Note: Descriptions are shown in the official language in which they were submitted.
CA 02543187 2006-04-21
WO 20051041919 PCTIEP20041011320
Medicamentously targeted local lipolysis
The invention relates to aqueous phospholipid systems comprising at least
one phospholipid, at least one bile acid and water, which are suitable for
producing medicaments for the treatment of adipose tissue disorders and
for regression of pathologically proliferated adipose tissue.
Aqueous phospholipidic phospholipid systems are known for various
applications. Thus, these systems are employed for example in the
cosmetic sector or for producing pharmaceutical products. These systems
are distinguished by having spherical vesicles which are also referred to as
liposomes. The boundary of said liposomes to the outside is formed by a
lipid bilayer membrane, and they contain an aqueous phase inside.
Aqueous phospholipid systems comprising at least one phospholipid, at
least one bile acid and water are described for example in European patent
application EP 0 615 746. A marketed product is Lipostabil~ N i.V. (Rote
Liste, March 2003) which constitutes an aqueous phospholipid system
which comprises phospholipids, bile acid, DL-alpha-tocopherol, ethanol and
water and is approved for the prophylaxis and treatment of fat embolisms.
It is reported that fat pads like those occurring in overweight people
underneath the eyes, on the abdomen or on the hips shrink, and esthetic
improvements in the appearance of the treated people are said to occur
when these people received subcutaneous injection of Lipostabil~ N i.V.
(Patricia Guedes Rittes, The Use of Phosphatidylcholine for Correction of
Lower Lid Bulging Due to Prominent Fat Pads, Dermatol Surg. 2001; 27:
391-392).
With the aim of finding effective compounds for the treatment of disorders
of adipose tissue, it has now been found that the liposome system
employed according to the invention leads to a regression in pathologically
proliferated adipose tissue. Lipolysis of the adipose tissue takes place, and
the relevant pathologically proliferated adipose tissue region recedes. As
stated below, these disorders involve not just esthetically upsetting
proliferations of adipose tissue, but painful conditions and impairments of
body functions.
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The invention therefore relates to the use of aqueous phospholipid systems
comprising
a) at least one phospholipid,
b) at least one bile acid and
c) water
for producing a medicament for the treatment of adipose tissue disorders.
The invention further relates to the use of said aqueous liposome system
for producing a medicament for regression of adipose tissue tumors.
The term "phospholipid" means compounds such as 3-sn-phosphatidyl-
choline, soya (Phospholipon 90), 3-sn-phosphatidylcholine, reduced soya
(Phospholipon 90H), 3-(3sn)-phospohatidyl)glycerol soya (Phospholipon
G), dimyristoylphosphatidylglycerol, lyso-phosphatidylcholine or dipalmitoyl-
phosphatidylglycerol and the physiologically tolerated salts thereof.
The term "bile acid" means compounds such as deoxycholic acid, cholic
acid, lithocholic acid, chenodeocycholic acid, hyodeoxycholic acid,
trihydroxycoprostanic acid, ursodeoxycholic acid, taurocholic acid or glyco-
cholic acid, and the physiologically tolerated salts thereof.
The term "adipose tissue disorders" means for example the following
disorders:
Lipomas are adipose tissue tumors, which are benign, slow-growing,
usually spherical, possibly pedunculated (= I. pendulum) or even villous
(= I. arborescens, for example of the synovial villi) mesenchymal tumors
composed of - enlarged - adipose tissue cells, preferentially in a
subcutaneous cell tissue, possibly with central ossification (= I.
ossificans),
becoming mucoid (= I. myxomatodes) or calcifying (= I. petrificans), also
with increased connective tissue and capsule formation (= I. fibrosum),
neoangiogenesis (= I. teleangiectodes), rarely showing malignant
degeneration (= I. sarcomatodes, liposarcoma). They are to be categorized
as pathological because they grow and their connective tissue envelope
may be painful per se, as well as the compression derived therefrom on
blood vessels, which may cause neuralgia.
Dercum's disease, called lipomatosis dolorosa, is a special type of hyper-
trophic proliferation of adipose tissue, which is located between the dermal
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fat fascia (Kampa's fat fascia) and the underside of the dermis. Hormonal
effects lead to an enhanced water-binding capacity of these fat cells which
themselves in turn bring about, through pressure phenomena, lymph tract
obstructions in the region of the initial fern-like lymph vessels and with
which additional compressive and irritant effects are exerted on the
peripheral sensory nerves, so that these patients display an extremely
painful sensitivity to touch. Over the course of several years up to decades
there is formation of irregular fatty nodules in disseminated locations
underneath the dermis, which becomes thinner during the aging process,
some of which nodules have painful and highly dysesthetic characteristics.
Madelung's neck (Lanois-Bensaude syndrome) is an adipose tissue
inflammation with adipose tissue proliferation in which a dystrophic adipose
tissue tumor formation is accompanied by subcutaneous scar-like
connective tissue compaction. In such cases, surgical procedures can often
be only partially successful, because essential anatomic structures are
involved in this process and the disorder is manifested essentially in the
region of the head, neck and shoulders.
