U.S. patent application number 10/138777 was filed with the patent office on 2003-05-01 for non-steroidal antiinflammatory drug formulations for topical application to the skin.
Invention is credited to Gyurik, Robert J., Krauser, Scott F., Samour, Carlos M..
Application Number | 20030082226 10/138777 |
Document ID | / |
Family ID | 25444855 |
Filed Date | 2003-05-01 |
United States Patent
Application |
20030082226 |
Kind Code |
A1 |
Samour, Carlos M. ; et
al. |
May 1, 2003 |
Non-steroidal antiinflammatory drug formulations for topical
application to the skin
Abstract
Topical alcoholic or aqueous alcoholic gels containing ibuprofen
or other NSAIDs, such as, naproxen, in substantially neutral salt
form, have enhanced penetration through skin and may provide rapid
pain/inflammation relief by including in the formulation
2-n-nonyl-1,3-dioxolane or other hydrocarbyl derivative of
1,3-dioxolane-or 1,3-dioxane or acetal, as skin penetration
enhancing compound. The amount of propylene glycol may be varied to
adjust the initial flux of the NSAID through the skin, especially
for ibuprofen, naproxen, and ketorolac.
Inventors: |
Samour, Carlos M.; (Bedford,
MA) ; Krauser, Scott F.; (Tyngsboro, MA) ;
Gyurik, Robert J.; (Exeter, NH) |
Correspondence
Address: |
Pillsbury Winthrop LLP
Intellectual Property Group
1600 Tysons Boulevard
McLean
VA
22102
US
|
Family ID: |
25444855 |
Appl. No.: |
10/138777 |
Filed: |
May 6, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10138777 |
May 6, 2002 |
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09416420 |
Oct 12, 1999 |
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10138777 |
May 6, 2002 |
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08921057 |
Aug 29, 1997 |
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5976566 |
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Current U.S.
Class: |
424/449 |
Current CPC
Class: |
A61K 9/06 20130101; A61K
47/22 20130101; A61K 47/10 20130101; A61K 31/192 20130101; A61K
9/0014 20130101; A61P 29/00 20180101; Y10S 514/944 20130101; A61K
47/08 20130101; Y10S 514/946 20130101 |
Class at
Publication: |
424/449 |
International
Class: |
A61K 009/70 |
Claims
What is claimed is:
1. A substantially neutral ibuprofen containing alcoholic or
aqueous alcoholic composition which comprises, on a weight basis,
of the total composition: a therapeutically effective amount of
ibuprofen in the form of a pharmacologically acceptable salt of; a
skin penetration enhancing effective amount of a C.sub.7 to
C.sub.14-hydrocarbyl substituted 1,3-dioxolane, 1,3-dioxane or
acetal; 0 to about 18% of glycol having from 3 to 6 carbon atoms;
at least about 40% of volatile alcohol selected from the group
consisting of ethanol, propanol and mixture thereof; 0 to about 40%
water; base to provide a pH in the range of from about 6 to about
8, and, optionally, a gelling agent effective to thicken the
composition to avoid or minimize run-off when applied to the
skin.
2. The composition according to claim 1 which comprises from about
2 to 10% ibuprofen; from about 4 to 15% of the enhancer wherein the
hydrocarbyl group substituent has from about 7 to 10 carbon atoms;
from about 0 to 15% propylene glycol; from about 55 to 70% ethanol;
from about 4 to 35% water; base in amount to adjust the pH of the
composition in the range of from about 6.5 to about 7.5, and, 0 to
about 2% of cellulosic thickener.
3. A substantially neutral alcoholic or aqueous alcoholic topical
composition effective for the transdermal delivery of non-steroidal
anti-inflammatory drug which comprises, based on the weight of the
total composition, a therapeutically effective amount of a
pharmacologically acceptable salt of a non-steroidal
antiinflammatory drug selected from the group consisting of
heteroaryl acetic acids, arylpropionic acids (other than
ibuprofen), anthranilic acids, enolic acids, alkanones, sulindac
and etodolac; from about 0.5 to 25% of C.sub.7 to
C.sub.14-hydrocarbyl derivative of 1,3-dioxolane, 1,3-dioxane or
acetal as skin penetration enhancer; 0 to about 40% of glycol
having from 3 to 6 carbon atoms; at least about 40% of volatile
alcohol selected from the group consisting of ethanol, propanol and
mixtures thereof; up to about 40% water; base in an amount to
provide a pH of from about 6 to about 8, and up to about 5% gelling
agent.
4. The composition according to claim 3 which comprises: from about
0.1 to 10% diclofenac, ketorolac, naproxen, flurbiprofen,
ketoprofen or piroxicam; from about 2 to 15% of the skin
penetration enhancer; 0 to about 30% propylene glycol; from about
35 to 70% ethanol, isopropanol or mixture thereof; 0 to about 20%
water; from about 0.1 to 3% gelling agent, and base to provide a pH
in the range of from about 6.5 to about 7.5.
5. A glycol-free topical composition effective for the transdermal
administration of naproxen, which comprise, on a weight basis of
the total composition: a pharmaceutically effective amount of
naproxen, from about 2 to 20% of 2-C.sub.7-C.sub.14 hydrocarbyl
substituted 1,3-dioxolane, 1,3-dioxane, or acetal skin penetration
enhancer; from about 35 to 85% ethanol, iso-propanol, or mixture
thereof; 0 to about 40% water; base in an amount to provide a pH in
the range of from about 6 to about 8, and up to about 5% gelling
agent.
6. A method for the transdermal administration of ibuprofen to a
patient in need thereof which comprises topically applying to the
skin of the patient a substantially neutral composition comprising
from about 5 to 15 weight percent of ibuprofen in a vehicle
comprising a lower alcohol selected from the group consisting of
ethanol, isopropanol and mixture thereof, alkyl glycol having from
3 to 6 carbon atoms, and water in a mixing ratio of
alcohol:glycol:water of 40-80:0-20:0-40, said vehicle comprising
from about 70 to 90 weight percent of the composition, and from
about 5 to 15 weight percent of a skin penetration enhancing
compound selected from the group consisting of
2-hydrocarbyl-1,3-dioxolan- e, 2-hydrocarbyl-1,3-dioxane and
hydrocarbyl substituted-acetal, wherein the hydrocarbyl group has
from 7 to 14 carbon atoms.
