Note: Descriptions are shown in the official language in which they were submitted.
i~390~3
PENETRATION ENHA~CEMENT WITH BINARY SYSTEM OF CELL
E~VELOPE DISORDERING COMPOUNDS AND LOWER ALCOHOLS
This invention relates to compositions which
enhance the penetration of pharmaceutically-active
agents through the integument. More particularly, this
invention relates to binary combinations of per.etration
enhancers which facilitate percutaneous and
transepidermal delivery of a broad range of
pharmaceutically-active agents.
The resistance of the skin to being penetrated by
pharmaceutically-active agents is well documented. As
compared to mucosal tissues, the stratum corneum is
compact and highly keratinized. The lipids and
proteins of the stratum corneum, although relatively
thin, is compact and quite impermeable. Such
impermeability of the skin is highly essential to the
well being of a living organism in that it serves as a
barrier to the ingress of pathogens and toxic
materials, and the egress of physiologic fluids.
1339073
The impermeability of pharmaceutical agents
through the skin is due to the nature of the very thin
stratum corneum layer which is only 10-15 cells, i.e.
about 10 microns thick. This layer is formed naturally
by cells migrating toward the skin surface from the
basal layer. Cells slowly move from the basal layer to
the surface where they are sloughed off. As they
progress toward the surface they become progressively
more dehydrated and keratinized.
Because of the advantages of dermal application
of pharmaceutically-active agents, various penetration
enhancers have been sought. A penetration enhancer is
one or more compounds which alter the skin as a barrier
to increase the flux of a desired pharmaceutical
permeant across the skin.
Penetration enhancers have been primarily
categorized according to their ability to enhance
permeant flux via three pathways. The first is the
continuous polar or aqueous pathway composed of
proteins. It is t'nought that solvent swelling or
protein conformational changes provide the key to
altering the penetration of the polar pathway.
Surfactants alter the transport of polar permeant
molecules to a much greater extent than the transport
of nonpolar permeants. Solvents such as DMSO,
2-pyrrolidone and dimethylformamide can swell the
stratum corneum to also enhance the polar pathway.
The second pathway is a continuous non-polar
pathway consisting of lipids. The key to altering this
pathway appears to be fluidizing the lipids which, in
the stratum corneum, appear to be crystalline.
Solvents such as DMSO, 2-pyrrolidone, and
dimethylformamide, previously mentioned also appear
able to solubilize or fluidize lipids. Other solvents
include diols such as glycerol and propylene glycol.
_ 3 1 3 39 0 73 69912-120
The third pathway is a heterogeneous polar-nonpolar
multilaminate of lipids and proteins. Binary vehicles appear best
suited to act as enhancers on this multilaminate pathway. Prior
art binary systems consist of a particular category of a polar
solvent combined with a variety of compounds generally referred to
as "cell-envelope disordering compounds".
U.S. Patent 4,537,776, Cooper, issued August 27, 1985
contains an excellent summary of prior art and background
information detailing the use of certain binary systems for
permeant enhancement. That patent teaches using a binary system
wherein N-(2-hydroxyethyl)pyrrolidone is used as the solvent and
the cell-envelope disordering compounds are selected from the
group consisting of methyl laurate, oleic acid, oleyl alcohol,
moloolein, myristyl alcohol and mixtures thereof.
Similarly, European Patent Application 43,738, published
January 13, 1982, teaches using selected diols as solvents along
with a broad category of cell-envelope disordering compounds for
delivery of lipophilic pharmacologically-active compounds. This
reference also teaches that cosmetically acceptable solvents may
also be combined with permeant and the diol and cell-envelope
disordering compounds provided the solvent evaporates rapidly and
completely to leave only the active components of the composition
at the site of application. The acceptable solvents are stated to
be ethanol or isopropanol.
4 1339073
Most of the cell-envelope disordering compounds
mentioned in these publications are unsaturated lipid
components having polar head groups.
A binary system for enhancing metoclopramide
penetration is disclosed in UK Patent Application GB
2,153,223 A, published August 21, 1985 and consists of
a monovalent alcohol ester of a C8-32 aliphatic
monocarboxylic acid (unsaturated and/or branched if
C18-32) or a C6-24 aliphatic monoalcohol (unsaturated
and/or branched if C14-24) and an N-cyclic compound
such as 2-pyrrolidone, N-methylpyrrolidone and the
like. It is postulated that the N-cyclic compound
serves a solvent function which carries the active
aqent whereas the esters or alcohols serve as adjuvants
to open up the stratum corneum, i.e. as cell-envelope
disordering compounds.
2~ In referring to the epidermal permeability of
lower alkanols, Drug Delivery Systems, Characteristics
and Biomedical Applications, Oxford University Press,
NY, 1981, edited by R. L. Juliano, teaches at page 159
that simple alcohols through n-butanol have epidermal
permeabilities no different than that of water.
However, Campbell et al, U.S. Patent 4,379,454;
Campbell et al, U.S. Patent 4,460,372 and Gale et al,
U.S. Patent 4,588,580 refer to the use of gelled
ethanol as an enhancer in specialized transdermal or
percutaneous drug delivery devices.
From the above cited art and incorporated
disclosures, it is apparent that some binary enhancers
favor lipophilic permeants. There appears to be no
recognition of an enhancer system that favors the
penetration of salts and other hydrophilic permeants.
Moreover, those binary systems containing diols and
N-cyclic solvents may cause considerable skin
irritation even at low concentrations. However, diols
s 1339073
or N-cyclic solvents are taught to be necessary
components of a binary system. In general, simple
alcohols are taught to be cosolvents to help bring
various mixtures into solution but are to be evaporated
rapidly from the skin surface and do not function as
penetration enhancers any better than water.
