Note: Descriptions are shown in the official language in which they were submitted.
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Transdermal Delivery of Pergolide
This application claims the benefit of the filing date of U.S. Provisional
Application No. 60/280,533, filed March 30, 2001.
Field of the Invention
This invention relates to the administration of pergolide to a patient. More
particularly, this invention relates to the transdermal delivery of pergolide.
Pergolide is a drug that is used to treat various health conditions that
affect
individuals. For example, pergolide has been used in the treatment of the
symptoms of
Parkinson's disease and in the reduction of plasma concentrations of prolactin
in
conjunction with the treatment of hyperprolactinemia. In the treatment of
Parkinson's
disease, the typical course of medication is a gradual increase in the oral
dose over 14
days, with a concomitant gradual increase in blood serum levels. Blood serum
levels
ranging between a maximum of about 500 picograms/ml (maximum serum level 2-3
hours following a 2.5 mg oral dose) to about 60 picograms/ml (serum level 8
hours
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following a 0.5 mg oral dose) have been considered within a therapeutic range
from
oral dosing studies of pergolide mesylate in the treatment of Parkinson's
disease.
Typically, oral dosing is 3 mg/24 hours, divided into three doses, with serum
concentrations peaking at approximately 200pg/ml.
The oral administration of pergolide offers the advantage of being simple to
administer. However, with oral administration, blood serum levels fluctuate
between
dosages and the drug must pass through the liver before systemic distribution
in the
blood stream, requiring a dosage level high enough to account for metabolic
losses in
the hepatic system. Accordingly, there are disadvantages associated with the
administration of oral doses of pergolide.
It is known also to administer pergolide by transdermal delivery, such means
of
delivery having advantages relative to oral delivery. The present invention
relates to the
transdermal delivery of pergolide.
Reported Developments
European published patent application EP 0913128A1 discloses a transdermal
device for delivering a variety of medicaments, for example, pergolide. The
device
utilizes a layer of polymeric adhesive in which the medicament is dispersed
homogeneously. The medicament-containing adhesive layer is prepared by
dissolving
the constituents in a solvent(s). The resulting solution solidifies to form
the
medicament-containing layer upon evaporation of the solvent. The device
includes also
a backing layer on one side of the adhesive layer to protect the adhesive
layer during
use and storage and a strippable release layer on the other side of the
adhesive layer to
protect the otherwise exposed side of the adhesive layer during storage. The
strippable
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layer is removed before application of the adhesive layer of the device to the
body
membrane.
Transdermal delivery of pergolide is disclosed also in U.S. Patent No.
6,001,390 to Yum. The '390 patent discloses the delivery of pergolide mesylate
in vitro
across samples of human skin. In one embodiment of the delivery devices
disclosed in
the Yum patent, a liquid pergolide-containing composition is held within the
device in a
space from which the pergolide is delivered to the body membrane by diffusion
through
a micro-porous membrane in contact therewith. The device includes a strippable
layer
which covers the face of the micro-porous membrane that is placed in contact
with the
body membrane and which is removed at the time of use. In another embodiment
disclosed in the Yum patent, the pergolide is contained in a solid polymeric
film which
is prepared by forming a solution of the pergolide and polymeric carrier and
evaporating the solvent to form the polymeric film.
One of the shortcomings of the present means for delivering pergolide
transdermally is that relatively large amounts of pergolide must be used in
the delivery
device in order to achieve desired therapeutic pergolide blood serum levels.
The
present invention relates to improved means for the transdermal delivery of
pergolide to
a patient.
Summary of the Invention
In accordance with the present invention, there is provided a transdermal
delivery device comprising a multi-phase matrix which includes a solid liquid-
retaining
member and associated therewith pergolide in liquid form. In a preferred
embodiment,
the liquid-retaining member is, for example, a non-woven medical absorbent and
the
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pergolide is dissolved in an aqueous based solvent.
Another aspect of the present invention is the provision of a method for the
transdermal delivery of pergolide comprising delivering to a body membrane
pergolide
in liquid form and from a liquid pergolide-carrying member which is in direct
contact
with the body membrane. In this embodiment of the invention, the pergolide is
delivered from a supply source directly to the body membrane unimpeded by a
material
interposed between the source and the surface of the body membrane.
The present invention provides the means to efficiently deliver relatively
high
amounts of pergolide transdermally and to achieve desired blood serum levels
of the
pergolide. And this can be accomplished without irritating the membrane of the
patient.