7. A method for the transdermal administration of a non-steroidal
antiinflammatory drug selected from the group consisting of
heteroaryl acetic acids, arylpropionic acids (other than
ibuprofen), anthranilic acids, enolic acids, alkanones, sulindac
and etodolac to a patient in need thereof which comprises topically
applying to the skin of the patient a substantially neutral
composition comprising from about 0.1 to 10 weight percent of the
non-steroidal antiinflammatory drug in a vehicle comprising a lower
alcohol selected from the group consisting of ethanol, isopropanol
and mixture thereof, alkyl glycol having from 3 to 6 carbon atoms,
and water in a mixing ratio of alcohol:glycol:water of
40-80:0-40:0-40, said vehicle comprising from about 70 to 90 weight
percent of the composition, and from about 0.5 to 25 weight percent
of a skin penetration enhancing compound selected from the group
consisting of 2-hydrocarbyl-1,3-dioxolane,
2-hydrocarbyl-1,3-dioxane and hydrocarbyl substituted-acetal,
wherein the hydrocarbyl group has from 7 to 14 carbon atoms.
8. A method for the transdermal administration of naproxen to a
patient in need thereof which comprises topically applying to the
skin of the patient a substantially neutral composition comprising
a therapeutically effective amount of naproxen in a glycol-free
vehicle comprising a lower alcohol selected from the group
consisting of ethanol, isopropanol and mixture thereof, and water
in a mixing ratio of alcohol:water of 35-85:10-40, said vehicle
comprising from about 70 to 90 weight percent of the composition,
and from about 2 to 20 weight percent of a skin penetration
enhancing compound selected from the group consisting of
2-hydrocarbyl-1,3-dioxolane, 2-hydrocarbyl-1,3-dioxane and
hydrocarbyl substituted-acetal, wherein the hydrocarbyl has from 7
to 14 carbon atoms.
Description
FIELD OF INVENTION
[0001] This invention relates to topical compositions for
transdermal administration of a non-steroidal antiinflammatory drug
(NSAID) through the skin of a patient and to the method for
transdermally administering the non-steroidal antiinflammatory drug
using the topical composition.
DISCUSSION OF THE PRIOR ART
[0002] All drugs must be administered in such a manner that they
reach the intended site in the body in an optimal concentration
(amount of drug per unit volume of blood) to achieve the desired
effect at the proper time, and for an appropriate length of time.
Customarily, drugs are taken orally, injected, inhaled, or applied
topically. These conventional routes of administration often fail
to meet the stated objectives, however. For example, when drugs are
absorbed into the blood stream by whatever route, peaks and valleys
in the blood concentration of the drug occur and may cause
undesirable effects (e.g., peak levels), or loss of activities
(e.g., valleys). To meet these problems, a variety of approaches
have been investigated. These include, for example, special drug
coatings, combining the drug with other materials, suspensions or
emulsions, and compressed tablets. Although these formulations
attempt to control the release of drugs from their carriers, the
desired effects are often not reproducible, may be subject to
patient-to-patient variations, and may not be suitable for
prolonged periods of delivery, such as days or even months.
[0003] Recent research has, produced systems in which a drug is
implanted in the body, released from skin sites, introduced in to
the body by minipumps, and/or released in minute quantities through
the skin. These innovative drug-delivery systems are improving drug
effectiveness and also are opening opportunities for new
pharmaceuticals.
[0004] The administration of drugs and other biological materials
to the bloodstream via a transdermal route of administration has
received much attention in recent years. The skin of an average
adult covers more than two square meters of surface area and
receives about one-third of all blood circulating through the body.
It is elastic, rugged, and generally self-generating. The skin
consists of three layers: the stratum corneum (S.C.), the
epidermis, and the dermis. The stratum corneum represents the
rate-limiting step in diffusion of chemical through the skin. The
S.C. is composed of dead, keratinized, metabolically inactive cells
which are closely packed together, and consists of an amorphous
matrix of mainly lipoid and nonfibrous protein within which keratin
filaments are distributed. The cells-of the S.C. generally contain
20% water, while the cells below, in the stratum germinativum,
contain 70% water. The S.C. does not become hydrated readily. Thus,
transdermal permeation is primarily controlled by diffusion through
the S.C.
[0005] There are several major reasons for the interest in devices
for transdermal delivery of drugs:
[0006] elimination of uncertainties of absorption from, and
irritation to, the gastrointestinal tract which arise when drugs
are administered orally.
[0007] bypassing the portal circulation, thereby eliminating
first-pass metabolism in the liver; this is extremely important for
drugs with short half-lives, or with potential unwanted actions on
the liver.
[0008] delivery of medication directly into the systemic
circulation at a constant rate (similar to intravenous
infusion).
[0009] infrequent dosing (daily, weekly or longer) for certain
drugs.
[0010] ease of use; foster patient compliance.
[0011] However, present transdermal delivery systems have major
drawbacks. For example, they are restricted to low-molecular weight
drugs and those with structures having the proper
lipophilic/hydrophilic balance. High molecular weight drugs or
drugs with too high or low hydrophilic balance often cannot be
incorporated into current transdermal systems in concentrations
high enough to overcome their impermeability through the stratum
corneum.
[0012] Transdermal delivery is generally restricted to those
medications requiring delivery rates less than 10 mg/day. In order
to obtain higher blood levels, the rate of drug delivery must be
increased. There have been many proposals to accomplish the higher
rate of drug delivery via the use of absorption promoters and by
the development of prodrugs that can be more readily absorbed.
Examples of existing absorption enhancers include dimethyl
sulfoxide (DMSO), ethylene glycol, hexanol, fatty acid and esters,
and pyrrolidone derivatives, among others. One such enhancer
compound which has received much attention is Azone (N-dodecyl
azacycloheptan-2-one) developed by Nelson Research Labs., Irvine
Calif.
[0013] One of the present applicants has previously developed a new
class of compounds which are derivatives of 1,3-dioxanes and
1,3-dioxolanes for use as skin penetration enhancing compounds.
These compounds, which have been made commercially available under
the trademark SEPA.RTM., are described in detail in U.S. Pat. No.
4,861,764. Work with the dioxolane enhancers has been described in
several literature and patent publications. For example, Samour, et
al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 16: 183-184
(1989); Marty, et al., Proc. Int. Symp. Control. Rel. Bioact.
Mater. 16:179-180 (1989); Marty,.et al., Proc. Int. Symp. Control.
Rel. Bioact. Mater. 17:415-416 (1990); Michniak, et al., Drug
Delivery 2:117-122 (1995); Marty, et al., "Indomethacin and
Ibuprofen Percutaneous Absorption In Vivo & In Vitro: Influence
of 2-n-Nonyl-dioxolane On The Bioavailability" Abstract of Paper
Presented at American Association of Pharmaceutical Scientists,
Washington, D.C., Mar. 26-28, 1990.
[0014] In the article by Michniak, et al., the effect of the
vehicle selected for the formulation was noted to play a very
important role in the optimization of activity. In particular, it
was noted that in certain cases propylene glycol was shown to
possess a synergistic effect with Azone, depending on the model
drug tested.