Other patents or publications relating to
1~ transdermal administration of active permeants are
Cooper, European Patent Application 95,813,A2,
published July 12, 1983, entitled Penetrating Topical
Pharmaceutical Compositions Containing
9-(2-Hydroxyethoxymethyl)Guanine; Durrant et al,
European Patent Application 117,080, published August
29, 1984 entitled Skin Treatment Composition.
The present invention relates to improved
compositions and methods for improving the penetration
of a broad category of pharmaceutically-active agents
which are lipophilic or hydrophilic including salts and
which produce little or no skin irritation to human or
animal tissue systems. The invention provides
penetrating topical compositions based on the use of a
~5 pharmaceutically-active agent dissolved in, or admixed
with, a penetration-enhancing binary mixture of (a) one
or more cell-envelope disordering compounds and (b) a
C2 or C3 alcohol.
By employing this binary mixture it has been
found that significant penetration of salts and other
hydrophilic permeants as well as lipophilic permeants
is obtained and that skin irritation often associated
with cell-envelope disordering compounds and/or
solvents is essentially nonexistent.
The invention is therefore not limited to any
specific category or categories of permeants but is
inclusive of all therapeutically active compounds and
6 1339073
their use which are responsive by being incorporated
into the binary mixture as more fully set forth herein.
Also, the invention is drawn to treatment methods
by means of which an effective amount of a permeant,
combined with the binary mixture, is topically applied
to a human or animal subject.
The following definitions, when used and as they
1~ apply to the present invention, are consistent with
those contained in U. S. Patent 4,537,776.
By "topical administration" or "topical
application" is meant directly laying or spreading upon
epidermal tissue, especially outer skin or membrane,
including the skin or membrane of the oral or vaginal
cavities.
By "safe and effective", is meant a sufficient
2~ amount of the permeant composition to provide the
desired systemic effect and performance, or local
activity, or both at a reasonable benefit/risk ratio
attendant any medical treatment. Within the scope of
sound medical judgment, the amount of permeant used
will vary with the particular condition being treated,
the severity of the condition, the duration of the
treatment, the specific permeant compound employed, its
concentration, the condition of the patient, concurrent
therapies being administered and other factors within
3~ the knowledge and expertise of the patient or the
attending physician or other practitioner.
By "toxicologically- or
pharmaceutically-acceptable" is meant the
pharmaceutical actives (or permeants), as well as the
other compatible drugs, medication or inert ingredients
which the term describes, are suitable for use in
contact with the tissues of humans and animals without
-- 7 1339073
undue toxicity, irritation, allergic résponse, and the
like, commensurate with a reasonable benefit/risk
ratio.
By the term "comprising" is meant that various
other compatible drugs and medicaments, as well as
inert ingredients, occlusive agents, and cosmetic
vehicles, can be conjointly employed in the
compositions and methods of this invention, as long as
the critical binary penetration enhancement vehicle and
pharsnaceutically active permeant are used.
By "afflicted situs" is meant a localized area of
pathology, discomfort, infection, inflammation or
lesion, and the immediately surrounding area.
By "application situs" is meant a site suitable
for topical application with or without the means of a
2~ mechanical sustained release device, patch or dressing,
e.g. behind the ear, on the arm, back, chest, stomach,
leg, top of foot, etc.
By "penetration-enhancing" is meant that the
binary penetration enhancing carriers or vehicles of
this invention provide marked transepidermal or
percutaneous delivery of an incorporated active
permeant, when compared to other compositions at equal
chemical potential. Equal chemical potential is
important since varying solubilities of drugs in
different carrier vehicles will affect their transport
across skin. As stated in U. S. Patent 4,537,776, if a
drug is soluble in vehicle A to the extent of 24%, and
in vehicle B to the extent of 4%, were the compositions
to be compared at equal percentage concentration,
rather than equal chemical potential, the lower
solubility carrier would show a misleading six-fold
difference in transport over the more soluble vehicle.
Therefore, the simplest way of assuring equal chemical
-_ 8 1 3 3 9 0 73
potential for evaluating penetration enhancement is to
use saturated solutions or solutions of equal
percentage of saturation of active permeants in the
various enhancer combinations, e.g. 50% saturated. In
the examples used herein, the enhancer combinations are
saturated with the active permeant components.
As used herein, all percentages and ratios are by
weight of the total composition unless otherwise
specified.
The terms "permeant", "active", "pharmaceutical
active",
"pharmacological active", "pharmaceutical agent",
"pharmacological agent", "pharmaceutically-, or
pharmacologically-active agent", "chemical agent",
"therapeutic agent", and "drug", are used
interchangeably herein.
The compositions of this invention require, at a
minimum, a permeant capable of producing systemic
effects, or producing or possessing local activity, in
a binary vehicle or carrier comprising a cell-envelope
disordering compound and a lower alcohol selected from
the group consisting of ethyl alcohol, propyl alcohol
or isopropyl alcohol.
The composition may also contain other optional
3~ components which enhance their cosmetic appeal or
acceptability, i.e., thickeners, pigments, fragrances,
perfumes and the like.. The binary penetration
combinations are essentially free of skin irritation
characteristics. However, a permeant combined with the
penetration enhancers may cause some irritation.
Therefore, if desired other components which tend to
reduce skin irritation may be incorporated into the
compositions.
9 1339073
The binary penetration enhancement combinations of the present invention
significantly enhance the penetration of a host of ph~ çeutically-active permeants
including salts. These permeants may be lipophilic or hydrophilic or partially lipophilic or
hydrophilic.
The binary combinations comprise one or more cell-envelope disordering compound
and a lower alkanol selected from the group consisting of ethanol, propanol and
isopropanol.
