Note: Descriptions are shown in the official language in which they were submitted.
Z 27 753
METHOD FOR PERCUTANEOUSLY ADMINISTERING P~-~SIOLOGICALLY ACTIVE
AGENTS USING AN AGENT, A SOLVENT AND A DILL MODERATOR
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention relates to a method for acceder-
cling the percutaneous absorption of a physiologically act
5tive agent (hereafter often merely an "active agent" for
brevity).
. DESCRIPTION OF THE PRIOR ART
Active agents are commonly administered to the skin
or mucosal tissues to treat local problems and systemic ad-
ministration of active agents is commonly accomplished by
ingesting pills or by injections. However, recently at-
tempts have been made to achieve systemic administration of
active agents by topical applications to the skin or mucosal
tissues. Such topical means of achieving systemic ad minis-
15tration has the advantage that desired blood levels can be
readily achieved and maintained so that duration of therapy
can be readily controlled. Thus, side effects due to an
overdose of the active agent can be prevented. Also, metal-
holism due to a first pass through the liver and gastric disk
20turbances, which are characteristic of certain drugs such
as indomethacin when administered orally, can also be elm-
noted.
However, normal skin is relatively impermeable to most
therapeutic agents in that desired blood levels of the
25~ therapeutic agent cannot be achieved by means of percutane-
out absorption. The percutaneous absorption of therapeutic
--- ` '
~227753
-I 1 agents can, however, be enhanced by means of adjutants or
penetration enhancers.
One of the best known of such penetrating adjutants is
dim ethyl sulfoxide, the use of which is described in detail
in US. Patent 3,551,554 Herschler et at, which patent
broadly suggests the use of dim ethyl sulfoxide as a penes
treating adjutant for psychopharmacological drugs such as
benzodiazepine derivatives.
British Patent 1,504,302 Brooked et at deals with soda-
live methods and compositions and discloses the administer-
lion of sedatives by applying to the skin of a non-human an-
imal a sedating amount of one or more sedative compounds in
various penetrating adjutants such as hydrocarbons such as
- aromatic hydrocarbons or paraffins, halogenated aliphatic
hydrocarbons, kittens, esters, ethers, alcohols, asides or
sulfones. Brooked et at broadly indicates that one or more
of the above liquids can be used in combination, but exempt
iffy the halogenated aliphatic hydrocarbons only with carbon
tetrachloride and exemplify the asides only with dim ethyl-
formamide.
Japanese Patent Application 52-148,614 (unexamined)
Yonemushi discloses, without supporting data or explanation
of substance, the use of sulfones by-produced in the resin--
in of petroleum "as solvents to enhance the efficacy of
drugs for skin disease" and assay drug penetration enhancers".
US. Patent 4,202,888 Eckert et at discloses absorbable
pharmaceutical compositions comprising at least one cardiac
glycoside distributed in a vehicle comprising an absorption-
enhancing amount of at least a partial glyceride of a fatty
acid of medium chain length.
~ZZ7753
1 US. Patent 3,472,931 Stoughton relates to percutaneous
absorption using lower alkyd asides, and exemplifies binary
systems which comprise dimethylacetamide and ethanol, dip
methylacetamide and isopropyl alcohol and dimethylacetamide
and isopropyl palpitate. Stoughton does not exemplify or
disclose the combination of dimethylacetamide with higher
molecular weight alcohols or lower molecular weight esters.
US, Patent 4,017,641 DiGiulio deals with skin moisture
icing compositions comprising 2-pyrrolidones which can be
used with suitable oils and waxes including aliphatic
straight chain fatty acids and alcohols of from about 10 to
about 20 carbon atoms. This patent does not, however, deal
with percutaneous administration of physiologically active
agents.
Canadian Patent 1,165,240 discloses binary percutaneous
administration systems which comprise a monoglyceride, a doll
or a dill ether in combination with a second component such
as an alcohol, ester, aside or the like.
The present invention involves multi component carrier
systems for the percutaneous administration of physiologic
gaily active agents which differ from the systems disclosed
in the above prior art.
SUMMARY OF THE INVENTION
Per the present invention, it has been discovered that
a
certain multi component carrier systems provide enhanced and
controlled percutaneous administration of physiologically
active agents.
