RU2431501C2 - Prolonged release lipolytic compounds for local treatment of lipopexia - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered compounds for injections in local lipopexia regions, containing a prolonged selective beta-2-adrenergic receptor agonist selected from salmeterol, formoterol, their salts and their solvates; a compound for decreasing fatty tissue desensitisation to the beta-adrenergic receptor agonist (or a compound for decreasing target tissue desensitisation to the beta-adrenergic receptor agonist - a version); and a liquid carrier, a related method of local treatment of lipopexia regions (versions), a method of decreasing fatty tissue. It is shown that combined use of the ingredients surpasses an effect (e.g., waist size) as compared with intake of only one of them.

EFFECT: development of the method of decreasing fatty tissue.

30 cl, 1 dwg

Description

Technical field

The invention generally relates to a medical method of treatment, and more particularly to the treatment of fat deposits.

State of the art

Adipose tissue is the main tissue that stores energy reserves. Fat cells, or adipocytes, store this energy in the form of triglycerides. Triglycerides are mobilized from the fat reserve to provide energy in the body by hormonal induction of hydrolysis of triglycerides. This process releases free or unesterified fatty acids and glycerin into the blood for use by other body tissues. The release of triglycerides from the fat reserve is called lipolysis. There is also a growth of new adipocytes called adipogenesis.

Weight loss programs that include physical activity can stimulate lipolysis through adrenergic stimulation, leading to a decrease in fat. The primary hormones and neurotransmitters that control lipolysis in the body are catecholamines. Adipose tissue contains beta-1,2 and 3-adrenergic receptors and alpha-2-adrenergic receptors. Binding of beta agonists to beta receptors in adipose tissue can lead to lipolysis of adipocytes, while binding of alpha receptor agonists can inhibit lipolysis. Beta receptor activation may also inhibit adipogenesis. In humans, beta-2 receptors are often found in large numbers on the surface of fat cells and the primary mediator of beta-receptor stimulated lipolysis. Stimulation of lipolysis by beta-agonists is mediated by adenylate cyclase and increased formation of cyclic adenosine monophosphate (cyclic AMP, cAMP).

The accumulation of fat in the body can occur unevenly. For example, in humans, fat can accumulate mainly in the abdominal cavity, while in others it occurs in the subcutaneous tissue. The gender difference is also obvious, when in women fat accumulates in the femoral region and in the buttocks, and in men in the waist area. Women accumulate fat deposits in the hips when the skin has a wrinkled appearance or the appearance of an “orange peel”, a condition called cellulite. Cellulite can be associated with the structure of the skin, which can lead to subcutaneous fat hernia, sometimes called papillary swelling of fat. Other factors that may relate to cellulite include altered and / or diminished septa of the connective tissue, changes in blood vessels and lymph, which lead to fluid accumulation and inflammation. Adipose tissue can also accumulate in the form of fibrous deposits of fat, known as lipoma.

Similarly, running out of fat can occur unevenly. People who have largely lost weight may still have local pockets of accumulated fat that are resistant to reduction unless unhealthy excessive weight loss occurs. Physical activity can affect the subcutaneous fat deposits in different ways, deeper tissues respond to the lipolysis process, and surface fat stores are more stable. Cellulite can still remain despite weight loss, lipomas are also usually not affected by weight loss.

The differential use of fat reserves may be partially due to the action of adrenergic receptors. Thus, some sites may have greater activity of alpha-2 receptors or a greater number of alpha-2 receptors compared to beta receptors, which leads to a decrease in lipolysis. Studies have shown a difference in lipolytic activity in response to stimulation by beta-adrenergic receptors in the adipose tissue of the omentum and in the subcutaneous region of the abdomen and thighs, while the omentum is characterized by the highest activity and the hips by the least activity.

The difference in lipolytic activity can be eliminated by the addition of an alpha-2 receptor antagonist, assuming that excessive alpha-2 receptor activity causes a lower lipolytic response to adrenergic stimulation in various areas of adipose tissue.

Delivery of adrenergic active ingredients into the subcutaneous tissue of both beta-agonists and alpha-2 antagonists has been proposed, it has been shown that this leads to local fat loss and an improvement in the appearance of body fat. For example, isoprotenerol 11 and yohimbine 8 reduce femoral volume. These studies required subcutaneous injections of beta-agonists three to five times a week at many points in the thigh area. This is impractical because the patient is uncomfortable. Since these lipolytic agents, especially beta-agonists, are short-acting agents and can be quickly removed from adipose tissue, lipolysis is likely to occur only for a short time after injection, which reduces the potential magnitude of the effect despite multiple injections. In addition, the prolonged action of beta-agonists on adipocytes leads to desensitization of receptors and weakening of regulation and loss of lipolytic activity. Remedies for attenuating or preventing these effects for the receptor can also improve the results of therapy.

SUMMARY OF THE INVENTION

Compositions, compositions, methods and systems for treating local fat deposits according to the present invention include contacting a target fat deposition site with a composition comprising a long-acting beta-2 adrenergic receptor agonist and a compound that reduces desensitization of the target tissue to a beta-2 adrenergic receptor agonist long-acting, such as glucocorticosteroid and / or ketotifen.

In some embodiments, there is provided a composition for injection into an adipose tissue accumulation region, comprising a long-acting beta-2 adrenergic receptor agonist, a compound for reducing adipose tissue desensitization to a beta adrenergic receptor agonist, and a liquid carrier.

In some embodiments, the selective long-acting beta-2 adrenergic receptor agonist is lipophilic.

In some embodiments, the selective long acting beta-2 adrenergic receptor agonist contains at least one agent selected from salmeterol, formoterol, their salts and solvates.

