WO2025071429A1 - Pharmaceutical composition based on menthyl ester of indomethacin - Google Patents

Abstract

The invention relates to the field of medicine and concerns anti-inflammatory agents, and more particularly pharmaceutical compositions based on menthyl ester of indomethacin, which are provided in the form of solid self-emulsifying systems.

Description

PHARMACEUTICAL COMPOSITION BASED ON INDOMETHACIN MENTHYL ESTER

Field of technology to which the invention relates The invention relates to the field of medicine and concerns anti-inflammatory agents, in particular pharmaceutical compositions based on indomethacin menthyl ester in the form of a solid self-emulsifying system.

Prior art

Indomethacin menthyl ether (MEI) is a prodrug that is converted in the body by esterase enzymes into indomethacin, a non-steroidal anti-inflammatory drug (NSAID) that has powerful anti-inflammatory, analgesic and antipyretic effects. MEI itself is practically not bioavailable, so for its medical use it is necessary to use special delivery systems that ensure its bioavailability. Earlier, patent US8,097,646 [1] described a pharmaceutical ophthalmological composition containing MEI, which can be used as a drug for topical application in the treatment of inflammatory eye diseases. The work of Sawraj et al. [2] described the synthesis of a number of indomethacin derivatives, including MEI, and their use as NSAIDs. Patent RU2685257 describes pharmaceutical compositions containing MEI, which can be used as drugs for systemic (oral or parenteral) use in the treatment of various inflammatory diseases.

The closest prototype to the claimed agent are pharmaceutical compositions based on MEI, described in patent RU2685257 [3]. The pharmaceutical compositions described there, when administered orally, combined good bioavailability and anti-inflammatory activity with low gastrointestinal toxicity (did not have an ulcerogenic effect). The pharmaceutical compositions for oral administration described in the prototype are either liposomes or liquid self-emulsifying systems based on non-polar solvents, such as mono-, di- and triglycerides of fatty acids, and other pharmaceutically acceptable non-polar and polar solvents, emulsifiers and surfactants. The described compositions have their advantages and disadvantages. Thus, pharmaceutical compositions based on liposomes are suitable for the manufacture of hard gelatin capsules or tablets - the most popular, easy to manufacture and inexpensive dosage forms in which NSAIDs are usually produced. On the other hand, liposomes are very complex and expensive to manufacture, and have problems with stability during storage. Therefore, there are very few liposome-based drugs, they are used where the price is not of great importance and/or other solutions are not possible, for example, in oncology. The pharmaceutical compositions described in the prototype based on liquid self-emulsifying systems are easy to manufacture (at the stage of mixing the components), but they must be poured into special dosage forms, such as soft gelatin capsules or hard gelatin capsules with a protective rim. Such dosage forms are more difficult to manufacture than tablets or conventional hard gelatin capsules, in the form of which NSAIDs are most often produced. In addition, dosage forms based on liquid dispersed systems are more sensitive to the action of external factors (oxygen, temperature, light), which lead to a violation of stability (the formation of impurities) during storage. To ensure the required stability, antioxidants are used, but their content is limited by the requirements of the Pharmacopoeia due to the health hazard. Another way to ensure stability is to store the drug at low temperatures, which is inconvenient for pharmacies and consumers. Due to the above reasons, pharmaceutical compositions in the form of liposomes and liquid self-emulsifying systems have limited application in medicine.

Therefore, there remains a need to develop pharmaceutical compositions containing MEI that are free from the above-mentioned disadvantages.

Disclosure of invention

The problem that the invention is aimed at solving is the creation of a pharmaceutical composition containing MEI in the form of a solid self-emulsifying system.

The technical result of the present invention is the development and creation of a pharmaceutical composition containing MEI in the form of a solid self-emulsifying system, which is characterized by high stability during storage, bioavailability and anti-inflammatory activity and does not cause pronounced ulcerogenic side effects in therapeutic doses. More specifically, the pharmaceutical composition according to the invention is characterized by improved pharmacokinetic properties - higher bioavailability and a prolonged profile (in particular, compared to the prototype), which ensures a rapid onset of effect and at the same time a long-term anti-inflammatory effect with a single dose. Moreover, the pharmaceutical composition according to the invention is suitable for the manufacture of simple dosage forms - hard and soft gelatin capsules. In this case, the pharmaceutical composition is stable during storage, including at room temperature, does not require storage at low temperatures.

