U.S. patent application number 14/792250 was filed with the patent office on 2015-10-29 for topical application of ivermectin for the treatment of dermatological conditions/afflictions.
The applicant listed for this patent is GALDERMA S.A.. Invention is credited to Vincent MANETTA, Gary R. WATKINS.
Application Number | 20150306027 14/792250 |
Document ID | / |
Family ID | 33104376 |
Filed Date | 2015-10-29 |
United States Patent
Application |
20150306027 |
Kind Code |
A1 |
MANETTA; Vincent ; et
al. |
October 29, 2015 |
TOPICAL APPLICATION OF IVERMECTIN FOR THE TREATMENT OF
DERMATOLOGICAL CONDITIONS/AFFLICTIONS
Abstract
Dermatological conditions/afflictions such as rosacea, common
acne, seborrheic dermatitis, perioral dermatitis, acneform rashes,
transient acantholytic dermatosis, and acne necrotica miliaris,
most notably rosacea, are treated by topically applying onto the
affected skin area of an individual in need of such treatment, a
topical pharmaceutical composition which comprises a thus effective
amount of ivermectin.
Inventors: |
MANETTA; Vincent;
(Bordentown, NJ) ; WATKINS; Gary R.; (Piscataway,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALDERMA S.A. |
Cham |
|
CH |
|
|
Family ID: |
33104376 |
Appl. No.: |
14/792250 |
Filed: |
July 6, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14337966 |
Jul 22, 2014 |
|
|
|
14792250 |
|
|
|
|
14063897 |
Oct 25, 2013 |
8815816 |
|
|
14337966 |
|
|
|
|
13851816 |
Mar 27, 2013 |
8598129 |
|
|
14063897 |
|
|
|
|
13310633 |
Dec 2, 2011 |
8415311 |
|
|
13851816 |
|
|
|
|
12483604 |
Jun 12, 2009 |
8093219 |
|
|
13310633 |
|
|
|
|
11255910 |
Oct 24, 2005 |
7550440 |
|
|
12483604 |
|
|
|
|
PCT/EP2004/004950 |
Apr 22, 2004 |
|
|
|
11255910 |
|
|
|
|
60468994 |
May 9, 2003 |
|
|
|
Current U.S.
Class: |
514/30 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 31/35 20130101; A61K 31/7048 20130101; A61P 17/08 20180101;
A61P 17/00 20180101; A61K 9/107 20130101; A61P 17/10 20180101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/7048 20060101 A61K031/7048 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 24, 2003 |
FR |
0305048 |
Claims
1.-38. (canceled)
39. A method for treating rosacea, common acne, seborrheic
dermatitis, perioral dermatitis, an acneform rash, transient
acantholytic dermatitis or acne necrotica milliaris, comprising
topically applying onto the affected skin area of an individual in
need of such treatment, a topical pharmaceutical composition which
comprises: a thus effective amount of ivermectin of 1% by weight
relative to the total weight of the composition; an oily phase; at
least one surfactant-emulsifier selected from the group consisting
of polyoxyethylenated fatty acid esters and sorbitan esters; a
mixture of solvents and/or propenetrating agents for the
ivermectin, said solvents and/or propenetrating agents being
selected from the group consisting of propylene glycol, ethanol,
isopropanol, butanol, N-methyl-2-pyrrolidone, DMSO, polysorbate 80,
phenoxyethanol, glyceryl triacetate and oleyl alcohol; one or more
gelling agents but excluding aluminum magnesium silicate/titanium
dioxide/silica; and water; said composition having lamellar layers
of liquid crystals and being chemically stable over a period of 8
weeks; said composition being in a form selected from the group
consisting of an ointment, a cream, a milk, a pomade, an
impregnated pad, a syndet, a towelette, a gel, a spray, a foam, a
lotion, a stick, a shampoo, a suspension of microspheres, a
suspension of nanospheres, a suspension of lipid vesicles, a
suspension of polymeric vesicles, a polymeric patch, and a hydrogel
for controlled release.
40. The method as defined by claim 39, wherein the composition is
in the form of a cream, a gel, a foam or a lotion.
41. A method for treating rosacea, comprising topically applying
onto the affected skin area of an individual in need of such
treatment, a topical pharmaceutical composition which comprises: a
thus effective amount of ivermectin of 1% by weight relative to the
total weight of the composition; an oily phase; at least one
surfactant-emulsifier selected from the group consisting of
polyoxyethylenated fatty acid esters and sorbitan esters; a mixture
of solvents and/or propenetrating agents for the ivermectin, said
solvents and/or propenetrating agents being selected from the group
consisting of propylene glycol, ethanol, isopropanol, butanol,
N-methyl-2-pyrrolidone, DMSO, polysorbate 80, phenoxyethanol,
glyceryl triacetate and oleyl alcohol; one or more gelling agents
selected from the group consisting of carbomers, cellulose
derivatives, xanthan gums, guar gums, polyacrylamides, modified
starches and aluminum magnesium silicates but excluding aluminum
magnesium silicate/titanium dioxide/silica; and water; said
composition having lamellar layers of liquid crystals and being
chemically stable over a period of 8 weeks; said composition being
in a form selected from the group consisting of an ointment, a
cream, a milk, a pomade, an impregnated pad, a syndet, a towelette,
a gel, a spray, a foam, a lotion, a stick, a shampoo, a suspension
of microspheres, a suspension of nanospheres, a suspension of lipid
vesicles, a suspension of polymeric vesicles, a polymeric patch,
and a hydrogel for controlled release.
