HK1096857B - Medicamentously targeted local lipolysis - Google Patents

Description

Drug-targeted local lipolysis

Technical Field

The present invention relates to an aqueous phospholipid system comprising at least one phospholipid, at least one bile acid and water, which is suitable for the preparation of a medicament for the treatment of adipose tissue disorders and for the regression of pathologically proliferating adipose tissue.

Technical Field

Aqueous phospholipid systems are known for a variety of applications. These systems are thus used, for example, in the cosmetics industry or for the production of pharmaceuticals. These systems are known with spherical vesicles, also known as liposomes. The boundary surface of the liposome with the exterior is formed by a lipid bilayer, and it contains an internal aqueous phase. For example, an aqueous phospholipid system comprising at least one phospholipid, at least one bile acid and water is described in european patent application EP 0615746. The commercially available product isN i.v. (rote list, 3 months 2003), which constitutes an aqueous phospholipid system comprising phospholipids, bile acids, DL-alpha-tocopherol, ethanol and water, and has been approved for use in lipidsPrevention and treatment of fatty embolism.

Reportedly, as one acceptsWhen injected subcutaneously, N.V., treated persons are said to have improved appearance in both Fat Pads (like those present under The eye circles, on The abdomen or at The buttock folds in overweight people) and aesthetics (Patricia guidelines Rittes, The Use of Phosphotophilephholine for Correction of Low light lipid bathing Dual efficacy Pads, DermatolSurg 2001; 27: 391-.

Disclosure of Invention

With the aim of finding effective compounds for the treatment of disorders of adipose tissue, it has now been found that the liposomal system according to the invention causes regression of pathologically proliferating adipose tissue. Lipolysis of adipose tissue occurs and the associated pathologically proliferating adipose tissue area is reduced. As described below, these disorders include not only aesthetically displeasing hyperplasia of adipose tissue, but also painful conditions and impairment of body function.

Accordingly, the present invention relates to the use of an aqueous phospholipid system for the preparation of a medicament for the treatment of an adipose tissue disorder, comprising:

a) at least one kind of phospholipid selected from the group consisting of phospholipids,

b) at least one bile acid, and

c) and (3) water.

The invention further relates to the use of the aqueous liposomal system for the preparation of a medicament for the regression of adipose tissue tumors.

The term "phospholipid" refers to compounds such as soy 3-sn-phosphatidylcholine (Phospholipon 90), reduced soy 3-sn-phosphatidylcholine (Phospholipon 90H), soy 3- (3sn) -phosphatidylglycerol (Phospholipon G), dimyristoylphosphatidylglycerol, lysophosphatidylcholine or dipalmitoylphosphatidylglycerol, and physiologically tolerated salts thereof.

The term "bile acid" refers to compounds such as deoxycholic acid, cholic acid, lithocholic acid, chenodeoxycholic acid, hyodeoxycholic acid, trihydroxycoprostanic acid, ursodeoxycholic acid, taurocholic acid or glycocholic acid, as well as physiologically tolerated salts thereof.

The term "adipose tissue disorder" refers to disorders as follows:

lipomas are adipose tissue tumors that are benign, slow growing, usually spherical, most likely phyllotactic (═ phyllotaid lipoma (l.pendulum)) or even villous (═ dendritic lipoma (l.arborescens), e.g. of synovial villi) stromal cell tumors, consisting of enlarged adipose tissue cells, preferably located in the subcutaneous cell tissue, possibly with central ossification (═ lipoma ossification), becoming mucoid (═ lipoma mucomatosis), or calcifying (═ lipoma petrochemical (l.petrisis)), also with increased connective tissue and integumentary formation (═ fibrolipoma), angiogenesis (═ l.telenegigectomy), rarely show malignant degeneration sarcoidosis (═ lipoma (l.sarcomatosis), liposarcoma). They are classified as pathological because they grow and their connective tissue capsule itself can be painful and because the pressure from their blood vessels can cause neuropathic pain.

