Note: Descriptions are shown in the official language in which they were submitted.
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"Skin treatment formulation and uses thereof"
DESCRIPTION
Technical field
The present invention relates to a compound for
the treatment of skin pathologies and unaesthetic
conditions and optionally of pathologies of the skin and
related tissues. More particularly, the invention relates
to a product for the treatment of:
1. skin atrophy striae,
2 skin wrinkles,
3. ageing of the skin,
4. hair loss and alopecia,
5. chapping of the skin,
6. slow cicatrization,
7. skin atrophy pathologies of various types,
8. scars.
The invention also relates to the uses of the
said compound.
Backqround art
Skin atrophy and the phenomena associated
therewith are mainly due to a deficiency in the two
proteins of the skin, collagen and elastin, the first
being responsible for nourishing and revitalizing the
skin tissues while the second has the functiDn of making
the skin tissues elastic.
More generally, three main aspects which
characterize skin atrophy may be identified:
a) deficiency or lack of collagen in the skin;
b) deficiency of lack of elastin in the skin;
c) lack of or reduction in vascularization.
There are two approaches to treating skin
atrophy, involving the integration of the two proteins
into the skin: supplying the two proteins directly and
supplying the corresponding amino acids, which allow the
body to reproduce these proteins by itself, that is to
say to metabolize them. Treatment of sk n pathologies by
integration of collagen and elastin proteins has already
been attempted, in particular by topi~al application of
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ointments containing-the said prcteins.
Direct a~m;~tration of the proteins is
theoretically the fastest route, since the body is
supplied directly with the proteins it lacks rather than
the components (amino acids) via which it me.tabolizes
these proteins.
However, the treatment methods and the relevant
compounds used hitherto have not given satisfactory
results. The reason for this is that the mainly topical
administration of the two proteins affords a transient
and therefore unsatisfactory result, or even shows no
results at all owing to the fact that the protein is not
absorbed on account of the skin barrier.
Disclosure of the invention
1~ The subject of the present invention is a
product for the treatment of skin pathologies and
unaesthetic conditions and optionally of pathologies of
the skin, based on elastin and collagen, which product
makes it possible to obtain better and especially longer
lasting results.
Basically, the product of the invention
contains a combination of at least the following
components:
1) collagen,
2) elastin,
3) preferably at least one local vasodilatory substance
4) at least one acid chosen from deoxyribonucleic acid
(DNA) and ribonucleic acid (RNA), or a salt thereof,
in combination with a suitable vehicle which may also
consist of a physiologically acceptable solution,
depending on the type of a~m; ni ~tration for ~hich the
formulation is intended.
The combination of these four components makes
it possible to obtain results which are markedly superior
3~ to those which can be obtained with the products
currently available, by virtue of the simultaneous
presence not only of the two fundamental prot:eins but
also of an optional vasodilator and at least one of the
. .
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RNA or DNA acids, which play a fundamental role in the
treatment, as will ~e clarified later.
In certain cases, a reduction in
vascularization accompanies the unaesthetic skin
conditions mentioned. In these cases, administration of
the optional local vasodilator together with the collagen
and elastin, makes it possible to re-establish peripheral
blood circulation in the zone treated, thereby giving
rise to localized vasodilation and thus allowing the two
proteins to reach the treated zones. Moreover, the
temporary vasodilation produced by the vasodilatory
substance helps vascularization in the tissues and
facilitates the provision of nutrients by the blood.
If th~re is poor vascularization of the tissues
1~ treated, despite the administration of a vasodilator
together with the proteins, some of the proteins
administered may not be bound to the tissues concerned
but will be absorbed by the body. The simultaneous
provision of at least one of the ribonucleic and
deoxyribonucleic acids, or of a salt thereof, allows the
tissues treated autonomously to reproduce the two types
of protein administered. The reason for this is that DNA
helps the tissues receiving it to manufacture proteins
with characteristics similar to the proteins
2~ administered, while RNA serves to create a memory, in the
tissues receiving it, for the two proteins supplied in
order to allow the tissues themselves to reproduce these
proteins.