42. The method as defined by claim 41, wherein the composition is
in the form of a cream, a gel, a foam or a lotion.
43. The method as defined by claim 39, wherein said topical
pharmaceutical composition further comprises: 6 to 20% of said oily
phase; 2 to 12% of said surfactant-emulsifier; 0.1 to 20% of said
mixture of solvents and/or propenetrating agents; 0.01 to 5% of
said gelling agents; and water; the amounts being in percents by
weight relative to the total weight of the composition.
44. The method as defined by claim 43, said oily phase comprising a
synthetic oil and/or a silicone oil.
45. The method as defined by claim 44, said synthetic oil and/or
silicone oil comprising dimethicone, cyclomethicone, isopropyl
palmitate and/or isopropyl myristate.
46. The method as defined by claim 39, said at least one
surfactant-emulsifier comprising sorbitan monostearate, sorbitan
palmitate, sorbitan oleate, sorbitan sesquioleate, sorbitan
isostearate, Steareth-20, Steareth-2, Steareth-21 and/or
Ceteareth-20.
47. The method as defined by claim 39, said oily phase further
comprising fatty substances selected from the group consisting of
cetostearyl alcohol, cetyl alcohol, stearyl alcohol, stearic acid,
palmitostearic acid and self-emulsifiable wax.
48. The method as defined by claim 39, said one or more gelling
agents comprising a carbomer and/or aluminum/magnesium silica.
49. The method as defined by claim 48, said carbomer being an
acrylate C.sub.10-30 alkyl acrylate crosspolymer.
50. The method as defined by claim 41, wherein said topical
pharmaceutical composition further comprises: 6 to 20% of said oily
phase; 2 to 12% of said surfactant-emulsifier; 0.1 to 20% of said
mixture of solvents and/or propenetrating agents; 0.01 to 5% of
said gelling agents; and water; the amounts being in percents by
weight relative to the total weight of the composition.
51. The method as defined by claim 50, said oily phase comprising a
synthetic oil and/or a silicone oil.
52. The method as defined by claim 51, said synthetic oil and/or
silicone oil comprising dimethicone, cyclomethicone, isopropyl
palmitate and/or isopropyl myristate.
53. The method as defined by claim 41, said at least one
surfactant-emulsifier comprising sorbitan monostearate, sorbitan
palmitate, sorbitan oleate, sorbitan sesquioleate, sorbitan
isostearate, Steareth-20, Steareth-2, Steareth-21 and/or
Ceteareth-20.
54. The method as defined by claim 41, said oily phase further
comprising fatty substances selected from the group consisting of
cetostearyl alcohol, cetyl alcohol, stearyl alcohol, stearic acid,
palmitostearic acid and self-emulsifiable wax.
55. The method as defined by claim 41, said one or more gelling
agents comprising a carbomer and/or aluminum/magnesium silica.
56. The method as defined by claim 55, said carbomer being an
acrylate C.sub.10-30 alkyl acrylate crosspolymer.
57. A topically applicable, stable pharmaceutical composition, said
composition comprising: an effective amount of ivermectin of 1% by
weight relative to the total weight of the composition; an oily
phase; at least one surfactant-emulsifier selected from the group
consisting of polyoxyethylenated fatty acid esters and sorbitan
esters; a mixture of solvents and/or propenetrating agents for the
ivermectin, said solvents and/or propenetrating agents being
selected from the group consisting of propylene glycol, ethanol,
isopropanol, butanol, N-methyl-2-pyrrolidone, DMSO, polysorbate 80,
phenoxyethanol, glyceryl triacetate and oleyl alcohol; one or more
gelling agents but excluding aluminum magnesium silicate/titanium
dioxide/silica; and water; said composition having lamellar layers
of liquid crystals and being chemically stable over a period of 8
weeks; said composition being in a form selected from the group
consisting of an ointment, a cream, a milk, a pomade, an
impregnated pad, a syndet, a towelette, a gel, a spray, a foam, a
lotion, a stick, a shampoo, a suspension of microspheres, a
suspension of nanospheres, a suspension of lipid vesicles, a
suspension of polymeric vesicles, a polymeric patch, and a hydrogel
for controlled release.
58. The topically applicable, stable pharmaceutical composition as
defined by claim 57, said composition being in the form of a cream,
a gel, a foam or a lotion.
59. The topically applicable, stable pharmaceutical composition as
defined by claim 57, further comprising: 6 to 20% of said oily
phase; 2 to 12% of said surfactant-emulsifier; 0.1 to 20% of said
mixture of solvents and/or propenetrating agents; 0.01 to 5% of
said gelling agents; and water; the amounts being in percents by
weight relative to the total weight of the composition.