Lipedema is a painful adipose tissue swelling which occurs especially on
the lower legs of women and shows a progressive course and
characteristics with increasing age.
Piezogenic nodules are nodules on the edges of the hands and the heels
which are caused by pressure and occur as multiple adipose tissue
hernias, mainly in the medial region of the heel in obese people. They are
usually defects in the septation of the subcutaneous adipose tissue which
are regarded by patients as cosmetically or functionally disturbing.
Xanthelasma is a pale yellow, slightly raised plaque-like deposit of
cholesterol in the region of the eyelids. They are soft and easily
displaceable and usually occur symmetrically on both eyes. It is caused by
local derangements of lipid metabolism. Postmenopausal women are
affected particularly frequently. Diabetes mellitus and elevated blood liquid
levels are also associated with an increased risk of developing it.
Xanthelasmas may cause psychological stress because of their
appearance.
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Various types of lipodystrophy, such as lipodystrophy syndrome which
may occur in HIV patients after treatment with protease inhibitors,
dystrophia adiposogenitalis, which is an endocrine disorder in adolescent
girls, sphingolipidoses, which usually have hereditary characteristics, such
as angiokeratoma corpis (Fabry's syndrome) or gangliosidoses with
cutaneous manifestations.
The term "regression" means the lipolysis of the adipose tissue and
regression of the proliferated adipose region.
The abovementioned adipose tissue disorders show, in contrast to the
food-related obesity-correlated lipohypertrophy, tissue conditions or
identities which can be pathologically differentiated unambiguously and
which can be described by histological parameters of scarring and
inflammation, but also by connective tissue encapsulations and by changes
in the histological adipose tissue morphology itself.
The invention therefore relates to the use of aqueous phospholipid systems
comprising
a) at least one phospholipid,
b) at least one bile acid and
c) water
for producing a medicament for the treatment of cellulite.
Cellulite is a special type of hypertrophic proliferation of adipose tissue,
which is located between the dermal fat fascia (Kampa's fat fascia) and the
underside of the dermis. Hormonal effects lead to an enhanced water-
binding capacity of these fat cells which themselves in turn bring about,
through pressure phenomena, lymph tract obstructions in the region of the
initial fern-like lymph vessels. Over the course of several years up to
decades there is formation of irregular fatty nodules in disseminated
locations underneath the dermis, which becomes thinner during the aging
process, some of which nodules have painful and highly dysesthetic
characteristics.
The invention also relates to the use of at least one phospholipid or at least
one bile acid for producing a medicament for the treatment of adipose
tissue disorders or cellulite.
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If only phospholipid or bile acid are employed alone, the same conditions
and definitions apply as for the abovementioned mixtures of phospholipid
and bile acid.
5 The invention also relates to the use of phospholipid in which the phospho-
lipid is in the form of a physiologically tolerated salt, for example as
sodium,
potassium and/or ammonium salt.
The phospholipid can be isolated from oil seeds, rapeseed, soybean or
sunflowers and, after appropriate application, be employed in the liposome
system. Lecithin, for example from chicken egg, is also suitable. Phospho-
lipids from soybeans are preferred. The invention also relates to the use of
phospholipid in which the phospholipid is the phosphatidylcholine from
soybean and is isolated therefrom. Especially when the phospholipid
consists of at least 90 percent by weight (% by weight) of soybean
phosphatidylcholine, in particular 95% by weight.
The invention also relates to the use of a bile acid in which the bile acid is
in the form of a physiologically tolerated salt. This may be for example a
sodium, potassium and/or ammonium salt of deoxycholic acid, cholic acid,
lithocholic acid, chenodeocychoiic acid, hyodeoxycholic acid, trihydroxy-
coprostannic acid, ursodeoxycholic acid, taurocholic acid or glycocholic
acid.
The mass ratio of phospholipid to bile acid is, in °l° by
weight, from 30:1 to
1:0.03, preferably from 1:0.7 to 1:0.1, in particular 1:0.6 to 1:0.3.
The phospholipid concentration in the fiposome system is from 0.5% by
weight to 30% by weight, preferably from 5% by weight to 25% by weight,
in particular from 10°!° by weight to 20°!° by
weight. The liposomes have a
diameter of from 30 nm to 180 nm, preferably from 30 nm to 130 nm, in
particular from 50 nm to 90 nrn. These liposomes can be sterilized by
filtration without difficulty, employing filters with a pore diameter of 0.2
pm.
The pH of the liposome system is around the neutral point, preferably from
5.0 to 8.0, in particular from 6.2 to 7.4.
The liposome system is produced for example by dissolving or dispersing
at least one phospholipid and at least one bile acid in the abovementioned
ratio to one another in an organic solvent. This solution or dispersion is
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then concentrated, and thereafter water is added to form the liposome
system. Production of the liposome system can be promoted after addition
of the water by extrusion, high-pressure homogenization andlor ultrasound
treatment. The treatment takes place below 40°C, preferably from
20°C to
30°C. Suitable organic solvents are ethanol, propanol, isopropyl
alcohol or
benzyl alcohol, in each case alone or in a mixture. The volumes of alcohols
remaining after concentration should be from 0 percent by volume (% by
volume) to 20% by volume, preferably from 0% by volume to 10% by
volume. Processes for producing the liposome systems are also described
in European patent application EP 0 470 437 or EP 0 615 746.