[0015] Propylene glycol was also used as a vehicle, usually
together with ethanol and water, in the studies reported in the
articles by Marty, et al. More specifically, in the above noted
abstract, Marty et al report the effect of 2-n-nonyl-1,3-dioxolane
(0.5%, w/w) with Ibuprofen or Indomethacin delivery in a vehicle
system of propylene glycol (PG)/ethanol (EtOH) (50:50, v/v) or
PG/EtOH/H.sub.2O (20/60/20, v/v), respectively. These studies were
performed on the dorsal skin of hairless female rats or, in some
cases, human skin. The formulations containing the enhancer were
more effective than control and more effective than compositions
containing Azone as the enhancer.
[0016] The use of an aqueous alcoholic gel for the percutaneous
delivery of Ibuprofen is the subject of U.S. Pat. No. 5,093, . The
gel contains, by weight of the total formulation, about 1 to 15%
S-ibuprofen, 0 to 20% propylene glycol; about 40 to 60% alcohol;
about 2.0 to 5.0% gelling agent and pH modifier to obtain an acidic
pH in the range of 3.5 to 6.0. The rate of delivery of Ibuprofen is
stated to be pH dependent. Use of skin penetration enhancing
compound is not disclosed.
[0017] In addition to the background literature referred to in the
5,093,133 patent, the following patents relate to topical
formulations for the transdermal delivery of NSAIDs: U.S. Pat. Nos.
4,185,100; 5,164,416, 5,374,661. The latter of these patents is
particularly concerned with a neutral pH composition for
transdermal delivery of diclofenac and uses a mixture of water, low
molecular weight alcohol and a glycol. The addition of the glycol
is stated to enhance the transdermal delivery of diclofenac. Data
in this patent shows that dipropylene glycol and hexylene glycol
provided higher skin flux through human skin than with propylene
glycol. This patent further states that the effectiveness of
topical diclofenac in treating inflammation and/or painful joints
and muscles depends significantly on the particular skin
penetrating vehicle with which it is used. These patentees use
ether alcohols or fatty alcohol esters to enhance the transdermal
permeation of diclofenac.
[0018] The present inventors have continued to study the effect of
the 1,3-dioxane and 1,3-dioxolane derivatives and related acetals
as skin penetration enhancer compounds for ibuprofen and other
NSAIDs. Surprisingly, it has been found that when propylene glycol
is used in the vehicle for the ibuprofen formulations, but not for
other NSAIDs, such as diclofenac, ketoprofen, piroxicam, the
initial flux rate of ibuprofen decreased as the amount of propylene
glycol (PG) increased. Just the opposite effect was observed for
the other tested NSAID compounds. In both cases, however, the total
payload over a twenty-four hour period is substantially the same.
That is, the area under the curve obtained by plotting flux rate
over time is the same at 24 hours but the profile of the curves for
ibuprofen is dramatically different than for the other tested NSAID
compounds.
[0019] The present inventors also discovered that at the lower pH's
most effective for enhancing the flux of ibuprofen, the
1,3-dioxolane and 1,3-dioxane penetration enhancing compounds
become unstable. Applicants have been able to overcome this problem
by incorporating the ibuprofen in the form of its substantially
neutral (e.g., pH=about 6 to about 8, preferably about 6.5 to 7.5)
salt by neutralizing the formulation using an appropriate base,
such as sodium hydroxide. This observation of enhancement of the
transdermal drug delivery at neutral pH was unexpected since it was
originally thought that neutralization of the drug would make it
less lipophilic and inhibit its diffusion through the strateum
corneum.
[0020] It has further been discovered that the flux rates and/or
total delivery of NSAIDs, such as, for example, diclofenac, are
substantially improved using the 1,3-dioxolane, 1,3-dioxane or
corresponding acetal compound skin penetration enhancing
compounds.
[0021] Another surprising discovery by the present inventors is
that for certain of the NSAID active ingredients, such as,
naproxen, the permeation through the skin is further enhanced when
glycol, e.g., propylene glycol, is omitted from the
formulation.
SUMMARY OF INVENTION
[0022] The present invention has as a principal object to provide
stable topical compositions effective for the transdermal
application of ibuprofen or other NSAID compounds by the
application of the composition to the skin.
[0023] The above and other objects of the invention, which will
become more apparent from the following more detailed description
and preferred embodiments is achieved, according to a first aspect
of the invention, by an ibuprofen containing alcoholic or aqueous
alcoholic composition which comprises, on a weight basis, of the
total composition:
[0024] a therapeutically effective amount of ibuprofen in the form
of its pharmacologically acceptable salt;
[0025] a skin penetration enhancing effective amount of a C.sub.7
to C.sub.14-hydrocarbyl substituted 1,3-dioxolane, 1,3-dioxane or
acetal;
[0026] 0 to about 18% of glycol having from 3 to 6 carbon
atoms;
[0027] at least 40% of volatile alcohol selected from the group
consisting of ethanol, propanol and mixture thereof;
[0028] 0 to about 40% water; and,
[0029] base to provide a pH in the range of from about 6 to about
8; and
[0030] optionally, a gelling agent effective to thicken the
composition to avoid or minimize run-off when applied to the
skin.
[0031] In a preferred embodiment of this aspect of the invention
the ingredients are included in the formulation in the following
ranges:
[0032] from about 2 to 10% ibuprofen;
[0033] from about 2 to 15% of the enhancer wherein the hydrocarbyl
group substituent has from about 7 to 10 carbon atoms;
[0034] from about 0 to 15% propylene glycol;
[0035] from about 55 to 70% ethanol, isopropanol or mixture
thereof;
[0036] from about 4 to 35% water; and, base to provide a pH in the
range of from about 6.5 to about 7.5; and
[0037] 0 to about 2% of cellulosic thickener.
[0038] According to another aspect of the invention there are
provided alcoholic or aqueous alcoholic topical compositions
effective for the transdermal delivery of non-steroidal
anti-inflammatory drug which comprises, based on the weight of the
total composition,
[0039] a therapeutically effective amount of a non-steroidal
antiinflammatory drug selected from the group consisting of
heteroaryl acetic acids, arylpropionic acids (other than
ibuprofen), anthranilic acids, enolic acids, alkanones, sulindac
and etodolac;
[0040] 0.5 to about 25% of C.sub.7 to C.sub.14-hydrocarbyl
derivative of 1,3-dioxolane, 1,3-dioxane or acetal as skin
penetration enhancer;
[0041] 0 to about 40% of a glycol having from 3 to 6 carbon
atoms;
[0042] at least about 40% of volatile alcohol selected from the
group consisting of ethanol, propanol and mixtures thereof;
[0043] 0 to about 40% water; and
[0044] base to provide a pH of from about 6 to about 8; and
[0045] 0 to about 5% gelling agent.
[0046] According to a preferred embodiment of this second aspect of
the invention the composition comprises:
[0047] from about 0.1 to 10% diclofenac, ketorolac, naproxen,
flurbiprofen, ketoprofen or piroxicam;
[0048] from about 2 to 15% of the skin penetration enhancer;
[0049] 0 to about 30% propylene glycol;
[0050] from about 35 to 70% ethanol or isopropanol or mixture
thereof;
[0051] 0 to about 20% water;
[0052] base to provide a pH in the range of from about 6.5 to about
7.5; and
[0053] up to about 3% gelling agent.