60. The topically applicable, stable pharmaceutical composition as
defined by claim 57, said one or more gelling agents being selected
from the group consisting of carbomers, cellulose derivatives,
xanthan gums, guar gums, polyacrylamides, modified starches and
aluminum magnesium silicates but excluding aluminum magnesium
silicate/titanium dioxide/silica.
61. The topically applicable, stable pharmaceutical composition as
defined by claim 57, said oily phase comprising a synthetic oil
and/or a silicone oil.
62. The topically applicable, stable pharmaceutical composition as
defined by claim 61, said synthetic oil and/or silicone oil
comprising dimethicone, cyclomethicone, isopropyl palmitate and/or
isopropyl myristate.
63. The topically applicable, stable pharmaceutical composition as
defined by claim 57, said at least one surfactant-emulsifier
comprising sorbitan monostearate, sorbitan palmitate, sorbitan
oleate, sorbitan sesquileate, sorbitan isostearate, Steareth-20,
Steareth-2, Steareth 21 and/or Ceteareth-20.
64. The topically applicable, stable pharmaceutical composition as
defined by claim 57, said oily phase further comprising fatty
substances selected from the group consisting of cetostearyl
alcohol, cetyl alcohol, stearyl alcohol, stearic acid,
palmitostearic acid and self-emulsifiable wax.
65. The topically applicable, stable pharmaceutical composition as
defined by claim 57, said one or more gelling agents comprising a
carbomer and/or aluminum/magnesium silica.
66. The topically applicable, stable pharmaceutical composition as
defined by claim 65, said carbomer being an acrylate C.sub.10-30
alkyl acrylate crosspolymer.
67. The topically applicable, stable pharmaceutical composition as
defined by claim 66, said composition being in the form of a cream,
a gel, a foam or a lotion.
Description
CROSS-REFERENCE TO EARLIER APPLICATIONS
[0001] This application is a continuation of earlier copending U.S.
patent application Ser. No. 13/310,633, filed Dec. 2, 2011, now
allowed, which is a continuation of U.S. patent application Ser.
No. 12/483,604, filed Jun. 12, 2009, now U.S. Pat. No. 8,093,219,
which is a continuation of U.S. patent application Ser. No.
11/255,910, filed Oct. 24, 2005, now U.S. Pat. No. 7,550,440, which
is a continuation of International Application No.
PCT/EP2004/004950, filed Apr. 22, 2004 and designating the U.S.
(published in the English language on Nov. 4, 2004 as WO
2004/093886 A1), which claims benefit of U.S. Provisional
Application No. 60/468,994, filed May 9, 2003, and also claims
priority under 35 U.S.C. .sctn.119 of Application No. 03/05048,
filed in France on Apr. 24, 2003, each earlier application hereby
expressly incorporated by reference herein and each assigned to the
assignee hereof.
CROSS-REFERENCE TO RELATED APPLICATION
[0002] Application Ser. No. 12/468,287, filed May 19, 2009, now
U.S. Pat. No. 8,080,530, is also a continuation of earlier
copending U.S. patent application Ser. No. 11/255,910, filed Oct.
24, 2005, now U.S. Pat. No. 7,550,440, based on the same earlier
domestic and foreign applications as identified above, said
application Ser. No. 12/468,287 also hereby expressly incorporated
by reference herein and assigned to the assignee hereof.
Application Ser. No. 13/529,971, filed Jun. 21, 2012, now allowed,
is also a continuation of earlier copending application Ser. No.
13/310,623, filed Dec. 2, 2011, now allowed and based on the same
earlier domestic and foreign applications as the present
application, said application Ser. No. 13/529,971 also hereby
expressely incorporated by reference herein and assigned to the
assignee hereof.
BACKGROUND OF THE INVENTION
[0003] 1. Technical Field of the Invention
[0004] The present invention relates to the formulation of
ivermectin into topical pharmaceutical compositions useful for the
treatment of rosacea. This invention also relates to topical
pharmaceutical compositions suited for administration to humans,
comprising ivermectin.
[0005] 2. Description of Background and/or Related and/or Prior
Art
[0006] Ivermectin is a mixture of two compounds belonging to the
avermectin class, 5-O-demethyl-22,23-dihydroavermectin A.sub.1a and
5-O-demethyl-22,23-dihydroavermectin A.sub.1b. They are also known
as 22,23-dihydroavermectin B.sub.1a and 22-23-dihydroavermectin
B.sub.1b. Ivermectin contains at least 80% of
22,23-dihydroavermectin B.sub.1a and less than 20% of
22,23-dihydroavermectin B.sub.1b. This active agent is part of the
avermectin class, a group of macrocyclic lactones produced by the
bacterium Streptomyces avermitilis (Reynolds J E F (Ed) (1993)
Martindale). The extra pharmacopoeia, 29.sup.th Edition,
Pharmaceutical Press, London).
[0007] In the middle of the 1980s, ivermectin was presented as a
broad-spectrum anti-parasitic medicinal product for veterinary use
(W. C. CAMPBELL, et al., (1983). Ivermectin: a potent new
anti-parasitic agent, Science, 221, 823-828). It is effective
against most common intestinal worms (except tapeworms), most
acarids and some lice. It in particular exhibits considerable
affinity for the glutamate-dependent chloride channels present in
invertebrate nerve cells and muscle cells. Its binding to these
channels promotes an increase in membrane permeability to chloride
ions, resulting in hyperpolarization of the nerve or muscle cell.
