U.S. patent application number 13/722458 was filed with the patent office on 2013-07-18 for lidocaine patch and methods of use thereof.
This patent application is currently assigned to JAR LABORATORIES. The applicant listed for this patent is JAR LABORATORIES. Invention is credited to JAMES CIULLO.
Application Number | 20130184351 13/722458 |
Document ID | / |
Family ID | 48780396 |
Filed Date | 2013-07-18 |
United States Patent
Application |
20130184351 |
Kind Code |
A1 |
CIULLO; JAMES |
July 18, 2013 |
LIDOCAINE PATCH AND METHODS OF USE THEREOF
Abstract
This invention is directed to a transdermal delivery patch
comprising local anesthetic agent and optionally a permeation
enhancement agent for reducing neuropathic pain.
Inventors: |
CIULLO; JAMES; (ELMHURST,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JAR LABORATORIES; |
ELMHURST |
IL |
US |
|
|
Assignee: |
JAR LABORATORIES
ELMHURST
IL
|
Family ID: |
48780396 |
Appl. No.: |
13/722458 |
Filed: |
December 20, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61578264 |
Dec 21, 2011 |
|
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|
Current U.S.
Class: |
514/626 ; 600/15;
604/501 |
Current CPC
Class: |
A61K 9/7023 20130101;
A61N 1/30 20130101; A61N 1/0448 20130101; A61K 9/0009 20130101;
A61K 31/167 20130101 |
Class at
Publication: |
514/626 ;
604/501; 600/15 |
International
Class: |
A61K 31/167 20060101
A61K031/167; A61K 9/70 20060101 A61K009/70; A61K 9/00 20060101
A61K009/00 |
Claims
1. A patch for transdermal delivery of lidocaine for reducing pain
comprising, a patch comprising a composition comprising a
therapeutically effective amount of lidocaine, wherein said amount
of lidocaine is less than 4 percent by weight, and wherein said
pain is selected from neuropathic pain, osteoarthritis pain, back
pain, pain associated with fibromyalgia, pain associated with
carpal tunnel syndrome, pain associated with muscle strain, pain
associated with muscle sprain or degenerative bone pain, or any
combination thereof.
2. The patch of claim 1, wherein said composition further comprises
a treatment enhancing amount of a permeation enhancement agent.
3. The patch of claim 2, wherein said permeation enhancement agent
is menthol.
4. The patch of claim 3, wherein said treatment enhancing amount of
menthol is up to 16 percent by weight.
5. The patch of claim 4, wherein said treatment enhancing amount of
menthol is about 3 to 5 percent by weight.
6. The patch of claim 1, wherein said therapeutically effective
amount of lidocaine is 3.95 percent by weight.
7. The patch of claim 1, wherein said lidocaine is its
pharmaceutically acceptable free base.
8. A method for reducing pain in a subject comprising, applying on
a skin surface of said subject, at or near the site of pain, a
patch comprising a composition comprising a therapeutically
effective amount of lidocaine, wherein said amount of lidocaine is
less than 4 percent by weight, and wherein application of said
patch provides transdermal delivery of an amount of lidocaine
sufficient to reduce said pain in the subject, wherein said pain is
selected from neuropathic pain, osteoarthritis pain, back pain,
pain associated with fibromyalgia, pain associated with carpal
tunnel syndrome, pain associated with muscle strain, pain
associated with muscle sprain or degenerative bone pain, or any
combination thereof and wherein said patch induces analgesia.
9. The method of claim 8, wherein said applying is for about 8 to
12 hours.
10. The method of claim 8, wherein said neuropathic pain comprises
back pain, diabetic neuropathic pain, nerve compression or nerve
trauma, or any combination thereof.
11. The method of claim 8, wherein said composition further
comprises a treatment enhancing amount of a permeation enhancement
agent.
12. The method of claim 11, wherein said permeation enhancement
agent is menthol.
13. The method of claim 12, wherein said treatment enhancing amount
of menthol is up to 16 percent by weight.
14. The method of claim 13, wherein said treatment enhancing amount
of menthol is about 3 to 5 percent by weight.
15. The method of claim 8, wherein said therapeutically effective
amount of lidocaine is 3.95 percent by weight.
16. The method of claim 8, wherein said lidocaine is its
pharmaceutically acceptable free base.
17. The method of claim 8, wherein said pain is reduced for at
least 12 hours.
18. The method of claim 17, wherein said pain is reduced for at
least 24 hours.
19. The method of claim 19, wherein said pain is reduced for
greater than 24 hours.
20. The method of claim 8, further comprising an additional step
for enhanced delivery of said lidocaine.
21. The method of claim 20, wherein said enhanced delivery
comprises accelerated delivery by iontophoresis, a battery powered
electronic stimulant or magnetophoresis.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 61/578,264, filed on Dec. 21, 2011, hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention is directed to a transdermal delivery patch
comprising a local analgesic agent and optionally a permeation
enhancement agent, for reducing pain.
BACKGROUND OF THE INVENTION
[0003] It is known that neuropathic pain including back pain,
diabetic nerve pain, complex regional pain syndrome type II
(CRPS-II), carpal tunnel syndrome, phantom limb pain,
chemotherapy-induced neuropathy, or HW sensory neuropathy and other
nerve pain disorders have a predominantly neurological cause.
[0004] Presently, the symptoms of pain are predominantly treated
pharmacologically with systemically active, oral or injectable
analgesics and antiphlogistics, and, in part, in combination with
psychosomatic or physical therapy, sometimes also in combination
with other methods, such as, acupuncture. The last resort for
diseases causing neuropathic pain, such as those of the
intervertebral disk, is surgery.
[0005] An oral analgesic is carried into the patient's circulatory
system and prevents the recognition of pain systemically by
interrupting the transmission of pain signals from sensory neurons
to the pain centers in the brain. Traditional oral analgesics
include opioids (narcotics) such as morphine, codeine, methadone,
Demerol.RTM. (meperidine hydrochloride) or Darvon.RTM.
(propoxyphene hydrochloride); and non-steroidal anti-inflammatory
drugs (NSAIDs), such as aspirin, ibuprofen or naproxen.
[0006] The systemic use of these drugs carries patient risk. Opioid
use causes a variety of undesired side-effects, including sedation,
dizziness, depression, nausea and constipation. Prolonged opioid
usage carries a risk of patient addiction. The large and sometimes
prolonged doses of non-steroidal anti-inflammatory drugs ("NSAIDs")
required to treat intense pain can cause gastric disorders, erosion
of the stomach lining and intestinal mucus membrane,
nephrotoxicity, hepatotoxicity, as well as internal bleeding.
Orally administered drugs also cause side-affects that restrict
physical activity (primarily in the case of opioids, due to
sedation) and inhibit effective physical therapy.
[0007] In addition, neuropathic pain is often resistant to
available drug therapies; a hallmark of neuropathic pain is its
intractability. Typical non-steroidal anti-inflammatory drugs
(NSAIDs) such as aspirin, indomethecin, and ibuprofen do not
relieve neuropathic pain. The neuropathic pain observed in animal
models predictive of human clinical outcome does not respond to
NSAIDs.
[0008] Unfortunately, all systemic analgesics have a considerable
number of undesirable side effects in common. The salicylic acid
derivatives and nonsteroidal antiphlogistics are associated
considerably and frequently with gastric disorders as a result of
the antiproliferative active mechanism. Paracetamol, with a weaker
effect, is associated with metabolic stress of liver and kidney
functions, especially when used for a prolonged period of time and
at required higher doses. Therefore, application of these therapies
is limited by the spectrum of undesirable, product-specific effects
in each case, because systemic interventions involve all of the
organs and the organ systems. In addition, therapies such as
surgery, in themselves present significant medical risks to the
patient. These pharmacotherapies, do not represent sufficiently
tolerable and effective forms of treatment.
[0009] Pain can also be treated locally by delivering a pain
reliever directly to the site of pain or in a region near or
surrounding the site of pain, through use of a local
anesthetic.
[0010] Systemic application of local anesthetics might be applied
invasively by means of injection. However, this option is
practically eliminated due to the danger of systemic overdosage
with, among others, serious cardiac side effects. Direct
application of local anesthetics through local injection is
technically possible and is performed in different ways. However,
local injections are not only painful, but can also never be done
directly by the patient. The local surface injection technique
involves so-called neural therapy with muscular trigger points and
requires experienced medical handling and technique (J. T. Travell,
D. G. Simons, Myofascial Pain and Dysfunction, Vol. I/II, Williams
& Wilkins, Baltimore, 1983). Therefore, this option is limited
to use in clinically severe disorders. There is also the drawback
that a local anesthetic injected into a highly vascularized area of
the body can be carried away by the circulatory system and create
the same risks as systemically administered anesthetics. This risk
is increased when local anesthetic dosages are increased to manage
intense pain. Further, use of conventional topical formulations,
for example, creams, allows neither exact dosage nor continuous
penetration over a prolonged period of application.
