WO2008113421A1

WO2008113421A1 - New pharmaceutical compositions for lipolysis and method for the production thereof

Info

Publication number: WO2008113421A1
Application number: PCT/EP2008/000263
Authority: WO
Inventors: Harald Greve; Christian Nauert
Original assignee: Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh
Priority date: 2007-03-19
Filing date: 2008-01-15
Publication date: 2008-09-25
Also published as: DE102007015701A1

Abstract

The invention relates to a composition, particularly a pharmaceutical composition, which is preferably suitable for particularly subcutaneous application and/or injection for lipolysis, said composition comprising a combination of (a) at least one phospholipid and/or the physiologically acceptable salts thereof and (b) at least one non-gallic acid-based oil emulsifier in effective, particularly pharmaceutically effective amounts.

Description

New pharmaceutical compositions for lipolysis and process for their preparation

The present invention relates to the field of lipolysis.

In particular, the present invention relates to novel compositions, in particular pharmaceutical compositions, which are preferably suitable for particular subcutaneous administration and / or injection for the purposes of lipolysis, and a method for producing this composition and their use in the field of medicine or pharmacy for different Application areas.

Phospholipid systems are known for various applications. For example, these systems are used in the cosmetic sector or for the production of pharmaceutical products. These systems generally include vesicles, preferably spherical vesicles, also referred to as liposomes; these liposomes are generally bounded on the outside by a lipid double membrane and contain an aqueous phase in their interior. Aqueous based phospholipid systems containing a phospholipid, a bile acid and water are described, for example, in European Patent Application EP 0 615 746 A1. Commercially available is the product of Lipostabil ^® N of Artegodan GmbH, Lüchow comprising an aqueous Phospholipidsystem containing phospholipids, bile acid, tocopherol, ethanol, benzyl alcohol and water; This commercial preparation is approved for the prophylaxis and treatment of fat embolisms.

Furthermore, it has been reported that fat pads, such as those in overweight people z. As under the eyes, abdomen and occur at the hips, shrink and of people treated it hen comes to aesthetic improvements in Ausse- if these individuals include subcutaneous injections of Lipostabil ^® N (see. Eg. BP Guedes ride, Aesth. Plast., Surg. 27: 315-318, 2003 "The Use of Phosphatidyl Choline for Correction of Localized Fat Deposits"). Furthermore, DE 103 49 979 A1 and DE 103 61 067 A1 describe aqueous phospholipid systems comprising phospholipid, bile acid and water and, if appropriate, a fat-assisting component which, in the case of dietary subcutaneous fat accumulations or of Adipose tissue disorders are used for drug-directed, targeted local lipolysis.

Disadvantage of the above-described phospholipid systems which contain a bile acid-based fat emulsifier (ie, in particular deoxycholic acid, cholic acid, lithocholic acid, chenodeoxycholic acid, trihydroxcoproic acid, presodeoxycholic acid, taurocholic acid or glycocholic acid) is the fact that when used subcutaneously for purposes Lipolysis often causes undesirable side effects, especially the formation of edema, redness, itching, sensation of warmth and bruising. Also, the lipolytic effect is not always sufficient in all cases to provide the therapeutically desired result.

Consequently, there is a need for a therapeutic agent suitable for subcutaneous administration or injection for purposes of lipolysis which at least largely avoids or at least attenuates the previously described disadvantages of the agents of the prior art used for this purpose. It is therefore an object of the present invention to provide a composition, in particular a pharmaceutical composition, which is suitable for lipolytic use, in particular on subcutaneous administration or injection, and at least largely avoids or at least attenuates the disadvantages of the prior art described above. In particular, such a composition, in particular a pharmaceutical composition, should enable lipolytic lipolysis of adipose tissue, in particular a lipolytic reduction or regression, both of pathologically conditioned and non-pathologically caused adipose tissue, and advantageously be subcutaneously administrable or injectable.

The Applicant has now surprisingly found that the above-described problem can be solved by formulating a combination of at least one phospholipid or its physiologically acceptable salts together with at least one non-gallic acid-based fat emulsifier. Such a composition, in particular pharmaceutical composition, is particularly suitable for use in the medicinal and cosmetic lipolysis of adipose tissue, in particular for local, in particular targeted, local lipolysis of adipose tissue.

The present invention - according to a first aspect of the present invention - is thus a composition, in particular a pharmaceutical composition, which is preferably suitable for subcutaneous administration or injection in particular for purposes of lipolysis, wherein the composition - in combination and in each case, in a pharmaceutically effective quantities -

(a) at least one phospholipid and / or its physiologically acceptable salts; and

(B) contains at least one non-bile acid-based fat emulsifier.

In general, the composition according to the invention is in liquid form or in injectable form at room temperature (20 ^° C.) and under normal pressure (1013.25 hPa) (for example as liquid micellar solution or emulsion).

In addition to the aforementioned constituents or ingredients, the composition according to the invention also contains at least one physiologically acceptable carrier and / or excipient. Advantageously, this is water.

In general, the composition contains water, especially for injection purposes, d. H. In general, the composition according to the invention is formulated as an aqueous-based composition, which, however, for formulation purposes may also contain alcoholic components (for example ethanol and / or benzyl alcohol).

As far as the phospholipid or its physiologically acceptable salt of component (a) is concerned, it may in principle be a synthetically produced phospholipid or else a phospholipid of natural origin. Preferably, a phospholipid or its salt of natural origin, in particular a phospholipid or its salt of natural origin is used on a vegetable or animal basis, preferably on a vegetable basis, most preferably on a soybean basis. In the case of the use of a phospholipid or its salt of natural origin on a vegetable basis, this can be made, for example, from oil - A -

be won, rapeseed, soybeans or sunflowers. The use of a phospholipid based on soybeans is particularly preferred according to the invention. According to a particular embodiment, the phospholipid or its salt is used in the form of a soybean extract, in particular in the form of an alcoholic, preferably ethanolic soybean extract. According to the invention, it is particularly preferred if the soybean extract is at least 70% by weight, in particular at least 80% by weight, preferably at least 85% by weight, particularly preferably at least 90% by weight or more, based on the soybean extract, to phospholipid (s), preferably in the form of 3-sn-phosphatidylcholine or its physiologically acceptable salts. Alternatively, a phospholipid of animal origin can also be used, in particular a phospholipid obtained from chicken egg yolk.