In some embodiments, a compound for reducing desensitization of targeted tissue to a beta adrenergic receptor agonist comprises a glucocorticosteroid. In some embodiments, a compound for reducing desensitization of a target tissue to a beta adrenergic receptor agonist comprises an antihistamine compound. In some embodiments, a compound for reducing desensitization of a target tissue to a beta adrenergic receptor agonist comprises a glucocorticosteroid and an antihistamine compound. In some embodiments, the compound for reducing desensitization of the target tissue to a beta adrenergic receptor agonist comprises at least one agent selected from dexamethasone, prednisolone, fluticasone budsonide propionate, ketotifen, and their analogs.

In some embodiments, the liquid carrier is a lipophilic liquid. In some embodiments, at least one of the selective long-acting beta-2 adrenergic receptor agonists and desensitization reducing compounds load a sustained release agent. In some embodiments, the sustained release agent is at least one component of a biodegradable polymer, a biodegradable copolymer, a hydrogel, and a liposome.

In other embodiments, the sustained release agent is poly (lactide-glycolide). In some embodiments, the poly (lactide-glycolide) loading active ingredient is in an amount of up to about 75%.

In some embodiments, this agent is at least one agent of salmeterol, a salt or solvate thereof, and fluticasone. In some embodiments, the agent is one compound of formoterol, a salt or solvate thereof, and budesonide. Some options include at least one agent of salmeterol, formoterol, their salts and their solvates and ketotifen.

Other options include an injection composition for treating fat deposition, comprising at least one long-acting beta-2 adrenergic receptor selective agonist, a means for reducing target tissue desensitization to a beta adrenergic receptor agonist, and a liquid carrier. In some embodiments, the at least one long-acting beta-2 adrenergic receptor selective agonist comprises one agent of salmeterol, formoterol, their salts and their solvates.

Other options include a method for treating fat accumulation, comprising contacting the stored fat with a pharmaceutically effective amount of a selective long-acting beta-2 adrenergic receptor agonist and contacting the stored fat with a pharmaceutically effective amount of a compound that reduces the desensitization of the targeted tissue to the beta adrenergic receptor agonist.

In some embodiments, the selective beta-2 long-acting drenergic receptor agonist comprises at least one agent of salmeterol, formoterol, their salts and solvates.

In some embodiments, the compound for reducing the desensitization of the targeted tissue to the beta adrenergic receptor agonist contains at least one agent selected from dexamethasone, prednisolone, fluticasone propionate, budesonide.

In some embodiments, the at least one long-acting beta-2 adrenergic receptor selective agonist and the desensitizing compound are loaded into a sustained release agent.

In some embodiments, the selective beta-2 long-acting agonist is salmeterol, and the pharmaceutically effective amount of salmeterol is up to about 100 μg / day. In some embodiments, the long-acting selective beta-2 agonist is formoterol and a pharmaceutically effective amount of formoterol is up to about 50 mg / day.

In some embodiments, a long-acting selective beta-2 adrenergic receptor agonist and a compound to reduce desensitization are delivered almost simultaneously. At least one long-acting beta-2 adrenergic receptor selective agonist and a compound to reduce desensitization are sometimes delivered as an injection with one needle.

In some embodiments, at least one long-acting beta-2 adrenergic receptor selective agonist and a desensitization-reducing compound are delivered as an injection without a needle. In some embodiments, at least one selective long-acting beta-2 adrenergic receptor agonist and a compound for reducing desensitization are administered transdermally.

Other options include a method for reducing adipose tissue deposition, comprising: administering a pharmaceutically effective amount of a compound that increases the content of beta-2 adrenergic receptors in adipose tissue; and introducing a pharmaceutically effective amount of a selective beta-2 receptor agonist into adipose tissue, thereby causing at least one process to occur from lipolysis and inhibited adipogenesis.

In some embodiments, at least one administration of the compound and administration of a beta-2 receptor agonist is less frequent than once a day.

Other options include a method of treating local accumulation of fat or cellulite, comprising: introducing into the local area of the accumulated fat or cellulite a composition comprising a long-acting selective beta-2 agonist and at least one compound of a glucocorticosteroid and ketotifen, wherein the composition exhibits prolonged lipolytic activity, promoting lipolysis in the area of local accumulation of fat or cellulite.

In some embodiments, the selective beta-2 agonist comprises at least one compound of salmeterol, formoterol, their salts and their solvates.

Some options include a controlled release formulation comprising a controlled release carrier, a selective beta-2 adrenergic receptor agonist, and a glucocorticosteroid. A controlled release carrier reduces the amount of fat in the treatment of local fat deposition. In some embodiments, the controlled release carrier is a biodegradable polymer. In some embodiments, the biodegradable polymer is a polymer of lactide and glycolide. In some embodiments, the biodegradable polymer is administered as microparticles. In some embodiments, at least a portion of the composition is delivered to the fat storage site by needle-free injection using a special device.

In other embodiments, needleless injection promotes lateral distribution of the composition in the area of fat accumulation. Some options provide a method for reducing adipose tissue by treating a fat area, comprising administering pharmacologically effective amounts of a glucocorticosteroid or ketotifen to the fat storage area. A glucocorticosteroid or ketotifen increases the content of beta-2 adrenergic receptors in adipocytes in the area of fat deposition, thereby increasing lipolytic activity and / or inhibition of adipogenesis by a selective long-acting beta-2 receptor agonist in the area of fat accumulation.

In some embodiments, the selective beta-2 long-acting agonist is salmeterol. In some embodiments, the pharmacologically effective amount of salmeterol is up to about 100 μg / day. In some embodiments, formoterol is a selective beta-2 long-acting agonist. In some embodiments, the pharmacologically effective amount of salmeterol is up to about 50 μg / day.

Some options provide a method for treating a fat area, comprising administering a pharmacologically effective composition comprising a lipophilic, essentially selective beta-2 receptor agonist with prolonged adrenergic activity in adipose tissue, which causes prolonged lipolysis. Some options additionally include co-administration of a glucocorticosteroid or ketotifen to prolong and facilitate lipolysis. Some variants of the method include the introduction of the composition less than once a day.

