U.S. patent application number 15/383381 was filed with the patent office on 2017-04-06 for ibuprofen for topical administration.
The applicant listed for this patent is BioChemics, Inc.. Invention is credited to Stephen G. Carter, Diane Kozwich, Kanu Patel, Zhen Zhu.
Application Number | 20170095433 15/383381 |
Document ID | / |
Family ID | 41447140 |
Filed Date | 2017-04-06 |
United States Patent
Application |
20170095433 |
Kind Code |
A1 |
Carter; Stephen G. ; et
al. |
April 6, 2017 |
Ibuprofen for Topical Administration
Abstract
Set forth herein is a preparation of ibuprofen
(2-(4-isobutylphenyl) propionic acid) in the free acid form that is
suitable for topical administration. The topical ibuprofen
formulation is prepared by dissolving the free acid form of
ibuprofen, or preparing a homogeneous suspension of the free acid
form of ibuprofen, in the presence of a pharmaceutically acceptable
solvent so as to produce a topical drug formulation compatible with
the penetration of 2-(4-isobutylphenyl) propionic acid through the
skin tissue. Topical formulations of ibuprofen can be based on a
pharmaceutically acceptable solvent such as, e.g., a pyrrolidone
solvent or dimethylacetamide.
Inventors: |
Carter; Stephen G.;
(Andover, MA) ; Zhu; Zhen; (Andover, MA) ;
Patel; Kanu; (Londonderry, NH) ; Kozwich; Diane;
(Nottingham, NH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BioChemics, Inc. |
Danvers |
MA |
US |
|
|
Family ID: |
41447140 |
Appl. No.: |
15/383381 |
Filed: |
December 19, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13604040 |
Sep 5, 2012 |
9561174 |
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15383381 |
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12557470 |
Sep 10, 2009 |
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13604040 |
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61095672 |
Sep 10, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 47/22 20130101; A61K 31/192 20130101; A61K 47/32 20130101;
A61K 47/16 20130101; A61K 9/7023 20130101; A61K 9/0014
20130101 |
International
Class: |
A61K 31/192 20060101
A61K031/192; A61K 47/22 20060101 A61K047/22; A61K 47/16 20060101
A61K047/16; A61K 9/00 20060101 A61K009/00 |
Claims
1. A physically and chemically stable topical pharmacological
composition prepared by a process comprising the steps of: (a)
creating a first mixture by dissolving ibuprofen in a solvent; (b)
creating second mixture comprising at least one water soluble
ingredient; (c) creating a third mixture comprising at least one
hydrophobic ingredient; (d) creating a fourth mixture by combining
the second mixture and the third mixture; and (e) combining the
first mixture and the fourth mixture to create the physically and
chemically stable topical pharmacological composition.
2. The composition of claim 1, wherein step (b) further comprises
heating the at least one water soluble ingredient.
3. The composition of claim 2, wherein the at least one water
soluble ingredient is heated to about 70.degree. C.
4. The composition of claim 1, wherein step (c) further comprises
heating the at least one hydrophobic ingredient.
5. The composition of claim 4, wherein the at least one hydrophobic
ingredient is heated to about 70.degree. C.
6. The composition of claim 1, wherein step (d) further comprises
cooling the fourth mixture.
7. The composition of claim 6, wherein the fourth mixture is cooled
to about 40.degree. C.
8. The composition of claim 1, wherein the solvent is a pyrrolidone
solvent.
9. The composition of claim 8, wherein the solvent is selected from
the group consisting of N-methyl-2-pyrrolidone and
2-pyrrolidone.
10. The composition of claim 1, wherein the solvent is water.
11. The composition of claim 1, wherein the solvent is
dimethylacetamide.
12. The composition of claim 1, wherein the solvent is selected
from the group consisting of dimethylsulfoxide, dimethylformamide,
and dimethylisosorbide.
13. A method for treating inflammation in a patient in need of
therapy, comprising applying to the skin of the patient the stable
topical pharmacological composition of claim 1.
