U.S. patent application number 15/041200 was filed with the patent office on 2018-03-15 for composition using cross-linked hyaluronic acid for topical cosmetic and therapeutic applications.
The applicant listed for this patent is Luromed LLC. Invention is credited to Nancy E. Larsen, Adelya K. Leshchiner, Edward G. Parent.
Application Number | 20180071194 15/041200 |
Document ID | / |
Family ID | 42223008 |
Filed Date | 2018-03-15 |
United States Patent
Application |
20180071194 |
Kind Code |
A9 |
Leshchiner; Adelya K. ; et
al. |
March 15, 2018 |
COMPOSITION USING CROSS-LINKED HYALURONIC ACID FOR TOPICAL COSMETIC
AND THERAPEUTIC APPLICATIONS
Abstract
Disclosed are compositions comprising crosslinked hyaluronic
acid gels, preferably vinyl sulfone cross-linked hyaluronic acid
known as hylan B gel, for use in topical cosmetic and
dermatological formulations. The hylan B gel in these formulations
provides prolonged delivery of incorporated substances to the
surface of the skin, to provide a hydrated film on the surface of
the skin, and to provide a substantive and compatible film on the
skin.
Inventors: |
Leshchiner; Adelya K.;
(Cresskill, NJ) ; Larsen; Nancy E.; (Highland
Mills, NY) ; Parent; Edward G.; (North Bergen,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Luromed LLC |
Orangeburg |
NY |
US |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20160213592 A1 |
July 28, 2016 |
|
|
Family ID: |
42223008 |
Appl. No.: |
15/041200 |
Filed: |
February 11, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14604061 |
Jan 23, 2015 |
9345778 |
|
|
15041200 |
|
|
|
|
14217869 |
Mar 18, 2014 |
8940281 |
|
|
14604061 |
|
|
|
|
12315087 |
Nov 28, 2008 |
8679470 |
|
|
14217869 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/37 20130101; A61K
8/4973 20130101; A61K 45/06 20130101; A61K 31/573 20130101; A61K
2800/28 20130101; A61K 31/79 20130101; A61K 31/00 20130101; A61K
2800/524 20130101; A61K 8/42 20130101; A61K 9/0046 20130101; A61K
8/60 20130101; A61K 47/36 20130101; A61K 9/06 20130101; A61K
2800/592 20130101; A61Q 17/04 20130101; A61K 8/676 20130101; A61K
31/165 20130101; A61K 31/4015 20130101; A61K 38/12 20130101; A61K
8/36 20130101; A61K 8/735 20130101; A61K 2800/10 20130101; A61K
2800/74 20130101; A61K 9/0014 20130101; A61K 33/18 20130101; A61Q
19/00 20130101; A61K 8/042 20130101; A61K 8/345 20130101; A61K
31/4015 20130101; A61K 2300/00 20130101; A61K 31/573 20130101; A61K
2300/00 20130101; A61K 33/18 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 8/73 20060101
A61K008/73; A61K 9/00 20060101 A61K009/00; A61K 47/36 20060101
A61K047/36; A61K 8/04 20060101 A61K008/04; A61K 9/06 20060101
A61K009/06; A61K 8/34 20060101 A61K008/34; A61K 8/60 20060101
A61K008/60; A61K 8/49 20060101 A61K008/49; A61K 8/36 20060101
A61K008/36; A61K 8/97 20060101 A61K008/97; A61K 8/37 20060101
A61K008/37; A61Q 19/00 20060101 A61Q019/00; A61Q 17/04 20060101
A61Q017/04; A61K 8/42 20060101 A61K008/42; A61K 38/12 20060101
A61K038/12; A61K 31/573 20060101 A61K031/573; A61K 31/79 20060101
A61K031/79 |
Claims
1. A topical composition comprising: a polysaccharide gel matrix;
and a substance, alone, or in combination with, an effective amount
of a therapeutic agent deliverable to a skin surface, wherein the
therapeutic agent is a salt, a solvate, a prodrug, or a derivative
of the therapeutic agent, and wherein the substance, alone or in
combination, is entrapped within the matrix.
2. A composition according to claim 1, wherein the polysaccharide
is a cross-linked polymer of hyaluronic acid, a salt or a
derivative of the polymer.
3. A composition according to claim 2, wherein the polymer is in an
equilibrium form and is hylan B.
4. A topical composition according to claim 2, wherein the polymer
is in a non-equilibrium form and is hylan B.
5. A composition according to claim 1, wherein the substance is a
hydrophilic organic ingredient.
6. A composition according to claim 5, wherein the hydrophilic
organic ingredient is an .alpha.-, .beta.-, .gamma.- or
.delta.-hydroxy acid, an .alpha.-amino acid, a .beta.-amino acid, a
.gamma.-amino acid, a .delta.-amino acid, a glycerin, a vitamin, a
vitamin derivative, a sugar, an essential oil, a water-soluble oil,
a fragrance, a natural polymer, a synthetic polymer, a cross-linked
natural polymer, a cross linked synthetic polymer, a peptide, a
protein, a polysaccharide or a nucleic acid.
7. A composition according to claim 6 wherein the hydrophilic
organic ingredient is an .alpha.-hydroxy acid, namely, lactic
acid.
8. A composition according to claim 1, wherein the substance is a
hydrophobic organic ingredient.
9. A composition according to claim 8, wherein the hydrophobic
organic ingredient is a petrolatum, a fatty acid, a fatty alcohol,
an oil, a lipid or a silicone.
10. A composition according to claim 1, wherein the substance is an
inorganic ingredient.
11. A composition according to claim 10, wherein the inorganic
ingredient is titanium dioxide, silica, calcium chloride, kaolin,
talc or tantalum.
12. A composition according to claim 1, wherein the therapeutic
agent is an anti-inflammatory agent, an antiseptic agent, an
anti-infective agent, a mucous membrane agent, a cleansing agent, a
preservative, an astringent, an antihistamine, an analgesic, an
anesthetic, an acne medication, an antifungal agent, an
anti-pruritic agent, a hormone, a growth factor, a moisturizing
agent, a sunscreen, a hyperpigmentation agent, an antioxidant or a
nutritional agent.
