U.S. patent number 3,742,951 [Application Number 05/169,977] was granted by the patent office on 1973-07-03 for bandage for controlled release of vasodilators.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Alejandro Zaffaroni.
United States Patent |
3,742,951 |
Zaffaroni |
July 3, 1973 |
**Please see images for:
( Certificate of Correction ) ( Reexamination Certificate
) ** |
BANDAGE FOR CONTROLLED RELEASE OF VASODILATORS
Abstract
Medical bandage for use in the continuous administration to
circulation of controlled quantities of systemically active
coronary vasodilators over a prolonged period of time by absorption
through the external body skin or mucosa is comprised of a backing
member, a pressure-sensitive adhesive coating, and a reservoir
containing the drug confined within a wall member. The wall member
is formed from drug release rate controlling material to
continuously meter the flow of a therapeutically effective amount
of the drug from the reservoir to the skin at a controlled and
predetermined rate over a period of time.
Inventors: |
Zaffaroni; Alejandro (Atherton,
CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
22617994 |
Appl.
No.: |
05/169,977 |
Filed: |
August 9, 1971 |
Current U.S.
Class: |
424/434; 424/448;
424/449; 604/304 |
Current CPC
Class: |
A61K
9/7061 (20130101); A61K 9/7084 (20130101); A61K
9/7092 (20130101) |
Current International
Class: |
A61K
9/70 (20060101); A61K 9/70 (20060101); A61f
007/02 () |
Field of
Search: |
;128/155,156,260,268,296
;424/18-22 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Gaudet; Richard A.
Assistant Examiner: McGowan; J. C.
Claims
What is claimed is:
1. A medical bandage for the continuous administration to the skin
or mucosa of controlled quantities of systemically active
vasodilator drugs over a prolonged period of time by absorption
through the external body skin or mucosa, said bandage comprising a
laminate of (1) a backing member defining one face surface of the
bandage; (2) a pressure-sensitive adhesive adapted for contact with
the skin or mucosa, the external surface of said pressure-sensitive
adhesive defining the other face surface of the bandage and,
disposed between the face surfaces defined by (1) and (2); (3) at
least one reservoir comprised of a systemically active vasodilator
drug formulation confined within a wall member, said wall member
being formed from drug release rate controlling material to
continuously meter the flow of drug from the said reservoir to the
skin or mucosa at a controlled and predetermined rate over a
prolonged period of time.
2. The bandage as defined by claim 1, wherein said reservoir
comprises a discrete, middle reservoir layer sandwiched between
said backing member (1) and said pressure-sensitive adhesive
(2).
3. The bandage as defined by claim 2, wherein the reservoir layer
is comprised of a walled container having an interior chamber
containing the systemically active vasodilator drug
formulation.
4. The bandage as defined by claim 3, wherein only that portion of
the walled container which is adapted to be brought contiguous with
the skin or mucosa is formed from the drug release rate controlling
material.
5. The bandage as defined by claim 2, wherein the reservoir layer
is comprised of a matrix of the drug release rate controlling wall
material, said matrix having the systemically active vasodilator
drug formulation distributed therethrough.
6. The bandage as defined by claim 2, further comprising a
solubility membrane (4) interposed between said reservoir layer and
said pressure-sensitive adhesive (2).
7. The bandage as defined by claim 2, wherein one outer surface of
the wall member comprising the reservoir layer also defines the
said backing member (1).
8. The bandage as defined by claim 1, wherein said reservoir
comprises a plurality of discrete microcapsules distributed
throughout the said pressure sensitive adhesive.
9. The bandage as defined by claim 8, wherein each of said
microcapsules is comprised of systemically active vasodilator drug
formulation microencapsulated with the said drug release rate
controlling wall material.
10. The bandage as defined by claim 8, wherein each of said
microcapsules is comprised of a matrix of the drug release rate
controlling wall material, said matrix having the systemically
active vasodilator drug formulation distributed therethrough.
11. The bandage as defined by claim 1, wherein the
pressure-sensitive adhesive is permeable to passage of the
systemically active vasodilator drug formulation.
12. The bandage as defined by claim 1, wherein the vasodilator drug
formulation comprises a pharmacologically acceptable solvent.
13. The bandage as defined by claim 1, wherein said drug release
rate controlling material is silicone rubber.
14. The bandage as defined by claim 1, wherein said drug release
rate controlling material is a hydrophilic polymer of an ester of
an olefinic acid.
15. The bandage as defined by claim 1, wherein the
pressure-sensitive adhesive is covered with a protective release
coating.
16. The bandage as defined by claim 1, wherein the outer surface of
the backing member is coated with a low adhesion backsize.
17. The bandage as defined by claim 1, wherein the vasodilator is
nitroglycerin.
18. The bandage as defined by claim 1, wherein the organic nitrate
vasodilator is present in an amount of from about 1 microgram to
about 1 gram.
