Note: Descriptions are shown in the official language in which they were submitted.
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~IEI~D OF THE INVENTIONS
This invention relates to the preparation of a
transdermal delivery system. The preparations is designed
to deliver therapeutic levels of a drug to specific sites
below the dermal level of the skin including, but not
limited to, knees, ankles, hands, feet, and neck.
DRUG PREPARATIONS
nF~rRrpTrc~N OF THE PRIOR ART
Over the years, methods have been developed to achieve
the efficient delivery of a therapeutic drug to a mammalian
body part requiring pharmaceutical treatment. Use of an
aqueous liquid which can be applied at room temperature as
a liquid but which forms a semi-solid gel when warmed to
body temperature has been utilized as a vehicle for some
drug delivery since such a system combines ease of
application with greater retention at the site requiring
treatment than would be the case if the aqueous composition
were not converted to a gel as it is warmed to mammalian
body temperature. In the U.S. Patent No. 4,188,373,
PLURONIC~ polyols are used in aqueous compositions to
provide thermally gelling aqueous systems. Adjusting the
concentration of the polymer provides the desired sol-gel
transition temperature, that is, the lower the
concentration of polymer, the higher the sol-gel transition
temperature, after crossing a critical concentration
minimum, below which a gel will not form.
In U.S. Patent Nos. 4,474,751 and 4,478,822 drug
delivery systems are described which utilize thermosetting
gels; the unique feature of these systems is that both the
gel transition temperature and/or the rigidity of the gel
can be modified by adjusting the pH and/or the ionic
strength, as well as by the concentration of the polymer.
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Other patents disclosing pharmaceutical compositions
which rely upon aqueous gel composition as a vehicle for
the application of a drug are U.S. Patent Nos. 4,883,660;
4,767,619; 4,511,563; 4,861,760; and 5,318,780.
Thermosetting gel systems are also disclosed for
application to injured mammalian tissue of the thoracic or
peritoneal cavities in U.S. Patent No. 4,911,926.
Ionic polysaccharides have been used in the
application of drugs by controlled release. Such ionic
polysaccharides as chitosan or sodium alginate are
disclosed as useful in providing spherical agglomerates of
water-insoluble drugs in the Journal of Pharmaceutical
Science, Volume 78, Number 11, November 1989, Bodmeier et
al. Calcium alginate gel formulations have also found use
as a matrix material for the controlled release of
herbicides, as disclosed in the Journal of Controlled
Release,(1986), pages 229-233, Pfister et al.
In U.S. Patent No. 3,640,741, a molded plastic mass
composed of the reaction product of a hydrophilic colloid
and a cross-linking agent such as a liquid polyol, also
containing an organic liquid medium such as glycerin, is
disclosed as useful in the controlled release of medication
or other additives. The hydrophilic colloid can be
carboxymethyl cellulose gum or a natural alginate gum
which is cross-linked with a polyol. The cross-linking
reaction is accelerated in the presence of aluminum and
calcium salts.
In U.S. Patent No. 4,895,724, compositions are
disclosed for the controlled release of pharmacological
macromolecular compounds contained in a matrix of chitosan.
Chitosan can be cross-linked utilizing aldehydes,
epichlorohydrin and benzoquinone.
In U.S. Patent No. 4,795,642, there are disclosed
gelatin-encapsulated, controlled-release compositions for
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release of pharmaceuticals compositions, wherein the
gelatin encloses a solid matrix formed by the cation-
assisted gellation of a liquid filling composition
incorporating a vegetable gum together with a
pharmaceutically-active compound. The vegetable gums are
disclosed as polysaccharide gums such as alginates which
can be gelled utilizing a cationic gelling agent such as
an alkaline earth metal cation.
While the prior art is silent with respect to aqueous
drug delivery vehicles and isotonicity thereof, osmotic
drug delivery systems are disclosed in U.S. Patent No.
4,439,196 which utilize a multi-chamber compartment for
holding osmotic agents, adjuvants, enzymes, drugs, pro
drugs, pesticides, and the like. These materials are
enclosed by semipermeable membranes so as to allow the
fluids within the chambers to diffuse into the environment
into which the osmotic drug delivery system is in contact.
The drug delivery can be sized for oral ingestion,
implantation, rectal, vaginal, or ocular insertion for
delivery of a drug or other beneficial substance. Since
this drug delivery device relies on the permeability of the
semipermeable membranes to control the rate of delivery of
the drug, the drugs or other pharmaceutical preparations by
definition, are not isotonic with mammalian blood.