B
I` ~L2Z7753
1 The carrier systems of the present invention
comprise at least one adjutant (Component A), at least one
solvent (Component B) and at least one dill moderator.
The adjutants of the present invention are
selected from aliphatic hydrocarbons or halogen
substituted aliphatic hydrocarbons, alcohol esters of
aliphatic carboxylic acids, moo- or dithers, kittens,
higher aliphatic monoalcohols or mixtures thereof. It is
necessary that the adjutant of the present invention have
a melting point below 38C.
The solvents of the present invention are
selected from thioglycerols, lactic acid or esters
thereof, cyclic ureas, compounds represented by the
general formula RlR2NCONR3R4, pyrrolidone-type compounds,
Andes, lactones or mixtures thereof.
Per the present invention, a physiologically
alive agent can be percutaneously administered by
blending the same with a combination of Component A.
Component B and a dill moderator and applying the same to
I the skin.
The above-described compositions can be used as
bases for medical preparations comprising active agents
applicable to the outer skin.
One object of the present invention is to
provide base compositions or percutaneous absorption
- 4 -
12Z7753
1 enhancing combinations of Component A, Component B and a
dill moderator (often abbreviated as PACE or Paces
hereafter) for medical preparations for external use which
enhance the permeability of active agents through the skin
and the percutaneous absorption of active agents.
- pa -
12Z7753
second object of the present invention is to provide
pharmaceutical compositions comprising a Pace for external
use itch provides good permeability of active agents
through the skin and percutaneous absorption of active
s agents.
A third object of the present invention is to provide a
method for enhancing the permeability of active agents
through the skin and percutaneous absorption of active
agents using a PACE per the present invention.
In a preferred embodiment, the combination of the
present invention which enhances percutaneous absorption
comprises one or more members selected from the group con-
sitting of certain pyrrolidone-type compounds and asides and
mixtures thereof, one or more members selected from the
group consisting of certain alkyd halides, fatty acid
esters, higher aliphatic monoalcohols, hydrocarbons and
mixtures thereof and one or more dill moderators.
A fourth object of the present invention is to provide
Paces which ensure rapid and controlled transepidermal
delivery of physiologically active agents in man or other
- animals.
A fifth object of the present invention is to provide
such rapid and controlled transepidermal delivery which
provides drug blood levels in the therapeutic range fourth
treatment of humans and other animals.
A sixth object of the present invention-is to provide,
through transepidermal delivery, at appropriately adjusted
rates, relatively constant therapeutic blood levels so as to
avoid the side effects and reduced therapeutic effects that
may result from wide fluctuations in blood levels over time.
lZ277S3
,,
BRIEF DESCRIPTION OF THE DRAWING
The Figure is a plot of diazepam flux versus time in
hours for various compositions per the present invention and
a comparison composition.
DESCRIPTION OF PREFERRED EMBODIMENTS
Examples of Component A include the following
compounds.
(1) Straight, branched or cyclic aliphatic hydrocar-
buns having 5 to 24 carbon atoms which may be
substituted with one or more halogens.
As halogen substituents, bromide and chlorine are
preferred. -
Straight or branched hydrocarbons having 5 to 24
(preferably 6 to 18) carbon atoms can be used which may be
saturated or unsaturated with preferably 1 to 2 unsaturated
bonds. In the case of cyclic hydrocarbons, 6 to 10 member Ed
moo- or 10 to 12 member Ed di-cyclic hydrocarbons are pro-
furred and such may be substituted with saturated or
unsaturated alkyd groups having 1 to 4 carbon atoms such as
methyl, bottle, isopropenyl, etc.
Specific examples include n-pentane, Nixon, nope-
lane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane,
n-tetradecane, n-hexadecane, n-octadecane, 2-methylpentane,
2-methylhexane, 2,3-dimethylhexane, 2-methylnonane, 2,6-
25dimethyloctane, 2,2,4,4,6,8,8-heptamethylnonane, pristine,
limonene, hydrogenated limonene diver, cyclohexane, 1,3-
dimethylcyclohexane, cyclooctane, isobutyl-cyclohexane,
cyclododecane, methyldecaline, decline, octal chloride,
t decal chloride, dodecyl chloride, hexadecyl chloride,
dodecyl bromide, dichlorododecane, etc.