The phospholipid used according to the invention may in particular be selected from the group of 3-sn-phosphatidylcholine, in particular soya-based, and derivatives thereof; hydrogenated 3-sn-phosphatidylcholine, especially soy-based; 3-sn-phosphatidylglycerol, especially on a soybean basis; dimyristoyl; lysophosphatidylcholine; Dipalmitoylphosphatidylglycerol; and physiologically acceptable salts of the aforementioned compounds and mixtures of two or more of the aforementioned compounds.

According to the invention, the phospholipid used is particularly preferably 3-sn-phosphatidylcholine or its physiologically tolerated salts.

The amounts of phospholipid (s) in the composition of the invention can vary widely. It is preferred according to the invention if the composition according to the invention comprises phospholipid (s) in amounts of 0.001 to 50 g / 100 ml of composition, in particular 0.01 to 45 g / 100 ml of composition, preferably 0.1 to 40 g / 100 ml of composition preferably 0.5 to 35 g / 100 ml of composition, most preferably 1 to 30 g / 100 ml of composition. However, on a case-by-case or application-related basis, it may be necessary to Deviating quantities mentioned, without departing from the scope of the present invention.

It is preferred in accordance with the invention for the phospholipids or their salts used to be present in the composition in the form of finely divided, preferably at least substantially spherical or globular phospholipid structures, in particular phospholipid droplets or vesicles. It is particularly preferred for the phospholipid structures, in particular phospholipid droplets or vesicles, to have mean diameters of at most 1 μm, in particular at most 0.5 μm, preferably at most 0.25 μm, particularly preferably in the range from 20 to 500 Å. This has a number of advantages: On the one hand, this results in an increased effectiveness of the composition according to the invention, since in this way the phospholipids are finely distributed upon application or injection and strike the fat deposits or fatty tissue areas to be lysed with a large surface area. On the other hand, in this way the stability, in particular storage stability and long-term stability, of the composition according to the invention is increased since such small particles or vesicles are better stabilized or more stably dispersed. Furthermore, such small particle sizes of the phospholipids used effectively prevent the side effects described at the outset (for example, the occurrence of edemas, burning, itching, reddening, bruising, etc.) associated with the compositions of the prior art. The small particle size of the phospholipid structures, in particular phospholipid droplets or vesicles, also has the advantage that in this way in the preparation of the composition of the invention in the first place a sterile filtration of the composition is made possible, which is not or at least not readily possible with larger particle sizes of the phospholipids , Finally, this particular embodiment also has the advantage that, in the case of improper applications (eg in the case of injury to blood vessels and the like), undesired embolisms can not be triggered due to the small particle size of the phospholipid droplets or vesicles. For the aforementioned reasons, therefore, the Phospholipidteilchengröße is advantageously set in the aforementioned range, which will be explained below.

As far as the non-gallic acid-based fat emulsifier is concerned, a synthetically produced non-gallic acid-based fat emulsifier may in principle be used or a non-bile acid-based fat emulsifier of natural origin. Preferably, in the context of the present invention, a non-bile acid-based fat emulsifier of natural origin, in particular a non-bile acid-based fat emulsifier of natural origin based on plants or animals, preferably plant-based, very particularly preferably soybean-based.

As described above, the use of a non-bile acid-based fat emulsifier has the decisive advantage that, on the one hand, unlike the prior art, according to which bile acid-based fat emulsifiers are used, unwanted side effects of the aforementioned type (eg formation of reddening of the skin, itching, edema, Bruising etc.) can be effectively avoided and on the other hand, the lipolytic activity can be significantly increased.

According to the invention, the term "non-gallic acid-based fat emulsifier" refers in particular to those compounds which are able to emulsify or emulsify fats and / or to stabilize fats, but which do not differ from bile acids and their derivatives, as described in connection with the description of the prior art Are or are not based on this, d. H. So have a different chemical composition and / or structure than bile acid or its derivatives. As described above, it is preferred according to the invention to use a non-gallic acid-based fat emulsifier of natural origin. In principle, the non-bile acid-based fat emulsifier of natural origin may be one based on plants or animals. In the case of using a plant-based non-gallic acid-based fat emulsifier, it is preferable that the fat emulsifier based on soybean is obtained. In the case of using a non-bile acid-based fat emulsifier on an animal basis, it is preferred according to the invention if it is obtained on the basis of chicken egg yolk. The use of a non-bile acid-based vegetable-based fat emulsifier, particularly preferably soybean-based, is preferred according to the invention.

In particular, the non-gallic acid-based fat emulsifier may be selected from the group of phosphatidylethanolamines and polyalkylene- or poly- oxyalkylene-based polymers or copolymers and mixtures of two or more of these compounds.

Preferred according to the invention is the use of a non-bile acid-based fat emulsifier in the form of phosphatidylethanolamine, in particular in the form of a phosphatidylethanolamine of natural origin, in particular a phosphatidylethanolamine of natural origin on a vegetable or animal basis, more preferably on a vegetable basis, most preferably on a soybean basis. Alternatively, however, it is also possible to use a non-gallic acid-based fat emulsifier in the form of an animal-based phosphatidylethanolamine, preferably based on chicken egg yolk.

In the context of the present invention, however, synthetically produced non-gallic acid-based fat emulsifiers may alternatively be used. These may, for example, be selected from the group of polyalkylene- or polyoxyalkylene-based polymers or copolymers, in particular from the group of polyoxyethylene / polyoxypropylene copolymer, polyethylene glycol sorbitan oleate, polyoxyethylene 35 castor oil and mixtures thereof.

As far as the amount of non-gallic acid-based fat emulsifier (s) in the composition according to the invention is concerned, this may vary within wide ranges. It is preferred according to the invention if the composition according to the invention comprises non-gallic acid-based fat emulsifier (s) in amounts of 0.001 to 15 g / 100 ml of composition, in particular 0.01 to 10 g / 100 ml of composition, preferably 0.1 to 8 g / 100 ml composition, more preferably 0.5 to 7 g / 100 ml composition, most preferably 1 to 5 g / 100 ml composition contains. However, on a case-by-case or application basis, it may be necessary to deviate from the aforementioned quantities without departing from the scope of the present invention.

