U.S. patent application number 14/711160 was filed with the patent office on 2015-11-12 for injectable combination of adrenergic receptor agonists with fillers, for decreasing skin reactions due to injection.
The applicant listed for this patent is Galderma Research & Development, Sylviane Villard. Invention is credited to Isabelle Bertholon, Florence Brunel, Benjamin Herbage, Christophe Villard.
Application Number | 20150320743 14/711160 |
Document ID | / |
Family ID | 43012748 |
Filed Date | 2015-11-12 |
United States Patent
Application |
20150320743 |
Kind Code |
A1 |
Bertholon; Isabelle ; et
al. |
November 12, 2015 |
INJECTABLE COMBINATION OF ADRENERGIC RECEPTOR AGONISTS WITH
FILLERS, FOR DECREASING SKIN REACTIONS DUE TO INJECTION
Abstract
The present invention concerns an injectable composition
comprising a filler or a botulinum toxin and an adrenergic receptor
agonist, and its use for diminishing, decreasing or avoiding skin
reactions due to injection, specially redness, ecchymosis,
bruising, bleeding, erythema, oedema, necrosis, ulceration,
swelling and/or inflammation.
Inventors: |
Bertholon; Isabelle; (Lyon,
FR) ; Brunel; Florence; (Pierre-Benite, FR) ;
Herbage; Benjamin; (La Mulatiere, FR) ; Villard;
Christophe; (Le Tignet, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Villard; Sylviane
Galderma Research & Development |
Le Tignet
Biot |
|
FR
FR |
|
|
Family ID: |
43012748 |
Appl. No.: |
14/711160 |
Filed: |
May 13, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13322803 |
Feb 7, 2012 |
9050246 |
|
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PCT/EP10/57493 |
May 28, 2010 |
|
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14711160 |
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61213322 |
May 29, 2009 |
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Current U.S.
Class: |
514/18.8 ;
514/249; 514/626 |
Current CPC
Class: |
A61P 17/00 20180101;
A61K 9/0014 20130101; A61K 31/498 20130101; A61P 43/00 20180101;
A61K 31/167 20130101; A61K 38/164 20130101; A61P 29/00 20180101;
A61K 31/498 20130101; A61K 45/06 20130101; A61L 2400/06 20130101;
A61K 31/728 20130101; A61L 2300/40 20130101; A61K 31/728 20130101;
A61L 2300/204 20130101; A61L 27/54 20130101; A61L 2300/402
20130101; A61K 31/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61P 7/04 20180101; A61L 27/20 20130101; A61P 17/02
20180101 |
International
Class: |
A61K 31/498 20060101
A61K031/498; A61K 31/167 20060101 A61K031/167; A61K 38/16 20060101
A61K038/16; A61L 27/20 20060101 A61L027/20; A61L 27/54 20060101
A61L027/54 |
Claims
1. An injectable composition for treating a skin defect comprising:
i. hyaluronic acid (HA); ii. an .alpha.-adrenergic receptor
agonist; and iii an anaesthetic, wherein the anaesthetic is
lidocaine or a pharmaceutically acceptable salt thereof.
2. The composition of claim 1, wherein the .alpha.-adrenergic
receptor agonist is an .alpha.2-adrenergic receptor agonist.
3. The composition of claim 2, wherein the .alpha.2-adrenergic
receptor agonist is brimonidine.
4. The composition of claim 1, wherein the .alpha.-adrenergic
receptor agonist is brimonidine, xylometazoline, or
oxymetazoline.
5. The composition of claim 1, wherein the HA represents 1% to 2.5%
by weight of the composition.
6. The composition of claim 1 wherein the lidocaine or the
pharmaceutically acceptable salt thereof represents 0.01% to 3% by
weight of the composition.
7. A kit comprising at least one syringe and the composition of
claim 1.
8. A method for treating a skin defect comprising the step of
injecting simultaneously an individual in need thereof with: i.
hyaluronic acid (HA); ii. an .alpha.-adrenergic receptor agonist;
and iii an anaesthetic, wherein the anaesthetic is lidocaine or a
pharmaceutically acceptable salt thereof.