[0011] The topical administration of a local anesthetic overcomes
some of the drawbacks of injection. There is no need for the
painfully invasive procedure and professional administration is not
needed. The risk of the locally applied anesthetic acting as a
systemically administered drug also is much reduced.
[0012] Dermal patches are well known to administer local
anesthetics topically to patients at wound sites and to treat skin
ailments. Dermal pain patches have a number of benefits, not the
least of which is convenience. Amide and ester group-containing,
for example, lidocaine of the amide type, exhibit, as a
pharmacological active mechanism, an inhibition of the rapid sodium
ion influx in nerve fibers. In this manner, the impulse conduction
of the nerve path is blocked, which in principle involves all
regional nerve fibers.
[0013] A prescription strength 5 percent lidocaine patch marketed
as Lidoderm.RTM. (lidocaine patch 5%) is available from Endo
Pharmaceuticals, Inc. The patch may make the patient warmer, and
thus be a burden in hot environments. Moreover, an overdose of
lidocaine can cause fatal side effects if too much lidocaine is
absorbed through your skin and into your blood.
[0014] A more effective pharmacological principle might be a
suitable form of low-dosed local analgesics delivered in a dermal
patch. It is therefore an object of the present invention to
provide a low-dosage topical dermal patch comprising lidocaine that
can be used to provide relief from neuropathic pain over a period
of time.
[0015] Given the high incidence of neuropathic pain and its effect
on the general population, new innovative remedies are needed to
reduce pain in a subject. Advantageous remedies include those that
can be applied locally, do not cause negative side-effects, are
easy for a patient to apply, do not require professional
administration or painful injections and allow a single
administration to treat one or more pain sites for a prolonged
period of time.
SUMMARY OF THE INVENTION
[0016] In one embodiment of the present invention, a patch for
transdermal delivery of lidocaine for reducing pain, including
neuropathic pain, osteoarthritis pain, back pain, pain from
fibromyalgia, pain from muscle strains, pain from muscle sprains or
degenerative bone pain or any combination thereof, comprises a
patch comprising a composition comprising a therapeutically
effective amount of lidocaine, wherein the amount of lidocaine is
less than 4 percent by weight.
[0017] In one embodiment, the composition further comprises a
treatment enhancing amount of a permeation enhancement agent. In
another embodiment, the permeation enhancement agent is menthol. In
yet another embodiment, the amount of menthol is up to 16 percent
by weight. In still another embodiment, the amount of menthol is
between about 3 to 5 percent.
[0018] In one embodiment of this invention, the therapeutically
effective amount of lidocaine is 3.95 percent by weight.
[0019] In one embodiment, the lidocaine may be a pharmaceutically
acceptable lidocaine base.
[0020] In one embodiment, the methods of this invention include
reducing pain, including neuropathic pain, osteoarthritis pain,
back pain, pain from fibromyalgia, pain from muscle strains, pain
from muscle sprains or degenerative bone pain or any combination
thereof, in a subject comprising applying on a skin surface of the
subject at or near the site of pain, a patch comprising a
composition comprising a therapeutically effective amount of
lidocaine, wherein the amount of lidocaine is less than 4 percent
by weight, and wherein application of the patch provides
transdermal delivery of an amount of lidocaine sufficient to reduce
the pain in the subject.
[0021] In one embodiment, the patch is applied for about 8 to 12
hours.
[0022] In one embodiment, methods of this invention provide that
application of a patch of this invention reduces neuropathic pain
including back pain, diabetic neuropathic pain, nerve compression
or nerve trauma, or any combination thereof.
[0023] In one embodiment, methods of this invention include
compositions further comprising a treatment enhancing amount of a
permeation enhancement agent. In one embodiment, methods include
the use of menthol as a permeation enhancement agent. In one
embodiment, the amount of method used in a method of this invention
is up to 16 percent by weight. In one embodiment the amount of
menthol used in a method is between about 3 to 5 percent by
weight.
[0024] In one embodiment, the methods of this invention employ a
therapeutically effective amount of lidocaine, wherein that amount
is 3.95 percent by weight.
[0025] In one embodiment of the invention, the lidocaine employed
in a method of this invention is its pharmaceutically acceptable
salt, free base or any combination thereof. In another embodiment
of the invention, the lidocaine employed in a method of this
invention is its pharmaceutically acceptable free base.
[0026] In one embodiment, methods of this invention reduce pain for
at least 12 hours. In another embodiment, methods reduce pain for
at least 24 hours. In yet another embodiment, methods reduce pain
for more than 24 hours.
[0027] In some embodiments, methods of this invention include an
additional step for enhanced delivery of said lidocaine. In one
embodiment, methods include the use of iontophoresis, a battery
powered electronic stimulant or magnetophoresis for enhanced
deliver of an active ingredient, e.g., lidocaine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] The subject matter regarded as the invention is particularly
pointed out and distinctly claimed in the concluding portion of the
specification. The invention, however, both as to organization and
method of operation, together with objects, features, and
advantages thereof, may best be understood by reference to the
following detailed description when read with the accompanying
drawings in which
[0029] FIG. 1 is a schematic block diagram of a method of reducing
neuropathic pain in a subject, in accordance with embodiments of
the invention;
[0030] FIG. 2 illustrates delivery of a medication, e.g., a
lidocaine solution, into the skin using iontophoresis.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[0031] In the following detailed description, numerous specific
details are set forth in order to provide a thorough understanding
of the invention. However, it will be understood by those skilled
in the art that the present invention may be practiced without
these specific details. In other instances, well-known methods,
procedures, and components have not been described in detail so as
not to obscure the present invention.
[0032] The present invention is directed to a patch for transdermal
delivery of lidocaine for reducing pain, including neuropathic
pain, osteoarthritis pain, back pain, pain from fibromyalgia, pain
from muscle strains, pain from muscle sprains or bone degeneration
pain or any combination thereof, comprising a composition
comprising a therapeutically effective dosage of lidocaine and
methods of use thereof.
[0033] The patch of the present invention may be used to reduce
neuropathic pain, including back pain and/or discomfort. In
addition, the patch of the present invention may be used to reduce
osteoarthritis pain, pain from fibromyalgia, pain from muscle
strains, pain from muscle sprains or bone degeneration pain or any
combination thereof. The patch of the present invention may, in
addition to a dosage of lidocaine, include treatment enhancing
amounts of a permeation enhancement agent. The present invention
may be used to reduce pain for extended time periods, e.g., 24
hours. The patch and methods of use thereof according to the
present invention may be better understood with reference to the
drawing and accompanying descriptions.
[0034] Before explaining at least one embodiment of the present
invention in detail, it is to be understood that the invention is
not limited in its application to the details of construction and
the arrangement of the components as set forth in the following
description or illustrated in the drawing. The invention is capable
of other embodiments or of being practiced or carried out in
various ways. Also, it is to be understood that the phraseology and
terminology employed herein are for the purpose of description and
should not be regarded as limiting.
I. Definitions
[0035] As used herein, the term "patch" refers to a medicated
patch, e.g., a patch, comprising a composition comprising at least
one active ingredient that is placed on the skin to deliver a
continuous dosage of the active ingredient through the skin and
into the surrounding tissue. In one embodiment, the active
ingredient may penetrate deeply below the skin to a site of pain
for deep tissue pain relief. In one embodiment, the active
ingredient penetrates just below the skin to a site of pain
localized therein for local pain relief. In one embodiment, the
continuous dosage of the active ingredient provides minimal entry
of the active ingredient into the blood stream. In another
embodiment, the continuous dosage provides no entry of the active
ingredient into the blood stream.
[0036] As used herein, the term "patch" may also be referred to
herein as a "topical delivery system", a "topical patch delivery
system", an "adhesive patch", a "transdermal patch", a "transdermal
delivery system", an "analgesic patch", a "dressing", a "topical
carrier system".
[0037] Transdermal patches are a well-accepted technology used to
deliver a wide variety of pharmaceuticals. Patches of the present
invention may be placed on the skin for specified therapeutic time
periods and remain in place for up to 12 hours. Therapeutically
effective dosages of pharmaceuticals are the choice for use with a
patch of this invention.