Without wishing to be bound by any particular theory, the fat emulsifier has to fulfill a complex, multiple task in the context of the composition according to the invention. First, it supports the emulsification and distribution process of the phospholipid structures, in particular phospholipid droplets or vesicles, in the aqueous phase and thus helps to stabilize the composition of the invention. On the other hand The fat emulsifier also supports fat reduction or lipolysis, in particular by the fat emulsifier accelerating the lipolysis and / or promoting the removal of the lysed fats. In addition to the absolute amounts of the aforementioned ingredients (a) and (b), the weight ratio of phospholipid (s) to non-gallic acid-based fat emulsifier (s) is also important for the effectiveness of the composition according to the invention. It has turned out to be particularly advantageous if the composition according to the invention comprises phospholipid (s) and non-gallic acid-based fat emulsifier (s) in a weight ratio of phospholipid (s) to non-gallic acid-based fat emulsifier (s) of at least 2: 1, in particular at least 3: 1, preferably at least 4: 1, more preferably at least 5: 1, more preferably at least 6: 1, and / or up to 100: 1, in particular up to 50: 1 contains. Nevertheless, depending on the application or the individual case, it may be necessary to deviate from the abovementioned values without departing from the scope of the present invention.

Moreover, it is advantageous if the composition according to the invention additionally comprises at least one antioxidant, preferably tocopherol or its derivatives (for example its esters, for example tocopherol acetate), in particular DL-α-tocopherol or derivatives thereof (for example Ester, such as acetate). In this way, the long-term stability or storage stability of the composition according to the invention in the manner according to the invention is increased, in particular by the antioxidant action with respect to the phospholipids, and the effectiveness of the composition according to the invention is increased in its use. The amount of oxidant in the composition of the invention can vary widely. According to the invention, it is preferred, however, if the composition according to the invention contains the antioxidant, preferably tocopherol or its derivatives, in particular DL-α-tocopherol or derivatives thereof, in amounts of 0.0001 to 1 g / 100 ml of composition, in particular 0.001 to 0.5 g / 100 ml of composition, preferably 0.001 to 0.1 g / 100 ml of composition, more preferably 0.005 to 0.09 g / 100 ml of composition, most preferably 0.015 to 0.03 g / 100 ml of composition. However, it may be necessary on a case-by-case or application basis to depart from the aforementioned amounts, without departing from the scope of the present invention.

Furthermore, the composition according to the invention may also contain at least one pH adjuster and / or pH buffering agent in order to adjust the pH of the composition according to the invention to an optimum pH or pH range for the application. Examples of pH-adjusting agents and / or pH-buffering agents which can be used according to the invention are organic and inorganic acids and / or bases and / or salts thereof, such. As hydroxides, halides, phosphates and / or organic acids, such as. For example, citric acid. The amount of pH adjuster and / or pH buffering agent in the composition of the invention can vary widely. According to the invention, it is preferred if the composition according to the invention contains the pH adjuster and / or pH buffering agent in amounts of 0.0001 to 1 g / 100 ml of composition, in particular 0.001 to 0.008 g / 100 ml of composition, preferably 0.002 to 0.006 g / 100 ml composition containing. However, it may be necessary on a case-by-case or application basis to deviate from the aforementioned quantities without departing from the scope of the present invention.

Furthermore, the composition according to the invention may additionally contain at least one isotonizing agent. The isotonizing agent is preferably selected from the group of inorganic acids and / or their salts, in particular halides, more preferably sodium chloride. The amount of isotonizing agent in the composition of the invention can vary widely. According to the invention, however, it is preferred if the composition according to the invention contains the isotonizing agent in amounts of 0.001 to 1 g / 100 ml of composition, in particular 0.01 to 0.5 g / 100 ml of composition, preferably 0.1 to 0.3 g / 100 ml Composition containing. However, it may be necessary on a case-by-case or application basis to deviate from the aforementioned quantities without departing from the scope of the present invention.

Furthermore, the composition according to the invention may also contain at least one preservative. The preservative may preferably be selected from the group of alcohols, especially ethanol and / or benzyl alcohol. The amount of preservative (s) of the composition of the invention can vary widely. According to the invention, it is preferred if the composition particularly preferably contains the preservative in amounts of 0.001 to 5 g / 100 ml of composition, in particular 0.01 to 4 g / 100 ml of composition, preferably 0.5 to 2.5 g / 100 ml of composition 1 to 2 g / 100 ml composition. However, it may be necessary on a case-by-case or application-related basis to deviate from the abovementioned amounts without departing from the scope of the present invention.

Finally, the composition according to the invention may also contain at least one fat-assisting substance; According to the invention suitable examples of such substances are, for. B. riboflavin and / or carnitine. The amount of fat-loss promoting substances in the composition of the invention can vary widely. According to the invention, however, it is preferred if the composition according to the invention supports the fat-reducing substance in amounts of 0.0001 to 15 g / 100 ml of composition, in particular 0.001 to 10 g / 100 ml of composition, preferably 0.001 to 5 g / 100 ml of composition , more preferably 0.001 to 2.5 g / 100 ml composition. However, it may be necessary on a case-by-case or application basis to deviate from the aforementioned quantities without departing from the scope of the present invention.

The present invention according to a particular embodiment of the present invention is a composition, in particular a pharmaceutical composition, which is preferably suitable for subcutaneous administration or injection for purposes of lipolysis and in particular has the properties described above, wherein the composition in combination and contains in each case effective, in particular pharmaceutically effective amounts the following constituents or ingredients:

(A) at least one phospholipid and / or its physiologically acceptable salts, in particular in amounts of 0.001 to 50 g / 100 ml composition, in particular 0.01 to 45 g / 100 ml composition, preferably 0.1 to 40 g / 100 ml composition , more preferably 0.5 to 35 g / 100 ml of composition, most preferably 1 to 30 g / 100 ml of composition; (B) at least one non-bile acid-based fat emulsifier, in particular in amounts of 0.001 to 15 g / 100 ml composition, in particular 0.01 to 10 g / 100 ml composition, preferably 0.1 to 8 g / 100 ml composition, particularly preferably 0.5 to 7 g / 100 ml composition, most preferably 1 to 5 g / 100 ml composition;

(C) optionally at least one antioxidant, preferably tocopherol or its derivatives, in particular DL-α-tocopherol or its derivatives, in particular in amounts of 0.0001 to 1 g / 100 ml composition, in particular 0.001 to 0.5 g / 100 ml composition , preferably