De rking's disease, known as painful hyperlipidosis, is a particular form of hypertrophic hyperplasia of adipose tissue that is distributed between the dermal fatty fascia (Kampa's fatty fascia) and the basal dermis. The hormonal effect causes an increase in the water-binding capacity of these adipocytes, which in turn cause the early occlusion of lymphatic vessels in the sheep's odontoid lymphatic regions due to the phenomenon of compression, thereby creating an additional squeezing and stimulating effect exerted on the peripheral sensory nerves, so that these patients exhibit an extreme pain sensitivity to touch. In the course of the disease for years up to decades, irregular fatty nodules form in the subdermal diffuse sites, while the dermis becomes thinner and thinner during aging, some of the nodules being characterized by pain and being very unattractive.

Multiple symmetric liposis (Madelung's rock) (Lanois-bensude syndrome) is an inflammation of adipose tissue with proliferation of adipose tissue in which dystrophic adipose tissue tumors are formed with subcutaneous scar-like connective tissue bundles. In this case, the surgical operation is usually only partially successful, since this procedure involves the primary anatomy, while the disorder essentially manifests itself in the head, neck and shoulder regions.

Lipoedema is a painful swelling of adipose tissue, especially on the calf of a woman, and shows a progressive course and features with increasing age.

Painful fatty nodules (Piezogenic nodules) are the knots at the edges of the palms and heels, which are caused by compression and appear as multiple hernias of adipose tissue, mainly in the middle area of the heels of obese people. They often have a defect in the separation of subcutaneous adipose tissue, which is perceived by the patient as a cosmetic or functional annoyance.

Macular tumors are yellowish, plaque-like accumulations of cholesterol that bulge slightly in the eyelid area. They are soft, prone to migration, and usually appear symmetrically on both eyes. This is caused by local disturbances of lipid metabolism. Postmenopausal women tend to be affected frequently. Diabetes and elevated blood levels are also associated with an increased risk of macular neoplasia. Macular tumors may cause psychological stress due to their appearance.

Different types of lipodystrophy, such as lipodystrophy syndrome, which occurs in HLV patients receiving protease inhibitor therapy; dystrophic, obese genital degeneration, which is an endocrine disorder occurring in adolescent girls; sphingolipid metabolism disorders (sphingolipidoses) which are often characterized genetically, such as, for example, by somatic angiokeratomas (Fabry syndrome) or gangliosidoses with skin features.

The term "regression" refers to lipolysis of adipose tissue and regression of sites of hyperplastic fat.

In contrast to obesity-related fat hypertrophy involving food products, the adipose tissue disorders described above exhibit tissue conditions or characteristics that can be clearly identified pathologically and described by histological parameters of scarring and inflammation, but also by connective tissue encapsulation and changes in its own histological adipose tissue morphology.

The present invention thus relates to the use of an aqueous phospholipid system for the preparation of a medicament for the treatment of cellulitis, comprising:

a) at least one kind of phospholipid selected from the group consisting of phospholipids,

b) at least one bile acid, and

c) and (3) water.

Cellulitis is a particular type of hypertrophic adipose tissue that is distributed between the dermal fat fascia (Kampa's fat fascia) and the bottom surface of the dermis. The hormonal effect causes an increase in the water binding capacity of these adipocytes, which in turn cause the early occlusion of lymphatic vessels in the region of the sheep's odontoid lymph vessels due to the phenomenon of compression. In the course of the disease for years up to decades, irregular fatty nodules form in the subdermal diffuse sites, while the dermis becomes thinner and thinner during aging, some of the nodules being characterized by pain and being very unattractive.

The invention also relates to the use of at least one phospholipid or at least one bile acid for the preparation of a medicament for the treatment of an adipose tissue disorder or cellulitis.

If only phospholipids or bile acids are used alone, the same conditions and definitions apply as for the above-mentioned mixtures of phospholipids and bile acids.

The invention also relates to the use of phospholipids, wherein the phospholipids are in the form of physiologically tolerated salts, such as sodium, potassium and/or ammonium salts.