Neuromuscular paralysis which can lead to the death of certain
parasites results therefrom. Ivermectin also interacts with other
ligand-dependent chloride channels, such as those involving the
neuromediator GABA (gamma-aminobutyric acid).
[0008] Ivermectin is more particularly an anthelmintic. It has
already been described in humans in the treatment of river
blindness caused by Onchocerca volvulus, of gastrointestinal
strongyloidiasis (anguillulosis) (product Stromectol.RTM.), and of
human scabies (Meinking T L et al., N. Engl. J. Med., 1995 Jul. 6;
333(1):26-30, "The treatment of scabies with ivermectin") and also
in the treatment of microfilaraemia diagnoses or suspected in
individuals suffering from lymphatic filariasis due to Wuchereria
bancrofti.
[0009] U.S. Pat. No. 6,133,310 discloses the use of ivermectin
topically in the form of a prototype of a lotion consisting of a
mixture of ivermectin and water, and also mentions the possibility
of a prototype of a cream consisting, for its part, of a mixture of
ivermectin and an excipient such as propylene glycol or sodium
lauryl sulfate, but describes no pharmaceutical composition as
such. These mixtures are similar to experimental preparations used
in the context of initial results of proof of concept. In fact, the
elements disclosed in that patent provide no teaching to those
skilled in the art regarding the feasibility of industrially
acceptable pharmaceutical compositions containing ivermectin, in
particular having good cosmetic properties and a shelf-life which
is sufficiently long for an industrial pharmaceutical product
(minimum of 2 years).
SUMMARY OF THE INVENTION
[0010] Despite the fact that all these uses in humans are limited
to oral administration or to the use of experimental preparations,
topical pharmaceutical compositions have now been developed suited
for the treatment of humans, containing ivermectin. In addition, it
has now been found that the compositions according to the invention
exhibit very good stability, in particular at different pHs, and
good tolerance on the skin. In fact, it has now been found that
same are particularly suitable for the treatment of dermatological
conditions, and more particularly well suited for the treatment of
rosacea.
[0011] The present invention also features the formulation of
ivermectin into topical pharmaceutical compositions useful for the
treatment of rosacea, topical pharmaceutical compositions suited
for human administration, comprising ivermectin, and the use of
these topical pharmaceutical compositions for the treatment of
rosacea (whether regime or regimen).
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
[0012] The ivermectin according to the invention contains at least
80% of 22,23-dihydroavermectin B.sub.1a and less than 20% of
22,23-dihydroavermectin B.sub.1b.
[0013] The pharmaceutical compositions according to the invention
are suited for treating the skin and may be in liquid, pasty or
solid form, and more particularly in the form of ointments, creams,
milks, pomades, powders, impregnated pads, syndets, towelettes,
solutions, gels, sprays, foams, suspensions, lotions, sticks,
shampoos or washing bases. They may also be in the form of
suspensions of microspheres or nanospheres or of lipid or polymeric
vesicles or of polymeric patches and of hydrogels for controlled
release. These compositions for topical application may be in
anhydrous form, in aqueous form of in the form of an emulsion.
[0014] In a preferred embodiment of the invention, the
pharmaceutical compositions according to the invention are in the
form of an emulsion of the cream or lotion type, of a gel, or of a
solution.
[0015] More preferably, the compositions according to the invention
are in the form of an emulsion.
[0016] Conventional emulsions as described in the prior art are
unstable virtually homogeneous systems of two immiscible liquids,
one of which is dispersed in the other in the form of fine droplets
(micelles). This dispersion is stabilized by virtue of the action
of surfactant-emulsifiers which modify the structure and the ratio
of the forces at the interface, and therefore increase the
stability of the dispersion by decreasing the interface tension
energy.
[0017] Surfactant-emulsifiers are amphiphilic compounds which
possess a hydrophobic component having affinity for oil and a
hydrophilic component having affinity for water, thus creating a
link between the two phases. Ionic or nonionic emulsifiers
therefore stabilize oil/water emulsions by adsorbing to the
interface and forming lamellar layers of liquid crystals.
[0018] The emulsifier power of nonionic surfactants is closely
linked to the polarity of the molecule. This polarity is defined by
the HLB (hydrophilic/lipophilic balance). Conventional emulsions
are generally stabilized by a mixture of surfactants, the HLBs of
which can be quite different but the proportion of which in the
mixture corresponds to the required HLB of the fatty phase to be
emulsified.
[0019] The compositions according to the invention will contain
this type of ingredient.
[0020] The compositions according to the invention are described as
stable emulsions in that they exhibit good physical and chemical
stability over time, even at a temperature above ambient
temperature (for example 45-55.degree. C.), as shown in the
examples described hereinafter.
[0021] The ivermectin in the compositions according to the
invention also, surprisingly, exhibits good chemical stability in
the case of pH variation.