To date, prescriptions pain and anti-inflammatory
medications which have been formulated for topical use have
not been approved for sale in the United States. This is
due in part to their lack of efficacy and a formulation
failure to demonstrate measurable amounts of drug in the
blood and urine of patients treated with these
preparations. Thus, proof of their ability to be
transdermally transported through the skin has been
heretofore unsuccessful.
In contrast, over-the-counter drugs which include
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counter-irritants such as menthol, eucalyptus, and camphor
are solid for mild relief of minor problems. These
products are designed to counter-irritation and are not
intended for deep penetration of tissue structures below
the skin, namely into areas which include joints,
ligaments, tendons and cartilage. The over-the-counter
drugs described above may be purchased without
prescription.
A need thus exists for the administration of active
therapeutic agents that can be applied topically and
transported through the skin.
SUI~IARY OF THE INVENTION
The present invention relates a semi-solid
supersaturated solution of hyaluronic acid and its salts,
as well as methods of making and using these solutions to
treat skin wounds. More particularly, this invention
relates a method for preparing a sustained-release delivery
composition which comprises dissolving hyaluronic acid and
its salts in water to provide a first aqueous solution
substantially saturated with hyaluronic acid and its salts;
concentrating the first aqueous solution by removing
between about 10 percent by weight and about 70 percent by
weight of the water from said first aqueous solution,
thereby converting the first aqueous solution to a
semisolid, sustained-release delivery composition
containing hyaluronic acid and its salts; and recovering
the sustained-release delivery composition including the
semisolid hyaluronic acid and its salts.
Another embodiment of this invention involves a
semisolid supersaturated solution of hyaluronic acid and
its salts having sustained drug delivery.
An alternative embodiment of this invention
involves a method for preparing a sustained-release
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delivery composition which comprises dissolving hyaluronic
acid and its salts in water to provide a first aqueous
solution substantially saturated with hyaluronic acid and
its salts; mixing the first aqueous solution with a
pharmaceutically acceptable nonionic polymer to form a
first viscous solution; C. removing about 10 percent to
about 70 seventy percent water from the first viscous
solution thereby converting the first viscous solution to
a semisolid sustained-release delivery composition
containing semisolid hyaluronic acid and its salts; and
recovering the semisolid, sustained-release delivery
composition including the hyaluronic acid and its salts.
An additional embodiment of this invention involves a
method for preparing a sustained-release delivery
composition which comprises dissolving the sodium salt of
hyaluronic acid in water at about 15°C to about 40°C to
provide a first aqueous solution substantially saturated
with the sodium salt of hyaluronic acid; B. mixing the
first aqueous solution with a pharmaceutically acceptable
viscous liquid nonionic polymer which is hydroxy ethyl
cellulose to form a first viscous solution; removing water
from the first viscous solution by heating the first
viscous solution at a temperature between about 20°C and
about 50°C until the sodium salt of hyaluronic acid in the
first viscous solution is converted to the semisolid state
thereby converting the first viscous solution to a
semisolid, sustained-release delivery composition
containing hyaluronic acid and its salts; and recovering
the sustained-release delivery composition including the
semisolid sodium salt of hyaluronic acid.
Another embodiment of this invention involves a method
for treating a skin wound condition in a patient with a
sustained-release drug delivery dressing which comprises a
solid polymer matrix complex comprising an aqueous
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solution; a formable, flexible and moveable sheet of
hyaluronic and its salts; wherein the aqueous solution
comprises hyaluronic acid and its salts in water; and
wherein the sheet of hyaluronic acid is a concentrate of
the aqueous solution.
An alternative embodiment of this invention involves
a method for treating a skin wound condition in a patient
with a sustained-release drug delivery dressing which
comprises applying a formable, flexible and moveable sheet
of hyaluronic and its salts to the area of the skin wound
condition; securing the formable, flexible and movable
sheet to said area with a layer of dressing fixative; and
wherein the sheet of hyaluronic acid is a concentrate of
the aqueous solution.
