U.S. patent application number 11/494493 was filed with the patent office on 2008-01-31 for compositions containing quaternary ammonium compounds.
Invention is credited to Frederic Lallemand, Gregory Lambert, Betty Philips, Laura Rabinovich-Guilatt.
Application Number | 20080026013 11/494493 |
Document ID | / |
Family ID | 38986541 |
Filed Date | 2008-01-31 |
United States Patent
Application |
20080026013 |
Kind Code |
A1 |
Rabinovich-Guilatt; Laura ;
et al. |
January 31, 2008 |
Compositions containing quaternary ammonium compounds
Abstract
This invention relates to compositions containing quaternary
ammonium compounds in which the nitrogen atom is substituted by at
least one alkyl group having at least 12 carbon atoms,
characterized in that the composition includes at least 20% in
weight by weight of the total composition, of ammonium halides in
which the nitrogen atom is substituted by at least one alkyl group
having at least 14 carbon atoms and more than 5%, preferably more
than 7% in weight by weight of the total composition, of ammonium
halides in which the nitrogen atom is substituted by at least one
alkyl group having at least 16 carbon atoms. This invention also
relates to ophthalmic oil-in-water emulsions containing such
compositions, said ophthalmic emulsions being useful for eye care
or for the treatment of eye conditions.
Inventors: |
Rabinovich-Guilatt; Laura;
(Paris, FR) ; Lambert; Gregory; (Chatenay Malabry,
FR) ; Lallemand; Frederic; (Fresnes, FR) ;
Philips; Betty; (Antony, FR) |
Correspondence
Address: |
YOUNG & THOMPSON
745 SOUTH 23RD STREET, 2ND FLOOR
ARLINGTON
VA
22202
US
|
Family ID: |
38986541 |
Appl. No.: |
11/494493 |
Filed: |
July 28, 2006 |
Current U.S.
Class: |
424/400 ;
514/642; 514/643 |
Current CPC
Class: |
A61K 8/06 20130101; A61K
8/062 20130101; A61K 8/416 20130101; A61P 43/00 20180101; A61Q
17/005 20130101; A61K 9/0048 20130101; A61K 9/1075 20130101; A61Q
19/00 20130101 |
Class at
Publication: |
424/400 ;
514/642; 514/643 |
International
Class: |
A61K 31/14 20060101
A61K031/14; A61K 9/00 20060101 A61K009/00 |
Claims
1. Composition comprising at least one quaternary ammonium halide
in which the nitrogen atom is substituted by at least one alkyl
group having at least 12 carbon atoms, characterized in that said
composition includes: a) at least 20% in weight by weight of the
total composition, of quaternary ammonium halides in which the
nitrogen atom is substituted by at least one alkyl group having at
least 14 carbon atoms and b) more than 5%, preferably more than 7%
in weight by weight of the total composition, of quaternary
ammonium halides in which the nitrogen atom is substituted by at
least one alkyl group having at least 16 carbon atoms.
2. Composition according to claim 1, wherein said composition
includes a) at least 20% in weight by weight of the total
composition, of quaternary ammonium halides in which the nitrogen
atom is substituted by at least one alkyl group having at least 14
carbon atoms and b) at least 10%, preferably at least 15%, more
preferably at least 20% in weight by weight of the total
composition, of quaternary ammonium halides in which the nitrogen
atom is substituted by at least one alkyl group having at least 16
carbon atoms.
3. Composition according to claim 1, wherein said quaternary
ammonium halides are benzyl dimethyl ammonium chlorides or
bromides, wherein the nitrogen atom is further substituted by an
alkyl group having at least 12 carbon atoms.
4. Composition according to claim 1, comprising C14- and C16-alkyl
benzyl dimethyl ammonium chlorides.
5. Composition according to claim 1, wherein said quaternary
ammonium halide is a trimethyl ammonium chloride or bromide,
wherein the nitrogen atom is further substituted by an alkyl group
having at least 12 carbon atoms.
6. Composition according to claim 1, wherein the amount of ammonium
halides in which the nitrogen atom substituted by at least one
alkyl group having 14 or 16 carbon atoms represents at least 50%
w/w in dry weight of the weight of all ammonium halides present in
the composition.
7. Composition according to claim 1, wherein the dry weight ratio
of C12-alkyl ammonium halides to the sum of C14-alkyl ammonium
halides and C16-alkyl ammonium halides, is less than 1.5,
preferably less than 1.35, more preferably less than 1.20.
