Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ 3 B3~59
POLYMERIC DIFFUSION MATRIX
FOR ADMINISTR~TION OF D~UGS
SUMMARY OF THE INVENTION
The present invention relates to a polymeric diffusion
matrix containing one or more drugs suitable for transdermal
administration to a patient. More particularly, the invention
xelates to a polymeric diffusion matrix containing one or more
of such drugs characterized by a sustained relase o-E such
drugs. Among the drugs suitable for administration in the
polymeric diffusion matrix of this invention are terbutaline,
ephedrine, clonidine, phenylephrine, estradiol esters, phenyl-
propanolamine, and chlorpheniramine maleate.
A self-supporting polymeric diffusion matrix is provided
for the sus-tained release of a drug or drugs in order to
transdermally deliver said drug to a patient, and provide said
patient with a therapeutic effect, said matrix comprising from
about 2 to about 60% by weight of a polar plasticizer; from
about 6 to about 20% by weight polyvinylalcohol; from about 2
to about 10% by weight polyvinylpyrrolidone; and a pharmaceu-
tically effective amount of drug to provide a sustained
release of sa;d drug over a prolonged period.
In one embodiment the polar plasticizer is glycerol pre-
sent in an amount of from about 2 to about 60~ by weight. In
another embodiment -the polar plasticizer is polyethylene gly-
col present in an amount of from about 2 to about 15% by
weight. ~ still further embodiment contemplates a mixture of
glycerol and polyethylene glycol wherein the la-tter is present
in an amount by weight of from about 1 to about 5 parts per
weight glycerol.
The self-suppor-ting polymeric diffusion matrix generally
'~ .
355g
-- 2
contains a mixture of polyvinylalcohol and polyvinylpyrroli-
done, although it will be understood that other polymeric mix-
tures may be used provided they yield the desired sustained
release effect. For example, both the polyvinylalcohol and
the polyvinylpyrrolidone may be completely replaced with from
about 1 to ahout 9% agar or agarose, and preferably from about
1.5 to 3% agar or agarose, 2% agar or agarose being particu-
larly preferred.
As the polyvinylalcohol used in the present invention
there is generally contemplated one having a molecular weight
from about 50,000 to about 150,000, and more preferably about
100,000 to about 150,000, 115,000 having been used in related
systems of the present inven-tors with success. The polyvinyl-
alcohol should be hydrolyzed, generally at least to the extent
of 90%, with a preferred embodiment being at least ~5% hydro-
lyzed. Polyvinylpyrrolidone should have a molecular weigh-t of
from about 15,000 to about ~5,000, and more preferably from
about 20,000 to about 60,000. Polyvinylpyrrolidone with a
molecular weight of 40,000 is a particularly preferred
embodiment.
The amount by weight of the ingredients other than the
polar plasticizer generally should be in the following ranges:
polyvinylalcohol is generally present in an amount of -from
about 6 to about 20% by weight, with 10% being a preferred
embodiment; polyvinylpyrrolidone is present generally in an
amount of from about 2 to about 10% by weight.
~ he water-soluble polymer can be replaced with (in addi-
tion to agar~ yum arabic, gum tragacanth t polyacrylic acid,
polymethacrylic acid, polyvinyloxazolidone, polyvinylmorpho-
linone, and polyvinylpiperidone.
Polyalkylene glycols such as polyethylene glycol andpolypropylene glycol may replace all or part of the glycerol.
It is possible to replace the polyvinylalcohol with poly-
mers of hydroxyethylacrylate, polymers of hydroxyethylmetha-
crylate, polymers of hydroxypropylacrylate, and polymers of
~ ~ ~;3~59
hydroxypropylmethacrylate.
In forming the matrix, excess water is not required. In
accordance with a preferred aspect o.E the present invention,
about 2~ by weigh-t of any of the drugs listed above are inclu-
ded in the difEusion matrix. The resultant homogeneous mix-
ture is poured into forms preferably made of glass or stain~
less steel, these forms or templates producing a diffusion
matrix having a thickness of about 1 to about 3 mm. in accor-
dance with a preferred aspect of the present invention~ This
diffusion is either cast or cut into pieces of the desired
size.
The following methods may be used for preparing the dif-
fusion matrix of the present invention.
~n a first method, the matrix is formed at atmospheric
pressure. Water and glycerol are first mixed together.
A polar plasticizer such a glycerol is a necessary compo-
nent in the matrix. A matrix formed without a polar plastici-
zer is not flexible and has poor diffusional contact with the
skin causing unreliable diffusion release.
The polyvinylalcohol and polyvinylpyrrolidone are then
added to the polar plasticizer-water mixture at room tempera-
ture, with agitation. The mixture is heated to a temperature
within the range of from about ~0 to about 95C at atmospheric
pressure to extend the polymers. If desired, the mixture may
be maintained at an elevated temperature for a period of time,
based on polymer stability, prior to addition of the drug.