Description
REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 13/604,040 filed Sep. 5, 2012, which itself is a continuation
of U.S. application Ser. No. 12/557,470 filed Sep. 10, 2009, which
itself claims benefit of U.S. provisional application Ser. No.
61/095,672, filed Sep. 10, 2008, the entire disclosures of all of
which are hereby incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to topical compositions of
ibuprofen and methods for making and using the compositions.
BACKGROUND
[0003] Ibuprofen, an anti-inflammatory, analgesic, and anti-pyretic
agent, is a member of a group of drugs known as non-steroidal
anti-inflammatory drugs (NSAIDs). Past formulations of ibuprofen
have chiefly made use of the water-based form (salt form) of
ibuprofen. Ibuprofen in its salt form forms the basis of such drug
products as Advil.RTM. (potassium salt form of ibuprofen). Use of
ibuprofen in its free acid form has been limited to formulations
intended for oral administration, e.g., Motrin.RTM. in tablet and
oral suspension. IBU.RTM. Ibuprofen Tablets USP (Knoll
Laboratories, Mount Olive, N.J.) is supplied in tablets for oral
administration.
[0004] NSAIDs are highly effective in treating pain and
inflammation in joints, muscles and soft tissue, and are generally
given orally for a systemic effect. However, some individuals are
unable to tolerate oral intake of ibuprofen. For example, ingestion
may result in vomiting, thus leading to ineffective dosing. Others
are able to ingest ibuprofen but, as a result, develop gastric
mucosal lesions. These lesions lead to gastric discomfort and
abdominal pain.
SUMMARY OF THE INVENTION
[0005] The adverse side effects commonly associated with ibuprofen
can be avoided by directly administering ibuprofen to an afflicted
site in the form of a topical formulation. The inventive ibuprofen
formulations set forth herein provide an alternate, topical, form
of delivery to relieve pain and inflammation, e.g., in muscles,
joints and soft tissue, while overcoming many difficulties in
formulating a therapeutically effective topical pharmacological
composition containing ibuprofen, including low solubility of the
free acid form of the drug in aqueous solvents, as well as chemical
and physical stability and cosmetic appeal.
[0006] In a first illustrative embodiment of the ibuprofen
composition of the invention (hereinafter an "ibuprofen
composition"), the ibuprofen composition includes the free acid
form of 2-(4-isobutylphenyl) propionic acid, a pharmaceutically
acceptable solvent, e.g., a pyrrolidone solvent or
dimethylacetamide solvent, and at least one excipient.
[0007] In related embodiments, the 2-(4-isobutylphenyl) propionic
acid can have a half-life of at least six months at 25 degrees
Celsius. The solvent can be, e.g., a pyrrolidone solvent, e.g.,
N-methyl-2-pyrrolidone or 2-pyrrolidone, or dimethylacetamide. The
2-(4-isobutylphenyl) propionic acid can be either dissolved or
suspended, preferably homogeneously suspended, in a particle or
nanoparticle form. The excipient can include one or more of water,
a water-soluble excipient, or a water-insoluble excipient. The
composition can also include an emulsifier.
[0008] The 2-(4-isobutylphenyl) propionic acid can be in a
protonated form. As used here, "protonated form" means that the
ibuprofen is in substantially protonated form, i.e., at least 90%
protonated, preferably 95% protonated or even 100% protonated. The
excipient can also include a buffer having at least one acid
ionization constant, pKa, that is chosen so as to maintain the
2-(4-isobutylphenyl) propionic acid in a substantially protonated
form. The buffer can have a pKa of less than 7.
[0009] In accordance with a further embodiment of the invention is
a method of treating inflammation. The method includes selecting a
patient in need of therapy and applying a topical composition to
the skin of the patient. The composition includes
2-(4-isobutylphenyl) propionic acid, a pharmaceutically acceptable
solvent, e.g., dimethylacetamide, N-methyl-2-pyrrolidone, or
2-pyrrolidone, and at least one excipient.