Phospholipids can be isolated from oilseeds, rapeseed, soy or sunflower and can be used in the liposome system after appropriate manipulation. For example, lecithin from chicken eggs is also suitable. Phospholipids from soy are preferred. The invention also relates to the use of a phospholipid, wherein the phospholipid is phosphatidylcholine, derived from soy and isolated therefrom. Especially in the case that the phospholipids consist of at least 90% by weight (% by weight) of soy phosphatidylcholine, especially 95% by weight.

The invention also relates to the use of bile acids, wherein the bile acids are in the form of physiologically tolerated salts. This may be, for example, the sodium, potassium and/or ammonium salt of deoxycholic acid, cholic acid, lithocholic acid, chenodeoxycholic acid, hyodeoxycholic acid, trihydroxycoprostanic acid, ursodeoxycholic acid, taurocholic acid or glycocholic acid.

The mass ratio of phospholipids to bile acids, in% by weight, is from 30:1 to 1:0.03, preferably from 1:0.7 to 1:0.1, in particular from 1:0.6 to 1: 0.3.

The phospholipid concentration in the liposome system is 0.5 to 30% by weight, preferably 5 to 25% by weight, in particular 10 to 20% by weight.

The liposome diameter is from 30nm to 180nm, preferably from 30nm to 130nm, in particular from 50nm to 90 nm. These liposomes can be sterilized by filtration without difficulty using a filter having a pore size of 0.2 μm.

The pH of the liposome system is in the vicinity of the neutral point, preferably 5.0-8.0, in particular 6.2-7.4.

For example, liposomal systems are prepared by dissolving or dispersing at least one phospholipid and at least one bile acid in the above-mentioned ratio to each other in an organic solvent. The solution or dispersion is then concentrated, after which water is added to form the liposome system. The production of the liposomal system can be promoted by extrusion, high pressure homogenization and/or sonication after the addition of water. The treatment is carried out at a temperature below 40 ℃, preferably between 20 ℃ and 30 ℃. Suitable organic solvents are ethanol, propanol, isopropanol or benzyl alcohol, in each case used individually or in mixtures. The volume of the remaining alcohol after concentration should be 0% by volume (% by volume) to 20% by volume, preferably 0% to 10% by volume.

Methods for producing liposomal systems are also described in european patent applications EP 0470437 or EP 0615746.

The liposomal systems used in the present invention are administered by subcutaneous, intra-articular, intraperitoneal, intramuscular, or intravenous injection. Subcutaneous injection is preferred.

Transdermal administration in the form of various carrier media is also possible, with various adjuvants, such as iontophoresis.

The uniform introduction of the liposomal system used in the present invention should be done by the tumescent method, which uses hydrostatic pressure to ensure uniform distribution.

Suitable dosage forms are, for example, suspensions, emulsions or injections, and also products with delayed release of the active ingredient, in the production of which, for example, customary auxiliaries can be used.

The pharmaceutical products are preferably manufactured and administered in the form of unit doses, each unit containing a specific dose of the liposomal system as active ingredient. In the case of an injection in the form of an ampoule, the dose may be about 10mg to about 2000mg, more preferably 50mg to 2000mg, and preferably about 250mg to 500mg, based on the phospholipid.

The daily dose required to treat an adult patient, depending on the size of the adipose tissue to be treated, is administered as an injection, each injection being 5mg to 500mg, preferably 250mg to 500mg, based on the phospholipid. The injection solution may also be diluted before administration, preferably with physiological saline. However, in some cases higher or lower daily doses may also be suitable. The dosage also depends on the size of the lipoma and for small lipomas a dosage of 1mg to 50mg, preferably 2mg to 20mg, per injection based on phospholipids is fully sufficient. Administration of a daily dose can be effected either as a single dose in the form of a single dosage unit or a plurality of smaller dosage units, or as multiple administrations of divided doses over a defined time interval.

The present invention will be explained in more detail below by way of examples.