Some options include a method for treating local accumulation of fat or cellulite, comprising administering a composition comprising a practically selective long-acting beta-2 agonist and a glucocorticosteroid or ketotifen. Variants of this method include the acceleration of lipolysis in resistant adipose tissue and prolonged lipolytic activity, thereby reducing local fat accumulation and improving the appearance of cellulite sites.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawing schematically shows the lipolysis of adipocytes.

DETAILED DESCRIPTION OF THE INVENTION

Pharmaceutical compositions, compositions, methods and systems reach sites of local fat, adipose tissue and provide adipocyte reduction by modulating the adrenergic system. The term “modulation” as used herein is commonly used in its usual sense and more specifically refers to adrenergic receptor agonism, adrenergic receptor antagonism and / or changes in receptor signaling pathways. One example of a change in the signaling pathways of receptors includes an increase in cyclic AMP, as, for example, shown schematically in the drawing. In some embodiments, modulation refers to up-regulation of receptors or to an increase in the number of adrenergic receptors, a decrease in deactivation or sequestration of receptors, or changes in receptor activity (for example, an increase in activity) and / or a change in receptor affinity.

It is believed that some variants of prolonged modulation of adrenergic receptors in adipose tissue lead to some combination of prolonged lipolysis, reduced lipid content in the adipocyte, reduced adipocyte size, reduced adipose tissue mass or accumulated fat and / or improved appearance. Some options provide selective reduction of local and / or subcutaneous accumulations of adipose tissue and adipocytes, including cellulite, due to prolonged adrenergic modulation. Prolonged adrenergic modulation leads to a prolonged inhibition of the proliferation of fat cells (adipogenesis). In some embodiments, the composition is suitable for treating accumulations of cellulite fat and / or lipomas.

Variants of the described pharmaceutical composition include one or more selective beta-2 adrenergic receptor agonists in combination with one or more compounds that reduce the desensitization of targeted tissue to beta-adrenergic receptor agonist (s), for example, glucocorticosteroids or ketotifen or their analogs . The term “desensitization” includes both short-term desensitization (tachyphylaxis) and prolonged desensitization, as well as desensitization for other periods of time. Beta-2 adrenergic receptor agonists are also referred to in this application as "beta-2 agonists" and "beta-2 receptor agonists." Unless otherwise indicated, references to beta-2 receptor agonists also include their analogues, physiologically acceptable salts and / or solvates known in the art. Some variants of the composition have a ratio of a selective beta-2 long-acting agonist and glucocorticosteroid from about 100: 1 to about 1: 100.

As discussed above, lipolytic activity and inhibition of adipocyte proliferation are believed to be mediated by modulation of adrenergic receptors in adipose tissue and / or on adipocytes. In some embodiments, reconstitution therapy is facilitated by the prolonged action or prolonged activity of one or more adrenergic receptor agonists and / or compounds that stimulate receptor pathways known in the art, for example catecholamines, beta agonists, alpha antagonists, forskolin, aminophylline, their analogues or their combinations.

Some options provide sustained adrenergic modulation when using pharmaceutical compositions containing one or more substantially selective beta-2 long-acting receptor agonists. Some variants of a prolonged-activity pharmaceutical composition include one or more suitable selective beta-2 long-acting agonists known in the art, for example, salmeterol 1, formoterol 2, bambuterol 3, their physiologically acceptable salts or solvates, or combinations thereof.

Prolonged adrenergic modulation is not observed with subcutaneous delivery of typical adrenergic compositions, since the adrenergic compound is usually quickly removed from adipose tissue through the blood and / or lymph. In addition, it is believed that the prolonged exposure of adrenergic agents to adipose tissue, especially beta-receptor agonists, leads to desensitization of receptors due to phosphorylation and sequestration of receptors. It is believed that these effects limit the ability of the adrenergic modulating composition to treat adipose tissue and lead to tachyphylaxis, a condition in which the body exhibits a rapidly decreasing response to the action of the agonist after administration of the initial doses, to the desired lipolytic and anti-adipogenesis effect. Accordingly, the effect of treatment is short-term and frequent dosing is required.

Short-acting beta-2 agonists often lead to tachyphylaxis, as described above. However, long-acting selective beta-2 agonists have essentially selective beta-receptor activity and high lipophilicity, the activity of long-acting beta-2 agonists lasts a long time in fatty tissues compared to short-acting beta-3 agonists. The activity of a partial beta-2 receptor antagonist prevents desensitization, which can occur with continuous exposure to adipocytes of complete adrenergic agonists. Accordingly, long-acting selective beta-2 agonists lead to a decrease in tachyphylaxis. Compared to short-acting beta-2 agonists, lipolysis also lasts longer after administration, since long-acting selective beta-2 agonists have a longer half-life. The combination of a longer half-life and activity reduces the frequency of administration of pharmaceutical compositions. Accordingly, in some embodiments, daily administration of the composition is not required. Moreover, preferred long-acting selective beta-2 agonists are also more selective for beta-2 receptors, which provides a substantially similar therapeutic effect to short-acting beta-2 agonists at lower doses.

As discussed above, lipolysis and / or inhibition of adipogenesis are stimulated by subtypes of beta-1, 2- or 3-receptors. Thus, agonists of one, two and / or all three receptors are able to stimulate lipolysis and / or inhibition of adipogenesis. In humans, beta-2 receptor activity is believed to be more important for stimulating lipolysis, especially in the presence of an anti-inflammatory steroid or glucocorticosteroid.

Long-acting selective beta-2 agonists, for example, salmeterol 1 (± 2- (hydroxymethyl-4- [1-hydroxy-2- [6- (4-phenylbutoxy) -hexylamino] ethyl] phenol, CAS Register No. 94749-08- 03) and formoterol-2 (+ N- [2-hydroxy-5- [1-hydroxy-2 [1- (4-methoxyphenyl) propan-2-ylamino] ethyl] phenyl] methanamide, CAS Register. No. 73573- 872), in some embodiments are preferred.