An additional embodiment of this invention involves
a method for making a sustained-release drug delivery
dressing skin wound dressing with a which comprises
dissolving hyaluronic acid and its salts in water to
provide a first aqueous solution substantially saturated
with hyaluronic acid and its salts; concentrating the first
aqueous solution by removing between about 10 percent by
weight and about 70 percent by weight of the water from
said first aqueous solution, thereby converting the first
aqueous solution to a semisolid, sustained-release delivery
composition containing hyaluronic acid and its salts;
recovering the sustained-release delivery composition
including the semisolid hyaluronic acid and its salts;
further concentrating the sustained-release delivery system
by spreading said delivery system into a dressing mold and
further removing about 1 percent by weight to about 20
percent by weight of the water from the sustained-release
delivery system; and wherein the further concentration of
the sustained-release delivery dressing results in a
formable, flexible and moveable sheet of hyaluronic and its
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salts.
DETAILED DESCRIPTION OF THE INVENTION
It has been unexpectedly discovered that an effective
therapeutically level of a drug may be administered
topically and transdermally delivered through the skin into
various sites where the drug is therapeutically effective.
In order for this to be accomplished, it has been
discovered that the active drug must be suspended or
entrapped in a specially designed polymer matrix containing
a specific molar ratio of negatively charged polymers and
a non-ionic polymer suspended or dissolved in water and
solubilizers.
This system is believed to form a matrix which
microencapsulates, suspends and/or entraps the active drug
entity such that when it is administered, it is slowly
released into the systemic circulatory systems or muscular
tissue providing a method of delivering an active to an
affected site in the body through the skin.
The molar ratio of the polymers present in the matrix
is critical in this invention. It has been found that
molar ratios of the negatively charged polymer to the non-
ionic polymer must be from 1:0.5 to 4, and preferably from
1:0.5 to 2.0, and most preferably from 1:0.7 to 2.5. For
transdermal delivery of drugs, it has been found that
ratios either higher or lower than these levels will result
in a polymer shearing effect which produces unacceptable
turbulence and air pockets in the composition resulting in
loss of potency and efficacy. Furthermore, the solutions
tend to separate and form distinct polymer layers when
ionic molarity is not appropriate.
At least one of the polymers used to form the matrix
of this invention must be sufficiently negatively charged
to aid in the dispersion, encapsulation or solubilization
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of the drug. Particularly preferred polymers which have
average molecular weights below about 800,000 and
preferably molecular weights between 650,000 to 800,000
have been found acceptable to form usable polymer matrixes
for transdermal delivery. Polymer with mean average
molecular weights between 700,000 and 775,000 are most
preferred. Polymers having molecular weights have about
800,000 form solid gels in solution and are unable to serve
as part of a transdermal delivery system. Furthermore, the
polymers must be sterilizable and be stable during
sterilization so that the polymer does not lose molecular
weight once formulated into the final transdermal delivery
form.
Exemplary, non-limiting examples of compounds that may
be used as a source of this molecular weight polymer
include polysulfated glucosoglycans, glucosaminoglycans,
and mucopolysaccharides, derivatives thereof and mixtures
thereof. Particularly preferred mucopolysaccharides are
chondroitin sulfate and hyaluronic acid salts. Exemplary
hyaluronate salts include sodium, calcium, potassium and
magnesium salts with hyaluronate sodium being most
preferred.
Hyaluronic acid (HA) occurs naturally in joint
synovial fluid, where it plays a lubricating role, and may
have biological activity was well. HA is a
mucopolysaccharide, and may alternatively be referred to as
a glycosaminoglycan. The repeating unit of the hyaluronic
acid molecule is a disaccharide consisting of D-glucuronic
acid and N-acetyl-D-glucosamine. Because hyaluronic acid
possesses a negative charge at neutral pH, it is soluble in
water, where it forms highly viscous solutions. The D-
glucuronic acid unit and N-acetyl-D-glucosamine unit are
bonded through a glycosidic, beta (1-3) linkage, while each
disaccharide unit is bonded to the next disaccharide unit
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through a beta (1-5) linkage. The beta (1-4) linkages may
be broken through hydrolysis with the enzyme hyaluronidase.
A variety of substances, commonly referred to as
hyaluronic acid, have been isolated by numerous methods
from various tissue sources including umbilical cords,
skin, vitreous humour, synovial fluid, tumors, haemolytic
streptocci pigskin, rooster combs, and the walls of veins
and arteries. It has also been synthesized artificially
and by recombinant technology.