The use of one of the two acids RNA or DNA
therefore makes it possible to accelerate the healing
process by stimulating the autonomous production of
collagen and elastin by the skin tissues being treated.
The two acids (or their salts) are preferably
used in combination, but appreciable results may also be
3~ obtained with only one of the two acids or the respective
salt.
According to an improved feature of the
invention, the compound may comprise, besides the four
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main components referred to above, one or mor-e secondary
components chosen from one or more of the following
groups:
- - amino acids;
S - enzymes and coenzymes;
- Vitamin C
- keratin (restricted to treatment of the scalp).
Among the amino acids which may be used in the
product according to the invention, mention may be made
of the following: glycine, proline, hydroxyproline,
lysine, tyrosine, isodesmosine. Among the useful enzymes
for the use according to the invention are the following:
pepsin, pyridoxine (Vitamin B6 coenzyme), biotin or
Vitamin H (Vitamin B6 coenzyme).
1~ The amino acids added to the formulation
metabolize the proteins, that is to say they are involved
in the formation of collagen and elastin. The enzymes and
coenzymes are catalysts of the process of protein
metabolism, that is to say they increase the rate of
biochemical reaction of the amino acids to proteins.
Their presence in combination with amino acids therefore
accelerates the metabolization of protein.
The presence of antioxidant, represented by
Vitamin C, makes it possible to reduce the oxygen
requirement of the cells.
Keratin, the use of which is limited to
formulations for treating the scalp, constitutes specific
nourishment for promoting the regrowth and strengthening
of the hair.
Detailed descriPtion of preferred embodiments
The composition of the product varies depending
on the mode of administration, in particular as regards
the vehicles and the excipients. As regards the four
fundamental components (or five in the case of the use of
both DNA and RNA), they may be used in the following
amounts, expressed in parts by weight, including in the
absence of other components:
Hydrolysed collagen: 3-10 parts
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Hydrolysed elastin: -1-4 parts
Procaine hyrochloride (vasodilator) 1-3 parts
Sodium deoxyribonucleate (DNA) 3-10 parts
Sodium ribonucleate (RNA)3-10 parts
5 Excipients and vehicles qs
The sodium deoxyribonucleate and ribonucleate
can be used independently of or in combination with each
other.
Particularly good results are obtained with
compositions varying within the following ranges, again
expressed in parts by weight:
Hydrolysed collagen: 5-9 parts
Hydrolysed elastin: 2-4 parts
Procaine hyrDchloride (vasodilator) 1.5-2. 5 parts
15 Sodium deoxyribonucleate (DNA) 4-8 parts
Sodium ribonucleate (RNA)4-8 parts
in the presence of appropriate vehicles and/or
excipients. The latter may vary depending on the
applications and the form of administration. For
administration by subcutaneous or intradermal injection
or infiltration, the components mentioned above are
prepared in a physiological solution, which in this case
represents the vehicle. Typically, the parts by weight
shown above are combined with 1000 parts by weight of
physiological solution. Appropriate excipients and
vehicles are used for topical administration, and a few
examples of these will be given in the following text
together with respective amounts, with respect to a few
particularly effective formulations.
As mentioned above, faster results may be
obtained with the addition of secondary components, such
as certain enzymes and amino acids. A formulation to
which all the secondary components mentioned above have
been added is given below. The composition relates to an
amount of 10 ml, equivalent to 10 g in physiological
solution:
Hydrolysed collagen: 30-100 mg
Hydrolysed elastin: 10-40 mg
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Procaine hyrochloride: 10-30 mg
Sodium deoxyribonucleate 30-90 mg
Sodium ribonucleate 30-90 mg
Glycine 25-75 mg
Proline 100-300 mg
Hydroxyproline 25-75 mg
Lysine 75-225 mg
Tyrosine 5-15 mg
Isodesmosine 20-60 mg
10 Pepsin 375-1125 mg
Pyridoxine 250 750 mg
Biotin 25-75 mg
Vitamin C 250-750 mg
Hydrolysed keratin (*) 15-45 mg
1~ (*) only for treatment of the scalp
Physiological solution qs
The best results were obtained with
formulations having compositions encompassed within the
following ranges, again relative to 10 g of product:
20 Hydrolysed collagen: 45-85 mg
Hydrolysed elastin: 15-35 mg
Procaine hyrochloride: 15-25 mg
Sodium deoxyribonucleate 40-80 mg
Sodium ribonucleate 40-80 mg
2~ Glycine 35-65 mg
Proline 140 260 mg
Hydroxyproline 35-65 mg
Lysine 100 200 mg
Tyrosine 7-13 mg
30 Isodesmosine 30-50 mg
Pepsin 525~975 mg
Pyridoxine 350-650 mg
Biotin 35-65 mg
Vitamin C 350-650 mg
- 3~ Hydrolysed keratin (*) 20-40 mg
(*) only for treatment of the scalp
Physiological solution qs
The compositions given above remain valid for
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topical application as regards the first fifteen
components, except that they would be in a different and~
higher concentration, in view of the increased difficulty
of absorption and the increased dispersion. Moreover, the
physiological solution would be replaced by a combination
of various vehicles and excipients.
