RU2721282C2 - Method for treating multiple sclerosis (versions) - Google Patents

Abstract

FIELD: medicine; neurology.SUBSTANCE: invention refers to treating multiple sclerosis. That is ensured by administering somatotropin in amount of 0.05 to 0.5 IU/kg of body weight, or insulin-like growth factor 1 (IGF-1) in amount of 50 to 500 mcg/kg of body weight, or their physiological inducers.EFFECT: this provides effective reduction of the disease symptoms with no side effects.4 cl, 2 tbl, 2 ex

Description

FIELD OF THE INVENTION

The present invention relates to medicine, in particular to methods for the treatment and / or prevention of multiple sclerosis (MS) by the administration of growth hormone (somatotropin) and / or somatomedin C (IGF-1) or their physiological inducers in need of this subject.

BACKGROUND OF THE INVENTION

Myelin is a multilayer plasma membrane that forms the myelin sheath around nerve fibers, in particular around oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system, around the axons of neurons, which acts as an electrical insulator, which helps increase the speed of the nerve impulse. Destruction of the myelin sheath, which is approximately 70% lipid and approximately 30% protein, leads to sclerosis and autoimmune diseases.

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the myelin sheath of nerve fibers due to an attack by the immune system on the central nervous system. As a result of the formation of foci of myelin damage (demyelination) of the white matter of the brain and spinal cord, the conductivity of signals between nerve cells is disrupted. MS is a multifactorial disease in the pathogenesis of which external factors, such as viral infections, as well as internal factors, namely, a genetic predisposition, can be involved. The etiology of MS is still not clear, which is an obstacle to the development of etiotropic treatment.

Clinical manifestations of MS are evaluated using subject condition scales that assess the severity of symptoms of lesions of various brain conducting systems and the degree of disability, such as the Functional System Status Scale (FSS) and the Extended Disability Assessment Scale (EDSS) (Kurtzke JF (1983). "Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). "Neurology 33 (11): 1444-1452; Collins et al. A comparative analysis of Patient-Reported Expanded Disability Status Scale tools. Mult Scler. 2016 Sep; 22 (10 ): 1349-1358).

Four types of MS are described (Neurology (1996) 46; 901-911): remitting-relapsing (RRRS, RRMS), in which periods of exacerbation are replaced by periods of recovery (remission) without worsening symptoms between relapses; secondary progressive (SPMS, SPMS), characterized by a relapsing-relapsing course of the disease with subsequent deterioration of neurological manifestations; primary progressive (PPMS, PPMS), characterized in that in patients with this type of MS there are no periods of remission after the initial symptoms; progressive-relapsing (PRRS, PRMS), manifested in sustained neurological deterioration from the very beginning of the disease and the development of obvious exacerbations against the background of slow progression.

Symptoms of MS are diverse and occur during periods of relapse with a gradual progressive depletion of neurological functions. Symptoms can be expressed by muscle weakness, impaired coordination of muscle movements (ataxia) of the trunk and limbs, paresis, tremor, visual impairment. Often observed a decrease in sensitivity, including without a clear localization, impaired function of the pelvic organs, decreased intelligence, depression, impaired behavior. The first clinical symptoms of multiple sclerosis usually appear in patients aged 18 to 45 years, although the debut of MS is described for both children and the elderly.

WO 2010/128035 discloses the use of an antibody specific for GM-CSF (granulocyte macrophage colony stimulating factor) or its receptor in the treatment or prevention of multiple sclerosis. Introduction to the subject of antibodies to GM-CSF leads to a decrease in the proliferation of T cells, their release of IL-17 (interleukin-17).

WO 2010/147665 discloses a method for reducing the recurrence rate and reducing the development of physical disability in relapsing-remitting MS (RRRS) by daily oral administration of 0.6 mg of laquinimod, which is a phenylquinolone derivative.

US 2017290842 and WO 2012/123938 describe the use of a family of compounds including CX-5461 and its derivatives having anti-inflammatory activity for the treatment and / or regulation of PPPs by administering CX-5461, which inhibits the activity of RNA polymerase I, and thus inhibits inflammation and enhances apoptosis of autoreactive lymphocytes.

WO 2017165367 describes a method for inducing remyelination for the treatment of PPP using a composition containing siRNA (small interfering RNA) that inhibits the activity, synthesis or expression of a protein bound to low density lipoprotein 1 (LRP1).

