U.S. patent application number 11/080812 was filed with the patent office on 2005-07-21 for vehicle for topical delivery of anti-inflammatory compounds.
This patent application is currently assigned to AlphaRx Inc.. Invention is credited to Schwarz, Joseph, Weisspapir, Michael.
Application Number | 20050158348 11/080812 |
Document ID | / |
Family ID | 32029201 |
Filed Date | 2005-07-21 |
United States Patent
Application |
20050158348 |
Kind Code |
A1 |
Schwarz, Joseph ; et
al. |
July 21, 2005 |
Vehicle for topical delivery of anti-inflammatory compounds
Abstract
A vehicle for topical application which contains a liquid
eutectic mixture of hydrophobic compounds to improve solubility of
pharmaceutically active component and enhance topical and
transdermal delivery.
Inventors: |
Schwarz, Joseph; (Richmond
Hill, CA) ; Weisspapir, Michael; (Richmond Hill,
CA) |
Correspondence
Address: |
OGILVY RENAULT LLP
1981 MCGILL COLLEGE AVENUE
SUITE 1600
MONTREAL
QC
H3A2Y3
CA
|
Assignee: |
AlphaRx Inc.
Markham
CA
|
Family ID: |
32029201 |
Appl. No.: |
11/080812 |
Filed: |
March 16, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11080812 |
Mar 16, 2005 |
|
|
|
10255951 |
Sep 27, 2002 |
|
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Current U.S.
Class: |
424/400 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 31/05 20130101; A61P 29/00 20180101; A61K 31/125 20130101;
A61K 47/08 20130101; A61K 31/00 20130101; A61K 9/0014 20130101;
A61P 25/04 20180101 |
Class at
Publication: |
424/400 |
International
Class: |
A61K 009/00 |
Claims
We claim:
1. A vehicle for topical delivery of a pharmaceutically active
component, comprising a liquid eutectic mixture containing a
hydrophobic component.
2. The vehicle as set forth in claim 1, wherein said hydrophobic
component is selected from the group consisting of pharmaceutically
acceptable glycerin esters, aliphatic esters, aromatic esters,
waxes, lipids, fats, lipid soluble vitamins, hydrocarbons, silicone
polymers, tocopherols, tocotrienols and related compounds, or
mixture thereof.
3. The vehicle as set forth in claim 1, wherein the ratio of said
hydrophobic component and liquid eutectic mixture are in a ratio of
between 1:10 to 10:1.
4. The vehicle as set forth in claim 1, wherein the ratio of said
hydrophobic component and liquid eutectic mixture are in a ratio of
between 1:3 to 3:1.
5. The vehicle as set forth claim 1, wherein said eutectic mixture
comprises at least two compounds selected from the group consisting
of camphor, menthol, thymol, resorcinol, phenol or substituted
phenol derivativesThe vehicle as set forth claim 5, wherein said
eutectic mixture is liquid at ambient temperature.
6. A composition for topical delivery comprising an oil-in-water or
water-in-oil emulsion or microemulsion, wherein the oil phase of
said emulsion comprises a vehicle as set forth in claim 3.
7. The composition as set forth in claim 6, wherein said
pharmaceutically active component is dissolved in said oil phase of
said emulsion or microemulsion.
8. The composition as set forth in claim 7, wherein said oil phase
comprises between 5% and 80% of said composition.
9. The composition as set forth in claim 7, further including a
surfactant.
10. The composition as set forth in claim 9, wherein said
pharmaceutically active component is selected from
anti-inflammatory drugs.
11. The composition as set forth in claim 10, wherein said
anti-inflammatory drugs are selected from group of non-steroidal
anti-inflammatory drugs (NSAIDs).
12. The composition as set forth in claim 11, wherein said
anti-inflammatory drugs are selected from the group consisting of
indomethacin, diclofenac, ketorolac, piroxicam, meloxicam,
tenoxicam, ketoprofen, flurbiprofen, ibuprofen, nimesulide,
naproxen, rofecoxib, celecoxib and salicylic acid.
13. The composition as set forth in claim 10, further including
additional pharmaceutically active components, pharmaceutically
acceptable surfactants, viscosity regulating agents, antibacterial
preservatives, skin penetration enhancers, fragrances and
colorants.
14. The composition as set forth in claim 9, wherein said
surfactant is non-ionic surfactant, phospholipid or mixture
thereof.