[0038] Patches may comprise an adhesive to remain in place when
placed on the skin or may be adhered by other means including
adhesive tape or strips. In addition, patches of the present
invention may be perforated and/or stretchable in order that they
may be wrapped around an appendage or body part. In certain
embodiments, a stretchable patch may be wrapped fully around an
appendage or body part. In alternative embodiments, a stretchable
patch may be wrapped partly around an appendage or body part. For
example a patch of the present invention may be wrapped around a
knee, ankle, leg, elbow, wrist, finger, arm or neck. By wrapping
the patch, pain relief may be provided at sites recalcitrant to a
patch that would otherwise be expected to remain in place using
just an adhesive, for example a moving joint such as an elbow, knee
or wrist joint.
[0039] In one embodiment, the patch is an adhesive patch. In
another embodiment, the patch is not adhesive. In yet another
embodiment, the patch may be wrapped around a bodily appendage. In
still another embodiment, the patch may be both adhesive and able
to be wrapped around an appendage.
[0040] Conventional dermal patches include a carrier that holds a
drug and allows the drug to be released onto a patient's skin for
absorption. Many different kinds of dermal patches are known,
including matrix type patches, reservoir-type patches,
multi-laminate drug-in-adhesive type to patches, and monolithic
drug-in-adhesive type patches, and many others. Such patches can be
readily prepared using technology which is known in the art such as
described in Remington's Pharmaceutical Sciences, 18.sup.th or
19.sup.th editions, published by the Mack Publishing Company of
Easton, Pa.
[0041] Patches of the present invention may include: (1) a backing
layer, having an adhesive thereon; (2) an analgesic component for
delivery of the analgesic, preferably, an analgesic in a carrier,
referred to herein as an "analgesic composition" or "composition";
wherein the analgesic components are collectively referred to
herein as the "active components" or "active ingredients". These
components are described in more detail below. In another
embodiment, the analgesic composition comprises lidocaine.
[0042] Patches of the present invention can be any shape or size or
can be customized to fit irregularly shaped body parts associated
with pain, e.g., joints, back, neck, arms, legs, shoulders, hips,
wrists, ankles, knees and/or fingers. For example, patches of the
invention can be rectangular, square, round or oval in shape.
Patches may also be perforated and stretchable for wrapping around
different body appendages and/or joints, e.g., arms, legs, wrists,
ankles, knees and/or fingers. Varying the size of the patch used
varies the dosage. Often a patch is cut and only a portion is used.
In some instances, the use of more than one patch may be
advisable.
[0043] In one embodiment, patches are 10 cm.times.14 cm. In another
embodiment, patches are smaller than 10 cm.times.14 cm. In yet
another embodiment, patches are larger than 10 cm.times.14 cm.
[0044] In one embodiment, patches are cut to the size and shape
needed for use in pain reduction. In one embodiment, the patch
remains intact while the size of the patch changes upon
stretching.
[0045] Patches suitable for use in the present invention include,
but are not limited to, (1) the matrix patch; (2) the reservoir
patch; (3) the multi-laminate drug-in-adhesive patch; and (4) the
monolithic drug-in-adhesive patch; as described in Transdermal And
Topical Drug Delivery to Systems, pp. 249-297 (Tapash K. Ghosh et
al. eds., 1997), hereby incorporated in full herein by reference.
These patches are well known in the art and generally available
commercially.
[0046] The matrix patch comprises a drug containing matrix, an
adhesive backing film overlay, and preferably, a release liner. In
some cases, it may be necessary to include a impermeable layer to
minimize drug migration into the backing film (e.g., U.S. Pat. No.
4,336,243, incorporated in full herein by reference). The
drug-containing matrix is held against the skin by the adhesive
overlay. Examples of suitable matrix materials include, but are not
limited to, lipophilic polymers, such as polyvinyl chloride,
polydimethylsiloxane, and hydrophilic polymers like
polyvinylpyrrolidone, polyvinyl alcohol, hydrogels based on
gelatin, or polyvinylpyrrolidone/polyethylene oxide mixtures.
[0047] The reservoir type patch design is characterized by a
backing film coated with an adhesive and a reservoir compartment
comprising a drug formulation, preferably in the form of a solution
or suspension that is separated from the skin by a semipermeable
membrane (e.g., U.S. Pat. No. 4,615,699, hereby incorporated in
full herein by reference). The adhesive coated backing layer
extends around the reservoir's boundaries to provide a concentric
seal with the skin and hold the reservoir adjacent to the skin.
[0048] The monolithic/single drug-in-adhesive patch design is
characterized by the inclusion of the drug formulation in the skin
contacting adhesive layer, a backing film, and preferably, a
release liner. The adhesive functions both to release the analgesic
and adhere the analgesic matrix to the skin. The drug-in-adhesive
system does not require an adhesive overlay and thus the patch size
is minimized. Also, drug-in-adhesive type patches are thin and
comfortable (e.g., U.S. Pat. No. 4,751,087, incorporated in full
herein by reference).
[0049] The multi-laminate drug-in-adhesive patch design further
incorporates an additional semi-permeable membrane between two
distinct drug-in-adhesive layers or multiple drug-in-adhesive
layers under a single backing film. See Peterson, T. A. and Dreyer,
S. J. 21 Proceed. Intern. Symp. Control. Rel. Bioact. Mater.
477-478 (Nice, France 1994), hereby incorporated in full herein by
reference).
[0050] The backing layer or backing serves as the upper surface of
the patch and functions as the primary structural element and
provides the patch with its flexibility. The material selected for
the backing material should be selected so that it is substantially
impermeable to the local analgesic and any other materials present;
the backing is preferably made of a sheet or film of a flexible
elastomeric material. The backing supports the active layers by way
of an adhesive and holds the active layers against the application
site. The combination of backing and adhesive should be
biocompatible, non-irritating to the skin, breathable and able to
hold the patch firmly against the skin.
[0051] Backings for use in patches of the invention are preferably
made of a flexible, biocompatible material that imitates the
elastic properties of skin and conforms to the skin during
movement. Preferred have a moisture-vapor transmission rate similar
to human skin. This reduces the chance of an infection developing
under the patch after it is applied to a patient's skin.
[0052] Preferably, the backing layer is derived from synthetic
polymers like polyolefin oils polyester, polyethylene,
polyvinylidine chloride, and polyurethane or from natural materials
like cotton, wool, etc. Non-occlusive backings allow the area to
breathe (i.e., promote water vapor transmission from the skin
surface). In one embodiment, the backing film is an occlusive
polyolefin foil (Alevo, Dreieich, Germany). The polyolefin foil is
preferably about 0.6 to about 1 mm thick. Other suitable backings
are commercially available; for example, suitable backings can be
purchased from 3M (St. Paul, Minn.) and Bertek (St. Albans,
Vt.).
[0053] In one embodiment, the patch includes an occlusive dressing.
In another embodiment, the patch includes a non-occlusive dressing.
For example, a non-occlusive patch can enable moisture vapor on the
surface of the skin to evaporate through the patch so as to prevent
the undesired accumulation of moisture which, if it occurred, could
cause the patch to fall off or even facilitate the growth of
bacteria beneath the patch.
[0054] Permeable membranes can be used with patches of the present
invention to overlay the portion of the patch adjacent to the skin
to permit delivery of the patch's active ingredients to the
application site. Preferably, the permeable membrane comprises a
breathable material that is agreeable to the surface of a
surgically closed wound and permits local delivery of local
anesthetic into the skin of the patient at the wound site.
Permeable membranes permit controlled delivery of the active
components of the patch.
[0055] Permeable membranes useful in the present invention include
thin non-porous ethylene vinyl acetate films or thin micro-porous
films of polyethylene and polypropylene. Preferably, the permeable
membrane is an ethyl vinyl acetate copolymer membrane. Suitable
permeable membranes are commercially available; for example,
suitable permeable membranes can be purchased from 3M (St. Paul,
Minn.).
[0056] Adhesives may be used with patches of the present invention
to adhere the active components to the backing and to adhere the
backing to the patient's application site. Preferably, adhesives
useful in the present invention can function under a wide range of
conditions, such as, high and low humidity, bathing, sweating etc.