The cell envelope disordering compounds are known in the art as being useful in
topical pharmaceutical preparations. These compounds are thought to assist in penetration
by disrupting or disordering the lipid structure of the stratum corneum cell-envelopes. A
comprehensive list of these compounds is described in European Patent Application 43,738,
published June 13, 1982. Some additions to the structural formulae disclosed therein have
been made to include certain glycerol esters. It is sufficient for purposes of this disclosure
to state that the cell envelope disordering compounds are encompassed by the formula R-X
wherein R is a straight-chain alkyl of about 7 to about 16 carbon atoms, a non-terminal
alkenyl of about 7 to about 22 carbon atoms, or a branched-chain alkyl of from about 13 to
about 22 carbon atoms, and X is -OH, -COOCH3,
-COOC2H5, -OCOCH3, -SOCH3, -P(CH3)20,
-COOC2H40C2H40H,-COCH(CHOH)4CH20H,
-COOCH2CHOHCH3,-COOCH2CHCH20R2,
-(OCH2CH2)m
oR2
or -COOR', or -CON-Rl, where Rl is -H, -CH3,
-C2H5,
Rl
X
1339073
_ 10
-C3H7 or -C2H4OH; R is -H, or a non-terminal
alkenyl of about 7 to about 22 carbon atoms; and m is
2-6; the ratio of cell envelope-disordering compound:
C2 or C3 alcohol compound being in the range of
from about 1:50 to about 50:1 by weight.
Numerous specific cell envelope disordering
compounds are listed in European Patent Application
43,738. The cell envelope disordering compounds
preferred for use in combining with ethanol, propanol
or isopropanol to form penetration enhancing
compositions of the present invention include oleic
acid, oleyl alcohol, glycerol trioleate, glycerol
dioleate, glycerol monoleate (monoolein) methyl oleate
and methyl laurate and mixtures thereof. Particularly
preferred are oleic acid and glycerol dioleate and
mixtures thereof.
2~ Binary mixtures of a C2-C3 alcohol and any of
the above referenced cell-envelope disordering
compounds, in a weight:weight ratio of alcohol to
cell-envelope disordering compound of about 50:1 to
about 1:50, provide significantly enhanced penetration
for the permeants described herein. A weight:weight
ratio of alcohol:cell-envelope disordering compounds of
from about 1:9 to 9:1 is preferred.
The compositions of the invention typically
contain from about 40 to 99.99~, and preferably about
70 to 99.9~, by weight of the overall composition, of
the penetration enhancing binary mixture of C2 or
C3 alcohol and the cell-envelope disordering compound
employing the ratios described above. The exact
percentages may be readily determined by one having
ordinary skill in the art. All that is required is
that an effective amount of the active permeant be
incorporated into the penetration enhancing composition
with or without being combined with other ingredients.
'- 11 13~gO73
-
The binary penetration enhancers of the present
invention may be formulated to incorporate a broad
range of pharmaceutically-active permeants. One of the
distinct advantages of these enhancer combinations is
that they function to enhance penetration of both
lipophilic and hydrophilic permeants including salts
and are virtually free from skin irritation effects.
1~ The compositions of this invention may be utilized in
delivering active permeants to the "target" areas as
mentioned in U. S. Patent 4,537,776, i.e. (l) at the
surface of the skin; (2) in the stratum corneum itself;
(3) in the viable epidermis and upper dermis, just
below the stratum corneum; (4) in the various glands
and structures in and beneath the dermis (e.g.,
subcutaneous adipose, dermal vasculature); and/or (5)
the general system (i.e. systemic effects).
In view of this, the invention is not limited to
any specific type or class of active permeants. Based
on the parameters contained herein it is within the
ability of one having ordinary skill in the art to
determine which permeants can be utilized. Some
routine experimentation or testing may be required to
determine optimum conditions such as exact
concentrations of permeants, ratios of cell-envelope
disordering compounds to alcohols, and the like. Also,
some permeants may work best with one particular class
of cell-envelope disordering compounds and/or alcohols.
The screening of all possible combinations and ratios
of permeants, cell-envelope disordering compounds and
C2 and C3 alcohols has not been attempted.
However, based on the formulation of a
representative sampling of diverse active permeants, it
is apparent that the binary combination of a
cell-envelope disordering compound and a C2 or C3
alcohol will function to enhance the penetration of a
~ 12 i339073
broad spectrum of pharmaceutically-active permeants.
Such agents include, without limitation, those
mentioned in U. S. Patent 4,537,776 such as
antimicrobials, antibacterials, antibiotics,
antimyobacterials, antimalarials, antiamebics,
anthelmintics, antifungals, antivirals, neoplastic
agents, agents affecting the immune response, blood
calcium regulators, peptide and protein hormones, male
sex hormones, female sex hormones, agents useful in
glucose regulation, anticoagulents, antithrombotics and
hemostatics, antihyperlipidemic agents, cardiac drugs,
thyromimetic and antithyroid drugs, adrenergics,
antihypertensive agents, cholinergics,
anticholinergics, antispasmodics, antiulcer agents,
skeletal and smooth muscle relaxants, histamine
H2-receptor agonists and antagonists, prostaglandins,
general inhibitors of the allergic response,
antihistamines, local anesthetics, analgesics,
antitussives, sedative-hypnotic agents,
anticonvulsants, antipsychotics, anti-anxiety agents,
antidepressant agents, anorexigenics, non-steroidal
anti-inflammatory agents, steroidal anti-inflammatory
agents, bone-active agents, antiarthritics, vitamins,
diagnostic agents and sunscreens. These agents can be
used for systemic effect, local activity, or both, as
appropriate. Examples of pharmaceutically-active
permeants are well-known in the art and can be found
listed in sources identified in U. S. Patent 4,537,776
as well as others. For example, active agents, in
approved commercially available formulations, their
recommended dosages, adverse reactions, side effects
and the like are listed in the annual publication of
the Physicians' Desk Reference, published by Medical
Economics Company, a division of Litton Industries,
Inc.
The pharmaceutically-active permeants may be used
in the compositions and methods of the present
13 1339073
invention at any safe and effective level, or in any safe and effective amount. Dosages
will obviously be a function of various variables, such as how active the agent is, how
soluble it is in the penetration enhancing composition, how often it is to be applied,
whether the use is to be topical (applied to the "afflicted situs") or systemic (applied to the
"application situs"), whether two or more active permeants are to be combined, the
particular patient being treated, and the like. In any event the dosage will be the smallest
that will achieve the desired result and the period of aflministration will be as short as
possible to attain this result.