Some variations of the compositions contain one or more long-acting selective beta-2 agonists, as well as their physiologically acceptable salts and solvates, known in the art, for example, salmeterol xinafoate and / or formoterol fumarate. It will be apparent to those skilled in the art that in many cases, salts and / or solvates of beta-2 agonists will have the desired activity. Accordingly, unless otherwise specified, references to the active ingredient, for example, salmeterol 1, formoterol 2, isoproterenol 4, albuterol 5, phenoterol and forskolin, include these compounds themselves, as well as their physiologically acceptable analogues, salts and / or solvates, or combinations thereof .

Some preferred long-acting beta-agonists exhibit high inherent activity with respect to adenylate cyclase, which accelerates synthesis with AMP. For example, some options include formoterol 2 as a selective beta-2 long-acting agonist, which is characterized by a combination of high activity, reduced systemic activity, high activation of adenylate cyclase and / or increased cyclic AMP, which is a lipolysis mediator.

In some preferred embodiments, formoterol 2 is contained in the form of a physiologically acceptable salt or solvate thereof. Suitable physiologically acceptable salts of formoterol 2 are known from the prior art, for example, acid addition salts derived from inorganic and organic acids such as hydrochloride, hydrobromide, sulfate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2-hydroxybenzoate, 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulfonate, methanesulfonate, ascorbate, salicylate, acetate succinate, lactate, glutarate, gluconate, tricarballylate, hydroxy naphthalene carboxylate, oleate, combinations thereof and the like. Preferred options include formoterol 2 as a salt thereof with fumaric acid and / or as a dihydrate. A suitable concentration of formoterol 2 in the tissue for the treatment of body fat is from about 1 pM to about 100 μM, more preferably from about 10 pM to about 100 nM.

Some preferred options use salmeterol as a long-acting beta-2 agonist. Salmeterol exhibits a partial agonist activity, which is believed to reduce receptor desensitization. In some preferred embodiments, salmeterol is contained in the form of a physiologically acceptable salt and / or solvate thereof. Suitable physiologically acceptable salts of salmeterol 1 are known, for example, acid addition salts derived from inorganic and organic acids such as hydrochloride, hydrobromide, sulfate, phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2-hydroxybenzoate, 4- hydroxybenzoate, 4-chlorobenzoate, p-toluenesulfonate, methanesulfonate, ascorbate, salicylate, acetate, fumarate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalene carboxylate, 1-hydroxy-2-naphthalene carboxyl, 2-naphthalene carboxyl, carboxyl, 2 oleate, combinations thereof, etc. Some preferred options include the use of salmeterol 1, as well as salts of 1-hydroxy-2-naphthalene carboxylate (hydroxy naphthoate). A suitable concentration of salmeterol 1 in adipose tissue tissue is from about 1 pM to about 100 μM, preferably from about 10 nm to about 10 μM.

Some options include the use of optically pure beta-adrenergic agonist isomers, which promote lipolysis and inhibition of adipogenesis and reduce possible side effects. In some embodiments, these optically pure isomers make it possible to obtain formulations containing large loads of the active ingredient, for example, by eliminating one or more isomers that do not give a physiological effect, giving a lower physiological effect, negative effect and / or chronic physiological effect. Removal of undesirable components from the racemic mixture provides the release of the active isomer, or eutomer, thereby you can load a large amount of eutomer into the composition by removing inactive components.

Two stereogenic centers in a molecule usually result in two diastereomers, referred to in this application as (R *, R *) and (R *, S *), and their enantiomers. Diastereomers are stereoisomers that are not enantiomers, that is, the mirror image of one diastereomer does not overlap the image of another diastereomer. Enantiomers are mirror images of each other. The racemate is a 1: 1 mixture of enantiomers. The enantiomers of (R *, R *) - diastereomers are referred to as (R, R) - and (S, S) -enantiomers, which are mirror images of each other and, therefore, have some common chemical and physical properties, for example, melting points. Similarly, the (R, S) - and (S, R) -isomers are enantiomers of the (R *, S *) enantiomer. For example, formoterol 2 is available as a racemate of (R, R) - and (S, S) -isomers in a 1: 1 ratio, usually in the form of a dihydrate or fumaric acid salt. Some preferred options use the (R, R) -enantiomer, (R, R) -formoterol, which is more active as a long-acting beta-2 agonist. Some variants use optically pure isomers of other beta-2 agonists, for example, (R) -salmeterol.

In addition, in some embodiments of the pharmaceutical composition, the at least one long-acting selective beta-2 agonist is highly lipophilic, while providing a pharmaceutical composition with prolonged activity in adipose tissue. It is believed that high lipid solubility increases the residence time of the beta-2 agonist in adipose tissue, thereby eliminating or reducing the need for sustained release and / or controlled release from the carrier according to some options. The elimination of a sustained release and / or controlled release carrier provides a combination of simplified formulation, lower cost, and / or increased safety. In formulations comprising a sustained release carrier, such as a sustained release polymer, a highly lipophilic beta-2 agonist facilitates incorporation into a sustained release carrier, as described in detail below.

Salmeterol 1 and formoterol 2 have high lipid solubility, which increases the residence time in adipose tissue and / or in one or more fat cells. Some formulations include a highly lipophilic beta-agonist that reduces or eliminates the need for a sustained or controlled release carrier due to distribution and sequestration in adipose tissue, which prolongs the therapeutic effect. In some embodiments, beta-agonists are preferred with a partition coefficient between oil and water of at least about 1000: 1. For example, salmeterol 1 is at least 10,000 times more lipophilic than albuterol 5, a short-acting hydrophilic beta agonist. In addition, salmeterol 1 and formoterol 2 have anti-inflammatory properties used in the treatment of cellulite, as discussed below. In some cases, they also improve favorable changes in the extracellular matrix and reduce fluid accumulation, which improves the treatment results of cellulite and reduces local fat accumulation.