The specified technical result is achieved through the development and creation of a pharmaceutical composition characterized by anti-inflammatory action, including:

- indomethacin menthyl ester in an amount of 5-25 wt.%, - at least one tocopherol or its pharmaceutically acceptable salt in an amount of 0.5-2 wt.%,

- at least one medium chain triglyceride in an amount of 10-50 wt.%,

- at least one polyethyleneglycol fatty acid ester with a melting point of 46-50 °C in an amount of 23-75 wt.%, wherein the ratio of medium-chain triglyceride and polyethyleneglycol fatty acid ester is in the range of 1:2 - 1:3.

In particular embodiments of the invention, the amount of at least one medium chain triglyceride is 20-30 wt.%.

In particular embodiments of the invention, the amount of at least one polyethylene glycol fatty acid ester is 50-70 wt.%.

In particular embodiments of the invention, glyceryl caprylocaprate is used as medium-chain triglycerides in an amount of 20-30 wt.%.

In particular embodiments of the invention, PEG-32 ester of palmitic and stearic acid is used as a complex ester of polyethylene glycol and fatty acids in an amount of 50-70 wt.%.

In particular embodiments of the invention, the tocopherol is alpha tocopherol, beta tocopherol, gamma tocopherol or delta tocopherol.

In particular embodiments of the invention, the pharmaceutically acceptable salt of tocopherol is acetate. In some embodiments of the invention, the tocopherol or its pharmaceutically acceptable salt is D-alpha tocopherol acetate.

In particular embodiments of the invention, the pharmaceutical composition according to the invention includes: indomethacin menthyl ester 25 mg

D-a-tocopherol acetate 2 mg glyceryl caprylocaprate 73 mg

PEG-32 esters of palmitic and stearic acid 175 mg

In particular embodiments of the invention, the pharmaceutical composition according to the invention is a solid self-emulsifying system.

The technical result is also achieved by using the pharmaceutical composition according to the invention for the manufacture of an oral dosage form.

In particular embodiments of the invention, the oral dosage form is a capsule. In more specific embodiments of the invention, the capsule is a hard or soft gelatin capsule. The subject of the present invention is also a capsule characterized by an anti-inflammatory effect, comprising a composition according to the invention, intended for oral administration.

In particular embodiments of the invention, the capsule is a hard gelatin or soft gelatin capsule.

In particular embodiments of the invention, the capsule is coated with an enteric coating.

In particular embodiments of the invention, the amount of the composition according to the invention in a capsule is 100-600 mg.

The present invention also includes the preparation of a pharmaceutical composition and/or capsule according to the invention.

Definitions (terms)

For a better understanding of the present invention, some terms used in the present description of the invention are provided below. The following definitions apply herein unless otherwise explicitly stated.

In the present description and in the following claims, unless the context otherwise requires, the words "have," "include," and "comprise," or variations thereof, such as "has," "having," "includes," "including," "contains," or "comprising," are to be understood as including the stated whole or group of wholes, but not excluding any other whole or group of wholes. These terms are not intended to be construed as "consists only of."

The term "and/or" means one, more, or all of the listed elements.

Also here, listing numeric ranges by endpoints includes all numbers within that range.

The term "optional" or "optional" or "optionally" as used herein means that the subsequently described event or circumstance may, but need not, occur and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur.

The term "self-emulsifying system" in this document means a self-emulsifying drug delivery system, which is a mixture of oils (lipid solvents), surface-active substances (surfactants) and, sometimes, co-solvents and co-surfactants, which spontaneously emulsifies in an aqueous medium to micro- and nano-sized particles. Self-emulsifying systems are used to improve the oral bioavailability (absorption in the gastrointestinal tract) of lipophilic, poorly water-soluble drugs. Depending on the consistency, self-emulsifying systems are liquid or solid. The term "medium chain triglycerides" in this document means triglycerides with two or three fatty acids having an aliphatic tail of 6-12 carbon atoms, i.e. fatty acids with an average chain length from C6 to C12 (in particular, the fatty acids are independently selected and are caproic, caprylic, capric or lauric acid). In particular embodiments of the invention, medium chain triglycerides are glyceryl caprylocaprate (glyceryl capryl ate/caprate), sold, in particular, under the trade names Miglyol® 812N, Kollisolv® MCT 70 and others. Medium chain triglycerides are used as oils (lipid solvents) for obtaining self-emulsifying systems.