Thus, the mixture is stable for a period of time and may be
kept for such a period before being mixed with the drug to be
delivered to the patien-t. Thereafter, the mixture is tempera-
ture-adjusted and the drug to be applied to the pa-tient is
then added to the mixtuxe, with thorough agitation. Once a
homogeneous mixture of the polymer solution and drug is ob-
tained, the mixture is ready to be cast to form in a drug-
containing diffusion matrix. After cas-ting the mixture is
cooled to a temperature such that gelation occurs. In a
~ 1 ~355~
preferred embodiment, the drug may be dissolved by agitation
in a suitable solvent such as gl~cerin and water. The thus-
obtained solution can be maintained at room temperature for
prolonged period without deterioration.
It has been found that curing is facilitated by subjec-
ting the matrix to a temperature down -to about -20C immedi-
ately after casting. The setting period is quickened
considerably.
Sodium dodecyl sulfate or sorbitan (Tween-20) or other
detergents may be added in an amount of 0.1 to 10~ by weight,
based on the matrix, as a dispersing agent, if desired.
An absorption facilitator to insure skin penetration such
as dimethylsulfoxide, decylmethylsulfoxide, or other penetra-
tion enhancers may be added.
The present drug delivery device comprises the drug-
containing diffusion matrix and means for fastening the matrix
to the skin of a patient. Such means can take various forms,
such as an occlusive backing layer forming a kind of "bandage"
with the diffusion ma-trix being held against the skin of a pa-
tient being treated. A polyethylene or Mylar tape is contem-
plated as one form of occlusive layer in accordance with thepresent invention. It can also take the form of an elastic
band, such as a cloth band, a rubbery band or other material.
Here, the diffusion matrix is placed directly on -the skin and
held in place by such elastic band which typically will be
placed over the arm or wrist of the patient. An intermediate
adhesive layer between the diffusion matrix and the skin capa-
ble of permitting the transdermal application of the drug can
also be used.
3~ The amount of the drug to be delivered per day to the pa-
tient is in each case generally lower that the oral dosage.
This is accounted for by the fact that in oral applications
much of the drug can be expected to be lost by the first pass
through the liver. To assure that the desired quantity of the
drug i.s delivered, an excess of the drug should be
. . .
`~ ~ 63559
, -- S
incorporated in the ma-trix. Where ter~utali~e i5 used to pro-
vide a bronchodilator effect, the daily amount to be delivered
is generally about 1 to about 20 mg., preferably abou-t l-m~.
With ephedrine a decongestant effect is provided by delivering
a daily amount of generally about 5 to about 30 mg., prefer-
ably about 20 mg. With clonidone an antihypertensive effect
is provided by delivering a daily amount of generally about
0.2 to about 0.6 mg., preferably about 0.4 mg. With phenyl-
ephrine a decongestant effect is provided by delivering a
daily amount of generally about ~ to about 50 mg., perferably
about 2.5 mg. With phenylpropanolamine bronchodilator and
nasal decongestant effects are provided by delivering a daily
amount of generally about 2 to about 50 mg., preferably abou-t
10 mg. With chlorphenixamine maleate an antihistaminic effect
is provided by delivering a daily amount of generally about 1
to about 30 mg., preferably about 3 mg. The estradiol esters
used with this invention provide a uterine wall maintenance
effect.
It will be appreciated that the above drugs may be added
to the above mixture not only in the form of the pure chemical
compound, but also in admixture with other drugs that may be
transdermally applied or with other ingredients which are not
incompatible with the desired objective of transdermally ad-
ministering the drug to a patient. Thus, simple pharmacologi-
cally acceptable derivatives of the drugs such as ethers,esters, amides, acetals, salts, and the like may be used.
With some drugs derivatives may actually be preferred.
The estradiol ester derivatives suitable for use accord-
ing to this invention are pharmacologically acceptable esters
particularly the 3-benzoate and 3-valerate es-ters of estra-
diol. Estradiol diacetate and other esters of a pharmocologi-
cally active type small enough to pass through the skin may
~lso be used. The esters suitable for this invention provide
a source of pharmacologically active estradiol in the
~ 3 ~3559
-- 6
bloodstream. It must also be understood that the estradiol
esters contemplated herein may be administered in admixture
with other drugs which are not incompatible with the clesired
therapeutic objective.
The invention is illustrated by the following non-
limiting Examples:
EXAMPLE I
Together there are mixed 30 gm. glycerol and 45 ml.
water. This mixture is heated to 90C; after reaching at
least 70C there are slowly added 15 gm. polyvinylalcohol
(P~A 100% hydrolyzed, molecular weight 115,000) and 8 gm.
polyvinylpyrrolidone (mw. 40,000). The mixture is stirred at
90C until solution is eEfected, whi~h may -take about 10
minutes; it will be appreciated that with larger quantities,
a considerably longer period of time may be needed. 9~ ml. of
this solution is then mixed with 2 gm. terbutaline, this mix-
ture then being mechanically stirred until homogeneous. The
homogeneous mixture is then poured into forms made o-f glass or
stainless steel which serve as templates to produce a diffu-
sion matrix having a thickness oE about 2 to ahout 3 mm. This
diffusion matrix is then cut into pieces with a total surface
area suitable for the administration of a pharmaceutically
effective amount of terbutaline.