Prolonged activity is increased by preventing desensitization (tachyphylaxis), which can occur with the constant action of adrenergic agonists on adipocytes, as described above. Compounds that reduce the desensitization of target tissue to beta-adrenergic receptor agonists are generally referred to as “glucocorticosteroids”, although this term encompasses all suitable compounds that reduce the tolerance of targeted tissue to beta-adrenergic receptor agonists, including glucocorticosteroids and suitable antihistamines, for example, ketotifen.

Glucocorticosteroids are also referred to herein as “anti-inflammatory steroids”, “glucocorticoids” and / or “corticosteroids”. Glucocorticoids sensitize stable fat accumulation by increasing the number of beta-2 receptors, which contributes to lipolysis or a decrease in fat content. Glucocorticoids are also believed to reduce the amount of alpha-2 receptors. Estrogen can induce the expression of alpha-2 adrenergic receptors in subcutaneous adipose tissue in women, which leads to a ratio of beta-2 receptors to alpha-2 receptors exceeding about 1, causing a decrease in fat formation, rather than fat accumulation in adipocytes.

Certain embodiments of a composition comprising one or more glucocorticosteroids are more effective in treating areas of fat containing a reduced amount of beta-2 receptors and / or an increased amount of alpha-2 receptors that are resistant to beta-adrenergic stimulation of lipolysis or inhibition of adipogenesis, for example, subcutaneous adipose tissue , especially in women.

A glucocorticosteroid is believed to improve lipolysis, inhibition of adipogenesis, and / or a decrease in local fat during exposure to a beta agonist. In some embodiments, treatment of adipocytes with a glucocorticosteroid that increases lipolytic activity supports and / or increases both lipolytic activity and the number of beta receptors in the targeted tissue. Examples of suitable corticosteroids include dexamethasone 6, prednisolone, fluticasone propionate 7, budesonide 8 and their analogs.

In some preferred embodiments, the glucocorticoid is dexamethasone 6 (9-fluoro-11,17-dihydroxy-17- (2-hydroxyacetyl) -10,13,16-trimethyl-6,7,8,11,12,14,15, 16-octahydrocyclopenta- [a] phenanthren-3-one. Register. No. CAS 50-02-2) and / or fluticasone propionate. As indicated above, another preferred compound for reducing desensitization is ketotifen 9, which is also an antihistamine. Some embodiments of the composition include one compound that reduces the desensitization of adipose tissue to a beta-2 agonist. Other options include many desensitizing compounds, for example, many glucocorticosteroids. Some preferred options include at least one glucocorticosteroid and an antihistamine, ketotifen. The combination of glucocorticosteroid with ketotifen is believed to be more effective in reducing desensitization, since ketotifen prevents beta-receptor sequestration, while glucocorticosteroid increases the number of beta receptors, thereby causing a synergistic effect on the beta receptor. Ketotifen analogs are also acceptable.

In some embodiments, at least beta-2 receptor activity or at least density increases in human subcutaneous adipocytes in response to the administration of an anti-inflammatory steroid or ketotifen, especially in the presence of a beta agonist. In some embodiments, increasing the activity and / or density of beta-2 receptors enhances the action of long and short-acting beta-2 agonists. In addition, in some cases, the action of a glucocorticosteroid is believed to be down-regulating antilipolytic alpha-2 adrenergic receptors, which is especially beneficial, for example, in the case of subcutaneous fat, which often contains a large number of these receptors. Thus, in some embodiments, the glucocorticosreoid sensitizes subcutaneous fat for stimulation, lipolysis, inhibition of adipogenesis and / or apoptosis using beta-2 receptors and / or increases the ratio of beta-2 adrenergic receptors to alpha-2 adrenergic receptors, thereby shifting the balance of adipose tissue from fat accumulation to fat loss.

Some compositional options include additional possible ingredients. For example, some areas of accumulated fat, such as areas of cellulite and lipomas, contain fibrous connective tissue. In some cases, it is favorable to destroy this fibrous connective tissue, for example, to improve the appearance of the skin located on top. Some variants of the composition contain an enzyme, such as collagenase, which destroys collagen in fibrous connective tissue.

Some variants of the composition contain one or more antilipolytic blocking agents known in the art, for example, selective alpha-5 receptor antagonists such as phentolamine 10 (Register No. CAS 73-05-02) or yohimbine 11 (Register No. CAS 146-48 -5), block antilipolytic effects in the field of local accumulation of fat. Anti-lipolytic effects in adipocytes and adipose tissue are usually observed in the subcutaneous and local areas of fat accumulation. For example, when exposed to beta-agonists, subcutaneous fat is characterized by a lower rate of lipolysis than visceral fat. The action of antilipolytic blocking agents on subcutaneous fat increases lipolytic activity in some embodiments.

Some variants of the composition include other adrenergic agents that enhance the action of the selective beta-2 agonist long-acting. For example, aminophylline 12 (1,3-dimethyl-7H-purin-2,6-dione diethylamine. Register. No. CAS58-55-9) are lipolytic agents that block rupture of cyclic AMP.

Other possible ingredients increase the secondary signals generated by beta-agonist binding. For example, in some embodiments, the composition comprises forskolin 14 (Register. No. CAS 66575-29-9), which stimulates adelate cyclase, thereby increasing the formation of cyclic AMP initiated by a long-acting beta-agonist. An increased concentration of cyclic AMP helps maintain lipolytic activity.

Some variants of the composition include growth hormone in combination with a long-acting beta-agonist and glucocorticosteroid, which, as it turned out, stimulates lipolysis.

Other compositional options further include one or more non-selective beta-agonists, for example isoproterenol 4 and / or selective short-acting beta-agonists, for example terbutaline. Some compositions contain at least one alpha-2 antagonist or physiologically acceptable salts or solvates thereof.

The compositions are formulated for administration by any suitable method known in the art, for example, methods described in Remington: The Science and Practice of Pharmacy (21 st ed., Lippincott Williams and Wilkins). In some embodiments, a composition is prepared for injection into an area where treatment is desired, for example, into the area of subcutaneous fat deposition.