9. The method of claim 8 wherein the skin defect is a fold,
wrinkle, skin depression or scar.
10. The method of claim 8, wherein the .alpha.-adrenergic receptor
agonist is an .alpha.2-adrenergic receptor agonist.
11. The method of claim 10, wherein the .alpha.2-adrenergic
receptor agonist is brimonidine.
12. The method of claim 8, wherein the .alpha.-adrenergic receptor
agonist is brimonidine, xylometazoline, or oxymetazoline.
13. A method for diminishing, decreasing or avoiding a skin
reaction in an individual due to injection of a dermal filler,
comprising the step of injecting simultaneously: i. hyaluronic acid
(HA); ii. an .alpha.-adrenergic receptor agonist; and iii an
anaesthetic, wherein the anaesthetic is lidocaine or a
pharmaceutically acceptable salt thereof.
14. The method of claim 13 wherein the skin reaction due to
injection is redness, ecchymosis, bruising, bleeding, erythema,
oedema, necrosis, ulceration, swelling and/or inflammation.
15. The method of claim 13, wherein the .alpha.-adrenergic receptor
agonist is an .alpha.2-adrenergic receptor agonist.
16. The method of claim 15, wherein the .alpha.2-adrenergic
receptor agonist is brimonidine.
17. The method of claim 13, wherein the .alpha.-adrenergic receptor
agonist is brimonidine, xylometazoline, or oxymetazoline.
18. An injectable composition for treating a skin defect
comprising: i. a botulinum toxin; ii. an .alpha.-adrenergic
receptor agonist; and iii an anaesthetic, wherein the anaesthetic
is lidocaine or a pharmaceutically acceptable salt thereof.
19. The composition of claim 18, wherein the .alpha.-adrenergic
receptor agonist is an .alpha.2-adrenergic receptor agonist.
20. The composition of claim 19, wherein the .alpha.2-adrenergic
receptor agonist is brimonidine.
21. The composition of claim 18, wherein the .alpha.-adrenergic
receptor agonist is brimonidine, xylometazoline, or
oxymetazoline.
22. The composition of claim 18 wherein the lidocaine or the
pharmaceutically acceptable salt thereof represents 0.01% to 3% by
weight of the composition.
23. A kit comprising at least one syringe and the composition of
claim 18.
24. A method for treating a skin defect comprising the step of
injecting simultaneously an individual in need thereof with: i. a
botulinum toxin; ii. an .alpha.-adrenergic receptor agonist; and
iii an anaesthetic, wherein the anaesthetic is lidocaine or a
pharmaceutically acceptable salt thereof.
25. The method of claim 24 wherein the skin defect is a fold,
wrinkle, skin depression or scar.
26. The method of claim 24, wherein the .alpha.-adrenergic receptor
agonist is an .alpha.2-adrenergic receptor agonist.
27. The method of claim 26, wherein the .alpha.2-adrenergic
receptor agonist is brimonidine.
28. The method of claim 24, wherein the .alpha.-adrenergic receptor
agonist is brimonidine, xylometazoline, or oxymetazoline.
29. A method for diminishing, decreasing or avoiding a skin
reaction in an individual due to injection of a dermal filler,
comprising the step of injecting simultaneously: i. a botulinum
toxin; ii. an .alpha.-adrenergic receptor agonist; and iii an
anaesthetic, wherein the anaesthetic is lidocaine or a
pharmaceutically acceptable salt thereof.
30. The method of claim 29 wherein the skin reaction due to
injection is redness, ecchymosis, bruising, bleeding, erythema,
oedema, necrosis, ulceration, swelling and/or inflammation.
31. The method of claim 29, wherein the .alpha.-adrenergic receptor
agonist is an .alpha.2-adrenergic receptor agonist.
32. The method of claim 31, wherein the .alpha.2-adrenergic
receptor agonist is brimonidine.