15. A method for increasing the solubility of a pharmaceutically
active component in a vehicle for topical delivery of said
pharmaceutically active component, comprising: providing a
pharmaceutically active component; providing at least two compounds
selected from the group consisting of camphor, menthol, thymol,
resorcinol, phenol or substituted phenol derivatives; and forming a
eutectic mixture containing said pharmaceutically active component
and said at least two members whereby said mixture contains a
greater amount of solubilzed active component relative to a non
eutectic mixture.
16. The method as set forth in claim 15, wherein said two selected
compounds are camphor and menthol.
17. The method as set forth in claim 15, wherein said
pharmaceutically active component comprises a non steroidal
anti-inflammatory drug (NSAID).
18. A composition for topical delivery having an increased amount
of a solubilized pharmaceutically active component comprising an
emulsion selected from the group consisting of an oil-in-water,
water-in-oil and microemulsion, wherein said oil phase of said
emulsion comprises a vehicle as set forth in claim 3, wherein said
hydrophobic component is selected from the group consisting of
pharmaceutically acceptable glycerin esters, aliphatic esters,
aromatic esters, waxes, lipids, fats, lipid soluble vitamins,
hydrocarbons, silicone polymers, tocopherols, tocotrienols and
related compounds, or mixture thereof, said eutectic; mixture
comprising at, least two members selected from the group consisting
of camphor, menthol, thymol, resorcinol, phenol or substituted
phenol derivatives; and a pharmaceutically active component, said
composition having an increased solubilized amount of said
pharmaceutically active component relative to a non eutectic
composition.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 10/255,951, filed Sep. 27, 2002.
FIELD OF THE INVENTION
[0002] The present invention relates to the preparation of
semisolid formulations for topical delivery of pharmaceutically
active ingredients, designed for pain control and inflammation
treatment.
BACKGROUND OF THE INVENTION
[0003] Topical pharmaceutical preparations of different types have
been used for treatment of rheumatic and arthritic pain for
decades. Semisolid compositions comprise plant derivatives, such as
capsaicin (red hot pepper stinging substance) or turpentine (pine
tar component) ointments, homeopathic extract and liniments
(Opodeldoc Rus), mustard plasters, menthol rubs, essential oil
balms and many others were used for a long time, mainly as local
irritants. Such irritation improves local blood flow, accelerates
injured tissue recovery, and switches attention from chronic pain
from inflammation.
[0004] By including non-steroid anti-inflammatory drugs (NSAIDs)
into ointment or cream application onto the desired location allows
for effective control of muscle and joint pain intensity. Moreover,
when NSAIDs are applied topically, local drug concentration in
muscle and joint tissues is significantly higher than in
non-treated sites. Additionally, there is no intensive metabolism
in liver (so called "first-pass effect") because such drugs do not
pass through the liver before action.
[0005] The required amount of NSAIDs is lower than an oral dose to
achieve similar anti-inflammative and analgesic effects. The most
common side effect of NSAIDs is serious irritation of stomach and
gastro-intestinal mucosa. This is substantially diminished with
local topical applications.
[0006] Topical NSAID formulations are very popular in Europe, Asia
and Far East regions. Examples of such compositions include
Voltaren Emulgel.RTM. (Voltarol.TM. in UK), a 1.16% Diclofenac
diethylammonium emulsion cream with isopropyl alcohol, Feldene.RTM.
Gel (0.5% Piroxicam water-ethyl alcohol gel), Ibuprofen and
Ketoprofen gels of different strengths (5-10%), and 1-10%
Indomethacin in alcohol. DMSO-containing creams and many other
formulations are widespread in many countries as OTC (over the
counter) remedies for muscle pain, minor sport injuries, rheumatic
and back pain treatment, etc.
[0007] Generally, topical NSAID preparations do not have
attributable side-effects such as gastric irritation and internal
bleeding. Advantageously, the compounds provide relatively fast
action onset and moderate efficacy in treatment of local muscle and
joint pain. The main problems of these products is low drug loading
due to low solubility in the cream components. High loading can be
reached by use of concentrated alcohols, i.e. ethyl alcohol,
isopropyl alcohol with polyethylene glycol and propylene glycol
suitable as solvents for NSAIDs. Drug loading is high and can
easily reach 5-10% or greater, e.g., 5% Ibuprofen gel with
isopropyl alcohol, 1% Indomethacin gel based on ethyl alcohol or
even 10% Indomethacin ointment with dimethylsulfoxide.
[0008] These solvents are widely used for gel preparation, but
widespread use is often limited due to the proclivity for skin
irritation. A further limitation is realized in fast termination of
action for gel preparations since the drug precipitates from
solution subsequent to water absorption from the body tissue.