[0022] The compositions according to the invention are
advantageously emulsions which comprise: [0023] a) an oily phase
comprising fatty substances; [0024] b) at least one
surfactant-emulsifier; [0025] c) ivermectin; [0026] d) one or more
solvent(s) and/or propenetrating agent(s) for the active agent;
[0027] e) and water.
[0028] More particularly, the compositions according to the
invention are emulsions which comprise: [0029] a) an oily phase
comprising fatty substances; [0030] b) at least one
surfactant-emulsifier; [0031] c) ivermectin; [0032] d) one or more
solvent(s) and/or propenetrating agent(s) for the active agent;
[0033] e) one or more gelling agent(s); [0034] f) and water.
[0035] The oily phase of the composition according to the invention
may comprise, for example, vegetable, mineral, animal or synthetic
oils, silicone oils, Guerbet alcohols or other substances, and
mixtures thereof.
[0036] As an example of a mineral oil, mention may be made, for
example, of paraffin oils of various viscosities, such as Primol
352, Marcol 82 or Marcol 152 marketed by Esso.
[0037] As a vegetable oil, mention may be made of sweet almond oil,
palm oil, soybean oil, sesame oil and sunflower oil.
[0038] As an animal oil, mention may be made of lanolin, squalene,
fish oil and mink oil.
[0039] As a synthetic oil, mention may be made of esters, such as
cetearyl isononanoate marketed in particular under the name Cetiol
SN by Cognis France, diisopropyl adipate, for instance the product
marketed under the name Ceraphyl 230 by ISF, isopropyl palmitate,
for instance the product marketed under the name Crodamol IPP by
Croda, or caprylic capric triglyceride such as Miglyol 812 marketed
by Huls/Lambert Riviere.
[0040] As a silicone oil, mention may be made of a dimethicone,
such as the product marketed under the name Dow Corning 200 fluid,
or a cyclomethicone, such as the product marketed under the name
Dow Corning 244 fluid by Dow Corning, or the product marketed under
the name Mirasil CM5 by SACI-CFPA.
[0041] As other fatty substances, mention may be made of fatty
acids such as stearic acid, fatty alcohols such as stearyl alcohol,
cetostearyl alcohol and cetyl alcohol, or derivatives thereof,
waxes such as beeswax, carnauba wax or candelilla wax, and also
gums, in particular silicone gums.
[0042] The ingredients of the oily phase may be selected in a
varied manner by those skilled in the art in order to prepare a
composition having the desired properties, for example of
consistency or of texture.
[0043] The oily phase of the composition according to the invention
preferably comprises a synthetic oil and/or a silicone oil; as
synthetic oil, isopropyl palmitate such as the product marketed
under the name Crodamol IPP by Croda or isopropyl myristate such as
the product marketed under the name Crodamol IPM by Croda is
preferred; as silicone oil, a dimethicone is preferred.
[0044] The oily phase of the emulsion according to the invention
may be present at a content of from 3 to 50% by weight relative to
the total weight of the composition, and preferably from 6 to 20%
by weight.
[0045] The compositions according to the invention contain
surfactant-emulsifiers. Among these compounds, mention may be made,
by way of examples, of the glyceryl/PEG 100 stearate marketed under
the name Arlacel 165FL by UNIQEMA or under the name Simulsol 165 by
SEPPIC; polyoxyethylenated fatty acid esters such as Arlatone 983
from the company UNIQEMA or the polyoxyethylenated (2) stearyl
alcohol marketed under the name Brij72 combined with the
polyethylenated (21) stearyl alcohol marketed under the name
Brij721 by UNIQEMA; sorbitan esters such as the sorbitan oleate
marketed under the name Arlacel 80 by ICI or marketed under the
name Crill 4 by Croda, the sorbitan sesquioleate marketed under the
name Arlacel 83 by ICI or marketed under the name Montane 83 by
SEPPIC, or else sorbitan isostearate; fatty alcohol ethers.
[0046] The compositions according to the invention advantageously
comprise up to 15% by weight of suitable surfactant-emulsifier,
preferably from 2 to 12% by weight, and more particularly from 2 to
6% by weight, relative to the total weight of the composition.
[0047] The compositions according to the invention comprise from
0.001 to 10% of ivermectin by weight relative to the total weight
of the composition. Preferably, the compositions according to the
invention contain from 0.1 to 5% of ivermectin by weight relative
to the total weight of the composition.
[0048] By way of example of a solvent and/or propenetrating agent
for the ivermectin active agent, mention will preferably be made of
propylene glycol, alcohols such as ethanol, isopropanol, butanol,
N-methyl-2-pyrrolidone or DMSO, polysorbate 80, phenoxyethanol, and
mixtures thereof.
[0049] The table below illustrates the solubility of ivermectin in
various solvents:
TABLE-US-00001 Maximum % solubility of ivermectin in the solvent
Solvents concerned (weight/weight) Triacetin 7.22 Propylene glycol
21.83 N-methyl-2-pyrrolidone 58.13 Propylene glycol/oleyl alcohol
(4 27.31 parts/2 parts)
[0050] The compositions of the invention contain from 0.1 to 20%,
and preferably from 1 to 10%, of a solvent and/or propenetrating
agent for the ivermectin active agent.