` 6
~Z27753
, .
1 (2) Alcohol esters of aliphatic carboxylic acid
having a total number of carbon atoms of
from 7 to 18, preferably 7 to 17:
As the alcohol moiety, monovalent alcohols
having 1 to 6 carbon atoms such as methyl alcohol, ethyl
alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl
alcohol, iso-butyl alcohol, sec-butyl alcohol, t-butyl
alcohol, namely alcohol, iso-amyl alcohol, n-hexyl
alcohol, etc., are preferred. Further, as the carboxylic
acid moiety, fatty acids having 6 to 16 carbon atoms are
preferred and saturated fatty acids having 8 to 14 carbon
atoms are most preferred. Specific examples of such
esters include methyl laureate, ethyl laureate, bottle
laureate, isopropyl myristate, etc.
(3) Moo- or dithers having 10 to 18 carbon
atoms:
Specifically, there are alkyd monoethers such as
dihexyl ether, ductile ether, methoxydodecane,
ethoxydodecane, etc., ethers having an alicyclic group
such as sunnily, etc., alkyd dithers such as ethylene
glycol dibutyl ether, ethylene glycol ductile ether, etc.
I Kittens having 10 to 18 carbon atoms:
Aliphatic kittens are preferred, examples of
which include 2-undecanone, 3-undecanone, 4-undecanone, 5-
undecanone, 6-undecanone, 2-dodecanone, 4-dodecanone~ 5-
dodecanone, 7-tridecanone, etc.
lZZ7~7S3
1 (5) Higher aliphatic monoalcohols having from
10 to 26 carbon atoms which may be branched, straight
chain, saturated, unsaturated or cyclic and which may be
primary, secondary or tertiary.
Examples of Component include the following
compounds:
- 12Z77S3
(1) Thioglycerols:
Any Mooney, dip and trithioglycerols can be used, an
example of which includes ~-monothioglycerol.
(2) Lactic acid and esters thereof:
As the alcohol moiety in the esters, monovalent caliph-
attic alcohols having l to 4 carbon atoms are preferred,
specific examples of which include lactic acid, methyl
lactate, ethyl lactate, bottle lactate, etc.
(3) Cyclic ureas:
lo 5-Membered or 6-membered rings are preferred, specific
examples of which include ethylene urea, N,N-dimethyl-
ethylene urea and the corresponding propylene ureas, etc.
(4) Compounds represented by the general formula:
R1 O / 3
N - C - N
R2 / \ R4
wherein R1, R2, R3 and R4 each represents a hydrogen atom, a
lower alkyd group having 1 to 4 carbon atoms (methyl, ethyl,
n-propyl, isopropyl, n-butyl, etc.) or an azalea group having
1 or 2 carbon atoms:
Specific examples thereof include urea, N-methylurea,
N-ethylurea, N-butylurea, l,l-dimethylurea, 1,3-dimethyl-
urea, 1,1,3,3-tetramethylurea, N-acetyl-N'-methylurea, etc.
(5) Compounds represented by the general formula:
C
R5
(SHEA) n
.
27~7$3
wherein R5 represents a hydrogen atom or a lower alkyd
group having 1 to 4 carbon atoms (methyl, ethyl,
n-propyl, isopropyl, etc.) and n represents an integer
of 3 to 5:
s Specific examples thereof include 2-pyrrolidone,
N-methyl-pyrrolidone, N-methylpiperidone, caprolactam,
N-methylcaprolactam, etc.
(6) Compounds represented by the general formula:
R
RON
wherein R6 represents a hydrogen atom or an alkyd group
having 1 to 3 carbon atoms (methyl, ethyl, n-propyl,
etc.) and I and R8 each represents an alkyd group
having 1 to 3 carbon atoms, with the proviso that R6,
R7 and R8 have in total at least 3 carbon atoms:
- Specific examples thereof include N,N-diethyl
formamide, N,N-dimethylacetamide, N,N-diethylacetamide,
N,N-dimethylpropionamide, N,N-diethylpropionamide, etc.
(7) Lactones having 4 to 6 carbon atoms:
Specific examples thereof include y-butyrolactone,
~-valerolactone, etc.