In general, dosages and means of application as taught in U.S. Patent 4,337,776 are
appropriate to the present invention. Levels of active permeants may vary from about
0.01% to about 40% by weight of the total composition with levels of from about 0.01 to
30% being preferred. Levels from about 0.05 to 15% being especially preferred and levels
of from about 0.1 to 10% being most especially preferred for some active permeants.
However, for some active permeants it may be required to use more or less than stated
above to attain the desired results. Hence, the invention is not directed to any particular
amount of active ingredient as long as it is safe and effective.
A compendium of active permeants is contained in U.S. Patent 4,537,776 and
published European Patent Application 43,738. However, for purposes of illustration a
more concise listing of active agents follows.
Typical antihypertensive agents which may be utilized include, without limitation,
minoxidil, nadolol, pargyline, pindolol, propranolol, reserpine,
_ 1339073
14
timolol, trimethaphan, metoprolol, hydrochlorothiazide,
hydralazine, furosemide, clonidine and chlorthalidone.
S Diuretics include, without limitation,
benzthiazide, buthiazide, cyclopenthiazide,
cyclothiazide, metolazone, triamterelene, chlorazamil,
clazolimme, and hydroflumethiazide.
Exemplary of anorexigenics are, without
limitation, amphetamine, methamphetamine,
chlorphentermine, chlortermine, phentermine,
phendimetrazine, mazindol, oxazoline, and
phenoxyalbyleneamine.
Fungistatic and fungicidal agents encompass,
without limitation, thiabendazole, chloroxine,
fungimycin, griseofulvin, chlordantoin, salicylic acid,
nystatin, clotrimazole, fezatione, socium pyrithione,
amphotericin B, 5-fluorocytosine, haloprogin, vifampin,
and pimaricin.
A broad range of analgesics may be utilized
including without limitation, morphine, codeine,
heroine, methadone, thebaine, orpiarine, buprenorphine,
morphinans, benzomorphans, acetaminophen, butorphanol,
diflunisal, fenoprofen, fentanyl, fentanyl citrate,
hydrocodone, ibuprofen, oxymorphone, pentaxicine,
naproxen, nalbuphine, mefenamic acid, meperidine and
dihydroergotamine.
Exemplary antitussive agents include, without
limitation, diphenhydramine, guaifenesine,
hydromorphone, ephedrine, phenylpropanolamine,
theophylline, codeine, noscapine, levopropoxyphene,
carbetapentane, chlorpehndianol and benzonatate.
Among the sedatives which may be utilized are,
without limitation, chloralhydrate, butabarbital,
1S 1339073
alprazolam, amobarbital, chlordiazepoxide, diazepam,
mephobarbital, secobarbital, diphenhydramine,
ethinamate, flurazepam, halazepam, haloperidol,
prochlorperazine, oxazepam, and talbutal.
Examples of cardiac drugs are, with limitation,
quinidine, propranolol, nifedipine, procaine,
dobutamine, digitoxin, phenytoin, sodium nitroprusside,
nitroglycerin, verapamil HCl, digoxin, nicardipine HCl,
and isosorbide dinitrate.
Antimicrobial agents are includive of, ~ithout
limitation, erythromycin, suflonamide, lincomycin,
clindamycin, tetracycline, chlortetracycline,
demeclocycline, doxycycline, and methacycline.
Examples of useful antibacterial agents are,
without limitation, phenols, hydroxy benzoic acid,
hydroxy quinoline, nitrofuran, nitroimidazoles,
oxolinic acid, actinomycetin, bacitracin, tyrothricin,
kanamycin, neomycin and chloramphenicol.
Steroidal anti-inflammatory agents are
illustrated by, without limitation, triamcinolone
acetonide, beclomethasone dipropionate, hydrocortisone
acetate, fluocinolone acetonide, betamethasone
valerate, prednisolone, prednisone, methyl prednisolone
and paramethasone.
3~
Inclusive of non-steroidal anti-inflammatory
agents are acetyl salicylic acid, fenoprofen calcium,
ibuprofen, indomethacin, meclofenamate sodium,
mefenamic acid, naproxen sodium, phenylbutazone, and
oxyphenbutazone.
Anti-emetics are illustrated by, without
limitation, thiethylperazine, metoclopramide,
cyclizine, meclizine, prochlorperazine, doxylamine
_ 16 1339073
succinate, promethazine, triflupromazine, and
hydroxyzine.
Exemplary amino acid, peptide and protein
hormones include, without limitation, thyroxine, growth
hormone (GH), interstital cell stimulating hormone
(ICSH), follicile-stimulating hormone (FSH),
thyrotropic hormone (TSH), andrenocorticotropic hormone
1~ (ACTH), vasopressin and their active degradation
products. Some products may have sufficiently high
molecular weights that absorption through the stratum
corneum or mucous membranes may be difficult.
Therefore, the invention is applicable only to those
hormones which have molecular weights and
stereoconfigurations which will allow passage through
the skin.
Female sex hormones which can be used include,
~~ without limitations, estradiol, diethylstilbestrol,
conjugated estrogens, estrone, northindrone,
medroxyprogesterone, progesterone, and norgestrel.
Typical male sex hormones which may be utilized
may be represented by, without limitation,
testosterone, methyltestosterone, and fluoxymesterone.
The above listed active permeants may, along with
others not specifically disclosed, be used separately
or in combination according to the treatment regimen
desired.
Preferred categories of active permeants include
anti-hypertensive agents, cardiac drugs, analgesics,
sedative-hypnotic agents, anti-anxiety agents,
steriodal anti-inflammatory agents, non-steroidal
anti-inflammatory agents, male sex hormones, and female
sex hormones. Those active permeants specifically
1339073
_ 17
listed above under each category are particularly
preferred.
