WO2008113421A1 - Nouvelles compositions pharmaceutiques pour la lipolyse et procédé de production - Google Patents

Nouvelles compositions pharmaceutiques pour la lipolyse et procédé de production Download PDF

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Publication number
WO2008113421A1
WO2008113421A1 PCT/EP2008/000263 EP2008000263W WO2008113421A1 WO 2008113421 A1 WO2008113421 A1 WO 2008113421A1 EP 2008000263 W EP2008000263 W EP 2008000263W WO 2008113421 A1 WO2008113421 A1 WO 2008113421A1
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Prior art keywords
composition
phospholipid
composition according
amounts
fat
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PCT/EP2008/000263
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German (de)
English (en)
Inventor
Harald Greve
Christian Nauert
Original Assignee
Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh
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Publication of WO2008113421A1 publication Critical patent/WO2008113421A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to the field of lipolysis.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • compositions in particular pharmaceutical composition, are 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 -
  • (B) contains at least one non-bile acid-based fat emulsifier.
  • 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).
  • composition according to the invention also contains at least one physiologically acceptable carrier and / or excipient.
  • physiologically acceptable carrier preferably water.
  • the composition contains water, especially for injection purposes, d. H.
  • 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).
  • the phospholipid or its physiologically acceptable salt of component (a) may in principle be a synthetically produced phospholipid or else a phospholipid of natural origin.
  • 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.
  • this can be made, for example, from oil - A -
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m, in particular at most 0.5 ⁇ m, preferably at most 0.25 ⁇ m, particularly preferably in the range from 20 to 500 ⁇ .
  • the small particle size of the phospholipid structures 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 .
  • 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.
  • the Phospholipidteilchen protective is advantageously set in the aforementioned range, which will be explained below.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the fat emulsifier based on soybean is obtained.
  • 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.
  • 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.
  • a non-gallic acid-based fat emulsifier in the form of an animal-based phosphatidylethanolamine, preferably based on chicken egg yolk.
  • 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.
  • the amount of non-gallic acid-based fat emulsifier (s) in the composition according to the invention 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.
  • the fat emulsifier has to fulfill a complex, multiple task in the context of the composition according to the invention.
  • 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.
  • 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.
  • 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.
  • 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- ⁇ -tocopherol or derivatives thereof (for example Ester, such as acetate).
  • at least one antioxidant preferably tocopherol or its derivatives (for example its esters, for example tocopherol acetate), in particular DL- ⁇ -tocopherol or derivatives thereof (for example Ester, such as acetate).
  • tocopherol or its derivatives for example its esters, for example tocopherol acetate
  • DL- ⁇ -tocopherol or derivatives thereof for example Ester, such as acetate
  • the amount of oxidant in the composition of the invention can vary widely.
  • the composition according to the invention contains the antioxidant, preferably tocopherol or its derivatives, in particular DL- ⁇ -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.
  • the antioxidant preferably tocopherol or its derivatives, in particular DL- ⁇ -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
  • 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.
  • 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.
  • hydroxides, halides, phosphates and / or organic acids such as.
  • citric acid citric acid.
  • the amount of pH adjuster and / or pH buffering agent in the composition of the invention can vary widely.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • (C) optionally at least one antioxidant, preferably tocopherol or its derivatives, in particular DL- ⁇ -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
  • 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.).
  • the predetermined final volume eg 5 ml, 100 ml, 1,000 ml, 10,000 ml, etc.
  • the pH of the composition according to the invention can equally vary within wide ranges.
  • 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.
  • the adjustment of the pH takes place with the pH adjusters specified above and / or pH buffer substances.
  • 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.
  • an osmolality in the range from 200 to 400 mosmol / kg, in particular 250 to 350 mosmol / kg, preferably 275 to 325 mosmol / kg.
  • the adjustment of osmolality is carried out using the aforementioned isotonizing agents.
  • 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 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.
  • energy and / or under pressure for example high pressure
  • 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;
  • a predispersion is prepared comprising the phospholipid component (a), the emulsifier component (b) and optionally the antioxidant contains;
  • 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.
  • 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.
  • the pH - Adjusting agent and / or pH buffer substances and the isotonizing agent preferably in each case in the form of aqueous solutions
  • water water
  • 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 ⁇ , be set.
  • 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.
  • the phospholipid structures are adjusted to the desired particle or vesicle sizes.
  • a so-called sterile filtration generally follows. This is made possible only by the small particle size of the phospholipid structures;
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition according to the invention 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.
  • the composition according to the invention can be used for the medicinal and / or cosmetic lipolysis of adipose tissue.
  • 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.
  • composition according to the invention is also suitable for use for the curative and / or prophylactic treatment of cellulite ("orange peel").
  • adipose tissue diseases by subcutaneous local lipolysis for the purpose of regression (regression) or reduction (reduction) of the abnormally profiled fatty tissue
  • 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.
  • 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
  • Xanthelasma ie plate-like, mostly yellowish cholesterol deposits in the eyelids.
  • 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.
  • non-pathologically induced fat deposits for example non-pathological fat pads, which, for example, can also be influenced by physical exercise can
  • the erf ⁇ ndungssiee 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.
  • composition according to the invention for subcutaneous injection for the purpose of targeted local lipolysis
  • 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- ⁇ - 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 ⁇ m.
  • 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
  • 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.
  • VAS 10-level visual analogue scale
  • 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).
  • n 2 patients (4%), there were transient adverse drug reactions (edema, redness, itching, sensation of warmth), which resolved within 24 hours of injection.
  • n 2 patients (4%)
  • 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.
  • 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- soxycholklare) and tocopherol (among other ingredients, such.
  • 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- soxycholklare) and tocopherol (among other ingredients, such.
  • the second comparative composition corresponds to the composition according to the invention except that the phospholipid particle size is above 1 ⁇ m since the comparative dispersion is homogenized with a lower energy input.
  • the proportion of emulsifier is completely replaced by water, ie the third comparative composition contains no emulsifier at all.
  • 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)%.
  • 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)%.
  • n 7 patients (46.7%), circumscribed bruising occurred.
  • 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).
  • n 2 patients (13.3%), circumscribed bruising occurred.