19. The method of effecting vasodilation in a mammalian organism,
comprising direct application to the skin or mucosa of such
organism, the bandage as defined by claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
Alejandro Zaffaroni copending application, Ser. No. 812,116, filed
Apr. 1, 1969, assigned to the assignor of the present invention and
now issued on Aug. 10, 1971 as U.S. Pat. No. 3,598,122;
Alejandro Zaffaroni copending application, Ser. No. 812,117, filed
Apr. 1, 1969, also assigned to the assignor of the present
invention and also now issued on Aug. 10, 1971 as U.S. Pat. No.
3,598,123.
BACKGROUND OF THE INVENTION
This invention relates to a medical bandage and, more especially,
to a medical bandage for use in the continuous administration to
circulation of controlled quantities of systematically active
coronary vasodilators over a period of time by absorption through
the external body skin or mucosa.
Clinically, systemic vasodilators, e.g., nitroglycerin (glyceryl
trinitrate, glonoin), have long been used to abate vasomotor spasm.
These have a place in the treatment of peripheral, coronary, and
pulmonary arterial embolism or occlusion, angina pectoris, coronary
disease, and certain forms of peripheral vascular disease; they are
not of value in hypertension. Nitroglycerin, for example, may also
be extremely effective for relief of visceral smooth-muscle spasm,
especially intestinal, biliary, or ureteral colic.
The systemic coronary vasodilators such as nitroglycerin are
moreover conventionally administrated in the form of peroral or
sublingual tablets, particularly the latter. While the desired
vasodilation effect usually commences within a minute or two after
placing sublingual tablet under the tongue of the patient, such
effect is not long lived. For example, orally or sublingually
administered nitroglycerin usually loses its vasodilation capacity
in from about 30 to 45 minutes. The other systemic vasodilators are
effective only for a period of up to a maximum of about six hours
with dangerously large doses. It is therefore necessary in most
instances to establish a dosage regimen of multiple unit doses over
a prolonged period of time, e.g., 12 or 24 hours.
Even with the oral administration of these drugs at periodic
intervals according to a well defined schedule, it is difficult to
achieve a constant desired vasodilation effect in the patient. The
almost inevitable result of oral administration of these drugs is
that the level of the agent in circulation surges to a peak level
at the time the drug is administered followed by a decline in
concentration in the blood and body compartments. Thus, a plot of
drug in circulation after administration of several tablets a day
has the appearance of a series of peaks, which may surpass the
desired toxic threshold, and valleys which fall below the critical
point needed to achieve the desired therapeutic effect.
Administration of systemically active medicinal coronary
vasodilators by injection is inconvenient, painful, and not any
more effective than the sublingual route which is employed in
generally all cases. Moreover, the typical result of administration
by injection also is a surge in the blood level concentration of
the vasodilator immediately after injection, followed by a decline
and another surge in concentration upon subsequent injection. Some
ointment preparations also have been developed, but these too have
met with little success.
Therefore, there exists a serious need for a reliable dosage unit
for the administration to circulation of controlled quantities of
the coronary vasodilators which does not interfere with normal
functions of the patient and which is lasting for a period of up to
12 hours, and even longer.
SUMMARY OF THE INVENTION
Accordingly, it is an object of this invention to provide a device
for the administration of vasodilators which overcomes the
aforesaid disadvantages inherent in prior art modes of
administration.
Another object of this invention is to provide a reliable and
easily applied device for continuously administering controlled
quantities of vasodilators through the skin or mucosa.
A further object of this invention is to provide a complete dosage
regimen of vasodilators for a particular time period, the use of
which requires patient intervention only for initiation and
termination.
In accomplishing these objects, one feature of this invention
resides in a therapeutic bandage for the systemic administration of
controlled quantities of coronary vasodilators into the circulatory
system by direct application of said bandage to the skin or mucosa.
The bandage is comprised of a laminate of: (1) a backing member
defining one face surface of the bandage; (2) a pressure-sensitive
adhesive adapted for contact with the skin or mucosa, the external
surface of said pressure-sensitive adhesive defining the other face
surface of the bandage and disposed between the face surfaces
defined by (1) and (2); and (3) at least one reservoir comprised of
a coronary vasodilator drug formulation confined within a wall
member, said wall member being formed from drug release rate
controlling material to continuoualy meter the flow of drug from
the said reservoir to the skin or mucosa at a controlled and
predetermined rate over a prolonged period of time.
The term "reservoir" as used herein refers both to microcapsules as
well as distinct reservoir compartments or matrix layers.
An embodiment of the invention described above resides in a bandage
comprised of a laminate of: (1) a backing member; bearing (2) a
discrete middle reservoir layer containing a coronary vasodilator
agent confined within a wall member, said wall member being formed
from drug release rate controlling material permeable to the
passage of agent, to continuously meter the flow of a
therapeutically effective amount of the agent to the skin from the
reservoir at a controlled and predetermined rate over a period of
time; and (3) a pressure-sensitive adhesive surface adapted for
contact with the skin and positioned on one wall of the reservoir
remote from the backing member.