As earlier indicated, a dill moderator is used in
combination with the active agent and Components A and B of
the prevent invention. The dill can be straight or branched
chain and the dill selected is -preferably a dill comprising
3 to 8 carbon atoms, most preferably 3 to 6 carbon atoms,
,
.
~L2277S3
e.g., an aliphatic dill such as 1,2-propane dill, 1,3-butane
dill, 2,3-butane dill, pontoon dill or 1,6-hexane dill.
However, other dills can be used. --
The amount of dill moderator used is not unduly limp
tied, but is typically on the order of about 10 to about 400
weight percent, more preferably about 25 to about 200 weight
percent, based on the weight of solvent Component s. The
resulting combination of materials must, of course, be
liquid.
The dill moderator reduces the activity of Components A
and B of the present invention which provides a means of
further controlling the rate of active agent absorption.
Greater amounts of dill moderator decrease the rate of
active agent flux while lesser amounts of dill moderator
increase the rate of active agent flux as compared to
greater amounts.
It is to understood that the dill moderator does not
enhance percutaneous absorption per the present invention,
rather, in all amounts it reduces the rate of percutaneous
absorption, which effect has not been suspected in the art.
In addition to the above, there are certain most pro-
furred Paces per the present invention, and these are
discussed below.
We are unsure why the most preferred combination of
Paces of the present invention offers enhanced percutaneous
absorption; however, the data we have generated indicate
that there is a synergistic effect between Components A and
B which can be appropriately moderated, as desired, by
varying the amount of dill moderator.
We consider the materials such us the pyrrolidone-type
compounds and asides to basically serve a solvent function
Jo
` 10
lZ~7753
and materials such as the alkyd halides, fatty acid esters,
higher aliphatic monoalcohols and aliphatic hydrocarbons to
serve as adjutants which enhance the salivating function of
the solvent. We further believe that the solvents carry the
active agent whereas the adjutants open up the stratum
corneum. We do not wish to be bound by these theories, and
we merely use the terminology "solvent" and "adjutant" to
maintain a line of distinction between the two classes of
materials which are mandatorily used in combination.
The most preferred adjutants as Component A of the
present invention include one or more members selected from
the group consisting of alkyd halides, fatty acid esters,
higher aliphatic monoalcohols, aliphatic hydrocarbons and
mixtures thereof.
Of the alkyd halides, those having from 8 to 16 carbon
atoms are most preferred, with chloride being the preferred
halogen. Both alkyd bromides and iodizes are potentially
useful, but alkyd bromides and alkyd iodizes tend to be
unstable. Alkyd fluorides are also useful.
The alkyd moiety may be straight or branched chain, may
be cycloaliphatic or unsaturated, e.g., alikeness and alikeness
are useful.
Most preferred alkyd halides are later exemplified.
The aliphatic hydrocarbons most preferably have 10 to
18 carbon atoms. They may be straight or branched chain and
may be cycloaliphatic or unsaturated, erg,, alikeness and
alikeness are useful.
The fatty acid esters are conveniently represented by
the formula RlCOOR2, Al representing the acid moiety and R2
t representing the alcohol moiety. It is most preferred that
1227~7S3
the total number of carbon atoms ill Al and R2 be from 10
to 17.
Al and R2 may be linear, branched, saturated,
unsaturated.
Preferred higher monoalcohols are the aliphatic moo-
alcohols with from 12 to 24 carbon atoms. The aliphatic
monoalcohols may be branched chain, straight chain, Saturn
axed, unsaturated or cyclic.
The most preferred solvents as Component B include the
pyrrolidone-type compounds and the asides.
The pyrrolidones are most preferably alkyd pyrrolidones
of the formula:
R
N
C = O
(c~2 no
where Al is an alkyd group containing up to 4 carbon atoms
and n is 3 to 5.
The asides are most preferably represented by the
formula:
R2CON 3
R4
where R2 can be hydrogen or an alkyd group with up two 3
carbon atoms and R3 and R4 can be an aliphatic group with up
to 3 carbon atoms.
The base compositions of the present invention can be
prepared by dissolving Component A in Component B and then
12
:~ZZ7753
mixing the dill moderator therein. The order of Mooney is
not important. The amount of Component A to be used is
generally from 0.1 to 80% by weight based on the total
weight of Components A and B, preferably 0.5 to 50% by
- 5 weight. Preferred properties of dill moderator have earlier
been given. Of course, pharmaceutically acceptable add-
lives such as water, etc., can also be added to the base
compositions.