Adhesives for use with patches of the present invention are well
known in the art and selection is readily accomplished by an
ordinary practitioner. Suitable adhesives include, but are not
limited to, polyisobutylene-based adhesives, silicone-based
adhesives, and acrylic-based adhesives. Preferably the adhesive is
a composition to based on natural or synthetic rubber; a
polyacrylate such as, polybutylacrylate, polymethylacrylate,
poly-2-ethylhexyl acrylate; polyvinylacetate; polydimethylsiloxane;
and hydrogels (e.g., high molecular weight polyvinylpyrrolidone and
oligomeric polyethylene oxide). Patches of the present invention
deliver their medicine directly to the site of a person's pain.
This may eliminate some of the side effects that come with oral
dosing or local injections. For instance, some analgesics are
likely to cause an upset stomach unless they're taken with food.
And, because patches of the present invention provide minimal
release of their active ingredient into the blood stream and
provide release of their active ingredient slowly into the body
tissues through the skin, people should also get more consistent
pain relief than they do with oral dosing or injections.
[0057] The composition of the present invention is a pharmaceutical
composition. The pharmaceutical composition of the invention
includes pharmaceutically acceptable carriers.
[0058] As used herein, the terms "pharmaceutically acceptable
carrier", "carrier", or "vehicle" refers to carrier materials
suitable for transdermal drug administration. Carriers and vehicles
useful herein include any such materials known in the art which are
nontoxic and do not interact with other components. As used herein
the term "a pharmaceutically acceptable carrier" refers to any
substantially non-toxic carrier conventionally useable for
transdermal administration of pharmaceuticals in which an active
ingredient will remain stable and bioavailable. In one embodiment
of the present invention, the local-analgesic of the composition of
the present invention comprises a pharmaceutically acceptable
carrier to contain and deliver the active component to the
application site. As used herein, the term "carrier" may herein be
interchangeable with the term "patch"
[0059] In certain embodiments, carriers are sterile and
pharmaceutically acceptable for topical application and delivery of
an active ingredient into or through a patient's skin. Preferred to
functional characteristics of carriers are low adhesive strength,
breathability, and conformability to the application area.
[0060] Pharmaceutically acceptable carriers for use in the
invention are standard in the art, for example, matrix-type
carriers, reservoir-type carriers, multi-laminate-type carriers,
and monolithic drug-in-adhesive type carriers, such as those
disclosed in "Transdermal And Topical Drug Delivery Systems"
(Tapash K. Ghosh et al. eds., 1997); see also Kristine Knutson and
Lynn K. Pershing, Topical Drugs, in Remington: The Science And
Practice Of Pharmacy 866-885 (Alfonso R. Gennaro ed., 1995), the
disclosures of which is hereby incorporated herein in full by
reference.
[0061] In a preferred embodiment, the carrier is a matrix-type drug
carrier. Matrix-type drug carriers are well known in the art.
Suitable matrix-type drug carriers include, but are not limited to,
the adhesives discussed below, such as polyisobutylene-based
adhesives, silicone-based adhesives, and acrylic-based
adhesives.
[0062] In another embodiment, the carrier is a hydrogel. Hydrogels
are a mixture of water and a gelling agent, such as a hydrophilic
polymer. In general, hydrogels form a three-dimensional lattice of
polymer chains that retains an aqueous solution in a flexible,
stable shape. Preferred hydrogels contain gelling agents
distributed substantially uniformly throughout the carrier liquid,
which is typically aqueous and may contain an alcohol and/or an
oil.
[0063] Preferred gelling agents include, but are not limited to,
crosslinked acrylic acid polymers such as carboxypolyalkylenes;
hydrophilic polymers such as polyethylene oxides,
polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol;
cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxypropyl methylcellulose, hydroxypropyl
methylcellulose phthalate, and methylcellulose; gums such as
tragacanth and xanthan gum; sodium alginate; and gelatin. In order
to prepare a uniform gel, dispersing agents such as alcohol or
glycerin can be added, or the gelling agent can be dispersed by
trituration, mechanical mixing, and/or stirring.
[0064] Suitable hydrogels are commercially available, for example,
suitable hydrogels can be purchased from BASF (St. Paul, Minn.) or
Noveon (Cleveland, Ohio).
[0065] As used herein, the term "active ingredient" refers to a
suitable drug that provides local analgesia or deep tissue
analgesia, or a combination thereof, or a drug that provides a
regional blockage of nervous pathways that carry pain signals. As
used herein, the term "active ingredient" may also be referred to
as "drug" or "active component".
[0066] As used herein, the term "analgesia" refers to a
neurological or pharmacological state characterized by an absence
of normal sensibility to pain, without an effect on consciousness.
Accordingly, painful stimuli are either not perceived at all, or
they are moderated such that, even though they may still be
perceived, they are no longer painful.
[0067] In one embodiment, an active ingredient may act as an
analgesic. The analgesic may operate as a local analgesic and/or
penetrate deeper and enter the blood stream. In one embodiment, the
active ingredient functions as a local analgesic. In another
embodiment, the active ingredient functions as an analgesic for
deeper tissue. In yet another embodiment, the active ingredient
does not enter the blood stream. In another embodiment, the active
ingredient only minimally enters the blood stream.
[0068] In one embodiment, administration of a patch comprising a
composition comprising the active ingredient, acts to reduce pain,
including neuropathic pain, osteoarthritis pain, back pain, pain
from fibromyalgia, pain from muscle strains, pain from muscle
sprains or bone degeneration pain or any combination thereof, in a
subject.
[0069] As used herein, the term "reducing pain" refers to
alleviating pain localized at a site of interest. The reduction of
pain may include alleviating pain in an area around the site of
interest.
[0070] As used herein, "pain," includes both acute pain and chronic
pain, which may be centralized pain, peripheral pain, or
combination thereof.
[0071] As used herein, the term "acute pain" refers to centralized
or peripheral pain that is intense, localized, sharp, or stinging,
and/or dull, aching, diffuse, or burning in nature and that occurs
for short periods of time.
[0072] As used herein, the term "chronic pain" refers to
centralized or peripheral pain that is intense, localized, sharp,
or stinging, and/or dull, aching, diffuse, or burning in nature and
that occurs for extended periods of time (i.e., persistent and/or
regularly reoccurring).
[0073] As used herein, the term "neuropathic pain" refers to any
and all types of neuropathic pain regardless of the cause.
Neuropathic pain refers to pain that originates from pathology of
the nervous system. Neuropathic pain reflects both peripheral and
central sensitization mechanisms.
[0074] Abnormal signals arise not only from injured axons but also
from the intact nociceptors that share the innervation territory of
the injured nerve. Neuropathic pain may result from lesions of the
central nervous system, or from the peripheral nervous system.
Neuropathic pain may also arise from disorders of ion channels,
such as the sodium channels. The nervous system can system can
generate and perpetuate pain (i.e., neuropathic), without any
ongoing stimuli from injury. Neuropathic pain is often puzzling and
frustrating for both patients and physicians because it seems to
have no cause, responds poorly to standard pain therapies, can last
indefinitely and even escalate over time, and often results in
severe disability. The reduction of neuropathic pain as described
herein refers to the alleviation or elimination of the neuropathic
pain associated with a neuropathy.
[0075] Four pathological mechanisms are associated with the
generation of pain in peripheral tissues in neuropathic pain
conditions. These are: 1) nociceptor sensitization, whereby
nociceptors have enhanced sensitivity to stimuli; 2) spontaneous
activity related either to to abnormal activity of transduction
channels, or abnormal sensitivity of spike generation mechanisms;
3) abnormal coupling between sympathetic efferent fibers and
nociceptors (sympathetically maintained pain); and 4)
deafferentation, a central mechanism of pain whereby pain results
from abnormal activity in neurons concerned with pain in the
central nervous system as a result of altered input from primary
afferents.
[0076] The primary sensory neurons that carry signals related to
pain are called C-fiber and A-delta nociceptors. Normally, they
fire action potentials in response to noxious mechanical, thermal,
and/or chemical stimuli. Lumbar disk herniation with its
accompanying chemical irritants to the adjacent nerve root can
produce sciatic nerve pain. Carpal tunnel syndrome is due to a
combination of repetitive stretching of the median nerve,
compression caused by edema and hypertrophy of surrounding tissues,
and inflammation producing chemical irritation of the median nerve.
Trigeminal neuralgia has been attributed to vascular compression on
the trigeminal nerve near the brain stem and may also relate to
conditions such as multiple sclerosis.