The term "polyethylene glycol fatty acid esters" as used herein means a water-soluble or water-dispersible surfactant based on esters of polyethylene glycol (e.g., PEG-32 or other) and fatty acids (stearic, palmitic, lauric or other) or a mixture of polyethylene glycol fatty acid esters with mono-, di- and triglycerides of fatty acids.

Esters of polyethylene glycol and fatty acids reduce the surface tension between the lipid and aqueous phases in a self-emulsifying dispersed system and promote the formation of an emulsion. In particular embodiments of the invention, esters of polyethylene glycol and fatty acids are used, obtained from polyethylene glycol with 32 monomers and a molecular weight of 1500 (PEG-32) and palmitic (C16) and stearic (C18) fatty acids, known in particular as Gelucire® 48/16. Esters of polyethylene glycol and fatty acids are used as surfactants for obtaining self-emulsifying systems.

а-токоферол , R-| = R2 = R3 = СН₃ у-токоферол , R₁ = R₂ = СН₃ R3 = Н p-токоферол, R-, = R₃ = СН₃; R₂ = Н 6-токоферол , R₁ = R₂ = R₃ = Н The term "tocopherol" (vitamin E) in this document refers to a class of chemical compounds, methylated phenols, including stereoisomers. According to the number and location of methyl groups, a-tocopherol, P-tocopherol, y-tocopherol and 5-tocopherol are distinguished, the structure of which is as follows:

a-tocopherol, R-| = R2 = R3 = CH ₃ y-tocopherol, R ₁ = R ₂ = CH ₃ R3 = H p-tocopherol, R-, = R ₃ = CH ₃ ; R ₂ = H 6-tocopherol, R ₁ = R ₂ = R ₃ = H

Tocopherol in the context of the present invention may exist in free form or, if desired, in the form of a pharmaceutically acceptable salt. The used herein the term "pharmaceutically acceptable salt" refers to such salts which, within the framework of the medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, etc., and meet a reasonable benefit-risk ratio. Pharmaceutically acceptable salts in the form of salts of inorganic and organic acids, amino acids and other types of compounds are well known in medicine. Examples of pharmaceutically acceptable, non-toxic acid salts include acetate, carbonate, lactate, glycolate, succinate, glutamate, ascorbate, chloride, sulfate, phosphate. In some embodiments of the invention, the pharmaceutically acceptable salt of tocopherol is D-o-tocopherol acetate.

Some embodiments of the invention include a dosage form for oral delivery, in particular a dosage form in the form of a capsule. Further embodiments of the invention include a capsule containing a composition of the invention, and in various embodiments, the capsule is a hard or soft gelatin capsule, and in general, the capsule can optionally be coated with an enteric coating.

The term "capsules" in this document means a dosage form consisting of a hard or soft gelatin shell. In particular embodiments of the invention, the capsules are hard or soft gelatin capsules. Hard gelatin capsules have a cylindrical shape and consist of two parts that fit into each other without forming gaps. Hard gelatin capsules of various sizes can be used, preferably from 3 (capsule volume up to 0.27 ml) to 00 (capsule volume up to 0.95 ml), depending on the weight and volume of the capsule contents. Soft gelatin capsules are whole hermetically sealed capsules of various shapes (spherical, oblong, etc.) and various sizes depending on the weight and volume of the capsule contents.

По внешнему виду это мелкокристаллический порошок белого или почти белого цвета, без запаха, который хорошо растворим в хлороформе, растворим в спирте, умеренно растворим в диметилформамиде, практически нерастворим в воде, имеет температуру плавления от 73 до 75°С, не имеет каких-либо посторонних примесей. In this document, indomethacin menthyl ether (MEI), also having the chemical name 2-isopropyl-5-methylcyclohexyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1 H-indol-3-yl)acetate, is characterized by the following structural

In appearance, it is a finely crystalline powder of white or almost white color, odorless, which is well soluble in chloroform, soluble in alcohol, moderately soluble in dimethylformamide, practically insoluble in water, has a melting point of 73 to 75 ° C, and does not have any foreign impurities.

Detailed disclosure of the invention

As noted above, to solve the problem, the authors of the present invention developed a composition based on MEI in the form of a solid self-emulsifying system that combines manufacturability, storage stability, high bioavailability and anti-inflammatory activity when administered orally. Various approaches to obtaining such compositions using combinations of various lipid solvents, hydrophilic surfactants [4] and/or gelatin and other excipients [5] are known from the prior art. However, it should be taken into account that there is no universal approach to creating such compositions and the result is largely determined by the individual characteristics of the active substance - its physicochemical properties, its ability to interact with other components of the composition, as well as the influence of the biological environment (stomach contents) on the active substance and dispersion particles. Thus, the problem is not trivial.