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Abstract

L'invention concerne une composition, en particulier une composition pharmaceutique, de préférence adaptée à une application et/ou une injection notamment sous-cutanée aux fins de lipolyse. Cette composition contient, en association et en quantités respectivement efficaces, notamment pharmaceutiquement efficaces, (a) au moins un phospholipide et/ou ses sels physiologiquement compatibles; et (b) au moins un émulsifiant lipidique non basé sur l'acide biliaire.
PCT/EP2008/000263 2007-03-19 2008-01-15 Nouvelles compositions pharmaceutiques pour la lipolyse et procédé de production WO2008113421A1 (fr)

Applications Claiming Priority (4)

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DE102007013704.6 2007-03-19
DE102007013704 2007-03-19
DE102007015701.2 2007-04-02
DE102007015701A DE102007015701A1 (de) 2007-03-19 2007-04-02 Neue pharmazeutische Zusammensetzungen für die Lipolyse und Verfahren zu deren Herstellung

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010028365A1 (de) 2010-04-29 2011-11-03 Lichtblick Gmbh Verwendung einer Phospholipid enthaltenden Zusammensetzung zur Entfernung von subkutanen Fettansammlungen
WO2016138136A1 (fr) * 2015-02-27 2016-09-01 John Daniel Dobak Réduction des tissus adipeux
US10058553B2 (en) 2013-10-21 2018-08-28 Alevere Medical Corporation Fused heterotricyclic organic coumpounds, pharmaceutical compositions, and medical uses thereof

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EP0547422A2 (fr) * 1991-12-14 1993-06-23 BASF Aktiengesellschaft Compositions des vitamines et/ou carotinoides stables en poudre et procédé de leur préparation
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HUE038247T2 (hu) * 2004-05-19 2018-10-29 Los Angeles Biomedical Res Inst Harbor Ucla Medical Ct Nátrium-deoxikolátot tartalmazó injektálható készítmény
US7754230B2 (en) * 2004-05-19 2010-07-13 The Regents Of The University Of California Methods and related compositions for reduction of fat
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EP1676568A1 (fr) * 2004-12-30 2006-07-05 Merckle Gmbh Particules comprenant des phospholipides, procédé de préparation et utilisation comme médicament

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EP0470251A1 (fr) * 1989-04-25 1992-02-12 The Green Cross Corporation Composition liquide de prostaglandine
EP0547422A2 (fr) * 1991-12-14 1993-06-23 BASF Aktiengesellschaft Compositions des vitamines et/ou carotinoides stables en poudre et procédé de leur préparation
DE4405545A1 (de) * 1994-02-22 1995-08-31 Dietl Hans Fettlösliche Vitamine enthaltende Zubereitung zur oralen Applikation
WO1995024893A1 (fr) * 1994-03-16 1995-09-21 R.P. Scherer Limited Systemes d'administration s'appliquant a des medicaments hydrophobes
DE19609476A1 (de) * 1996-03-11 1997-09-18 Basf Ag Stabile zur parenteralen Verabreichung geeignete Carotinoid-Emulsionen
US20010053385A1 (en) * 1998-12-18 2001-12-20 John M. Lipari Novel formulations comprising lipid-regulating agents
US20020032171A1 (en) * 1999-06-30 2002-03-14 Feng-Jing Chen Clear oil-containing pharmaceutical compositions containing a therapeutic agent
US6416793B1 (en) * 2000-07-11 2002-07-09 Bioresponse, L.L.C. Formulations and use of controlled-release indole alkaloids

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010028365A1 (de) 2010-04-29 2011-11-03 Lichtblick Gmbh Verwendung einer Phospholipid enthaltenden Zusammensetzung zur Entfernung von subkutanen Fettansammlungen
WO2011135020A1 (fr) 2010-04-29 2011-11-03 Lichtblick Gmbh Utilisation d'une composition contenant un phospholipide et un acide glycyrrhizique pour l'élimination d'accumulations de graisse sous-cutanée par lipolyse sous-cutanée
US10058553B2 (en) 2013-10-21 2018-08-28 Alevere Medical Corporation Fused heterotricyclic organic coumpounds, pharmaceutical compositions, and medical uses thereof
US10888563B2 (en) 2013-10-21 2021-01-12 Alevere Medical Corporation Fused heterotricyclic organic compounds, pharmaceutical compositions, and medical uses thereof
US11382916B2 (en) 2013-10-21 2022-07-12 Alevere Medical Corporation Fused heterotricyclic organic compounds, pharmaceutical compositions, and medical uses thereof
WO2016138136A1 (fr) * 2015-02-27 2016-09-01 John Daniel Dobak Réduction des tissus adipeux
US9844520B2 (en) 2015-02-27 2017-12-19 John Daniel Dobak, III Reduction of adipose tissue
CN107530359A (zh) * 2015-02-27 2018-01-02 约翰·丹尼尔·杜巴克 脂肪组织的减少
US10485767B2 (en) 2015-02-27 2019-11-26 John Daniel Dobak, III Reduction of adipose tissue
CN107530359B (zh) * 2015-02-27 2020-02-18 10X生物有限责任公司 脂肪组织的减少
US11065210B2 (en) 2015-02-27 2021-07-20 10Xbio, Llc Reduction of adipose tissue

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