0.001 to 0.1 g / 100 ml of composition, more preferably 0.005 to 0.09 g / 100 ml of composition, most preferably 0.015 to 0.03 g / 100 ml of composition; (D) optionally at least one pH adjusting agent and / or pH buffering agent, preferably selected from the group of organic or inorganic acids and / or salts, in particular hydroxides, halides, phosphates and / or citric acid, in particular in amounts of from 0.0001 to 1 g / 100 ml of composition, in particular 0.001 to 0.008 g / 100 ml of composition, preferably 0.002 to 0.006 g / 100 ml of composition;

(E) optionally at least one isotonizing agent, preferably selected from the group of inorganic acids and their salts, in particular halides, preferably sodium chloride, in particular in amounts of 0.001 to 1 g / 100 ml composition, in particular 0.01 to 0.5 g / 100 ml of composition, preferably 0.1 to 0.3 g / 100 ml of composition; (F) optionally at least one preservative, preferably selected from the group of alcohols, in particular ethanol and / or benzyl alcohol, in particular in amounts of 0.001 to 5 g / 100 ml composition, in particular 0.01 to 4 g / 100 ml composition, preferably 0 , 5 to 2.5 g / 100 ml of composition, more preferably 1 to 2 g / 100 ml of composition;

(g) if appropriate, at least one fat-reducing substance, preferably selected from the group of riboflavin and / or carnitine, in particular in amounts of from 0.0001 to 15 g / 100 ml of composition. in particular from 0.001 to 10 g / 100 ml of composition, preferably from 0.001 to 5 g / 100 ml of composition, more preferably from 0.001 to 2.5 g / 100 ml of composition; (h) water, in particular for adjusting the predetermined final volume (eg 5 ml, 100 ml, 1,000 ml, 10,000 ml, etc.).

As far as the pH of the composition according to the invention is concerned, it can equally vary within wide ranges. In general, the pH of the composition according to the invention is in the range from 5 to 11, in particular 6 to 9, preferably 6 to 8.5. However, on a case-by-case or application basis, it may be necessary to deviate from the above values without departing from the scope of the present invention. The adjustment of the pH takes place with the pH adjusters specified above and / or pH buffer substances.

To achieve good efficacy or compatibility, the composition according to the invention generally has an osmolality in the range from 200 to 400 mosmol / kg, in particular 250 to 350 mosmol / kg, preferably 275 to 325 mosmol / kg. However, on a case-by-case or application basis, it may be necessary to deviate from the above values without departing from the scope of the present invention. The adjustment of osmolality is carried out using the aforementioned isotonizing agents.

For the subsequent application, the composition is usually present in a sterile packaged form, in particular in containers or packaging units of defined volume, wherein these packs or packaging units can be any sterile packable containers, containers and the like, in particular ampoules (eg Disposable cartridges, vials, cylindrical vials, etc.), bottles (eg, vials or vials, etc.), syringes (eg, pre-filled syringes, disposable syringes, dual-chamber syringes, etc.) and the like. The present invention - according to a second aspect - is a process for the preparation of the composition according to the invention. The present invention according to this aspect of the invention is thus a process for the preparation of a composition according to the invention as described above, wherein in a first process step the ingredients of the composition according to the invention, as described above, are first dispersed in water and the resulting dispersion subsequently in a second process step with introduction of energy and / or under pressure (for example high pressure), preferably by means of a gap homogenizer Ultrasound, homogenized by means of an extruder or the like.

In general, in the preparation of the dispersion, the procedure is such that not all ingredients of the composition according to the invention are dispersed in the first process step, but rather first a predispersion is prepared comprising the phospholipid component (a), the emulsifier component (b) and optionally the antioxidant contains; In general, the preparation of the predispersion is carried out at temperatures in the range of 20 to 40 ⁰ C, in particular 25 to 30 ⁰ C. Subsequently, the homogenization is then carried out in the manner described above, followed by the addition of the other ingredients, in particular with the addition of the pH - Adjusting agent and / or pH buffer substances and the isotonizing agent, preferably in each case in the form of aqueous solutions, and finally with the addition of water to adjust the desired final volume. Of crucial importance is that in the preparation of the predispersion at least the aforementioned components (a) and (b) are present so that they are homogenized and the phospholipids are adjusted to the desired final size.

In general, the homogenization of the second process step is carried out in such a way, in particular under such an energy input and / or for such a period of time that the phospholipids in the dispersion, in particular in the form of finely divided, preferably at least substantially circular or spherical phospholipid structures, in particular phospholipid droplets or vesicles, to an average diameter of at most 1 .mu.m in particular at most 0.5 .mu.m, preferably at most 0.25 .mu.m, more preferably in the range of 20 to 500 Ä, be set. As described above, the homogenization, in particular the introduction of energy, preferably takes place by means of high pressure, in particular using gap homogenizers, or alternatively by means of ultrasound or extrusion. In this way, the phospholipid structures are adjusted to the desired particle or vesicle sizes. After preparation of the finished dispersion (ie after preparation of predispersion, homogenization, addition of the remaining ingredients and adjustment of the final volume with water), a so-called sterile filtration generally follows. This is made possible only by the small particle size of the phospholipid structures; Here, a further advantage of the small particle size of the phospholipid structures used according to the invention is to be seen. Sterile filtration is carried out in a manner known per se to the person skilled in the art. Subsequently, the composition prepared, in particular after sterile filtration, introduced into a sterilizable container, where it is usually autoclaved, especially at temperatures above 100 ⁰ C, preferably in the range of 100 ⁰ C to 150 ⁰ C, preferably in the range of 100 ⁰ C to 130 ⁰ C, preferably over a period of 0.1 to 2 hours, preferably 0.1 to 0.5 hours. The containers which can be used for this purpose have already been described above.

For further details of the process according to the invention, reference may be made to the above statements on the composition according to the invention, which apply correspondingly with regard to the process according to the invention.

The object of the present invention - according to another aspect of the present invention - is the use according to the invention of the composition according to the present invention in the field of medicine and pharmacy.