The stated task is solved by creating a pharmaceutical composition containing MEI as an active substance and medium-chain triglycerides, polyethylene glycol esters of fatty acids, and tocopherol or its pharmaceutically acceptable salt as auxiliary substances, which provide high bioavailability and anti-inflammatory activity of MEI in the absence of ulcerogenic side effects.

To determine the solubility of MEI, excess MEI was mixed with fixed amounts of excipients (including medium-chain triglycerides and surfactants) or their mixtures and shaken for 48 hours at 25 °C to achieve equilibrium. The samples were then centrifuged to remove undissolved MEI, filtered through a 0.45 μm membrane filter, and the supernatant was used for spectrophotometric determination of the amount of MEI dissolved in each surfactant and/or lipid solvent.

The emulsifying ability of surfactants was assessed by mixing the surfactant with the selected lipid phase in a 1:1 weight ratio. The mixtures were vortexed and diluted to 200-fold dilution. The ease of emulsion formation was assessed by observing the number of inversions of the measuring flask required to obtain a homogeneous emulsion.

The development of the composition began with the evaluation of lipid solvents taking into account their stability, compatibility with MEI, fatty acid content, hydrophilic-lipophilic balance value and digestibility. It was unexpectedly discovered that the best solubility of MEI was provided by medium-chain triglycerides, such as glyceryl caprylocaprate, in particular - Miglyol® 812N (glyceryl caprylocaprate). The studies showed that the maximum solubility of MEI in Miglyol® 812N is 100 mg/1000 mg at a temperature of +20 °C. However, when the temperature decreases to +2 °C, the solubility decreases and MEI crystals precipitate.

Some polyethylene glycol fatty acid esters, water-soluble or water-dispersible surfactants based on polyethylene glycol esters (e.g., PEG-32 or other) and fatty acids (stearic, palmitic or others), have demonstrated good ability to dissolve MEI. Examples of polyethyleneglycol fatty acid esters include Gelucire® 44/14 (lauroyl polyoxyl-32 glycerides containing mono, di and triglycerides and PEG-32 mono- and diesters of lauric acid), Gelucire® 50/13 (stearoyl polyoxyl-32 glycerides containing mono, di and triglycerides and PEG-32 mono- and diesters of palmitic and stearic acids), Gelucire® 48/16 (polyoxyl-32 stearate containing PEG-32 esters of palmitic and stearic acids), which differ in melting point and hydrophilic-lipophilic balance index.

However, the required level of solubility of MEI was achieved only by using polyethylene glycol esters of fatty acids with a melting point in the range from 46 to 50 °C and a hydrophilic-lipophilic balance of 12 (Gelucire® 48/16). The use of such a hydrophilic-lipophilic balance makes it possible to combine the simplicity of the technology (MEI easily dissolves in a melt of polyethylene glycol esters of fatty acids and other auxiliary substances at a temperature of 45-55 °C) with the possibility of obtaining a solid self-emulsifying system.

As the conducted studies have shown, the ratio of medium-chain triglycerides (Miglyol® 812N) and polyethyleneglycol esters of fatty acids (Gelucire® 48/16) is of great importance for obtaining a stable composition based on MEI. The optimal ratio is in the range of 1:2 - 1:3. The studies have unexpectedly shown that when the ratio of these components is less than 1:2, the compositions delaminate. When the ratio is higher than 1:3, the compositions harden too quickly, which makes it difficult to fill the capsules.

The pharmaceutical composition obtained according to the invention acquires a solid consistency at room temperature and retains it at temperatures up to 32-35 °C. Such a pharmaceutical composition can be used for the manufacture various dosage forms, including both soft and hard gelatin capsules and tablets, which are common for NSAIDs.

As shown by the conducted studies, the pharmaceutical composition obtained according to the invention has high bioavailability and anti-inflammatory activity; it does not cause ulcerogenic action. Moreover, it was unexpectedly found that pharmaceutical compositions based on MEI and including polyethyleneglycol and fatty acid esters as surfactants provide better pharmacokinetic parameters - higher bioavailability and prolonged profile, which ensures rapid onset of effect and at the same time long-term anti-inflammatory action with a single dose. At the same time, despite the higher bioavailability, the claimed pharmaceutical compositions do not cause side ulcerogenic action with single and multiple administration.