The pharmaceutical compositions for topical application
per the present invention can be prepared by blending active
agents with the above-described composition. There is no
particular limit on the active agents used so long as the
active agents are systemically active and percutaneously
applicable.
Specific examples of active agents include benzodiaze-
pines (e.g., Diazepam, Nitrazepam, Flunitrazepam, Lorazepam,
Fludiazepam, Clonazepam), diuretic agents [e.g., thiazides
(e.g., Bendroflumethiazide, Polythiazide, Methyclothiazide,
Trichlorométhiazide, Cyclopenthiazide, ~entylhydrochloro-
thiazide, Hydrochlorothiazide, Bumetanide)], antihyperten-
size agents (e.g., Clonidine), antihistamic agents [e.g.,
amino ethers (e.g., diphenhydramine, Carbinoxamine, Diphenyl-
praline), ethylenediamines (e.g., Fenbenzamine), monoamine
(e.g., Chlorophenylamines)]; non-steroid antiinflammatory
agents (e.g., Indomethacine, Ibuprofen, Ibufenac, Alkali-
fence, Diclofenac, Mefenamic acid, Flurbiprofen, Flufenamic
acid, Ketoprofen), anti-tumor agents (e.g., 5-fluorouracil,
1-(2-tetrahydrofuryl)-5-fluorouracil, Cytarabine, Flexor-
dine). Steroid antiinflammatory agents (e.g., Cortisone,
Hydrocortisone, Prednisolone, Predonisone, Triamcinolone,
Dexamethasone, Betamethasone), anti epileptic agents (e.g.,
13
- ~lZZ77S3
Ethosuximide), antiarrytl~ic agents (e.g., Ajmalin,
Purajmalin. Pindolol, Propranolol, Quinidine), psychotropic
agents [e.g., Clofluperol, Trifluperidol, Haloperidol,
Moper one), scopolamine (e.g., methyl scopolamine, bottle
scopolamine), metoclopramide, chlorpromazine, atropines
(e.g., methyl atropine bromide, methylanisotropine bromide),
vascular dilating agents (e.g., isosorbide dinitrate, vitro-
glycerine, pentaerythritol tetranitrate, propanyl nitrate,
dipyridamole), antibiotics, e.g., te~racyclines (e.g.,
Tetracycline, Oxytetracycline, metacycline, doxycycline,
Minocycline), chloramphenicols, erythromycines], etc. The
method of the present invention can also be utilized to
percutaneously administer peptizes such as LH-RH, insulin
and the like. Of course, pharmaceutically acceptable salts
such as the hydrochloride, sodium, potassium, hydrobromide,
etc., salts can be used.
Since the present invention is of particular applique-
lion with respect to the benzodiazepine materials, these are
discussed in more detail below. Particularly preferred bent
zodiazepine materials are those which illustrate the buoyancy-
diazepine skeleton as schematically illustrated as follows:
Roy, Jo
.
14
~2277S3
wherein is Of, Bra or NO
and Y is
with varying degrees of unsaturation and substitution-at
positions 1, 2, 3, 4, and 5 as follows:
a) 1, 2 and 4, 5 are unsaturated: Al and R3 are H; R2 is
NOR (R is H or SHEA) and N-Z is N O.
b) 1, 2 are saturated and 4, 5 are unsaturated; R3 is H
or OH; -R2 is -H or JO or ON*; R1 is NOR (R is H, SHEA
or SHEA Jo SHEA CHINOOK or Al is CON*
(R is H or SHEA) and is joined to R2 via "*" (a single
bond) as follows:
R N
I \ . .
:~1`2D
I 1 2 and 4, 5 are saturated: Al is H; -R2 is JO; R3 is
H and positions 4 and 5 constitute a second ring system
as follows:
Y 4 R ._
.; o, <
where R and Al are H and SHEA.