Example (b):

example 1 preparation of the Liposomal System

250g of highly pure soy phosphatidylcholine containing more than 90% by weight phosphatidylcholine and 126.5g deoxycholic acid were dissolved in 1 liter of ethanol. The resulting solution was then evaporated to dryness under reduced pressure. The resulting residue was dispersed in 5 liters of water and homogenized by high pressure to give an average liposome diameter of 30nm to 100 nm. The resulting liposomal system was then filtered aseptically through a 0.2 μm filter and dispensed aseptically into ampoules containing 5ml of liposomal system per vial.

Example 2 regression of lipomas

a) Female patients were enrolled in a consultation on abdominal liposuction, under this treatment frame, the following medical history was recorded:

as a child and young adult, she is an acrobatic actor performing physical movements like those on gymnastic equipment. During this period she suffered blunt trauma with severe blood seepage under the left scapula. Later, particularly during specific exercises, a significant protrusion developed in the scapula, which was caused by a tumor of tissue that remained for years.

During the treatment, the problem of the treatment possibility of removing the lipoma is discussed immediately and the lipoma removal by means of local anesthesia with swelling is recommended to the patient. The partial resection performed later is without difficulty, but not completely. Acute improvement measures were reduced and there was a partial regression process under the scapula, which was then observed by Computed Tomography (CT).

Evaluation according to the radiation results was as follows: no bone changes occurred in the scapula; in CT, significant residual tissue was suspected in the medial inferior border of the scapula within the trapezius muscle diaphragm. This muscle is distended and exhibits a buildup of fat, differentially diagnosed as tumor residue. In view of the above, it is proposed to carry out supplementary NMR tomography, in particular whether or not a renewed surgery is planned.

Subsequently, when the patient is consulted again after about 4 months of the operation, 5ml of the solution is used with a 10cm long injection needleN i.v. (Rote list, 3 months 2003) was infiltrated and published in this finding. The patient reported a slight tingling sensation lasting one day, but they later disappeared. Lipomas regress relatively rapidly until the symptoms completely disappear.

Thereafter, the patient is asymptomatic.

b) Male patients had lipomas of about walnut kernel size on the right upper arm. The patient had no disorder of lipid metabolism and serum fat was within the normal range. Mixing 0.2ml ofThe solution was diluted with 0.2ml of NaCl for injection and then injected into patients. After the first 10 days, a clear regression of the lipomas appeared.

Example 3 significant regression of cellulitis

Two female patients had no disorder of lipid metabolism and serum fat was within the normal range.

Two patients received 0.4ml in one consultationInjections, which were diluted with 0.6ml of NaCl solution for injection (total injection amount was 1.0 ml). 0.1ml of solution was injected into each "cellulitis hump" for a total treatment of approximately the area of the palm size on the outer thigh of both (injection protocol is similar to the Botox protocol for hyperhidrosis). In the first two weeks of the day,the bulge subsided and was only mildly tender and sensitive to touch with moderate erythema. An ultrasound examination was also performed.

Claims (25)

1. Use of a liposomal system for the manufacture of a medicament for the treatment of an adipose tissue disorder, the liposomal system comprising:

a) at least one kind of phospholipid selected from the group consisting of phospholipids,

b) at least one bile acid, and

c) the amount of water is controlled by the amount of water,

wherein the mass ratio of the phospholipid to the bile acid is 30:1 to 1:0.03 in percentage by weight,

the concentration of phospholipids in the liposomal system is 0.5% to 30% by weight, and

the adipose tissue disorder is lipoma, Delken's disease, multiple symmetrical lipodystrophia, lipoedema, macular tumor, or painful fatty nodules.

2. The use as claimed in claim 1, wherein one of the following compounds and their physiologically tolerated salts is employed: soybean 3-sn-phosphatidylcholine, reduced soybean 3-sn-phosphatidylcholine, soybean 3-sn-phosphatidylglycerol, dimyristoylphosphatidylglycerol, lysophosphatidylcholine or dipalmitoylphosphatidylglycerol, or a mixture of these compounds as phospholipids.