Pharmaceutical compositions based on MEI and polyethylene glycol esters of fatty acids are stable with minimal use of antioxidants (only 0.5-2 wt.%), such as tocopherol or its pharmaceutically acceptable salts, in particular alpha-tocopherol acetate.

Example 1 Pharmaceutical compositions based on MEI in the form of a solid self-emulsifying system for the preparation of oral dosage forms

To obtain pharmaceutical compositions, the active substance used was MEI in an amount of 5-25 wt.% and auxiliary substances, including: medium-chain triglycerides, such as glyceryl caprylocaprate (Miglyol® 812N) in an amount of 10-50 wt.%; surfactants, including: polyethylene glycol esters of fatty acids, such as PEG-32 esters of palmitic and stearic acid (Gelucire® 48/16) in an amount of 23-75 wt.%; polyethylene glycol oxystearate glycerol (Kolliphor® RH40) in an amount of up to 20 wt.%; alpha-tocopherol polyethylene glycol succinate (TPGS) in an amount of 3-8 wt.%, which combines the properties of a surfactant and an antioxidant; antioxidant D-a-tocopherol acetate in an amount of 0.5-2 wt.%.

Preparation of the compositions. Pre-weighed medium chain triglyceride (in particular Miglyol® 812N), polyethylene glycol fatty acid ester (in particular Gelucire® 48/16) and a-tocopherol derivative (in particular Da-tocopherol acetate or TPGS) were loaded into a 100 ml beaker and heated with stirring in an ultrasonic bath until 45-55 °C until a homogeneous melt was obtained. Then the temperature was lowered to 38-43 °C and the pre-weighed MEI substance was added with thorough mixing until complete dissolution. The resulting mass was an oily yellow liquid, without foreign inclusions, and acquired a pasty consistency when cooled to room temperature. When testing for self-emulsification ability, about 100 mg of the pharmaceutical composition was added to 100 ml of distilled water at room temperature. As a result, a white emulsion with a blue tint stable for at least 24 hours was obtained. To obtain an oral dosage form, the pharmaceutical composition, heated to 40-45 °C, was added using an automatic dispenser into capsules, including hard gelatin capsules or soft gelatin capsules, the size of which was selected in accordance with the weight of the capsule contents. When cooled to room temperature, the contents of the capsules acquired a dense, pasty consistency.

Table 1 shows some of the studied samples of pharmaceutical compositions based on MEI in the form of a solid self-emulsifying system.

Table 1 - Compositions of samples of compositions based on MPEI

Composition No. 1 included polyethylene glycol fatty acid ester (Gelucire® 48/16) and alpha-tocopherol polyethylene glycol succinate (TPGS). In the absence of a lipid solvent (Miglyol® 812N), MEI dissolves in Gelucire® 48/16 at a ratio of at least 1:10, which leads to a high content of excipients. But the main disadvantage of such a composition is that it quickly solidifies (within 5-10 minutes at room temperature), which creates problems when packing (pouring) into capsules. The addition of a lipid solvent (Miglyol® 812N) provides better solubility of MEI and allows to reduce the absolute and relative content of Gelucire®48/16 and excipients in general (compositions No. 2-6).

In compositions with a low Gelucire 48/16 content, where the ratio of Miglyol® 812N and Gelucire® 48/16 reaches 2:1 (compositions No. 3, 4 and 5), partial delamination occurs during storage for 2 days at room temperature, especially for compositions No. 4 and 5. In addition, in these compositions, the release of MEI was impaired in the dissolution test (less than 75% was released within 45 minutes). The addition of other surfactants (including Kolliphor® RH40 and TPGS) did not eliminate the problem of low release.

Although the derivative of a-tocopherol TPGS is often used to obtain stable self-emulsifying systems, the results of the studies showed that TPGS does not have a significant positive effect on the solubility, stability and other characteristics of compositions with MEI. To ensure the stability of self-emulsifying systems with MEI according to the invention during storage, a-tocopherol acetate is used in a minimum amount - in the range from 0.5 to 2 wt.%, in particular 0.73 wt.% (composition No. 6).

Example 2 Study of the stability of pharmaceutical compositions during storage

Samples of pharmaceutical compositions No. 3 (comparison composition) and No. 6 (composition according to the invention), the compositions are indicated in Table 1 above, packaged in hard gelatin capsules, were placed in climatic chambers to study stability using two methods: accelerated study at elevated temperature (40±2)°C and humidity (70+5)%; long-term study at temperature (25±2)°C and humidity (60±5)%.