[0010] In accordance with another embodiment of the invention is a
method of preparing a pharmaceutical composition by solubilizing
ibuprofen in a pharmaceutically acceptable solvent, creating an
active drug-containing solution by combining the solubilized
ibuprofen with a skin conditioner and a preservative, creating an
aqueous solution containing a conditioner, a pH stabilizer and a
preservative, creating an emollient phase by combining an
emulsifier, a preservative, an oil and a stabilizer, combining the
emollient phase and the aqueous solution, homogenizing to create a
homogenized mixture, and adding the active drug containing solution
to the homogenized mixture under temperature conditions avoiding
degradation of the ibuprofen.
[0011] In related embodiments, the pyrrolidone solvent can be
either N-methyl-2-pyrrolidone or 2-pyrrolidone. At least one of the
steps of creating an aqueous mixture, creating an emollient phase,
combining and homogenizing can include adding a first amount of
heat. A second amount of heat can then be removed prior to the
adding the active drug containing solution to create the
temperature conditions that avoid degradation of the ibuprofen.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The foregoing features of the invention will be more readily
understood by reference to the following detailed description,
taken with reference to the accompanying drawings, in which:
[0013] FIG. 1 is a flow diagram for a process of formulating a
topical ibuprofen composition in accordance with an embodiment of
the invention; and
[0014] FIG. 2 is a flow diagram for formulating a topical ibuprofen
composition in accordance with another embodiment of the invention
in which the composition includes both aqueous and oily
ingredients.
DETAILED DESCRIPTION
[0015] Set forth herein is a preparation of ibuprofen in the free
acid form that is suitable for topical administration. The topical
ibuprofen formulation is prepared by dissolving the free acid form
of ibuprofen in solution, or suspending the free acid form of
ibuprofen in the presence of a pharmaceutically acceptable solvent
so as to produce a topical drug formulation compatible with the
penetration of the ibuprofen through the skin tissue. Topical
formulations of ibuprofen using a pharmaceutically acceptable
solvent, e.g., a pyrrolidone solvent or dimethylacetamide.
[0016] Definitions. The following terms shall have the meanings
indicated, unless the context otherwise requires.
[0017] Forms of ibuprofen useful in the invention include the acid
form, or free acid form, of ibuprofen, known by the chemical names:
(.+-.)-2-(4-isobutylphenyl) propionic acid; 2-(4-iso-butylphenyl)
propionic acid; (4-isobutyl-alpha-methylphenylacetic acid; and
4-iso-butyl-alpha-methylphenylacetic acid and synonyms thereof
known to those skilled in the art (hereafter collectively referred
to as "2-(4-isobutylphenyl) propionic acid"). Forms of ibuprofen
suitable for the invention expressly include racemic mixtures of
2-(4-isobutylphenyl) propionic acid and individual stereoisomers
thereof. It is understood that "ibuprofen in the acid form"
indicates that the ibuprofen molecules in the composition are
predominantly or entirely protonated, as distinguished from a salt
of the conjugate base or a buffered mixture of acid and base
forms.
[0018] A "nanoparticle" is a particle having one or more dimensions
of 1000 nanometers or less.
[0019] "Half life" of an active ingredient of a composition means
the duration of time elapsing from creation of the formulation
until degradation of the formulation reduces by 50% the
concentration of the active ingredient in the formulation.
[0020] "Degradation" of a formulation including an active
ingredient includes a process operative over time by which
increasing amounts of the active ingredient are inactivated by at
least one of chemical reaction and physical separation (such as
precipitation).
[0021] A "formulation" is a preparation in which various chemical
substances are combined with an active ingredient, e.g., ibuprofen.
As used herein, a formulation includes a composition of the
invention in the form of an ointment, cream, lotion, gel, salve or
the like, or a composition by itself, for topical application or
delivery of the drug to a patient. In some embodiments, as
appropriate, a formulation can also include a delivery system (such
as a patch) impregnated with or containing a composition including
an active ingredient, suitable for topical application. The
ibuprofen of the composition can permeate the skin to provide
therapeutically effective transdermal delivery of the ibuprofen to
a locally affected region.