Suitable excipients for injection compositions are known. In some embodiments, one or more beta-2 receptor agonists or glucocorticosteroids are mixed in a liquid carrier, for example, in a solution, suspension, gel and / or emulsion. Some options include any suitable lipophilic excipient known in the art, for example modified oils (e.g. Cremophor® BASF), soybean oil, propylene glycol, polyethylene glycol, derivatized polyethers, combinations thereof, and the like. Some options include a carrier in the form of microparticles and / or nanoparticles for at least one of the beta-receptor agonists and / or glucocorticosteroids, as described in more detail below. Some options include one or more sustained or controlled release carriers or agents, for example polymeric microspheres.

Formulations for injection are administered by any known means, for example, using a single needle, multiple needles and / or using a needleless injection device. In some embodiments, a dose of the active ingredients in the tissue is administered in a suitable vehicle by injection.

In some embodiments, delivery involves injection with a single needle. In other options, the delivery involves injection using a device with many needles, which in some cases provides a wide distribution of the composition in the target tissue. In some embodiments, the compositions are injected in such a way that dispersion of the subcutaneous fat is provided in an appropriate layer in areas where a reduction in local fat, such as the area under the chin, waist / hips, buttocks or hips, or areas of fat around the orbit, is desired. In some embodiments, the composition is injected in the form of aliquots of from about 0.5 ml to about 1.0 ml. In some embodiments, aliquots of the composition are injected into an area of about 10 cm ² to about 20 cm ² .

Another delivery method includes a needleless injection device operating under pressure. In some embodiments, using these devices, the composition is compressed under pressure generated mechanically or pneumatically, for example, using a gas such as helium or carbon dioxide, and then is supplied through a small hole in the body’s tissues, and the composition is delivered under the skin. Suitable needleless injection formulations are known in the art and can be, for example, in the form of liquids, solutions, suspensions, gels, colloidal solutions, emulsions and dry powders.

The advantage of this system is that it spreads the drug over a large area compared to conventional needle injection systems. Needle-free injection under appropriate pressure delivers the composition to a flat area, while it spreads radially along the path of least resistance.

In contrast, delivery by typical needle injection leads to globular delivery of the formulation. Needle-free injection also allows precise control of the penetration depth by adjusting the injection pressure and hole size.

Thus, needleless injection is the preferred delivery method for subcutaneous injection of the composition in the treatment of excessive accumulations of fat, which is useful, for example, to smooth out depressions caused by accumulation of fat. In some embodiments, needleless injection is also used for deeper subcutaneous subfascial injections directed to deeper areas of fat accumulation. The needle-free device also provides simple and convenient multiple injections of the composition in a specific area with a large lateral spread.

In some embodiments, a beta-2 agonist and a compound that reduces desensitization are administered separately, for example, by injection of separate formulations. Co-administration of a beta-2 agonist and a compound that reduces desensitization is preferred in some embodiments, but reduced desensitization is observed in some cases only in the presence of beta-2 agonists.

Some formulation options contain one or more sustained or controlled release agents known in the art to provide sustained or controlled release of a beta-2 agonist and / or glucocorticosteroid, which, for example, are encapsulated in a sustained or controlled release agent or carrier, with this agent and / or conjugated with this agent. In some embodiments, biocompatible, biodegradable, sustained and / or controlled release formulations provide local tissue activity for weeks and months. Suitable sustained release or controlled release agents or carriers are known, for example, polymers, macromolecules, conjugates of active ingredients, hydrogels, their contamination, and the like. Some sustained release carrier variants are intended for fat, such as liposomes. Sustained release materials are preferred to facilitate the delivery of an almost equal amount of active substance per unit time, in particular for at least about 3 days, at least for about 4 days, up to one year or more. For treatment of one area, several sustained release injections of the formulation may be given.

In some embodiments, the sustained release agent includes a polymer, for example polylactides, polyglycolides, poly (lactide glycolides), polylactic acids, polyglycolic acids, polyanhydrides, polyorthoesters, mixed polyesters, polycaprolactones, polyesters, polycarbonates, polyacrylates, polymers, polyurethanes, polyurethanes compounds that are used to encapsulate, bind or form conjugates of the active ingredient (s) (e.g., beta-agonists and / or glucocorticosteroids roidov). Some preferred sustained release polymer variants include polyethylene glycol groups to which one or more active ingredients are coupled. In some preferred embodiments, the sustained release agent comprises a poly (lactide glycolide) copolymer (PLGA, copoly (lactic-glycolic acid)) 15.

Some embodiments of a sustained release agent include one or more hydrogels known in the art, such as modified alginates. Examples of suitable modified alginates include the compounds described in WO98 / 12228. Some embodiments of a sustained release agent include an albumin-based carrier or excipient.

In some embodiments, a prepolymer solution composition is injected into the target site in a tissue, where it is then polymerized (e.g. by photopolymerization) or solidified (e.g., using temperature-sensitive gelling materials) in vivo.

In some embodiments, controlled release materials have release characteristics intended for a particular tissue application. In some cases, a sustained or controlled release agent is formed in microparticles, such as microspheres, that are introduced into the injection solution and / or gel. In some embodiments, the microparticles have a diameter of from about 10 microns to about 100 microns and are usually uniform in size. For example, in some cases, compositions containing alginates and / or copolymers (lactide-glycolides) 15 are prepared as an injection gel or as microspheres by methods known in the art. Other examples of suitable injectable biodegradable, biocompatible materials suitable for the preparation of microparticles include chitosan, dextran, hydroxyapatite and silicone.