During storage, the following parameters were monitored:

Description or appearance - the samples studied were capsules filled with a viscous, pasty, light yellow, almost odorless substance.

Related impurities. Determination of related impurities in compositions with MEI was carried out by high-performance liquid chromatography (HPLC). The peak area of any foreign impurity on the chromatogram of the test solution should not be greater than the peak area on the chromatogram of the comparison solution (no more than 0.2%); the sum of the peak areas of all foreign impurities should not exceed 1.0%.

где S_n - сумма площадей пиков всех посторонних примесей на хроматограмме испытуемого раствора. The content of the sum of impurities in the substance in percent (A) was calculated using the formula: p

where S _n is the sum of the peak areas of all foreign impurities in the chromatogram of the test solution.

S is the area of the MEI peak on the chromatogram of the test solution;

Peaks whose area was less than 0.1% of the peak area on the chromatogram of the comparison solution (0.05%) were not taken into account.

Quantitative determination of the MEI content in capsules was carried out using the HPLC method.

где S - площадь пика МЭИ на хроматограмме испытуемого раствора; The content of MEI in percent (X) was calculated using the formula: 100,

where S is the area of the MEI peak on the chromatogram of the test solution;

S _n is the sum of the peak areas of all related impurities on the chromatogram of the test substance.

The MEI content in the capsule must be at least 99% of the sum of the peak areas on the chromatogram of the test solution.

The results of the stability study of samples of compositions No. 3 and No. 6 using the accelerated research method at elevated temperature (40±2)°C and humidity (70±5)% are presented in Table 2.

Table 2 - Results of stability testing of compositions using the accelerated study method

The results of the study of the stability of samples of compositions No. 3 and No. 6 using the long-term study method at a temperature of (25±2)°C and humidity of (60±5)% are presented in Table 3. Table 3 - Results of the stability test of the compositions using the long-term study method

As shown by the data presented in Tables 2 and 3, composition No. 3 is unstable under accelerated and long-term study conditions - an increase in the content of related impurities is noted, the sum of which after 6 months of storage exceeds the established limit of 1.0%. Composition No. 6 is stable in all indicators, including related impurities, throughout the study.

Example 3 Study of the pharmacokinetics of pharmaceutical compositions

The pharmacokinetic characteristics of the compositions based on MEI in the form of a solid self-emulsifying system (composition No. 6, see Table 1) were evaluated. For comparison, a composition based on MEI in the form of a liquid self-emulsifying system according to the prototype (RU2685257) was used - composition No. 0, containing the following excipients: lipid solvents Miglyol® 812N and Lipoid S 80, surfactants Kolliphor® RH40 and TPGS, as well as the antioxidant D-a-tocopherol acetate. All compositions, when dissolved in water, yielded a white emulsion with a blue tint that was stable for at least 24 hours, consisting mainly of nanosized particles with a diameter of less than 100 nm.

Sprague Dawley rats were used for the study. All pharmaceutical compositions were administered to the rats orally at a dose of 10 mg/kg. At certain time points (0; 0.25; 0.5; 1, 2, 4, 8, 16 and 24 hours), blood was collected from the animals for analysis. Blood was collected from the rats' heart cavity. The collected blood was centrifuged at 374 g to precipitate formed elements. Centrifuged plasma was collected in Eppendorf tubes in a volume of at least 1.0 ml. For analysis The content of the active metabolite of MEI - indomethacin (which provides the anti-inflammatory activity of the composition based on MEI) in the blood plasma of animals was determined using the HPLC method with detection on a photometric detector at an absorption wavelength of 320 nm, corresponding to the maximum absorption of MEI.

The following pharmacokinetic parameters were calculated:

Cmax is the maximum measured value of the concentration of indomethacin in the animal's blood plasma;

Tmax is the time until the maximum measured concentration of indomethacin in the animal's blood plasma is reached;

kei — константа скорости первого порядка, связанная с терминальной частью кривой. Данный параметр вычисляли путем анализа регрессии наименьших линейных квадратов с использованием не менее трех последних и более значений концентрации плазмы крови крыс, не равных нулю; AUCo-t is the area under the concentration-time curve in the interval from 0 to the moment t of collection of the last blood sample, calculated by the linear trapezoidal method:

kei is the first-order rate constant associated with the terminal portion of the curve. This parameter was calculated by least-squares linear regression analysis using at least the last three or more non-zero values of rat blood plasma concentration;

T1/2 is the half-life of the active substance:

Ti/2 = ln(2)/kei.

