Note: Descriptions are shown in the official language in which they were submitted.
-
~WO9J/~X3~ 2 ~ 7~ 6 ~ 5 PCT/US94/09517
--1--
TRANSDE~MAL DEVICE CONTAINING (E)-2-(P-FW OROPHENETHYL)-3-FLUOROALLyLAMINE
FOR THE TREATMENT OF A UHEIMER'S DISEASE
.
BACKGROUND OF T~E INVENTION
The class of compounds known as monoamine oxidase (MAO)
inhibitors have long been utilized for the treatment of
depression. MAO is an enzyme which plays an important role
in the metabolic regulation of naturally occurring
monoamines. MAO catalyzes the biodegradation of monoamines
through oxidative deamination. Among the physiologically
active monoamines which are known substrates for MAO are:
(a) the so-called "neurotransmitter" monoamines, such as
the catecholamines (e.g. dopamine, epinephrine and
norepinephrine) and the indoleamines (e.g. tryptamine and
5-hydroxytryptamine), (b) the so-called "trace" amines
(e.g. o-tyramine, phenethylamine, tele-N-methylhistamine)
and (c) tyramine.
Biochemical and pharmacological studies indicate that
the MAO enzyme exists in two forms known as "MAO Type A"
(MAO-A) and "MAO Type B" (MAO-B). The two forms differ in
-
21 72605
W095/08325 PCT~S94/09517
--2--
their distribution in body organs, in their substrate
specificity and in their sensitivity to inhibitors. In
general, MAO-A selectively oxidizes the so-called
"neurotransmitter" monoamines (epinephrine, norepinephrine
and 5-hydroxytryptamine), while MAO-B selectively oxidizes
the "trace" monoamines (o-tyramine, phenethylamine and
tele-N-methylhistamine). Both MAO-A and MAO-B oxidize
tyramine, tryptamine and dopamine. However, in man,
dopamine has been shown to be a preferred substrate for
MAO-B. MAO-A and MAO-B also differ in their sensitivity to
inhibition, and thus can be selectively inhibited depending
upon the chemical structure of the inhibitor and/or the
relative concentrations of the inhibitor and the enzyme.
It should be observed that the "selectivity" o an MAO
inhibitor arises because the inhibitor has a greater
affinity for one form of the enzyme over the other. Thus
the selectivity of an inhibitor for MAO-A or MAO-B will be
dose-dependent, selectivity being lost as the concentration
of inhibitor is increased. For example, L-deprenyl,3 is a
selective inhibitor of MAO-B in vivo at lower doses but
becomes a non-selective inhibitor of both MAO-A and MAO-B
as the dose is increased.
There is now evidence that patients with Alzheimer's
disease have higher cerebral MAO-B activity than healthy,
elderly people. Monoamines are known to play a fundamental
role in the cognitive processes linked to memory and
learning, and it has been shown that patients with
Alzheimer's disease have reduced activity of different
neurotransmission systems mediated by monoamines such as
dopamine, noradrenaline and 5-hydroxytryptamine. Finally,
the MAO-B inhibitor L-deprenyl now appears to be an
effective treatment for patients with Alzheimer's disease.
35 [See Mangoni et al., Eur. Neurol. 31, lO0 (l99l)].
c c t ~ f r ~ ~ ~ ~ c
2 6 0 5 / r r ~ ~ c c
3
The compound (E)-2-(p-fluorophenethyl)-3-
fluoroallylamine is a known selective inhibitor of MAO-B
with activity as an antiparkinsonian agent.
SUMMARY OF TEE INVENTION
The present invention provides a transdermal device for
administration of (E)-2-(p-fluorophenethyl)-3-
fluoroallylamine or a pharmaceutically acceptable saltthereof.
DETAILED DESCRIPTION OF T~E INVENTION
The compound (E)-2-(p-fluorophenethyl)-3-
fluoroallylamine is generically disclosed in U.S. Patent
No. 4,454,158, issued June 12, 1984, as an MAO-B inhibitor.
This patent is incorporated herein by reference in its
entirety. The compound (E)-2-(p-fluorophenethyl)-3-
20 fluoroallylamine is specifically disclosed in European
Patent Application Publication No. 0 295 604, published
December 21, 1988.