13. A composition according to claim 12, wherein the nutritional
agent is a vitamin.
14. A composition according to claim 12, wherein the sunscreen is
Parsol MCX.
15. A composition according to claim 12, wherein the therapeutic
agent is an anti-inflammatory agent in combination with an
anti-infective agent.
16. A composition according to claim 15, wherein the
anti-inflammatory agent is a steroid agent.
17. A composition according to claim 16, wherein the steroid agent
is hydrocortisone, hydrocortisone acetate or prednisone.
18. A composition according to claim 15, wherein the anti-infective
agent is an antibiotic.
19. A composition according to claim 18, wherein the antibiotic is
bacitracin.
20. A composition according to claim 12, wherein the antiseptic
agent, is povidone iodine.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to compositions containing
cross-linked hyaluronic acid (HA) gels including, but not limited
to, hylan B gel, for use in topical cosmetic and dermatological
applications.
[0003] 2. Description of Related Art
[0004] Topical skin care product compositions often contain a
variety of natural and/or synthetic polymeric substances, for the
purpose of delivering active ingredients to the surface of the skin
and/or providing moisturization of the skin. For example, U.S. Pat.
No. 5,911,980 describes the use of lipophilic and amphiphilic or
hydrophilic film-forming polymer compositions as a topical agent
for the delivery of agents to the skin.
[0005] U.S. Pat. No. 6,824,785 discloses multi-compartment or
multi-layered structures that may be loaded with an active
ingredient for dermal delivery. Lipids, typically in the form of
liposomes are used to provide an epidermal barrier when applied
topically to the skin, which reduces trans-epidermal water
loss.
[0006] U.S. Pat. No. 6,719,740 describes a delivery system,
comprised of a top layer and a bottom layer attached to each other,
with a pouch that contains the skin care ingredient between the two
layers.
[0007] U.S. Pat. No. 6,746,689 describes method for administering
an active ingredient where a local anesthetic is combined with an
intradermal penetration agent.
[0008] U.S. Pat. No. 6,316,011 describes a reverse thermally
viscosifying composition including a linear block copolymer,
wherein at least one block comprises a polyoxamer having a
hydrophobic region and a hydrophilic region effective to form
micelles in response to a change in temperature, and at least one
block comprises a bioadhesive polymer or oligomer in an aqueous
medium for the administration of a pharmaceutical agent to the
skin.
[0009] U.S. Pat. No. 6,495,149 describes the use of a liquid
carrier for delivery of an active comprised of cyclomethicone
liquid for topical, leave-on compositions.
[0010] U.S. Pat. No. 6,235,312 describes the use of liquid
crystalline phase drug delivery systems for topical delivery to the
skin, wherein the liquid crystalline phase is comprised of a mono
glyceride.
[0011] Several patents disclose compositions containing
cross-linked hyaluronic acid gels for use in topical formulations.
For example, U.S. Pat. No. 4,582,865 describes cross-linked gels of
hyaluronic acid or mixed cross-linked gels of hyaluronic acid,
wherein the gels further comprise at least one other hydrophilic
polymer having a functional group capable of reacting with divinyl
sulfone and either an inert water insoluble substance or a low
molecular weight substance covalently bonded to the macromolecular
network, and methods of making these gels.
[0012] U.S. Pat. No. 4,605,691 describes methods of preparing a
cross-linked gel of hyaluronic acid comprising subjecting sodium
hyaluronate in a dilute aqueous alkaline solution at a pH of not
less than about 9 to a cross-linking reaction with divinyl sulfone
at about 20.degree. C. and a cross-linked gel of hyaluronic acid
produced by this method.
[0013] U.S. Pat. No. 4,636,524 describes a delivery system for a
substance having biological or pharmacological activity comprising
a molecular cage formed of a cross-linked gel of hyaluronic acid or
a mixed cross-linked gel of hyaluronic acid and at least one other
hydrophilic polymer and containing a diffusible substance having
biological or pharmacological activity.
[0014] U.S. Pat. No. 5,143,724 describes biocompatible gel slurries
consisting of two phases: a particulate gel phase comprised of a
chemically cross-linked polymeric gel and a second, fluid phase
comprising a polymer solution of a water-soluble biocompatible
polymer in the aqueous medium, wherein the fluid phase has a pH in
the range of 5.0-8.0.
[0015] U.S. Pat. No. 5,246,6913 describes methods of making the
slurries of U.S. Pat. No. 5,143,724.
[0016] U.S. Pat. No. 5,399,351 describes methods of using these
slurries to control adhesion formation between tissues of a living
body resulting from surgical intervention.
[0017] European Patent 0224987 describes drug delivery systems
based on hyaluronic acid and its salts and derivatives thereof in
soluble or non-soluble cross-linked forms, which serve as a vehicle
for slow release of a drug from a system.
BRIEF SUMMARY OF THE INVENTION
[0018] The present invention, in one aspect thereof, provides
compositions comprising cross-linked hyaluronic acid (HA) gels
including, but not limited to, hylan B gel, for use in topical
cosmetic and dermatological applications. The hylan B gel acts as a
hydrated molecular cage as that term is described in U.S. Pat. No.
4,636,524, and into which one may incorporate and entrap
substances, including water, for delivery thereof to the surface of
the skin. Typically, the composition contains an active ingredient
at a concentration of 0-100%, preferably 0.1-50% and most
preferably, 10-20% by weight of the total composition.