[0022] A "pharmaceutically acceptable solvent" is one or more of
the solvents listed as being acceptable by the Federal Food and
Drug Administration (FDA) in its Inactive Ingredients Database
(www.accessdata.fda.gov/scripts/cder/lig/index.cfm, last visited 10
Sep. 2009). A pharmaceutically acceptable solvent must be one which
facilitates solubility of the free acid form of ibuprofen, or must
be one which facilitates formation of a homogeneous suspension of
the free acid form of ibuprofen, to at least 1%, or to at least 5%
or 7.5%, preferably to at least 10%, and most preferably to at
least 20%, of the formulation on a weight percent basis.
[0023] In illustrative embodiments of the invention, ibuprofen
compositions are physically and chemically stable and so resist
degradation. In an embodiment, topical application of the
compositions are used to treat inflammatory-related disorders of a
patient. In specific embodiments, pharmaceutically acceptable
solvent, e.g., a pyrrolidone solvent or a dimethylacetamide
solvent, dissolves the free acid form of ibuprofen. A further
embodiment of the invention includes a method for manufacturing the
composition.
[0024] In an embodiment, ibuprofen is formulated into an ointment
composition (e.g. a cream, lotion, gel, salve or like formulation)
for topical application. The ibuprofen of the composition can
permeate the skin to provide therapeutically effective transdermal
delivery of the ibuprofen to a locally affected region (such as an
inflamed muscle or joint), to provide anti-inflammatory and/or pain
relief. Optionally, the ibuprofen can permeate to a degree that is
sufficient to effect systemic therapy (e.g., to treat a headache or
flu). The topical application of therapeutic doses of ibuprofen can
result in faster and more effective relief from pain and
inflammation than is typically achieved by oral ingestion. When
applied topically for local relief, total body dosages should be
much lower than with orally ingested ibuprofen, thus reducing
side-effects.
[0025] The table below shows ingredients that can be used in
compositions according to embodiments of the invention. The
ibuprofen can be enantiomerically pure (e.g., the active S
enantiomer) or can be racemic. The ibuprofen can be dissolved or in
particulate form. Examples of particulate ibuprofen include
micoparticles or nanoparticles with diameters ranging from
10.sup.-4 (100 microns) to 10.sup.-9 meters (1 nanometer).
Preferably, a particulate acid form of ibuprofen useful for
preparing a homogeneous suspension in a pharmaceutically acceptable
solvent according to the invention is between 1 and 20 microns in
diameter, and more preferably less than 1 micron in diameter.
[0026] Particles can be produced by microfluidizing and fluid
energy milling (see, e.g., U.S. Pat. Nos. 4,851,421; 4,826,689;
4,540,602; 5,145,684 and 6,555,130, each of which is hereby
incorporated by reference), a cavitation process, or other suitable
methods known to those skilled in the art. Microfluidics-based
homogenizers, also referred to as "nano-equipment", are designed to
reduce particle sizes by different mechanisms, from multiple
microns in diameter to submicron or nanometer sized diameters.
These in turn can assist in maximizing the penetration of an agent
through the skin and/or into the body by other means of
delivery.
[0027] In an embodiment, the ibuprofen is either dissolved or
suspended in a pharmaceutically acceptable solvent. In an
embodiment the solvent is pharmaceutically acceptable solvent,
e.g., a pyrrolidone solvent, for example, a solvent that includes
one or more of N-methyl-2-pyrrolidone, and 2-pyrrolidone.
Alternately or in addition, the solvent can include
dimethylsulfoxide, dimethylformamide, dimethylacetamide, or
dimethylisosorbide. The ibuprofen can be dissolved in its free acid
form.
[0028] The formulation can also include at least one excipient,
which is a substance serving as a vehicle for the ibuprofen. A
variety of excipients can be used. The excipients can be present
at, e.g., between 1 to 20% wt % of the solvent system. The
excipient can include a skin conditioner, an emulsifier, an
emulsion stabilizer, a viscosity modifier, a pH buffer, a
preservative, an emollient, or a combination thereof.