[0051] The compositions according to the invention may also
comprise aqueous phase gelling compounds ranging from 0.01 to 5% by
weight relative to the total weight of the composition. Among the
gelling agents which can be used in the composition according to
the invention, mention may be made of carboxyvinyl polymers
(carbomers) and, by way of non-limiting examples, of carbomer,
Carbopol 981, Carbopol ETD 2020, Carbopol 980, Carbopol Ultrez 10
NF and Pemulen TR1, marketed by NOVEON.
[0052] As aqueous phase gelling agents, mention may also be made of
cellulose derivatives such as, for example,
hydroxypropylmethylcellulose or hydroxyethylcellulose; xanthan
gums, aluminum/magnesium silicates such as Veegum K or Veegum Ultra
remarketed by Vanderbilt, guar gums and the like, polyacrylamides
such as the mixture polyacrylamide/C13-14 isoparaffin/laureth-7,
for instance that marketed, for example, by SEPPIC under the name
Sepigel 305, or the mixture acrylamide, AMPS copolymer dispersion
40%/isohexadecane under the name Simulgel 600PHA, or the family of
modified starches such as Structure Solanace remarketed by National
Starch, or mixtures thereof.
[0053] The compositions of the invention preferentially contain
from 0.01 to 5%, and preferably from 0.1 to 3%, of gelling
agent.
[0054] As gelling agent according to the invention, use will
preferably be made of carbomers, and preferably Pemulen TR1 or
aluminum/magnesium silicas such as Veegum K.
[0055] The compositions of the invention also contain water ranging
from 30 to 95%, and preferably from 60 to 80%, by weight relative
to the total weight of the composition. The water used in the
composition according to the invention will preferably be purified
water.
[0056] The pharmaceutical compositions according to the invention
may also contain inert additives or combinations of these
additives, such as [0057] flavor enhancers; [0058] preservatives;
[0059] stabilizers; [0060] humidity regulators; [0061] pH
regulators; [0062] osmotic pressure modifiers; [0063] UV-A and UV-B
screening agents; [0064] and antioxidants.
[0065] Of course, one skilled in this art will take care to choose
the optional compound(s) to be added to these compositions in such
a way that the advantageous properties intrinsically associated
with the present invention are not, or are not substantially,
altered by the envisaged addition.
[0066] These additives may be present in the composition at from
0.001 to 20% by weight relative to the total weight of the
composition.
[0067] The compositions according to the invention are
advantageously emulsions which comprise: [0068] a) 6 to 20% of an
oily phase; [0069] b) 2 to 12% of a surfactant-emulsifier; [0070]
c) 0.1 to 5% of ivermectin; [0071] d) 0.1 to 20% of solvent; [0072]
e) 0.01 to 5% of gelling agents; [0073] f) and water.
[0074] The pH will preferably range from 6.0 and 6.5. Verification
of the natural pH of the mixture and possible correction with a
solution of a neutralizing agent, and also the incorporation of the
optional additives, may be carried out, according to their chemical
nature, during one of the steps of the method of preparation,
described above.
[0075] Examples of compositions according to the present invention
are illustrated in Examples 1 to 6 to follow.
[0076] The present invention also features topical compositions
suited for human use, characterized in that they are emulsions
comprising: [0077] a) an oily phase comprising fatty substances;
[0078] b) at least one surfactant-emulsifier; [0079] c) ivermectin;
[0080] d) one or more solvent(s) and/or propenetrating agent(s) for
the active agent; [0081] e) and water.
[0082] More particularly, this composition may comprise: [0083] a)
an oily phase comprising fatty substances; [0084] b) at least one
surfactant-emulsifier; [0085] c) ivermectin; [0086] d) one or more
solvent(s) and/or propenetrating agent(s) for the active agent;
[0087] e) one or more gelling agent(s); [0088] f) and water.
[0089] Preferably, the composition comprises: [0090] a) 6 to 20% of
an oily phase; [0091] b) 2 to 12% of a surfactant-emulsifier;
[0092] c) 0.1 to 5% of ivermectin; [0093] d) 0.1 to 20% of solvent;
[0094] e) 0.01 to 5% of gelling agents; [0095] f) and water.
[0096] The ingredients being as defined above.
[0097] This invention also features formulation of the compositions
according to the invention into pharmaceutical preparations useful
to treat dermatological conditions/afflictions.
[0098] The formulation of ivermectin into topical pharmaceutical
compositions for human use according to the invention is
particularly useful for the treatment of rosacea, of common acne,
of seborrhoeic dermatitis, of perioral dermatitis, of acneform
rashes, of transient acantholytic dermatosis, and of acne necrotica
miliaris.
[0099] The formulation of ivermectin into topical pharmaceutical
compositions for human use according to the invention is more
particularly useful in a regime or regimen for the treatment of
rosacea.
[0100] In order to further illustrate the present invention and the
advantages thereof, the following specific examples of compositions
comprising ivermectin and the stability and tolerance thereof are
given, it being understood that same are intended only as
illustrative and in nowise limitative. In said examples to follow,
all parts and percentages are given by weight, unless otherwise
indicated.