[0054] In still yet another aspect of the invention, the NSAID is
naproxen and the glycol component is eliminated from the
formulation. According to this third aspect of the invention, there
are provided glycol-free topical compositions effective for the
transdermal administration of naproxen, which comprise, on a weight
basis of the total composition:
[0055] a pharmaceutically effective amount of pharmacologically
acceptable salt of naproxen,
[0056] from about 2 to 20% of 2-hydrocarbyl group substituted
1,3-dioxolane, 1,3-dioxane, or acetal skin penetration enhancer
wherein the hydrocarbyl group has from 7 to 14 carbon atoms;
[0057] from about 50 to 85% ethanol and/or iso-propanol;
[0058] 0 to about 40% water; and
[0059] base in amount to provide a pH in the range of from about 6
to about 8; and
[0060] up to about 5% gelling agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0061] FIG. 1 is a ternary phase diagram showing the miscibility of
2-n-nonyl-1,3-dioxolane skin penetration enhancer at 10 wt.%
(.box-solid.) or 2 wt.% (.circle-solid.) in an ethanol-propylene
glycol-water vehicle;
[0062] FIG. 2 is a ternary phase diagram showing the miscibility of
the 1,3-dioxolane skin penetration enhancer at 10 wt.%
(.circle-solid.) or 2 wt.% (.largecircle.) in an
isopropanol-propylene glycol-water vehicle;
[0063] FIG. 3 is a bar graph plotting the flux of ibuprofen Na in
an in vitro study as a function of time at 2, 4 or 6 hours post
topical application for formulations containing 5% ibuprofen and 0%
(bar A), 5% (bar B), 10% (bar C), 15% (bar D) or 20% (bar E) of
propylene glycol in an aqueous-alcoholic (ethanol) gel
formulation;
[0064] FIG. 4 is a graph plotting flux of ibuprofen Na versus time
in an in vitro study (Example 3) for an aqueous alcoholic gel
according to the invention and containing 10 wt.% of
2-n-nonyl-1,3-dioxolane skin penetration enhancer (.diamond.), or a
similar gel without skin penetration enhancer (.gradient.), or for
four commercial topical ibuprofen preparations: Gelufene.RTM.
(.quadrature.), Deep Relief.TM. (.largecircle.), Ibutop.RTM.
(.DELTA.) and Dolgit.RTM. (.diamond-solid.);
[0065] FIG. 5 is a graph plotting cumulative diffusion of ibuprofen
Na versus time for the same samples used in the study of FIG. 4;
and
[0066] FIG. 6 is a graph plotting the number (percentage) of
respondents reporting pain relief as a function of time (minutes)
in a clinical trial as described in Example 6 using either a
formulation according to this invention (.largecircle.) or a pooled
vehicle (.quadrature.).
[0067] FIG. 7 is a graph plotting flux of ibuprofen Na versus time
in the in vitro study of Example 4 for aqueous alcoholic gels
containing 5 wt. % ibuprofen, sodium, 10 wt. % of
2-n-nonyl-1,3-dioxolane skin penetration enhancer and 0% propylene
glycol (PG) (.box-solid.), 5 wt. % PG (.circle-solid.), 10 wt. % PG
(.tangle-solidup.), 15 wt. % PG (.diamond.), 20 wt. % PG
(.diamond-solid.) or 20 wt. % isopentyldiol (IP)
(.largecircle.).
[0068] FIG. 8 is a graph plotting flux of ibuprofen Na versus time
in the in vitro study of Example 5 for aqueous alcoholic gels
containing 10 wt. % of penetration enhancer and either 2.5 wt. %
ibuprofen, sodium with (.box-solid.) or without (.diamond.)
propylene glycol (PG); 5 wt. % IB with (.circle-solid.) or without
(.diamond-solid.) propylene glycol; and 10 wt. % IB with
(.tangle-solidup.) or without (.largecircle.) propylene glycol.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
[0069] The compositions of the invention are intended for topical,
non-invasive, application to the skin, particularly to the region
where the non-steroidal anti-inflammatory active ingredient is
intended to exert its pharmacological activity, usually to a region
of inflammation, injury or pain to the muscles or joints, or other
form of cutaneous disorders or disruptions characterized by skin
inflammation and/or hyperproliferative activity in the
epidermis.
[0070] Examples of the non-steroidal antiinflammatory drug (NSAID)
which is advantageously administered by the topical formulations of
this invention include heteroaryl acetic acids., such as, for
example, tolmetin, diclofenac, ketorolac; arylpropionic acids, such
as, for example, ibuprofen, naproxen, flurbiprofen, ketoprofen,
fenoprofen, oxaprozin; anthranilic acids (fenamates), such as, for
example, mefenamic acid, meclofenamic acid, fhilenamic acid; enolic
acids, such as, for example, oxicams (e.g., piroxicam, tenoxicam),
pyrazolidinediones (e.g., phenylbutazone, oxyphenthatrazone);
alkanoes, such as, for example, nabumetone. Among these, especially
preferred, based on the current level of knowledge in the
pharmacological arts, are ibuprofen, diclofenac, ketorolac,
naproxen, flurbiprofen, ketoprofen and piroxicam. More generally,
however, any of the government approved NSAIDs, such as listed in,
for example, the most current edition of The Merck Index, may be
advantageously used.
[0071] According to the present invention the NSAID is administered
in the form of its pharmacologically acceptable substantially
neutral salt. The formulations are made substantially neutral by
addition of a pH modifying agent (base) in an amount to provide a
pH in the range of from 6.0 to 8.0, preferably from 6.5 to 7.5,
especially preferably from 6.8 to 7.4, such as 7.0. Any of the well
known and pharmacologically safe inorganic or organic basic
compounds can be used for this purpose and examples include
inorganic salt, such as the sodium or other alkali or alkaline
earth metal salts such as hydroxides, e.g., sodium hydroxide or
potassium hydroxide; ammonium salt; or organic salt, especially
amine salt, such as, for example, diethylamine; diethanolamine,
triethanolamine, diisopropanolamine, N-methylglucamine,
ethanolamine, isopropylamine, tetrahydroxypropyl ethylene diamine
methylamine, ethylamine, propylamine, and the like.
[0072] For any particular formulation the NSAID and other
ingredients may be selected to achieve the desired drug delivery
profile and the amount of penetration desired. The optimum pH may
then be determined and will depend on, for example, the nature of
the NSAID, the base, and degree of flux required.