33. The method of claim 29, wherein the .alpha.-adrenergic receptor
agonist is brimonidine, xylometazoline, or oxymetazoline.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S. patent
application Ser. No. 13/322,803 filed Feb. 7, 2012, which is a
national stage application under 35 U.S.C. .sctn.371 of PCT
Application No. PCT/EP2010/057493, filed May 28, 2010, which claims
priority to and the benefit of U.S. provisional patent application
Ser. No. 61/213,322, filed May 29, 2009, each of which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is in the surgical and dermatological
domain.
[0003] The present invention relates to an injectable composition
comprising an adrenergic receptor agonist, preferably brimonidine,
and a filler, preferably hyaluronic acid. It concerns its use in
preventing and/or treating superficial bruising and bleeding caused
by aesthetic procedures.
BACKGROUND OF THE INVENTION
[0004] Superficial bruising and, to a lesser extent, bleeding are
not uncommon consequences--reported on average about one-third of
the time--of many aesthetic procedures, including dermal fillers,
botulinum toxins and laser resurfacing.
[0005] More significant bruising occurs with surgical procedures
such as liposuction, breast augmentations/lifts, face lifts and
tummy tucks.
[0006] The management of secondary immediate reactions due to
subcutaneous or intradermal injection of fillers with vascular
damages or vascular breaking wall inducing ecchymosis, bruising,
leakage of blood components having immediate action on inflammation
setting up, redness and oedema, are of particular interest.
[0007] Although redness, erythema, bruising and bleeding are not
generally considered as a big problem, most physicians prepare
their patients for this possibility by alerting them to it prior to
the procedure. Particularly, physicians often caution against using
aspirin or other anticoagulant drugs before and after the
procedure, extensively use ice packs immediately after the
procedure and quite commonly recommend Arnica, an herb used to
promote healing. This kind of drawbacks may discourage some
patients and particularly towards aesthetic procedures. In
particular with regards to the consequences of bruising/bleeding,
physicians report that one of the most significant concerns for
patients is downtime as when bruising occurs, patients prefer to
stay home rather than return to work and social activities
[0008] Therefore, there is a need for alleviating bruising/bleeding
that occur during aesthetic or surgical procedures, especially when
fillers are injected.
[0009] The present invention is based on the demonstration by the
Applicant that the injection of an adrenergic receptor agonist
together with the filler reduces the occurrence of skin reactions
due to injection.
DESCRIPTION OF THE INVENTION
[0010] The present invention provides a combination of quantity of
adrenergic receptor agonist, and preferably product known as
brimonidine, with fillers or botulinum toxins, and preferably with
hyaluronic acid. Said combination is systemically administrated to
an individual in need.
[0011] The present invention provides the use in an individual in
need, of a quantity of adrenergic receptor agonist, and preferably
product known as brimonidine, in combination with botulinum toxins
or fillers, and preferably with hyaluronic acid.
[0012] The present invention provides a method for diminishing or
decreasing or avoiding bruising and, to a lesser extent, bleeding
and particularly in aesthetic procedures, including dermal fillers
and preferably hyaluronic acid, by providing to an individual in
need thereof a quantity of adrenergic receptor agonist, and
preferably product known as brimonidine.
[0013] In a first aspect, the invention concerns a composition
comprising: [0014] a filler or a botulinum toxin; [0015] an
adrenergic receptor agonist.
[0016] As it clearly appears from the present description, the
present invention concerns the prevention and the treatment of skin
defects, especially those due to skin aging (folds, wrinkles, skin
depressions, . . . ) or skin damages (scars, . . . ).
[0017] Over the last years, the treatment of skin defects has
become of great interest. As a result, it has been proposed to
intradermally or subcutaneously inject compounds.
[0018] As a first possibility, botulinum toxins which are able to
provoke muscle paralysis or contraction can be locally
injected.
[0019] Alternatively and in a preferred embodiment, a filler can be
injected. A filler is generally defined as a biomaterial able to
fill dermal tissues. The claimed composition to be injected,
comprising said filler in an aqueous medium and displaying filling
properties, can also be defined as a "dermal filler".