As described above, the composition according to the invention, as described above, is particularly suitable for purposes of lipolysis, preferably by means of injection, preferably in the context of subcutaneous administration. The present invention thus relates to the use of the composition according to the present invention for preferably subcutaneous lipolysis. In particular, the composition according to the invention can be used for the medicinal and / or cosmetic lipolysis of adipose tissue. Usually, the composition according to the invention is used for local, in particular targeted, local lipolysis of adipose tissue. Another object of the present invention in the context of the use according to the invention is the use of the composition according to the present invention for the curative and / or prophylactic treatment of adipose tissue disorders, in particular for the lipolytic reduction and / or regression of abnormal fat tissue.

Another object of the present invention in the context of the use according to the invention is the use of the composition according to the invention for the lipolytic reduction and / or regression of non-pathologically induced adipose tissue.

Furthermore, the composition according to the invention is also suitable for use for the curative and / or prophylactic treatment of cellulite ("orange peel").

With regard to the treatment of adipose tissue diseases by subcutaneous local lipolysis for the purpose of regression (regression) or reduction (reduction) of the abnormally profiled fatty tissue, the following diseases can be mentioned. All indications are pathologically delineated tissue diseases, which can also be histopathologically verified (eg by inflammation, connective tissue encapsulation or changes in the fatty tissue morphology or distribution). They usually lead to an impairment of body functions or pain. Moreover, they are often associated with a psychologically extremely damaging stigma. These are not alimentary adipose hypertrophies of the fat cells. The following fatty tissue diseases can be treated, for example, with the composition according to the invention:

Lipomas (i.e., benign slow-growing fatty tissue tumors, preferably in the subcutaneous tissue): Lipomas are considered pathological because they grow and their connective tissue can be painful. Likewise, the compression of blood vessels (blood vessels, nerves, lymphatics, etc.) from them can lead to pain or functional restrictions.

- Lipodystrophy (loss of adipose tissue), especially after antiretroviral

Therapy in HIV patients or in Cushing's disease (eg so-called "Buffalo Hump") - Dercum's disease (special form of hypertrophic proliferation of adipose tissue between the dermal fat fascia and the underside of the dermis, also called "lipomatosis dolorosa") - lipoedema (ie painful swelling of the adipose tissue, especially on the lower legs of women)

- Madelung's fat glands (ie fatty tissue-proliferating, usually symmetric fatty tissue inflammation on the neck).

- Pieced nodules (ie pressure-related hand-edge or heel nodules)

- Xanthelasma (ie plate-like, mostly yellowish cholesterol deposits in the eyelids).

- Dystrophia adiposogenitalis (i.e., endocrine disorder in adolescents with female fat distribution type). As described above, the composition according to the invention can also be influenced, for example, with respect to the regression (reduction) or reduction (reduction) of non-pathologically induced fat deposits (for example non-pathological fat pads, which, for example, can also be influenced by physical exercise can), so z. B .:

- in the case of fat deposits on the face and neck area (eg bags under the eyes, nasolabial folds, hocks, double chin, etc.)

- in the case of fat pads on the upper body (eg fat bulges on the back and on the hip (so-called "love handles"), in male gynecomastia, with limited fatty deposits on the upper and lower abdomen and upper arm, in the case of "washboard belly" structuring with bodybuilders etc ,

- in the case of fat pads on the lower body (eg so-called "riding trousers", fat bulges at the transition from the buttocks to the thighs ["banana rolls"] and on the inner thigh or knee etc.)

- for the post-treatment of liposuction As already described above, the erfϊndungsgemäße composition can finally, for example, for the treatment of Cellulite ("orange peel") use. Cellulite is a special form of hyper- trophene Proliferation of adipose tissue with formation of disseminated localized fatty nodules under the dermis, some of which have a painful or dysaesthetic character. With regard to further details of the use according to the invention, reference may be made to the above statements regarding the composition according to the invention and to the method according to the invention, which apply correspondingly with respect to the use according to the invention. Further embodiments, modifications and variations of the present invention will be readily apparent to those skilled in the art upon reading the description and practicable without departing from the scope of the present invention. The present invention will be illustrated by the following embodiments, which by no means limit the present invention.

EMBODIMENTS

Preparation of a composition according to the invention for subcutaneous injection for the purpose of targeted local lipolysis

5 kg phosphatidylcholine from soybeans with 94% 3-sn-phosphatidylcholine and 1.5 kg phosphatidylethanolamine-based emulsifier (phosphatidylethanolamine content: at least 20% by weight, based on the emulsifier) as non-gallic acid-based emulsifier component and 0.015 kg DL-α- Tocopherol were dispersed with vigorous stirring at temperatures of 25 to 30 ⁰ C in water for injection. The predispersion thus obtained was homogenized by means of high pressure to a phospholipid particle size of <0.2 μm. By adding a dilute NaCl solution and a dilute NaOH solution, the liquid was adjusted to a pH of about 7 and to an osmolar pressure corresponding to about 0.9% NaCl. With water for injection was adjusted to 100 1 final volume and then sterile filtered. The sterile injection solution was filled into brown 5-ml ampoules and finally autoclaved for 15 minutes at 121 ⁰ C. Specification:

Appearance: slightly cloudy, transparent, opalescent

Liquid pH: approx. 7.0 Osmolality: approx. 279 mosmol / kg (approx. 0.9% NaCl)

Sterility: sterile, according to Pharm. Eur.

Bacterial endotoxins: max. 50 EU / ml

Application studies: Treatment of circumscribed fat pads in three different body regions by liposysis with highly purified phospholipids in combination with a non-bile acid-based fat emulsifier. The application compositions described below were carried out using the previously prepared composition according to the invention.

1. Methods A. Patients

Fifty adult patients (n = 43 female, n = 7 male) with circumscribed thighs (so-called "breeches"), on the hip (so-called "love handles") and on the abdomen were included in the study.

The following exclusion criteria had to be met: allergy to soy protein; Pregnancy or lactation; Body mass index> 17 and <40; Kidney or liver disease, diabetes mellitus or thyroid disease, any other serious illness, previous surgery or previous skin diseases in the areas to be treated; unrealistic expectations of the patients regarding the therapeutic success.

B. Therapy The drug used corresponds to the composition prepared in the preceding embodiment.

The drug was administered in 1 to 3 treatment sessions at 28-day intervals. The injection was made with a 30 G needle and a 10 ml syringe to a depth of 1 cm below the surface of the skin. Per Injection 0.4 ml were injected. The distance between the injection sites was 1 to 2 cm. The number of applications varied with each patient depending on the area of the fat pads, with a maximum total dose of 50 ml per session was not exceeded. Follow-up visits were made 30 and 60 days after the last treatment.