[0077] Nerve fibers that have been damaged by injury or disease can
fire spontaneously at the site of injury or at ectopic foci along
the damaged nerve. Resulting paroxysms of pain are often described
as lancinating, stabbing, or shooting. It is believed that when
many nerve fibers are affected and fire asynchronously, neuropathic
pain has a quality of continuous burning results. In addition
however, the nerve fibers that share the innervation territory of
the injured nerve can also discharge abnormally. This discharge
arises in the skin and therefore lends itself to topical therapy.
Clonidine applied topically has been discovered to relieve pain
after delivery to the painful site, for example.
[0078] Under normal conditions, sensations are transmitted from
peripheral tissues via a connected chain of neurons in the spinal
cord, brain stem, and brain. Interruption of any portion of that
chain provides the potential for increased irritability and firing
of nerves further up the to pathway. This phenomenon explains how
phantom limb pain can occur: Loss of sensory input from a limb can
produce spontaneous firing of second- and third-order neurons,
resulting in pain and other sensory experiences in the missing
limb. Similarly, nerves damaged by diabetic neuropathy,
post-herpetic neuropathy, or peripheral nerve trauma may generate
firing in the higher-order nerves and, thus, ongoing pain.
[0079] Examples of specific sources of neuropathic pain for which
the methods of the present invention can be used include autoimmune
diseases, e.g., multiple sclerosis; metabolic diseases, e.g.,
diabetic neuropathies; back pain, spine or back surgery;
postherpetic neuralgia; vascular disease; trauma; complex regional
pain syndrome type II (CRPS-II); carpal tunnel syndrome; phantom
limb pain; chemotherapy-induced neuropathy; central pain syndrome;
trigeminal neuralgia; reflex sympathetic dystrophy syndrome; nerve
compression; stroke; spinal cord injury; or HW sensory neuropathy,
or other nerve pain disorders having a predominantly neurological
cause.
[0080] In contrast to feelings of immediate pain upon tissue
injury, neuropathic pain can develop days or months after a
traumatic injury. Furthermore, while pain caused by tissue injury
is usually limited in duration to the period of tissue repair,
neuropathic pain frequently is long lasting or chronic. Moreover,
neuropathic pain can occur spontaneously or as a result of
stimulation that normally is not painful.
[0081] As used herein, the term "osteoarthritis pain" refers to
pain associated with a degenerative joint disease where the
cartilage that normally cushions the joint and protects it from
impact erodes.
[0082] As used herein, the term "pain from fibromyalgia" refers to
pain associated with a chronic condition characterized by diffuse
or specific muscle, joint, or bone pain, along with fatigue and a
range of other symptoms. Previously, fibromyalgia was known by
other names such as fibrositis, chronic muscle pain syndrome,
psychogenic rheumatism and tension myalgias.
[0083] As used herein, the term "back pain" refers to pain
associated with all regions of the back including lower, mid and
upper back pain.
[0084] As used herein, the term "bone degeneration pain" refers to
pain associated with conditions leading to degenerative bone
disorders characterized by low bone mass and microarchitectural
deterioration of bone tissue, leading to enhanced bone fragility
and increased fracture risk.
[0085] As used herein, the term "pain from muscle strains" refers
to pain associated with muscle tears and/or pulled muscles. Muscle
strains occur when an excessive amount of force or pressure is
directed onto muscles that cause damage or tearing to the muscle
fibers and/or surrounding tendons. common muscle strains, torn
muscles and pulled muscles are: Achilles tendon tear, pulled backs,
lower back muscle strain, tearing the rotator cuff, abs (abdominal)
muscle strains, calf muscle strain, hamstring muscle strain, quads
(quadriceps) muscle strain, leg muscle strain, knee (or plantaris)
muscle strain, chest muscle strain, groin pull or muscle strain,
bicep muscle strain, and arm muscle strain.
[0086] As used herein, the term "pain from muscle sprains" refers
to pain associated with a stretch or tear of a ligament, the band
of connective tissues that joins the end of one bone with another.
Sprains are caused by trauma such as a fall or blow to the body
that knocks a joint out of position and, in the worst case,
ruptures the supporting ligaments.
[0087] The patches of the present invention can be used to reduce
pain such as neuropathic pain. For example, the patches of the
present invention may be used to reduce pain associated with
diabetic neuropathy, back pain, carpel tunnel syndrome or other
pains associated with nerve injury or any combination thereof. In
addition, the patches of the present invention may also be used to
reduce pain associated with fibromyalgia, muscle strains, muscle
sprains, osteoarthritis or bone degeneration or any combination
thereof.
[0088] Compositions of this invention are described below. In some
embodiments, any of the compositions of this invention will
comprise lidocaine, in any form or embodiment as described herein.
In some embodiments, any of the compositions of this invention will
comprise a combination of lidocaine and menthol, in any form or
embodiment as described herein. In some embodiments, any of the
compositions of this invention will consist of lidocaine, in any
form or embodiment as described herein. In some embodiments, any of
the compositions of this invention will consist of a combination of
lidocaine and menthol, in any form or embodiment as described
herein. In some embodiments, any of the compositions of this
invention will consist essentially of lidocaine, in any form or
embodiment as described herein. In some embodiments, any of the
compositions of this invention will consist essentially of a
combination of lidocaine and menthol, in any form or embodiment as
described herein. The term "comprise" refers to the inclusion of
the indicated active agents, such as the a combination of lidocaine
and menthol, as well as inclusion of other active agents, and
pharmaceutically acceptable carriers, excipients, emollients,
stabilizers, etc., as are known in the pharmaceutical industry. The
term "consisting essentially of" refers to a composition, whose
only active ingredients are the indicated active ingredients,
however, other compounds may be included which are for stabilizing,
preserving, etc. the formulation, but are not involved directly in
the therapeutic effect of the indicated active ingredients. The
term "consisting essentially of" may refer to components which
facilitate the release of the active ingredients. The term
"consisting" refers to a composition, which contains the active
ingredient and a pharmaceutically acceptable carrier or
excipient.
[0089] As used herein, the term "transdermal delivery" refers to
the delivery of a compound, e.g., an active ingredient of this
invention or other therapeutic agent, through one or more layers of
the skin (e.g., epidermis, dermis, etc). Transdermal delivery of an
active ingredient of this invention, e.g., lidocaine, may include
administration of the active ingredient to the skin surface of a
subject, including a human subject, so that the active ingredient
passes through the skin tissue and, for example, into deeper tissue
thereby providing deep tissue relief of pain.
[0090] Administration of the active ingredient or compositions of
this invention includes topical administration. As used herein, the
term "topical" refers to administration of a patch of this
invention at the point of application. The phrase "topically
applying" describes application onto one or more surfaces(s)
including epithelial surfaces. Although topical administration, in
contrast to transdermal administration, generally provides a local
rather than a systemic effect, as used herein, unless otherwise
stated or implied, the terms topical administration and transdermal
administration are used interchangeably. Ideally, the substance
will not reside in the skin for any extended period of time, but
will penetrate into localized tissue, deep tissue and/or synovial
fluids in order to provide localized, deep tissue or "joint" pain
relief or any combination thereof. In one embodiment, transdermal
delivery is enhanced, wherein enhancement may be through chemical
or physical means.
[0091] As used herein, the term "therapeutically effective amount"
refers to that amount of any active ingredient, e.g., lidocaine,
which provides a therapeutic or beneficial effect for a given
condition and administration regimen to a subject. The
concentration of the substance is selected so as to exert its
pharmaceutical effect at dosages. In certain circumstance, such
dosages are low enough to avoid significant side effects to a
subject. The effective amount of an active ingredient may vary with
the particular site at which a patch of this invention is placed,
e.g., the thickness of the skin tissue at the treatment site, the
age and physical condition of the biological subject being treated,
the severity of the condition, the duration of the treatment, the
nature of concurrent therapy, the specific compound, composition or
other active ingredient employed, the particular carrier utilized,
and like factors. The effective amount of any of the active
ingredients comprised in the compositions of the present invention
may, for example, be the amount that results in a therapeutic or
beneficial effect following its administration to a subject. The
concentration of an active ingredient is selected so as to exert
its pharmaceutical effect, but low enough to avoid significant side
effects within the scope and sound judgment of the skilled artisan.
The effective amount of the composition may vary with the
particular epithelial tissue being treated, the age and physical
condition of the biological subject being treated, the severity of
the condition, the duration of the treatment, the nature of
concurrent therapy, the specific compound, composition or other
active ingredient employed, the particular carrier utilized, and
like factors. As used herein, the term "therapeutically effective
amount" may also be referred to herein as a "pharmaceutically
effective amount".