Pharmaceutically acceptable salts are such organic and
25 inorganic salts of the compound (E)-2-~p-fluorophenethyl)-
3-fluoroallylamine which are non-toxic and allow for
bioavailability. For example, the following salts are
pharmaceutically acceptable: hydrochloric, hydrobromic,
sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric,
30 benzoic, ascorbic, pamoic, succinic, methanesulfonic,
acetic, propionic, tartaric, citric, lactic, malic,
madelic, cinnamic, palmitic, itaconic and benzenesulfonic.
AMENDE~ S~IEI~
5~
W095/08325 2 t 7 2 6 0 5~ PCT~S94/09~17
In general, (E)-2-(p-fluorophenethyl)-3-
fluoroallylamine may be prepared by procedures which are
well known and appreciated in the art such as the
procedures described in U.S. Patent No. 4,454,158, issued
June 12, 1984, and European Patent Application Publication
No. 0 295 604, published December 21, 1988.
In general, (E)-2-(p-fluorophenethyl)-3-
fluoroallylamine may be prepared by procedures wherein adiester of p-fluorophenylethylbutyric acid is
difluoromethylated in a known manner by first treating the
diester with a strong base to produce the corresponding
carbanion and then contacting the carbanion with a suitable
halomethylating agent. The strong base must be non-
nucleophilic and be of sufficient strength to remove a
proton from the methine moiety adjacent to the carboxy
group of the starting ester. Suitable bases are known in
the art, such as are disclosed in European Patent
Application Publication No. 0 295 604, published December
21, 1988.
Following difluoromethylation, it is preferred to
selectively remove one of the ester groups by acid
hydrolysis. To accomplish selective cleavage it is
preferred to have a mixed diester wherein one ester group
is easily cleaved (e.g. one ester group bears t-butyl,
benzyl, diphenylmethyl or triphenylmethyl) while the other
bears a straight chain alkyl (e.g. methyl, ethyl, propyl or
n-butyl).
The easily cleaved ester group can be selectively
hydrolyzed by treatment with an organic or inorganic acid,
either with or without an added solvent, using a
temperature range of about 0 to about 25 C and a reaction
time of about 1 to 10 hours. Ambient temperature is
preferred. The choice of the acid for the hydrolysis is
not critical, except that the acid should be chosen so that
'; ' ~?l~F- 1~ r-~
~ W095/08325 2 1 7 ~ 6 ~ ~ PCT~S94/09517
it can be easily removed after the hydrolysis stage.
Trifluoroacetic acid is preferred since its low boiling
point permits it to be easily removed from the hydrolysis
product. When one ester group bears benzyl,
diphenylmethyl, or triphenylmethyl and the other is a
straight-chain Cl-C4 alkyl group, the easily cleaved ester
group can also be selectively cleaved by subjecting the
mixed diester to catalytic hydrogenolysis using
conventional procedures: for example, by treatment under a
hydrogen atmosphere in the presence of a catalyst (e.g.,
Pd/C) at ambient temperature for l to 48 hours. As will be
apparent to those skilled in the art, the ester groups can
be chosen so that both groups can be cleaved simultaneously
by acid-hydrolysis or catalytic hydrogenolysis.
Following selective hydrolysis, the difluoromethylated
monoester is converted to its acrylate ester by treatment
with a base. The reaction can be performed using an
aqueous or non-aqueous solvent with strong bases such as
sodium hydroxide and the like, or with weak bases, such as
triethylamine or sodium bicarbonate. With strong bases,
care must be exercised to avoid using an excess of base to
prevent interaction with the double bond. The choice of
the base, the reaction solvent and reaction conditions will
be apparent to those skilled in the art. A preferred
procedure is to use aqueous sodium hydroxide in THF at
ambient temperature. In general, a temperature range of 0
to 25C and a reaction time of 15 minutes to 2 hours can be
used.