[0019] In another aspect thereof, the invention provides a topical
composition comprising (a) a polysaccharide gel matrix, in
combination with (b) another substance, which may be (i) a
hydrophilic organic ingredient, such as an .alpha.-, .beta.-,
.gamma.- or .delta.-hydroxy acid, an .alpha.-amino acid, a
.beta.-amino acid, a .gamma.-amino acid, a .delta.-amino acid, a
glycerin, a vitamin or their derivatives, a sugar, an essential
oil, a water-soluble oil, a fragrance, a natural polymer, a
synthetic polymer, a cross-linked natural polymer, a cross-linked
synthetic polymer, a peptide, a protein, a polysaccharide or a
nucleic acid; wherein the concentration of the hydrophilic organic
ingredient may be from 0-100%, preferably, 0.1-10% and most
preferably, from 1-5% by weight based on the entire composition
(ii) a hydrophobic organic ingredient, such as a petrolatum, a
fatty acid, a fatty alcohol, an oil, a lipid or a silicone; wherein
the concentration of the hydrophobic organic ingredient may be from
0-100%, preferably 0.1-50% by weight based on the weight of the
entire composition; (iii) an inorganic ingredient such as titanium
dioxide, silica, calcium chloride, kaolin, talc or tantalum, alone,
wherein the concentration of the inorganic ingredient may be from
0-100%, preferably 0.1-4% by weight based on the weight of the
entire composition, said inorganic ingredient being present alone,
or in combination with, an effective amount of a therapeutic agent
deliverable to a skin surface, wherein the therapeutic agent is a
salt, a solvate, a prodrug, and a derivative of the therapeutic
agent, and wherein the substance, alone or in combination, is
entrapped within the matrix. In this embodiment, the therapeutic
agent is an anti-inflammatory agent such as a steroid, for example,
hydrocortisone, hydrocortisone acetate or prednisone, an antiseptic
agent, such as iodine, an anti-infective agent, i.e., an antibiotic
such as bacitracin, a mucous membrane agent, a cleansing agent, a
preservative, an astringent, an antihistamine, an analgesic, an
anesthetic, an acne medication, an antifungal agent, an
anti-pruritic agent, a hormone, a growth factor, a moisturizing
agent, a sunscreen such as Parsol MCX, a hyperpigmentation agent,
an antioxidant or a nutritional agent which is a vitamin or a
mineral. The amount of the therapeutic agent present in the
composition may be anywhere from 0% up to the specific recommended
dosage for each such specific therapeutic agent. For example, in
the case of an antibiotic such as bacitracin, the specific dosage
will typically be about 500 units per gram of the composition in
the form of an ointment. In the case of a steroid, such as
hydrocortisone, the specified dosage will typically be about
0.25-1% by weight, and in the case of a therapeutic agent such as
capsaicin, the specified dosage will typically be in the amount of
about 0.25% by weight of the entire composition.
[0020] In another embodiment, the therapeutic agent of the
composition is a mixture of the anti-inflammatory agent and the
anti-infective agent.
[0021] In another embodiment, the invention provides a composition
wherein the polysaccharide of the composition is a cross-linked
polymer of hyaluronic acid, a salt of the polymer or a derivative
of the polymer.
[0022] In yet another embodiment of the invention, the polymer is
in an equilibrium or non-equilibrium form and is hylan B, where the
hylan B concentration is from about 0.4-20% by weight.
BRIEF DESCRIPTION OF THE FIGURE
[0023] FIG. 1 illustrates higher levels of sunscreen on the surface
of skin in the presence of HY. 0.1 gm samples of each sunscreen
composition were weighed out onto weigh paper squares, and then
each applied to designated, marked areas on the washed forearm of
human volunteers. After 2 hours each area was swabbed with a cotton
tip applicator, then the site was stripped 8 times using
Cuderm.RTM. stripping disks. Each disk was placed into a test tube
containing 3 ml of isopropanol, 2 disks were placed per tube, to
elute the Parsol sunscreen from the skin on the disk. The
absorbance of the isopropanol in each tube was measured at .lamda.,
max 311 nm). The data in the graph indicate that higher levels of
sunscreen are present on the uppermost layers of the skin, and that
there is more sunscreen on the surface of the skin in the sample
containing Hylasome (far left side of graph). Deeper layers of the
skin contain less sunscreen, but show a trend toward more sunscreen
being absorbed into the skin from the control (non-Hylasome)
samples. Surface Retention of sunscreen at 2 hours is shown for
four surfaces.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The compositions of the present invention, which contain
crosslinked hyaluronic acid (HA) gels including, but not limited
to, hylan B gel, are compositions for use in topical cosmetic and
dermatological applications and in which hylan B gel is used as a
hydrated molecular cage into which one may incorporate, entrap and
deliver substances, including water, to the surface of the skin.
The hylan B gel may be either in equilibrium or non-equilibrium
form. In the non-equilibrium form, the gel is not fully swollen,
while in the equilibrium form, the gel is swollen fully and cannot
swell further. Hylan B gel matrix is derived from hyaluronic acid,
otherwise known as hyaluronan or HA, and is a vinyl sulfone
cross-linked derivative of hyaluronic acid. The hylan B gel matrix
has an unusually high capacity to bind water, and in particular, to
a greater degree than other natural and synthetic polymers
[Takigami et al., Carbohydrate Polymers 26N: 11-18 (1995)]. Water,
which is a slightly bound portion of the gel matrix and which forms
reservoirs in which ingredients can be incorporated or trapped, is
effectively delivered to the skin because of its bound state.
[0025] The ingredients which are incorporated into, or entrapped,
within the hylan B gel matrix (equilibrated or non-equilibrated)
include, but are not limited to, some classes of organic compounds,
inorganic compounds, and mixtures thereof.
[0026] Among the organic compounds included are hydrophilic organic
substances including, but not limited to an .alpha.-, .beta.-,
.gamma.- or .delta.-hydroxy acid, .alpha.-, .beta.-, .gamma.-, and
.delta.-amino acids, glycerin, vitamins and their derivatives,
sugars, essential oils, water soluble oils and fragrances, low
molecular weight and high molecular weight substances including
natural and synthetic polymers, cross-linked natural and synthetic
polymers, peptides, proteins, water soluble hydrophilic proteins,
such as albumins, polysaccharides, nucleic acids, and mixtures
thereof. The organic compounds also include, but are not limited
to, hydrophobic organic substances, including, but not limited to,
petrolatum, fatty acids, fatty alcohols, oils, lipids, silicones,
and mixtures thereof. Among the inorganic compounds and substances
included are substances such as, but not limited to, titanium
dioxide, silica, calcium chloride, kaolin, talc, tantalum and
mixtures thereof.