[0092] As used herein, the term "permeation enhancement" refers to
enhancement of the percutaneous penetration of the active
ingredient, allowing for a fast onset of action. As used herein,
the term "permeation enhancement" may also be referred to as
"transdermal enhancement" or "penetration enhancement". In one
embodiment, permeation enhancement may be performed through the use
of chemical permeation enhancers. In another embodiment, permeation
enhancement may be performed through the use of physical permeation
enhancers. Physical permeation enhancer techniques include
magnetophoresis, iontophoresis or a battery powered electronic
stimulant.
[0093] Iontophoresis, also known as Electromotive Drug
Administration (EMDA), is a technique using a small electric charge
to deliver a medicine, drug, active ingredient or other chemical
through the skin. It may function similar to an injection without
the needle, for example EMDA may be used for localized entry of a
drug into the skin. In addition, EMDA may be used for concentrated
application of a medication under the skin (FIG. 2). As used
herein, "iontophoresis" refers to a non-invasive method of
propelling high concentrations of a charged substance, for example
a medication, a drug, an active ingredient or a bioactive agent,
transdermally by repulsive electromotive force using a small
electrical charge applied to an iontophoretic chamber containing a
similarly charged active agent and its vehicle. One or two chambers
may be filled with a solution containing an active ingredient and
its solvent, also called the vehicle. The positively charged
chamber, called the anode, will repel a positively charged
chemical, whereas the negatively charged chamber, called the
cathode, will repel a negatively charged chemical into the
skin.
[0094] Iontophoresis is well known for use in transdermal drug
delivery. Unlike transdermal patches, this method relies on active
transportation within an electric field. In the presence of an
electric field electromigration and electroosmosis are the dominant
forces in mass transport. These movements are measured in units of
chemical flux, commonly .mu.mol/cm2 h. As described herein,
iontophoresis may be used in conjunction with a patch of this
invention for "permeation enhancement" of an active ingredient
(FIG. 2).
[0095] At the same time, the active ingredient must not penetrate
so effectively through the skin as to be rapidly lost to the
systemic circulatory systems, as shown for example in FIG. 2 where
the lidocaine solution is not entering the blood stream. Thus, the
ideal vehicle would also enhance the skids ability to retain the
pharmacologically active ingredient or, in other words, to increase
skin residence times.
[0096] As used herein, the term "pain-relieving amount" refers to
the amount of any of the active ingredients of this invention that
results in the reduction of pain following its administration to a
subject.
[0097] As used herein, the term "subject" refers to all animals
including humans. Examples of patients or subjects include humans,
cows, dogs, cats, goats, sheep, and pigs. As used herein, the term
"subject" may also be referred to as a "patient".
[0098] The terms "treating" or "treatment" includes, but is not
limited to, the application of the patch comprising a composition
comprising at least on active ingredient to the skin of a patient
to prevent, reduce or inhibit the sensation of pain in the vicinity
or region of the application of the patch. Further, the terms
"treating" or "treatment" as used herein refer to reducing in
severity and/or frequency of symptoms and/or their underlying cause
of neuropathic pain.
II. Patches for Pain Reduction
[0099] The present invention provides patches comprising a low-dose
lidocaine pharmaceutical composition, wherein the lidocaine may act
as an analgesic. In this way, the lidocaine can provide a regional
blockage of nervous pathways that carry pain signals, thereby
reducing pain suffered by a subject. As used herein, the term
"low-dose" refers to an amount of lidocaine less than 5% by weight.
In another embodiment, the term "low-dose" refers to an amount of
lidocaine less than 4% by weight.
[0100] As used herein, "pharmaceutical composition" means a
"therapeutically effective amount" of the active ingredient, e.g.,
lidocaine, together with a pharmaceutically acceptable carrier or
diluent. The pharmaceutical compositions of the present invention
may be a sustained or extended release composition or an immediate
release composition comprising lidocaine. An example of a
pharmaceutical composition of this invention includes a
therapeutically effective amount of lidocaine in a physiologically
acceptable vehicle. As used herein the term "pharmaceutical
composition" may also be referred to herein as a "composition". The
methods to prepare the compositions useful in the present invention
are within the ordinary skill of persons in the art.
[0101] In one embodiment, a composition of this invention is
administered to reduce the intensity of pain in a subject.
[0102] In one embodiment, this invention provides a patch for
transdermal delivery of lidocaine for reducing pain comprising, a
patch comprising a composition comprising a therapeutically
effective amount of lidocaine, wherein the amount of lidocaine is
less than 4 percent by weight. As used herein, the term "lidocaine"
may also be referred to herein as the "analgesic" or "local
analgesic".
[0103] The patches of this invention employ lidocaine as an active
ingredient in a form capable of transdermal transport into the
dermis or deeper. In one embodiment, the lidocaine can be
formulated at least in part, as the free base. In another
embodiment, lidocaine active ingredients can be formulated as
neutralized pharmaceutically acceptable salt forms.
Pharmaceutically acceptable salts include the acid addition salts,
which are formed with inorganic acids such as, for example,
hydrochloric, sulfuric or phosphoric acids, or such organic acids
as acetic, oxalic, tartaric, mandelic, citric and the like. Salts
formed from the free carboxyl groups can also be derived from
inorganic bases such as, for example, sodium, potassium, ammonium,
calcium, or ferric hydroxides, and such organic bases as
isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine,
procaine, and the like.
[0104] The patch delivery system of this invention comprises a
composition comprising a low-dose of lidocaine. As used herein, the
terms "dose" or "dosage" refer to the measured quantity of an
active ingredient administered at one time. As used herein, the
term "dosage" may also herein be referred to as "dose" or "amount".
In one embodiment, the composition comprises less than 4 percent
lidocaine by weight. In one embodiment, the amount of lidocaine is
between 1 percent and 3.95 percent. In another embodiment, the
amount of lidocaine is about 1 percent. In yet another embodiment,
the amount of lidocaine is about 2 percent. In still another
embodiment, the amount of lidocaine is about 3 percent. In a
further embodiment, the amount of lidocaine is 3.95 percent.
[0105] In yet another embodiment, the patches of the present
invention can further include one or more additional compatible
active ingredients which are aimed at providing the composition
with another pharmaceutical effect in addition to that provided by
lidocaine. "Compatible" as used herein means that the components of
such a composition are capable of being combined with each other in
a manner such that there is no interaction that would substantially
reduce the efficacy of the composition under ordinary use
conditions.
[0106] Such additional active ingredients include, but are not
limited to penetration enhancers, and agents that reduce skin
discomfort such as anti-inflammatory agents. In one embodiment, a
combination of local anesthetics, such as are known in the art, can
be comprised in a single patch.
[0107] In one embodiment, the patch of the present invention is
infused with penetration enhancers or permeation enhancing agent
which aid in treatment effectiveness by facilitating delivery of
the lidocaine. The term "penetration enhancer" as used herein
refers to an agent known to accelerate the delivery of a substance
through the skin. Suitable penetration enhancers usable in the
present invention include, but are not limited to,
dimethylsulfoxide (DMSO), dimethyl formamide (DMF), allantoin,
urazole, N,N-dimethylacetamide (DMA), decylmethylsulfoxide
(C.sub.10 MSO), polyethylene glycol monolaurate (PEGML), propylene
glycol (PG), propylene glycol monolaurate (PGML), glycerol
monolaurate (GML), lecithin, the 1-substituted
azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark
Azone.RTM. from Whitby Research Incorporated, Richmond, Va.),
alcohols including menthol, and the like. In one embodiment, the
permeation enhancement agent is menthol.
[0108] The permeation enhancer may also be a vegetable oil. Such
oils include, for example, safflower oil, cottonseed oil and corn
oil. Additional penetration enhancers may generally be found in
Remington's Pharmaceutical Sciences, 18.sup.th or 19.sup.th
editions, published by the Mack Publishing Company of Easton, Pa.
which is incorporated in full herein by reference.
[0109] In one embodiment, the patch of this invention further
comprises a permeation enhancement agent in an amount effective to
enhance treatment. In certain embodiments, the permeation
enhancement agent is a component of the composition. In alternate
embodiments, the permeation enhancement agent is an active
ingredient. In some embodiments, the composition of this invention
comprises a permeation enhancement agent. In another embodiment,
the permeation enhancement agent is menthol.