Further, solvents in high concentration often irritate the skin due
to drying and delipidisation and may initiate contact dermatitis
and allergy. The drug which is insoluble in water media and body
fluids, precipitates in the upper skin layers and does not
penetrate, thus seriously limiting the anti-inflammatory action.
Similar behavior has been observed for polyethylene glycol (mixture
of PEG-4000 and PEG-400) hydrophilic topical base compositions.
[0009] Traditional hydrophobic vehicles such as fixed oils, mineral
oil, petrolatum, lanolin and wax based ointments, along with
emulsion creams (either O/W or W/O type) are less irritating to
human skin, but these present another complication--solubility.
Drug loading in such vehicles is limited by the solubility of the
drug in the lipid phase. For example, the solubility of
Indomethacin in olive or corn oil is below 0.2%, whereas Ketoprofen
is about 1.5% and Piroxicam below 0.05%. According to Benita et at.
"Submicron Emulsions as Colloidal Drug Carriers for Intravenous
Administration: Comprehensive Physicochemical Characterization", J.
Pharm Sci., 1993, Nov. 82 (11), pp. 1069-79, even for low drug
loading, stability of the dispersed system is questionable. A 0.1%
Indomethacin submicron emulsion lost stability after 1 month
storage.
[0010] Use of more polar hydrophobic compounds may help to improve
solubility of NSAIDs. Tocopherol acetate, triethyl citrate,
glycerin monolaurate, glycerin monooleate (Myverol.TM. 18-9)
dissolve between 1.5 and 2 times more Indomethacin or Diclofenac
(in acidic form). Nevertheless, this loading is insufficient to
obtain an effective NSAID emulsion. Transdermal adhesive systems
such as skin patches and plasters with Indomethacin or Diclofenac
present low efficacy by the same reasoning.
[0011] A further method to increase drug solubility in the oil
phase is to use highly polar compounds, miscible with the oil
phase. Solvents such as Ethoxyethylene glycol (Transcutol.TM.),
dimethylisosorbide (DMIS), Isopropylideneglycerin (Solketal.TM.),
ethoxylated furanyl alcohol (Glucofurol.TM.) visibly boost drug
implementing in the separate hydrophobic phase. However, upon
mixing with water, most of the solvent is extracted into the water
and the dissolved drug precipitates immediately and almost entirely
from the oil phase.
[0012] Recently developed submicron emulsions (SME) employed as a
base for NSAIDs, provide very effective delivery and exert
pronounced improvement for drug action as discussed in Friedman et
al. (U.S. Pat. No. 6,113,921). However, low solubility of NSAIDs in
a lipid phase of such emulsions leads to shortened periods of
efficacy and drug precipitation from the oil phase during storage.
High loading, desirable for optimal activity of topical NSAID
preparation for SME is achievable only for highly lipophilic
compounds, such as Naproxen, Ketoprofen or Ibuprofen with
significantly lower anti-inflammatory activity.
[0013] Eutectic mixture use in topical applications is rather
limited. An example is EMLA cream, developed by Astra-Zeneca. The
liquid, formed by mixing two crystalline bases of local
anesthetics, Lidocain and Prilocaln due to eutectic formation
serves as an oil phase in the cream for topical application. The
cream, containing 5% of the oil phase, provides excellent stability
and anesthetic action.
[0014] In view of the limitations in the anti-inflammatory drug
art, there exists a need for an improved composition which
overcomes the shortcomings presently encountered.
SUMMARY OF THE INVENTION
[0015] It has been found that a eutectic mixture of camphor,
menthol, thymol and similar compounds is a powerful solvent for
non-steroidal anti-inflammatory drugs and other substances. The
solubility of Indomethacin, Diclofenac, or Ketoprofen in the
mixture increased between 3 and 20 fold. As a particular advantage,
the eutectic mixture was found to be safe, non-toxic and present
synergistic behavior in the anti-inflammatory action of NSAIDs due
to the anti-inflammatory properties of camphor and skin penetration
enhancing properties of menthol.
[0016] The eutectic mixture can be combined with pharmaceutically
acceptable oils and lipids and included, into topical formulations.
The compositions were found to allow much higher drug loading than
existing ointment bases and creams, showed no skin irritation and
provided enhanced delivery properties for incorporated drugs.
[0017] Prior to embracing on a discussion of the preparation, some
general properties of menthol and camphor will be established.
[0018] The menthol used was (1R, 2S,
5R)-5-methyl-2-(1-methyethyl)-cyclohe- xanol with a molecular
weight of 156.27 and melting point of 42.degree. C. Menthol
generally has a peppermint odor. It is well known as a skin
irritant and penetration enhancer, as discussed in Tsuk (U.S. Pat.