[0029] Examples of skin conditioners include L-arginine, menthol,
and eucalyptus oil or combinations of these. The skin conditioner
can be, for example, 0.1 to 20%, e.g., 0.5% or 1.0%, of the
composition by weight. In one preferred embodiment, the formulation
can contain L-arginine 0.5% as a vasodilator. Nitric oxide (NO) is
produced endogenously from arginine in a reaction catalyzed by
nitric oxide synthase. NO is one of the primary agents eliciting a
vasodilatory response by relaxing vascular smooth muscle, thereby
producing an increase in skin blood flow and assisting the
ibuprofen to the painful area (e.g., synovial tissue in
osteoarthritis).
[0030] Examples of emulsifiers include glyceryl stearate, lecithin,
and polyoxyl 40 hydrogenated castor oil. The skin emulsifier can be
1 to 40% of the composition by weight.
[0031] Examples of viscosity modifiers include xantham gum,
Veegum.RTM. (R.T. Vanderbilt Co., Inc., Norwalk, Conn.), and
Permulen.TM. (Lubrizol Corporation, Cleveland Ohio). The viscosity
modifier can be, for example, 0.1 to 15% of the composition by
weight.
[0032] Ibuprofen has a logarithmic acid dissociation constant, or
acid ionization constant (pKa) of about 4.4. An example of a pH
buffer (i.e., a pH stabilizer) is citric acid, adjusted to an
appropriate pK. Citric acid has three ionization constants, with
pKa's of 3.15, 4.77, and 6.40 respectively. Thus, as is known in
the art, by choosing a buffer of appropriate pH and concentration
for a given concentration of ibuprofen, citric acid is capable of
buffering ibuprofen in a substantially protonated form, e.g., about
90% protonated to about 100% protonated. The buffer concentration
can be, for example, 0.1 to 15% of the composition by weight.
Alternately, ibuprofen can be used as a free acid without the use
of a buffer.
[0033] A preservative can be used to prevent spoilage due to
microbial growth or oxidation. Examples of preservatives include
methylparaben and propylparaben, or combinations of these. The
preservative is usually included at 0.1 to 5% of the composition by
weight, as adjudged by one skilled in the art.
[0034] An emollient can be included in the composition to soften
and soothe the skin, or to correct dryness or scaling of the skin.
Examples of useful emollients include without limitation lemon oil,
olive oil, silicone oil, mineral oil, petrolatum, vegetable wax and
mixtures thereof. Emollients can be included at a concentration of,
e.g., 1 to 20% of the composition by weight.
[0035] In an optional embodiment, the excipient can includes water,
so as to be at partially aqueous. Care should be taken however that
the water concentration is not so high as to cause degradation of
the ibuprofen under relevant storage conditions. Alternatively, the
excipient can be non-aqueous.
[0036] The composition can be effective in treatment of conditions
including rheumatoid arthritis, osteoarthritis, periarticular
disorders and soft tissue injuries, postoperative pain,
musculoskeletal pain or the pain or discomfort associated with gout
or morning stiffness.
[0037] The composition can be applied to the affected area and
massaged in. Alternately, in another "formulation" (as that term is
defined above), the ibuprofen composition can be combined with or
impregnated into a patch or other device that is applied to the
surface of the skin. In an embodiment, a reservoir of solvent
(e.g., 2-pyrrolidone or N-methyl-2-pyrrolidone) is slowly released
from a patch reservoir, enabling a layer of ibuprofen to be
dissolved. In an embodiment, the composition can deliver ibuprofen
with a time-release or extended-release action (e.g., delivery over
1-8 hours).
[0038] In embodiments, because the ibuprofen is substantially
protonated and compatible with the solvent/excipient system, it can
have an extended shelf-life (e.g., a half-life of 6 months or more
at 25.degree. C.).