Brief Description of the Drawings
Figures 1 to 4 are graphical representation of in vitro pergolide delivery
flux
from a transdermal delivery device of the present invention.
Figure 5 is a graphical representation of in vivo pergolide blood serum levels
attained by a transdermal delivery device of the present invention.
Figure 6 is a graphical representation of in vitro pergolide delivery flux
involving the use of a comparative composition comprising a solid solution of
pergolide.
Figures 7 to 9 are graphical representations of in vitro pergolide delivery
flux
from direct application to the skin of a liquid pergolide composition.
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Detailed Description of the Invention
The present invention relates to the transdermal delivery of liquid pergolide
from
a transdermal delivery device held in contact with a membrane of an animal to
which
pergolide is to be delivered. The delivery device of the present invention
comprises a
mufti-phase matrix which includes a solid material for holding the liquid
pergolide. The
device may include other elements which relate to the use or functioning of
the device.
Examples of such elements are a layer to secure the device in place during
use, a
barrier layer on that surface of the matrix which is not in contact with the
body
membrane to prevent the liquid pergolide from exiting that surface, and a
release layer
which shields the other surface of the matrix from the ambient when the device
is not in
use.
The mufti-phase matrix of the delivery device has at least two elements,
pergolide in liquid form and a solid material which has an affinity for the
liquid and so
1 S functions as a liquid-retaining member. The affinity between the
composition
comprising the liquid pergolide and the solid liquid-retaining member may be
due, for
example, to adsorption such as physi- or chemi-sorption or to absorption
within void
spaces in the material.
Typically, the liquid pergolide is contained in a composition which can
include
other constituents, as described below. The composition is held by the liquid-
retaining
member with sufficiently strong force to withstand pressure that the device
may be
subjected to in the ordinary course of use and handling without expelling the
composition therefrom.
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The liquid-retaining member of the delivery device of the present invention
can
be made of any suitable material. Speaking generally, the material should
exhibit an
affinity for some or all of the components of the composition which comprises
the
liquid pergolide. The material should not irreversibly react or interact with
any of the
components of the composition. For example, it should resist being degraded by
the
composition. Conversely, the material should not affect adversely any
components of
the composition. In this respect, materials which are inert toward the
components of the
composition and do not dissolve therein are suitable materials for use in
fabricating the
liquid-retaining member. Examples of suitable materials are reticulated
materials
represented by the natural and synthetic fibers in the form of woven gauze,
relatively
long staple absorbent masses, non-woven fiber web, and a non-woven web which
is
surface-treated with a porous polymer. A preferred material is a non-woven
material
comprising rayon web covered with porous polyethylene, for example, 1603 non-
woven medical absorbent available from 3M.
I S Such materials are capable of retaining the composition comprising the
liquid
pergolide in cavities, pores or channels that comprise the materials. The
liquid-
retaining member can also comprise a material which adsorbs the liquid
pergolide. For
example, a surface of a component of the liquid composition can be adsorbed to
a
surface of the material comprising the liquid-retaining member and, by
cohesive
interaction with un-adsorbed components of the liquid composition, the bulk of
the
composition is retained by the member.
The solid liquid-retaining member of the delivery device of the present
invention
has associated therewith pergolide in liquid form. The term "pergolide" is
used herein
to mean any pharmaceutically acceptable species of ergoline having
pharmaceutical
properties like those of the free base 8 (3-[(methylthio)methyl]-6-propyl
ergoline. It is
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recognized that there are many species of pergolide which are suitable for the
treatment
of abnormal bodily conditions, for example, treating the symptoms of
Parkinson's
disease and hyperprolactinemia. In addition to the aforementioned free base,
acid salts
of the free base and compounds which have structural variations of the
ergoline ring are
known to be pharmaceutically active. Examples of pharmaceutically acceptable
salts of
pergolide and compounds with structural variations of the ergoline ring that
exhibit
pharmacological properties and that may be used in the practice of the present
invention
are disclosed in U. S. Patent No. 4,166,182 to Kornfeld et. al. . A mixture of
two or
more species of pergolide may be used in the practice of the present
invention.
Preferred forms of pergolide for use in the practice of the present invention
are
pergolide mesylate and pergolide free-base, both of which are a solid at room
temperature and are sufficiently soluble in water or nonaqueous solvents to
provide a
solution which contains pharmaceutically effective amounts of the dissolved
pergolide
species.