Microspheres and / or microparticles are formed by a known method, for example by evaporation of a solvent and / or by emulsion polymerization. In some embodiments, the microspheres have an average diameter of from about 5 microns to about 60 microns, preferably about 20 microns. In some embodiments, PGLAs are prepared with different ratios of lactide to glycolide depending on the desired release rate of the active ingredient (s). Since the decomposition rate of this copolymer is proportional to its crystallinity and glycolide content in the composition, non-racemic mixtures of lactide and / or glycolide increase the degree of crystallinity and slow down the decomposition rate. A higher glycolide content increases the rate of decomposition. In some embodiments, at a content of about 65-75% lactide and about 25-35% glycolide, the release of the active ingredients occurs over a period of about 2 weeks to about 45 days. In other embodiments, the ratio of lactide to glycolide from about 0: 100 to about 100: 0 provides other values for the rate of release.

Some variants of microspheres or microparticles have hollow and / or porous inner regions. Sometimes microspheres contain a solid or porous outer shell. Some formulations containing a porous outer shell and / or microspheres have a biphasic release profile of the active ingredient (s) with an initial burst of release of the active ingredient (s) followed by a prolonged release associated with polymer breakdown microspheres. An initial burst saturates the tissue with an effective concentration of the active ingredient (s), followed by a slower release, maintaining the desired concentration. In some embodiments, various microsphere structures and active ingredient release profiles optimize the effect of treating adipose tissue and adipocytes by modulating adrenergic receptors. In some preferred embodiments, sustained local concentrations in the tissues of long-acting selective beta-2 adrenergic agents, such as salmeterol 1 and / or formoterol 2, are from about 10 pm to about 10 μM.

In some embodiments, one or more active ingredients are encapsulated in a polymer, coupled and / or conjugated to it in an amount of about 10-12% by weight based on microspheres. The amount of active ingredient in percent by weight based on the carrier (eg, microparticles) is referred to herein as the “active ingredient load”. As used herein, the terms “loaded” or “load” refer to active ingredients that are substantially encapsulated in a carrier, bound and / or conjugated to a carrier. Sometimes the load of the active ingredient is up to about 75%. Thus, some preferred formulations contain one or more beta-2 adrenergic active ingredients, such as salmeterol 1, formoterol 2 and / or their physiologically active salts and solvates, loaded in polymer microspheres in an amount of from about 1 mg to about 20 mg of the active ingredient about 10-200 mg of polymer. In some embodiments, a composition with such an active ingredient load provides release of the active ingredient over a period of about 15 days to about 45 days in a concentration capable of providing lipolysis and / or inhibition of lipogenesis.

In some embodiments, two or more active ingredients load the same microsphere, for example a liposome. So, in some cases, the glucocorticosteroid and adrenergic compound encapsulated in the polymer are delivered to the adipose tissue simultaneously. Or two active ingredients load different microspheres. Then, both types of microspheres are mixed to obtain a composition with the desired ratio of beta receptor agonist and glucocorticosteroid for subsequent simultaneous administration. Alternatively, both types of microspheres are administered sequentially.

Microspheres containing the active ingredient (s) are suspended in about 10-20 ml of an appropriate physiologically acceptable liquid carrier. In some embodiments, using different microspheres with the active ingredients, the microspheres are mixed together in a liquid carrier.

In other embodiments, each type of microsphere is separately mixed with a liquid carrier. In some embodiments, the microsphere suspension is then administered by subcutaneous injection immediately immediately below the dermis in 1.0 ml aliquots to cover an area of about 2.0 cm ² per ml microsphere suspension, for example, for the treatment of cellulite. In some embodiments, about 10 to about 20 injections are made to cover an area of about 20 cm ² to about 40 cm ² . Larger and smaller areas are treated with other options. Or, in the area of fat accumulation, a bolus of 1.0-10.0 ml is injected by injection, these can be periorbital areas, the area under the chin, the lateral surface of the thighs and buttocks.

In an alternative embodiment, the injections described above are made separately and sequentially in the same areas using two microsphere formulations in which the active ingredient is encapsulated.

When using needle-free injection, the microparticle formulations are injected as suspensions or as powder loaded microparticles, i.e. without a liquid carrier.

In some embodiments, a glucocorticosteroid, such as dexamethasone 6, budesonide 8 and / or fluticasone propionate 7, acts in the same way as an anti-inflammatory agent, thereby reducing inflammation caused by the administration of the composition, for example, caused by polymers, polymer microspheres and / or liposomes in the composition with prolonged release

Microsphere PLGA 15 encapsulates hydrophobic compounds more easily than hydrophilic compounds. To increase the load of hydrophilic active compounds, in some embodiments, the microspheres are modified with polyethylene glycol units, as described above. Microspheres of certain sizes are practically not absorbed by the blood and are not removed with lymph, so they provide the release of the active ingredient (s) in the desired location. For example, in some embodiments, the microspheres have a diameter of from about 20 microns to about 200 microns. In other embodiments, the size of the microspheres also affects the release profile of the active ingredient (s) in the tissue. In general, larger microspheres provide a longer and more uniform release profile.

An exemplary sustained release formulation contains from about 0.5 mg to about 7.5 mg of salmeterol 1 and / or formoterol 2 and from about 1.5 mg to about 7.5 mg of dexamethasone 6, fluticasone propionate 7 and / or budesonide 8, encapsulated in approximately 100 mg of poly (lactide glycolide) microspheres (PLGA) 15, the active ingredient delivers up to about 1.0 μg per day of salmeterol 1 and / or up to about 0.5 μg of formoterol and up to 5 μg per day of fluticasone and / or budesonide 6 per about 1 mg of copolymer for about 30 days.

Some options include sustained release formulations. In some embodiments, the activity of selective long-acting beta-2 agonists in sustained release formulations after a signal dose is greater than about 4 hours, preferably up to about 12 hours or up to about 24 hours. In contrast, selective short-acting beta-2 agonists exhibit similar conditions activity for less than about 4 hours and less than about 1 hour. The sustained release injection composition contains from about 100 μg to about 250 μg of salmeterol xin Foata and from about 500 micrograms fluticasone propionate 7 in about 10 mL lipid based excipient, such as Cremophor®, or its equivalents.