Another aspect of this invention resides in a bandage as described
immediately above including a solubility membrane interposed
between the wall of the reservoir and the pressure-sensitive
adhesive layer.
Still, another embodiment of this invention resides in a medicated
adhesive bandage comprising a laminate of: (1) a backing member;
bearing (2) a pressure-sensitive adhesive on one surface thereof
adapted for contact with the skin, said pressure-sensitive adhesive
having distributed therethrough, (3) a plurality of discrete
microcapsules, each of which microcapsules comprises a coronary
vasodilator agent confined within a wall member, the wall member
being formed from drug release rate controlling material, to
continuously meter the flow of a therapeutically effective amount
of the agent to the skin from the microcapsules at a controlled and
predetermined rate over a period of time.
Still a further feature of this invention resides in a method for
effecting vasodilation by directly applying to the skin or mucosa
of a patient a bandage releasing a therapeutically effective amount
of a coronary vasodilator to circulation.
Other objects, features and advantages of the invention will become
more apparent from the following description when taken in
conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
FIG. 1 is a perspective view of the medical bandage of the
invention wherein the coronary vasodilator is microencapsulated
with a material permeable to passage of the agent and the
microcapsules are uniformly distributed throughout the
pressure-sensitive adhesive coating;
FIG. 2 is a cross-sectional view of the medical bandage of the
invention shown in FIG. 1;
FIG. 3 is a cross-sectional view of another embodiment of the
invention wherein the coronary vasodilator is uniformly distributed
throughout a matrix laminated to the backing member and bearing a
coating of the pressure-sensitive adhesive;
FIG. 4 is a cross-sectional view of another embodiment of the
invention wherein a solubility membrane is interposed between the
reservoir layer and the pressure-sensitive adhesive coating;
and
FIG. 5 is a cross-sectional view of still another embodiment of the
invention wherein the reservoir laminated to the backing member is
a hollow container permeable to passage of the coronary vasodilator
and having the drug within an interior chamber thereof.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with this invention, there is provided a medical
bandage containing a coronary vasodilator therein for the
predetermined controlled metering of the drug to the skin over a
period of time.
As illustrated in FIGS. 1 and 2, the adhesive bandage 10 of the
invention has a backing member 11 bearing a pressure-sensitive
adhesive coating 12. Dispersed throughout pressure-sensitive
adhesive coating 12 are microcapsules 13 of coronary vasodilator
encapsulated with a material permeable to passage of drug.
Materials used to encapsulate the drug and form the microcapsules
to be distributed throughout the adhesive must be permeable to the
drug to permit passage of the drug, as by diffusion, through the
walls of the microcapsules at a relatively low rate. Normally, the
rate of passage of the drug through the walls of the microcapsules
is dependent on the solubility of the drug therein or the porosity
of the wall, as well as on the microcapsule wall thickness. This
means that selection of appropriate encapsulating materials will be
dependent on the particular drug used in the bandage. By varying
the encapsulating material and the wall thickness, the dosage rate
per area of bandage can be controlled and movement of drug to the
adhesive regulated.
Suitable materials for use in encapsulating the drug include
hydrophobic polymers such as polyvinylchloride either unplasticized
or plasticized with long-chain fatty amides or other plasticizer;
plasticized nylon; unplasticized soft nylon; silicone rubber;
polyethylene, and polyethylene terephthalate; and hydrophilic
polymers such as esters of acrylic and methacrylic acid (as
described in U.S. Pat. Nos. 2,976,576 and 3,220,960 and Belgian
Pat. No. 701,813); modified collagen; cross-linked hydrophilic
polyether gels (as described in U.S. Pat. No. 3,419,006);
cross-linked polyvinylalcohol; and cross-linked partially
hydrolyzed polyvinylacetate.
One presently preferred class of materials are the
organopolysiloxane rubbers, commonly known as silicone rubbers.
Suitable silicone rubbers are the conventional heat-curable
silicone rubbers and the room temperature vulcanizable silicone
rubbers.
Conventional silicone rubbers which are converted to the rubbery
state by the action of heat are predominantly linear
organopolysiloxanes having an average degree of substitution of
about two organic groups attached directly to silicon per silicon
atom. Preferably, the organic groups are monovalent hydrocarbon
radicals such as alkyl, aryl, alkenyl, alkaryl, aralkyl, and of
these, the methyl, phenyl and vinyl radicals are most preferred.
Variation of the organic groups in the silicone rubber can be used
to vary the solubility of the drug in the polymer and hence can
control the speed of migration of the drug through the polymer.