C. Evaluation

In each of the treated regions, the fat layer thickness was measured in millimeters on each day of treatment and at the follow-up visits using a skin thickness shear gage. The fat layer thickness measurements were made in triplicate on each observation day and the results were averaged. From these results, the percentage reduction in fat layer thickness between the baseline and the last observation day was calculated. Treatment success was also assessed on the last day of observation by the patients and the attending physician using a 10-level visual analogue scale (VAS) ("0 = no improvement" to "10 = very good improvement"). All adverse drug reactions were recorded and documented.

2 results

The distribution of patients according to the regions treated was as follows: abdomen n = 19 (38%), hip n = 21 (42%), thigh n = 10 (20%). The number of treatments averaged 2.01 sessions (rank from 1 to 3). The demographic data of the treated patients are shown in the table below:

* x ± SD The fat layer thicknesses varied between 1 1 mm and 53 mm in the individual regions before the start of treatment and between 6 and 33 mm at the end of the observation. The percentage reduction in fat layer thickness between the start of treatment and the last observation day averaged (24.8 ± 1.2)%. The improvement in the reduction of fat pads was rated on average by the patients on the visual analogue scale with a score of (7.8 ± 1.2) and by the doctors on average (7.7 ± 1.0).

In only n = 2 patients (4%), there were transient adverse drug reactions (edema, redness, itching, sensation of warmth), which resolved within 24 hours of injection. In n = 2 patients (4%), circumscribed bruising occurred, which regressed within the observation period.

3. Conclusion

Subcutaneous injection of highly purified soybean phospholipids in combination with a non-bile acid-based fat emulsifier is a safe and effective treatment option for reducing circumscribed fat deposits in different parts of the body. It can be used in addition to liposuction or replace it in certain regions.

4. Comparative experiments

According to the experiments with the composition according to the invention, comparative studies with three non-inventive compositions were carried out on 15 adult patients each (n = 1 1 female, n = 4 male) with circumscribed thigh, hip and abdomen fat pads. The first comparative composition corresponds to the marketed product Lipostabil ^® N of Artegodan GmbH, comprising an injection solution with phospholipids from soybean with 93% 3-sn-phosphatidylcholine, a bile acid-based fat emulsifier (namely De- soxycholsäure) and tocopherol (among other ingredients, such. B. Ethanol, benzyl alcohol, sodium chloride, sodium hydroxide and water). The second comparative composition corresponds to the composition according to the invention except that the phospholipid particle size is above 1 μm since the comparative dispersion is homogenized with a lower energy input. Finally, in the third comparative composition, the proportion of emulsifier is completely replaced by water, ie the third comparative composition contains no emulsifier at all. In the first comparison composition based on Lipostabil ^® N, 86.7% of the treated patients (n = 13) had adverse drug reactions (edema, reddening, itching and / or warm sensation) which receded within 48 hours after injection , In n = 13 patients (86.7%) circumscribed bruising occurred. The percentage reduction in fat layer thickness between the start of treatment and the last observation day for the same treatment period as in the case of the composition according to the invention was on average only (15.5 ± 1.3)%. The improvement in the reduction in fat deposits was averaged by the patients on the visual analog scale with a score of (5.9 ± 1.3)% and by the physicians on average (6.0 ± 0.9)%.

In the second comparative composition, the percent reduction in fat layer thickness between the start of treatment and the last day of observation over the same treatment period averaged only (5, 1 ± 0.6)%. The improvement in fat pad reduction was averaged by the patients on the visual analogue scale at (2.3 ± 0.6)% and by the physicians on average (2.2 ± 0.7)%. In n = 7 patients (46.7%), there were transient adverse drug reactions (edema, redness, itching, and / or warmth) that resolved within 48 hours of injection. In n = 7 patients (46.7%), circumscribed bruising occurred.

Finally, in the third comparative composition, the percent reduction in fat layer thickness between the start of treatment and the last observation day in the same treatment period averaged only (4.9 ± 0.4)%. The improvement in the reduction in fat deposits was rated on average by the patients on the visual analog scale with a score of (1.9 ± 0.3) and by the physicians with (1.4 ± 0.2). N = 3 patients (13.3%) had transient adverse drug reactions (edema, redness, itching and / or warmth). In n = 2 patients (13.3%), circumscribed bruising occurred.

In the case of the three comparison compositions, a lower to significantly lower effect is achieved with respect to the lipolysis of fat pads, in contrast to the composition according to the invention. Treatment with a bile acid-based fat emulsifier also leads to much more adverse drug reactions than in the case of non-bile acid-based drugs. based fat emulsifier. In the case of the omission of a fat emulsifier, the i-polytische effect is drastically reduced (see third comparative composition). The comparative experiments also show that the effectiveness of the treatment composition also depends crucially on the particle size of the phospholipid structures or vesicles (compare second comparative composition).

Claims

claims:

1. Composition, in particular pharmaceutical composition, preferably for the particular subcutaneous administration and / or injection for purposes of lipolysis, wherein the composition in combination and in each case effective, in particular pharmaceutically effective amounts

(b) contains at least one non-gallic acid-based fat emulsifier.

A composition according to claim 1, wherein the composition is in liquid form and / or in injectable form at room temperature (20 ^° C) and under normal pressure (1013,25 hPa).

3. The composition of claim 1 and / or 2, further comprising at least one physiologically acceptable carrier and / or excipients.

Composition according to one or more of the preceding claims, wherein the composition additionally contains water, in particular for injection purposes, and / or wherein the composition is formulated as an aqueous-based composition.

5. Composition according to one or more of the preceding claims, wherein the phospholipid is a synthetically produced phospholipid or a phospholipid of natural origin, preferably a phospholipid of natural origin, in particular a phospholipid of natural origin on a vegetable or animal basis, preferably on a vegetable basis, especially preferably soybean based.

6. The composition according to one or more of the preceding claims, wherein the phospholipid based on soybean is obtained.

7. The composition according to one or more of the preceding claims, wherein the phospholipid in the form of a soybean extract, in particular in the form of an alcoholic, preferably ethanolic soybean extract, is used, in particular wherein the soybean extract at least 70 wt .-%, in particular at least 80 wt .-% , preferably at least 85 wt .-%, more preferably at least

90 wt .-% or more, based on the soybean extract, of phospholipid (s), preferably in the form of 3-sn-phosphatidylcholine or its physiologically acceptable salts.