The acrylate ester is reduced to yield the allyl
alcohol. The reducing agent employed for this
transformation can be any reagent which is known in the art
to be capable of selectively reducing an ester function or
carboxylic acid function to the corresponding carbinol in
the presence of a double bond. A preferred reducing agent
is diisobutylaluminum hydride (DIBAL-H) in hexane, THF,
W095/08325 2 1 7 2 6 ~ 5 -6- PCT~S94/09517
diethyl ether, dichloromethane, or mixtures thereof. In a
preferred procedure, a solution of the acrylate methyl
ester in THF is cooled to about 0 to -78C (preferably -60
to -70C), the DIBAL-H dissolved in hexane is added, and
the temperature of the mixture is allowed to rise to
ambient temperature. The reaction time can be about 2 to
24 hours.
The allyl alcohol can be converted to the desired allyl
primary amine using procedures known in the art to be
useful for replacing an allylic hydroxyl group by an
allylic primary amino group. A preferred laboratory method
involves the direct formation of an imido derivative,
preferably the phthalimide, and subsequent cleavage of the
imido group to generate the primary amino group. The imido
derivative can be prepared conveniently by treating the
allyl alcohol with the appropriate imide (i.e.,
phthalimide, succinimide, or maleimide) in the presence of
a triarylphosphine (e.g., triphenylphosphine) or a
trialkylphosphine and diethyl azodicarboxylate in an
aprotic organic solvent (e.g., THF or dioxane). The
reaction can be performed using a temperature range of
about 0 to 70C and a reaction time of about l to 24
hours. Ambient temperature is preerred. The imido
derivative can be cleaved, preferably by reaction with
hydrazine in an organic solvent, such as an alkanol (e.g.,
ethanol) at reflux temperature (50 to 100C) and a
reaction time of about 30 minutes to lO hours. It is
preferable to add an acid (e.g., hydrochloric acid) after
the hydrazine treatment to convert the product to the acid
addition salt. Other reagents can be used to cleave the
imido function. For example, the imide can be heated with
a strong mineral acid (e.g., hydrochloric or sulfuric acid)
or a mixture of hydrochloric acid and acetic acid. Acids
such as hydrobromic acid which are reactive towards olefins
usually cannot be used. The final products are
~ W095/08325 2 1 7 2 6 0 5 PCT~S94/09517
conveniently purified and isolated as the acid addition
salt using conventional purification methods.
The foregoing procedures may be illustrated by the
following example.
EXAMPLE 1
(E)-(p-Fluorophenethyl)-3-fluoroallylamine HCl
Step A: Ethyl 2-(tert-butoxycarbonyl)-p-fluorophenyl-
butyrate
Treat a solution of p-fluorophenylbutyric acid (25g) in
tert-butyl acetate (349mL) with perchloric acid (1.77mL)
and then stir at ambient temperature for 1.5 hours. Pour
the solution into water (350mL) containing NaOH (48g) and
isolate the tert-butyl ester by ether extraction to give a
pale yellow oil. Prepare a solution of lithium
diisopropylamide from diisopropylamine (22.74g) and 1.6M n-
butyl lithium (143.7mL) in THF (200mL), cool to -78C and
slowly add a solution of tert-butyl p-fluorophenylbutyrate
(26.76g) in THF (lOOmL). After 1 hour, add a solution of
ethyl chloroformate (12.19g) in THF (lOOmL) and continue
stirring at ambient temperature for 24 hours. Then pour
the mixture into water, neutralize with dilute aqueous HCl
and isolate the product by ether extraction to give an
orange oil (32.27g).
Step B: Ethyl 2-(tert-butoxycarbonyl)-2-(difluoromethyl)-
p-fluorophenylbutyrate
To a solution of crude ethyl 2-(tert-butoxycarbonyl)-p-
fluorophenylbutyrate (32.14g) in THF (400mL), add sodium
tert-butoxide (19.81g). Stir the mixture for 1 hour, then
heat to 45C and add ClCHF2 gas ra`pidly for about 15
minutes. Continue stirring for 1 hour under an atmosphere
of ClCHF2 and allow the temperature to fall to ambient.