Also, drugs which are insoluble in one type of silicone rubber may
be soluble in a different type of polymer. One especially preferred
class of silicone polymers are the pure dimethylpolysiloxanes. Room
temperature vulcanizable silicone rubbers are also commercially
available and are known to the art. In general, they employ the
same silicone polymers as discussed above although the polymers
often contain a greater amount of silicon bonded hydroxy groups.
This type of silicone rubber will cure at room temperature in the
presence of an appropriate catalyst, such as stannous
2-ethylhexoate. Exemplary patents disclosing the preparation of
silicone rubbers are U.S. Pat. Nos. 2,541,137; 2,723,966;
2,863,846; 2,890,188; 2,927,907; 3,002,951; and 3,035,016.
To provide the microcapsules, the encapsulating material can be
uniformly impregnated with the drug to form microcapsules which are
a matrix having the drug distributed therethrough. Alternatively,
particles of drug can be encapsulated with thin coatings of the
encapsulating material to form microcapsules having an interior
chamber containing the drug. If desired, particles of a matrix,
such as starch, gum acacia, gum tragacanth, and polyvinylchloride,
can be impregnated with the drug and encapsulated with other
materials such as the encapsulating materials previously described
which function as a solubility membrane to meter the flow of drug
to the adhesives; use of a matrix and a different solubility
membrane coating can slow the passage of the drug from the
microcapsules which is desirable with drugs that are released too
rapidly from available encapsulating materials.
Any of the encapsulation or impregnation techniques known in the
art can be used to prepare the microcapsules to be incorporated
into the pressure-sensitive adhesive in accord with the embodiment
of FIGS. 1 and 2. Thus, the drug can be added to the encapsulating
material in liquid form and uniformly distributed therethrough by
mixing and subsequently converting to a solid by curing or cooling;
or solid encapsulating material can be impregnated with a drug by
immersion in a bath of the drug to diffuse into the material.
Subsequently, the solid material can be reduced to fine
microcapsules by grinding, each of the microcapsules comprising
drug coated with and distributed throughout the encapsulating
material. Alternatively, fine particles of the drug can be
encapsulated with the coating. One suitable technique comprises
suspending dry particles of the drug in an air stream and
contacting that stream with a stream containing the encapsulating
material to coat the drug particles. Usually, the microcapsules
have an average particle size of from 1 to 1,000 microns, although
this is not critical to the invention. The microcapsules, however
made, are then mixed with any of the previously described
pressure-sensitive adhesives and the mixture coated onto the
backing member to provide the therapeutic medical bandage, usually
the coating being sufficient to provide an adhesive layer 0.01 to 7
millimeters thick, although these limits can be exceeded if more or
less drug is required. The purpose of the backing, as in the
embodiment of FIGS. 1 and 2, is to provide support for the bandage
and to prevent passage of the drug through the adhesive surface
away from the body surface to which the bandage is applied.
Further embodiments of the adhesive bandage of the invention are
illustrated in FIGS. 3, 4 and 5. As illustrated in FIG. 3, adhesive
bandage 30 of the invention is comprised of a coronary vasodilator
agent 34 uniformly distributed in a reservoir 32 which is a
polymeric matrix material. The matrix material is laminated to
backing member 31 and bears a pressure-sensitive adhesive coating
33 thereon. The polymeric matrix material has a release rate for
the particular drug used which continuously controls the dosage of
drug administered.
FIG. 4 illustrates a further modified form of the invention wherein
the adhesive bandage 30 of the invention is comprised of a backing
member 31 having a reservoir 32 on one surface thereof. A
solubility membrane 35 is interposed between the reservoir 32 and a
pressure-sensitive adhesive coating 33. Coronary vasodilator drug
34 is confined in polymeric matrix material 32 which acts as the
reservoir for the drug and controls the rate of release therefrom.
The solubility membrane, as with the walls of the reservoir,
usually is formed of a material in which the drug is soluble and
capable of diffusing through. Any of the materials previously
mentioned for use in microencapsulation may be used as the
solubility membrane. Of course, in each instance, the solubility
membrane will have different characteristics than the reservoir
wall of the particular device. This use of a pair of solubility
membranes, that is, the reservoir wall and the further solubility
membrane, allows for precise metering of drug to the adhesive layer
for the thickness and composition of both membranes can be varied
to provide for wide range of dosage levels for a given area of
bandage. It will be appreciated that this solubility membrane can
be used with either the matrix or container type of reservoir.
FIG. 5 illustrates a further form of the bandage 40 including a
backing member 41 and a reservoir 42 in the form of a hollow
container having an interior chamber 43 containing coronary
vasodilator drug 44. Wall 45 of reservoir 42, remote from backing
member 41, is permeable to passage of drug 44, as by diffusion, to
meter the flow of drug to pressure-sensitive adhesive layer 46 on
the outer surface thereof.