[0027] Ingredients included in these chemical-categories include
active ingredients, drugs, prodrugs and nondrugs. They include, but
are not limited to, the pharmaceutical categories of
anti-inflammatory agents, antiseptics, anti-infectives, mucous
membrane agents, cleansing agents, preservatives, astringents,
antihistamines, analgesics, capsaicin, acne medications,
antifungals, antipruritics, hormones, growth factors, moisturizers,
sunscreens, hyperpigmentation agents, antioxidants, nutritional
substances, including, but not limited to, vitamins and minerals,
substances of botanical, marine and animal origin, homeopathic
substances and mixtures thereof. As should be clear from the
foregoing description, very many different types of materials can
be and are capable of being incorporated into the hylan B gel for
the purpose of delivering them to the skin of a host, typically, a
human, but not necessarily a human.
[0028] An advantage of this invention is the ability to provide
prolonged and effective delivery of incorporated ingredients to the
surface of the skin and, where applicable to provide increased
protection from the irritant effects of some active ingredients,
for example, from the burning sensations produced by some active
ingredients, e.g., capsaicin. Additionally, one can provide a
hydrated film on the surface of the skin in which certain
ingredients have been incorporated, and which contains water in the
form of slightly bound water, and as well, to provide a substantive
and compatible film on the surface of the skin.
[0029] Hyaluronan or hyaluronic acid (HA) is a naturally occurring
polysaccharide that consists of alternating N-acetyl-D-glucosamine
and D-glucuronic acid monosaccharide units linked with alternating
[beta]1-3 glucoronidic (?) and [beta]1-4 glucosaminidic (?) bonds.
The molecular weight of hyaluronic acid is generally within the
range of 5.times.10.sup.4 up to more than 8.times.10.sup.6 Daltons.
Cross-linked HA gels include, but are not limited to, hylan B gel
matrix, which is a vinyl sulfone cross-linked derivative of
hyaluronic acid. Cross linked simple and mixed gels based on
hyaluronan, products containing such gels, and methods to prepare
same are described in U.S. Pat. Nos. 4,582,865, 4,605,691 and
4,636,524, which are noted above in the Description of Related Art,
and the contents of which are incorporated by reference herein. It
should also be clearly understood that hyaluronan of any origin may
be successfully used for the purposes of this invention.
[0030] The compositions or--the present invention may be
administered in dosage unit formulations containing conventional
nontoxic pharmaceutically acceptable carriers, adjuvants, and
vehicles as desired. Topical administration also may involve the
use of transdermal administration such as transdermal patches or
iontophoresis devices which are prepared according to techniques
and procedures well known in the art.
[0031] The amount of the compositions of the present invention
which will be effective in the treatment of a particular disorder
or condition will depend on the nature of the disorder or
condition, and can be determined by standard clinical techniques.
See, for example, Goodman and Gilman; The Physician's Desk
Reference, Medical Economics Company, Inc., Oradell, N.J., 1995;
and Drug Facts and Comparisons, Facts and, Comparisons, Inc., St.
Louis, Mo., 1993. The precise dose to be employed in any particular
formulation will also depend on the seriousness of the disease or
disorder, and should be decided upon and determined according to
the judgment of the practitioner and each patient's specific
circumstances.
[0032] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art to which this invention pertains.
Although any methods and materials similar or equivalent to those
described herein can also be used in the practice or testing of the
present invention, the preferred methods and materials will now be
described. All publications mentioned herein. are incorporated
herein by reference to disclose and describe the methods and/or
materials in connection with which the publications are cited.
Unless indicated otherwise, parts are parts by weight, molecular
weight is weight average molecular weight, temperature is in
degrees Centigrade, and pressure is at or near atmospheric.
[0033] The term "effective amount" is used herein to denote that
amount of an agent that will elicit the response of a mammal,
including a human, that is being sought for the purpose of
effecting a desired therapeutic effect. The term "therapeutically
effective amount" is used herein to denote that amount of a drug or
pharmaceutical agent or a pharmaceutically acceptable salt, solvate
or prodrug thereof, that will elicit the therapeutic response of an
animal or human that is being sought.
[0034] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower
limit, unless the context clearly dictates otherwise, between the
upper and lower limit of that range and any other stated or
intervening value in that stated range is encompassed within the
invention. The upper and lower limits of these smaller ranges which
may independently be included in the smaller ranges is also
encompassed within the invention, subject to any specifically
excluded limit in the stated range. Where the stated range includes
one or both of the limits, ranges excluding either both of those
included limits are also included in the invention.
[0035] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed.
[0036] The invention has been described with reference to the
preferred embodiments to illustrate the principles of the invention
and not to limit the invention to the particular embodiments
illustrated. Modifications and alterations may occur to others upon
reading and understanding the preceding detailed description. It is
intended that the scope of the invention be construed as including
all modifications and alterations that may occur to others upon
reading and understanding the preceding detailed description
insofar as they come within the scope of the following claims or
equivalents thereof.
[0037] The invention is described in more detail and with respect
to only some, but not all embodiments thereof in the following
examples, which are not intended to limit the scope of the
claims.
[0038] As will be evident from the following examples, the
properties of the topical compositions of the present invention are
superior to those described in the prior art mentioned above. The
present compositions all form a permeable, hydrated film on the
surface of the skin, require no environmental stimulus, such as
temperature change, to deliver, since delivery of the active occurs
upon application of the compositions to the skin, and they suffer
from little or no temperature sensitivity, and therefore experience
no marked changes in the physical state of the composition upon
exposure to high and low ambient temperatures.