EXAMPLE 1
Composition 1
[0101] The Compositions of Examples 1 to 4 are Formulated According
to the Following Procedure:
[0102] In a first suitable container, weigh the aqueous phase, mix
at 700 rpm and heat to 65.degree.-70.degree. C.
[0103] In a second suitable container, weigh the oily phase, mix at
425-475 rpm and heat to 70.degree.-75.degree. C.
[0104] In a third suitable container, weigh the active phase and
heat to 60-65.degree. C.
[0105] Where the oily and aqueous phases are at 70.degree. C., mix
the two phases with Rayneri stirring at 900 rpm until complete
homogeneity, and then cool.
[0106] Allow the emulsion to cool to 55-60.degree. C., add the
active phase with stirring at 600 rpm. Decrease, at 600 rpm, to
30.degree. C.
[0107] Adjust the pH to 6.0.
TABLE-US-00002 % by weight relative to the total weight of the
Ingredients composition Ivermectin 1.00 Glycerol 4.0 Aluminum
magnesium silicate 1.0 Methyl para-hydroxybenzoate 0.2 Disodium
EDTA 0.05 Citric acid monohydrate 0.05 Isopropyl palmitate 4.0
Glyceryl/PEG 100 stearate 3.0 Self-emulsifiable wax 2.0
Palmitostearic acid 2.5 Steareth-20 3.0 Sorbitan stearate 2.0
Dimethicone 20 0.5 Propyl para-hydroxybenzoate 0.1 Propylene glycol
4.0 Glyceryl triacetate 1.0 Phenoxyethanol 0.5 10% sodium hydroxide
qs pH Water qs 100
EXAMPLE 2
Composition 2
TABLE-US-00003 [0108] % by weight relative to the total weight of
the Ingredients composition Ivermectin 1.00 Glycerol 4.0 Steareth-2
1.0 Steareth-21 2.0 Aluminum magnesium silicate/titanium 1.0
dioxide/silica Methyl para-hydroxybenzoate 0.2 Propyl
para-hydroxybenzoate 0.1 Disodium EDTA 0.05 Citric acid monohydrate
0.05 Isopropyl palmitate 4.0 Glyceryl/PEG 100 stearate 2.0
Self-emulsifiable wax 1.0 Palmitostearic acid 2.00 Dimethicone
200-350 cS 0.5 Propylene glycol 4.0 Glyceryl triacetate 1.00
Phenoxyethanol 0.5 10% sodium hydroxide qs pH Water qs 100
EXAMPLE 3
Composition 3
TABLE-US-00004 [0109] % by weight relative to the total weight of
the Ingredients composition Ivermectin 1.00 Glycerol 4.0 Acrylate
C10-30 alkyl acrylate 0.15 crosspolymer Methyl para-hydroxybenzoate
0.2 Disodium EDTA 0.05 Citric acid monohydrate 0.05 Isopropyl
myristate 4.0 Cetyl alcohol 3.0 Stearyl alcohol 2.0
Self-emulsifiable wax 0.8 Palmitostearic acid 0.5 Steareth-20 2.0
Sorbitan palmitate 1.0 Dimethicone 20 0.5 Propyl
para-hydroxybenzoate 0.1 Propylene glycol 4.0 Glyceryl triacetate
1.0 Phenoxyethanol 0.5 10% sodium hydroxide qs pH Water qs 100
EXAMPLE 4
Composition 4
TABLE-US-00005 [0110] % by weight relative to the total weight of
the Ingredients composition Ivermectin 1.00 Glycerol 4.0 Aluminum
magnesium silicate 1.0 Methyl para-hydroxybenzoate 0.2 Disodium
EDTA 0.05 Citric acid monohydrate 0.05 Isopropyl palmitate 4.0
Glyceryl/PEG 100 stearate 3.0 Self-emulsifiable wax 2.0
Palmitostearic acid 3.0 Steareth-20 3.0 Sorbitan palmitate 2.0
Dimethicone 20 0.5 Propyl para-hydroxybenzoate 0.1 Propylene glycol
4.0 Glyceryl triacetate 1.0 Phenoxyethanol 0.5 10% sodium hydroxide
qs pH Water qs 100
EXAMPLE 5
Composition 5
[0111] The Compositions of Examples 5 and 6 are Formulated
According to the Following Procedure:
[0112] Aqueous Phase:
[0113] In a first beaker, disperse the acrylate/c10-30 alkyl
acrylate crosspolymer in water with Rayneri stirring at 800 rpm
until a homogeneous gel is obtained. Begin heating up to 65.degree.
C.-70.degree. C., and then add the glycerol and the additives.
[0114] Oily Phase:
[0115] In a second beaker, incorporate the constituents of the oily
phase and heat up to 70.degree. C.-75.degree. C., homogenize with
Rayneri stirring at 400 rpm.
[0116] Active Phase:
[0117] In a third beaker, weigh the constituents of the active
phase (solvent+additives).
[0118] Homogenize at approximately 500 rpm and introduce a magnetic
bar.
[0119] Weigh the ivermectin in a weighing boat and then introduce
it into the beaker container the active phase.
[0120] Place this beaker on a magnetic stirrer until the ivermectin
has dissolved.