8. The composition according to one or more of the preceding claims, wherein the phospholipid is of animal origin and is obtained in particular from chicken egg yolk.

9. Composition according to one or more of the preceding claims, wherein the phospholipid is selected from the group of 3-sn-phosphatidylcholine, in particular soya-based, as well as its derivatives; hydrogenated 3-sn-phosphatidylcholine, especially soy-based; 3-Sn-phosphatidylglycerol, especially soybean-based; Dimyristoylphosphatidylglycerol; lysophosphatidylcholine; Dipalmitoylphosphatidylglycerol; and physiologically acceptable salts of the aforementioned compounds and mixtures of two or more of the aforementioned compounds.

10. The composition according to one or more of the preceding claims, wherein the phospholipid is 3-sn-phosphatidylcholine or its physiologically acceptable salts.

Composition according to one or more of the preceding claims, wherein the composition comprises phospholipid (s) in amounts of 0.001 to 50 g / 100 ml of composition, in particular 0.01 to 45 g /

100 ml of composition, preferably 0.1 to 40 g / 100 ml of compound Composition, more preferably 0.5 to 35 g / 100 ml composition, most preferably 1 to 30 g / 100 ml composition contains.

12. The composition according to one or more of the preceding claims, wherein the phospholipids in the form of finely divided, preferably at least substantially circular or spherical phospholipid structures, in particular phospholipid droplets or vesicles, are present in the composition, in particular the phospholipid structures, in particular phospholipid droplets or vesicles, medium

Diameter of at most 1 .mu.m in particular at most 0.5 .mu.m, preferably at most 0.25 .mu.m, more preferably in the range of 20 to 500 Ä.

13. The composition according to claim 1, wherein the non-gallic acid-based fat emulsifier is a synthetically produced non-gallic acid-based fat emulsifier or a non-gallic acid fat emulsifier of natural origin, preferably a non-bile acid-based fat emulsifier of natural origin, in particular a non-bile acid-based fat emulsifier of natural origin on a vegetable or animal basis, preferably on vegetable base, most preferably soybean based.

14. Composition according to one or more of the preceding claims, wherein the non-gallic acid-based fat emulsifier based on

Soybeans is won.

Composition according to one or more of the preceding claims, wherein the non-gallic acid-based fat emulsifier is derived from chicken egg yolk.

16. The composition according to one or more of the preceding claims, wherein the non-gallic acid-based fat emulsifier is selected from the group of phosphatidylethanolamines and polyalkylene- or polyoxyalkylene-based polymers or copolymers and mixtures of two or more of these compounds.

17. The composition according to claim 1, wherein the non-gallic acid-based fat emulsifier is a phosphatidylethanolamine, in particular a phosphatidylethanolamine of natural origin, in particular a phosphatidylethanolamine of natural origin on a vegetable or animal basis, preferably on a vegetable basis

Base, most preferably soybean based.

18. A composition according to one or more of the preceding claims, wherein the non-gallic acid-based fat emulsifier is an animal-based phosphatidylethanolamine, preferably based on chicken egg yolk.

19. A composition according to one or more of the preceding claims, wherein the non-gallic acid-based fat emulsifier is selected from the group of polyalkylene- or polyoxyalkylene-based polymers or copolymers, in particular from the group of polyoxyethylene / polyoxypropylene copolymer, polyethylene glycol sorbitan oleate, polyoxyethylene 35- Castor oil and mixtures thereof.

20. Composition according to one or more of the preceding claims, wherein the composition comprises non-gallic acid-based fatty emulsifier (s) in amounts of 0.001 to 15 g / 100 ml of composition, in particular 0.01 to 10 g / 100 ml of composition, preferably 0 , 1 to 8 g / 100 ml of composition, more preferably 0.5 to 7 g / 100 ml of composition, most preferably 1 to 5 g / 100 ml of composition.

21. A composition according to one or more of the preceding claims, wherein the composition comprises phospholipid (s) and non-gallium acid based fat emulsifier (s) in a weight ratio of

Phospholipid (s) to non-bile acid based (s) Fettemulgator (s) of at least 2: 1, in particular at least 3: 1, preferably at least 4: 1, more preferably at least 5: 1, more preferably at least 6: 1, and / or up to 100: 1, in particular up to 50: 1.

22. Composition according to one or more of the preceding claims, further comprising at least one antioxidant, preferably tocopherol or its derivatives, in particular DL-α-tocopherol or its derivatives, in particular wherein the composition of the antioxidant in amounts of 0.0001 to 1 g / 100 ml of composition, in particular 0.001 to 0.5 g / 100 ml of composition, preferably 0.001 to 0.1 g / 100 ml of composition, more preferably 0.005 to 0.09 g / 100 ml of composition, most preferably 0.015 to 0.03 g / 100 ml composition containing.

23. The composition according to one or more of the preceding claims, further comprising at least one pH adjusting agent and / or pH buffering agent, preferably selected from the group of organic or inorganic acids and / or bases and / or their salts, in particular hydroxides, halides, Phosphates and / or citric acid, in particular wherein the composition comprises the pH adjuster and / or pH buffering agent in amounts of 0.0001 to 1 g / 100 ml of composition, in particular 0.001 to 0.008 g / 100 ml of composition, preferably 0.002 to 0.006 g / 100 ml composition containing.

24. Composition according to one or more of the preceding claims, further comprising at least one isotonizing agent, preferably selected from the group of inorganic acids and / or their salts, in particular halides, preferably sodium chloride, in particular wherein the composition contains the isotonizing agent in amounts of 0.001 to 1 g / 100 ml of composition, in particular 0.01 to 0.5 g / 100 ml of composition, preferably 0.1 to 0.3 g / 100 ml of composition.

25. Composition according to one or more of the preceding claims, also containing at least one preservative, preferably selected from the group of alcohols, in particular ethanol and / or benzyl alcohol, in particular wherein the composition contains the preservative in amounts of from 0.001 to 5 g / 100 ml. Composition, in particular 0.01 to 4 g / 100 ml composition, preferably 0.5 to 2.5 g / 100 ml of composition, more preferably 1 to 2 g / 100 ml of composition.