Example 1
[0039] This example illustrates the preparation of nonequilibrium
gel of hyaluronic acid (Hylasome a sodium hyaluronate
cross-polymer) with a polymer concentration of approximately 1%. 30
gm of sodium hyaluronate (HA) of bacterial origin were dissolved in
853 gm of distilled water. To this solution 100 gm of 1N NaOH were
added to achieve a final concentration of 0.1N alkali. The mixture
was stirred carefully until uniform. To this solution a mixture of
7 gm (6 ml) of divinyl sulfone (DVS) in 10 gm of water was added
and stirred until a strong gel was formed with an HA concentration
of approximately 3%; typically 15-20 minutes for completion of the
cross-linking reaction. The resultant gel (approximately 1 kg) was
placed into dialysis tubing (32 mm diameter, 12000-14000 molecular
weight cut-off, Spectrum) so that the gel occupied approximately
one-third of the length of the dialysis tubing. The end of the
dialysis tubing was sealed and the gel manually distributed
throughout the length of the tubing in order to facilitate uniform
swelling. The sealed tubing containing gel was placed into a clean
container with five liters of purified water; the water was changed
twice daily until the pH of the gel inside the tubing was neutral
(pH 6-7). The neutral, washed gel was expelled from the dialysis
tubing. The gel was carefully mixed with a preservative (15 gm of
phenonip dispersed in about 100 gm of water, to a final phenonip
concentration of 0.5%) until uniform. The concentration of HA in
the nonequilibrium gel was approximately 1% (10 mg/ml). The
designation "%" refers to the concentration of HA in the gel,
calculated based on the amount of dry HA polymer present in the
gel.
Example 2
Hylasome (HA 0.1%)
[0040] This example illustrates the preparation of a swollen HA gel
with a polymer concentration of 0.1%. To prepare 1 kg of this gel
Hylasome (HA 1%) in an amount of 100 gm was used. The Hylasome (HA
1%) was prepared according to Example 1. To 896 gm of RO (reverse
osmosis) water-were added 4 gm of phenonip-preservative and the
mixture was stirred until a uniform fine dispersion formed and then
added to 100 gm of Hylasome (HA 1%). The resultant swollen gel was
then disintegrated using a high shear mixer (Silverson) using a low
shear mixer blade, at a speed of 4000 rpm, for 4 minutes per 1 kg
volume. The homogenized gel had a swelling ratio of 1,000. This
material was used in some cosmetic and dermatological formulations
as a highly effective hydrating component which slowly delivers
water. Hylasome (HA 0.1%) is a partially equilibrated gel and can
be further swollen with additional water and/or other active
ingredients.
Example 3
Hylasome (HA 0.05%)
[0041] This example illustrates the preparation of 1 kg of fully
swollen equilibrated gel with an HA concentration of 0.05%. This
equilibrated gel can be made either from Hylasome (HA 1%) by adding
50 gm of this gel to 896 gm of RO water and 4 gm of phenonip
preservative or by adding 500 gm of Hylasome (HA 0.1%) to 500 gm of
RO water and 2.23 gm of phenonip. The subsequent procedures are the
same as described in Example 2. Hylasome (HA 1%) was prepared
according to Example 1, and Hylasome (HA 0.1%) was prepared
according to Example 2. The resultant Hylasome (HA 0.05%) has a
swelling ratio of 2,000.
Example 4
[0042] This example illustrates the preparation of a formulation
containing Hylasome swollen with a solution of the sugars, glucose
and mannitol.
Step 1: Preparation of the Active Ingredient--Hylasome Swollen with
a Solution of Glucose and Mannitol.
[0043] To prepare 100 gm of this composition, to 62.6 gm of water
was added 0.4 gm of phenonip and mixed until a uniform dispersion
formed. To this mixture were added 10.0 gm of D-mannitol and 13.5
gm of glucose. This mixture was stirred until the sugars dissolved.
Upon dissolution 13.5 gm of Hylasome (HA 1%) were added and the
mixture stirred until the slurry was uniform. The Hylasome gel
slurry was then homogenized according to the procedure described in
Example 1. The concentration of sugars in the gel was 23.5%. The
polymer concentration was 0.135%.
TABLE-US-00001 % Parts Ingredients (g/100 gm) 1A 1 Carbopol 940
0.36 2 water 53.67 3 EDTA 0.14 4 Germaben II 0.75 1B 1 Cucumber
extract 0.24 2 Aloe vera gel 0.16 3 Chamomile extract 0.24 4 Glucam
E-20 3.15 5 Apricot extract 0.24 6 Carrot extract 0.24 7 Tea
extract 1.3 8 Eye bright extract 0.24 9 TEA (triethanolamine) 0.7
1C 1 Cellosize Polymer PCG019, 2% with 5% 4.72 alcohol 2 HA 1% 1.58
3 Polyox Coag 1% 0.24 4 Hydrosoy 2000 0.48 1D Rose Natural, water
soluble 0.16 1E Dye - Orange/Red 2:1, 0.1% 0.12 Part 2 1 Mannitol
2.97 Hylasome 2 Gluose 4.00 sugars 3 water 18.58 4 Hylasome 4.00 5
Phenonip 0.12 TOTAL 29.67 Part 3 1 HA 1% 0.32 2 Hydrosoy 2000 0.16
3 DxS 0.004 4 Water 1.09 5 TEA (triethanolamine) 0.0006 6 phenonip
0.16 TOTAL 1.73
Step 2: Preparation of a Dermatological Formulation Containing
Hylasome Swollen with a Solution of 23.5% Sugars.
[0044] This formulation was prepared as follows: Carbopol was
dispersed in water and the mixture was stirred until a uniform
dispersion formed. The preservatives EDTA and Germaben II were then
added. The ingredients in Parts B and C were blended. Parts A and B
were heated to 45-50.degree. C. while mixing separately, then
combined together, stirred well and cooled to 40'C. The components
of Part C were blended and then heated to 40.degree. C. and added
to the combined Parts A and B, mixed carefully until uniform and
then cooled to room temperature (20-25.degree. C.). Part D was
added and mixed, and then Part E was added and mixed by careful
stirring. This mixture constitutes Part 1. To Part 1 was added the
Hylasome/sugars slurry and after mixing, Part 3 was added. Part 3
was prepared by blending the listed ingredients. The pH of the
composition was neutral (6-7). The sugar content was approximately
7%. This dermatological composition is used as a remedy for
puffiness and minor swelling.