Many of the species of pergolide suitable for use in the present invention are
solids at ambient temperatures. Accordingly, the matrix of the delivery device
will
typically contain a composition which comprises a "pergolide" solvent in
addition to the
pergolide. It is likely that a solvent will be used also with those
pharmaceutically
acceptable species of pergolide that are liquids under ambient conditions to
function as
a diluent or carrier of the liquid pergolide
Any suitable liquid solvent (inorganic or organic) which is capable of
dissolving
the pergolide in an amount which is considered sufficient for including in the
matrix of
the delivery device can be used. Water, alcohols, for example, ethanol,
dimethyl
sulfoxide (DMSO), and glycols, for example, polyethylene glycol and
polypropylene
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glycol are examples of solvents that can be used.
It is known that skin and mucous membranes are irritated by direct application
thereto of a relatively high amount of pergolide. The "pergolide" solvent
serves also as
a diluent and functions to reduce undesirable irritation. The solvent can act
also to
improve the permeability of the skin or mucous membrane to the pergolide. In
addition, the solvent can function as a diffusion media which helps to conduct
the
pergolide to the body membrane through which it enters the body.
The pergolide-containing composition can comprise a single phase composition,
for example, a liquid solution of pergolide, or it can comprise a mufti-phase
composition, for example, an emulsion, a gel, or a dispersion which includes
the
pergolide in liquid form. An emulsion can comprise liquid droplets of a
solution of
pergolide dispersed in a continuous liquid phase A gel can comprise a phase of
continuous solution thickened by an appropriate gelling agent which comprises
a
dispersed phase. A dispersion can comprise a liquid solution of dissolved
pergolide
having dispensed therein solid particles of pergolide, for example,
nanoparticles of
pergolide.
In preferred form, the composition comprises a solution of pergolide having a
viscosity at room temperature such that the solution flows readily, for
example, from a
pipette which is used to deliver the solution to the liquid-returning member
of the
matrix. An aqueous-based solution which includes a hydrocarbon-based solvent
is
particularly preferred.
The pergolide-containing composition can include one or more additives which
function to impart desired properties to the composition. For example, the
composition
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can include a co-solvent to improve the solubility of the pergolide in the
principal
solvent. The use of an alcohol as a co-solvent to improve the solubility of
pergolide in
water is exemplary. The composition can include an enhancer which functions to
enhance the ability of the pergolide to be delivered transdermally. Examples
of
enhancers are alcohols, glycols, fatty acids, and fatty acid esters. Another
example of
an additive is a thickening agent, for example, hydroxymethyl cellulose, which
functions to impart to the composition a desired viscosity.
Other exemplary additives are, for example, stabilizers, preservatives, and
antioxidants. A stabilizer is an art-recognized compound defined in the "
Handbook of
Pharmaceutical Additives," Ash, Michael and Irene, Gower 1995, to be a
pharmaceutical additive that thickens, prevents separation, retards oxidation
by
increasing viscosity, and gives a smoother product. An antioxidant is also an
art-
recognized compound and is defined by the Handbook of Pharmaceutical Additives
to
be a substance that retards oxidation, deterioration, rancidity, and gum
formation in
organic substances. A preservative is also an art-recognized compound defined
by the
Handbook of Pharmaceutical Additives to be a substance, either natural or
synthetic,
that protects a pharmaceutical composition against spoilage, discoloration, or
decay and
is used to retard or prevent microbial or chemical spoilage. The "Handbook of
Pharmaceutical Excipients," Kibbe H. Arthur, 3'd ed. American Pharmaceutical
Association 2000 lists many compounds which are recognized: as stabilizers,
for
example, L-Methionine; as antioxidants, for example, citric acid, ascorbic
acid,
butylated hydroxy anisole (BAH), and butylated hydroxy toluene (BHT); and as
preservatives, for example, benzyl alcohol, ethyl alcohol, and citric acid.
Compositions of the present development can include also one more of such
compounds.
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Some additives may improve more than one property of the composition. For
example, DMSO may enhance the solubility of the pergolide and its ability to
be
delivered transdermally.
Additives of the type referred to herein, as well as other additives for use
in
pergolide compositions, are known. Accordingly, it should be understood that
compounds other than those referred to above can be used in the pergolide-
containing
composition. In preferred form, the additives are present in dissolved form in
the
composition.