The liposome system employed according to the invention is administered
by subcutaneous, intra-articular, intraperitoneal, intramuscular or
intravenous injection. Subcutaneous injection is preferred.
Also possible is percutaneous administration in various carrier media and
with use of various aids, for example iontophoresis.
Uniform introduction of the liposome system employed according to the
invention should take place by a tumescent method which makes use of
the hydrostatic pressure in order to ensure uniform distribution.
Suitable formulations are, for example, suspensions, emulsions or
injectable solutions, and products with protracted release of active
ingredient, in the production of which conventional aids such as are used.
The pharmaceutical products are preferably produced in and administered
in dosage units, each unit comprising a particular dose of the liposome
system as active ingredient. In the case of solutions for injection in ampoule
form, this dose can be from about 10 mg to about 2000 mg, preferably from
about 50 mg to about 2000 mg, with preference from about 250 mg to
500 mg, based on the phospholipid.
Daily doses required for the treatment of an adult patient are, depending on
the size of the treated adipose tissue, on administration of solutions for
injection, from 5 mg to 500 mg, preferably 250 mg to 500 mg, per injection
based on the phospholipid. The solutions for injection can also be diluted
before administration, preferably with saline solution. However, in some
circumstances, higher or lower daily doses may also be appropriate. The
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dose also depends on the size of the lipomas, and for small lipomas
amounts of from 1 mg to 50 mg, preferably 2 mg to 20 mg, per injection,
based on the phospholipid, are entirely sufficient. Administration of the
daily
dose can take place both through a single dose in the form of a single
dosage unit or else a plurality of smaller dosage units and by multiple
dosage of divided doses at defined intervals.
The invention is explained in more detail below by means of examples.
Examples:
Example 1 Production of the liposome system
250 g of high-purity soybean phosphatidylcholine which contains more than
90% by weight of phosphatidylcholine, and 126.5 g of deoxycholic acid
were dissolved in 1 liter of ethanol. The resulting solution was subsequently
evaporated to dryness under reduced pressure. The resulting residue was
dispersed in 5 liters of water and then brought by high-pressure
homogenization to an average liposome diameter of from 30 nm to 100 nm.
The resulting liposome system was then filtered under sterile conditions
through a 0.2 Nm filter and dispensed under sterile conditions into
ampoules each containing 5 ml of liposome system.
Example 2 Regression of lipomas
a) The female patient attended for consultation about liposuction
of the abdomen, and in the framework of this treatment the following
history was taken:
As a child and young adult she was an acrobat and performed movements
of the body like those on gymnastic apparatus. During this she suffered a
blunt injury with severe effusion of blood underneath the left shoulder
blade. Subsequently, especially during particular movements, there was a
pronounced raising of the shoulder blade due to a tissue tumor which
remained constant over many years.
During the treatment, the question of the therapeutic possibility of removal
was then discussed, and removal of the lipoma with the aid of tumescent
local anesthesia was recommended to the patient. The subsequently
performed partial removal proceeded without difficulty but incompletely.
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The acute improvement diminished and there was partial regression of the
process underneath the shoulder blade, which was then investigated by
computed tomography (CT).
The assessment from the radiological findings was as follows: no bony
changes in the scapula; in the CT there is suspicion of a distinct residual
tissue at the medial underedge of the scapula in the compartment of the
trapezius muscle. This muscle is distended and shows accumulations of
fat, differential diagnostically a tumor residue. Supplementary NMR
tomography recommended in accordance with the above statements,
especially if a renewed operation is intended.
Subsequently, when the patient attended again about 4 months after the
operation, infiltration with 5 ml of Lipostabif~ N i.V. (Rote Liste,
March 2003) with a 10 cm-long needle was performed and distributed in
this finding. The patient reported slight stinging sensations for one day, but
they then disappeared. The lipoma regressed relatively rapidly until
symptoms had completely disappeared.
The patient remained free of symptoms thereafter.
b) The male patient had a lipoma about the size of a walnut on
the right upper arm. The patient had no disturbances of lipid metabolism,
and the serum lipids were in the normal range. An amount of 0.2 ml of
Lipostabif~, diluted with 0.2 ml of NaCI ad inj., was injected into the
patient.
There was clear regression o~ the lipoma after the first 10 days.
Example 3 Regression of pronounced cellulite
The two female patients had no disturbances of lipid metabolism, and the
serum lipids were in the normal range.
Both patients received injections of 0.4 ml of Lipostabil~, diluted with 0.6
ml
of NaCI solution inj., (total amount injected 1.0 ml) in one session. 0.1 mi
of
the solution was injected for each "cellulite mound", and the total amount
was used to treat an area approximately the size of the palm of the hand on
the outer sides of both thighs (injection scheme similar to the Botox
scheme for hyperhidrosis). With only slight tenderness and sensitivity to
touch and moderate erythema there was regression of the raised areas
within the first two weeks. A sonographic check was also performed.