[0073] The penetration of the active ingredient through the skin is
enhanced to an acceptable level by including in the composition a
skin penetration enhancing effective amount of an enhancer compound
of the substituted 1,3-dioxacyclopentane and substituted
1,3-dioxacyclohexane types disclosed in U.S. Pat. No. 4,861,764,
the disclosure of which is incorporated herein in its entirety by
reference thereto, or the corresponding substituted acetal
compound. Representative examples of the skin penetration enhancing
compounds include:
[0074] 2-substituted 1,3-dioxolanes of the formula (I): 1
[0075] 2-substituted 1,3-dioxanes of the formula (II): 2
[0076] substituted-acetals of the formula (III): 3
[0077] In the above formulas (I), (II) and (III) R preferably
represents a C.sub.7 to C.sub.14 hydrocarbyl group,
[0078] R.sub.0, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and
R.sub.6, each, independently, represent hydrogen or a C.sub.1 to
C.sub.4 alkyl group.
[0079] R'.sub.1 and R'.sub.2, each, independently, represent
C.sub.1 to C.sub.4 alkyl group.
[0080] The hydrocarbyl group for R may be a straight or branched
chain alkyl, alkenyl or alkynyl group, especially alkyl or alkenyl.
Preferably, R represents a C.sub.7 to C.sub.12 aliphatic group;
especially C.sub.7 to C.sub.10 aliphatic group. Examples of
suitable alkyl groups include, for example, n-hexyl, n-heptyl,
n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 2-methyl-octyl,
4-ethyl-decyl, 8-methyl-decyl, and the like. The straight chain
alkyl groups, such as n-heptyl, n-octyl, n-nonyl and n-decyl, are
especially preferred. Examples of alkenyl groups include, for
example, 2-hexenyl, 2-heptenyl, 2-octenyl, 2-nonenyl, 2',
6'-dimethyl-2', 6'-heptadienyl, 2', 6'-dimethyl-2'heptaenyl, and
the like. The R group may also be substituted by, for example,
halo, hydroxy, carboxy, carboxamide and carboalkoxy.
[0081] The C.sub.1 to C.sub.4 alkyl group may be, for example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and the
like. The preferred alkyl groups for R.sub.0, and for R.sub.1 to
R.sub.6 and for R'.sub.1 and R'.sub.2 are alkyl having 1 or 2
carbon atoms, most especially ethyl. R.sub.0, and R.sub.1 to
R.sub.6 may also, preferably, all be hydrogen.
[0082] Specific enhancer compounds include, for example,
2-n-pentyl-1,3-dioxolane, 2-n-heptyl-1,3-dioxolane,
2-n-nonyl-1,3-dioxolane, 2-n-undecyl-1,3-dioxolane,
2-n-nonyl-1,3-dioxane, 2-n-undecyl-1,3-dioxane,
2-n-heptylaldehyde-acetal- , 2-n-octyl-aldehyde-acetal,
2-n-nonylaldehyde-acetal, 2-n-decylaldehyde-acetal,
3,7-dimethyl-2,6-octadienal (citral), citronal and the like.
2-n-nonyl-1,3-dioxolane is especially preferred and is commercially
available from MacroChem Corporation of Lexington, Mass., under the
trademark SEPA.RTM..
[0083] The amount of the enhancer compound is selected to provide
the desired delivery rate for the active compound but, taking into
consideration such additional factors as, product stability, side
effects, carrier system and the like. Generally, depending on the
particular NSAID and other vehicles, amounts in the range of from
about 0.5 to 25%, preferably from about 2 or 3 to 12 or 15 percent,
especially from about 5 to 10 percent, of the composition, will
provide optimal flux rate and 24 hour payload of the active
ingredient. Usually, for cream formulations the amount of enhancer
compound may be lower than for gel formulations, such as from about
2 to 10 percent of the formulation.
[0084] The compositions are generally formulated as gels,
especially aqueous-alcoholic gels. However, other forms, such as,
for example, lotions, creams, mousses, aerosols, ointments,
lubricants, etc., may be used so long as when applied to the
affected area of the skin the formulation will stay in place, i.e.,
without run-off, for sufficient time, to permit an individual to
spread and retain the composition over and on the affected
area.
[0085] The vehicle for any of the forms of the compositions of the
invention will include glycol, e.g., propylene glycol, butylene
glycol, hexylene glycol, etc. (except in the case of the third
embodiment described above), lower alcohol, e.g., ethanol,
isopropanol, and, usually, water. A thickening or gelling agent is
also usually and preferably included to facilitate application of
the formulation to the skin. In addition, of course, the skin
penetration enhancing dioxolane, dioxane or acetal is included in
the formulations in an amount effective to enhance the penetration
of the active NSAID ingredient through the skin, including the
stratum corneum.
[0086] Accordingly, the vehicle or carrier system for the NSAID and
enhancer components is preferably an aqueous or non-aqueous
alcoholic carrier containing sufficient alcohol, especially ethanol
and/or isopropanol and, often, glycol, e.g., propylene glycol, to
solubilize the NSAID and be miscible with the enhancer. Generally,
however, depending on the amounts of enhancer and NSAID in the
formulations the aqueous alcoholic carrier can contain from about
35% to about 70% of ethyl alcohol and/or isopropyl alcohol,
preferably, from about 50 to about 70 percent of ethanol or from
about 45 to 55 percent of isopropanol. Mixtures of ethanol and
isopropanol in proportions providing the desired solubility of
NSAID and compatibility with the enhancer can also be used. More
generally, however, the present inventors have developed
miscibility data for combinations of alcohol (ethanol or
isopropanol), glycol (propylene glycol) and water for the enhancer
(2-n-nonyl 1,3-dioxolane). This data is graphically represented by
the ternary phase diagrams provided as FIG. 1 (for ethanol) at 2
wt. % (.circle-solid.) and 10 wt. % (.box-solid.) of the enhancer
compound and FIG. 2 (for isopropanol) at 2 wt. % (.largecircle.)
and 10 wt. % (.circle-solid.) of the enhancer compound. In each of
these phase diagrams, the upper portions (above the lines
connecting the data points) represent the proportions at which the
vehicle components are miscible with each other and with the
enhancer; conversely, the region below the lines connecting the
data points represent the proportions where the vehicle components
are immiscible.
[0087] Again, the total amount of the aqueous or non-aqueous,
alcoholic carrier will depend on the amount of NSAID, amount and
type of enhancer, and the form of the composition, e.g., gel,
cream, ointment, etc. Usually amounts of the aqueous or non-aqueous
alcoholic carrier within the range of from about 70% to about 95%
may be used.
[0088] In the preferred compositions which are in the form of a
gel, a thickening agent, such as hydroxypropyl cellulose, will be
included as a gelling agent. However, any other pharmaceutically
acceptable thickening/gelling agent may be used. For example,
mention may be made of other cellulosic ethers, polymeric
thickening agents, e.g., acrylic acid polymers, Carbopol.RTM.
thickeners, etc., xanthan gum, guar gum, and the like, as well as
inorganic thickeners/gelling agents. The amount of-the thickening
agent is not particularly critical and can be selected to provide
the desired product consistency or viscosity to allow for easy
application to the skin but which will not be too watery or loose
so that it will stay where applied. Generally, depending on its
molecular weight, amounts of thickening agent up to about 5%, such
as, for example, from 0.1 to about 2%, of the composition will
provide the desired effect.