8. Oil-in-water emulsion comprising a composition according to
claim 1, said emulsion comprising 0.0005 to 0.1% of quaternary
ammonium halides.
9. Oil-in-water emulsion according to claim 8, further comprising
hydroxypropyl guar, polyethylene glycol-400 or a mixture of
both.
10. Oil-in-water emulsion according to claim 8, further comprising
an oil phase comprising MCT, castor oil or mineral oil, surfactants
preferably chosen among at least one of tyloxapol, poloxamer,
tocopherol polyethyleneglycol succinate and polysorbate, and
optionally antioxidants and/or isotonicity agents preferably chosen
among at least one of glycerol and mannitol.
11. Oil-in-water emulsion according to claim 8, said emulsion
having a positive zeta potential.
12. Oil-in-water emulsion according to claim 8, said emulsion
having a droplet size of 100 to 500 nm.
13. Oil-in-water emulsion according to claim 8, said emulsion being
preserved.
14. Oil-in-water emulsion according to claim 8, said emulsion being
unpreserved.
15. Oil-in-water emulsion according to claim 8, said emulsion
comprising C16-alkyl quaternary ammonium halide as only source of
quaternary ammonium halide.
16. Oil-in-water emulsion according to claim 8, further comprising
an active principle.
17. Medicament comprising of an oil-in-water emulsion according to
claim 8.
18. Use of an oil-in-water emulsion according to claim 8 for the
manufacture of a medicament or an ophthalmic composition for the
treatment of an eye condition or disease.
19. Cosmetic composition comprising an oil-in-water emulsion
according to claim 8.
20. A non-therapeutical process for caring for, removing makeup
from and/or cleansing the skin, the lips and/or the eyes, and/or
for hair care, comprising applying an oil-in-water emulsion
according to claim 8.
Description
[0001] This invention relates to pharmaceutical, ophthalmic or
cosmetic compositions containing quaternary ammonium compounds,
more preferably to ophthalmic emulsions being useful for eye care
or for the treatment of eye conditions. This invention also relates
to compositions including at least one quaternary ammonium compound
as cationic agent.
[0002] Quaternary ammonium compounds are organic compounds usually
used as an antiseptic or antimicrobial agent. For example,
benzalkonium chloride is a nitrogenous cationic surface-acting
agent belonging to the quaternary ammonium group. Benzalkonium
chloride is generally defined as a mixtures of compounds of general
formula C.sub.6H.sub.5CH.sub.2N(CH.sub.3).sub.2RCl, wherein R is a
C12-C24 alkyl group.
[0003] Benzalkonium chloride, as usually provided by the
manufacturers wanting to comply with the European and/or American
Pharmacopeia, is a mixture of n-alkyl dimethyl benzyl ammonium
chlorides of various alkyl chain lengths. For example, FeF
Chemicals A/S (Denmark) supplies, under reference 8100301U (BAK
USP/NF), a mixture of three alkyl dimethyl benzyl ammonium
chlorides including: (1) 60-70% of C.sub.12-alkyl dimethyl benzyl
ammonium chloride (2) 30-40% of C.sub.14-alkyl dimethyl benzyl
ammonium chloride, and less than 5% of C.sub.16-alkyl dimethyl
benzyl ammonium chloride
[0004] Benzalkonium chloride, as a mixture of alkyl dimethyl benzyl
ammonium having various alkyl chain lengths is used as preservative
agent in topical ophthalmic products. Benzalkonium chloride also
has cationic agent properties, and was used as cationic agents for
emulsions, especially ophthalmic emulsions.
[0005] When mixtures of benzalkonium chlorides having various alkyl
chain lengths are used in emulsions, they may act both as
preservative agents and cationic agents.
[0006] The Applicant worked on long chain quaternary ammonium
compounds, and noticed that the length of the alkyl chain was
important with regards to the function performed by the quaternary
ammonium compounds: acting on the length of the alkyl chain
resulted in enhancing or reducing the cationic power of the
quaternary ammonium compounds. Without wanting to be linked by any
theory, the Applicant observed on working on oil-in-water
emulsions, that long chain quaternary ammonium compounds are
preferentially localized at the oil/water interface of the
emulsions, resulting in (1) emulsions with higher zeta potential
and (2) more stable emulsions. As quaternary ammonium may be
considered as undesirable or toxic, it is thus a goal of this
invention to provide cationic composition having a reduced content
of quaternary ammonium compound.