The amount of pergolide comprising the composition should be an amount
sufficient to deliver transdermally a pharmaceutically effective amount of
pergolide to
the body. Such amount will vary depending on numerous factors, for example,
the
species of pergolide used, the condition to be treated, the nature of the
material
comprising the liquid-retaining member of the matrix, and the area of the
matrix
surface which is in contact with the body membrane. It is believed that a
composition
comprising about 0.1 to about 10 wt. % of pergolide will be effective for most
applications. However, it should be understood that there may be applications
where
the composition comprises a lower or higher proportion of pergolide.
Similarly, the amount of any particular additive comprising the composition
will
depend on numerous factors. For most applications, it is believed that the
additive will
typically comprise about 0.01 to about 50 wt. % of the composition. Lower or
higher
amounts can be used, depending on the particular additive and the involved
application.
For example, an additive such as a stabilizer, preservative, or an antioxidant
can
comprise about 0.4 to about 2 wt. % of the composition.
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A preferred composition comprising about 90 to about 96 wt. % water, about
0.4 to about 2 wt. % (3-cyclodextrine, about 3 wt. % to about 6 wt. % hydroxy
propyl
cellulose, and about 0.1 wt. % to about 1 wt. % pergolide mesylate is
particularly
useful both as a form of liquid pergolide and as a base composition to which
stabilizers,
antioxidants, and preservatives can be added to yield a liquid pergolide
composition.
Addition of up to about 0.4 wt. % of an antioxidant, for example, about 0.05
to 0.4 wt.
ascorbic acid and/or citric acid, and/or up to about 4 wt % of a preservative,
for
example, about 0.05 to about 4 wt. % benzyl alcohol and/or lactic acid, has
been found
to yield a particularly stable composition which is particularly preferred.
Another preferred composition includes up to about 5 wt. % ethyl alcohol (for
example, about 1 to about 5 wt. % ) which can be added to the base composition
as a
preservative and co-solvent and to which additional antioxidants, stabilizers,
and
preservatives can be added to yield a composition which is particularly
stable.
The matrix of the present invention may be prepared by selecting a liquid-
retaining material which has a suitable affinity for the pergolide-containing
composition, forming it or cutting it into a desired shape which has surface
area of
desired magnitude and applying, to the material the desired amount of
composition.
Alternatively, the composition can be applied to a bulk of the liquid-
retaining material
which is then shaped or cut to the desired size. Any suitable shape of
retaining
material can be used. Typically the material is in the form of a disk or pad
having two
faces and an edge.
The transdermal delivery device of the present invention can include other
elements of the type that are normally present in transdermal delivery devices
including, for example, a barrier layer which covers one of the faces of the
matrix, a
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layer which holds the device to the body surface to be treated, and a
removable layer
that protects the other face of the matrix and which can be removed when the
device is
ready for use.
In preferred form, the liquid-retaining material of the matrix is in direct
contact
with the body membrane during use. However, there may be applications where it
is
useful to include in the device a permeable layer, for example, a microporous
membrane, through which the pergolide is capable of flowing on its way to the
body
surface and which covers that face of matrix membrane which faces toward the
body
membrane. In this type of embodiment, the face of the permeable layer not in
contact
with the face of the matrix which can be covered with the removable layer.
In accordance with the present invention, transdermal delivery devices were
fabricated and pergolide delivery flux was determined from their use in
separate in
vitro and in vivo measurements. In vitro measurements of pergolide delivery
flux in all
cases were carried out using a diffusion cell to which samples of human skin
were fixed
such that the stratum corneum was accessible for application of the delivery
device or
of a composition comprising pergolide in liquid form.
In a typical determination, a skin sample was fastened onto a diffusion cell
filled
with saline solution as a receiver liquid. After application of either an
aliquot of a liquid
pergolide-containing composition or a transdermal delivery device of the
present
invention to the stratum corneum of the affixed sample, the cell was placed in
an
environment in which an even temperature was maintained throughout the
evaluations.
In a typical determination, the diffusion cell was equilibrated for, a
predeterminted time then a sample of the receiver liquid was withdrawn to
establish a
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baseline. Subsequent samples of receiver liquid were removed at predetermined
time
intervals.