Suitable materials for forming the reservoir, whether of the matrix
or hollow container type, are those materials permeable to passage
of the drug previously described as suitable encapsulating
materials. The reservoir can be formed by molding into the form of
a hollow container with the drug trapped therein. Alternatively,
the reservoir can be in the form of an envelope formed from sheets
of polymeric material permeable to passage of the drug and
enclosing the drug. While the walls of the reservoir can be of any
convenient thickness, usually they have a thickness of from 0.01 to
7 millimeters. When the reservoir comprises a matrix with the drug
distributed therethrough, it can be prepared by adding the drug to
the matrix material in liquid form or solvent solution form and
subsequently converting the matrix to a solid by curing, cooling or
evaporation of solvent.
Thus, the reservoir of the therapeutic bandage is a hollow drug
container or a solid matrix. Drug is metered from the reservoir to
the adhesive layer, at a rate controlled by the composition and
thickness of the reservoir or of the reservoir wall. From the
adhesive layer, drug is directly transmitted to and through the
skin to which the therapeutic adhesive bandage is applied. The
purpose of the backing is to prevent passage of the drug through
the surface of the reservoir distant from the adhesive layer. An
ancillary purpose of the backing is to provide support for the
bandage, where needed. When the outer surface of the reservoir is
impermeable to the drug and strong enough, the backing becomes
unnecessary.
In the embodiment of the invention illustrated in FIG. 4, metering
of the drug from the reservoir to the adhesive is further
controlled by interposing a further solubility membrane
therebetween. The solubility membrane is formed of a material in
which the drug is soluble and capable of diffusing through. Any of
the materials previously mentioned for use in microencapsulation
may be used as the solubility membrane. Of course, in each
instance, the solubility membrane will have different
characteristics than the reservoir wall of the particular device.
This use of a pair of solubility membranes, that is, the reservoir
wall and the further solubility membrane, allows for precise
metering of drug to the adhesive layer for the thickness and
composition of both membranes can be varied to provide for wide
range of dosage levels for a given area of bandage. It will be
appreciated that this solubility membrane can be used with either
the matrix or container type of reservoir.
Coronary vasodilators which can be employed for use in the medical
bandage of the invention include generally those agents which are
suitable for systemic absorption thru the external body skin or
mucosa, e.g., nasal or oral mucosa, in accordance with their known
dosages and uses. Suitable coronary vasodilators include, without
limitation, compounds having a nitrate ion and a large number of
organic nitrates and nitrates such as amyl nitrate,
nitroglycerin(glyceryl trinitrate), sodium nitrate, erythrityl
tetranitrate, pentaerythritol tetranitrate, isosorbide dinitrate,
mannitol hexanitrate, trolnitrate phosphate(triethanolamine
biphosphate), and the like, with nitroglycerin being the preferred
coronary vasodilator. Also suitable is propranolol. Drugs mentioned
above can be used alone or in combination with each other.
In addition to the aforementioned drugs, simple pharmacologically
acceptable derivatives of the drugs, such as ethers, esters,
amides, acetals, salts, etc., or formulations of these drugs,
having the desired polymeric permeability or transport properties
can be prepared and used in practicing the invention. Drugs
mentioned above can be used alone or in combination with others and
each other. Of course, the derivatives should be such as to convert
to the active drugs within the body through the action of body
enzyme assisted transformations, pH, etc.
The above drugs and other drugs can be present in the reservoir
alone or in combination form with pharmaceutical carriers. The
pharmaceutical carriers acceptable for the purpose of this
invention are the art known carriers that do not adversely affect
the drug, the host or the material comprising the drug delivery
device. Suitable pharmaceutical carriers include sterile water;
saline, dextrose; dextrose in water or saline; condensation
products of castor oil and ethylene oxide combining about 30 to
about 35 moles of ethylene oxide per mole of castor oil; liquid
glyceryl triester of a lower molecular weight fatty acid; lower
alkanols; oils such as corn oil; peanut oil, sesame oil and the
like, with emulsifiers such as mono- or di-glyceride of a fatty
acid, or a phosphatide, e.g., lecithin, and the like; glycols;
polyalkylene glycols; aqueous media in the presence of a suspending
agent, for example, sodium carboxymethylcellulose; sodium alginate;
poly(vinylpyrrolidone); and the like, alone, or with suitable
dispensing agents such as lecithin; polyoxyethylene stearate; and
the like. The carrier may also contain adjuvants such as
preserving, stabilizing, wetting, emulsifying agents, and the
like.
The drug can also be mixed in the reservoir with a transporting
agent, that is, a material that aids or assists the drug delivery
device to achieve the administration of a drug to a drug receptor.