The components of this invention are inclusive of
the active permeants combined with the binary
penetration enhancing mixture of cell-envelope
disordering compounds and C2 and C3 alcohols. It is
contemplated that compositions containing only these
ingredients will be sufficient in most instances to
1~ obtain the desired results. However, in preparing
formulations for actual use, it may be desirable to add
other components such as excipients, dyes, perfumes,
fragrances, opacifiers, thickening agents,
preservatives, anti-oxidants, gelling agents,
surfactants and stabilizers. For example, when forming
gels or cremes, it may be desirable to add significant
amounts of water, i.e. up to 50~ in some cases for
gels. Such materials, when added, should not unduly
interfere with the penetration enhancement of these
compositions. Such formula modifications to improve
cosmetic acceptability are well within the skill of
workers in the art and do not form part of the present
invention.
In any form of medical practice, there are many
variables which afrect the particular treatment
regimen. In that regard, the final diagnosis and
treatment is left to the expertise of the practitioner
and patient. As previously stated, in clinical
practice, it is the goal that the dosage of any active
permeant be as small as possible to achieve the result
desired and that the duration of the administration of
the permeant be as short as possible. To attain these
conditions, it is imperative that the amount of active
ingredient utilized is a safe and effective amount
whether applied to an afflicted situs or an application
situs. When local treatment is desired, the
compositions are applied to the afflicted situs. When
1339073
18
systemic treatment is desired, the compositions are applied to an application situs,
preferably from a sustained release device such as a patch, bandage, web, film or the like.
When both local and systemic treatments are indicated, the compositions can be applied at
both the afflicted situs and application situs, or both. The selection of active permeant or
combination of permeants, particular penetration enhancement combination and the like are
necessarily left to the skill of the practitioner provided the parameters outlined herein are
followed.
The dosage, rate of application, place of application, and other treatment parameters
are generally outlined in U.S. Patent 4,537,776. What is a safe and effective amount of
any ingredient will obviously depend upon the active ingredient being used, the site of
application, the effectiveness of the penetration enhancer and other parameters outlined
herein.
A practitioner being skilled in the art will be able to determine the application
parameters of each specific formulation based on the needs of each patient.
The following examples demonstrate the penetration enhancement which is obtainedby the binary cell envelope disordering compounds-lower alkanol compositions. In making
these tests human skin consisting of heat-separated abdominal epidermis, taken at autopsy,
was placed in a standard Franz diffusion apparatus in a horizontal position between a
lower, capped diffusion cell and an upper open cell. A normal saline solution was added
to the lower diffusion cell in contact with the subcutaneous side of the skin, and the test
composition, consisting of a saturated
X
1339073
' _ 19
solution of an active drug being monitored formulated
in the binary penetration enhancer, was added to the
diffusion cell in contact with the upper or epidermal
side of the skin.
The cell assembly was kept in a
constant-temperature room at about 37 degrees C. At
predetermined intervals, the diffusate from the cell on
the subcutaneous side of the skin was withdrawn and the
amount of drug in the diffusate was measured using
standard analytical techniques. Each test was run on a
separate skin sample. In each case the amount of
active drug used was that required to form a saturated
solution. The results are reported in terms of flux,
[mcg/cm2/day~ or relative flux.
EXAMPLE I
To show the penetration enhancement effects of
the binary cell envelope disordering compound-lower
alkanol compositions are applicable to active agents
inclusive of hydrophilic, salts and hydrophobic agents
the following compositions were tested.
Flux [mcg/cm2/day]
Test No. Active Propylene Glycerol
30 GDO/Ethanol
Ingredient
Glycol
Dioleate(GDO)
(80:20 w/w)
I-A Estradiol
14.9
14.3
20.9
-
_ 20
1339073
I-B Na-Salicylate
138.6
6,626.0
13,696.4
I-C Ara-A
0.44
0.48
3.98
The combination of ethanol and GDO shows
substantial penetration enhancement effects as compared
to a diol (propylene glycol) or GDO alone for all three
active agents.
EXA~PLE II
A series of tests similar to Example I were
conducted utilizing a greater variety of active agents
with various component combinations forming penetration
enhancement systems which were directly compared with
individual components making up the systems as follows:
FLUX [mcg/cm2/day]
ENHANCEMENT
Propranolol
Minoxidil
Sodium
Test No.
SYSTEM(%w/w)
Estradiol
Prednisilone
HCl
HCl Salicylate
40% OA
- 21
II-A 40% GDO 133907~
75.6 915.7
1,216.0
383.6
12,838.0
20 % EtOH
80~ oA
1~ II-B 20 ~ EtOH
21.2 462.0
889.0
303.0
22,905.0
80 ~ GDO
II-C 20~ EtOH
48.6 571.0
767.0
197.0
12,541.0
95% PG
II-D 5% OA
120.1164.0
2,259.0
1,155.0
834.0
II-E100% OA
31.8291.0
258.0
221.5
18,349.0
II-F 100% EtOH
18.7 81.0
45.0
~- _ 22
23.4 I 3 39 0 73
1,094.0
5 II-G 100% PG
2.6 5.0
25.0
14.6
231.8
II-H 100~ GDO
12.1 92.0
257.0
62.1
15 ____
EtOff=Ethanol
PG=Propylene Glycol
GDO=Glycerol Dioleate
QA=Oleic Acid
The penetration enhancer composition utilized in
Test II-D is taught in the prior art and shown in
Example XIY of European Patent Application 43,738 and
generally provides for excellent skin penetration
enhancement. However, as shown in following Example
VI, this combination of oleic acid and propylene glycol
causes severe skin irritation. The penetration
enhancement systems of Tests II-A, II-B and II-C, with
minor exceptions, showed across the board improvement
in penetration enhancement over the individual
components used alone and generally greater than
additive enhancement effects which one would expect
when combining these ingredients.