Specific examples of benzodiazepines which can be
percutaneously administered using the active ingredient/
12;~7753
penetration adjutant combinations of the present invention-
include:
a) Chlordiazepoxide; 7-Chloro-2-methylamino-5-phenyl-3H-l,
4-benzodiazèpine-4-oxide
b) Diazepam; 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-
2H-1,4-benzodiazepine-2-one
c) Oxazepam; 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-
2H-1,4-benzodiazepine-2-one
d) Temazepam; 7-Chloro-1,3-dihydro-3-hydroxy-1-methyl-5-
2H-1,4-benzodiazepine-2-one
e) Lorazepam; 7-Chloro-5-(o-chlorophenyl)-1,3-dihydro-3-
hydroxy-2H-1,4-benzodiazepine-2-one
f) Prazepam; 7-Chloro-1-cyclopropylmethyl-1,3-dihydro-
5-phenyl-2H-1,4-benzodiazepine-2-one
g) Fludiazepam; 7-Chloro-1,3-dihydrG-5-(2-fluorophenyl)-1-
methyl-2H-1,4-be~zodiazepine-2-one
0 h) Flurazepam; 7-Chloro-1-(2-(dimethylamino)ethyl)-5-
(o-fluorophenyl)-1~,3-dihydro-2H-1,4-
benzodiazepine-2-one
i) Medazepam; 7-Chloro-2,3-dihydro-1-methyl-5-phenyl-lH-
5,4-benzodiazepine
j) Bromazepam;. 7-Bromo-5-(2-pyridyl)-3H-1,4-benzodiaze-
pine-2(lH)-one
k) Nitrazepam; 1,3-Dihydro-7-nitro-5-phenyl-2H-1,4-
benzodiazepine-2-one
1) Nimetazepam; 1-Methyl-7-nitro-5-phenyl-1,3-dihydro-
2H-1,4-benzodiazepine-2-one
m) Clonazepam; 5-(o-Chloro~henyl)-7-nitro-lH-1,4-
benzodiazeplrle-2(3H)-one
n) Flunitrazepam; 5-(o-Fluorophenyl)-1~3-dihydro-l-meth
,7-nitro-2H-1,4-benzodiazeplne-2-one
o) Estazolam; 8-Chloro-1~6-phenyl-4H-s-triazolo(4l3 -A)
(1,4)-benzodiazeplne
p) Triazolam; 8-Chloro-6-(o-chlorophenyl)-l-methyl-aH
s-triazolo(4,3-A)(1,4)-benzodiazeplne
0 q) Alprazolam; 8-Chloro-l-methyl-6-phenyl-4H-s-triazolo
(4,3-A)(1,4~-benzodiazeplne
r) Oxazolam; 10-Chloro-2,3,5,6,7,11b-hexahydro-2-methyl-
llb-phenylbenzo(6,7)-1,4-diazepino(5,4-b-
oxazol-6-one
16
,
~L2Z7753
1 s) Cloxazolam; 10-Chloro-llb-(o-chlorophenyl)-2,3,5,6,7,
llb-hexahydrobenzo(6,7)-1,4-diazepino-
(S,4-b)oxazol-6-one
t) Haloxazolam; 10-Bromo-llb-(o-fluorophenyl)-2,3,7,11b-
tetrahydro-oxazolo(3,2,~d)(1,4)benzo-
diazepine-6(5H)-one
Especially preferred are benzodiazepines b), e), i), k), 1),
n) and o).
The amount of active agent(s) blended is sufficient if
it is effective for achieving the desired pharmaceutical
effect, which varies depending upon the kind of active
agents, body weight of the patient, symptoms, etc. The
amount may thus be suitably chosen depending upon these
conditions. In general, it is preferred that active agents
be employed in an amount of 0.01 to 50% by weight, more
preferably 0.05 to 10% by weight, based on the total amount
of Component A and Component B.
The dose of the active agents administered can be
controlled by increasing or decreasing the area of skin to
which the pharmaceutical compositions are applied. Accord-
tingly, the amount of the active agent is not necessarily
limited to the above-described ones.
As will be apparent to one skilled in the art, with
increasing concentrations of active agent increasing amounts
of active agent will be absorbed by the subject. The lot-
lowing discussion is given in texts of flood levels of drug
(ng/ml of plasma), this being dependent upon the total area
; of dermal application, as there is a substantially linear
increase in amount of active agent absorbed with area.
For a constant area of application and a constant
absolute amount of adjutant, the blood level of active agent
at any given time is a function of the concentration of
I 27'753
i active agility in the composition. That is, increased concern-
tractions of active agent in the formulation result in more
rapid active agent penetration and higher blood levels.