TABLE-US-00001 % (by Component Class weight) Examples Active
ingredient 1-50 Ibuprofen Racemic Enantiomerically pure Particulate
Nanoparticulate Solvent 1-20 N-methyl-2-pyrrolidone, 2-pyrrolidone,
dimethylsulfoxide, dimethylformamide dimethylacetamide,
dimethylisosorbide Skin conditioner 0.1-20 L-arginine, menthol,
eucalyptus oil Emulsion stabilizer 0.5-15 Vitamin E TPGS Emulsifier
1-40 glyceryl stearate, lecithin, polyoxyl 40 hydrogenated castor
oil Viscosity modifiers 0.1-15 Xanthum gum, Veegum, Permulen Buffer
0.1-15 Citric acid Preservative 0.1-5 Propylparaben, methylparaben
Emollient 1-20 Lemon oil, olive oil, silicone oil
[0039] The flow diagram of FIG. 1 shows a process for manufacturing
an ibuprofen composition according to an embodiment of the present
invention. First, ibuprofen is dissolved in a solvent (step 100).
The solvent can include N-methyl-2-pyrrolidone, 2-pyrrolidone,
dimethylsulfoxide, dimethylformamide. dimethylacetamide,
dimethylisosorbide or mixtures thereof in amounts sufficient to
dissolve the ibuprofen. The ibuprofen amount and concentration can
be selected to result in 1-50% ibuprofen in the final formulation.
Then, one or more excipients are added (step 110). In an
embodiment, one or more mixtures of excipients are heated. The
excipients can be blended or homogenized. Multiple pools of
excipient ingredients can be combined prior to adding the active
ibuprofen ingredient. The excipients can be cooled prior to
combining with the ibuprofen.
[0040] The flow diagram of FIG. 2 shows a process for manufacturing
an ibuprofen composition according to another embodiment of the
present invention. In a first vessel, ibuprofen is dissolved in a
solvent. The solvent can include N-methyl-2-pyrrolidone,
2-pyrrolidone, dimethylsulfoxide, dimethylformamide.
dimethylacetamide, dimethylisosorbide or mixtures thereof in
amounts sufficient to dissolved the ibuprofen. Optionally, one or
more skin conditioners and/or preservatives are added to the
ibuprofen-solvent mixture (step 210).
[0041] In a second vessel, the water soluble excipient ingredients
are combined to form an aqueous solution (step 220). Toward the
goal of obtaining homogeneity in the formulation, the ingredients
can be heated (by adding a first amount of heat) and/or mixed (step
230), either during or after the combination. For example, one or
more pH buffers, preservatives and skin conditioners can be
combined while heating to 70.+-.10.degree. C. The mixing process
can include stirring, blending or other homogenization techniques
known in the art.
[0042] In a third vessel, hydrophobic (oily) ingredients are
combined (step 240). To promote homogeneity in the formulation, the
ingredients can be heated and/or mixed (step 250), either during or
after the combination. The contents of the third vessel can be
heated, for example, to 70.degree. C. The mixing process can
include stirring, blending or other homogenization techniques known
in the art. Optionally, emulsifiers or other ampiphilic ingredients
can be combined with either the aqueous solution in the second
vessel or the oily ingredients in the third vessel.
[0043] The contents of the second vessel (aqueous phase) and third
vessel (oil phase) can then be combined (step 260) and optionally
homogenized. The combined mixture can then be cooled (e.g., heat
removal to reach 40.degree. C.) and combined with the contents of
the first vessel (dissolved ibuprofen and other optional
ingredients. Cooling of the mixture (by removing a second amount of
heat) creates conditions that avoid degradation of the ibuprofen.
For example, cooling prior to adding the ibuprofen can avoid
degradation of the ibuprofen to a substantial degree (e.g., <20%
degradation).
[0044] Stability Procedure:
[0045] Test formulations are stored in high density polyethylene
jars (2 and 4 ounce) with screw caps. The containers are placed at
40.degree. C., 22.degree. C. and 4.degree. C. (degrees Celsius) for
periods of time and evaluated for the integrity of the formulation
and emulsion stability as well as for quantitative analysis of the
ibuprofen content of the batch. The formulation and emulsion
integrity are evaluated visually for the presence of phase
separation, color, texture or other changes as noted at the time of
initial preparation. The quantitative analysis of the ibuprofen is
performed with a qualified rugged HPLC method.