Known drug for the treatment of multiple sclerosis Betaferon containing recombinant human interferon-β-1b, from the company Bayer Pharma AG. The disadvantages of this drug is the rather low efficiency of its use - a decrease in the frequency of exacerbations of the disease and their severity occurs only by 30%, as well as the presence of side effects such as increased depressive symptoms (Sokolova E.S., Totolyan N.A., Klimenko V.M. 2003. Psycho-emotional changes in the treatment of patients with multiple sclerosis with betaferon // Stress and Behavior VII Interdisciplinary Conference on Biological Psychiatry, Novosibirsk).

Known immunomodulating drug Copaxone containing the active ingredient glatiramer acetate from the company Teva, which is a polymer of four levorotatory isomers of the acetic acid salts of the synthetic polypeptides of glutamine, lysine, alanine and tyrosine. Copaxone does not show benefits in the treatment of primary progressive and secondary progressive multiple sclerosis.

Despite the variety of available therapeutic agents in this area, there remains a need for the development of effective approaches to the treatment of multiple sclerosis. This is primarily necessary in order to increase the arsenal of possible therapeutic agents for the choice of the attending physician, including providing new therapeutic opportunities for patients who are not responding or unsatisfactory to existing therapy, or suffering from side effects of such therapy, as well as to offer new opportunities combination therapy, offering new therapeutic approaches that can be combined with existing to achieve the above goals. It is also necessary to reduce the cost of treatment for patients, since the products available on the market are usually expensive. The present invention is directed to solving these problems.

SUMMARY OF THE INVENTION

The author of the present invention unexpectedly found that for the effective treatment of multiple sclerosis, active substances such as somatotropin and immunoglobulin growth factor 1 (IGF-1, also referred to as somatomedin C) can be used, and in quantities that exceed the quantities of these substances that were considered acceptable for administration to patients. In addition, the author found that the problem according to the invention is equally solved using physiological inducers of somatotropin and / or IGF-1. The treatment of multiple sclerosis is understood here, in particular, to alleviate the symptoms, reduce the frequency of relapses and stimulate the regeneration of the myelin sheaths of neurons, i.e., all that have beneficial effects on the course of the disease in the subject.

Thus, the present invention allows the treatment of multiple sclerosis effectively, but while providing the necessary safety in terms of the occurrence and / or severity of side effects.

Growth hormone (also called growth hormone or growth hormone) is a pituitary growth hormone having a molecular weight of about 22 kDa and 191 amino acid residues. Somatotropin is necessary for postnatal growth and for the normalization of carbohydrate, lipid, nitrogen and mineral metabolism. A number of substances are known to affect the secretion of growth hormone, including protein foods, certain amino acids, such as arginine, lysine, ornithine and glutamine, clonidine, moxonidine, baclofen, estrogens, dopamine, intestinal hormones, such as release of growth hormone peptides (GHRP) and ghrelin, serotonin, amphetamine, propanolol, glucagon, thyroid hormones, vasopressin and others.

Growth effects of growth hormone are mainly mediated by IGF-1, a protein similar to insulin. IGF-1 consists of 70 amino acid residues, has a molecular weight of 7.6 kDa and enters the bloodstream mainly from the liver, and its secretion is stimulated by growth hormone. It is known that IGF-1 has a direct regulatory effect on hematopoiesis, in particular lymphopoiesis and the functioning of the immune system (Clark P., 1997), stimulates the differentiation and transition of pro-B to pre-B cells (Landgreth K. et al, 1992 ) and in synergy with IL-7, activates B cell proliferation (Gibson LF et al, 1993), functions in the metabolism of oligodendrocytes and myelin in vivo (Komoly, S. et al. (1992) Proc. Natl. Acad. Sci. USA 89: 1894-1898). The secretion of IGF-1 is affected by such substances as glutamine, arginine, angiotensin-II, baclofen, ghrelin, thyroid hormones, growth hormone, sterilglucosides (SG), such as acylated sterile-β-glucosides (ASG) and others.

Thus, the above discovery of the inventor led to the creation of the following technical solutions that solve the problem.

In one embodiment of the invention, there is provided a method of treating multiple sclerosis, comprising administering a somatotropin in a therapeutically effective amount to a subject in need thereof.

In yet another embodiment of the invention, there is provided a method of treating multiple sclerosis, comprising administering to a subject in need thereof an insulin-like growth factor 1 (IGF-1) in a therapeutically effective amount.

In another embodiment of the invention, there is provided a method of treating multiple sclerosis, comprising administering to a subject in need thereof a physiological inducer of somatotropin and / or IGF-1 in a therapeutically effective amount.

Similarly, the invention encompasses the use of growth hormone as a medicine for treating multiple sclerosis in a subject, the use of IGF-1 as a medicine for treating multiple sclerosis in a subject, and finally the use of a physiological inducer of growth hormone and / or IGF-1 as a drug agents for treating multiple sclerosis in a subject.