[0007] The Applicant also observed that, in emulsions, quaternary
ammonium compounds having long alkyl chains, for example quaternary
ammonium compounds having C14-C18 alkyl chains, when compared to
C12-alkyl chains, did not have a good bactericidal activity,
whereas they conferred a greatest cationic power.
[0008] Moreover, the Applicant observed that long chain quaternary
ammonium compounds were present preferentially at the oil/water
interface of the emulsion droplets, and less in the aqueous phase.
The fact that quaternary ammonium compounds may be present in the
aqueous phase in a very small amount only, or not present, leads to
a loss of preservative effect or poor preservative effet, as well
as to less toxic emulsions.
[0009] Thus, one of the goals of this invention is to provide
stable cationic emulsions comprising a reduced amount of
benzalkonium chlorides, and still using said benzalkonium chlorides
as a source, or the only source, of cationic agents, said emulsions
being preserved or not.
[0010] Preferably, the emulsions of the invention are useful for
cosmetic or ophthalmic purposes.
[0011] Another goal of this invention is to provide ammonium halide
compositions, preferably benzalkonium compositions, suitable for
the preparation of cationic emulsions. Preferably, said cationic
emulsions are useful for ophthalmic or cosmetic purposes.
[0012] This invention thus relates to a composition comprising at
least one quaternary ammonium halide, more preferably ammonium
chloride or bromide, in which the nitrogen atom of the ammonium
group is substituted by at least one alkyl group having at least 12
carbon atoms, said composition including:
[0013] a) at least 20% in weight by weight of the total
composition, of ammonium halides in which the nitrogen atom is
substituted by at least one alkyl group having at least 14 carbon
atoms, preferably 14 or 16 carbon atoms and
[0014] b) more than 5%, preferably more than 7% in weight by weight
of the total composition, of ammonium halides in which the nitrogen
atom is substituted by at least one alkyl group having at least 16
carbon atoms.
[0015] According to an embodiment of the invention, the composition
includes at least 20% w/w of the total composition, of C14-alkyl
ammonium halides and at least 10%, preferably at least 15%, more
preferably at least 20% w/w of the total composition, of C16-alkyl
ammonium halides.
[0016] According to another embodiment, the composition includes as
only alkyl ammonium halide, C16-alkyl ammonium halide, preferably
C16-alkylbenzyldimethyl ammonium halide.
[0017] Preferably, the ammonium halides used in this invention are
benzyl dimethyl ammonium chlorides or bromides, wherein the
nitrogen atom is further substituted by an alkyl group having at
least 12 carbon atoms, preferably 12, 14 and/or 16 carbon
atoms.
[0018] According to an embodiment of the invention, the composition
comprises C14- and C16-alkyl benzyl dimethyl ammonium chlorides. In
a further embodiment, the composition of the invention does not
include any C12-alkyl ammonium halide.
[0019] According to another embodiment, the composition of the
invention includes trimethyl ammonium chloride or bromide, wherein
the nitrogen atom is further substituted by an alkyl group having
at least 12 carbon atoms, preferably 12 and/or 14 and/or 16 carbon
atoms. According to an embodiment, the trimethyl ammonium chloride
or bromide is cetyltrimethylammonium bromide.
[0020] According to a further embodiment, and whatever the ammonium
halides are, the amount of ammonium halides in which the nitrogen
atom is substituted by at least one alkyl group having 14 or 16
carbon atoms may preferably represent at least 50% w/w of the total
amount of all ammonium halides present in the composition, this
percentage being in dry weight.
[0021] According to another embodiment the amount of ammonium
halides in which the nitrogen atom is substituted by at least one
alkyl group having at least 16 carbon atoms may preferably
represent more than 90% w/w measured in dry weight of the total
amount of all ammonium halides present in the composition.
[0022] According to another embodiment the amount of ammonium
halides in which the nitrogen atom is substituted by at least one
alkyl group having at least 16 carbon atoms may preferably
represent more than 30% w/w measured in dry weight of the total
amount of all ammonium halides present in the composition.