[0089] As also well known in this art, it is possible to include
other ingredients in the formulations for particular aesthetic
and/or functional effects. For example, the formulations may,
optionally, include one or more moisturizers for hydrating the skin
and emollients for softening and smoothing the skin. Glycerin is an
example of such a suitable moisturizing additive. When present the
additive will usually be incorporated in an amount of up to about 5
percent by weight of the composition, for example, from about 0.1
to 5%.
[0090] The effects of the topical compositions according to the
invention are further illustrated by way of the following
representative examples which in no way are intended to limit the
scope of the invention.
EXAMPLE 1
[0091] This example compares the percutaneous absorption through
porcine skin, of ibuprofen from aqueous alcoholic gels containing 5
wt. % ibuprofen and either 5%, 10% or 15% of
2-n-nonyl-1,3-dioxolane, using an ethanol/water carrier at a 70:30
mixing ratio. The formulations include NaOH to adjust the pH to
7.4, but do not include a glycol. Hydroxypropyl cellulose (2 wt. %)
is used as the gelling agent. The test compositions are applied to
provide about 30 milligrams (mg) of the composition per square
centimeter (cm.sup.2) of porcine skin.
[0092] The tests are run in standard static cells with phosphate
buffered saline (PBS) as the receptor fluid (surface area 0.635
cm.sup.2, temperature 32.degree. C.). The following Table 1 shows
the total amount of ibuprofen applied to the skin for each
formulation. The differences result from the slightly different
thicknesses at which the test formulations are applied. Each test
was run for 24 hours under non-occluded conditions with the finite
dose of the test formulation.
1 TABLE 1 Total Amount of Ibuprofen applied Amount of Enhancer to
skin sample (.mu.g) Enhancer (wt. %) per 0.635 cm.sup.2 cell
2-n-nonyl-1,3- 5 988 dioxolane 2-n-nonyl-1,3- 10 1051 dioxolane
2-n-nonyl-1,3- 15 1038 dioxolane
[0093] The results are obtained and reported in Table 2 as the
average values for six (6) cells (samples). The initial flux over
the first two hours was significantly higher for each formulation
containing the 1,3-dioxolane, but especially at the higher level
(15%, maximum flux about 8.5 .mu.g/cm.sup.2/hr; 5% and 10%, maximum
flux about 4 .mu.g/cm.sup.2/hr) of the enhancer. The flux tended to
even out after 4 to 6 hours and continued at about the same level
for at least about 24 hours. The results for total amount of
ibuprofen vs. time (flux); and the payout of ibuprofen at 24 hours,
total and percent of dose, are shown in the following Table 2:
2TABLE 2 Amount Flux (.mu.g/cm.sup.2/hr) Delivery at 24 h Enhancer
(%) 2 h 4 h 6 h 24 h Total (.mu.g) % of Dose 5 4 2 1.5 1 20.2 .+-.
6.9 2.1 .+-. .7 10 4 2 1.5 1.5 26.6 .+-. 8.1 2.4 .+-. .6 15 8 4 3.5
3.5 57.7 .+-. 33.4 5.4 .+-. 2.5
[0094] When the procedure of Example 1 was repeated but using 5%,
10% or 15% of Azone.TM., the initial flux at 2 hours and 4 hours
was only between about 1 to 1.5 .mu.g/cm.sup.2/hr.
EXAMPLE 2
[0095] This example shows the effect of incorporating propylene
glycol in the aqueous alcoholic gel formulation containing 5%
ibuprofen and 10% 2-n-nonyl-1,3-dioxolane using an ethanol:water
vehicle at a 70:30 weight mixing ratio. The compositions used in
these tests are shown in Table 3 (NaOH is added to adjust the pH to
7.4):
3 TABLE 3 propylene ibuprofen enhancer glycol Ethanol Water Total
(%) (%) (%) (%) (%) (%) A 5 10 0 59.5 25.5 100 B 5 10 5 56 24 100 C
5 10 10 52.5 22.5 100 D 5 10 15 49 21 100 E 5 10 20 45.5 19.5
100
[0096] The test was run using the same conditions as described in
Example 1. The flux was measured at 2, 4 and 6 hours. The results
are shown graphically in FIG. 3. From this figure it is seen that
the flux at 2 hours decreases nearly linearly as the propylene
glycol (PG) content increases from 0% to 5% to 10% to 15% to 20%.
At four hours after the composition is applied to the test skin
sample the fluxes for each concentration of PG has increased but
more so for the compositions containing the higher amounts of PG.
Finally, at 6 hours the fluxes begin to even out.
[0097] This example, therefore, shows that only low or no propylene
glycol should be included in the ibuprofen topical-composition
using the 2-substituted-1,3-dioxolane, 2-substituted-1,3-dioxane or
substituted acetal as the penetration enhancer where the goal is to
administer large quantity of active ingredient as quickly as
possible such that relief from pain or inflammation can begin
rapidly, for example in the treatment of sunburn or other burn
injury or for relief of muscular pain caused by inflammation.
However, over the longer period of time essentially the same amount
of ibuprofen is percutaneously delivered at each amount of
propylene glycol.
EXAMPLE 3
[0098] This example is similar to Example 1 but compares a topical
aqueous alcoholic gel formulation with ibuprofen according to the
present invention with a similar gel but without the enhancer and
with four other commercially available topical ibuprofen
formulations. Also, human skin was used rather than porcine skin.
The composition according to the present invention and the
comparison were as follows:
4 Invention Comparison Ingredient Amount (wt. %) Amount (wt. %)
Ibuprofen 5 5 2-n-nonyl-1,3- 10 0 dioxolane Ethanol 59 65 Propylene
glycol 17 19 Water 7 9 Hydroxypropyl 2 2 cellulose Sodium Hydroxide
q.s. to pH 7 q.s. to pH 7
[0099] The commercially available products were: Gelufene.RTM.
(ibuprofen 5%, isopropyl alcohol, hydroxyethylcellulose, sodium
hydroxide, benzyl alcohol and purified water), Dolgit.RTM. cream
(ibuprofen 5%, medium chain triglycerides, mixture of glycerol
monostearate and polyoxyethylene stearates, polyoxyethylene fatty
acid esters, xanthan gum, lavender oil, neroli oil, water,
propylene glycol, parahydroxybenzoate of methyl soda), Ibutop.RTM.
(ibuprofen 5%) (Laboratoire Chefaro-Ardeval, Saint-Denis Cedex,
France) and Deep Relief.TM. gel (ibuprofen 5%, menthol, Carbomer,
propylene glycol, di-isopropanolamine, ethanol, purified
water).