In addition, the invention relates to the use of growth hormone and / or IGF-1 and / or their physiological inducers for the manufacture of a medicament for the treatment and / or prevention of multiple sclerosis or its individual symptoms.

The applied amount of growth hormone according to the invention can be, for example, from 0.05 to 0.5 IU / kg of the body weight of the subject. The amount of IGF-1 used according to the invention can be, for example, from 50 to 500 μg / kg of the body weight of the subject. The preferred mode of administration of growth hormone, IGF-1, as well as their physiological inducers, can be once or twice a day for 10-60 days. It should be noted that, depending on the therapeutic expediency, other doses and the administration regimen can be selected. The active substances of the invention are usually administered in the form of a pharmaceutical composition having a dosage form suitable for the desired administration.

The methods and active substances of the invention can be used in combination to treat the same subject, for example, somatotropin, IGF-1, and one or more physiological inducers thereof can be administered to the subject in any combination as a single combined composition or in several compositions separately.

It is also advisable to combine the methods and applications of the invention with other known therapeutic factors. In one embodiment of the invention, the administration of somatotropin, IGF-1 or their physiological inducers may be accompanied by the additional administration of interferon-β-1b, in particular recombinant human interferon-β-1b. Preferably, recombinant human interferon-β-1b is administered in an amount of 33 to 330 mg / kg of subject body weight; the administration regimen may coincide with the administration regimen of growth hormone, IGF-1 and their physiological inducers, preferably once or twice a day for 10-60 days.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise specified in this application, the scientific and technical terms used in connection with the present invention have meanings that are commonly understood by those skilled in the art. In general, the nomenclature and methods used for cell and tissue culture, molecular biology, immunology, microbiology, genetics and chemistry of proteins and nucleic acids, hybridization, analytical chemistry, synthetic organic chemistry and medical and pharmaceutical chemistry described in this application are nomenclature and methods well known and commonly used in the art.

The terminology used here is intended to describe specific embodiments of the invention and is not limiting. When used in the present description and claims, the singular forms include the plural, unless the context clearly indicates otherwise.

The term "inducer" refers to a molecule that stimulates the expression of genes in an inactive state. Inductors can also function by binding to activators. In the absence of an inducer, activators, as a rule, weakly bind to DNA, while the formation of a complex of an inductor with an activator increases the activity of the latter many times, after which such a complex binds to an activated sequence and initiates transcription of the target gene. Examples of such inducers can be arginine, lysine, ornithine and glutamine, clonidine, moxonidine, baclofen, estrogens, dopamine, intestinal hormones such as releasing growth hormone peptides (GHRP) and ghrelin, serotonin, amphetamine, propanolol, glucagonin thyre, , angiotensin-II, steryl glucosides (SG), such as acylated sterile β-glucosides (ASG) and other substances.

References to amino acid residues used in this application are denoted by a single letter or three letter code (see, for example, Lehninger, Biochemistry, 2 ^nd edition, Worth Publishers, New York, 1975, p. 72).

The term “peptide” or “polypeptide” refers to a polymer of amino acids regardless of the length of the polymer; thus, protein fragments, oligopeptides and proteins are included in the definition of a peptide or polypeptide. This term also does not define or exclude post-expression modifications of polypeptides, for example, polypeptides, which include the covalent attachment of glycosyl groups, acetyl groups, phosphate groups, lipid groups and the like, are expressly encompassed by the term “polypeptide”. The definition also includes polypeptides that contain one or more amino acid analogues (including, for example, non-naturally occurring amino acids, amino acids that are found in nature only outside the unrelated biological system, modified amino acids from mammalian systems, etc.), polypeptides with substituted bonds, as well as other modifications known in the art, both natural and non-natural.

The term “about” and similar ones, such as “about” and “about”, when used here together with a specific value, indicate that this value can vary within a typical measurement error.

The term "treatment" as applied to a person, animal or other subject refers to therapeutic treatment, prophylactic or preventive measures for research and diagnostic applications. The term "treatment" refers to the treatment, alleviation, inhibition of progression, or the prevention of a disorder or condition in relation to which the term is used, or one or more symptoms of such a disorder or condition. The term covers the full range of treatment methods for a particular condition from which the subject suffers, for example, administering an active substance or composition containing it in order to alleviate or alleviate symptoms or complications; slowing the progression of the condition, partial relief of the clinical manifestations of the disease or disorder; cure or eliminate the condition, disease or disorder and / or prevent or reduce the risk of developing the condition, disease or disorder. The terms "prevention" or "prophylaxis" mean a system of measures and patient care to prevent the development of a condition, disease or disorder and mean the introduction of active compounds to prevent or reduce the risk of symptoms or complications.