[0023] According to an embodiment of the invention, the composition
includes, dry weight by total dry weight, of all ammonium halides
present in the composition, 40% of ammonium halides in which the
nitrogen atom is substituted by an alkyl group having 12 carbon
atoms, 30% of ammonium halides in which the nitrogen atom is
substituted by an alkyl group having 14 carbon atoms and 30% of
ammonium halides in which the nitrogen atom is substituted by an
alkyl group having 16 carbon atoms; preferably, the composition
includes, measured in dry weight, in weight by total weight of all
ammonium halides present in the composition, a mixture of 40% w/w
of BAK C12, 30% w/w of BAK C14, and 30% w/w of BAK C16.
[0024] In another embodiment, the composition includes, in dry
weight by total dry weight, a mixture of 40% w/w ATAB C12, 30% w/w
ATAB C14 or 30% w/w ATAB C16.
[0025] In another embodiment, the mean molecular weight of the
ammonium halides present in the composition is less than 372, this
calculation based on the total alkyl basis.
[0026] In another embodiment, the composition consists of, in dry
weight by total dry weight of the halide ammonium composition, 85%
of ammonium halides in which the nitrogen atom is substituted by an
alkyl group having 14 carbon atoms and 15% of ammonium halides in
which the nitrogen atom is substituted by an alkyl group having 16
carbon atoms.
[0027] In another embodiment, the composition consists of 45% of
ammonium halides in which the nitrogen atom is substituted by an
alkyl group having 12 carbon atoms and 55% ammonium halides in
which the nitrogen atom is substituted by an alkyl group having 16
carbon atoms
[0028] According to an embodiment, the weight ratio of C12-alkyl
ammonium halides to the sum of C14-alkyl ammonium halides and
C16-alkyl ammonium halide, is less than 1.5, preferably less than
1.35, more preferably less than 1.20. More preferably, the weight
ratio of BAK C12 to the sum of BAK C14 and BAK C16, is less than
1.5, preferably less than 1.35, more preferably less than 1.20.
[0029] According to an embodiment of the invention, the composition
includes more than one ammonium halide: in a first embodiment the
composition includes three ammonium halides, preferably a C12-alkyl
ammonium halide and a C14-alkyl ammonium halide and a C16-alkyl
ammonium halide, more preferably BAK C12 and BAK C14 and BAK C16;
in another embodiment, the composition includes two ammonium
halides, preferably a C14-alkyl ammonium halide and a C16-alkyl
ammonium halide, preferably BAK C12 and BAK C16; in another
embodiment of the invention, the composition includes only one
ammonium halide, preferably C16-alkyl ammonium halide, more
preferably BAK C16.
[0030] This composition is obtained by mixing various components
obtained from commercial source, or by de novo synthesis of the
composition itself, or by purification of commercial products.
[0031] In the meaning of this invention,
[0032] "Cationic emulsions" are emulsions having a positive zeta
potential, preferably a zeta potential higher to 10 mV;
[0033] "long alkyl chain" are alkyl moieties having at least 14
carbon atoms;
[0034] "quaternary ammonium compounds" refer to ammonium halides in
which the nitrogen atom is substituted by at least one alkyl group
having at least 12 carbon atoms; quaternary ammonium compounds
also, but not exclusively, include n-alkyl dimethyl benzyl ammonium
chloride also called benzalkonium chloride (hereiafter also
referred to as BAK or ADBAC); n-alkyl dimethyl benzyl ammonium
bromide; n-alkyl trimethyl ammonium bromide (also referred to as
ATAB), n-alkyl meaning an alkyl group of at least 12 carbon
atoms;
[0035] "C14-alkyl ammonium halides" means ammonium halides in which
the nitrogen atom of the ammonium group is substituted by at least
one alkyl group having at least 14 carbon atoms.
[0036] "BAK C12" refers to benzododecinium chloride (CAS 139-07-1);
"BAK C14" refers to myristalkonium chloride (CAS 139-08-2); "BAK
C16" refers to cetalkonium chloride (CAS 122-18-9);
[0037] "ATAB C12" refers to lauryl trimethyl ammonium bromide (CAS
1119-94-4); "ATAB C14" refers to Myristil trimethyl ammonium
bromide (CAS 1119-97-7); "ATAB C16" or "CTAB" refers to Cetyl
trimethyl ammonium bromide (CAS 57-09-0),
[0038] "MCT" means Medium chain triglycerides; for the
experimentation, TCM.TM. (Societe des Oleagineux, France) was the
MCT used;
[0039] "ND" means "not determined".