[0020] In this context, same compounds like polyacrylamid gels,
polymethylmethacrylate (PMMA) particles or silicones can be
used.
[0021] The most preferred compounds are resorbable molecules such
as hyaluronic acid, collagen, alginate, dextran, elastine or
polyurethane gels.
[0022] Hyaluronic acid or hyaluronate is a non-sulfated
glycosaminoglycan widely distributed throughout connective,
epithelial, and neural tissues. It is one of the chief components
of the extracellular matrix. It contributes significantly to cell
proliferation and migration. It plays an important role in skin
hydration and skin elasticity. The level of hyaluronic acid
decreases with ageing both in quantity and quality, inducing skin
drying and wrinkles.
[0023] Hyaluronic acid is a naturally occurring biopolymer that
forms highly viscous solutions in water. Therefore, it is widely
used as a pharmaceutical product. Moreover, this compound is
considered to be very safe since no immunogenicity reaction has
been observed. So far, few minor adverse events have been
noticed.
[0024] Therefore and advantageously, the filler is hyaluronic acid
or a pharmaceutically acceptable salt or derivative thereof,
particularly the sodium or potassium salt. Hyaluronic acid can be
used under different forms: salts thereof, derivatives thereof such
as esters or amides, in a linear form or cross-linked. In
particular, the molecular weight, typically comprised between 500
kDa and 5 000 kDa, and the degree of cross-linking depends on the
application, especially on the depth of the wrinkles to be
filled.
[0025] The second component of the claimed composition is an
adrenergic receptor agonist. Adrenergic receptor agonists are known
to bind and activate the adrenergic receptors.
[0026] As it is well known in the art, adrenergic receptors
encompass both .alpha. and .beta. receptors. Among .alpha.
adrenoreceptors, .alpha.1 and .alpha.2 receptors were distinguished
in the 1970's. During the same decade, .alpha.2 receptors were
found to occur on vascular smooth muscles and exhibit mediation of
vasoconstrictor response ("Subtypes of functional .alpha..sub.1-
and .alpha..sub.2-adrenoceptors" J R Docherty; European Journal of
Pharmacology 361 (1998) 1-15). Thus, molecules exhibiting .alpha.
adrenergic agonism, advantageously .alpha.2 adrenergic agonism,
possess peripheral vasoconstrictive activity.
[0027] Agonists to be used in the claimed composition can be
directed to .alpha. and/or .beta. receptors. However, because of
their possible side-effects, molecules exhibiting .beta. adrenergic
agonism, are advantageously disclaimed. In the rest of the
application, a molecule having no affinity for the .beta.
adrenergic receptors will be named "an .alpha.-adrenergic receptor
agonist".
[0028] Among the .alpha. receptors, the agonist can be an agonist
of both .alpha.1 and .alpha.2 receptors, or can be specific for
.alpha.1 or .alpha.2. Preferably, the chosen molecule displays more
affinity for the .alpha.2 than for the .alpha.1 receptor, and will
generally be named, in the rest of the application, "an .alpha.2
adrenergic receptor agonist".
[0029] In a preferred embodiment, the adrenergic receptor agonist
is an adrenergic receptor agonist .alpha.2, preferably
brimonidine.
[0030] Agonists of the .alpha.2 adrenoceptors have been used
therapeutically for a number of conditions including hypertension,
congestive heart failure, angina pectoris, spasticity, glaucoma,
diarrhea, and for the suppression of opiate withdrawal symptoms (J.
P. Heible and R. R. Ruffolo Therapeutic Applications of Agents
Interacting with a-Adrenoceptors, p. 180-206 in Progress in Basic
and Clinical Pharmacology Vol. 8, P. Lomax and E. S. Vesell Ed.,
Karger, 1991).