[0110] As used herein, the term "enhance treatment" refers to an
amount of a permeation agent needed to enhance the permeation of an
active ingredient, to enhance the reduction of pain experienced by
a subject or to reduce side effects including skin discomfort
resulting from administration of a patch of this invention, or any
combination thereof. The term "enhance treatment" may herein also
be referred to as "increase effective treatment". Enhanced
treatment may result in an increase of an active ingredient
permeating the skin. Alternatively, enhancement may result in a
more rapid rate of an active ingredient permeating the skin then
would occur without such treatment.
[0111] In one embodiment, a treatment-enhancing amount of a
permeation enhancing agent can be about 1 percent to about 5
percent. In another embodiment, a treatment-enhancing amount of a
permeation enhancing agent can be about 1 percent to about 16
percent. In yet another embodiment, a treatment-enhancing amount of
a permeation enhancing agent can be about 3-5 percent, wherein
these percentages are expressed as weight per weight of the
composition comprised in the patch. In another embodiment, the
permeation enhancement agent is menthol.
[0112] As used herein, reference of a percent amount of an active
ingredient "by weight", herein refers to the percent expressed as
weight per weight of the composition comprised in the patch.
[0113] The patch of the present invention also can be infused with
an anti-inflammatory agent to reduce skin discomfort. As used
herein "inflammation" refers to a response to infection and injury
in which cells involved in detoxification and repair are mobilized
to the compromised site by inflammatory mediators. Thus, the body's
response may include edema, vasodilation, fever and pain. The term
"skin discomfort" is used herein to refer to burning, stinging,
itching, tingling, loss of feeling or heightened sensitivity of the
skin. "Steroidal anti-inflammatory agent", as used herein, refer to
any one of numerous compounds containing a 17-carbon 4-ring system
and includes the sterols, various hormones (as anabolic steroids),
and glycosides. Representative examples of steroidal
anti-inflammatory drugs include, without limitation,
corticosteroids such as hydrocortisone, hydroxyltriamcinolone,
alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone
dipropionates, clobetasol valerate, desonide, desoxymethasone,
desoxycorticosterone acetate, dexamethasone, dichlorisone,
diflorasone diacetate, diflucortolone valerate, fluadrenolone,
fluclorolone acetonide, fludrocortisone, flumethasone pivalate,
fluosinolone acetonide, fluocinonide, flucortine butylesters,
fluocortolone, fluprednidene (fluprednylidene) acetate,
flurandrenolone, halcinonide, hydrocortisone acetate,
hydrocortisone butyrate, methylprednisolone, triamcinolone
acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone,
difluorosone diacetate, fluradrenolone, fludrocortisone,
difluorosone diacetate, fluradrenolone acetonide, medrysone,
amcinafel, amcinafide, betamethasone and the balance of its esters,
chloroprednisone, chlorprednisone acetate, clocortelone,
clescinolone, dichlorisone, diflurprednate, flucloronide,
flunisolide, fluoromethalone, fluperolone, fluprednisolone,
hydrocortisone valerate, hydrocortisone cyclopentylpropionate,
hydrocortamate, meprednisone, paramethasone, prednisolone,
prednisone, beclomethasone dipropionate, triamcinolone, and
mixtures thereof. In one embodiment, a patch of this invention
includes at least one anti-inflammatory agent. In another
embodiment, a patch of this invention does not include an
anti-inflammatory agent.
[0114] Preferably, the additional active ingredients are added in a
treatment-enhancing amount. As used herein a "treatment-enhancing
amount" refers to an amount that is effective to accomplish the
desired effect. Typically, such an effective amount is an amount
between about 0.1 up to about 10 percent as weight per weight of
the composition. More typically a treatment-enhancing amount would
be between about 1 to about 5 percent. In one embodiment, the patch
and methods of this invention comprise lidocaine and additional
active ingredients in a treatment-enhancing amount.
[0115] Preferably, a treatment-enhancing amount of
anti-inflammatory agent used to reduce skin discomfort is about 1
percent to about 5 percent, preferably about 1 percent to about 3
percent, and most preferably about 1 percent, wherein these
percentages are expressed as weight per weight of the
composition.
[0116] In other embodiment, the patch of the present invention can
be used in conjunction with rehabilitation modalities, such as
ultrasound, magnetophoresis, iontophoresis or a battery powered
electronic stimulant. As used herein, the term "magnetophoresis"
refers to the motion of dispersed magnetic particles relative to a
fluid under the influence of a magnetic field. Magnetophoresis may
provide enhancing drug delivery across biological barriers,
including intact skin, as illustrated in FIG. 2. Introduction of a
drug or additional active ingredient through intact skin by the
application of a direct electric current in iontophoresis may
provide enhanced drug delivery when used in combination with a
patch of this invention. In other embodiments, other patches
described herein may be used in combination with iontophoresis. In
one embodiment, iontophoresis acts as a transdermal delivery system
in which a substance bearing a charge is propelled through the skin
by a low electrical current. This method can be used to drive a
drug across the skin barrier, as is done with pilocarpine to
stimulate sweating in the sweat chloride test for cystic fibrosis.
Iontophoresis can also be used in the reverse direction to draw a
molecule such as glucose through the skin.
[0117] Methods utilizing electromotive enhancement treatments such
as iontophoresis or magnetophoresis can provide faster relief to a
subject, can increased an amount of an active ingredient
penetrating into the skin or deeper tissue, can lead to an active
ingredient penetrating deeper than the skin layers (epidermis,
dermis), can provide longer relief from pain, can provide extended
relief from pain or can provide stronger relief from pain, or any
combination thereof. For example, in one embodiment, dependent on
the strength of the charge used a drug may enter into skin and
additionally into blood vessel found deeper under the skin.
[0118] In an additional embodiment, the patch of the present
invention can be used in conjunction with rehabilitation therapies,
such as heat, massage, manipulation, strength and stretching
exercises, to maximize healing results with the elimination of
muscle pain and spasm.
III. Patch Administration for Pain Reduction
[0119] Patches of the present invention have been described above.
The patches can be administered at or adjacent to a site of pain to
provide relief. In one embodiment, the pain is neuropathic pain,
wherein administration of a patch of this invention reduces the
neuropathic pain felt by a subject. In another embodiment, the pain
is osteoarthritis pain, wherein administration of a patch of this
invention reduces the osteoarthitic pain felt by a subject. In yet
another embodiment, the pain is back pain, wherein administration
of a patch of this invention reduces the back pain felt by a
subject. In still another embodiment, the pain is a result of bone
degeneration, wherein administration of a patch of this invention
reduces the bone degeneration pain felt by a subject. In a further
embodiment, the pain is associated with fibromyalgia, wherein
administration of a patch of this invention reduces the pain
associated with fibromyalgia felt by a subject. In another
embodiment, the pain is associated with muscle strain, wherein
administration of a patch of this invention reduces the muscle
strain pain felt by a subject. In yet another embodiment, the pain
is associated with muscle sprain, wherein administration of a patch
of this invention reduces the muscle sprain pain felt by a subject.
In still another embodiment, the pain is that associated with
carpal tunnel syndrome pain, wherein administration of a patch of
this invention reduces the carpal tunnel syndrome pain felt by a
subject. In a further embodiment, the pain is that associated with
any combination of diseases or disorders able to be relieved by
local and/or deep tissue pain relief, wherein administration of a
patch of this invention reduces the pain felt by a subject.
[0120] In one embodiment, a method for reducing pain in a subject
comprises applying on a skin surface of the subject, at or near the
site of pain, a patch comprising a lidocaine composition, wherein
the application provides for transdermal delivery of an amount of
lidocaine sufficient to reduce neuropathic pain in the subject. The
methods of this invention may reduce pain resulting from different
diseases, disorders or condition including neuropathic pain,
osteoarthritis pain, back pain, degenerative bone pain, pain
associated with carpal tunnel syndrome, pain associated with
fibromyalgia, pain associated with muscle strain or pain associated
with muscle sprain or any combination thereof.
[0121] As used herein, the term "administration" refers to
applying, e.g., adhering a patch comprising a lidocaine formulation
on a skin surface of a subject.
[0122] In one embodiment, administration of a patch provides
immediate or nearly immediate relief, e.g., reduction of pain. In
another embodiment, administration of a patch provides long term
relief, e.g., reduction of pain. In yet another embodiment,
administration of a patch provides both immediate or nearly
immediate and long-term relief, e.g., reduction of pain.