[0040] The invention also relates to a cationic oil-in-water
emulsion comprising a composition of the invention, as described
hereabove. According to an embodiment of the invention, the
oil-in-water emulsion comprises a composition as described above,
said emulsion comprising 0.0005 to 0.1% of quaternary ammonium
halides. By cationic oil-in water emulsion is understood an
oil-in-water emulsion having a positive zeta potential. The
emulsion of the invention has a positive zeta potential and is
stable, which means that it keeps a positive zeta potential
overtime. In a preferred embodiment, the oil-in-water emulsion
according to the invention includes droplets of size 100 to 500 nm,
preferably 110 to 250 nm.
[0041] In a first embodiment, the oil-in-water emulsion of the
invention is for cosmetic use. Preferably, the emulsion of the
invention is intended for making up or caring for the body and face
skin, including the lips, or for hair care. The cosmetic emulsion
of the invention can be a product for caring for the skin, such as
a care base for the skin, a care cream (e.g., day cream, night
cream, anti-wrinkle cream), a make-up base or a composition for
caring for the lips (e.g., lip balm), or make-up remover, including
eye make-up remover. The product of the invention may also be used
for enhancing moisture of hair and/or skin.
[0042] In a preferred embodiment, the oil-in-water emulsion of the
invention is useful for eye care or for the treatment of eye
diseases or eye conditions.
[0043] In the meaning of the invention, eye diseases or eye
conditions means a wide variety of ocular conditions such as
glaucoma, ocular inflammatory conditions such as keratitis,
uveitis, intra-ocular inflammation, allergy and dry-eye syndrome
ocular infections, ocular allergies, ocular infections, cancerous
growth, neo vessel growth originating from the cornea, retinal
oedema, macular oedema, diabetic retinopathy, retinopathy of
prematurity, degenerative diseases of the retina (macular
degeneration, retinal dystrophies), retinal diseases associated
with glial proliferation.
[0044] More preferably, the oil-in-water emulsion according to the
invention comprises:
[0045] a) an oil phase,
[0046] b) 0.0005 to 0.1% w/w of a composition of quaternary
ammonium halides, which contain at least 20% w/w, of ammonium
halides in which the nitrogen atom is substituted by at least one
alkyl group having at least 14 carbon atoms, preferably 14 or 16
carbon atoms and more than 5% w/w, preferably more than 7% w/w of
ammonium halides in which the nitrogen atom is substituted by at
least one alkyl group having at least 16 carbon atoms. in weight by
weight of the total emulsion
[0047] c) surfactants,
[0048] d) optionnaly antioxidants, isotonicity, viscosifying, pH
adjusting, buffering, preservative, solubilizers, chelating,
thickener agents,
[0049] e) water.
[0050] According to an embodiment of the invention, the
oil-in-water emulsion further comprises hydroxypropyl guar or
polyethylene glycol-400 or a mixture of both.
[0051] According to an embodiment of the invention, the emulsion
includes an oil phase, surfactants such as for example tyloxapol or
poloxamer or tocopherol polyethyleneglycol succinate or polysorbate
80 or any suitable surfactant, and 0.0005% to 0.1% w/w preferably
0.001 to 0.005% w/w of the total composition, of a composition of
ammonium halides according to the invention, as described
hereabove.
[0052] According to an embodiment of the invention, the emulsion
includes C12-alkyl benzyl dimethyl ammonium chloride or bromide,
C14-alkyl benzyl dimethyl ammonium chloride or bromide, and
C16-alkyl benzyl dimethyl ammonium chloride or bromide. According
to another embodiment of the invention, the emulsion comprises C14-
and C16-alkyl benzyl dimethyl ammonium chlorides. In a further
embodiment, the emulsion of the invention does not include any
C12-alkyl ammonium chloride or bromide. According to an embodiment,
the oil-in-water emulsion comprises C16-alkyl quaternary ammonium
halide as only source of quaternary ammonium halide.
[0053] According to another embodiment, the emulsion of the
invention includes trimethyl ammonium chlorides or bromides,
wherein the nitrogen atom is further substituted by an alkyl group
having at least 12 carbon atoms; or by an alkyl group having at
least 14 carbon atoms; or by an alkyl group having at least 16
carbon atoms; or by a mixture of such trimethyl ammonium chlorides
or bromides.
[0054] According to a preferred embodiment, the emulsion of the
invention includes MCT, glycerol, tyloxapol and poloxamer, and a
composition of the invention including at least one ammonium halide
as hereabove described.