[0121] When the oily and aqueous phases are at 70.degree. C., mix
the two phases with Rayneri stirring at 900 rpm for 10 min.
[0122] Allow the emulsion to cool to 40.degree. C., add the active
phase with Rayneri stirring at 800 rpm for 10 minutes. Decrease at
700 rpm to 30.degree. C.
[0123] Make up the volume with a sufficient quantity of water and
adjust the pH to 6.3+/-0.3.
TABLE-US-00006 % by weight relative to the total weight of the
Ingredients composition Ivermectin 1.00 Glycerol 4.0 Acrylate
C10-30 alkyl acrylate 0.2 crosspolymer Methyl para-hydroxybenzoate
0.2 Disodium EDTA 0.05 Citric acid monohydrate 0.05 Isopropyl
palmitate 4.0 Cetyl alcohol 3.5 Stearyl alcohol 2.5 Oleyl alcohol
2.0 Ceteareth-20 3.0 Sorbitan monostearate 2.0 Dimethicone 200 20
cs 0.5 Propyl para-hydroxybenzoate 0.1 Propylene glycol 2.0
Phenoxyethanol 1.0 10% sodium hydroxide qs pH Water qs 100
EXAMPLE 6
Composition 6
TABLE-US-00007 [0124] % by weight relative to the total weight of
the Ingredients composition Ivermectin 1.4 Glycerol 4.0 Acrylate
C10-30 alkyl acrylate 0.2 crosspolymer Methyl para-hydroxybenzoate
0.2 Disodium EDTA 0.05 Citric acid monohydrate 0.05 Isopropyl
palmitate 4.0 Cetyl alcohol 3.5 Stearyl alcohol 2.5 Oleyl alcohol
2.0 Ceteareth-20 3.0 Sorbitan monostearate 2.0 Dimethicone 200 20
cs 0.5 Propyl para-hydroxybenzoate 0.1 Propylene glycol 2.0
Phenoxyethanol 1.0 10% sodium hydroxide qs pH Water qs 100
EXAMPLE 7
Example of Stability of the Compositions Described in Examples 5
and 6
[0125] Assaying of the active agent by external calibration by
HPLC.
TABLE-US-00008 Composition % of ivermectin in the composition at
time t (in weeks) tested 0 4 8 12 Composition 5 100.2% 99.6% 100.7%
101.3% Composition 6 95.6% 97% 97.7% 95.8%
[0126] The results are expressed as % recovery relative to the
theoretical value, and demonstrate the very good chemical stability
of the ivermectin in the composition as a function of time.
EXAMPLE 8
Measurement of the Chemical Stability of Ivermectin as a Function
of pH in the Composition of Example 5
TABLE-US-00009 [0127] T0 T 1 month T 2 months % of % of % of pH
active agent pH active agent pH active agent 4.0 105.7 4.36 106.5
4.34 102.3 5.02 109.3 5.14 104.2 5.14 97.3 6.28 107.6 6.2 104.1
6.18 102.1
[0128] These results show the very good chemical stability of
ivermectin in the composition as a function of pH.
EXAMPLE 9
Study of Tolerance and of Acceptability of the Composition of
Example 5
[0129] A randomized single-blind intra-individual study was carried
out on 15 individuals with skin tending to be affected by rosacea.
The composition of Example 5 was tested in comparison with a gel
and with an emulsion having compositions different from the
compositions according to the invention.
[0130] The individuals presented themselves three times in order to
perform the various applications. In the course of each of the
visits, 2 of the three products were applied so as to cover each
half-face. Each product was tested twice during the study. After
application and at each visit, the individuals filled in, for each
product tested, a questionnaire for evaluating the clinical
tolerance and the cosmetic acceptability.
[0131] The following clinical tolerance parameters were evaluated:
stinging sensation, burning, dry skin, tightness or itching.
[0132] The following cosmetic acceptability parameters were
evaluated: creaminess, texture, lack of a sensation of greasy and
sticky skin, nourishing nature, feeling of comfort and of softness
to the touch.
[0133] For all the tolerance parameters, the composition according
to the invention was judged to be well tolerated by the
individuals, to the same extent as the two other compositions.
[0134] In general, for all the acceptability parameters, the
individuals gave their approval (good or excellent), with respect
to the parameters, regarding the composition of the Example 5 in
76.66% of the cases where it was tested. This formulation therefore
tends to distinguish itself from the gel-cream composition, having
a 66.66% approval, and from the other emulsion, having a 63.32%
approval.
EXAMPLE 10
Study of Irritation Over 21 Days
[0135] A study of irritation over 21 days was carried out in order
to test the irritation induced by the three compositions tested in
the preceding example. No product was considered to be irritant
under the conditions tested.
[0136] Each patent, patent application, publication and literature
article/report cited or indicated herein is hereby expressly
incorporated by reference.
[0137] While the invention has been described in terms of various
specific and preferred embodiments, the skilled artisan will
appreciate that various modifications, substitutions, omissions,
and changes may be made without departing from the spirit thereof.
Accordingly, it is intended that the scope of the present invention
be limited solely by the scope of the following claims, including
equivalents thereof.
* * * * *