[0031] Adrenoceptor agonists such as clonidine have been primarily
used orally, though a patch formulation is known. The .alpha.2
agonists are known to mediate vasoconstriction both in the core and
periphery of a patient. In particular .alpha.2 adrenoceptor
agonists are known to cause vasoconstriction of peripheral
arterioles, in response to stimulation due to cold or stress.
[0032] A number of patents describe the use of brimonidine for
treating ophthalmic conditions and eye diseases. In Canadian patent
No. CA2326690, there is described the use of topical ophthalmic
preparations for use only in the eyes, to treat eye diseases.
[0033] As already said above, the most preferred compound in the
context of the invention is
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine
(commonly referred to as brimonidine) and pharmaceutically
acceptable salts thereof, particularly the tartrate salt.
[0034] Other compounds known to be .alpha.2 adrenoceptor agonists
and which can be used in the frame of the present invention are:
clonidine, apoclonidine.
[0035] More generally, other compounds which are .alpha.
adrenoceptor agonists are: synephrine, octodrine, vasopressine and
analogs, ornipressine, midodrine, phenylephrine, xylometazoline,
oxymetazoline, norepinephrine, methoxamine.
[0036] Compounds which have also an affinity for the .beta.
receptors but which can be used in certain conditions are:
epinephrine, ephedrine, etilefrine.
[0037] Of course, the pharmaceutically acceptable salts of all
these compounds are also encompassed.
[0038] According to the instant invention, the term
"pharmaceutically acceptable salt (s)", as used herein, means those
salts of compounds of the invention that are safe and effective for
topical use in mammals and that possess the desired biological
activity. Pharmaceutically acceptable salts include salts of acidic
or basic groups present in the compounds of the invention.
[0039] Pharmaceutically acceptable acid salts include, but are not
limited to, hydrochloride, hydrobromide, hydroiodide, nitrate,
sulfate, bisulfate, phosphate, acid phosphate, isonicotinate,
acetate, lactate, salicylate, citrate, tartrate, pantothenate,
bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzensulfonate,
p-toluenesulfonate and pamoate (i. e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain
compounds of the invention can form pharmaceutically acceptable
salts with various amino acids.
[0040] Suitable base salts include, but are not limited to,
aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and
diethanolamine salts. For a review on pharmaceutically acceptable
salts see BERGE ET AL., 66 J. PHARM. Sci. 1-19 (1977).
[0041] According to a first embodiment, the claimed composition
only contains a filler, or a mixture thereof, and an adrenergic
receptor agonist, or a mixture thereof, advantageously hyaluronic
acid and brimonidine.
[0042] According to an alternative embodiment, the claimed
composition also contains one or more additional ingredients.
[0043] The one or more other ingredients can be active ingredients,
e. g. an anaesthetic. A preferred anaesthetic is lidocaine or a
pharmaceutically acceptable salt thereof. Other active ingredients
are for example growth factors, peptides, . . . .
[0044] The claimed composition can also contain other
pharmaceutical acceptable ingredients such as carriers, excipients,
preservatives, . . . .
[0045] In one embodiment, the compounds of the invention are
administrated to a patient in need thereof by systemic route,
preferably by injection. Therefore, in the context of the instant
invention the compounds are delivered to the affected area of the
skin in a pharmaceutically acceptable carrier. As used herein, a
pharmaceutically acceptable carrier is any pharmaceutically
acceptable formulation that can be applied to the skin for dermal,
intradermal, or transdermal delivery of a pharmaceutical or
medicament. The combination of a pharmaceutically acceptable
carrier and a compound of the invention is termed an injectable
formulation of the invention.
[0046] In the frame of the present invention, the composition is a
pharmaceutically acceptable injectable formulation. By
"pharmaceutically acceptable injectable formulation" it is meant in
the context of the invention any formulation which is
pharmaceutically acceptable for systemic delivery. Preferably, the
composition is administrated in the superficial, middle or deep
dermis, by subcutaneous or intradermal route. Typically, the
claimed composition consists in a solution or a gel, preferably an
aqueous solution or gel.