Conventional methods for obtaining hyaluronic acid
results with a product having differing properties and a
wide range of viscosities. U.S. Patent No. 2,585,546 to
Hadian, discloses an example of a method for obtaining
hyaluronic acid which involves extracting acetone-washed
umbilical cords with a dilute salt solution, acidifying the
resulting extract, removing the colt so formed,
precipitating some hyaluronic acid with protein from the
acidified extract with ammonium sulfate, agitating the
liquid with pyridine, precipitating another fraction highly
contaminated with protein, followed by more ammonium
sulfate which forces some pyridine out of solution along
with the high viscosity hyaluronic acid. The hyaluronic
acid collects at the interface between the two liquid
phases and may be separated by filtration, centrifugation
or another usual procedure. A modification of this process
involves the fractionation of the acidic salt extract from
the umbilical cords with alcohol and ammonium sulfate.
Alcohol is added to the acidic salt extract, and resulting
precipitate is removed. Solid ammonium sulfate is added to
the liquid until saturation and the solution forms two
phases with a precipitate of hyaluronic acid at the
interface.
U.S. Patent No. 4,517,296 to Brace et al. is directed
to the preparation of hyaluronic acid in high yield from
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Streptococcus bacteria under anaerobic conditions in a C0~
enriched growth medium, separating the bacteria from the
resulting broth and isolating hyaluronic acid from the
remaining constituents of the broth. Separation of the
microorganisms from the hyaluronic acid is facilitated by
killing the bacteria with trichloroacetic acid. After
removal of the bacteria cells and concentration of the
higher molecular weight fermentation products, the
hyaluronic acid is isolated and purifies by precipitation,
resuspension and reprecipitation.
One particular fraction of hyaluronic acid (HA) that
exhibits excellent matrix formation according to the
present invention is hyaluronic sodium having a mean or
average molecular weight between 650,000-800,000,
preferably 700,000-775,000 with a high decree of purity,
95-1050 free, and preferably at least 98o pure, from
contamination of related mucopolysaccharides. Furthermore,
this hyaluronic acid has a sulphated ash content of less
than 15o and a protein content of less than 50. Examples
of usable base salts include those safe for animal and
human use, such as sodium, potassium, calcium, and
magnesium salts or the like.
In contrast to HA, chondroitins are
mucopolysaccharides comprising repeating units of D
glucuronic acid and N-acetyl-D-galactosamine. Chondroitin
sulphates are important components of cartilage and bone
and are excellent for preparing the polymer matrix herein.
The negative charged polymers are generally present in
the system in amounts which enables a solid gel to be
formed. Generally, gels are formed using amounts of about
2.0 to about 4.0o by weight with amounts of about 2.1 to
about 2.5o by weight being preferred for use as a topical
gel.
The solutions used to prepare the gel of the present
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invention may be prepared in a variety of ways. For
example, the polymers may be dissolved in water and
purified either separately or jointly and then the optional
active drug added to the system.
A particularly preferred procedure involves separately
dissolving the nonionic polymer in water and centrifuging
the material to form a solution and then removing
impurities. This may be conveniently done at rotation
speeds of 2000 rpm for times of about 30 minutes to about
two hours.
In contrast, the negative charged polymer may be
blended and stirred in water until it is dissolved. This
process must be done while avoiding the formation of
bubbles and while freeing the polymer of its electrostatic
activity. Furthermore, the molecular weight of the polymer
must not be significantly changed during processing and as
such mild process conditions are required. Processing
conditions of 400 - 3000rpm for durations of 16-24 hours
have been found acceptable to produce stable solutions or
gels of the charged polymer.
Conventional pharmaceutically acceptable emulsifiers,
suspending agents, antioxidant (such as sodium meta-
bisulfate) and preservatives (such as benzyl alcohol)may
then be added to this system. Once all the components are
blended together, such as by mixing at 400-3000 rpm for one
to four hours, the system is filled into tubes and
sterilized. The resulting system is a clear gel which is
storage stable for several years.
The drug may be added to the homogenous solution or
gel separately once dissolved or disbursed in water.
Emulsifiers, suspending agents and preservatives may then
be added to this system. One particularly nonlimiting
effective material for solubilizing water insoluble drugs
is methoxypolyethleneglycol (MPEG). Once all the
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components are blended together, at 400 - 3000rpm for 1 to
4 hours, the system is filled into tubes and sterilized.
The resulting system is storage stable for several years.
The formulations may be used topically and also
contain conventional pharmaceutical acceptable excipients
well known to those skilled in the art, such as
surfactants, suspending agents, emulsifiers, osmotic
enhancers, extenders and dilutants, pH modifiers as well as
fragrances, colors, flavors and other additives.