The term "introduction" when applied to biological objects, such as an animal, human, experimental subject, cell, tissue, organ or biological fluid, refers to the contacting of an exogenous pharmaceutical, therapeutic agent, diagnostic agent or composition with a biological object comprising an animal, human, subject, cell, tissue, organ, or body fluid. The term “administration” may refer, for example, to therapeutic, pharmacokinetic, diagnostic, research and experimental methods. The treatment of cells includes bringing the reagent into contact with the cell, as well as bringing the reagent into contact with the fluid, where the fluid is in contact with the cell. The term “administration” also means methods of processing in vitro and ex vivo, for example, a cell, a reagent, a diagnostic agent, a binding compound, or another cell.

The term "autoimmune disease" is understood in its usual meaning, and refers to a disease that develops as a result of an immune response against own tissues or tissue components, including both a humoral immune response and cell-mediated responses.

The term “subject,” as used herein, refers to any mammal, including rodents, such as a mouse or rat, guinea pigs and primates such as Javanese macaque (Masasa fascicularis), rhesus macaques (Masasa mulatta) or humans (Homo sapiens). Preferably, the subject is a primate, most preferably a human.

As used herein, the terms “therapeutically effective dose” or “therapeutically effective amount” or “pharmaceutically effective dose” or “pharmaceutically effective amount” means a dose having effects for which it is administered. Typically, a therapeutic agent is administered in an amount effective to alleviate one or more diseases or conditions of a patient or population to be treated (either by inducing regressions of these diseases or conditions, or by inhibiting the progression of such diseases or conditions to any clinically measurable degree.

The term "pharmaceutical composition" refers to a mixture containing one or more active substances in accordance with the present invention together with other components, in particular physiologically / pharmaceutically acceptable excipients (excipients). The pharmaceutical composition should have a composition optimized for the desired route of administration of the active ingredient into the body and, ultimately, the manifestation of a biological effect.

"Pharmaceutical" or "pharmaceutically acceptable" refers to chemical compounds and compositions that do not lead to adverse, allergic or other undesirable reactions when administered to a mammal, in particular humans, or such reactions are minimized. Pharmaceutically acceptable excipient refers to a non-toxic solid, a soft or liquid filler, diluent, capsule material, or other excipient of any type.

The term "pharmaceutically acceptable salt" refers to a salt formed by the compounds used in the present invention and an acid or base that is suitable for inclusion in a drug. Pharmaceutically acceptable salts include inorganic and organic salts. A preferred type of salt is the salt formed by the compounds of the present invention and acid. Suitable salt-forming acids include: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and the like, but are not limited to. Another preferred type of salts are salts formed by the compounds of the present invention and bases, for example, alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts), ammonium salts (e.g. ammonium salts lower alkanols or other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethyl salt amine salts formed by morpholine, piperazine and lysine.

"Pharmaceutically acceptable carrier" means one or more compatible solid, semi-solid or liquid excipients that are suitable for administration to a subject and must be of sufficient purity and sufficiently low toxicity. “Compatibility” as used herein means that the components of a composition can be mixed with the compounds of the invention or with each other, and they will not significantly reduce the effectiveness of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), moisturizer (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The term "prodrug" refers to peptides that are rapidly converted in vivo to form the basic compound of the above formulas, for example, by hydrolysis in the blood or by metabolism in cells, such as, for example, basal ganglia cells. For a detailed discussion, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. Examples of prodrugs include pharmaceutically acceptable non-toxic esters of the compounds of the present invention. Esters of the compounds of the present invention may be prepared by conventional methods: «March's Advanced Organic Chemistry, 5 ^{th Edition» MB Smith & J. March} , John Wiley & Sons, 2001.

Methods of administering the active substances of the invention. Pharmaceutical composition

Somatotropin, IGF-1 or their inducers are usually administered in the form of a pharmaceutical composition. Accordingly, in one embodiment, the invention also relates to a pharmaceutical composition for treating and / or preventing multiple sclerosis containing somatotropin. In another embodiment, the invention relates to a pharmaceutical composition for treating and / or preventing multiple sclerosis containing IGF-1. In yet another embodiment, the invention relates to a pharmaceutical composition for the treatment and / or prophylaxis of multiple sclerosis containing somatotropin and IGF-1. In one embodiment, the invention also relates to a composition comprising one or more physiological inducers of somatotropin and / or IGF-1. The pharmaceutical compositions or substances of the invention may contain pharmaceutically acceptable excipients (excipients), including carriers, diluents, adjuvants, etc. Examples of excipients are well known in the art and, for example, are described in Remington: The Science and Practice of Pharmacy, 20 ^th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 2000.