EXA~PLE III
Following the procedure and penetration
enhancement systems of Example II, the relative flux of
- _ 23 1339073
haloperidol as active agent was determined. The
results are as follows:
ENHANCEMENT
RELATIVE FLUX
Test No.
SYSTEM (%w/wl
Haloperidol
40% OA
III-A 40% GDO
19.1
20% EtOH
80% OA
III-B 20% EtOH
10.8
80% GDO
III-C 20% EtOH
21.7
95% PG
III-D 5% OA
22.4
III-E 100% OA
5.2
III-F 100% EtOH
5 .1
III-G 100% PG
1.0
III-H 100% GDO
12.2
_ _ 2~ 1339073
EtOH=Ethanol
PG=Propylene Glycol
GDO=Glycerol Dioleate
OA=Oleic ~cid
It is evident from the above that the
combinations of glycerol dioleate and/or oleic acid
with ethanol provide penetration enhancement similar to
that obtained with propylene glycol and oleic acid and,
as will subsequently be demonstrated, does not possess
the skin irritation properties of propylene
glycol-oleic acid combinations. The enhancement
obtained by combining GDO and oleic acid cell-envelope
disordering agents with ethanol was far greater than
that obtained utilizing the individual components
alone.
EXAMPLE IV
To show the efficacy of other cell-envelope
disordering compounds in combination with lower
alkanols as penetration enhancers, a series of tests
were run with propranolol as the active agent. The
procedure as outlined in the above examples was
followed to determine flux. All enhancer combinations
consisted of 75% weight of a cell-envelope disordering
compound and 25~ weight isopropyl alcohol ~i-PrOH).
The results are as follows:
ENHANCEMENT
FL UX
Test No.
SYSTEM (75% w/25%w)
[mcg/cm2/day]
Esters
-
_ 25 1339073
IV-A GDO + i-PrOH
1,814.0
IV-B Methyl Laurate + i-PrOH
5,534.0
IV-C Lauryl Oleate + i-PrOH
571.0
IV-D Methyl Vaccenate + i-PrOH
406.0
IV-E Cis-5-Decenyl Acetate + i-PrOH
5,534.0
Higher Alcohols
IV-F Oleyl Alcohol + i-PrOH
2~ 4,553.0
IV-G Hexadecenol + i-PrOH
7,055.0
IV-H Dodecanol + i-PrOH
5,451.0
IV-I Vacenyl Alcohol + i-PrOH
6,481.0
IV-J Decanol + i-PrOH
7,102.0
IV-K Octanol + i-PrOH
6,852.0
Fatty Acids
- _ 26 1339073
IV-L Oleic Acid + i-PrOH
860.0
IV-M Petroselenic Acid + i-PrOH
856.0
IV-N Linoleic Acid + i-PrOH
2,358.00
IV-O Linolelaidic Acid + i-PrOH
1,384.0
IV-P Linolenic Acid + i-PrOH
1,204.0
IV-Q Vaccenic Acid + i-PrOH
673.0
While there i3 no direct comparison utilizing the
cell- envelope disordering components of the
enhancement combination alone, it has been previously
shown that the combinations of enhancers as shown in
Tests IV-A and IV-L, utilizing ethyl alcohol instead of
isopropyl alcohol, show marked penetration enhancement
of active ingredients. Using Tests IV-A and IV-L as
the standards, the other cell envelope disordering
components, with few exceptions, show comparable or
superior penetration enhancement of propranolol.
EXAMPLE V
Again, following the procedure of the preceding
- examples, a series of tests utilizing glycerol dioleate
and/or oleic acid as cell-envelope disordering
components combined with isopropyl alcohol as
penetration enhancers, were performed using propranolol
HCl and testosterone as active agents. Results are as
follows:
_ 27 1 3 3 9 0 73
ENHANCEMENT
FLUX
ACTIVE AGENT
Test No.
SYSTEM (%w/w)
~mcg/cm2/day]
Skin Sample #l
V-A 100% GDO
448.8
Propranolol HCl
V-B 100% i-PrOH
67.2
Propranolol HCl
80% GDO
V-C 20% i-PrOH
1,000.8
Propranolol HCl
~5
Skin Sample #2
V-D 100% GDO
120.0
Testosterone
V-E 100% QA
144.0
Testosterone
80~ OA
V-F 20% i-PrOH
456.0
Testosterone
'- 28
13~9û73
80% OA
V-G 10% i-PrOH
912.0
Testosterone
10% GDO
Skin Sample #3
V-H 100~ A
76.8
Testosterone
80% OA
V-I 20~ i-PrOH
374.4
Testosterone
80~ GDO
V-J 20% i-PrOH
384.0
Testosterone
25 i-PrOH=Isopropanol
GDO=Glycerol Dioleate
OA=Oleic Acid
The above show that enhancers consisting of both
cell- envelope disordering compounds and isopropanol
are clearly superior to the individual components used
separately.
EXAMPLE VI
The following test was conducted in order to show
that skin penetration enhancers, used in the above
examples, to facilitate the passage of medicinal
compounds through the skin and consisting of
combinations of cell-envelope disordering agents
~ 29 1339073
combined with a lower alkanol, produce less skin
irritation and sensitization than prior art
penetration agents consisting of a cell-envelope
disordering compound and a diol.
Twenty four healthy adults (sixteen females and
eight males) between the ages of 18-65 were selected
for the test. Each subject was selected without regard
lU to race or sex. However, each subject was required to
be in good health and meet required criteria regarding
allergies, skin cancer, medications, recent surgery,
etc.
Eight different enhancer compositions (Test
Substances I through VIII) were prepared as follows
(ingredients reported in % w/w):
I. Propylene glycol:Oleic Acid (95:5).
II. Glycerol dioleate:Ethanol (80:20).
2~ III. Glycerol dioleate:Ethanol (20:80).