W095/08325 2 ~ 7 ~ 6 0 5 PCT~S9~/09517 ~
Pour the reaction mixture into water/brine and isolate the
crude product by ether extraction to give an orange oil
t34 55g)~
Step C: (E)-Ethyl 2-(p-fluorophenethyl)-3-fluoroacrylate
Stir a solution of ethyl 2-(tert-butoxycarbonyl)-2-
(difluoromethyl)-p-fluorophenylbutyrate (30.28g) in
trifluoroacetic acid (168mL) for 1 hour and then remove the
excess trifluoroacetic acid by evaporation. Dissolve the
residual oil (25.82g) in THF (230mL) and slowly treat with
2M NaOH (80mL) so that the pH does not rise above 7.02.
After completion of addition of the solution, stir the
solution for another 15 minutes and then extract the
product into ether. Evaporate the ether and filter the
residue through a short column of silica using 5% ethyl
acetate in light petroleum as the solvent. Evaporate the
solvent to give an essentially pure product as a pale
orange oil (15.75g).
Step D: (E)-2-(p-Fluorophenethyl)-3-fluoroallyl alcohol
Cool a solution of (E)-ethyl 2-(p-fluorophenethyl)-3-
fluoroacrylate (15.70g) in hexane (350mL) to -10C and then
slowly treat with a solution of diisobutylaluminum hydride
in hexane (lM solution, 196mL). Stir at ambient
temperature for 90 minutes, then cool to 10C and treat
consecutively with methanol (196mL) and 6M a~ueous HCl
(245mL). Add water and isolate the product by ether
extraction followed by distillation of the solvents to give
almost pure alcohol (11.36g).
Step E: (E)-l-Fluoro-2-(p-fluorophenethyl)-3-
phthalimidopropene
Cool a solution of (E)-2-(p-fluorophenethyl)-3-
fluoroallyl alcohol (11.36g), phthalimide (8.43g) and
L-~ V V ~
~ f ' C S~ ~ C ~ C
c ~ e ~ c ~ c
2 1 7 ~ 6 ~ 5 9 r ~ r i
triphenylphosphine (15.3g) in THF (40QmL) to 0C, and treat
slowly with a solution of diethyl azodicarboxylate (9.99g)
in TEF (SOmL~. Continue stirring at ambient temperature
overnight, then evaporate the solution to leave an orange
paste (30g). Separate the pure product by using
chromatography on silica (20% ethyl acetate in petroleum
ether as eluant) to give a pale yellow solid (13.9g).
Step F: (E)-(p-Fluorophenethyl)-3-fluoroallylamine ~Cl
Reflux a mixture of (E)-l-fluoro-2-(p-fluorophenethyl)-
3-phthalimidopropene (0.26g) and hydrazine hydrate (80mg)
in ethanol (5mL) for 2.5 hours. Add 6N HCl (1.2mL) and
evaporate the mixture to dryness. Dissolve the residue in
NaO~ (lOmL) and isolate the crude amine by ether
extraction. Dissolve in T~F (lOmL) and treat with di-tert-
butyl dicarbonate (194mg). Reflux the solution for 2 hours
and then isolate the crude N-Boc derivative by ether
extraction. Purify by silica chromatography (25% ethyl
acetate in petroleum ether) to give pure material (180mg)
as an almost colorless oil. Dissolve in HC1-saturated
ether (12mL) and allow to stand overnight. Filter to dive
the title product (30mg) as colorless plates (m.p. 131C).
The present invention provides a method of treatment
for Alzheimer's disease in a patient in need thereof
comprising transdermally administering to said patient a
therapeutically effective amount of (E)-2-(p-
fluorophenethyl)-3-fluoroallylamine or a pharmaceutically
acceptable salt thereof. As used herein, the term
"patient" refers to a warm-blooded animal, such as a human,
which is afflicted with Alzheimer's disease. The term
"patient in need thereof" refers to a patient in need of
treatment for Alzheimer's disease.
Alzheimer's disease, also known as Senile Dementiz of
the Alzheimer's Type (SDAT), is a form of presenile
AMENGED SHEET 5
W095/08325 2 1 7~605 PCT/US94/09S17
--10--
degenerative dementia due to atrophy of frontal and
occipital lobes of the brain. Alzheimer's disease involves
a progressive loss of memory, deterioration of intellectual
functions, apathy, speech and gait disturbances and
disorientation. The course of the disease may take a few
months to four to five years to progress from the early
stages to a complete loss of intellectual function. An
attending diagnostician, as one skilled in the art, can
identify those patients who are afflicted with Alzheimer's
disease on the basis of standard diagnostic procedures and
tests.