The compositions of the invention can be prepared in various ways, in accordance with methods well known to those skilled in the art, for example, from Remington: The Science and Practice of Pharmacy (Lippincott Williams &Wilkins; Twenty first Edition, 2005), WO 1993025222, WO 1990011070, EU 1991462959. Pharmaceutically acceptable excipients that may be used are, in particular, those described in Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association (Pharmaceutical Press; 6th revised edition, 2009).

In one embodiment, the pharmaceutical composition of the invention comprises somatotropin and / or IGF-1 and / or one or more physiological inducers of samototropin and / or IGF-1 in an amount effective to provide therapy for multiple sclerosis (MS), in particular, to reduce and / or slowing the degree of disability in MS. In one preferred embodiment, the composition of the invention further comprises recombinant human interferon-β-1b in a therapeutically effective amount.

The administration of the composition of the invention can be accomplished in a variety of ways, including without limitation the oral, subcutaneous, intravenous, parenteral, intranasal, intraorthical, intraocular, rectal, vaginal, transdermal, intraperitoneal, intramuscular, intrapulmonary or intrathecal routes of administration.

The composition of the invention can be administered in parallel with other therapeutic agents, i.e., the therapeutic agents described herein can be administered in parallel, simultaneously or sequentially with other pharmacotherapeutic agents or against other therapeutic effects on the body, for example radiation therapy, physiotherapy , surgery, etc. Any of the active substances that make up the compositions of the invention can be administered indirectly by introducing an exogenous nucleic acid, for example, DNA or RNA encoding the corresponding active substance, resulting in expression of the introduced nucleic acid.

The pharmaceutical compositions of the invention are formulated into a dosage form suitable for the desired route of administration.

In some embodiments, the composition of the invention is in solid form, including capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compounds are mixed with at least one conventional inert excipient, for example, with any of the following components: (a) a filler or compatibilizing agent, for example starch, lactose, sucrose, glucose, mannitol or salicylic acid: ( b) binders, for example hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) a humectant such as glycerin; (d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain mixed silicates and sodium carbonate; (e) dissolution retarding agents such as paraffin; (e) absorption accelerators, for example, quaternary ammonium compounds; (g) plasticizers, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, such as talc, calcium stearin, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. Dosage forms may also contain buffering agents.

Solid dosage forms such as tablets, capsules, pills and granules may contain a coating and coatings, such as enteric coatings and any other materials known in the art. They may contain an opaque agent. The release of active compounds or compounds in the compositions may be delayed in a certain part of the digestive tract. Examples of encapsulating components include polymers and waxes. If necessary, the active compounds and one or more than one of the above excipients can form microcapsules.

The solid pharmaceutical composition of the invention may be in the form of a lyophilisate, suitable for the preparation of a liquid preparation for injection (intramuscular, subcutaneous, etc.) or oral administration.

Liquid dosage forms may, for example, be a solution or suspension of one or more of the present compounds and optionally pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerin, ethanol and the like. If necessary, the pharmaceutical composition for administration may also contain other non-toxic adjuvants, such as wetting or emulsifying agents, pH buffering agents, etc. Typical examples of such adjuvants are sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate and etc. Practical methods for preparing such dosage forms are known or will be apparent to those skilled in the art, for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 16th Edition, 1980. In one embodiment, for parenteral administration use solutions of the peptides used in the present invention in a sterile aqueous solution, in aqueous propylene glycol, or in sesame or peanut oil. Aqueous solutions should be appropriately buffered when appropriate, and the liquid diluent made isotonic, for example, using appropriate saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All sterile aqueous media used can easily be prepared by standard methods known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or excipients, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, magnesia, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and lower alkyl cellulose ethers. Examples of liquid carriers are syrup, peanut butter, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. In addition, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in admixture with a wax. Pharmaceutical compositions prepared by combining the compounds of the present invention and pharmaceutically acceptable carriers can then be readily administered in various dosage forms suitable for the described routes of administration. The preparations can be conveniently provided in unit dosage form using methods known in the pharmaceutical art.

The active substances of the invention can be found in the pharmaceutical composition when they are enclosed in microcapsules, for example from a lactide-glycolide copolymer (PLGA), as well as into liposomes or virus-like particles, etc.