IV. Glycerol dioleate:Oleyl alcohol:Ethanol
(40:40:20).
V. Glycerol dioleate:Methyl laurate:Ethanol
(40:40:20).
VI. Glycerol dioleate:Glycerol formal:Ethanol
(70:10:20).
VII. Methyl laurate:Isopropanol (75:25).
VIII. Glycerol dioleate:Oleic acid:Ethanol
(70:10:20).
Test solutions were prepared and stored at room
temperature until used. When ready for use 150 micro
liters of test solution was placed on an adhesive
bandage patch consisting of a 3/4 inch square nonwoven
cotton pad, Webril (TM) (Kendall Corporation) which
retained the test substance, backed by a 1.5 inch
square of blenderm type tape (3M Company) to hold the
_ 30 133907~
pad onto the surface of the skin. The patches were
individually packaged with a peeloff backing.
The backing was peeled off and the test solution
applied to the patch. The test area was cleaned with a
gauze pad saturated with 95% ethyl alcohol. The
patches were then applied to the lateral surface of one
upper arm of the subject in a designated sequence to
eliminate position and order grading bias.
The best subjects were divided into two
application groups (Group A and Group B) of twelve
subjects each. Each group was further subdivided into
four groups each containing three subjects. Each
subject in Group A was treated with test Substances I,
II, III and IV and each subject in Group B was treated
with test Substances V, VI, VII and VIII. The
positioning of substances was the same in each
subgroup, but the positioning varied from one subgroup
to another according to a randomization code.
The test consisted of nine 24 hour patch exposure
(induction period) to the same test site of each
subject with a 24 to 48 hour rest period between each
exposure. About two weeks after the last induction
patch was applied, the original test site and an
alternate test site were challenged with a 24 hour
patch exposure to the test material.
Each subject was instructed to keep all patches
as dry as possible and to remove and discard them after
approximately 24 hours. The patch area could be
cleaned in a normal manner after removal but the
subjects were cautioned not to swim when the patches
were in place. There were no bathing or showering
restrictions.
1339073
31
Induction patches were applied on Monday,
Wednesday and Friday for the first three weeks of the
test. The test sites were scored using an artificial
light source to illuminate the patch area prior to the
application of each new patch during the induction
tests with a final reading being taken on the Monday
following the ninth application. Two weeks after the
final reading of the induction tests, challenge patches
were applied simultaneously to both the original ~at
the original sites) and opposite arms (in a similar
position) of each subject. These patches were worn for
24 hours and then discarded. The challenge test sites
were graded on the second and fourth days following
their application.
Test sites were scored as follows: O=no visible
reaction; 1=mild reaction, erythema; lE=mild
erythematous reaction with papules and/or edema;
2=moderate reaction, erythelna; 2E=moderate erythematous
reaction with papules and/or edema; 3=strong reaction,
erythema; 3E=strong erythematous reaction with marked
edema, papules and/or few vesicles, 4=severe reaction
with erythema, edema, papules and vesicles (may be
evidence of weeping); 5=bullous reaction; [S]=reaction
spread beyond patch area; and N9G=~o 9th induction
grade. Gradings containing two numbers, e.g. l/lE, are
readings fr~n two application sites when skin
irritation at the initial test site required the moving
of test patches from one test site to another.
The patch site grades are as follows:
(
Test Substance - I
------Challenge Grades-----
Subject Drug Induction Grades Orig Alt Orig Alt
Number 1 2 3 4 5 6 7 8 9 1 1 2 2
01 1 0 1 1 1 1 lE 1/1 l/lE
02 1 1 0 1 1 lE 2E lE/0 1/3E 2E 2E 3E 3E
03 1 1 IE lE(S) l/lE 3E(S)/2E(S) 2E/1 IE/I 1/1 5(S) 4(S) 3E 2(S)
04 0 1 1 1 lE/(S) l/lE lE/l 2E/1 1/1 3E 2E 2E 2
05 lE 1 2E lE/3E(S) 2E/IE 1/4 1/2E 1/1 l/lE 1 0 1 0
06 1 1 lE 2E(S) 2/2E 3E/2E 3E/3 2/2 N9G * * * *
07 1 1 1 1 1 lE 2 l/lE lE/2E 2E 2E lE lE
08 1 1 1 1 1 1 lE l/lE 1/2E 2E 3 lE 2E
09 0 0 1 1 1 IE 2E IE/lE 1/2E 3E 3E 3E 3E
1 1 1 1 1 1 2E 0/lE 1/3E 5(S) 4 4 2E
11 1 1 1 1 lE 2E 2/5 1/3E l/lE 2E 2E lE lE
12 lE 1 1 1 2 1/2E 2/lE lE/lE 1/1 2E 3E lE 2E
* Patch not applied. C~
o
33 1339073
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34 ~339073
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1339073
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36 1339073
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1339073
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13390 73
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39 1339073
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1339073
_ 40
Because of severe reaction caused by Test
Substance #1, no induction patches were applied to
Subject No. 5 at the last two induction applications.
At challenge, patches free of any test substance were
applied to selected sites to evaluate the
Subject's reaction to the tape and the possible
exacerbation by the action of the test substances.
On Subject No. 6, severe reaction was observed at
1~ Test Substance #l site after the fifth test induction
application which spread to all patch sites. After the
sixth test induction application, no patches were
applied to any test site for the remainder of the
induction period. At challenge, patches containing no
test substance were applied to selected sites on both
arms of the subject.
The testing investigator's conclusions were that,
except for Test Substances 1 and 6, the adverse
2~ symptomatology was generally mild in nature and no
medical intervention was required. All twelve subjects
treated with Test Substance ~1 experienced significant
skin changes during the induction period. Nine of the
subjects also experienced exacerbation of the skin
changes following the challenge patch application. One
subject treated with Test Substance #6 experienced
significant skin changes both during induction and
challenge periods. Two subjects displayed mild
reactions to Test Substance #6 during induction which
became more severe during challenge. Medical
intervention in the form of patch relocation or
interruption of patch application was necessary for the
significant skin responses to Test Substances #1 and #6.