Typically, in a cream for the local treatment
of atrophy, the following compositions may be used,
relative to 10 g of product (where the preferred amounts,
again in mg, are shown in parentheses):
Hydrolysed collagen:65-200 mg (90-170)
Hydrolysed elastin:25-75 mg (30-70)
Procaine hydrochloride:20-60 mg (30-50)
Sodium deoxyribonucleate60-180 mg (80-160)
15 Sodium ribonucleate60-180 mg (80-160)
Glycine 50-150 mg (70-130)
Proline 200-600 mg (280-520)
Hydroxyproline 50-150 mg (70-130)
Lysine 150-450 mg (200-400)
2~ Tyrosine 10-30 mg (15-25)
Isodesmosine 40-120 mg (60-150)
Pepsin 750-2250 mg (1050-1950)
Pyridoxine 500-1500 mg (700-1300)
Biotin 50-150 mg ~70-130)
25 Vitamin C 500-1500 mg (700-1300)
Sodium hydroxide 0-15 mg (2-10)
Vehicle (hydrogenated
polyoxyethylenated castor oil) 100-300 mg (150-230)
Excipient (acrylic acid
3~ polymer) 50-200 mg (80-140)
Deionized water qs 10 grams
The same composition may be employed for a
product in ampules for topical use in the treatment of
atrophy, in which case the excipient is replaced by
water, with the addition of preserving agents. Ampules
for the treatment of the scalp may have the same
composition as ampules ~or the treatment of atrophy, with
the addition of keratin in an amount of from 60 to 120 mg
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per lO g of product.
In all the compQ~itions, the DNA and the RNA-
may also be used in the form of potassium
deoxyribonucleate and potassium ribonucleate or in
another compatible form.
In the case of a product for topical use,
vehicles other than the ones mentioned may also be used.
However, hydrogenated polyoxyethylenated castor oil has
given particularly advantageous results since it allows
the skin barrier to be crossed efficiently.
In the case of preparations for application by
subcutaneous or intradermal injection or infiltration, it
is advantageous to provide for the addition of sodium
bicarbonate in order to eliminate the burning sensation
caused by the acidity and the presence of the
physiological solution.
The application methods vary depending on the
type of treatment and on the route of administration. The
latter may be carried out topically or by infiltration
via subcutaneous, intra- or mesodermal injection of the
compound into the site of the atrophies. The number of
applications and the amount of product applied vary
according to the area of tissue to be treated and its
condition. A few general indications are given below,
2~ which a person skilled in the art will use as a guideline
for selecting the most suitable mode of application in
each individual case. In the case of treatment by
infiltration:
l. Treatment of cutaneous striae: subcutaneous
infiltrations are performed, using a syringe with a
microneedle, by inserting the needle parallel to the
surface of the stria along its entire length. On
inserting the needle, a tunnel is formed which is filled
with the solution as the needle is withdrawn.
3~ 2. Txeatment of skin wrinkles: intradermal infiltrations
are performed, using a syringe with a microneedle, by
inserting the needle parallel to the surface of the
wrinkle along its entire length. On inserting the needle,
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g
a tunnel is formed which is filled with the solution as
the needle is withdrawn. ~
3. Treatment of skin aqeinq: mesodermal infiltrations
(that is to say infiltrations into the dermis but to a
S deeper level than intradermal infiltrations) are
performed, with a syringe with a microneedle, in order to
provide deep and diffuse nourishment for the tissues
concerned.