In some embodiments, the formulations are delivered transdermally using any suitable method known in the art, for example, as a topically applied cream or using a patch. Other transdermal delivery vehicles known in the art, such as electric, can also be used. In particular, long-acting beta-2 agonists such as formoterol 2, salmeterol 1 or bambuterol 3, and glucocorticosteroids are suitable for topical application to the skin due to their hydrophobicity. Sustained-release sustained-release transdermal formulations are prepared by known methods, for example using a biodegradable biocompatible composition, the active ingredient is a polymer or a composition with liposomes, as described above.

Although some options have been described above, these options are only examples and do not limit the scope of the invention. It will be apparent to those skilled in the art that the compositions, methods, and systems described herein may be in the form of various other forms. In addition, you can make various exceptions, replacements and changes in the compositions, methods and systems described in this application, without going beyond the scope of this invention. The following claims and their equivalents cover these forms and modifications.

Claims (27)

1. The composition for injection into local deposits of adipose tissue of a person, including
long-acting selective beta-2 adrenergic receptor agonist selected from salmeterol, formoterol, their salts and their solvates;
a compound for reducing adipose tissue desensitization to a beta adrenergic receptor agonist; and liquid carrier. 2. The composition according to claim 1, characterized in that the selective beta-2 adrenergic receptor agonist is lipophilic. 3. The composition according to claim 1, characterized in that the compound for reducing desensitization of the target tissue to the beta-adrenergic receptor agonist is a glucocorticosteroid. 4. The composition according to claim 1, characterized in that the compound for reducing desensitization of the target tissue to the beta-adrenergic receptor agonist is an antihistamine compound. 5. The composition according to claim 1, characterized in that the compound for reducing desensitization of the target tissue to the beta-adrenergic receptor agonist is a glucocorticosteroid and antihistamine. 6. The composition according to claim 1, characterized in that the compound for reducing desensitization of the target tissue to the beta adrenergic receptor agonist is at least one compound from dexamethasone, prednisolone, fluticasone propionate, budesonide, ketotifen and their analogues. 7. The composition according to claim 1, characterized in that the liquid carrier is a lipophilic liquid carrier. 8. The composition according to claim 1, characterized in that at least one of the selective long-acting beta-2 adrenergic receptor agonists and a compound for reducing desensitization are introduced into a sustained release agent. 9. The composition of claim 8, wherein the extended release agent is at least one substance from a biodegradable polymer, a biodegradable copolymer, a hydrogel and a liposome. 10. The composition according to claim 9, characterized in that the sustained release agent is poly (lactide-glycolide). 11. The composition according to claim 10, characterized in that the active ingredient is loaded in poly (lactide-glycolide) in an amount up to about 75%. 12. The composition according to claim 1, containing salmeterol, its salts, its solvates and fluticasone. 13. The composition according to claim 1, containing formoterol, its salts, its solvates and budesonide. 14. The composition according to claim 1, containing at least one compound of salmeterol, formoterol, their salts, their solvates and ketotifen. 15. The composition for injection for the treatment of local accumulation of fat in humans, including
at least one selective long-acting beta-2 adrenergic receptor agonist selected from salmeterol, formoterol, their salts and their solvates;
a means for reducing desensitization of the target tissue to a beta adrenergic receptor agonist and a liquid carrier. 16. A method of treating local accumulation of fat in humans, including:
contacting the stored fat with a pharmaceutically effective amount of a selective long-acting beta-2 adrenergic receptor agonist selected from salmeterol, formoterol, their salts and their solvates; and contacting the stored fat with a pharmaceutically effective amount of a compound to reduce desensitization of the target tissue to the beta adrenergic receptor agonist. 17. The method according to clause 15, wherein the compound for reducing desensitization of the target tissue to the beta adrenergic receptor agonist is at least one compound of glucocorticosteroid, dexamethasone, prednisolone, fluticasone propionate, budesonide and ketotifen. 18. The method according to clause 15, wherein the at least one selective long-acting beta-2 adrenergic receptor agonist and a compound for reducing desensitization are introduced into the agent with a prolonged action. 19. The method according to p. 18, characterized in that the selective agonist of beta-2 adrenergic receptor long-acting is salmeterol, and a pharmaceutically effective amount is up to about 100 μg / day. 20. The method according to p. 18, characterized in that the selective beta-2 adrenergic receptor agonist of long-acting is formoterol, and a pharmaceutically effective amount thereof is up to about 50 μg / day. 21. The method according to clause 15, wherein the selective beta-2 adrenergic receptor agonist and the compound for reducing desensitization are delivered almost simultaneously. 22. The method according to clause 15, wherein the selective beta-2 adrenergic receptor agonist and the compound for reducing desensitization are delivered by injection using a single needle. 23. The method according to clause 15, wherein the selective beta-2 adrenergic receptor agonist long-acting and the compound to reduce desensitization are delivered by needleless injection. 24. The method according to clause 15, wherein the selective beta-2 adrenergic receptor agonist and the compound to reduce desensitization are delivered by injection via transdermal administration. 25. A method of reducing adipose tissue in humans, including:
the introduction of a pharmaceutically effective amount of a compound that increases the number of beta-2 adrenergic receptors in the area of adipose tissue and
the introduction of a pharmaceutically effective amount of a selective long-acting beta-2 receptor agonist selected from salmeterol, formoterol, their salts and their solvates into adipose tissue, which causes at least one process of lipolysis and inhibited adipogenesis in the adipose tissue region. 26. The method according A.25, characterized in that at least one of the introductions of the compound increasing the number of beta-2 adrenergic receptors of the beta-2 receptor agonist is carried out less often than once a day. 27. A method of treating local accumulation of fat or cellulite in humans, comprising: introducing into the area of local accumulation of fat or cellulite a composition comprising: a selective beta-2 long-acting agonist selected from salmeterol, formoterol, their salts and their solvates and at least one a compound of glucocorticosteroid and ketotifen, while the composition has a prolonged lipolytic activity, contributing to lipolysis in the area of local accumulation of fat or cellulite.

Images