Examples
The first group of examples are illustrative of transdermal delivery devices
of
the present invention. They include a multi-phase matrix comprising a liquid-
retaining
material in the form of disks of the various materials listed below in Table 1
(Example
Nos. 1-8) and a phase of pergolide in liquid form covering an area of 1 cm2
The liquid pergolide used in the devices of Example Nos. 1-5 of Table 1 was a
viscous liquid composition comprising 0.48 wt. % pergolide mesylate, 0.8 wt.
(3-cyclodextrin, 3.0 wt. % hydroxypropyl cellulose, and 95.7 wt. % water; this
is a
particularly preferred composition. The device of Example No. 6 included a
liquid
composition comprising 0.5 wt. % pergolide mesylate, 3.0 wt. % hydroxypropyl
cellulose, and 96.5 wt. % water. The device of Example No. 7 included a liquid
composition comprising 0.55 wt. % pergolide mesylate, 6.0 wt. % hydroxypropyl
cellulose, and 93.45 wt. % water, and that of Example No. 8 included a
composition
comprising 0.05 wt. % pergolide mesylate and 99.95 wt. % water.
Each of the compositions used in the transdermal devices of the examples was
made by dissolving solid particles of pergolide mesylate in deionized water
and adding
~3 cyclodextrin (if used) and hydroxypropyl cellulose (if used) to yield the
wt.
composition listed. The compositions were of sufficiently low viscosity to be
dispensed
onto the liquid-retaining material from a conventional pipette.
All of the examplary transdermal delivery devices described herein were
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fabricated by forming the selected liquid-retaining material into a desired
shape and
area (for example, a pad or a disk) and then laminating one face of the shaped
material
to a section of 9732 polyester film (3M) which functioned as a barrier layer.
The film
was sized so that the barrier layer of the resulting laminate extended beyond
the edges
of the retaining material. The laminate was affixed to the adhesive face of
9772 PVC
foam tape (3M) such that the barrier layer was interposed between the tape and
the
material. The PVC foam tape was sized to extend beyond the edges of the
barrier layer
so that the tape functioned as an adhesive layer to hold the laminate in
contact with a
membrane to which the device was applied.
The pergolide composition was applied to the exposed surface of the retaining
material over a controlled area of surface. The area to which the pergolide
composition was applied was selected to give an area of desired size over
which
transdermal delivery could occur (active area). The pergolide composition was
applied
in an amount of 70 p1 / cm2 of the selected area. For the devices of Example
Nos. 1-5
of Table 1, this yielded devices having approximately 0.346 mg pergolide
mesylate/
cm2 of liquid-retaining material. The devices of Example Nos. 6 and 7
contained 0.89
mg pergolide mesylate/cm2 of liquid-retaining materials and that of Example
No. 8
contained 0.07 mg pergolide mesylate /cmz of liquid-retaining material . The
area
stated for the liquid-retaining material is the area of the pad to which the
liquid
composition was applied measured as superficial area.
After application of the liquid composition to the liquid-retaining material,
its
exposed surface matrix and the exposed adhesive face of the PVC foam tape were
covered with a release liner made from 1642 Polyester-daubert release liner
(Sano
Corp.). Prior to use, the release liner was stripped from the transdermal
device and the
exposed surface of the liquid-retaining material and foam tape were applied to
a section
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of human skin mounted on a diffusion cell.
The devices were subjected to in vitro pergolide delivery flux determinations
according to the method described herein above. The results are summarized
next to
each entry in Table 1, which also references the Figures in which additional
data from
the in vitro determinations is presented.
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Table 1
Liquid-retainingPERGOLIDE DELIVERY
material FLUX
Ex. Fig. # [micrograms
No. cm z hr-']
INITIAL PEAK STEADY STATE
flux / time* flux / time* flux / time*
1 3M 1603 non-woven0.24 /14 hrs 0.41 / 22 hrs 0.34 - 0.40 /
22-70 hrs.
No Fig.
2 3M 1603 non-woven0.00 / S hrs 0.19 / 45 hrs 0.15 - 0.19 /
21-45 hrs.
Fig 1 - A steady rise
3 Veratec 20080800.11 /5 hrs 049 / 21 hrs 0.28 - 0.25 /
28-45 hrs.
Fig. 1 - B steady decrease
4 Veratec 94088070.22 / 14 hrs 0.41 / 22 hrs 0.42 - 0.37 /
22-70 hrs.