[0100] The results are shown in FIG. 4 for flux versus time and in
FIG. 5 for cumulative diffusion of ibuprofen through the skin
sample. The initial flux and cumulative amount of the ibuprofen are
both significantly higher for the invention formulation than for
the control or commercial products.
EXAMPLE 4
[0101] This Example is also similar to Example 1 but is designed to
compare the percutaneous absorption through porcine skin of
ibuprofen (as the sodium salt) from 5% ibuprofen formulations
containing 10% 2-n-nonyl-1,3-dioxolane with 5%, 10%, 15% or 20%
propylene glycol (PG) or 20% isopentyldiol (IP). The test
conditions were otherwise the same as used in Example 1. The
formulations tested are,shown in Table 4:
5TABLE 4 glycol Run Ibuprofen Enhancer PG or IP EtOH Water Total
No. (%) (%) % (%) (%) (%) 1 5 10 0 PG 59.5 25.5 100 2 5 10 5 PG
58.9 21.1 100 3 5 10 10 PG 58.3 16.7 100 4 5 10 15 PG 57.6 12.4 100
5 5 10 20 PG 56.9 8.1 100 6 5 10 20 IP 56.9 8.1 100
[0102] The flux of ibuprofen in the receptor cell was measured and
the results are shown in FIG. 7. In this case, the peak flux was
reached for the formulations of Run Nos. 1-4 within four hours
after application and reached values in the range of from about 60
to 72 .mu.g/cm.sup.2/hr. For the 20% PG formulation (run #5) the
peak flux was reached at 6 hours and was about 50
.mu.g/cm.sup.2/hr. For the 20% IP formulation (run #6) the peak
flux was only about 16 .mu.g/cm.sup.2/hr and was not reached until
8 hours after application.
[0103] The following Table 5 shows the results reported for the
cumulative amount of ibuprofen reaching the receptor cell after 24
hours, and the amount reaching the receptor cell as a percentage
(%) of the dose applied after 24 hours.
6 TABLE 5 Delivery at 24 h Run PG or IP (wt. %) Total (.mu.g) %
Dose 1 0 541.7 .+-. 4.8 60.1 .+-. 8.6 2 5 PG 519.8 .+-. 53.7 57.9
.+-. 5.7 3 10 PG 498.6 .+-. 58.9 56.5 .+-. 6.6 4 15 PG 443.5 .+-.
105.1 50.1 .+-. 11.4 5 20 PG 358.5 .+-. 73.5 40.7 .+-. 8.4 6 20 IP
144.5 .+-. 31.1 16.6 .+-. 3.6
EXAMPLE 5
[0104] This example is designed to demonstrate the effect of
concentration of ibuprofen (IB) on flux and total delivery (24h)
for formulations with and without propylene glycol. The test were
run under the same conditions as in Example 1 except that human
skin was used, an 80/20 mixture of PBS and ethanol was used as the
receptor fluid, and the pH was adjusted to 7.7 with sodium
hydroxide; the test compositions which were prepared and tested
(the enhancer was 2-n-nonyl-1,3-dioxolane) are shown in the
following Table 6:
7TABLE 6 Run Ibuprofen Enhancer PG EtOH Water Total No. (%) (%) (%)
(%) (%) (%) 1 2.5 10 17.5 61.25 8.75 100 2 5 10 17 59.5 8.5 100 3
10 10 16 56 8 100 4 2.5 10 -- 61.25 26.25 100 5 5 10 -- 59.5 25.5
100 6 10 10 -- 56 24 100
[0105] The flux as a function of time for each of the test
formulations is shown in FIG. 8. Comparing the results for Run Nos.
1 and 4, Run Nos. 2 and 5 and Run Nos. 3 and 6, it is seen that in
each case the maximum (peak) flux and time to reach peak flux were
higher and quicker for the formulations without propylene
glycol.
[0106] The results for the cumulative dose of ibuprofen at 24 hours
and the percentage of the original dose passing through the skin at
24 hours are shown in the following Table 7:
8 TABLE 7 Delivery at 24 h Run PG(wt %)/IB(wt %) Total (.mu.g) %
Dose 1 17.5/2.5 193.5 .+-. 37.3 37.6 .+-. 6.5 2 17/5 361.9 .+-.
116.3 38.2 .+-. 12.7 3 16/10 615.2 .+-. 152.6 29.8 .+-. 7.5 4 0/2.5
392.2 .+-. 189.1 80.4 .+-. 30.2 5 0/5 535.7 .+-. 189.1 53.6 .+-.
19.9 6 0/10 805.9 .+-. 214.4 41.2 .+-. 8.8
[0107] These results show, for example, that the formulation with
10% ibuprofen but without propylene glycol (Run No. 6) gives the
highest flux. Furthermore, the formulation of Run No. 4 (2.5g IB
per 100 g formula+0 PG) will deliver 80 mg of ibuprofen over a 100
cm.sup.2 area.
EXAMPLE 6
[0108] This example shows the results of a clinical study on human
patients experiencing severe pain. The same formulation as shown in
Example 3 (10% 2-nonyl-1,3-dioxolane and 5% ibuprofen and 17%
propylene glycol) is used in these-studies. As control, a pooled
vehicle (mixture of first formulation with no drug and no enhancer
and second formulation with no drug but with enhancer) was
similarly tested. The results are shown in FIG. 6.
EXAMPLE 7
[0109] This Example compares percutaneous absorption-through human
skin of Naproxen Na from various formulations containing 5% (w/w)
Naproxen gels with or without propylene glycol and with or without
skin penetration enhancer compound (2-n-nonyl-1,3-dioxolane). The
tests were run under the same conditions described in Example 5
(pH=7.7) using the gel formulations as shown in Table 8:
9TABLE 8 Run Naproxen Enhancer PG EtOH Water Total No. (%) (%) (%)
(%) (%) (%) 1 5 0 -- 66.5 28.5 100 2 5 5 -- 63 27 100 3 5 10 --
59.5 25.5 100 4 5 0 19 66.5 9.5 100 5 5 5 18 63 9 100 6 5 10 17
59.5 8.5 100
[0110] With these Naproxen gel formulations the highest flux and
highest total delivery was achieved with the formulation of Run No.
2 (0% PG+5% enhancer). The peak flux was observed 4 hours after
application of the gel on the skin.
[0111] The results for the cumulative dose of naproxen at 24 hours
and the percentage of the original dose passing through the skin at
24 hours are shown in the following Table 9:
10 TABLE 9 Delivery of Naproxen Na at 24 h Run PG(wt %)/enhancer(wt
%) Total (.mu.g) % Dose 1 0/0 51.5 .+-. 16.6 5.2 .+-. 1.4 2 0/5
499.0 .+-. 96.9 52.3 .+-. 10.9 3 0/10 369.1 .+-. 74.8 35.9 .+-. 7.5
4 19/0 29.4 .+-. 12.4 2.9 .+-. 1.1 5 18/5 149.5 .+-. 40.3 15.0 .+-.