Example 5
[0045] Preparation of a face mask using Hylasome swollen with 47%
lactic acid as active ingredient (INCI [International Nomenclature
Cosmetic Ingredient] name sodium hyaluronate cross-polymer and
lactic acid).
Step 1: Preparation of Hylasome Swollen with 47% Lactic Acid.
[0046] All ingredients in the following table except Hylasome were
mixed. When mixing was complete, Hylasome was added and mixed until
swollen. The mixture was homogenized until it became liquidy and
uniform.
TABLE-US-00002 INGREDIENT %, gm/100 gm D-mannitol 2 Tris-amino 10
Glycerol 2.6 Lactic acid 47 Phenonip 0.4 RO water 18 Hylasome (HA
1%) 20
Step 2: Preparation of the Basic Formulation, Containing the Active
Ingredient Hylasome Swollen with Lactic Acid.
[0047] This formulation was prepared in several stages, as follows:
Part A1 was prepared by dissolving pluronics (?) in water; Part A2
was made by dispersing Carbopol 940 in water and then adding the
preservatives EDTA and Germaben II. Then Parts A1 and A2 were
combined. The ingredients in Part B and C were blended; Parts A1,
A2, and B were then heated to 70-75.degree. C. while mixing
separately, then they were combined and mixing was continued at
70-75.degree. C. until uniform, followed by cooling to 45.degree.
C. Parts C and F were mixed, then combined and heated to 45.degree.
C., and added to Parts A1+A2+B. This blend was cooled to room
temperature, ca. 25.degree. C. The pH of this mixture was neutral
(6-7) adjusted by TEA (Part D). To this basic formulation was added
the active ingredient Hylasome swollen with 47% lactic acid (Part
E). The pH of the formulation was approximately 3.5.
TABLE-US-00003 Part Ingredients % (g/100 g) A.sub.1 1 Water 35.57 2
Pluronic 87 1.90 3 Pluronic 127 0.95 A.sub.2 1 Water 36.02 2 EDTA
0.14 3 Germaben II 0.50 4 Carbopol 0.48 B 1 TEA (triethanolamine)
0.19 2 Tween 20 0.95 3 Polydimethylsiloxane (fluid 200) 0.95 4
Phosal 50 PG 0.90 5 Beeswax 0.95 6 Robane (squalene) 1.43 7
Lanoxide -59 0.95 8 Coconut oil 0.48 9 Cetyl alcohol 1.90 10
Propylene glycol 1.90 11 Glycerol monostearate 0.95 12 Glucam E-20
1.90 13 Germaben II 0.50 14 Chamomile extract 0.19 15 Lemon
Bioflavonoids extract 0.48 16 Calendula extract 0.19 17 Apricot
fruit extract 0.10 18 Peppermint extract 0.05 C 1 HA 1% 0.95 2
Cellosize 2% (polymer PCG-10) 1.45 3 Jasmine/Rosewood Natural,
water 0.24 soluble 4 Lavender Natural, water soluble 0.24 5 Lemon
natural, water soluble 0.10 D TEA (triethanolamine) 0.6 E Hylasome
with 47% lactic acid (Step 2) 5.0 F 1 HA 1% 0.19 2 Hydrosay 2000
0.095 3 DxS 0.0024 4 Water 0.60 5 TEA 0.0033 6 Phenonip 0.0095
Step 3: Preparation of Face Mask
[0048] To the basic formulation containing the active component
Hylasome-lactic acid were added 5 gm of ascorbic acid dispersed in
5 gm of Tween 20, and 5 gm of water. To prepare 100 gm of the face
mask, 83.3 gm of this composition and 63 gm of titanium dioxide
(TiO.sub.2) which had been mixed with 10.4 gm of Tween 20 were
mixed. The pH of the face mask was approximately 3.0
Example 6
[0049] This example illustrates the preparation of an exfoliating
cream with the active ingredient Hylasome swollen with 34% glycolic
acid.
Step 1: Preparation of the active ingredient (Hylasome-34% glycolic
acid).
[0050] To prepare one (1) kg of this material, 20 gm of mannitol,
26 gm of glycerol, 100 gm of tris-amino (buffer) and 340 gm of
glycolic acid were added to 310 ml of RO water (reverse osmosis).
These components were stirred together, then 4.0 gm phenonip
(preservative) were added to this mixture. To the resulting
mixture, 200 gm of Hylasome (HA 1%) were added and the mixture
stirred until fully swollen. The equilibrated gel contained HA 0.2%
and 34% glycolic acid, with a pH of approximately 3.0
[0051] Step 2: Preparation of exfoliating cream. 100 gm of
exfoliating cream were made by adding 6 gm of the active ingredient
complex (Hylasome-34% glycolic acid) to 94 gm of the basic
formulation prepared according to Example 5 (Step 2).
Example 7
[0052] This example illustrates the preparation of compositions
containing Hylasome swollen with ascorbic acid (AA).
Step 1: Preparation of Compositions
TABLE-US-00004 [0053] Composition #1 Composition Components (%,
g/100 g) #2 (%, g/100 g) Ascorbic Acid 9.4 9.4 Propylene glycol
58.0 55.3 glycerol 4.6 4.6 Ethyl alcohol 4.6 4.6 Lemon
bioflavinoids 0.46 0.46 mannitol -- 2.7 Carbopol 940 0.47 0.47 EDTA
0.10 0.10 Phenonip 0.50 0.50 TEA 1.3 1.3 Hylasome (HA 1%) 10.2 10.2
Water (RO) 10.2 10.2 Natural lemon oil, water 0.17 0.17 soluble
[0054] To prepare composition #1, water was added to Hylasome (HA
1%), in equal volumes, and the gel allowed to swell with gentle
mixing; the HA concentration in the diluted Hylasome gel was 0.5%.