The transporting aids suitable for the purpose of the invention are
the therapeutically acceptable transporting aids that do not
adversely affect the host, the drug or alter or adversely affect
the materials forming the drug delivery device. The transporting
aids can be used alone or they can be admixed with acceptable
carriers and the like. Exemplary of transporting aids include
monovalent, saturated and unsaturated aliphatic cycloaliphatic and
aromatic alcohols having four to 12 carbon atoms, such as hexanol,
cyclohexane and the like; aliphatic cycloaliphatic and aromatic
hydrocarbons having from five to 12 carbon atoms such as hexane,
cyclohexane, isopropylbenzene and the like; cycloaliphatic and
aromatic aldehydes and ketones having from four to 10 carbon atoms
such as cyclohexanone; acetamide; N,N-di(lower) alkyl acetamides
such as N,N-diethyl acetamide, N,N-dimethyl acetamide,
N-(2-hydroxyethyl)acetamide, and the like; and other transporting
agents such as aliphatic, cycloaliphatic and aromatic esters;
essential oils; halogenated or nitrated aliphatic, cycloaliphatic
and aromatic hydrocarbons; salicylates; polyalkylene glycol
silicates; mixtures thereof; and the like.
The amount of drug to be incorporated in the bandage to obtain the
desired therapeutic effect will vary depending upon the desired
dosage, the permeability of the rate controlling materials of the
bandage which are employed to the particular agent to be used, and
the length of time the bandage is to remain on the skin. Since the
bandage of this invention is designed to control drug
administration for a period of time, such as 1 hour to 1 day or
more, there is no critical upper limit on the amount of agent
incorporated into the bandage. The lower limit is determined by the
fact that sufficient amounts of the agent must remain in the
bandage to maintain the desired dosage. In order to achieve a
therapeutic effect for anginal attacks in a human adult, the daily
release dosage of nitroglycerin should be in the range of between
0.1 and 5 milligrams per day. Thus, for example, using
nitroglycerin with a bandage intended to remain in place for 1 day,
and with a release rate of 5 milligrams of nitroglycerin per day,
at least 5 milligrams of drug would be incorporated in the bandage.
Generally, the drug delivery bandages made according to the
invention can release at a controlled rate about 25 nanograms to
about 1 gram of drug or larger amounts per day. Of course, other
devices for use for different time periods such as a week are also
readily made by the invention. The effective rate of release of the
active agent to the skin can be in the range of from 0.01
milligrams to 10 milligrams per square centimeter of bandage per
day. The exact amount will depend on the desired dosage. These
effective rates of release of active agent to the skin can be
obtained by altering the permeability and thickness of the release
rate controlling barrier. In the case of the microencapsulated
active agent, the release rate can also be controlled by varying
the number of microcapsules present in a given volume of the matrix
of the device. This is a particularly desirable feature of this
aspect of the invention. Additionally, the duration of action of
the device can be altered by controlling the amount of active agent
initially incorporated consistent with the release rate. Further,
the release rate of drug as well as the duration of release of the
drug from the device can be predetermined to be in consonance with
the optimum therapeutic values. Once this dosage level in, for
example, milligrams per square centimeter of bandage has been
determined, the total amount of drug to be incorporated in the
bandage can be established by obtaining the release rate of the
agent in the particular material or materials which are to be
used.
Those skilled in the art can readily determine the rate of
permeation of agent through a polymeric material or selected
combinations of polymeric materials. Standard techniques are
described in Encyl. Polymer Sci. and Technology, Vols 5 and 9,
pages 65 to 85 and 795 to 807, 1968; and the references cited
therein. Other methods of the determining passage of drugs by
diffusion through drug permeable polymeric material are available.
See Dziuk, P. J. and Cook, B., "Passage of Steroids Through
Silicone Rubbers," Endocrinology, 78:208, 1966; U.S. Pat. No.
3,279,996; Folkman and Edmonds, Circulation Research, 10:632, 1962;
Folkman and Long, J. Surg. Res., 43:139, 1964; and Powers, J.,
Parasitology, 51:53, April 1965, No. 2, Section 2.
Any of the well-known dermatologically acceptable
pressure-sensitive adhesives can be used in practicing this
invention. Exemplary adhesives include acrylic or methacrylic
resins such as polymers of esters of acrylic or methacrylic acid
with alcohols such as n-butanol, n-pentanol, isopentanol, 2-methyl
butanol, 1-methyl butanol, 1-methyl pentanol, 2-methyl pentanol,
3-methyl pentanol, 2-ethyl butanol, isooctanol, n-decanol, or
n-dodecanol, alone or copolymerized with ethylenically unsaturated
monomers such as acrylic acid, methacrylic acid, acrylamide,
methacrylamide, N-alkoxymethyl acrylamides, N-alkoxymethyl
methacrylamides, N-tert. butylacrylamide, itaconic acid,
vinylacetate, N-branched alkyl maleamic acids wherein the alkyl
group has 10 to 24 carbon atoms, glycol diacrylates, or mixtures of
these; natural or synthetic rubbers such as silicone rubber,
styrene-butadiene, butylether, neoprene, polyisobutylene,
polybutadiene, and polyisoprene; polyurethane elastomers; vinyl
polymers, such as polyvinylalcohol, polyvinyl ethers, polyvinyl
pyrrolidone, and polyvinylacetate; ureaformaldehyde resins;
phenolformaldehyde resins; resorcinol formaldehyde resins;
cellulose derivatives such as ethyl cellulose, methyl cellulose,
nitrocellulose, cellulose acetatebutyrate, and carboxymethyl
cellulose; and natural gums such as guar, acacia, pectins, starch,
dextrin, albumin, gelatin, casein, etc. The adhesives may be
compounded with tackifiers and stabilizers as is well known in the
art.