[0055] Preferably, the emulsion includes 1 to 2% of oil phase,
preferably of MCT, castor oil or mineral oil.
[0056] Preferably, the emulsion includes 0.1 to 1% of surfactants,
preferably tyloxapol and/or poloxamer and/or polysorbate 80 and/or
tocopherol polyethyleneglycol succinate.
[0057] In a preferred embodiment, the emulsion includes an oil
phase, preferably 2% MCT or 1% mineral oil, and surfactants,
preferably 0.3% Tyloxapol and 0.1% Poloxamer, optionally
antioxidants such as alpha-tocopherol and optionally isotonicity
agents such as mannitol or glycerol, and a composition of ammonium
halides, preferably BAK C12, BAK C14, BAK C16 or a mixture of at
least two thereof, or in another embodiment ATAB C12, ATAB C14 or
ATAB C16 or a mixture of at least two thereof, said ammonium
halides composition being in a concentration ranging from 0.0005 to
0.1% w/w of the total emulsion.
[0058] According to a first embodiment, the emulsion does not
contain any active principle. In this embodiment, the emulsion is
particularly useful as artificial tears, or for the treatment of
dry eye condition such as for example Dry Eye Syndrome or Chronic
Dry Eye Disease (CDED), both clinically known as
keratoconjuctivitis sicca.
[0059] According to a second embodiment, the composition of the
invention contains an active principle, preferably chosen among
antibiotics such as aminoglycosides, carbacephem, carbapenems,
cephalosporins, glycopeptides, penicillins, polypeptides,
quinolones, sulfonamides, tetracyclines and others; antiviral
agents such as cidofovir, ganciclovir, valaciclovir or acyclovir;
antifungals such as polyene antibiotics, imidazole and triazole,
allylamines, intraocular pressure lowering agents such as
alpha-adrenergic agonists, beta-adrenergic blockers, carbonic
anhydrase inhibitors, cannabinoids, prostaglandins, prostaglandins
analogues, derivatives and prodrugs; anti-inflammatory agents such
as COX-2 inhibitors, salicylates, 2-arylpropionic acids,
N-arylanthranilic acids, oxicams, sulphonanilides, pyrazolidines
derivatives, arylalkanoic acids, 3-benzolphenylacetic acids and
derivatives; steroids such as cortisone, hydrocortisone,
prednisone, prednisolone, methylprednisone, fluoromethalone,
medrysone, betamethasone, loteprednol, flumethasone, mometasone,
testosterone, methyltestosterone, danazol, beclomethasone,
dexamethasone, dexamethasone palmitate, tramcinolone, triamcinolone
acetonide, fluocinolone, fluocinolone acetonide and difluprednate;
antiallergic compounds such as olapatadine, ketotifen, azelastine,
epinastine, emedastine, levocabastive, terfenadine, astemizole and
loratadine; anti-angiogenic compounds such as thalidomide, VEGF
inhibitors, VEGF soluble receptors, VEGF-traps, VEGF-antibodies,
VEGF-traps, anti VEGF-siRNA; biological agents such as such as
antibodies or antibodies fragments, oligoaptamers, aptamers and
gene fragments, oligonucleotides, plasmids, ribozymes, small
interference RNA, nucleic acid fragments, peptides and antisense
sequences; growth factors such as epidermal growth factor,
fibroblast growth factor, platelet derived growth factor,
transforming growth factor beta, ciliary neurotrophic growth
factor, glial derived neurotrophic factor, NGF, EPO and P1GF;
immunomodulating agents such as glucocorticoids, drugs acting on
immunophilins, interferons, opioids; cytostatics such as alkylating
agents, antimetabolites and cytotoxic antibiotics; antioxidants
such as alpha-tocopherol, ascorbic acid, retinoic acid, lutein and
their derivatives, precursors or prodrugs; UV-filter compounds such
as benzophenones; anti-redness agents such as naphazoline,
tetrahydrozoline, ephedrine and phenylephrine; fatty acids such as
omega-3 fatty acids.