[0046] Ibuprofen formulations prepared according to embodiments
described herein are stable, including hydrolytically stable. For
example, more than 90% of the therapeutic or biochemical activity
of the ibuprofen in the formulation will be active after storage at
room temperature (.about.20-25 degrees Celsius) for at least six
months.
Example 1
TABLE-US-00002 [0047] TABLE 1 Wt % (of excipient) Phase A
L-Arginine Base 0.2 Methylparaben 0.2 Water 5 Phase B IBU (USP
grade) 3.5 Menthol 2 Eucalyptus Oil 2 N-methyl-2-pyrrolidone 1
Phenoxyethanol 0.7 Phase C Cetyl Alcohol 5 Soybean Oil 17.5
Glyceryl Stearate 6 Beeswax 22 Petrolatum 10 Ethyl Oleate 12.8
Vitamin E TPGS 2 Capric Glyceride 10 Propylparaben 0.1 TOTAL:
100
[0048] The formulation of Example 1 is prepared as follows. In Tank
1, dissolve (.+-.)-2-(4-isobutylphenyl) propionic acid into
N-methyl-2-pyrrolidone until completely solubilized. Add the
remaining ingredients of Phase B and mix until completely
dissolved. In the Main tank, add the ingredients of Phase C, mix
while heating to 70.degree. C. In tank 2, add the ingredients of
Phase A, mix while heating to 70.degree. C. Transfer the contents
in Tank 2 into the main tank, mix for 10 minutes, and cool to
40.degree. C. (degrees Celsius) or less. Transfer contents in Tank
1 into Main Tank at 40.degree. C. (degrees Celsius) or less. Mix
until blended (.about.20 minutes).
Example 2
TABLE-US-00003 [0049] TABLE 2 Wt % (of excipient) Phase A
L-Arginine Base 0.2 Methylparaben 0.2 Water 5 Phase B IBU (USP
grade) 20 Menthol 2 Soybean Oil 14.8 Eucalyptus oil 2
Phenoxyethanol 0.7 Dimethylacetamide 2 Phase C Beeswax 18
Petrolatum 10 Glyceryl Stearate 5 Cetyl Alcohol 5 Vitamin E TPGS 2
Capric Glyceride 10 Ethyl Oleate 3 Propylparaben 0.1 TOTAL: 100
[0050] The formulation of Example 2 is prepared as follows. In Tank
1, dissolve menthol into eucalyptus oil until completely
solubilized; add remaining ingredients of Phase B and pass through
nano-equipment to reduce the particle size. In the main tank, add
the ingredients of Phase C, mix while heating to 70.degree. C. In
tank 2, add the ingredients of Phase A, mix while heating to
70.degree. C. Transfer the contents from Tank 2 into Main Tank, mix
for 10 minutes; cool to 40.degree. C. (degrees Celsius) or less.
Transfer the contents of Tank 1 into the Main Tank at 40.degree. C.
(degrees Celsius) or less. Mix until blended (.about.20
minutes).
Example 3
TABLE-US-00004 [0051] TABLE 3 Preparation of Batch No. 176ZX03 (%
w/w) Ibuprofen in free acid form 10 KOH 2 L-Arginine Base 0.5
Carbopol .RTM. 980NF (2.5%) 4 Veegum .RTM. HV (10%) 35
Methylparaben 0.2 Syloid 244 FP 4 Phenoxyethanol 0.7 Water 14
Menthol 5 Eucalyptol 5 N,N-dimethylacetamide 3 Olive Oil 5 Lemon
Oil 0.5 Vitamin E TPGS 2 Propylparaben 0.1 Glyceryl Monostearate 7
DC Elastomer 10 2 TOTAL 100
[0052] One hundred grams (100 g) of a 2.5% Carbopol.RTM. 980NF
solution is prepared as follows. While heating 97.5 g water to
70.degree. C., add 2.5 g Carbopol.RTM. 980NF powder with strong
mixing (i.e., such that a vortex should turn). Mixing is continued
until the solution is hydrated and free of clumps at 70.degree. C.