In conclusion, it is evident that Test Substances
$2, #3, $4, #5, $7 and $8, all of which are within the
scope of the present invention, are substantially free
from skin irritation effects. On the other hand, Test
41 1339073
Substance #l, from the prior art, and Test Substance
#6, which had shown promising penetration enhancement
in preliminary testing, both showed significant skin
irritation.
Blood samples taken from all twenty-four subjects
before and after testing showed no clinically
significant changes in serum prolactin levels.
EXAMPL E VI I
The following are exemplary of other compositions
which can be formulated within the scope of this
invention. However, they are illustrative only and are
not intended to define the scope of the invention. The
compositions can be conventionally formulated simply by
mixing all components thoroughly. In some
formulations, exact percentages are given whereas
others are expressed by ranges. All compositions are
in percent by weignt.
FORMULATI ON VI-A
Testosterone 5-15%
~5 Glycerol Dioleate 50-90%
Ethanol 4-45%
FORMULATI ON VI -B
Methadone 10-30%
Glycerol Dioleate 60-80%
Ethanol 10-30%
3 5 FORM ULA TI ON VI - C
Estradiol 0, l-1.0%
Glycerol Dioleate 60-95%
. 42 1~9073
Ethanol 5-40
FORMULATION VI-D
Ketoprofen 10-20%
Glycerol Dioleate 50-90%
Ethanol 5-40%
O FORMULATION VI-E
Dihydroergotamine 1-10%
Glycerol Dioleate 50-95%
Ethanol 5-40%
FORMULATION VI-F
Nifedapine 2-10%
Glycerol Dioleate 50-95%
20 Ethanol 5-40
FORMULATION VI-G
Thiethylperazine 1.-5%
25 Glycerol Dioleate 50-95%
Ethanol 5-50%
FORMULATION VI-H
30 Metoclopramide 10-15%
Glycerol Dioleate 50-90%
Ethanol 5-40%
FORMULATION VI-I
Propranolol HCl 5~
Glycerol Dioleate 75%
Ethanol 20
431 3 3 g 0 7 3
FORMULATION VI-J
Propranolol 20%
S Glycerol Dioleate 60%
Ethanol 20%
FORMULATION VI-K
10 Propranolol HCl 5%
Glycerol Monooleate 80%
Ethanol 15%
FORMULATION VI-L
Propranolol HCl 5%
Methyl Laurate 75%
Ethanol 20%
FORMULATION VI-M
Propranolol 15%
Glycerol Trioleate 65%
Isopropanol - 20%
~5
FO~MULATION VI-N
Fentanyl Citrate 2%
Glycerol Monooleate 78%
30 Ethanol 20%
FORMULATION VI-O
Fentanyl 1%
35 Glycerol Trioleate 79%
Isopropanol 20%
FORMULATION VI-P
1339073
- 44
Nicardipine 5~
Oleyl Alcohol 75%
Isopropanol 20~
FORMULATION VI-Q
Nicardipine HCl 10%
Oleic Acid 10%
10 Glycerol Dioleate 50%
Ethanol 30%
FORMULATION VI-R
15 Naloxone HCl 10%
Glycerol Monooleate 60%
Oleic Acid 10%
Ethanol 20%
FORMULATION VI-S
Naloxone 5%
Glycerol Trioleate 65%
Propanol 30%
~5
FORMULATION VI-T
Griseofulvin 5
Methyl Oleate 75~
30 Isopropanol 20%
FORMULATION VI-U
Griseofulvin 5%
Glycerol Trioleate 65%
35 Isopropanol 30%
FORMULATION VI-V
Fluocinolone Acetonide l~
1339073
-
Methyl Laurate 79%
Ethanol 20
FORMULATION VI-W
Fluocinolone Acetonide 1%
Glycerol Trioleate 69%
Isopropanol 20
FORMULATION VI-X
Clindamycin 2.5%
Oleyl Alcohol 77.5%
15 Isopropanol 20%
FORMULATION VI-Y
Neomycin Sulfate 5%
20 Glycerol Monooleate 75%
Ethanol 20%
FORMULATION VI-Z
25 Clonidine HCl 1%
Glycerol Dioleate 79%
Ethanol 20%
FORMULATION VI-AA
Hydroflumethiazide 10%
Glycerol Dioleate 60%
Oleic Acid 10~
Isopropanol 20%
FORMULATION VI-BB
Phentermine 5%
Glycerol Trioleate 7S%
133gO73
_ 46
Propanol 20%
FORMULATION VI-CC
Phentermine HCl 10%
Glycerol Monooleate 60%
Ethanol 30%
FORMULATION VI-DD
1()
Mazindol 5%
Glycerol Trioleate 75%
Isopropanol 20%
FORMULATION VI-EE
Morphine 1%
Methyl Oleate 79%
Isopropanol 20%
FORMULATION VI-FF
Morphine Sulfate 5%
Glycerol Monooleate 65%
25 Oleic Acid 10%
Ethanol 20
FORMULATION VI-GG
30 Alprazolam 5%
Glycerol Trioleate 75%
Propanol 20%
FORMULATION VI-HH
Ibuprofen 10%
Glycerol Trioleate 70%
Isopropanol 20
3 39 0 73
FORMULATION VI-II
Naproxen Sodium 10%
5 Glycerol Dioleate 60%
Oleyl Alcohol 20%
Ethanol 10%
FORMULATION VI-JJ
1()
Naproxen Sodium 10%
Glycerol Monooleate 70%
Ethanol 20
FORMULATION VI-KK
Progesterone 5%
Methyl Oleate 75%
Isopropanol 20%
2U
FORMULATION VI-LL
Methyl Testosterone 5%
Glycerol Trioleate 65%
25 Isopropanol 30%