[0060] Preferably, the composition of the invention contains an
active principle chosen among the group consisting of ganciclovir,
acyclovir, ketoconazole, amphotericin B, brimonidine, dexanabinol,
forskolin, travoprost, latanoprost, amfenac, diclofenac,
flurbiprofen, flurbiprofen axetyl, ketorolac, dexamethasone
palmitate, rimexolone, triamcinolone, difluprednate, fluocinolone,
olapatadine, alpha-tocopherol, vitamin A, vitamin C, lutein,
eicosapentaenoic acid, docosahexaenoic acid, octylmethoxycinnamate,
benzophenone-3, octyl dimethyl PABA, cyclosporine A, mycophenolate,
sirolimus and tacrolimus and/or their derivatives; and/or their
prodrugs; and/or their precursors; and/or acceptable salts thereof;
alone or in combination.
[0061] In an embodiment of the invention, the oil-in-water emulsion
is preserved.
[0062] In another embodiment of the invention, the oil-in-water
emulsion is unpreserved; in an embodiment, the emulsion is packaged
in unitary doses; in another embodiment, the emulsion is packaged
in suitable multidose containers.
[0063] The invention relates to a medicament comprising an
oil-in-water emulsion as described above or a composition as
described above.
[0064] The invention also relates to the use of an oil-in-water as
described above or a composition as described above for the
manufacture of a medicament or an ophthalmic composition the
treatment of an eye condition or disease.
[0065] The invention also relates to a cosmetic composition
comprising an oil-in-water emulsion as described above or a
composition as described above.
[0066] The invention also relates to a non-therapeutical process
for caring for, removing makeup from and/or cleansing the skin, the
lips and/or the eyes, and/or for hair care, comprising applying an
oil-in-water emulsion as described above or a composition as
described above to the skin, the lips, the eyes, and/or the
hair.
[0067] The following examples and figures illustrate the invention
and should not be interpreted in any way as reducing the scope of
this invention.
[0068] FIG. 1 refers is a graph showing zeta potential values (mV)
of the emulsion of the invention depending of various BAK
concentrations, and is to be read in connexion with table 2 of the
examples.
[0069] FIG. 2 refers to a graph showing the unexpected decrease of
the toxicity of the emulsion comprising BAK C16.
EXAMPLES
[0070] All concentrations in the emulsion formulae are expressed in
weight/weight of the entire formulation percentages, unless stated
differently.
[0071] 1. Emulsions Composition
[0072] Emulsions containing different amounts and chain lengths of
BAK and ATAB were prepared. They contained 2% MCT or 1% mineral oil
as oil phase, 0.3% Tyloxapol and 0.1% Poloxamer as surfactants.
They could also contain antioxidants such as alpha-tocopherol and
isotonicity agents such as mannitol or glycerol. Concentrations
ranging from 0.001 to 0.1% of BAK C12, BAK C14, BAK C16 or a
mixture of all, and from 0.0025 to 0.005% of ATAB C12, ATAB C14 or
ATAB C16 were prepared.
[0073] 2. Emulsions Preparation
[0074] The oily and the water phases of the emulsion, which might
contain or not an active principle, may be separately heated to an
appropriate temperature. This temperature may be the same in both
cases. Surfactants might be dissolved in the oil, water phase or in
both. A first coarse emulsion is generated by magnetic stirring,
and the droplet size is reduced by high shear mixing, high pressure
homogenization, or both.
[0075] The oil-in-water emulsions of the present invention can be
sterilized after preparation using heat, for example, autoclave
steam sterilization.
[0076] 3. Impact of Chain Length on Emulsions Characteristics
[0077] a) Emulsion Droplet Size
[0078] The mean diameter of the oil droplets is determined by
dynamic light scattering using a High Performance Particle Sizer
type HPPS 5001 (Malvern Instruments, Worcestershire, UK).
Measurements are performed at 25.degree. C. following dilution of
the emulsion in double distilled water.
TABLE-US-00001 TABLE 1 Emulsions droplet size values (nm) 0.001%
0.0025% 0.005% 0.01% 0.02% 0.04% 0.1% ATAB C12 -- -- -- -- -- --
ATAB C14 -- 203 -- -- -- -- -- ATAB C16 -- 222 212 -- -- -- -- BAK
C12 -- -- 198 263 230 225 180 BAK C14 -- 204 190 190 155 238 185
BAK C16 220 210 148 180 155 188 183 65% BAK C12 -- -- 357 397 190
180 156 35% BAK C14 40% BAK C12 -- 220 210 145 -- -- -- 30% BAK C14
30% BAK C16
[0079] b) Emulsion Zeta Potential
[0080] Zeta potential can be measured by a zetameter such as
Zetasizer 2000, Malvern Instruments Ltd, UK. The zeta potential of
the emulsion droplet surface is determined by electrophoretic
mobility. Measurements are performed at 25.degree. C. following
dilution at 1:250 of the emulsion in double distilled water. The
electrophoretic mobility is converted into zeta potential values
through the Smoluchowsky equation.