Fig. 2 steady decrease
S 3M 1603 non-wovenMembrane a
Fig 3 0.1 / 3 hrs. 0.5 / 11.5 0.5 / 11.5 - 26.5
hrs hrs
Fig. 3 - A
Membrane b no steady state
0.25 / 3 hrs 0.85 / 26.5 0.25 - 0.85 /
hrs steady
Fig. 3 - B increase 11.5
- 26.5 hrs.
6 3M 1603 non-woven0.0 / at app. 0.90 / 49 hours0.35 - 0.90 /
(end steady rise
Fig. 4 - A of test - no 12-49 hours, no
peak) steady
state
7 3M 1603 non-woven0.0 / at app. 0.55 / 49 hours0.30 - 0.55 /
(end steady rise
Fig. 4 - B of test - no 12-49 hours, no
peak) steady
state
8 3M 1603 non-woven0.0 / at app. 0.45 / 49 hours0.05 - 0.45 /
(end steady rise
Fig. 4 - C of test - no 12-49 hours, no
peak) steady
state
* Time from initial contact of pergolide source to membrane
The data in Table 1 above shows that pergolide can be delivered from a
transdermal
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delivery device of the present invention at a delivery flux commensurate with
establishing therapeutic blood serum levels of pergolide.
The next group of examples illustrate the use on human subjects of delivery
devices similar to those described above. The liquid-retaining material of the
devices
comprised pads of 1603 non-woven medical absorbent (3M) having surface areas
sufficient to have a liquid form of pergolide applied to a 10 or 30 cm2 area.
The devices
included the same composition as that used in the devices of Example Nos. 1-6
of
Table 1 (0.48 wt. % pergolide mesylate, 0.8 wt. % ~3-cyclodextrin, 3.0 wt. %
hydroxypropyl cellulose, and 95.7 wt. % water). Twelve devices having a 10 cm2
active area and 4 devices having a 30 cmz active area were prepared. One
device
having a 10 cm2 active area was applied to four subjects. Four other subjects
received
two devices each having a 10 cm2 active area, and four other subjects each
received a
device having a 30 cm2 active area. The devices were applied to the skin on
the upper
outer arm of human subjects. Blood samples were drawn from test subjects at
regular
intervals and tested for pergolide levels. Pergolide blood serum levels were
determined by subjecting blood samples to liquid chromatography using mass
spectroscopic detection according to testing protocol #AN47849-101-PPD.
Blood serum levels obtained from samples from the 4 subjects wearing devices
having the same pad size were averaged. The averaged data, along with the
average of
the times at which the samples were obtained are set forth in Table 2.
Additional
averaged data from this study is presented graphically in Figure 5.
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Table 2
EX. NO. SURFACE AREA OF PAD* PERGOLIDE BLOOD SERUM LEVEL
[mean of 4 subjects / picograms
/ ml]
10 cm2 48.9
19.5 hours after application
11 20 cmz 133.7
28.5 hours after application
12 30 cmz 42.2
22.5 hours after application
13 30 cmz 119.4
24 hours after application
*Surface area determined by measurement of the area of the transdermal device
containing the liquid
composition of pergolide mesylate
For the purposes of comparison, there is set forth in Table 3 below
representative
10 examples of blood serum levels observed after oral dosing of human subjects
with
pergolide mesylate.
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Table 3
Oral Dose Pergolide Blood
(milligrams] Serum Level
[picograms/ ml]
0.25 47.75
0.50 100.08
1.00 199.33
2.00 398.66
3.00 597.99
A comparison of the results reported in Tables 2 and 3 above reveals that
transdermal
devices of the present invention deliver therapeutic levels of pergolide
mesylate.
Additionally, the transdermal devices applied to human subjects did not
produce skin
irritation at the site of application.
The next group of examples are comparative in nature.
Transdermal devices having a matrix comprising pergolide base and enhancers
were fabricated by blending pergolide free base and enhancers into aliquots of
acrylate-based pressure sensitive adhesive (PSA) and casting the composition
into a
film in which the pergolide free base was present as a solid solution. Cast
film
matricies were prepared using National starch adhesives 87-2074 (Matrix A), 87-
2620
(Matrix B), and 87-2696 (Matrix C) and Monsanto Adhesive 2873 Gelvea
multipolymer acrylic resin (Matrix D). Matricies A, B, and D had a composition
of 2
wt. % pergolide free base and 98.0 wt. % of the respective PSA used. The
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composition of Matrix C was 5 wt. % pergolide free base and 95 wt. % of the
PSA
used. The cast films were adhesive to skin as cast.