In effecting treatment according to the present
invention, Alzheimer's disease in a patient will be
controlled so that the progressive loss of memory,
deterioration of intellectual functions, apathy, speech and
gait disturbances and disorientation will be slowed,
interrupted, arrested or stopped. Treatment will not
necessarily result in total elimination of the disease or
in regression of the disease to a normal cognitive state.
A therapeutically effective amount of (E)-2-(p-
fluorophenethyl)-3-fluoroallylamine, or a pharmaceutically
acceptable salt thereof, is an amount which is effective,
upon single or multiple dose administration to the patient,
in controlling the Alzheimer's disease so that the
progressive loss of memory, deterioration of intellectual
functions, apathy, speech and gait disturbances and
disorientation will be slowed, interrupted, arrested or
stopped.
A therapeutically effective amount of (E)-2-(p-
fluorophenethyl)-3-fluoroallylamine, or a pharmaceutically
acceptable salt thereof, can be readily determined by the
attending diagnostician, as one skilled in the art, by the
use of known techniques and by observing results obtained
under analogous circumstances. In determining the
~ ~ t ~ ~ J . ~ i r
L~l U ' U / J .L:-
2 1 7 ;~ ~i O ~ c~ r ~ c ~ r r
therapeutically effective amount or d~se, a number offactors are considered by the attending diagnostician,
including, but not limited to: the patient's size, age and
general health; the severity of the disease; the response
of the individual patient; the mode of administration; the
bioavailability characteristics of the preparation
administered; the dose regimen seLected; the use of
concomitant medication; and other relevant circumstances.
lQ
A therapeutically effective amount of (E)-2-(p-
fluorophenethyl)-3-fluoroallylamine, or a pharmaceutically
acceptable salt thereof, will vary from about 0.001
mg/Rg/day to about 1.0 mg/Kg/day. Preferred amounts are
expected to vary from about 0.01 mg/Kg/day to about 0.25
mg/Kg/day.
In effecting treatment of a patient afflicted with
Alzheimer's disease, the compound (E)-2-(p-
fluorophenethyl)-3-fluoroallylamine, or a pharmaceutically
acceptable salt thereof, can be administered in any form or
mode which makes the compound bioavailable in effective
amounts. Transdermal administration is also preferred.
One skilled in the art of preparing formulations can
readily select the proper form and mode of administration
depending upon the particular characteristics of the
compound selected, the stage of the disease, and other
relevant circumstances.
The compounds can be administered alone or in the form
of a pharmaceutical composition in combination with
pharmaceutically acceptable carriers or excipients, the
proportion and nature of which are determined by the
solubility and chemical properties of the compound
AME~GEDS
5~
~-~ v ~ v ~
2 1 7 2 6 05 1~ -
selected, the chosen route of administration, and standard
pharmaceutical practice. The compounds of the invention,
while effective themselves, may be formulated and
administered in the form of their pharmaceutically
acceptable acid addition salts for purposes of stability,
convenience of crystallization, increase~ solubility and
the like.
The pharmaceutical compositions are prepared in a
manner well known in the pharmaceutical art. The carrier
or excipient may be a solid, semi-solid, or liquid material
which can serve as a vehicle or medium for the active
ingredient. Suitable carriers or excipients are well known
in the art. The pharmaceutical composition may be adapted
for oral or parenteral use and may be administered to the
patient in the form of tablets, capsules, suppositories,
solution, suspensions, transdermal device or the like.
Al~IIENDED SHEE~
~ogs/08325 2 1 7~60~ PCT~S94/09517
The tablets, pills, capsules, troches and the like may
also contain one or more of the following adjuvants:
binders such as microcrystalline cellulose, gum tragacanth
or gelatin; excipients such as starch or lactose,
disintegrating agents such as alginic acid, Primogel~, corn
starch and the like; lubricants such as magnesium stearate
or Sterotex~; glidants such as colloidal silicon dioxide;
and sweetening agents such as sucrose or saccharin may be
added or a flavoring agent such as peppermint, methyl
salicylate or orange flavoring. When the dosage unit form
is a capsule, it may contain, in addition to materials of
the above type, a liquid carrier such as polyethylene
glycol or a fatty oil. Other dosage unit forms may contain
other various materials which modify the physical form of
the dosage unit, for example, as coatings. Thus, tablets
or pills may be coated with sugar, shellac, or other
enteric coating agents. A syrup may contain, in addition
to the present compounds, sucrose as a sweetening agent and
certain preservatives, dyes and colorings and flavors.