It will of course be appreciated that the pressure-sensitive
adhesive surface need not form a continuous layer on the subject
bandages. Particularly in the case of a bandage having a distinct
reservoir layer, equally advantageous results are obtained by
providing an annular surface of adhesive around the periphery of
the bandage face. In this manner, a liquid-tight adhesive seal
between the bandage and the patient's skin is maintained, and at
the same time, drug may be directly absorbed by the skin from the
exposed surface of the drug reservoir layer without first migrating
through an adhesive layer. When the adhesive layer covers one face
surface of the bandage or when the reservoir is in the form of
microcapsules distributed throughout the adhesive, the adhesive
must be permeable to passage of the drug, to allow drug released
from the reservoir to reach the outer surface of the bandage in
contact with the patient. In such cases, the rate of release of
drug from the adhesive should exceed the rate of release of drug
from the reservoir so that release from the reservoir by passage
through the drug release controlling material is the rate limiting
step for drug administration by the device of the invention. Of
course, when the adhesive is disposed only about the periphery of
the bandage face, the adhesive need not be permeable to passage of
the drug.
To prevent passage of the drug away from the exposed surface of the
pressure-sensitive adhesive prior to use, the adhesive surface of
the bandage generally is covered with a protective release film or
foil, such as waxed paper. Alternatively, the exposed rear surface
of the backing member can be coated with a low-adhesion backsize
and the bandage rolled about itself. To enhance stability of the
systemically active compounds, the therapeutic bandage usually is
packaged between hermetically sealed polyethylene terephthalate
films under an inert atmosphere, such as gaseous nitrogen.
Various occlusive and non-occlusive, flexible or non-flexible
backing members can be used in the medical bandage of the
invention. Suitable backings include cellophane, cellulose acetate,
ethylcellulose, plasticized vinylacetate-vinylchloride copolymers,
polyethylene terephthalate, nylon, polyethylene, polypropylene,
polyvinylidenechloride, paper, cloth, and aluminum foil.
Preferably, a flexible occlusive backing is employed to conform to
the shape of the body member to which the bandage is applied and to
enhance absorption of the organic nitrate coronary vasodilator by
the skin.
To use the medical bandage of the invention, it is applied directly
to the skin or mucosa of a mammalian patient, to release a
predetermined therapeutically effective amount of the vasodilator
to circulation. Certain of the vasodilator drugs employed herein
have heretofore been conventionally administered for the treatment
of individual attacks of anginal pain or for the brief relaxation
of other smooth muscle rather than for maintaining drug effects for
any extended period. By the use of this invention, however,
prophylaxis treatment of these conditions is made possible by
ensuring that an accurately measured quantity of the drug is
continuously administered when the bandage is applied to the skin
or mucosa. Uncertainties previously encountered in administration
of vasodilators by peroral pellet or sublingual tablet, or in
application of these agents from creams or ointments are avoided
and a reliable, stable preparation is provided. When the patient
requires immediate relief, as in the case of angina pectoris, the
bandage of the present invention may be used in conjunction with
the sublingual method of administering nitroglycerin, that is, a
nitroglycerin tablet may be given the patient for immediate relief
and the bandage applied to the patient to continue the dosage of
nitroglycerin for a much longer period of time.
The adhesive layer should be in firm contact with the skin, forming
a tight seal therewith. Drug within the microcapsules or the
reservoir layer whether in solid form or solution, migrates through
the walls of the microcapsules or the reservoir layer, acting as a
solubility membrane. Ordinarily, one would expect the drug
migration to cease when sufficient drug has reached the outer
surface of the microcapsules or reservoir layer to create an
equilibrium or when the adhesive layer has become saturated with
the drug. However, when the adhesive layer is in contact with the
patient's skin, drug molecules which are continuously removed from
the outer surface of the microcapsules or reservoir layer migrate
through the adhesive to the outer surface of the adhesive layer and
are absorbed by the skin. Absorbed drug molecules pass through the
skin and enter circulation through the capillary network. While the
bandage may be applied to any area of the patient's skin, the lower
back and buttocks are the areas of choice. In like manner, the
bandage can be applied to the mucosa of the mouth, for example, by
application to the palate or the buccal mucosa, to obtain
absorption of the drug by the oral mucosa. Although obtaining a
liquid tight adhesive seal between the skin and bandage is
important, it becomes critical in the mouth. Without such a seal,
irrigation of the oral mucosa by saliva will transfer the drug to
the gastrointestinal tract, rather than to circulation through the
oral mucosa.