No. 4,933,184). It is widely used in many topical formulations for
relief of arthritic and rheumatic pain. Natural L-menthol exerts a
cooling or refreshing sensation due to direct interaction with cold
sensitive receptors in the skin. This was established in the
Handbook of Pharmaceutical Excipients, Third Edition, ed. A. H.
Kibbe, Pharmaceutical Press, London, U.K., 2000, pp. 334-335.
Menthol has been used as mild local anesthetic and as volatile
aromatic component for breath relief in obstruction and cold
treatment in Hughes et al., (U.S. Pat. No. 5,322,689).
[0019] Similar properties are known for camphor
1,7,7-trimethylbicyclo[2,2- ,1]heptanone-2, having a molecular
weight of 152.24. Camphor has a high melting point (180.degree. C.)
and is a very volatile substance with strong pine-like odor that
sublimes even at room temperature and pressure. Initially, camphor
found use as a stimulant, but now camphor is mainly used as a
component in topical preparations. It is often used in nasal
decongestants and aromatic compositions.
[0020] Either menthol or camphor separately or in combination are
widely used in topical formulations, mainly due to their irritant
action, receptor interaction and specific traditional odor,
frequently associated with time-honored remedies. Ben Gay.TM.
ointment, Tiger.TM. balm, Menthol Chest Rub and similar
compositions are well known and popular.
[0021] Certain external analgesic products containing between 10%
to 60% methyl salicylate, more than 3% to 11% camphor and 1.25% to
16% menthol, either singly or in combination, cause irritation or
mild inflammation of the skin for the purpose of relieving pain in
muscles, joints, or viscera distal to the site of application by
stimulating depressing cutaneous sensory receptors, discussed in
Ivy et al. (U.S. Pat. No. 5,013,726).
[0022] Topical preparations for joint relief include that provided
for in Lang et al. (U.S. Pat. No. 4,731,200) for an aqueous-alcohol
composition containing benzylidene-camphor derivatives, Ivy et al.
(U.S. Pat. No. 5,013,726) for a lotion containing methyl
salicylate, camphor and menthol, Ivy et al. (U.S. Pat. No.
5,124,320) for an analgesic lotion containing menthol and camphor,
Heywang et al. (U.S. Pat. No. 5,144,081) for a pharmaceutical
composition containing camphor and Singh (U.S. Pat. No. 5,175,152)
for a composition with methyl salicylate, menthol and camphor.
[0023] These substances have been advertised for use in relieving
joint pain, such as the elbow, knee, thumb area, ankle, neck,
wrist, hand and finger, shoulder, etc.
[0024] To improve solubility of non-steroidal anti-inflammatory
drugs, a complex mixture of surfactants, polyglycol(s) and
glycerides has been used in combination with polymers and sodium or
potassium hydroxide solutions as established in Morton et al. (U.S.
Pat. No. 5,376,688).
[0025] In Kaplun-Fischoff et al., "Testosterone Skin Permeation
Enhancement by Menthol Through Formation of Eutectic with Drug and
Interaction with Skin Lipids", J. Pharm Sci. 1997,. December, 86
(12) pp. 1394-9, the researchers observed that menthol forms a
eutectic mixture with crystalline testosterone. The formed mixture
is not liquid, but the composition demonstrated a significant
improvement in transdermal penetration of testosterone. According
Kaplun-Frischoff et al., menthol affects skin permeation by a dual
mechanism: by forming a eutectic with the penetrating compound,
thereby increasing its solubility in skin ceramides and by altering
the barrier properties of the stratum corneum.
[0026] A careful investigation of existing compositions containing
menthol and camphor in different ratios showed that there is no one
example of the specific use of menthol and camphor in combination
as eutectic mixture in order to improve solubility of an included
drug. All anti-inflammatory components used in such formulations
are liquid (methylsalycilate, benzylnicotinate, etc.) and easily
miscible with oil components of the creams or ointments. There is
no limitation for solubility, and these topicals can contain up to
60% of active component, e.g., methylsalycilate), Altadonna (U.S.
Pat. No. 5,853,768).
[0027] In the documentation there has not been a recognition of a
menthol-to-camphor ratio in the eutectic region. In all cases, the
existing preparations are used only due to their mild irritative or
anti-inflammatory activity (camphor, nicotinic acid derivatives) or
skin penetration enhancement properties of menthol itself.
[0028] It has now been recognized that a radical increase of drug
solubility in a eutectic mixture of polar hydrophobic compounds
allows preparation of effective and safe topical formulations with
these drugs for external application.