26. Composition according to one or more of the preceding claims, further comprising at least one fat-breakdown-promoting substance, preferably selected from the group of riboflavin and / or carnitine, in particular wherein the composition contains the fat-loss-promoting substance in amounts of 0, 0001 to 15 g / 100 ml of composition, in particular 0.001 to 10 g / 100 ml of composition, preferably 0.001 to 5 g / 100 ml of composition, particularly preferably 0.001 to 2.5 g / 100 ml of composition.

27. Composition, in particular pharmaceutical composition, preferably for in particular subcutaneous administration and / or injection for purposes of lipolysis, in particular according to one or more of the preceding claims, wherein the composition in combination and in each case effective, in particular pharmaceutically effective amounts, the following constituents and / or ingredients contains: (a) at least one phospholipid and / or its physiologically acceptable salts, in particular in quantities of 0.001 to 50 g / 100 ml of composition, in particular 0.01 to 45 g / 100 ml of composition, preferably 0, 1 to 40 g / 100 ml of composition, more preferably 0.5 to 35 g / 100 ml of composition, most preferably 1 to 30 g / 100 ml of composition;

(B) at least one non-bile acid-based fat emulsifier, in particular in amounts of 0.001 to 15 g / 100 ml composition, in particular 0.01 to 10 g / 100 ml composition, preferably 0.1 to 8 g / 100 ml composition, particularly preferably 0.5 to 7 g / 100 ml of composition, most preferably 1 to 5 g / 100 ml of composition;

(C) optionally at least one antioxidant, preferably tocopherol or its derivatives, in particular DL-α-tocopherol or its derivatives, in particular in amounts of 0.0001 to 1 g / 100 ml composition, in particular 0.001 to 0.5 g / 100 ml of composition, preferably 0.001 to 0.1 g / 100 ml of composition, more preferably 0.005 to 0.09 g / 100 ml of composition, most preferably 0.015 to 0.03 g / 100 ml of composition; (d) optionally at least one pH adjuster and / or pH

Buffering agent, preferably selected from the group of organic or inorganic acids and / or salts, in particular hydroxides, halides, phosphates and / or citric acid, in particular in amounts of 0.0001 to 1 g / 100 ml of composition, in particular 0.001 to 0.008 g / 100 ml of composition, preferably 0.002 to 0.006 g / 100 ml of composition;

(E) optionally at least one isotonizing agent, preferably selected from the group of inorganic acids or their salts, in particular halides, preferably sodium chloride, in particular in amounts of 0.001 to 1 g / 100 ml composition, in particular 0.01 to 0.5 g / 100 ml of composition, preferably 0.1 to 0.3 g / 100 ml of composition; (F) optionally at least one preservative, preferably selected from the group of alcohols, in particular ethanol and / or benzyl alcohol, in particular in amounts of 0.001 to 5 g / 100 ml composition, in particular 0.01 to 4 g / 100 ml composition, preferably 0 , 5 to 2.5 g / 100 ml of composition, more preferably 1 to 2 g / 100 ml of composition;

(g) optionally at least one fat-assisting substance, preferably selected from the group of riboflavin and / or carnitine, in particular in quantities of 0.0001 to 15 g / 100 ml of composition, in particular 0.001 to 10 g / 100 ml of composition, preferably 0.001 to 5 g / 100 ml of composition, more preferably 0.001 to 2.5 g / 100 ml of composition;

(h) water, in particular for setting the predetermined final volume.

28. The composition according to one or more of the preceding claims, wherein the composition has a pH in the range of 5 to 11, in particular 6 to 9, preferably 6 to 8.5, and / or wherein the composition has an osmolality in the range of 200 to 400 mosmol / kg, in particular 250 to 350 mosmol / kg, preferably 275 to

325 mosmol / kg.

29. The composition according to one or more of the preceding claims, wherein the composition is sterile packaged, in particular in containers of defined volume, preferably ampoules, bottles, syringes and the like.

30. A process for the preparation of a composition according to the preceding claims, wherein in a first process step, the ingredients of the composition as defined in the preceding claims, are first dispersed in water and the resulting dispersion subsequently in a second process step with energy input and / or is homogenized under pressure, preferably by means of a gap homogenizer, by means of ultrasound, by means of extrusion or the like.

31. Process according to claim 30, wherein first a predispersion is prepared which contains at least the phospholipid component (a), the emulsifier component (b) and the optionally present antioxidant, and subsequently the homogenization of the predispersion is carried out, followed by the addition of the other ingredients, in particular water and / or pH adjuster and / or pH buffer substance and / or isotonizing agent.

32. The method of claim 30 and / or 31, wherein the homogenization is carried out such, in particular under such an energy input and / or for such a period of time that the phospholipids in the dispersion, in particular in the form of finely divided, preferably at least substantially rounder or spherical phospholipid structures, in particular phospholipid droplets or vesicles, to an average diameter of at most 1 μm, in particular, at most 0.5 μm, preferably at most 0.25 microns, more preferably in the range of 20 to 500 A, can be adjusted.

33. The method according to one or more of the preceding claims, wherein the second step of the homogenization of a

Sterile filtration followed, after which the composition prepared is finally introduced into a sterilizable container, optionally followed by autoclaving, especially at temperatures above 100 ° C, preferably in the range of 100 ° C to 150 ⁰ C, preferably in the range of 100 ⁰ C. to 130 ⁰ C, and / or over a

Duration of 0.1 to 2 hours, preferably 0.1 to 0.5 hours.

34. Use of a composition according to the preceding claims for medical or cosmetic use, preferably for injection purposes, preferably for subcutaneous administration, in particular for the purposes of lipolysis, in particular for the purposes of subcutaneous lipolysis.

35. Use of a composition according to the preceding claims for the medicinal and / or cosmetic lipolysis of fatty tissue.

36. Use of a composition according to the preceding claims for the local, in particular targeted local lipolysis of adipose tissue.

37. Use of a composition according to the preceding claims for the curative and / or prophylactic treatment of fatty tissue diseases, in particular for the lipolytic reduction and / or regression of abnormal fat tissue.

38. Use of a composition according to the preceding claims for the lipolytic reduction and / or regression of non-pathologically induced adipose tissue.

39. Use of a composition according to the preceding claims for the curative and / or prophylactic treatment of cellulite.