The diffusion matrix is applied to the skin of a patient
in need of a bronchodilator effect, the terbutaline being
transdermally delivered to the skin of the patient. The dif-
fusion matrix is ideally applied to the skin of the patient by
means of a single-piece bandage having the diffusion matrix in
the center under the occlusive layer, the bandage being pro-
vided to the patient with a peel-of cover much like a
"band-aid".
E AMPLE II
In place of the glycerol of Example I, there is substi-
tuted 5 gm~ polyethylene glycol having a molecular weight of
1000 and 25 ml. water. The resultant diffusion matrix is more
., :
1 ~ ~3S5~ 3
rigid than that of Example I.
EXAMPLE III
In place of the glycerol of Example I, there is substi-
t~lted 5 gm. polyethylene glycol (mw. lrO00), 4 gm. glycerol
and 21 ml. water. The resultant dif~usion matrix shares the
improved rigidity of the dif~usion matrix of Example II, while
providing contact with the skin characteristic of the glyc~rol
in this type of diffusion matrix.
EXAMPLE IV
In place of the polyvinylalcohol and polyvinylpyrrilidone
of E~ample I, there is substi-tuted 2~ by weigh-t agarose,
yielding a diffusion matrix for the transdermal deli~ery of
terbutaline.
EXAMPLES V-XXIV
E~amples V-XXIV correspond to Examples I-IV, but for the
substitution for terbutaline of the same amounts of the fol-
lowing drugs:
EXAMPLES DRUG
V-VIII ephedrine
IX-XII clonidine
XIII-XVI phenylephrine
XVII-~X phenylpropanolamine
XXI-XXIV chlorpheniramine maleate
Each of these drugs exhibits its characteristic thera-
peutic effect when administered via diffusion matrix.
E AMPLE XXV
Together there are mixed 20 gm. glycerol and 55 ml.
water. This mixture is heated 90C; after reaching at least
7QC. There are slowly added 15 gm. polyvinylalcohol (PVA
100% hydrolyzed, molecular weight 115,000) ana 8 gm. polyvi-
nylpyrrolidone (mw. ~0,000). The mixture is stirred at 90C
unitl solution is effected, which may take about 10 minutes;
it will be appreciated that with larger guantities, a consi-
derably longer period of time may be needed. 98 ml. of this
solution is then mixed with 2 gm. estradiol diacetate, this
. _~
--- 1 3 63~
-- & -- .
mixture then being mechanically stirred until homogeneous.
The homogeneous mlxture is then poured into forms made of glass
or stainless steel which serve as templa-tes -to produce a dif-
fusion matrix having a thickness of about 1 to 2 mm. This -
diffusion matrix is then cut in-to square pieces of about 1
inch on each side, i.e., to provide a total surface area of
about 6.5 cm2.
The diffusion matrix is applied to the skin of a patient
in need of uterine wall maintenance, the estradiol ester deri-
vative being transdermally delivered. The diffusion matrix isideally applied to the skin of the patient by means of a
single-piece bandage having the diffusion ma-trix in the center
under the occlusive layer, the bandage being provided to the
patient with a peel-off cover much like a "band-aid".
EXAMPLE XXVI
Instead of casting the fluid homogeneous drug containing
matrix with a 1 to 2 mm. thickness as disclosed in Example
XXV, it is poured into oval forms 1 cm. thick. The cured dif-
fusion matrix is applied in the form of a vaginal insert into
a patient in need of uterine wall maintenancel the estradiol
ester derivative being delivered in the vicinity of the cervix
of the patient.
EXAMPLE XXVII
In place of the glycerol of Example XXV, there is substi-
tuted 10 gm. polyethylene glycol having a molecular weight of
1000 and 10 ml. water. The resultant diffusion matrix is more
rigid than that of Example XXV, thus improving its ease of
application in the form of a vaginal insert.
EXAMPLE XXVIII
In place of the glycerol of Example XXV, there is substi-
tuted 5 gm. polyethylene glycol (mw. 1000), 4 gm. glycerol,
and 11 ml. water. The resultant diffusion ma-trix shares the
improved rigidity of -the diffusion matrix of Example XXVII,
while providing contact with the skin characteristic of the
glycerol. This type of diffusion matrix is particularly
~ 1 ~355~ ~
9 ~
sultable for transdermal application
EXAMPLE XXIX
In place of the polyvinylalcohol and polyvinylpyrro~idone
of Example XXV, there is substituted 2 gm. agarose and 21 m~.
water, yielding a difusion matrix for the delivery of estra-
diol ester derivative. .
i