These cast films were cut into 1 cm2 units. The pergolide delivery flux
available
from these cast film matricies was determined by adhering a laminate
containing a 1
S em2 unit to a sample of human skin mounted on a diffusion cell according to
the in
vitro testing procedure described above.
The results of these determinations are shown graphically in Fig. 6 as traces
A-
D for matricies A-D respectively. The results from these examples when
compared
with those examples reported above show that even at 4X the wt % pergolide
loading,
pergolide delivery flux from solid solutions is too low to be effective in
yielding
therapeutic blood serum levels of pergolide for the treatment of Parkinson's
disease.
The next group of examples are illustrative of pergolide-containing
compositions
which can be used in the practice of the present invention. The compositions
are
identified in Table 4 below. The compositions were prepared by placing a
weighted
amount of the indicated solvent or solvents into a suitable mixing vessel and
adding
solid pergolide mesylate in the form of anhydrous powder and the additives
identified
in Table 4 into the solvent with stirring at 25 °C until the solid
constituents dissolved.
The various compositions prepared are reported in Table 4 as wt. % of the
listed
constituents.
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Table 4
Comp. Pergolide ENHANCER, SOLVENT,
No. Mesylate, WT. Wt. %
WT. %
WATER SOLVENT A SOLVENT B
A 2.5 HPC' [4.0]79.0 ethanol (14.5)------
B 1.2 HPC' [5.0]93.8 ------ ------
S C 1.2 ______ 98.8 ______ ______
D 1.7 ------ ------ ethanol (16.6)phospholipon
(81.7)
E 0.6 ------ ------ ethanol (37.4)GMOZ (62.0)
F 2.2 Gelatin 90.8 ------ ------
(7.0)
G 0.9 ------ 92.1 PVA' (7.0) ------
H 0.8 Gelatin/7.959.0 DMSO' (30.8)------
HPC' /5.0
I 1.0 BCDS (2.0)97.0 ------ ------
1. HPC = hydroxypropyl cellulose
2 GMO = glycerol monooleate
3 PVA = polyvinyl alcohol)
4. DMSO = dimethyl sulfoxide
5. BCD = /3 cyclodextrin
An aliquot of each liquid pergolide composition identified in Table 4 above
was
applied directly to a section of human skin mounted on a diffusion cell. The
delivery
flux available from the composition was determined according to the in vitro
method
described above. The results of these determinations are summarized in Table
5,
which also references figures containing additional data.
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Table 5
Comp. No. Pergolide Delivery
Flux
Figure 1/ (pg cm Z hr')
Initial/ Peak / Steady State /
hours post applicationhours post applicationhours post application
A 2.25 / 7 2.25 / 7 and again1.45 / 24-60
at
S Fig 7 - A 85
B 1.9 / 15 1.9 / 15 1.6 / 24-45
Fig 7 -B
C 1.7 / 6 1.7 / 6 1.2 / fluxuates
40-85 hours
Fig 7 - C post application
D increasing steadilyno steady state
Fig 8 - D 1.9 / 14 between 20 and
60 hours
from 1.7 - 2.5
E 0.95 / 15 0.95 / 15 0.9-0.8 / 22-45
Fig 8 - E
F 1.2 / 7 1.6 / 16 1.4-1.3 / 22-66
1$ Fig8-F
G 1.1 / 7 2.1 / 44 1.75-2.1 / 24-44
steady
Fig 8 - G rise to peak then
decline
H no peak increasing throughout0.75 - 0.8 / steady
test rise
Fig 9 - H 12-21 hours (test
duration )
I no peak increasing throughout0.9 - 1.0 / steady
test rise
Fig 9 - I 12-21 hours (test
duration )
In a separate experiment, composition D (Table 5), which contains no water,
was
applied to a 1 cm2 pad of 1603 non-woven medical absorbent (3M) and fixed to a
skin
sample mounted on a diffusion cell. An in vitro determination of the delivery
flux
from this patch showed a peak flux of 0.05 p,g/ cm2 hr of pergolide after 21
hours.
The compositions of Table 5 can be used in a transdermal delivery device to
treat
patients.