[0123] The patches described herein can be administered at or
adjacent to the sites of pain to provide relief. The patches can be
administered once a day, for example, for fast, long term pain
relief, e.g., pain relief is starts relatively quickly and is
maintained over an extended period of time. As used herein the
terms "reduction of pain" and "pain relief" are interchangeable
with all the same meanings. In one embodiment, application of a
patch may reduce the pain suffered by a subject completely or
almost completely. In another embodiment, application of a patch
may reduce the pain suffered by a subject by about 50 to almost 100
percent. In yet another embodiment, application of a patch may
reduce the pain suffered by a subject by about 50 to 90 percent. In
still another embodiment, application of a patch may reduce the
pain suffered by a subject by about 80 to 90 percent. In a further
embodiment, application of a patch may reduce the pain suffered by
a subject by about 70 to 80 percent. In one embodiment, application
of a patch may reduce the pain suffered by a subject by about 50 to
70 percent. In still another embodiment, application of a patch may
reduce the pain suffered by a subject by less than 50 percent.
[0124] In one embodiment a patch of this invention is applied for
between about 8 to 12 hours. In one embodiment a patch is applied
for about 8 hours. In another embodiment a patch is applied for
about 9 hours. In yet another embodiment, a patch is applied for
about 10 hours. In still another embodiment, a patch is applied for
about 11 hours. In a further embodiment, a patch is applied for
about 12 hours.
[0125] A patch of the present invention is applied on the skin
surface at a site or adjacent to a painful region. In some
embodiments, multiple patches may be applied at the same time.
Patches may be applied in the same region, an adjacent region or
regions distal from one another. Fresh patches may be reapplied
after a 24 hour period counted from the time the previous patch was
administered.
[0126] In some embodiments, the patch is applied to the painful
skin and subcutaneous structures in order to effect pain relief
while avoiding the side effects associated with systemic delivery.
Pain relief is obtained within minutes to hours and lasts for
periods of approximately three to six hours to 24 hours. The
patches are applied such that the dosage is sufficient to provide
an effective dose in the painful area or immediately adjacent
areas, to ameliorate or eliminate pain and other unpleasant
sensations such as itching. In one embodiment, pain is reduced for
at least 12 hours. In another embodiment, pain is reduced for at
least 24 hours. In yet another embodiment, pain is reduced for more
than 24 hours.
[0127] The appropriate dosages for pain treatment by way of patches
of the present invention are determined by a variety of factors.
The rate at which the active components are absorbed is a function
of skin permeability. Skin permeability varies between different
sites on a patient's body and depends on the thickness of the
stratum corneum. The stratum corneum is the outer-most layer of
skin and is the main source of penetration and permeation
resistance for dermally administered drugs. For example, the
permeability, in general, increases in order from planter foot
arch, lateral ankle, palm, ventral forearm, dorsal forearm, back,
chest, thigh, abdomen, scalp, axilla, forehead, and scrotum; see R.
C. Wester. & H. I. Maibach, Regional variation in Percutaneous
Absorption, in Percutaneous Absorption, Mechanism, Methodology,
Drug Delivery 111-119 (R. L. Bronaugh & H. I. Maibach eds., 2nd
ed. 1989), hereby expressly incorporated in full herein by
reference.
[0128] The delivery rate of an active ingredient from a patch,
e.g., lidocaine, of the present invention that is required for
proper pain relief is determined by a variety of factors. One
important factor regarding delivery rate is the surface areas of
the active ingredients in contact with a patient's skin. In
general, the larger the contact surface area, the higher the rate
of delivery. Different delivery rates of an active ingredient may
be needed depending on the severity of pain felt. The surface areas
of components can adjusted to provide the desired delivery rate of
an active ingredient to a patient.
[0129] In addition, delivery rate may be enhanced as describe above
using chemical enhancement agents, for example menthol and/or
physical enhancement methodologies, for example iontophoresis, a
battery powered electronic stimulant or magnetophoresis. In one
embodiment, methods of this invention for reducing neuropathic pain
include treatment enhancing amounts of a permeation agent. In one
embodiment, methods of this invention for reducing neuropathic pain
include treatment enhancing methodologies including iontophoresis,
a battery powered electronic stimulant or magnetophoresis.
[0130] Methods of this invention include transdermal administration
of active ingredients, e.g., lidocaine.
[0131] In one embodiment, methods of this invention for reducing
pain in a subject comprise applying on a skin surface of the
subject, at or near the site of pain a patch comprising
compositions comprising lidocaine at less then 4 percent by weight.
In another embodiment, methods of this invention use lidocaine at
between 1 and 3.95 percent by weight. In yet another embodiment,
methods of this invention use lidocaine at 1 percent by weight. In
still another embodiment, methods of this invention use lidocaine
at 2 percent by weight. In a further embodiment, methods of this
invention use lidocaine at 3 percent by weight. In one embodiment,
methods of this invention use lidocaine at 3.95 percent by
weight.
[0132] In one embodiment the composition of this invention
comprises local anesthetic and drugs not traditionally associated
with local anesthetic properties but which have a local anesthetic
effect. Non limiting examples of such drugs include for example,
non-narcotic analgesics, such as, acetylsalicylic acid, ketoprofen,
piroxicam, diclofenac, indomethacin, ketorolac, rofecoxib, and
celecoxib, and pharmaceutically acceptable salts thereof, or
mixtures thereof.
[0133] As used herein the term "drug" refers to a substance used in
the diagnosis, treatment, or prevention of a disease or medical
condition or an active component of a medication. Of course, the
term "drug" encompasses local anesthetics and/or analgesics. In one
embodiment, a drug of this invention is lidocaine.
[0134] Reference is made to FIG. 1 at 100. A first step in any
treatment method of this invention may be selection of an
appropriate patch for reduction of the pain suffered by a subject.
Patches may be cut to the size and shape need to administer an
appropriate dose and/or cover a particular surface of skin (See
FIG. 1, step 102). For instance, an appropriate patch may be
perforated to provide flexibility.
[0135] Following this, a patch may be applied to the skin surface
for an effective time period (See FIG. 1, step 104). For effective
use, a patch should be in contact with a surface of the skin and
remain in place for the duration of the treatment. In order that a
patch remains in place, an adhesive may be comprised as part of a
patch. Alternatively, an adhesive, such as an adhesive strip or
tape may be used to hold the patch in place. For example, a patch
may be adhered to a patient's back through the use of a
drug-in-adhesive patch. In an alternative example, a patch may both
included an adhesive and be perforated to allow the patch to
stretch, wherein a patch may be wrapped fully or partially around a
subject's body appendage, e.g., a leg, arm, finger or neck.
[0136] The selected patch may comprise a composition comprising
permeation enhancers. Alternatively, physical methodologies such as
iontophoresis, a battery powered electronic stimulant or
magnetophoresis may be employed to enhance the permeation of at
least one active ingredient. Examples of drug delivery by
iontophoresis are shown in FIG. 2. Technique using a small electric
charge to deliver active ingredient through the skin, e.g.,
iontophoresis, may enhance permeation of at least one active
ingredient. Iontophoresis may be imagined to be an injection
without the needle. The process is a non-invasive method of
propelling high concentrations of a charged substance, e.g.,
lidocaine, transdermally by repulsive electromotive force using a
small electrical charge applied to an iontophoretic chamber
containing a similarly charged active agent and its vehicle."
[0137] Following the recommended time period of application, the
patch may be removed from the skin surface (See FIG. 1, step 106).
Relief from pain may continue even though the patch has been
removed. Following a period of 24 from the initial administration,
this cycle of use may employed by a subject. This may be
significant for sufferers of chronic pain.
[0138] In one embodiment, the term "a" or "one" or "an" refers to
at least one. As used in the specification and claims, the forms
"a," "an" and "the" include singular as well as plural references
unless the context clearly dictates otherwise.
[0139] In one embodiment the phrase "two or more" may be of any
denomination, which will suit a particular purpose. In one
embodiment, "about" may comprise a deviance from the indicated term
of +1%, or in some embodiments, -1%, or in some embodiments,
.+-.2.5%, or in some embodiments, .+-.5%, or in some embodiments,
.+-.7.5%, or in some embodiments, .+-.10 to %, or in some
embodiments, .+-.15%, or in some embodiments, .+-.20%, or in some
embodiments, .+-.25%.
[0140] While certain features of the invention have been
illustrated and described herein, many modifications,
substitutions, changes, and equivalents will now occur to those of
ordinary skill in the art. It is, therefore, to be understood that
the appended claims are intended to cover all such modifications
and changes as fall within the true spirit of the invention.
* * * * *