Those skilled in the art will appreciate that the bandage of this
invention significantly differs from prior art wound dressings or
bandages. The bandage of this invention contains a systemically
active vasodilator drug and is applied to unbroken skin, to
introduce the drug to circulation in the blood stream and produce a
pharmacologic response at a site remote from the point of
application of the bandage. Thus, the bandage functions as an
external drug reservoir and provides a complete dosage regimen for
a particular time period.
The required surface area of the bandage will depend on the
activity of the drug and the rate of its absorption through the
skin. Usually, the adhesive face of the bandage has a surface area
of 0.5 to 400 square centimeters, although smaller or larger area
bandages can be used.
The following examples will serve to illustrate the invention
without in any way being limiting thereon.
EXAMPLE 1
100 grams of 2-hydroxyethyl methacrylate is mixed with 100 grams of
water and tertiary butyl peroxide (0.2 gram) is added. Ethylene
glycol dimethacrylate (0.2 gram) is added to the mixture and is
heated to 70.degree.C. The resultant friable, polymeric foam is
dried and ground to a powder to obtain average particle size of
about 20 micron.
A 10 gram portion of the polymeric powder is mixed with 1 gram
glyceryl trinitrate dissolved in ethyl alcohol and the resultant
mixture placed on a mechanical roller until the polymeric powder
has absorbed the glyceryl trinitrate to saturation. The solution is
then filtered.
The resulting microcapsules of glyceryl trinitrate are mixed with
100 grams of a 22 percent solution in heptane ethylacetate (70:30)
of a viscoelastic copolymer of iso-octyl acrylate and acrylic acid
(94:6) adhesive to uniformly distribute the microcapsules
throughout the adhesive solution. The resulting slurry is coated
onto a cellophane sheet, 10 centimeters in width by 100 centimeters
in length, and the solvent is removed by evaporation.
When applied to the skin of a subject, a 5 .times. 5 cm portion of
the resulting bandage is effective to administer nitroglycerin
through the skin to circulation to provide a continuous
administration of the daily dose of nitroglycerin for coronary
vasodilation. If desired, the amount of the nitroglycerin to be
administered may be increased or decreased by merely varying the
size of the above described bandage for application to the
skin.
EXAMPLE 2
49 grams of propylene glycol is mixed with 0.5 gram of high
molecular weight carboxy vinyl resin (e.g., Carbopol resin; B.F.
Goodrich) and the resultant slurry is neutralized using a ten
percent aqueous sodium hydroxide solution to a neutral pH. To the
resultant gel, 50 milligrams of nitroglycerin is added and
thoroughly mixed with a suitable mixing equipment. One gram of the
resultant gel contains 1 milligram of nitroglycerin.
Five grams of the resultant nitroglycerin gel is placed on a sheet
of polyethylene to cover a 5 .times. 5 cm area. Another sheet of
polyethylene is placed over the gel and the edges of the 5 .times.
5 cm area is sealed by a heat sealer to obtain a leak-proof packet
like sandwich.
The resultant nitroglycerin-polyethylene sandwich is laminated over
a pressure-sensitive adhesive sheet having a mylar backing member,
so that about 1/2 cm wide adhesive edges are left uncovered for
adhesion to the body surface.
The resultant device having a total dimension of 51/2 .times. 51/2
cm when applied to a body surface, is capable of delivering the
nitroglycerin for up to 12 hours into the circulation through the
skin.
Thus, this invention provides a reliable and easy to use device for
administering nitrate vasodilators to circulation, in controlled
quantities, over a prolonged period of time, by absorption through
the exterior body skin or mucosa. Uncertainties resulting from
administration of these agents, perorally, sublingually, or from
creams, ointments and solutions, are not encountered; and a
precisely determined amount of the drug is applied in a controlled
manner.
Although the product of this invention has been referred to as a
medical or therapeutic bandage, those skilled in the art will
appreciate that the term "bandage" as used herein includes any
product having a backing member and a pressure-sensitive adhesive
face surface. Such products can be provided in various sizes and
configurations, including tapes, strips, sheets, plasters, and the
like.
While there have been shown and described and pointed out the
fundamental novel features of the invention as applied to the
preferred embodiment, it will be understood that various omissions
and substitutions and changes in the form and details of the
bandage illustrated may be made by those skilled in the art without
departing from the spirit of the invention. It is intended,
therefore, that the invention be limited only as indicated by the
scope of the following claims.
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