A further factor which must be considered is that the
amount of active agent absorbed will depend on the site of
application, for example, scalp, ventral forearm, behind the
ear, chest, etc. Typically an area rich in blood vessels is
selected.
For most applications, the concentration of active
agent in the PACE will generally be on the order of 0.01
to 50% based on Components A and B, the amount of PACE
applied will be about 0.1 my to 100 my per cm and the total
. area of application will be on the order of about 0.5 cm2 to
about 100 cm2, which will provide therapeutic blood levels
of the desired active agent.
These ranges are not, however, to be considered as
limitative.
In general, the rate of transepidermal active agent
absorption will approach the rate of oral absorption depend-
in upon the factors previously discussed (nature and amount of PACE, concentration of active agent in the formulation,
and surface area of skin application). Thus, peak blood
levels of the active agent may be reached more slowly or at
about the same rate and wilt reach about the same level as
those obtained by oral administration. Alternatively, the
blood level of active agent attained by single dose oral
administration may be maintained for an extended period by
subsequent percutaneous administration of the active agent.
In the latter case, the initial oral dose may be smaller
than the normal therapeutic oral dose so that side effects
associated with higher-than-minimal therapeutic blood levels
18
~l2Z7753
- Tandy by a reduced oral dose may be maintained by the
subsequent transepideraml administration at a proper rate.
Therapeutic oral doses of diazepam in man produce blood
levels ox approximately 100 ng/ml plasma SUE. Kaplan,
MEL. Jack, K. Alexander, and RYE. We infield, J. Harm. sat.,
62, 1789-1796 (1973)]. Such a blood level is easily attain-
able by percutaneous administration by way of the present
invention and produces pharmacological (behavioral) signs of
therapeutic effectiveness in appropriate animal models for
man, e.g., the rhesus monkey.
The method of the present invention finds application
with mammals in general, most particularly man and domestic
animals such as Cassiopeia horses, dogs, cats and the
like. -
The pharmaceutical composition of the present invention
is administered to the outer skin as a simple mixture or as
a medical preparation by adding known pharmaceutically
acceptable third components in the form of solutions, joint-
mints (paste-including creams and gels) lotions, adhesive
tapes, a plaster, etc.
For example, solutions may simply comprise the active
agent dissolved in the PACE with optional components, e.g.,
glycerin, and the solutions may be incorporated into absorb
bunts, e.g., a gauze, porous membrane, etc.
Ointments, gels or creams may contain conventional
ingredients (e.g., polyethylene glycol and hydroxy propel-
cellulose, etc.) to form the same, and the same may be
spread onto backing materials, e.g., a plastic film.
Similarly, plasters or adhesives tapes may contain the
active agent and PACE in an adhesive base, e.g., acrylic
copolymers or other synthetic gums.
19
.
12277S3
The above listed components should essentially be inert
in the system and not increase or decrease the effect of the
PACE.
The PACE may be added to such a composition in varying
amounts as desired, generally from 10 to 99~ by weight.
In developing the present invention, we used both
diffusion cells and an animal model. The diffusion cell
methods provided a qualitative assessment of the active
agent/PAEC effect on percutaneous absorption. The animal
model rhesus monkey test also provides an acceptable
pharmacokinetic model for man as indicated in J. Sock
Comet. Chum., 30, 297-307. Sept./Oct. 1979 and Toxically.
Apply Pharmacol., 32, 394-398, 1975.
EXPERIMENTAL
In Vitro Skin Penetration Studies with Diffusion Cell
Technique
-
Rat full thickness skins were used in the diffusion
cell method of Michael, Ache Journal, 21 [5], 985-996,
1975. The rat skin was mounted in the diffusion cell in a
vertical position between the upstream and the downstream
compartments; the exposed area of the skin approximated
4.15 cm .
The skin was excised from the shaved abdominal site of
male albino rats weighing 250 300 g, and washed with
normal saline solution after the subcutaneous fat was
carefully removed with scissors. .
The active agent/PAEC solution of known concentration
was added to the upper compartment of the cell, which was
exposed to the epithelial side of the skin and a normal
saline solution was placed in the lower compartment.