[0081] The following table and graph show the evolution of the zeta
potential (indicative of the surface charge) at increasing
concentrations of QA. It can be observed that for more lipophilic
(longer) chain lengths, positive charges are attained more rapidly
and at lower concentrations, suggesting a preferential partition
within the oil droplet surface.
TABLE-US-00002 TABLE 2 Emulsions zeta potential values (mV) 0.001%
0.0025% 0.005% 0.01% 0.02% 0.04% 0.1% ATAB C12 -- -35.5 -14.6 -- --
-- -- ATAB C14 -- -11.4 -6.0 -- -- -- -- ATAB C16 -- +11.9 +20.2 --
-- -- -- BAK C12 -- -- -6.9 +4.2 +7.9 +16.8 +23.8 BAK C14 -- +11.4
+19.6 +22.9 +28.4 +39.3 +44.5 BAK C16 +16.2 +24.4 +31.4 +36.7 +44.1
+47.2 +48.9 65% BAK C12 -- -- +7.6 +17.7 +20.0 +35.0 +40.3 35% BAK
C14 40% BAK C12 -- +14.3 +21.6 +30.7 -- -- -- 30% BAK C14 30% BAK
C16
[0082] 3. Emulsion Stability Over Time
[0083] The stability of the emulsions can be evaluated by the
evolution of their aspect, with a visual score with a visual score
going from 13--best aspect to 1--total phase separation.
[0084] It can be observed from the following table that, at
equimolar concentration, longer (more lipophilic) chain length QA
results in more stable emulsion.
TABLE-US-00003 Type and conc. After Following 3 months Emulsion of
QA preparation (T0) at 40.degree. C. Z01EM207 0.25 mM BAK 12 2 C12
Z01EM208 0.25 mM BAK 13 7 C14 Z01EM209 0.25 mM BAK 13 9 C16
Z01EM204 0.5 mM BAK 10 2 C12 Z01EM205 0.5 mM BAK 13 7 C14 Z01EM206
0.5 mM BAK 11 9 C16
[0085] 4. Impact of Chain Length on Antimicrobial Activity of
QA
[0086] The antimicrobial effectiveness of the emulsions and
solutions of BAK C12, BAK C14 and BAK C16 at equimolar
concentrations corresponding to 0.005% w/w BAK C12 has been
determined according to the chapter 51 of the United States
Pharmacopeia.
TABLE-US-00004 TABLE 3 Antimicrobial effectiveness testing of
emulsions and solutions containing BAK C12, C14 or C16. Chain
length BAK C.sub.12 BAK C.sub.14 BAK C.sub.16 Solution NA (SOL226)
(SOL254) Emulsion x (EM212) (EM219) (EM234) : preserved, x: not
preserved, NA: not assessed
[0087] 5. Impact of Chain Length on Toxicity of QA
[0088] The ocular irritation of the emulsions and solutions has
been evaluated using an adaptation of the Draize test on white male
New Zealand rabbits (2.75-3.00 kg). Fifty .mu.L of emulsion or
solution were instilled unilaterally and 50 .mu.L of NaCl 0.9% in
the other eye of the three rabbits per group. General aspect
assessment of the animals was performed (behaviour, blinking,
itching of the eye with forelegs) as well as eye tissue evaluation
(conjunctiva, cornea, iris) after instillation, 1, 24, 48 and 72
hours. Observations were scored according to the Draize test
protocol.
[0089] The graph (FIG. 2) shows that the incorporation of BAK C16
within an emulsion results in an unexpected decrease of its
toxicity.
[0090] 6. Emulsions Containing Therapeutically Active Compound
[0091] Emulsions loaded with a therapeutically active compound
(0.05% w/w Cyclosporin A) and containing different amounts and
chain lengths of BAK were prepared as described previously.
TABLE-US-00005 Zeta w/w Emulsion potential (mV) BAK C16 0.002%
EM067 +23.0 0.0025% EM063 +23.2 0.003% EM070 +26.7 0.005% EM064
+29.2 40% BAK 0.005% EM065 +19.6 C12 0.01% EM066 +27.9 30% BAK C14
30% BAK C16
* * * * *