[0029] One object of one embodiment of the present invention is
thus to provide a vehicle for topical delivery of a
pharmaceutically active component, comprising a liquid eutectic
mixture containing a hydrophobic component.
[0030] A further object of one embodiment of the present invention
is to provide a composition for topical delivery comprising an
oil-in-water or water-in-oil emulsion or microemulsion, wherein the
oil phase of the emulsion comprises a vehicle as set forth in claim
3.
[0031] A still further object of one embodiment of the present
invention is to provide a method for increasing the solubility of a
pharmaceutically active component in a vehicle for topical delivery
of the pharmaceutically active component comprising providing a
pharmaceutically active component; providing at least two compounds
selected from the group consisting of camphor, menthol, thymol,
resorcinol, phenol or substituted phenol derivatives; and forming a
eutectic mixture containing the pharmaceutically active component
and at least two members whereby the mixture contains a greater
amount of solubilzed active component relative to a non eutectic
mixture.
[0032] Having thus described the invention, reference will now be
made to the accompanying drawings illustrating preferred
embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] FIG. 1 is a graphical representation of Diclofenac (free
acid) solubility in a mixture of MCT and a menthol/camphor
mixture;
[0034] FIG. 2 is a graphical representation of Indomethacin
solubility in oleaginous vehicles and in a menthol/camphor
vehicle;
[0035] FIG. 3 is a graphical representation of Piroxicam solubility
in oleaginous vehicles and in a eutectic vehicle;
[0036] FIG. 4 is a graphical representation of drug content change
during storage; and
[0037] FIG. 5 is a graphical representation of comparative
anti-inflammatory activity of topical formulations.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0038] A mixture of equimolar amounts of crystalline camphor and
menthol at room temperature immediately led to liquefied crystals.
This mixture was used in the preparations as an effective solvent
for some NSAID compounds.
[0039] FIG. 1 graphically represents the solubility of Diclofenac
(as free acid) in mixtures of medium chain triglycerides (MCT,
standard oil vehicle, Labrafac.RTM. TGCC) with different levels of
added menthol-camphor eutectic mixture. Diclofenac saturation
concentration at 25.degree. C. was evaluated by HPLC. Solubility in
a pure equimolar menthol-camphor eutectic mixture was found to be
11.8 times higher than in pure MCT.
[0040] Similar behavior was observed also for Indomethacin,
illustrated graphically in FIG. 2. The maximum solubility in an
equimolar eutectic menthol-camphor mixture is 160 mg/ml, compared
with 2 mg/ml in the soy oil or 4.8 mg/ml in MCT oil. For
comparison, Ho et. al. "Penetration Enhancement by Menthol Combined
with a Solubilization Effect in a Mixed Solvent System", J.
Controlled Release 1998, February 12; 51 (2-3), pp. 301-11,
investigated the influence of menthol addition (up to 12% by
weight) as solubility enhancer for Indomethacin in different
pharmaceutical vehicles such as water, ethanol, propylene glycol
and their combinations. In any case the maximum solubility hardly
reached 2% (approximately 20 mg/ml).
[0041] In FIG. 3, further graphic data are presented for
Piroxicam.
[0042] Piroxicam solubility is significantly lower than aromatic
NSAIDs, however, use of the eutectic menthol-camphor mixture
increased drug solubility at room temperature between 8 and 11
times, from 0.35 mg/ml in MCT to 2.9-3.2 mg/ml in pure eutectic
mixture and to 1.8 mg/ml in MCT with 60% menthol-camphor (1:1)
content.
[0043] If alpha-tocopherol or tocopherol acetate is used as the oil
phase, solubility can reach 30-35 mg/ml for a
tocopherol-menthol-camphor composition 5:3:3 (parts by weight).
[0044] Use of other ratios for menthol-camphor eutectic mixture
(e.g., 2:1 or 1:2; 3:4 or 4:3) also improves solubility for most of
the investigated substances, but to a slightly lower extent. Very
significant improvement in solubility was achieved with replacement
of menthol for another eutectic forming substance, thymol
(2-isopropyl-5-methylphenol, thyme oil component).
[0045] Obtained solutions of NSAIDs in lipid phase containing
menthol-camphor or another eutectic mixture vehicle are stable in
wide temperature range and non-irritating for human and animal skin
(Dreize' test). Based on these observations different topical
formulations with NSAIDs were prepared and will now be discussed in
the examples.