Growth hormone for use in the invention can be obtained by any known method; may be of natural or synthetic origin. The most convenient is the use of recombinant growth hormone (rhGH), methods for which are well known, for example from US 8178108.

Somatotropin can be presented in any modification in which the hormone activity is preserved and at the same time, preferential properties are given. For example, somatotropin may be in the form of complexes, in particular a complex with zinc. Another modification includes conjugates of growth hormone with polymers, for example, polyethylene glycol. In addition, a hybrid somatotropin may be used containing additional domains, for example, facilitating delivery of a protein to a target, for example, a somatotropin-transferrin fusion protein. Finally, various somatotropin isoforms can be used. In the present description and in the claims, all of these options are covered by the term "growth hormone", "growth hormone", etc.

Similarly, IGF-1 can also be a protein of natural or synthetic origin, for example, recombinant IGF-1, the method of preparation of which is known, for example, from US5262308. As in the case of growth hormone, IGF-1 can be a complex, conjugate, hybrid, isomorph, in which case activity is maintained and additional advantageous properties appear. In the present description and in the claims, all of these options are covered by the term "IGF-1", "somatomedin C", etc.

The physiological inducers of somatotropin and / or IGF-1 can be obtained by known methods, chemical or microbiological, and can also be obtained from natural sources, which also applies to amino acids, in particular lysine, arginine and glutamine, acylated sterile-β-glucosides and other inductors.

Treatment methods

In order to treat a subject suffering from multiple sclerosis, he is administered a therapeutically effective dose of the active substances as described above, in particular in the pharmaceutical composition of the invention.

In one embodiment, the present invention relates to a method for treating, preventing and / or preventing multiple sclerosis and / or one or more of its symptoms, which comprises administering to a subject an active substance that is somatotropin and / or insulin-like growth factor 1 (IGF-1) and / or their physiological inducers selected from the group consisting of arginine, lysine, glutamine and acylated sterile-β-glucoside, or a composition containing the specified active substance, in a therapeutically effective amount. In particular, a composition comprising one or more than one active substance according to the invention is administered to a subject. In an alternative embodiment, the subject is administered several compositions containing the individual active substances of the invention. Moreover, they can be administered simultaneously, sequentially or separately.

The treatment of a subject suffering from multiple sclerosis is not necessarily limited to the administration of the active substances or compositions of the invention; any other therapeutic effects known to those skilled in the art can be used, including other active substances, in particular interferon-β-1b. This substance can be included in the compositions described above or administered separately, in particular as part of another pharmaceutical composition, simultaneously, sequentially or separately relative to the active substances or compositions according to the invention.

Doses and duration of treatment

The amount of active substance administered according to the invention is determined, as a rule, based on the body weight of the subject.

Somatotropin is preferably used in an amount of from about 100 to 600 μg / kg of subject body weight. For example, this amount can be from 100, 125, 150, 175, 200, 225, 250, 275 or 300 μg / kg of body weight of the subject and up to 600, 575, 550, 500, 475, 450, 425, 400, 375, 350 or 325 μg / kg of subject body weight. The amount of growth hormone can be expressed in international units and range from 0.05 to 0.5 IU / kg of body weight of the subject. For example, this amount may be from 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16 , 0.17, 0.18, 0.19 or 0.2 IU / kg of subject body weight; and up to 0.49, 0.48, 0.47, 0.46, 0.45, 0.44, 0.43, 0.42, 0.41, 0.4, 0.39, 0.38, 0.37, 0.36, 0.35, 0.34, 0.33, 0.32, 0.31 or 0.3 IU / kg of body weight of the subject, including, in particular, the indicated values.

IGF-1 is preferably used in an amount of from 50 to 500 μg / kg of subject body weight. For example, this amount may be from 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160 165, 170, 175, 180, 185, 190, 195, or 200 μg / kg of subject body weight; and up to 495, 490, 485, 480, 475, 470, 465, 460, 455, 450, 445, 440, 435, 430, 425, 420, 415, 410, 405, 400, 395, 390, 385, 380, 375, 370, 365, 360, 355, 350, 345, 340, 335, 330, 325, 320, 315, 310, 305 or 300 μg / kg of subject body weight, including, in particular, the indicated values.