12;~7753
,
The penetration rate s sty Ed in a thermostat Ed bath
at 30C. At appropriate intervals samples were withdrawn
from the lower compartment and subsequently analyzed for
active agent concentration by standard analytical methods.
As an alternative, the finite dose technique of Franz,
Cuff. Prowl. Dermatol., Vol. 7, p. 58 68 (Larger, Beset,
1978) can also be followed where the rat skin is mounted
horizontally in a diffusion cell apparatus and the exposed
area of the skin approximates 0.7 cm2.
The active agent/PAEC solution of known concentration
was added to the upstream compartment to which the epithet-
tat side of the skin was exposed, and a normal saline
solution was added to the downstream compartment.
In Viva Rhesus Monkey Test
If desired, an in viva rhesus monkey test as described
below can also be used to determine the effect of the
PAEC/diol moderator combinations of the present invention.
Male rhesus monkeys weighing 10-14 Kg can be used as
the subject. An appropriate area of the monkey's chest is
shaved 24 hours before drug application.
Drug formulations comprising the PACE are applied to a
certain area of the chest. The monkey is restrained in a
chair to prevent it from touching its chest.
Blood samples are taken at appropriate intervals after
the application. The heparinized blood is centrifuged, and
the plasma removed and stored at -20C until analyzed.
Diazepam in plasma can be analyzed following the GLC
method of Angles, J. Chromatog., 75, 55-78, 1973.
.
1;~27~753
.
1 Hereafter the present invention will be illustrated
with reference to an example in more detail but it is not
to be deemed to be limited thereto,
Examples of certain combinations of Components A and B
per the present invention are given in Canadian Patent Apply-
cation No. 453,790 filed April 25~ 1984 in the names of S.
Swept et at and entitled METHOD FOR PERCUTANEOUSLY
ADMINISTERING PHYSIOLOGICALLY ACTIVE AGENTS wherein no dill
moderator is used, and in Canadian Patent Application No,
455,975 filed June, I 84 in renames of K, Swept et at
and entitled METHOD FOR PERCUTANEOUSLY ADMINISTERING PHYSIC-
LOGICALLY ACTIVE AGENTS USING ON ALCOHOL ADJUTANT AND A
SOLVENT,
Compositions were prepared by firstly dissolving
Component A with Component By then mixing the active agent
in the mixture and then mixing the dill therein. The order
of mixing is not important, In the case that Component B is
a solid at ambient temperature or will not homogeneously mix
with Component A 20 wt.% of ethylene glycol monobutyl ether
based on the weight of Components A and B was used as an
agent for assisting dissolution.
Further in the following example, the abbreviations
below are used:
C12H dodecanol
C12Cl - dodecyl chloride
DMAc - dim ethyl acetamide
MY - l-methyl-2-pyrrolidone
I
12Z7753
1 Unless otherwise indicated in the following examples
the active agent was diazepam or metoclopramide hydrochlor-
ides The flux of the active agent is given in the terms of
~g/cm2/8 hours. 25 Volume percent component A with respect
to component A and component B volume with or without dills
aye
I
~2Z77S3
was used in the composition along with 2.5 ~7eigllt percent of
the active agent. For purposes of comparison, in one
instance the result for an adjutant alone with a dill is
given.
Example 1
The Figure is a plot of a diazepam flux versus time (in
hours) illustrating the moderating effect of dills for the
systems 25% C12Cl in DMAc, 25% C12Cl in a 1:1 weight mixture
of DMAc/2,3-butane dill and 25% C12Cl in a 1:2 weight
mixture of DMAc/2,3-butane dill. 25% C12Cl in 2,3-butane
dill is also shown for comparison.
Example 2
This example shows the moderating effect of dills for
the systems 25% C120H in MY and 25% C120H in a 1:1 volume
mixture of MY / 1,2-propane dill. Table 2 shows the met-
clopramide HO flux for 8 hours with these systems.
Table 2
Flux (~q/cm2/8 his)
25% C120H in MY 4382
25% KIWI in a 1:1 volume mixture 1369
- of MP/1,2-propane dill
While the invention has been described in detail and
with reference to specific embodiments thereof, it will be
apparent to one skilled in the art that various changes and
modifications can be made therein without departing from the
spirit and scope thereof.
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