EXAMPLE 1
Indomethacin 1% Cream
[0046]
1 TABLE 1 CREAM INGREDIENTS % Per 250 g Indomethacin USP 1.00 2.5
Medium Chain Triglycerides (Labrafac .RTM. 4.00 10 CCTG) Soy
Lecithin (Phospholipon .RTM. S-80) 1.00 2.5 (.+-.) Camphor USP 3.00
7.5 L-(-)-Menthol USP 3.00 7.5 Tween .TM.-80 (Polysorbate 80, USP)
1.60 4.0 TPGS (Tocopherol polyethylene glycol 0.80 2.0 1000
succinate) Sodium Ethylenediamine tetraacetate 0.10 0.25 (EDTA
sodium) Carbopol .RTM. 971 P 1.50 3.75 Glycerin USP 2.50 6.25 Water
81.50 203.75
[0047] Vehicle (Eutectic Mixture) Preparation:
[0048] (.+-.) Camphor and L-Menthol were mixed together during
heating at between 40 and 50.degree. C. until a clear liquid was
obtained.
[0049] Oil Phase Preparation:
[0050] Soy lecithin, MCT oil and TPGS were mixed together at
45.degree. C. until a homogenous solution was obtained.
Tween.TM.-80 as then added, followed by the addition of the
eutectic mixture vehicle. The mixture was stirred until completely
dissolved. Indomethacin (USP grade) was added to the warm mixture
and stirred for 10 minutes at 45.degree. C. until completely
dissolved.
[0051] Water Phase Preparation:
[0052] EDTA disodium salt, glycerin and Tween.TM.-80 were added to
water (90% of calculated amount) and stirred until completely
dissolved.
[0053] Emulsification:
[0054] The solution was combined with the oil phase, mixed
thoroughly using appropriate mixer and homogenized using high
pressure homogenizer (Avestin.RTM. C-5) at 8,000-12,0009 psi,
(600-800 bar). The mixture was passed through the homogenizer
between 2 and 3 times.
[0055] Cream Preparation:
[0056] In a separate vessel Carbopol.RTM. 971 P was mixed with 10%
of calculated amount of water and soaked for between 2 and 6 hours.
Carbopol.RTM. paste was combined with the homogenized emulsion
using a high shear rotor-stator type mixer (Omni GLH mixer) at
18,000-24,000 rpm. Triethanolamine was added gradually while mixing
until the desired pH and viscosity were achieved.
EXAMPLE 2
Indomethacin 2% Cream
[0057] The composition was prepared in accordance with the
methodology of Example 1.
2 TABLE 2 CREAM INGREDIENTS Per 100 g Per 1000 Lipid Phase
Indomethacin USP 2.00 20.00 Medium Chain Triglycerides 8.00 80.00
Egg Lecithin S-75 2.00 20.00 (.+-.) Camphor USP 6.00 60.00
L-(-)-Menthol USP 6.00 60.00 Tween .TM.-80 (Polysorbate-80 USP)
2.00 20.00 TPGS (Tocopherol polyethylene glycol 0.80 8.00 1000
succinate) Water Phase Sodium Ethylenediaminetetraacetate 0.10 1.00
Bronopol .RTM. (2-Brom-2-nitro-1,3- 0.10 1.00 Triethanolamine 0.50
5.00 Ultrez .TM. 10 0.50 5.00 Glycerin 2.20 22.00 Water 69.80
698.00
[0058] Bronopol.RTM. (2-Brom-2-nitro-1,3-propanediol) was added to
the water phase as an antibacterial preservative. Ultrez.TM.was
used as a viscosity regulating component instead of Carbopol.RTM.
without the preliminary hydration step as set forth in Example
1.
EXAMPLE 3
Diclofenac Sodium 1% Cream
[0059] The composition of the emulsion for 1% Diclofenac cream
presented in Table 3. The cream contains approximately 14% of the
oil phase with a ratio MCT:Camphor:Menthol of 6:3:4.
3TABLE 3 Emulsion part of Diclofenac sodium 1% cream. Per 100 g
CREAM INGREDIENTS cream Medium Chain Triglycerides (Labrafac .RTM.
CCTG) 6.00 (.+-.) Camphor USP 3.00 L-(-)-Menthol USP 4.00
Tocopherol succinate 0.02 Soy Lecithin (Phospholipon .RTM. S-80)
0.12 Tween-80 (Polysorbate - 80) 2.00 DICLOFENAC Sodium USP 1.00
Water 80.38 Hydrochloric acid 1N 3.5
[0060] The oil phase was prepared by dissolving MCT, oil Tocopherol
succinate, lecithin, camphor, and menthol at 45.degree. C.
[0061] The water phase was prepared by dissolving Diclofenac sodium
and Tween.TM.-80 in hot 85.degree. C. purified water.