The pharmacokinetic parameters and plasma profiles of indomethacin after administration of the studied samples are presented in Table 4.

Table 4 - Pharmacokinetic parameters of indomethacin in rat blood plasma after intragastric administration of compositions at a dose of 10 mg/kg

Considering that the compared samples of solid and liquid self-emulsifying systems provided the same type of stable nanosized emulsion, it was expected to see similar pharmacokinetic characteristics. However, it unexpectedly turned out that the compositions declared in the invention in the form of solid self-emulsifying systems provide significantly higher bioavailability of MEI in comparison with the prototype - the AUCo-t value for composition No. 6 was 43% higher than the AUCo-t value for compositions No. 0 (p < 0.05). It is also worth noting the more prolonged pharmacokinetic profile of composition No. 6 in comparison with prototype, as evidenced by lower values of the elimination constant ( _Kei ) and higher values of the half-life (T1/2). The faster achievement of the maximum concentration was also unexpected - the value of _Tmax for composition No. 6 was only 1.6 hours compared to 4.4 hours for composition No. 0 (p < 0.05). Thus, despite the known risks of emulsification disorders and the unpredictability of the pharmacokinetic profile when using solid self-emulsifying systems, the composition according to the invention ensures faster absorption and higher bioavailability, which should lead to a more pronounced anti-inflammatory effect.

Example 4 Anti-inflammatory activity of pharmaceutical compositions

The anti-inflammatory activity of pharmaceutical compositions in the form of a solid self-emulsifying system (composition No. 6) and a liquid self-emulsifying system (composition No. 0, described in Example 3) was assessed upon their oral administration at a dose of 10 mg/kg in a model of acute inflammation - carrageenan-induced paw edema in rats. Indomethacin at a dose of 5 mg/kg, corresponding to the range of doses with the maximum anti-inflammatory activity of indomethacin in the carrageenan edema model [6], was used as a comparison drug. Male Sprague Dawley rats were used. The test substances were administered intragastrically 2 hours before the administration of the inflammation inducer - carrageenan. 2 hours after the administration of the substances, an injection of 1% aqueous solution of carrageenan was made under the plantar aponeurosis of the hind right paw of the rat. The inflammation value was assessed 4 hours after the introduction of the inflammation inducer using a UGO BASIL plethysmometer (Italy). The inflammatory reaction (edema) value was assessed as the difference between the weight of the control and experimental paws in ml. The edema value in the control group was taken as 100%. The anti-inflammatory activity of the studied substances was assessed as the edema value expressed as a % relative to the average edema value in the control group. The results of the study are presented in Table 5.

Table 5 - Anti-inflammatory activity of pharmaceutical compositions based on MEI and indomethacin in the carrageenan edema model in rats.

The obtained data show that the pharmaceutical compositions claimed in the invention in the form of solid self-emulsifying systems (composition No. 6) are, at a minimum, are not inferior to the prototype (composition No. 0) in anti-inflammatory activity in the acute inflammation model, approaching in the severity of the effect to indomethacin - one of the most powerful NSAIDs.

For the most effective pharmaceutical composition (No. 6), the dose-effect relationship was assessed. The results are presented in Table 6.

Table 6 - Anti-inflammatory activity of pharmaceutical composition No. 6 and indomethacin in the carrageenan edema model in rats

The presented data show that the pharmaceutical composition containing MEI in the form of a solid self-emulsifying system has high anti-inflammatory activity when administered orally. In particular, composition No. 6, containing MEI at a dose of 40 mg/kg, is not inferior in anti-inflammatory activity to indomethacin used at the maximum possible dose - 10 mg/kg, close to the half-lethal dose (LD50), which is 11.5 - 15 mg/kg for rats.

Example 5 Acute toxicity of pharmaceutical compositions

The acute toxicity of compositions based on MEI in the form of a solid self-emulsifying system (composition No. 6, described in Example 1) and a liquid self-emulsifying system according to the prototype (composition No. 0, described in Example 3 above) was assessed.

Acute toxicity was assessed using outbred pathogen-free female mice of the CD-1 stock. The animals were divided into groups (6 animals each). The studied compositions were administered to mice intragastrically once as a solution in water in a volume of no more than 1 ml at a dose (according to MPEI) of 2000, 1000, 500, 250, 125 and 0 mg/kg.