Physiological inductors are preferably used in an amount of from 1 ng / kg to 50 g / kg of subject body weight, depending on the type of inductor used. For example, this amount may be from 1, 5, 10, 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 , 950 or 1000 ng / kg of body weight of the subject and up to 10000, 9000, 8000, 7000, 6000, 5000, 4000, 3000 or 2000 ng / kg of body weight of the subject, including, in particular, the indicated values. For example, the amount of physiological inducer may be from 1, 5, 10, 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 μg / kg of body weight of the subject and up to 10000, 9000, 8000, 7000, 6000, 5000, 4000, 3000 or 2000 μg / kg of body weight of the subject, including, in particular, the indicated values. For example, the amount may be from 1, 5, 10, 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg / kg of body weight of the subject and up to 10000, 9000, 8000, 7000, 6000, 5000, 4000, 3000 or 2000 mg / kg of body weight of the subject. For example, the amount may be from 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6 1.7, 1.8, 1.9, 2.0, 2.1 2.2, 2.3, 2.4, 2.5 or 2.5 g / kg of subject body weight and up to 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3, 1 or 3.0 g / kg of subject body weight, including, in particular, the indicated values. For example, the amount may be from 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, or 40, and up to 50, 40, 30, 25, 20, 15, 10, 9, 8, 7, or 6 g / kg of subject body weight, including, in particular, the indicated values. For example, the amount can be expressed in international units and range from 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 25 IU / kg of subject body weight and up to 30 , 25, 20, 15, 109, 8, 7, 6, 5, 4, 3, or 2 IU / kg of subject body weight.

For example, arginine is administered in an amount of from 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, 350, 400, or 450 mg / kg of subject body weight and up to 500, 450, 400, 350, 300, 250, 200, 175, 150, 125, 100, 90, 80, 70 or 60 mg / kg of subject body weight, including, in particular, the indicated values. For example, arginine is administered in an amount of 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, or 40 and up to 50, 40, 30, 25, 20, 15, 10, 9, 8, 7, or 6 g / kg of subject body weight, including, in particular, the indicated values.

For example, glutamine or lysine is administered in an amount of from 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250 or 300 mg / kg of body weight of the subject and up to 350, 300, 250, 200, 175, 150, 125, 100, 90, 80, 70 or 60 mg / kg of body weight of the subject, including, in particular, the indicated values.

For example, acylated sterile β-glucoside is administered in an amount of from 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, or 1.5 mg / kg of subject body weight and up to 1.6, 1.5, 1.4, 1.3, 1.2, 1.1 , 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2 or 0.1 mg / kg of subject body weight, including but not limited to indicated values.

All of these doses are single and are preferably administered 1 or 2 times a day. However, depending on the need determined by the doctor, the frequency of administration can be either reduced or increased. For example, if a sustained release dosage form is used, the frequency of administration can be reduced to 1 time in 2 days, 1 time in 3 days, 1 time in 4 days, 1 time in 5 days, 1 time in 6 days or 1 time per week . On the other hand, the frequency can be increased to more than two times a day, for example 3, 4 or 5 times a day.

The duration of administration of the active substances or compositions according to the invention is preferably from 10 to 60 days, for example from 10, 14, 21, 28 days and / or up to 56, 49, 42, 35, 30 days. Of course, depending on the severity of the therapeutic effect and possible side effects, the duration of treatment can be either reduced or increased relative to the indicated values. Treatment may include several courses of administration of the active substances or compositions of the invention, or their substantially continuous administration.

The exact dosage will depend on the purpose of the treatment and should be determined by the attending physician using well-known recommendations. The amount of therapeutic agent that is effective in alleviating a particular disease or condition (also referred to as the “therapeutically effective amount”) may vary according to several factors, such as disease status, age and body weight of the patient, and others. The dosage can, if necessary, be adjusted directly during treatment, depending on the severity of the therapeutic effect and side effects.

The amount of growth hormone and / or IGF-1, and / or their physiological inducers in the compositions for use according to the invention can vary widely depending on the desired dosage form. In any case, the content of active substances in the compositions according to the invention can be selected based on the approximate doses indicated above, so that the finished dosage form provides the easiest way for the patient to follow the prescribed treatment regimen.

The present invention is not limited by the scope of exemplary embodiments that are intended only as illustrations or specific aspects of the present invention. Various modifications of the present invention, in addition to those disclosed herein, will be apparent to those skilled in the art, taking into account existing knowledge of the art. It is assumed that all such modifications are covered by the attached claims.

MODES FOR CARRYING OUT THE INVENTION

Example 1. An animal model of multiple sclerosis

Experimental allergic encephalomyelitis (EAE) is widely used as a pathomorphological experimental model of multiple sclerosis (Cross AH, Stark JL 2005. Humoral immunity in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis // Immunol. Res. 32, N 1-3. P .8598).