Materials used in preparing these various compositions
should be pharmaceutically pure and non-toxic in the
amounts used.
For the purpose of parenteral therapeutic
administration, such as intramuscular, intravenous, and
subcutaneous, the compounds of the present invention may be
incorporated into a solution or suspension. These
preparations should contain at least 0.01% of a compound of
the invention, but may be varied to be between 0.01 and
about 50~ of the weight thereof. The amount of the
inventive compound present in such compositions is such
that a suitable dosage will be obtained. Preferred
compositions and preparations according to the present
invention are prepared so that a parenteral dosage unit
contains between 0.01 to 10 milligrams of the compound of
the invention.
W095/08325 2 1 7 ~ 6 ~ ~ PCT~S94/09517 ~
The solutions or suspensions may also include one or
more of the following adjuvants: sterile diluents such as
water for injection, saline solution, fixed oils,
polyethylene glycols, glycerine, propylene glycol or other
synthetic solvents; antibacterial agents such as benzyl
alcohol or methyl paraben; antioxidants such as ascorbic
acid or sodium bisulfite; chelating agents such as ethylene
diaminetetraacetic acid; buffers such as acetates, citrates
or phosphates and agents for the adjustment of tonicity
such as sodium chloride or dextrose. The parenteral
preparation can be enclosed in ampules, disposable syringes
or multiple dose vials made of glass or plastic.
The compounds of this invention can also be
administered topically. This can be accomplished by simply
preparing a solution of the compound to be administered,
preferably using a solvent known to promote
transdermalabsorption such as ethanol or dimethyl sulfoxide
(DMSO) with or without other excipients~. Preferred topical
administration is by a transdermal device.
Factors to be considered in the use of transdermal
devices are well known in the art and include: the optimum
level of pharmaceutically active compound necessary to
obtain the desired therapeutic response, inherent
restrictions on the physical and chemical properties of the
delivery system materials dictated by the desired
application, the kinetics and mechanism of the delivery of
pharmaceutically active compound from the delivery system,
and the mechanism and rate of removal of the
pharmaceutically active compound from the patient.
In general, transdermal devices are a combination of
the compound to be administered and a excipient, commonly a
polymeric material, arranged to allow delivery of the
pharmaceutically active compound at controlled rate over a
specified period of time. Transdermal devices are a
~ W095/08325 2 1 7 ~ 6 ~ 5 PCT~S94/09517
laminate consisting of a backing member, a reservoir
containing the compound, and an adhesive layer or a means
for maintaining the device in contact with the skin or
mucosa.
The proper choice of a backing member is well known and
appreciated in the art. Backing members are usually
impermeable to the compound and thereby define one face of
the transdermal device.
The reservoir, the compound containing portion of the
transdermal device, encompasses a broad class of structures
capable of fulfilling the function. Reservoirs may be
walled containers containing the compound as a liquid,
solid, suspension, solution, or in a polymeric matrix. The
compound may be contained in a matrix that controls the
rate of delivery either by microporous flow or by
diffusion. A reservoir may consist of a plurality of
microcapsules containing the compound disbursed throughout
a matrix which is either solid or microporous. A
reservoir may consist of the compound adsorbed onto a
polymeric matrix. A reservoir may be formed of permeable
material or have permeable material on one face of the
reservoir to permit passage of the compound. A reservoir
may take the form of the compound surrounded by release
controlling materials, such as by encapsulation, layers, or
containers.
A transdermal device may have a permeable membrane
which determines the rate of delivery of the compound, such
membranes are well known and appreciated in the art.
Membranes may control the delivery of the compound by
microporous flow, diffusion through the membrane, or by
pressure induced viscous flow.
.
Examples of transdermal devices are described in U.S.
Pat. Nos. 3,742,951, 3,797,494, 3,996,934, and 4,031,894.