[0047] The claimed composition is composed of or contains
therapeutically effective amounts of adrenergic receptor agonists
and fillers. As used herein, a "therapeutically effective amount of
a compound of the invention" means the minimum amount of the
compound that is effective to obtain the desired effect in the
context of the invention.
[0048] Typically, the claimed composition contains: [0049] a
filler, preferably HA, representing 1% to 2.5% by weight of the
composition; [0050] an adrenergic receptor agonist, preferably
brimonidine, representing 0.0001% to 1% by weight of the
composition; [0051] optionally an anaesthetic, representing 0.01%
to 3% by weight of the composition
[0052] As already said, the claimed composition is meant to be
administered to a subject or a patient, especially by facial
injection (forehead, eyes, nasolabial fold, . . . ). As used
herein, the term "subject" or "patient" are used equivalently and
means any animal, preferably a mammal, more preferably, a human to
whom will be or has been administered compounds or formulations of
the invention. The term "mammals" used herein encompasses any
mammal.
[0053] Therefore, the invention also provides formulations to
deliver a systemic dose of the compound to the patient. In practice
and for a treatment sequence, the amounts of active compounds are
as follows: [0054] for the filler, preferably HA: between 0.05
mg/kg and 2 mg/kg of body weight. It represents from 5 mg to 100
mg. [0055] for the adrenergic receptor agonist, preferably
brimonidine: between 510.sup.-3 .mu.g and 0.8 mg/kg of body weight.
It represents from 0.5 .mu.g to 40 mg.
[0056] In a preferred embodiment, the volume of the claimed
composition to be injected varies between 0.1 and 10 ml, typically
between 0.5 and 4 ml. Preferably, said volume is presented as a
single dose syringe. Said injection can be repeated, for example
after 4 to 18 months.
[0057] Another aspect of the invention is an article of manufacture
that comprises a systemic formulation of the invention in a
suitable container with labelling and instructions for use. The
container is advantageously a single dose syringe.
[0058] Preferably, instructions are packaged with the formulations
of the invention, for example, a pamphlet or package label. The
labelling instructions explain how to administer formulations of
the invention, in an amount and for a period of time sufficient to
treat the patient. Preferably, the label includes the dosage and
administration instructions, the formulation's composition, the
clinical pharmacology, drug resistance, pharmacokinetics,
absorption, bioavailability, and contraindications.
[0059] The claimed injectable composition can then be integrated
into a kit comprising syringes containing said composition. In said
kit, the two active principles, i. e. the filler and the adrenergic
receptor agonist, can be presented as a mixture contained in a
syringe or can be contained in two separate syringes for
extemporaneous mixture.
[0060] The claimed composition is advantageously sterilized in
conditions suitable for preserving the active principles.
[0061] As already said, the claimed composition is dedicated to the
prevention and/or treatment of skin defects, especially folds,
wrinkles, skin depressions and scars. It concerns a cosmetic or a
therapeutic treatment.
[0062] According to the invention, it has been shown that the main
benefit of the claimed combination is to diminish, decrease or
avoid erythema, ecchymosis, bruising or bleeding, especially in
connection with the injection of a dermal filler.
[0063] Other potential benefits of the claimed composition are as
follows: [0064] When the composition further contains an
anaesthetic, e.g. lidocaine, the efficiency of said anaesthetic is
improved: vasoconstrictive effect provided by the .alpha.
adrenergic agonist limits anaesthetic diffusion in a large area,
thus making anaesthetic efficient in the strict injection site;
[0065] By reducing the inflammation, the filler persists longer,
possibly due to its slower degradation: the more inflammatory the
filler is, the more tissue reaction is severe and higher is the
level of inflammatory species, thus degrading faster the filler.
Introducing a vasoconstrictive molecule in the filler could limit
inflammatory species attraction to the injection site; [0066] A
reduction of oedema and swelling is observed: for the same reason
as the previous benefit, vasoconstrictive activity of the filler
limits liquid flood in reaction to the injection, so hindering
liquid concentration nearby the injection site.