As indicated above, the active drug agents may be
blended with the aqueous polymer matrix at the time of
manufacture. As such, the drug when in the form of a water-
soluble solid is simply diluted with sterilized water or
polymer matrix solution and prepared in gel form.
The dosage system can be formed with or without the
use of pharmaceutically acceptable preservatives. A
significant advantage of the dosage form of the present
system relates to its ability to allow the drug to slowly
diffuse through tissue when administered thus allowing for
an effective therapeutic dose to be present for many hours.
In this regard, it should be noted that reference to
therapeutically effective doses does not necessarily relate
to conventional dosage levels, but does relate to drug
levels that achieve an effective therapeutic level at the
dose employed, which may be the same level but not at the
same frequency of administration previously required for
drugs taken orally or by injection. This not only
significantly reduces the number of doses required to
achieve the same effect, but it also reduces costs,
maintenance and health hazards associated with conventional
treatment therapies. Additionally, it results in immediate
and continued drug release for long periods of time
spanning several hours in duration.
Doses may vary from patient to patient depending on
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the type and severity of the condition being treated and
the drug being administered. Generally, doses of 1 ml to
75 ml may be administered with preferred doses using 2 to
25 ml of the gelled matrix system.
PAIN APPLICATIONS
The formulations of this invention may be used to
treat a variety of mammal and animal conditions and
physical state. One system having a particular application
relates to pain management, namely the prevention,
treatment and alleviation of pain associated with any
disease condition or physical state.
Without being limited to the specific pain treated,
the preparations of this invention may treat the following
nonlimiting locations or sources of pain below the dermal
level of the skin, including, but not limited to knees,
ankles, hands, feet and neck.
The importance of this invention becomes apparent when
one considers the side-effects associated with
conventional, oral drugs for treating osteoarthritis,
including NSAIDs such as diclofenac.
Typically, NSAIDs have been known to produce gastric
and intestinal irritation. In addition, scarring and
ulceration of intestinal tract is quite common in patients
on short- or long-term NSAID therapy. Unfortunately, there
do not appear to be many alternatives to NSAID therapy, for
patients suffering from extremely painful, inflammatory
conditions which may include osteoarthritis and other
inflammatory disorders. Thus, new NSAIDs are constantly
entering the marketplace, each one, however, with the same
potential to cause unpleasant and often serious side-
effects .
The transdermal applications of NSAIDs and
particularly diclofenac described herein, are a much safer
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way of treating inflammatory disorders including those
related to osteoarthritis also known as Degenerative Joint
Disease (DJD).
When a person takes an oral form of diclofenac,
typically 100 mg to 150 mg per day, the drug must be
circulated through systemic blood and only a small amount
ends up in the specific site that is intended for
treatment, such as the knee. Individuals with
osteoarthritis are generally treated with NSAIDs including,
but not limited to, diclofenac, ibuprofen, Aspirin, etc.,
which as previously mentioned produce an anti-inflammatory
effect at the joint level. At therapeutic dosages for
diclofenac which are usually between 100 mg and 200 mg per
day, more than 50o of all treated patients will experience
some form of GI (gastrointestinal) distress.
The transdermal delivery system described herein
offers a major alternative especially for those individuals
who have a history of undesirable side-effects associated
with gastric and intestinal irritation. Also for those
patients who have already suffered damage, including
ulceration and loss of absorption from the intestinal
tract, the transdermal preparations described herein
present a new way of providing effective treatment and
relief of painful symptoms. It has become common practice
of rheumatologists and other specialists treating
osteoarthritis and associated disorders to use ulcer-type
drugs of the H2 blocking variety including, but not limited
to, ranitidine (Zantac), Pepsid and cimetidine (Tagamet) by
Smith Kline. The addition of these drugs to already high
regiments "(polypharmacy)" of therapeutic agents is not
desirable since these drugs often produce their own
undesirable side-effects. Although an occasional patient
will experience mild stomach upset from the transdermal
preparation described herein, the effect is transient and
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of mild severity. In addition, patients treated with the
present transdermal diclofenac, find that they can function
for longer periods of time (4 to 6 hours) and can simply
apply more of the therapeutic gel to maintain a continuous
reduction in pain and inflammation. In this way, patients
who apply the drug topically 3 to 4 times a day can
experience sustained around-the-clock relief.