4. Treatment of the scalP and of aloPecia: intradermal
10 infiltrations into the scalp (trichomesotherapy) are
performed using a syringe with a microneedle.
5. Treatment of skin chapPinq: intradermal infiltrations
are performed into the area concerned using a syringe
with a microneedle.
1~ 6. Treatment of slow cicatrization: intradermal
infiltrations are performed into the area concerned using
a syringe with a microneedle.
For all the applications listed above, the
number of applications depends on the seriousness of the
20 condition of the tissue treated. In general, the number
of applications may range from 5 to 50. The amount of
solution administered varies according to the size of the
area under treatment. Generally speaking, about 0.1 ml of
product per cm2 of tissue treated may be applied in the
2~ treatment of cutaneous striae.
Cosmetic treatment by means of topical
application of the compound is carried out by rubbing the
ampule preparation onto the area to be treated or by
massaging into the area concerned in the case of cream
30 preparations. Topical use involves application twice
daily over a period varying between one and six months,
depending on the seriousness of the condition of the skin
tissue.
With regard to treatment of the scalp, the
3~ administration of 2 ml of preparation per application may
be envisaged for treating the entire scalp, while for
atrophy and ageing of the skin, 1 cm3 of cream or
ampule containing 1 ml of solution is used per 500 cm2 of
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surface area.
_Preparation of the composition:
An example for the preparation of the following
formulation is given hereinafter:
5 NaCl ~ueous solution (0.9%):
stabilized pig-collagen 30 g/l
sterilized pig-elastin 10/15 g/l
glycine 2/4 g/l
proline 6/10 g/l
10 hydroxyproline 2/4 g/l
Lysine 5/15 g/l
Tyrosine 1/3 g/l
Pepsin 10/30 g/l
pyroxidine 10/30 g/l
1~ DNA 60 g/l
RNA 60 g/l
Biotin 3/6 g/l
Procaine 1/3 g/l
Collagen and elastin may be of a~limal or
vegetal origin. A process for obtaining hydrolysed cross-
linked collagen and hydrolysed cross-linked elastin is
described hereinbelow:
A.stabilised pig-collagen is mixed in a vacutainer under
nitrogen atmosphere at 35/38~ for 9C min.;
2~ B.the product is filtered on a 1-micrometre filter;
C.the filtered product is subject to centrifugation at
3500 rpm for 10 min.;
D.the supernatant is eliminated in order to obtain a
perfectly clear product;
E.after centrifugation the corpuscular part is brought to
its starting volume again, by replacing the removed
supernatant with a 3% glutoraldehyde or cross-linked
polyvinylpolyppyrrolidone solution;
F.the solution thus obtained is mixed for 30 min at
35/38~C;
G.steps C, D and E are repeated;
H.the solution is made to rest for 12 hours;
I.thereafter the solution si subject to centri~ugation at
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3500 rpm for 2 hours;
J.the supernatant is removed.
on the bottom of the container a translucent
homogeneous gelatine is collected. The gelatine may be
brought at the desired viscosity by addition of a
sterilized 0.9% acqueous solution of NaCl.
The same process can be used to produce cross-
linked elastin starting from sterilized pig-elastin.
Hydrolized aminoacids, hydrolized DNA and RNA
and hydrolized biotin as well as procaine hydrocloride
are added to the proteins treated as above described in
order to obtain the above preparation.
The same process can be used with twice the amount
of elastin and collagen (i.e. 60 g/l collagen and 20/30
g/l elastin.
The product thus obtained is sucked in a syringe or
other suitable container and the final package sterilized
with gamma-irradiation. The whole process is performed in
a white chamber (class "lO0") under laminar flux hood.
It should be understood that the formulations
mentioned constitute an example given solely by way of
practical demonstration of the invention, it being
possible for the composition to vary within the limits
defined in the attached claims without thereby departing
2~ from the scope of the underlying concept of this
invention.