4.0 6 17/10 409.6 .+-. 113.8 39.7 .+-. 12.3
[0112] These results appear to show that propylene glycol is not
functioning as an enhancer in the subject formulations (compare,
e.g., Run No. 1 with Run No. 4) and further, propylene glycol has
an adverse impact on the delivery of the NSAID, Naproxen.
EXAMPLE 8
[0113] This example illustrates the effect of propylene glycol (PG)
on delivery of various NSAIDs from aqueous formulations containing
10 wt. % of skin penetration enhancer, 2-n-nonyl-1,3-dioxolane. All
the tested formulations included ethanol and water at a 70:30
weight ratio and were neutralized with base to a pH of about 7. The
tests were run in standard static cells under substantially the
same conditions as described in Example 1 but using human skin
rather than procine skin. The tested compositions and results are
shown in the following Table 10.
11TABLE 10 Avg 24 Hour NSAID Drug Drug conc. % enhancer % PG % Dose
Ketoprofen 2.5% 10 0 9.1 10 5 10.3 10 10 12.0 10 20 27.0 Piroxicam
0.5% 10 0 66.3 10 10 55.1 10 20 63.5 Ibuprofen 5% 10 0 61.7 10 5
57.9 10 10 56.5 10 15 50.1 10 20 28.3 Diclofenac 1% 10 0 18.7 10 5
29.7 10 10 35.3 10 20 45.2 Ketorolac 1% 10 0 10.8 10 5 27.1 10 10
25.0 10 20 19.3 Naproxen 5% 10 0 35.9 10 20 39.7
[0114] As may be readily ascertained from these results the effects
of propylene glycol differs substantially from one NSAID to
another. The effect, in terms of total delivery (reported as
percent of original dose) at twenty four hours) of NSAID is
positive for ketoprofen and diclofenac; substantially neutral for
piroxican and naproxen; negative for ibuprofen (particularly at the
high levels of propylene glycol); and intermediate for
ketorolac.
EXAMPLE 9
[0115] This example further illustrates the effects of PG on drug
delivery (0.5% piroxicam) at two different levels of the enhancer,
2-n-nonyl-1,3-dioxolane (5% or 10%) versus a control (0% enhancer,
0% PG) and a commercial product, Geldene.RTM. (0.5% piroxicam in
the form of its diisopropanolamine (DIPA) salt; approximately 24%
ethanol; >0 PG). In the compositions according to the invention
and the control triethanolamine (TEA) was used as the base to
neutralize the piroxicam and the vehicle was ethanol:water (70:30).
The formulations and test procedures were, otherwise, as described
in Example 8. The results are shown below in Table 11.
12TABLE 11 Propylene Enhancer Peak Flux % of Dose Run No. Glycol
(wt %) (wt. %) .mu.g/cm.sup.2/h 24 h 9-1 0 10 8.7 66 9-2 10 10 8.5
55 9-3 20 10 9.8 64 9-4 0 5 7.0 54 9-5 10 5 6.4 46 9-6 20 5 6.6 47
9-7 (control) 0 0 3 11 9-8 (Gelden .RTM.) >0 -- 2 13
[0116] From these results it is observed that PG has little or no
effect on drug delivery at either 5% or 10% of enhancer. However,
all the formulations with enhancer provide significantly higher
peak and total drug delivery than either the control or the
commercial product. There is no significant different in
performance between-the control and the commercial product.
EXAMPLE 10
[0117] This example further illustrates the effects of the
invention with diclofenac as the NSAID. The test procedure was
substantially the same as previously described using either human
(H) or porcine (P) skin and an ethanol:water (70:30) vehicle.
2-n-nonyl-1,3-dioxolane was used as the skin permeation enhancer
compound according to the invention. The results are shown in Table
12 below. In Run Nos. 10-A through 10-G 1 wt. % of diclofenac (as
free acid) was used. In Run Nos. 10-I and 10-J (commercial product)
0.93 wt. % of diclofenac (as free acid) was used.
13TABLE 12 Enhancer Peak Flux % of dose Run No. Base PG (%) (%)
Skin .mu.g/cm.sup.2/h 24 h 10-A Na 20 10 P 12 40 10-B Na 10 10 P 10
36 10-C Na 5 10 P 6 30 10-D Na 20 5 P 8 28 10-E Na 0 10 P 2.5 19
10-F Na 20 0 P 1 8 10-G DEA.sup.b 20 10 H 15 76 10-H Na 20 10 H 10
46 10-I DEA 20 10 H 11 46 10-J.sup.a DEA -- -- H 1.5 10
.sup.aEmugel (Voltaren) .sup.bdiethylamine
[0118] From the above results reported in Table 12 the following
observations and conclusions may be drawn. The first set of
experiments, Run Nos. 10A-10C, show that PG exerts a positive
effect as a co-enhancer for diclofenac. In a second set of
experiments Run Nos. 10D-10F, it is seen that the combination of PG
with the dioxolane enhancer provides better performance than might
be expected from the results with dioxolane enhancer alone and with
PG alone. From the third set of experiments, Run Nos. 10-G and
10-H, it is observed that DEA as the counterion (base) provides
better performance than sodium (Na). Finally, from the fourth set
of experiments, Run Nos. 10-I and 10-J it is seen that the
formulation according to the present invention provides
significantly improved performance in comparison to a commercial
diclofenac topical formulation.
EXAMPLE 11
[0119] This example shows the effects of multiple daily
applications of a formulation according to the invention (10%
2-n-nonyl-1,3-dioxolane, 20% PG, 70:30 EtOH/H.sub.2O) and a
commercial topical NSAID formulation (Emulgel). Each product was
applied to human skin sample with second and third applications
following at 8 hour intervals. The results are shown below in Table
13.
14TABLE 13 Peak Flux Run No. .mu.g/cm.sup.2/h .mu.g at 24 h 11-A
(Diclofenac, Na, 0.93%) 1st Application (0 h) 13 125 2nd
Application (8 h) 11 230 3rd Application (16 h) 18 360 11-B
(Emulgen, Diclofenac-DEA, 0.93%) 1st Application (0 h) 9 100 2nd
Application (8 h) 4 100 3rd Application (16 h) 10 130
[0120] Accordingly, it is seen that a single application of the
topical diclofenac formulation according to the present invention
provides comparable performance to 3 applications of the commercial
diclofenac topical formulation. Whereas, 3 daily applications of
the topical NSAID formulation of this invention provides nearly a
three-fold higher delivery of drug than 3 applications of the
commercial product while a two-fold improvement in drug delivery is
obtained with 2 daily applications of the invention product as
compared to 2 daily applications of the commercial product.
* * * * *