WO 95/08325 2 ~ 7 ~ 6 0 5 PCT/US94/09517 ~
These devices generally contain a backing member which
defines one of its face surfaces, a compound permeable
adhesive layer defining the other face surface and at least
one reservoir containing the compound interposed between
the face surfaces. Alternatively, the compound may be
contained in a plurality of microcapsules distributed
throughout the permeable adhesive layer. The compound is
delivered continuously from the reservoir or microcapsules
through a membrane which is either; directly in contact
with the skin or mucosa of the recipient, or into an active
agent permeable adhesive which is in contact with the skin
or mucosa of the recipient. In the case of microcapsules,
the encapsulating agent may also function as the membrane.
If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient.
An example of a transdermal device which requires no
membrane is described in U.S. Pat. No. 3,921,636 and
comprises the pharmaceutically active compound contained
in a support matrix from which it is delivered in a desired
gradual, constant and controlled rate. At least two types
of release are possible in these systems. The support
matrix is permeable to the release of the compound through
diffusion or microporous flow. The release is rate
controlling. Release by diffusion occurs when the support
matrix is non-porous. The pharmaceutically effective
compound dissolves in and diffuses through the support
matrix itself. Release by microporous flow occurs when the
pharmaceutically effective compound is transported through
a liquid phase in the pores of the support matrix. The
rate of release controls the amount of compound
administered to a patient.
The following examples present the preparation of a
transdermal device for administration of (E)-(p-
fluorophenethyl)-3-fluoroallylamine. These examples are
095/08325 2 1 7 ~ 6 OS PCT~S94/09517
-17-
understood to be illustrative only and are not intended to
limit the scope of the invention in any way. As used in
these examples, the following terms have the meanings
5 indicated: "g" refers to grams, "~g" refers to micrograms,
"mmol" refers to millimoles, "mL" refers to milliliters,
"C" refers to degrees Celsius, "HPLC" refers to high
performance liquid chromatography, "~L" refers to
microliters, "cm" refers to centimeters, "cm2" re~ers to
10 centimeters squared, "mm" refers to millimeters, "M" refers
to molar, "nm" refers to nanometers, "hr" refers to hour.
EXAMPLE 2
(E)-(p-Fluorophenethyl)-3-fluoroallylamine
Combine (E)-(p-fluorophenethyl)-3-fluoroallylamine HCl
(26.5 g, 0.113 mmol) and water. Make the solution basic
with sodium hydroxide and extract with hexane. Combine the
organic layers, dry over MgSO4, filter, and evaporate ~n
vacuo to give 22.38 g of the title compound as an oil. lH
NMR (CDC13) ~ 1.20 (s, 2H), 2.45 (m, 2H), 2.73 (m, 2H), 3.13
(m, 2H), 6.55 (d, J=80.0, lH), 6.97 (m, 2H), 7.16 (m, 2H);
13C NMR (CDC13) ~ 161.31 (d, JC,F=243.2), 145.36 (d,
JC,F=255.2), 137.15 (d, JC,F=2.8), 129.65 (d, JC,F=8.3),
123.50 (d, JC,F=3-7)~ 115.01 (d, JC,F=20.4), 41.58 (d,
JC.F=9.2), 33.40 (d, JC,F=2-8)~ 26.83 (d, JC,F=3-7)-
EXAMPLE 3
Preparation of transdermal devices containinq (E)-(p-
fluorophenethyl)-3-fluoroallylamine.
Combine (E)-(p-fluorophenethyl)-3-fluoroallylamine and
- a matrix, National Starch Duro-Tak 1074; 10%, 20%, 30%,
40%, and 50~ (w/w) to form a drug/matrix. After drug
solubilization, coat drug/matrix on a sheet of polyethylene
using a Lab Hand Coater. Dry the coated sheets in an oven
at 50C for 15 minutes. Place a substrate layer on top of
the drug/adhesive coat and apply a roller to remove air
W095/08325 2 i 7 2 6 0 5 PCT~S94/09517
-18-
bubbles to give sheets from which transdermal devices
containing 10%, 20%, 30%, 40%, and 50% (w/w, drug/matrix)
can be cut.