To this gel was added dry powdered ascorbic acid, which dissolved
in the network of the hydrated HA gel. Heating was not used to
dissolve the AA in the gel. Propylene glycol, glycerol and ethyl
alcohol were added and the mixture stirred at room temperature for
approximately 1 hour. The Hylasome incorporated with the above
ingredients became clear in appearance. To this gel slurry was
added Carbopol 940, and after uniform dispersement, the
preservatives EDTA and phenonip were added, as well as natural
lemon oil (water soluble) and TEA. The gel slurry remained
transparent. Composition #2 was prepared following the same
procedure, with the exception that mannitol was added to the gel
slurry before Carbopol 940 had been dispersed. Composition #2 was
cloudy due to the presence of mannitol, which did not fully
dissolve in the gel slurry. Mannitol was included in the
composition in order to increase the stability of the gel slurry.
The pH of both compositions was approximately 4.0.
Step #2: Stability Study of AA in the Gel Slurry (Compositions #1
and #2)
TABLE-US-00005 [0055] Concentration of AA (%) g/100 g Reduction of
AA, % Composition Composition Composition Composition Time #1 #2 #1
#2 0 9.5 9.3 -- -- 1 month 9.6 (no 9.4 (no 0 0 change) change) 12
months 8.6 8.5 10 9
[0056] The stability study was carried out at room temperature
(20.degree.-25.degree. C.) and cold temperature
(4.degree.-7.degree. C.). Samples were placed into 20 cc
transparent glass containers with screw caps. The product occupied
two-thirds of the volume of the container. The rest (head-space)
was air. Samples which were stored at room temperature were placed
under artificial light, and the stability was evaluated by
measuring the concentration of AA using a spectrophotometric
method, using a Perkin Elmer spectrometer, Model PE Lamda 2.
Absorbance values were read at ?max243 (nm). All samples were
diluted 10.sup.4 times using HCl to achieve a pH of approximately
2.0. Each data point in the table represents the average of a
minimum of three values from samples of each composition.
Absorbance reading were measured two times. Samples which were
stored at cold temperatures produced absorbance values which were
very close to those from the samples stored at room temperature.
Color change was also monitored visually, and were consistent with
absorbance values. After 12 months of storage the color of the
samples were yellow-amber, this color remained stable for over 20
months.
Composition #3
TABLE-US-00006 [0057] Ingredients % (gm/100 gm) Ascorbic Acid 10
Glycerol 43 Mannitol 5 Hylasome 22 Propylene Glycol 20
[0058] Reduction of AA concentration at different pH after 3 and 6
months of storage (including daylight). The pH was adjusted using
TEA.
TABLE-US-00007 Adjusted AA conc, AA Reduction of AA Compo- Original
% concentration, % concentration, % sition AA conc, Original After
After After After Comp. #3 % pH 3 mo 6 mo 3 mo 6 mo 10.1 2.51 9.85
9.51 2.48 5.84 pH 3.0 9.67 9.48 9.25 1.94 4.34 pH 4.0 8.33 8.16
7.92 2.04 4.92 pH 5.0 6.43 6.3 6.18 2.02 3.89
[0059] The data presented in the preceding table shows that there
is no correlation between AA stability and pH in compositions in
which AA is stabilized by different polyhydroxy compounds.
Example 8
[0060] This example illustrates the preparation of a dermatological
composition using Hylasome swollen with 50% trichloroacetic acid
(TCA) as the active ingredient. To prepare 100 gm of a
dermatological peeling composition, 50 gm of TCA were added to 25
gm of water, 2.4 gm of glucose and 2.6 gm of glycerol and the
mixture was stirred. To the mixture were added 20 gm of Hylasome
(HA 1%) and it was stirred until fully swollen. The pH of the
peeling composition was approximately 1.8-2.0.
Example 9
[0061] This example illustrates the preparation of the active
ingredient Hylasome swollen with a solution in water or saline of
low molecular weight HA. To prepare 100 gm of Hylasome-HA gel, 99
gm of 0.1% HA (50,000 MW) were added to 1 gm of Hylasome (HA
concentration 1%). Mixing was continued until fully swollen. The
total HA content was 0.11% and the swelling ratio was 909. This
composition can be used to control the release of low molecular
weight HA.
Example 10
[0062] This example illustrates the preparation of a composition
with the active ingredient Hylasome swollen with high molecular
weight HA. To prepare 100 gm of this composition 25 gm of water
were added to 25 gm of Hylasome (HA 1%) and mixed until a uniform
swollen gel was obtained with a HA concentration of 0.5%. To this
gel 50 gm of 0.5% HA solution in water (MW 500,000-6,000,000) were
added and mixed until fully swollen. To 90 gm of equilibrated gel
10 gm of Centella Asiatica extract were added and stirred until
uniform. This composition is used to treat the skin following other
skin treatments such as skin peels and dermabrasion. The total HA
concentration was 0.75%, the swelling ratio was 133. This active
ingredient may be used as described as a final formulation, or as
an ingredient in a formulation to control the release of low
molecular weight actives into the skin.
Example 11
[0063] This example illustrates the preparation of a composition in
which Hylasome (HA 1%) is incorporated with a hydrophobic material
that is a sunscreen (Parsol MCX).