[0067] More generally, the claimed composition is then intended to
diminish, decrease or avoid all the undesirable skin reactions
(immediate and/or secondary) due to injection. It indeed includes
ecchymosis, bruising or bleeding but also possibly redness,
erythema, oedema, necrosis, ulceration, swelling and
inflammation.
[0068] The claimed composition containing the two active principles
can be used simultaneously, separately or sequentially. In other
words, the present invention provides a kit of part combining a
quantity of adrenergic receptor agonist, and preferably product
known as brimonidine, with fillers, and preferably with hyaluronic
acid.
[0069] In addition to the above, the following examples are
provided to illustrate particular embodiments and not to limit the
scope of the invention.
Examples
LEGENDS TO FIGURES
[0070] FIG. 1 shows the Irritating Primary Index (IPI) evolution
between Day 0 and Day 8 for the claimed composition (Test2) in
comparison with a filler alone (Test1).
[0071] FIG. 2 shows the total score of inflammatory reaction at Day
8 for the claimed composition (Test2) in comparison with a filler
alone (Test1).
SUMMARY OF THE STUDY
[0072] An intracutaneous test of a hyaluronic acid-based dermal
filler containing lidocaine and a vasoconstrictor drug
(Brimonidine) named RADACT014 was performed in order to evaluate
the potential of Brimonidine to reduce the irritation following
intradermal injection of filler in the rabbit.
[0073] Two adult rabbits received by intracutaneous route 0.2 mL of
test product RADACT014 (Test2), NaCl 0.9% (Test5: negative control)
and 10LDEEP010 (same hyaluronic acid filler as RADACT014 but with
no lidocaine nor Brimonidine; Test1: positive control).
[0074] The results obtained with the filler containing Brimonidine
(batch RADACT014 (Test2)) are compared with the dermal filler
without Brimonidine (positive control: Test 1).
[0075] The sites were examined from Day 0 to Day 8 after injection
for gross evidence of tissue reaction, such as erythema, oedema and
necrosis (FIG. 1) and the observation of microscopic tissue
response done on histological observations after sacrifice at Day 8
(FIG. 2).
[0076] The study was conducted according to the requirements of the
ISO 10993 standard: Biological Evaluation of medical devices, Part
10: Test for irritation and delayed type hypersensitivity.
Materials and Methods
Preparation of Control Crosslinked Hyaluronic Filler:
10LDEEP010
[0077] A crosslinked hyaluronic acid filler 10LDEEP010 (Test1) was
obtained by crosslinking with 25% of BDDE a sodium hyaluronate from
bacterial origin characterized by a macromolecular weight of around
2-4.times.10.sup.6 Da. At the end of the crosslinking, a lidocaine
hydrochloride was added to the crosslinked hyaluronic acid to reach
a concentration of 03%. Homogeneous blend of lidocaine is obtained
by extrusion of the mix through mesh. The resulting gel was packed
in 1 mL syringes at the concentration of 20 mg/mL and steam
sterilized.
Preparation of Crosslinked Hyaluronic Filler Containing
Brimonidine: RADACT014
[0078] The same crosslinking conditions were applied to the same
hyaluronic acid to obtain a filler without lidocaine. In parallel,
a 4N sodium hydroxide solution was prepared using 8 g of NaOH and
42 g of purified water. Another solution containing brimonidine and
lidocaine was obtained by dissolution of 0.22 g of brimonidine
tartrate and 0.33 g of lidocaine hydrochloride in 9.45 mL of
phosphate buffer. pH was adjusted to 6 by using the NaOH solution.
Then, brimonidine and lidocaine solution was filtered on 0.22
microns.
[0079] A filler containing brimonidine and lidocaine, called
RADACT014 (Test2), was obtained by gently mixing 5 g of the
solution containing the 2 actives and 50 g of the previous
crosslinked hyaluronic gel into 3 steps: 5 minutes of mechanical
mixing followed by 15 minutes of break and then additional 5
minutes mixing. The resulting gel was packed in 1 mL syringes and
steam sterilized. The final concentration of actives was determined
after hyaluronidase digestion for brimonidine by HPLC-MS-MS as
0.16% and for lidocaine by HPLC as 0.29%.