EXAMPLE 4
Skin permeation studies of (E)-(p-fluorophenethyl)-3-
fluoroallylamine.
Skin permeation of (E)-(p-fluorophenethyl)-3-
fluoroallylamine was conducted at 37C by Franz diffusion
cells (model FDC-400, Crown Glass Co.) using hairless mouse
skins and water (pH=7.0) as dissolution medium, according
to the method of M. Mahjour el al, J. of ControlledRele~e 14,
243-252, (1990). Hairless mouse skins were harvested from
six-week old hairless mice (Charles River Co.) and fitted
over the diffusion cell. The dermal side of the skin was
loaded with lOO~L, 150~L, and 200~L of a saturated solution
of (E)-(p-fluorophenethyl)-3-fluoroallylamine in water.
The saturated solution of (E)-(p-fluorophenethyl)-3-
fluoroallylamine in water had a density of 1.124 g/mL.
Concentration of drug in dissolution medium was measured at
4, 8, 12, 24, and 28 hours, using HPLC. HPLC was conducted
on a Waters 845 system with a Waters WISP 712 autoinjector,
Waters 600E pump, and Waters 486 W detector. A DuPont
Zorbax Rx C8 column, 4.6 mm by 25 cm, was used with
isocratic elution, 78% 0.05M sodium phosphate adjusted to
pH 2.9 with phosphoric acid and 22~ acetonitrile. Flow
rate of 1.5 mL/minute and detection at 265 nm.
Table 1 summarizes the results of the skin permeation
study of (E)-(p-fluorophenethyl)-3-fluoroallylamine.
~ W095/08325 2 1 7 2 6 0 5 PCT~S94/09517
--19--
Drug permeation at 100 ~L Drug permeation at 150 ~L Drug permeation at Z00 I~L
(~J9/cm2) (~9/cm2) (I~g/cm2)
time (hr) sample sample sample sample sample sample sample sample sample
4 4798.10 4592.82 4508.32 6391.68 5464.09 4582.53 6234.36 6256.11 5723.97
8 9626.69 8763.95 ~688.90 10014.32 9400.18 8276.54 10874.62 11033.97 10298.52
12 14828.55 13221.46 12931.25 15103.49 13509.45 12146.41 15447.40 15865.07 14819.10
24 24613.43 21888.35 21243.21 25527.66 21762.32 20271.37 24634.65 25613.63 23934.88
28 29029.84 25982.51 24795.02 30164.52 25183.02 23683.37 28760.30 30068.48 27996.68
skin
p . t , 974.06 859.01 815.96 976.51 796.97 773.67 903.37 956.15 893.90
rate
(~Jg/cmZ/hr)
;Iverage
+standard 883.01 + 81.74 849.05 +111.00 917.81 +33.54
deviation
(~Jg/an21hr)
EXAMPLE 5
Skin permeation studies of transdermal devices containinq
(E)-(p-fluorophenethyl)-3-fluoroallylamine.
Skin permeation study of transdermal devices containing
10%, 20%, 30%, 40~, and 50% (w/w, drug/matrix) of (E)-(p-
fluorophenethyl)-3-fluoroallylamine was conducted at 37C
by Franz diffusion cells (model FDC-400, Crown Glass Co.)
using hairless mouse skins and water tpH=7.0) as
dissolution medium, according to the method of M. Mah]our
et al, J. of Controlled Releo~e 14, 243-252, (1990). Hairless
mouse skins were harvested from six-week old hairless mice
(Charles River Co.) and fitted over the diffusion cell.
Transdermal devices containing 10%, 20~, 30%, 40~, and 50%
(w/w, ~E)-(p-fluorophenethyl)-3-fluoroallylamine/matrix)
were applied to the dermal side of the skin. The
concentration of drug in the dissolution medium was
measured by HPLC as taught above in Example 4 and the
wos5l~32s 2 1 7 2 6 0 5 PCT~S94/09517
-20-
permeation rate were determined. The results are
summarized in Table 2.
S Table 2
drug/matrix(w/w) (~g/crn2/hr)
10% 7.60 + 0.87
l 20% 36.73 + 2.11
30% 96.78 + 8.55
40% 181.16 + 10.35
50% 249.16 + 15.04