To induce autoimmune encephalomyelitis in animals, an encephalitogenic emulsion is obtained (homogenate of the animal’s homologous brain in Freund’s complete adjuvant), which is introduced into the pads of the hind legs of guinea pigs (Abdurasulova I.N., Serdyuk S.E., Gmiro V.E. 2007. // Neuroimmunology. V, N 1. C.4-10).

Then, guinea pigs, divided into groups of 20 individuals, were injected intramuscularly daily with drugs of the corresponding active substances daily: 3.3 mg / ml of human growth hormone in a soluble mixture (experiments 1 and 2), 3.3 mg / ml IGF- 1 person in a soluble mixture (experiment 3), human interferon-β as part of the standard commercially available drug Rebif (experiment 4).

To identify clinical efficacy, the neurological status of animals was evaluated daily. The timing of the onset of the disease, the severity of neurological disorders, which were scored by the clinical index, and fatal cases were recorded.

The clinical index (CI) was determined by the severity and prevalence of neurological manifestations: muscle weakness of one limb - 0.5 points, paresis - 1 point, paralysis - 1.5. With the defeat of several limbs, the points were summarized. In the presence of additional symptoms (paresis of sphincters), another 1 point was added for each symptom. The absence of visible violations was taken as 0 points, in case of death - 6 points.

To assess the effectiveness of the neuroprotective effect of the studied medicinal product on the EAE model for each group of animals, the following indicators were calculated:

1) the total number of sick animals (in% of the number of guinea pigs in the group);

2) the average clinical index (CI) at the peak of the disease;

3) the number of fatal cases.

All indicators were compared with the corresponding indicators of animals of the control group (with induced EAE, but without drug administration).

The results of studies on the development of manifestations of allergic encephalomyelitis in animals are presented in the table and indicate a high potential clinical efficacy of somatotropin in relation to multiple sclerosis.

Results.

In a control group of twenty guinea pigs, signs of the disease occurred in sixteen animals (80%). Ten guinea pigs died during three weeks of observation (50%).

Table 1. The effect of recombinant growth hormone, IGF-1 and interferon-β on the clinical manifestations of experimental allergic encephalomyelitis

Group

Treatment

Encephalomyelitis Frequency Average CI at the peak of the disease Death rate Control
n is 20 - 80% 5.2 fifty% Experience 1 growth hormone, 0.1 IU / kg 40% 2.2 * 10% Experience 2 growth hormone, 0.2 IU / kg thirty% 2.0 * twenty% Experience 3 IGF-1, 0.3 mg / kg 40% 2.5 * twenty% Experience 4 interferon-β-1b, 1 mcg / kg 70% 3.6 * 35%

* the significance of differences with control at P is less than 0.05.

Example 2. Clinical Study

Somatotropin in an amount of 4 IU was administered to 16 subjects with an average weight of 70 kg suffering from multiple sclerosis. The introduction of the composition was carried out daily in the morning 1 hour before a meal. Before treatment and throughout the study period, subjects were questioned, assessing subjective symptoms on a 10-point scale, with a rating of 10 corresponding to the most severe manifestation of the symptom, and rating 1 to the least weak manifestation of the symptom.

Results.

Table 2. Assessment of changes in clinical symptoms in a patient with MS as a result of somatotropin therapy, average score

Symptoms of Multiple Sclerosis Before treatment 1st week 2nd week 3rd week 4th week 5th week Dizziness 7 5 5 4 3 2 Fatigue in the evening 10 8 7 5 4 5 Irritability 7 4 4 4 3 2 Depression 8 4 3 2 1 1 How straight your legs are when walking 10 9 8 6 5 5 How is walking generally tolerated 10 10 9 7 6 5 Numbness of limbs 6 1 1 1 1 1

As can be seen from the results of the study, the introduction of growth hormone at a dose of approximately 0.05 IU / kg / day significantly reduced the manifestation of the symptoms of the disease, starting from the first week of treatment; By the end of the fifth week of treatment, the manifestations of dizziness, irritability, depression, numbness of the extremities are minimized, and the symptoms associated with fatigue and walking are significantly reduced.

Claims (4)

1. The use of growth hormone in an amount of from 0.05 to 0.5 IU / kg of body weight of a subject daily once or twice a day as a medicine for the treatment of multiple sclerosis in a subject. 2. The use of IGF-1 in an amount of from 50 to 500 μg / kg of the body weight of the subject daily once or twice a day as a medicine for the treatment of multiple sclerosis in the subject. 3. The use of a physiological inducer of somatotropin and / or IGF-1 in a therapeutically effective amount as a medicine for the treatment of multiple sclerosis in a subject. 4. The use according to any one of paragraphs. 1-3, where the treatment further comprises administering to said subject recombinant human interferon-β-1b.