Investigation of Immediate Adverse Events Reduction
[0080] The potential of irritation reduction by RADACT014 was
evaluated in an animal study conducted according to the
requirements of the ISO10993-10 requirements: Biological Evaluation
of Medical Devices--Test for irritation and delayed type
hypersensitivity.
Study Protocol
[0081] At Day 0 (D0), two adult rabbits received by intracutaneous
route 0.2 mL of test products (Test1: 10LDEEP010 and Test2:
RADACT014) and negative control (Test5: physiological saline),
injected using a 27G needle. In these conditions, 4 sites were
injected for each product.
[0082] Then, the injected sites were examined twice a day from Day
0 to Day 8 for gross evidence of tissue reaction such as erythema,
oedema, ulceration and necrosis, attributing a score with the
following criterions:
TABLE-US-00001 Criterion Control method Scale Formation of Visual
assessment (0) none oedema (1) slight (2) moderate (3) marked (4)
severe Formation of Visual assessment (0) none erythema, (1) slight
ulceration (2) moderate and necrosis (3) marked (4) severe
[0083] At Day 8, the animals were euthanized and injection sites
were collected and fixed for histological analysis. Microscopic
analyses were performed to assess the following criterions:
TABLE-US-00002 Control Criterion method Scale Type of cell/implant
reaction, Histological Score from 0 to 4 for local tolerance:
analysis each criterion Fibrin (0) None Necrosis (1) slight Tissue
degeneration (2) moderate Granulocyte (3) marked PMN eosinophils
(4) severe Lymphocytes Plasmocytes Macrophages Giant cells
Fibrocytes Neovessels Peri and intra-implant tissue reconstruction
Degradation of the material
Results Exploitation
[0084] No oedema, nor necrosis occurred in this study. Moreover,
only 10LDEEP010 showed a slight and persistent ulceration from day
2 to day 8.
1. IRRITATION PRIMARY INDEX (IPI)
[0085] IPI of test product is determined for each observation time
in the following way:
IPI Test = ( oedema score + erythema score ) Observations number -
IPI negative control ##EQU00001## [0086] Negative control being
test5: physiological saline [0087] IPI.sub.negative control quotes
0 for each observation time.
[0088] The results obtained are shown in FIG. 1.
[0089] 10LDEEP010 (Test1) showed the highest value of irritation
index during the experiment: the index increases between Day 0 and
Day 1 and then remains stable. This product is very irritant.
[0090] Test2 Product, called RADACT014 and containing Brimonidine,
showed the lowest value of IPI: it increases between Day 0 and Day
2 and then stabilizes to Day 7 and finally decreases at Day 8.
[0091] RADACT014 showed a reduction of inflammatory effect of the
dermal filler from Day 3 in a pronounced and persistent way, thus
demonstrating the positive effect of Brimonidine regarding
irritation.
2. HISTOLOGICAL ANALYSIS
[0092] Total scores of inflammation were determined from
histological observations according to local
tolerance-representative cells type and quantities.
[0093] FIG. 2 represents total score of inflammation of each
product.
[0094] At Day 8, moderate (10LDEEP010) to limited (RADACT014)
inflammatory infiltrates were noted, the main cell population being
macrophages with a few eosinophils. No specific reaction was
observed for the negative control (physiological saline,
Test5).
3. CONCLUSION
[0095] This study has shown that the dermal filler (Test1:
10LDeep010) injected in the dermal compartment provokes some
inflammatory response with slight ulceration. By incorporating an
active molecule (Brimonidine) in this kind of dermal filler
(RADACT014), it is possible to reduce the inflammatory response.
The gross evidence (erythema, oedema, ulceration and necrosis) and
the histological analyses demonstrate both the benefit provided by
using the Brimonidine molecule in combination with the filler.
* * * * *