[0062] After mixing the warm oil and hot water phases, hydrochloric
acid was added to coarse emulsion while intensive stirring. The pH
was adjusted to between 3.5 and 4.2. Homogenization was conducted
as described in Example 2. After a fine emulsion was obtained, it
was filtered through 0.45 micron PTFE membrane filter. The emulsion
was used for cream preparation by addition of Carbopol.RTM. 971 as
a gelling agent to a final concentration of 1.5% with pH adjustment
to between 4.5 and 5.0.
[0063] 1.5% Diclofenac sodium emulsion (Example 3A, high loading)
was prepared by a similar manner. The composition is identical to
that tabulated in Table 3. Balance was adjusted with water and
hydrochloric acid.
EXAMPLE 4
Ibuprofen 5% Cream
[0064] 5% Ibuprofen cream was prepared as described in The
composition of the emulsion for 5% Diclofenac cream is presented in
Table 4. The cream contains approximately 26% of the oil phase with
a ratio MCT:Camphor:Menthol of approximately 4.25:1:1.
4 TABLE 4 CREAM INGREDIENTS Per 100 g Per 300 Ibuprofen 5.00 15.00
Medium Chain Triglycerides 13.75 41.25 Soy Lecithin (Phospholipon
.RTM. S-80) 1.20 3.60 (.+-.) Camphor USP 3.25 9.75 L-(-)-Menthol
USP 3.25 9.75 Tween .TM.-80 (Polysorbate-80, USP) 2.00 6.00 TPGS
(Tocopherol polyethylene glycol 0.80 2.40 1000 succinate) Sodium
Ethylenediamine tetraacetate 0.10 0.30 (EDTA sodium) Bronopol .TM.
0.10 0.30 Triethanolamine 1.00 3.00 Carbopol .RTM. 934P 1.00 3.00
Glycerin 2.20 6.60 Water 66.35 398.10
EXAMPLE 5
Piroxicam 0.5% Cream
[0065] The composition was prepared by the method described in
Example 4, but L-(-)-menthol was replaced with thymol
(2-isopropyl-5-methylphenol). The cream contained approximately 28%
of the oil phase with a ratio MCT:Camphor:Thymol:Tocopherol acetate
of approximately 2:5:5:2.
5 TABLE 5 CREAM INGREDIENTS Per 100 g Per 250 Piroxicam 2.00 5.00
Medium Chain Triglycerides 3.00 7.50 Soy Lecithin (Phospholipon
.RTM. S-80) 2.00 5.00 (.+-.) Camphor USP 7.50 18.75 Thymol 7.50
18.75 Tween .TM.-80 (Polysorbate-80, USP) 2.50 6.25 Tocopherol
acetate (Vitamine E 2.00 5.00 acetate) EDTA 0.10 0.25 Carbopol
.RTM. 934P 1.50 3.75 Glycerin 2.20 5.50 Triethanolamine 0.90 2.25
Water 69.70 174.25
EXAMPLE 6
Reference
[0066] Emulsion with Indomethacin, prepared according to U.S. Pat.
No. 6,113,921.
6 TABLE 6 Per 100 g cream 0.5% Indo 1.0% Indo (low (high CREAM
INGREDIENTS (loading) loading) Indomethacin 0.5 1.0 Medium Chain
Triglycerides (MCT oil) 17.0 17.0 Egg Lecithin (Phospholipon .RTM.
E-80) 0.8 0.8 Emulphor EL-620 (polyethoxylated 1.6 1.6 castor oil)
Carbopol .RTM. 940 1.7 1.7 Glycerin 2.2 2.2 EDTA sodium salt 0.05
0.05 Tocopherol acid succinate 0.04 0.05 Triethanolamine 0.65 0.65
Water 75.3 74.5
[0067] Indomethacin (0.5 g for low loading and 1.0 g for high
loading emulsions) was dissolved in a preheated (60.degree. C.)
mixture of egg lecithin, tocopherol succinate and MCT oil. This
mixture was emulsified with a water phase (water with Emulfor
EL-620, EDTA sodium and glycerin) using a high shear mixer for 5
minutes at 20,000 rpm to form an emulsion.
[0068] Further treatment of the emulsion was conducted in a high
pressure homogenizer at 800 bar (12,000 psi) for 6 cycles.
Thereafter, the emulsion was cooled to room temperature, and pH was
adjusted to between 5.6 and 6.5. Part of emulsion was gelled using
Carbopol.RTM. 940 to form a cream; another part was stored at room
temperature in tightly closed amber glass containers for 6 months
to observe the physical stability.
EXAMPLE 7
Diclofenac Sodium 1.0% and 1.5% Creams
[0069] Diclofenac sodium (1.0% and 1.5% drug loading) emulsions
were prepared as described in Example 3 and 3A.