[0064] Hylasome (HA 1%) was prepared according to Example 1. To
Prepare 100 gm of the composition, 4.6 gm of lanoil AWS were added
to 4.6 gm of Vitamin E acetate (tocopheryl acetate) and 4.6 gm of
Tween 80, and mixed until dissolved. Upon dissolution 41.4 gm of
sunscreen Parsol MCX were added and the mixture stirred until a
uniform suspension formed. Then 18.4 gm of water were added and
mixed, and 18.4 gm of Hyalsome (HA 1%) were added, and mixed until
uniform. Then, 7.6 gm of noncrosslinked hyaluronic acid (HA) were
added and the mixture stirred. After mixing, 0.4 g of phenonip
preservative was added. The composition was homogenized according
to the procedure described in Example 2. The concentration of
sunscreen in this composition was 41.4%, the concentration of
Hylasome (HA 1%) was 18.4%, and the total HA concentration was
approximately 0.1% (1 mg/ml). To prepare 1 kg of the final
formulation with sunblock properties, 900 g of the basic
formulation which was prepared according to Example 2 were added to
100 gm of Hylasome-sunscreen (Parsol MCX) suspension and thoroughly
mixed until the consistency was that of a uniform cream. The final
formulation had an SPF of 19 (in vitro). The total concentration of
sunscreen was 5.04%, Hylasome (HA 1%) was 1.84% and the
concentration of HA was approximately 0.12% (1.2 mg/ml). The
Hyalsome-Parsol (MCX) composition was able to maintain the topical
sunscreen for longer periods of time, and hence the potential to
increase the duration of its effect (FIG. 1). There is also the
potential to reduce the absorption of sunscreen into the layers of
the skin. Sunscreen which has been absorbed into the skin is no
longer effective as a sunscreen, and also presents issues of safety
due to systemic absorption. The resulting cream was stable and had
good hydrating properties, as well as an excellent feel on the skin
and a pleasant smell due to the presence of natural oils and
botanical extracts.
Example 12
[0065] This example describes the preparation of a formulation with
the active ingredient capsaicin and Hylasome.
Step 1: Preparation of a Complex of Capsaicin with Hylasome (HA
0.125%).
[0066] Hylasome with an HA concentration of 0.125% was prepared
according to Example 2 with the exception that 1 part of Hylasome
gel was added to 7 parts of water, and phenonip was not added. The
resultant gel was loaded with capsaicin (Kalsec, 14% capsicum) at a
ratio of gel:capsaicin of 1.33 to 1. The gel was partially swollen
with capsaicin.
Step 2: Preparation of the Basic Formulation with Cooling
Effect.
[0067] This composition was prepared in separate stages as follows:
Part A of the mixture was prepared by dispersing Carbopol 940 in
water and then stirring until uniform dispersion forms.
TABLE-US-00008 Formula % Part Ingredients by weight 1 A 1 Carbopol
940 0.48 2 water 73.5 B 3 Cellosize polymer PCG-10 1% 7.68 4 Polyox
1% in water 0.34 5 HA 1% in water 0.98 6 Ketrol 1% in water 4.8 7
Phosal 50 0.44 C 1 Robane 0.14 2 Macadamia oil 0.48 3 Coconut oil
0.48 4 Olive oil 0.14 5 Cucumber extract 0.14 6 Chamomile extract
0.14 7 Calendula extract 0.48 8 Aloe Vera 0.14 9 Phenonip 0.75 10
Soy Protein 0.50 D 1 Menthol 5% in ethanol 0.96 E 1 Triethanolamine
0.48 F 1 Lemon Natural Water Soluble 1.44 2 Rose Natural water
soluble 1.44 3 Dye - FD&C BLUE #1/FD&C YELLOW 0.07 #6 9:1,
0.1% in water 2 1 Hylasome (HA 0.1%) 4.0
[0068] Parts B and C were prepared separately, and the three parts
(A, B and C) were heated separately to 50-55.degree. C. Then, Parts
A, B and C were combined and cooled to 30-35.degree. C. Then Parts
D, E, and F were added and mixed carefully until a uniform
gel-based cream formed. Part 2--Hylasome (HA 0.1%) was then
added.
Step 3: Preparation of the Final Formulation with Complex:
Hylasome-Capsaicin.
[0069] To prepare 100 gm of the final formulation, 5 gm of
TiO.sub.2 were added to 81.7 gm of the basic formulation (Step 2)
and stirred well. Then, 13.3 gm of the complex Hylasome (HA
0.125%)-capsaicin were added (Step 1).
[0070] Concentration of active ingredients: capsicum: 0.8%; HA:
total HA concentration was calculated based on dry polymer, 0.028%.
When applied to the skin a slight stinging sensation was observed;
this reaction was temporary and disappeared within minutes.
Example 13
[0071] This example illustrates the preparation of a formulation in
which Hylasome (HA 1%) was incorporated with drugs such as an
antibiotic (bacitracin), and a steroid (hydrocortisone or
hydrocortisone acetate).
Step 1: Preparation of a Composition in which Hylasome (HA 1%) is
Incorporated with Petrolatum.
[0072] To prepare 100 gm of this composition, first a mixture of 5
gm of vitamin E acetate with 5 gm of Lanoil AWS and 5 gm of Tween
20 was prepared. 45 gm of petrolatum were added to this composition
and mixed carefully. To this mixture were added 20 gm of water,
mixed until uniform suspension formed and then 20 gm of Hylasome
(HA 1%) were added.
Step 2: Preparation of Hylasome-Drug Composition.
[0073] To prepare 25 gm of this composition, 0.45 gm of bacitracin
and 1.25 gm of hydrocortisone (and/or hydrocortisone acetate) were
added to 23.3 gm of Hylasome-petrolatum and carefully mixed.
[0074] Step 3: Preparation of the final formulation with
Hylasome-Petrolatum-drugs.
[0075] To prepare 100 gm of the final formulation, a dermatological
cream, 80 gm of the formulation described in Example 2, Step 3,
were added to 20 gm of the composition described in Step 2 of this
example. The concentration of the antibiotic in this cream was
0.36%, the concentration of the cortisone was 1%. The concentration
of the petrolatum was 8.4%. The final dermatological composition
possessed highly hydrating, non-greasy properties due to the
presence of Hylasome. This cream was effective in treating dry,
cracked skin.
Example 14
[0076] This example illustrates the preparation of a composition in
which Hylasome (HA 0.1%) which has been very highly homogenized to
fine particles into which a drug (povidone iodine) was
incorporated. To hylasome (HA 1%) prepared according to Example 2
(100 g) was added 1-12% by wt. of povidone iodine. This composition
can be used as an antiseptic, antimicrobial, in the form of liquid
drops for the treatment of infections of the ear (otitis externa
and otitis media), nose and throat. The composition may also
contain seabuckthorn oil (antiseptic) and rose oil for natural
fragrance, and a pleasant smell to an otherwise unpleasant smelling
composition.
* * * * *