The solution is removed from heat and left at room temperature
overnight, and then mixed again before use.
[0053] One hundred grams (100 g) of a 10% Veegum.RTM. HV solution
is prepared as follows. While heating 90 g of water to 70.degree.
C., 10 g Veegum.RTM. HV is added with strong mixing (i.e., a vortex
should turn). Mixing is continued for 30 minutes at 70.degree. C.
The mixture is removed from the heat and mixing is continued for
another hour. The mixture is left at room temperature overnight,
and then mixed again before use.
[0054] The formulation of Example 3 is prepared as follows. In Tank
1, the menthol, eucalyptol, and dimethylacetamide (DMA) are mixed
together until the solution is completely dissolved and clear.
Syloid 244 FP is then added to form a homogenous gel. In Tank 2 is
placed the olive oil, lemon oil, Vitamin E TPGS, propylparaben,
glyceryl monostearate, and DC Elastomer 10, and heated to
70.degree. C. (degrees Celsius) while mixing. In Tank 3 (the main
tank) is added the designated amount of 10% Veegum.RTM. HV solution
and water together, and mixed for 15 minutes. The ibuprofen,
potassium hydroxide (KOH), methylparaben, and L-Arginine base are
then added, heated to 70.degree. C. (degrees Celsius) and mixed for
about 15 minutes until no solid exists. At 70.degree. C. (degrees
Celsius), the oil phase from tank 2 is added to tank 3 and mixed
for 5 minutes before starting to cool the tank. While cooling, 2.5%
Carbopol.RTM. 980NF solution is added. When at 40.degree. C.,
phenoxyethanol and the homogeneous gel from tank 1 are added to
tank 3, and mixed for another 30 minutes.
[0055] After testing for stability, the ibuprofen active ingredient
in the Batch 176ZX03 formulation was stable at 22 degrees Celsius
(22.degree. C.) for more than 7 months with no degradation in the
ibuprofen concentration and also no deterioration in the integrity
of the formulation or emulsion.
Example 4
TABLE-US-00005 [0056] TABLE 4 Preparation of Ibuprofen Batch No.
BC1-170C % (w/w) Ibuprofen 7.5 Arginine 0.5 Methylparaben 0.2
Citric Acid 0.2 Xanthan Gum 1 Menthol 5 Eucalyptus Oil 5
Phenoxyethanol 0.7 1-Methyl-2-Pyrrolidinone 2 Water 51.3 Olive Oil
5 Lemon Oil 0.5 Vitamin E TPGS 2 Glyceryl Stearate 8 Stearyl
Alcohol 8 ST Elastomer 10 3 Propylparaben 0.1 TOTAL: 100
[0057] The formulation of Example 4 is prepared as follows. In Tank
1, mix menthol, eucalyptus oil, 1-methyl-2-pyrrolidinone,
phenoxyethanol, and ibuprofen together until the solution is
completely dissolved and clear. In Tank 2 put the olive oil, lemon
oil, Vitamin E TPGS, propylparaben, glyceryl stearate, DC Elastomer
10 and stearyl alcohol together and heat to 70.degree. C. (degrees
Celsius) while mixing. In Tank 3 (Main tank), add the
methylparaben, L-arginine base, and citric acid into water. Add
xanthan gum in with strong mixing, heat to 70.degree. C. (degrees
Celsius) and mix for 15 minutes until no solid exists. At
70.degree. C. (degrees Celsius), add oil phase from tank 2 into
tank 3. Mix for 5 minutes, and start to cool the tank. At
40.degree. C. (degrees Celsius), add solution in tank 1, and mix
for another 30 minutes.
[0058] The formulation BC1-170C was found to be stable at
40.degree. C. (degrees Celsius) for 13 months.
[0059] The embodiments of the invention described above are
intended to be merely exemplary; numerous variations and
modifications will be apparent to those skilled in the art. All
such variations and modifications are intended to be within the
scope of the present invention as defined in any appended
claims.
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