3. Use according to claim 2, wherein sodium, potassium and/or ammonium salts of phospholipids are used as their physiologically tolerated salts.

4. Use according to claim 2, wherein soybean phosphatidylcholine is used as phospholipid.

5. The use as claimed in claim 4, wherein the phospholipid consists of at least 90% by weight of soy phosphatidylcholine.

6. Use as claimed in claim 5 wherein the phospholipid consists of 95% by weight of soy phosphatidylcholine.

7. Use according to any one of claims 1 to 6, wherein one of the following compounds and their physiologically tolerated salts is employed: deoxycholic acid, cholic acid, lithocholic acid, chenodeoxycholic acid, hyodeoxycholic acid, trihydroxycoprostanoic acid, ursodeoxycholic acid, taurocholic acid or glycocholic acid or mixtures of these compounds as bile acids.

8. Use according to claim 7, wherein the sodium, potassium and/or ammonium salts of bile acids are employed as their physiologically tolerated salts.

9. The use as claimed in any one of claims 1 to 6, wherein the mass ratio of phospholipid and bile acid is 1:0.7 to 1:0.1 in weight percent.

10. The use as claimed in any one of claims 1 to 6, wherein the mass ratio of phospholipid and bile acid is 1:0.6 to 1:0.3 in weight percent.

11. The use as claimed in any one of claims 1 to 6, wherein the concentration of phospholipids in the liposomal system is from 5% to 25% by weight.

12. Use as claimed in claim 11, wherein the concentration of phospholipids in the liposomal system is from 10% to 20% by weight.

13. The use of any one of claims 1-6, wherein the liposomal system is for the regression of adipose tissue tumors.

14. Use of a liposome system in the manufacture of a medicament for the treatment of cellulitis, said phospholipid system comprising:

a) at least one kind of phospholipid selected from the group consisting of phospholipids,

b) at least one bile acid, and

c) the amount of water is controlled by the amount of water,

wherein the mass ratio of the phospholipid to the bile acid is 30:1 to 1:0.03 in percentage by weight, and

the concentration of phospholipids in the liposomal system is 0.5% to 30% by weight.

15. The use as claimed in claim 14, wherein one of the following compounds and their physiologically tolerated salts is employed: soybean 3-sn-phosphatidylcholine, reduced soybean 3-sn-phosphatidylcholine, soybean 3-sn-phosphatidylglycerol, dimyristoylphosphatidylglycerol, lysophosphatidylcholine or dipalmitoylphosphatidylglycerol, or a mixture of these compounds as phospholipids.

16. Use according to claim 15, wherein sodium, potassium and/or ammonium salts of phospholipids are used as their physiologically tolerated salts.

17. Use according to claim 15, wherein soy phosphatidylcholine is used as the phospholipid.

18. Use as claimed in claim 17 wherein the phospholipid consists of at least 90% by weight of soy phosphatidylcholine.

19. The use as claimed in claim 18, wherein the phospholipid consists of 95% by weight of soy phosphatidylcholine.

20. Use according to any one of claims 14 to 19, wherein one of the following compounds and their physiologically tolerated salts is employed: deoxycholic acid, cholic acid, lithocholic acid, chenodeoxycholic acid, hyodeoxycholic acid, trihydroxycoprostanoic acid, ursodeoxycholic acid, taurocholic acid or glycocholic acid or mixtures of these compounds as bile acids.

21. Use according to claim 20, wherein as their physiologically tolerated salts sodium, potassium and/or ammonium salts of bile acids are employed.

22. The use of any one of claims 14-19, wherein the mass ratio of phospholipid and bile acid is 1:0.7 to 1:0.1, in weight percent.

23. The use of any one of claims 14-19, wherein the mass ratio of phospholipid and bile acid is 1:0.6 to 1:0.3 in weight percent.

24. The use as claimed in any one of claims 14 to 19, wherein the concentration of phospholipids in the liposomal system is from 5% to 25% by weight.

25. The use as claimed in claim 24, wherein the concentration of phospholipids in the liposomal system is 10% to 20% by weight.