13 17.0 15,000 17000 19000 20000 calcium 0.05 0.16 127.0 40500 50500 60250 67000 magnesium 0.05 0.15 414.0 61050 75,000 85550 95000 iron 0.008 0.01 2.0 128.0 155.0 230.0 300.0 cobalt 0.00006 0.0003 0.4 5.0 9.5 15.2 19.0

Claims (5)

CLAIM 1. A solid dosage form having anorexigenic effect, containing sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg: sibutramine hydrochloride monohydrate G10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0 2. A solid dosage form having anorexigenic effect, containing sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg: sibutramine hydrochloride monohydrate 1 10 ³ - 655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0 and ¹³ C carbon isotopes with a ratio of ¹³ C carbon isotopes to the total amount of carbon in solid dosage form from 0.003 to 0.75. 3. A solid dosage form having anorexigenic effect, containing sibutramine hydrochloride monohydrate, minerals in the following ratio of components in mg / kg: sibutramine hydrochloride monohydrate G10 ³ -655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01 - 128.0 cobalt 0.0003 - 5.0 and nitrogen isotopes ¹⁵ Ν with the ratio of the amount of nitrogen isotopes ¹⁵ Ν to the total amount of nitrogen in solid dosage form from 0.0001 to 0.1375. 4. A solid dosage form having anorexigenic effect, containing sibutramine hydrochloride monohydrate, mineral substances in the following ratio of components in mg / kg: sibutramine hydrochloride monohydrate 1 10 ³ - 655 10 ³ sodium 0.15-100000.0 potassium 0.13 - 15000.0 calcium 0.16-40500.0 magnesium 15.0-61050.0 iron 0.01-128.0 cobalt 0.0003 - 5.0 carbon isotopes ¹³ C with a ratio of ¹³ C carbon isotopes to the total amount of carbon in solid dosage form from 0.003 to 0.75; ¹⁵ ы nitrogen isotopes with a ratio of ¹⁵ Ν nitrogen isotopes to the total amount of nitrogen in solid dosage form from 0.0001 to 0.1375. 5. A solid dosage form according to any one of claims 1 to 4, characterized in that it is made in the form of a tablet or capsule.