[0070] To estimate drug precipitation, the stored emulsion samples
either for the reference Example 6, low and high loaded or
invention related (Examples 1 and 2) were filtered through PTFE
membrane filters. The Indomethacin content in the filtrates was
measured using the HPLC method. FIG. 4 illustrates the results.
[0071] A low loaded emulsion, prepared in accordance with U.S. Pat.
No. 6,113,921, showed reasonable stability during storage, but with
an increase in the initial Indomethacin loading, the final
concentration of non-precipitated drug decreased drastically. In
contrast, the eutectic mixture vehicle emulsion, prepared in
accordance with the present invention, maintained drug content.
[0072] Similar results have been obtained for Diclofenac sodium
emulsions. In a composition containing 1% of the drug, stability
for both formulations was observed. In a composition containing
1.5% Diclofenac sodium emulsion in the menthol-camphor eutectic
mixture, stability was observed for at least 3 months at room
temperature, while the identically loaded reference emulsion
demonstrated significant drug precipitation during the same
period.
EXAMPLE 8
Salicylic Acid Trolamine Cream
[0073]
7 TABLE 7 Component % Oil Phase Tocopherol acetate (synth.) 3.0
Myvacet .TM. 9-45K (Quest) 9.0 L-Menthol (USP) 2.0 DL-Camphor (USP)
2.0 Cremophor .RTM. EL (BASF) 4.0 Supersat .RTM. AWS (RITA) 2.0
Lecithin (Phosal 53 MCT) 1.5 Ethyl alcohol 1.5 Estol .RTM. 1540
(Ethylhexyl Cocoate, 3.0 Uniguema) Crotix .RTM. (Croda) 2.0
Surfhope .RTM. C-1601 (Mitsubishi) 2.0 Surfhope .RTM. C-1816
(75-25) 2.0 (Mitsubishi) Salicylic acid 7.30 Water phase
Triethanolamine USP/NF 7.70 Bronopol .TM. (BASF) 0.10 Water
purified 50.90 Total 100.00
[0074] Cream containing salicylic acid was prepared using a
different set of surfactants. Salicylic acid was dissolved in the
oil phase of the composition, with triethanolamine added to the
water phase. After emulsification viscosity was adjusted using
Crotix.RTM. (Croda) since Carbopol.RTM. was found inappropriate as
a thickener. Anti inflammatory activity "in vivo":
[0075] Investigations on animals (rats, carrageenan induced paw
edema model) showed significant anti-inflammatory action of the
topically applied compositions containing the eutectic vehicle. The
results are illustrated in FIG. 5. From a review of FIG. 5, it is
evident that the anti-inflammatory efficacy of the formulations of
the present invention (ARX) is superior. This is a consequential
result of the increased solubility and thus amount of the active
ingredient.
8TABLE 8 Area Under the Curve (AUC) ratio for edema volume
(calculated by trapezoidal rule for t = 0-6 hours). GROUP Ratio, %
(.+-.RSD) Control (nontreated) 100% (.+-.28%) Indomethacin cream
(ex. 2) 32% (.+-.12%) 2 mg of Indomethacin/rat Indomethacin gel
(Methacin .TM., Sumitomo Pharm.) 114% (.+-.39%) 2 mg of
Indomethacin/rat Diclofenac sodium cream (ex. 3) 30% (.+-.14%) 2 mg
of Diclofenac sodium/rat Voltaren .RTM. Emulgel .RTM. 82% (.+-.9%)
2 mg of Diclofenac/rat Salicylic acid trolamin cream (ex. 8) 65%
(.+-.18%) (15 mg of salicylate/rat) Marketed Trolamine Salicylate
cream (Aspercream) 89% (.+-.42%) (15 mg of salicylate/rat)
[0076] The area under the curve reflects the duration and intensity
of carrageenan induced inflammation(units are hr*mcl); the graeter
the edema volume, the higher the inflammation and vice versa. A
decrease of AUC corresponds to a decrease of inflammation. AUC for
the contol (non-treated) group was assigned to 100%. According to
table 8 Indomethacin in the eutectic-based formulation is almost 3
times more active than the same dose of Indomethacin in a
conventional cream. Salycilate trolamine in the proposed vehicle
demonstrates 50% higher anti-inflammatory activity.
[0077] Although embodiments of the invention have been described
above, it is not limited thereto and it will be apparent to those
skilled in the art that numerous modifications form part of the
present invention insofar as they do not depart from the spirit,
nature and scope of the claimed and described invention.
* * * * *