Clinical observation of animals was carried out continuously in the first hours after administration, then twice a day for 14 days after administration. Mortality was recorded, toxic manifestations and general condition of animals were assessed. After 14 days, euthanasia of surviving animals was performed with subsequent planned necropsy.

Table 7 shows the values of the half-lethal dose (LD50) for a female mouse.

Table 7 - Average LD50 values after a single intragastric administration of MEI-based compositions to mice (X ± SE, mg/kg)

The obtained data show that the samples of pharmaceutical compositions based on MEI according to the claimed invention and the prototype have similar parameters of acute toxicity (there are no statistically significant differences between different samples). The tendency towards lower LD50 values for compositions in the form of solid self-emulsifying systems (composition No. 6) is possibly associated with their higher bioavailability, as shown in Example 3. In any case, the LD50 values of pharmaceutical compositions based on MEI according to the claimed invention are in the range of 500-1000 mg/kg, i.e. 20-40 times higher than the LD50 of indomethacin, which demonstrates the high safety of using such compositions.

The examples provided convincingly demonstrate that the pharmaceutical compositions based on MEI in the form of solid self-emulsifying systems declared in the invention are easy to manufacture, unlike the prototype, are suitable for the manufacture of simple oral dosage forms (such as hard gelatin capsules) and are highly stable during storage. The declared compositions have high bioavailability, have a pronounced anti-inflammatory effect and are characterized by low toxicity.

List of references, which are included in this description of the invention as references:

1. US 8,097,646.

2. Sawraj Sh., Bhardawaj T.R., Sharma P.D Design, synthesis, and evaluation of novel indomethacin-antioxidant codrugs as gastrosparing NSAIDs. Med Chem Res (2012) 21:834–843.

3. RU2685257.

4. RU2321404.

5. WO2015078936.

6. Nezic L et al. Simvastatin and indomethacin have similar anti-inflammatory activity in a rat model of acute local inflammation. Basic Clin Pharmacol Toxicol. Mar 2009; 104(3): 185-91.

Claims

Invention formula 1. A pharmaceutical composition characterized by anti-inflammatory action, including: - indomethacin menthyl ester in an amount of 5-25 wt.%, - at least one tocopherol or its pharmaceutically acceptable salt in an amount of 0.5-2 wt.%, - at least one medium chain triglyceride in an amount of 10-50 wt.%, - at least one polyethyleneglycol fatty acid ester with a melting point of 46-50 °C in an amount of 23-75 wt.%, wherein the ratio of medium-chain triglyceride and polyethyleneglycol fatty acid ester is in the range of 1:2 - 1:3. 2. The pharmaceutical composition according to claim 1, wherein the amount of at least one medium chain triglyceride is 20-30 wt.%. 3. The pharmaceutical composition according to claim 1, wherein the amount of at least one polyethylene glycol fatty acid ester is 50-70 wt.%. 4. A pharmaceutical composition according to claim 1, in which glyceryl caprylocaprate is used as medium-chain triglycerides in an amount of 20-30 wt.%. 5. A pharmaceutical composition according to claim 1, in which the polyethylene glycol fatty acid ester used is PEG-32 palmitic and stearic acid ester in an amount of 50-70 wt.%. 6. The pharmaceutical composition according to claim 1, wherein the tocopherol is alpha tocopherol, beta tocopherol, gamma tocopherol or delta tocopherol. 7. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable tocopherol salt is acetate. 8. The pharmaceutical composition according to claim 1, wherein the tocopherol or its pharmaceutically acceptable salt is D-alpha tocopherol acetate. 9. A pharmaceutical composition according to claim 1, comprising: indomethacin menthyl ester 25 mg D-a-tocopherol acetate 2 mg glyceryl caprylocaprate 73 mg PEG-32 esters of palmitic and 175 mg stearic acid. 10. The pharmaceutical composition according to claim 1, which is a solid self-emulsifying system. 11. Use of a pharmaceutical composition according to any of claims 1-10 for the manufacture of an oral dosage form. 12. Use according to claim 11, wherein the oral dosage form is a capsule. 13. The use according to claim 12, wherein the capsule is a hard or soft gelatin capsule. 14. A capsule characterized by an anti-inflammatory effect, comprising a composition according to any one of claims 1-10, intended for oral administration. 15. The capsule of claim 14, wherein the capsule is a hard gelatin or soft gelatin capsule. 16. The capsule according to claim 14, wherein the capsule is coated with an enteric coating. 17. The capsule according to claim 14, in which the amount of the composition is 100-600 mg.