Several attempts have been made in the past to produce
effective transdermal preparations. These preparations
have not been approved in North America for some drugs,
like diclofenac, by the regulatory authorities as of this
time. Some of the reasons cited are lack of proven
transdermal delivery. In the case of the current
invention, transdermal delivery can be substantiated by:
1. Measurable blood levels of diclofenac.
2. Diclofenac presence in the urine of patients
treated with the transdermal drug.
3. The pressure of diclofenac in synovial fluid
where joints with synovial fluid are the target
sites for treatment.
4. Rapid absorption following topical
administration.
5. Rapid relief of painful symptoms in a significant
number of patients already being treated with the
products.
In Europe, Voltaren cream (Ciba-Geigy) is popular for
the treatment of osteoarthritic conditions. This
preparation contains diclofenac sodium. However, the
manufacturers have not demonstrated to the satisfaction of
North American regulators a proven ability of the cream to
be transdermally absorbed. Amounts of diclofenac delivered
by the cream are considered to be minimal at best.
It should be pointed out that diclofenac, as the
sodium or potassium salt, is a benzeneacetic acid
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derivative, designated chemically as 2-[2,6-di-
chlorophenyl)amino] benzeneacetic acid, monosodium or
monopotassium salt. It is freely soluble in methanol,
soluble in ethanol, and practically insoluble in chloroform
and in dilute acid. Diclofenac sodium is sparingly soluble
in water while diclofenac potassium is soluble in water.
Diclofenac, the anion in Voltaren~ and Calaflam~, is a
nonsteroidal anti-inflammatory drug (NSAID). In
pharmacologic studies, diclofenac has shown anti-
inflammatory, analgesic, and antipyretic activity. As with
other NSAIDs, its mode of action is not know; its ability
to inhibit prostaglandin synthesis, however, may be
involved in its anti-inflammatory activity, as well as
contribute to its efficacy in relieving pain related to
inflammation and primary dysmenorrhea. With regard to its
analgesic effect, diclofenac is not a narcotic.
The current invention represents a break-through in
that for the first time measurable, detectable levels of
diclofenac can be delivered to affected sites. For those
patients who experience mild intestinal discomfort
following administration, it is recommended that the
transdermal gel preparation described herein, be
administered after meals.
In addition to the negatively charged polymers, the
transdermal polymer matrix must contain a non-ionic polymer
which facilitates in retarding the absorption of the active
drug through the skin and delays or slows down the natural
absorption of the negatively charged polymer in an animal.
Without the presence of this component, the active
drug would not be delivered transdermally into the site
targeted for treatment at levels which are therapeutically
effective. In addition to the non-ionic polymers described
in this system, these materials are necessary to provide
thorough penetration of skin layers including the
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epidermis, dermis and fatty tissue layers. Evidence of
this absorption through the skin layers and into the
capillary bed and ultimately the systemic system is
evidenced by the fact that detectable, measurable blood
levels of active drug, such as diclofenac, can be found in
the urine of patients treated with the diclofenac
transdermal preparation described herein.
TEST PROCEDURE I
Patient LHN's complaint is of headache and pain in the
back of the neck.
Histor~m
She has been getting headaches for 30 years since she
was 5-years-old. She has several injuries in the past,
including many which resulted from being thrown down some
stairs.
In 1996, it was noted that the headaches were
bifrontal, sometimes behind the eyes and also in the sides
of the head and in the parietal region. They were often
associated with nausea and vomiting.
In June 1996, her headache was frontal, occipital and
in the left shoulder going down the left arm, and she also
had low back ache.
physical Examina iom
She was tender over the right cervical facets at 2-3,
4-5 and 5-6 and on the left at 2-3 and the greater
occipital nerve bilaterally.
Diaano~,i ~
Cervicogenic headaches.
This was confirmed by diagnostic blocks bilaterally at
2-3, 3-4 and 4-5 which reduced her head and neck pain
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respectively of 6/10 and 10/10 to 0/10.
'~'1~Patmar~i- Tnl; +h D"-.i «~r,~ _
1
This was rubbed on the facet joint areas of the
cervical spine bilaterally. The patient noticed marked
decrease of pain in the neck 4 to 8 hours after use.
When the gel was used 2 to 3 times daily, the
generalized neck ache was markedly reduced. In addition,
some of her headaches were also decreased. It was noted
that there was no skin irritation with the use of the gel.
TEST PROCEDURE II
This is a 32-year-old man who complains of headaches.
History
He complains of headaches in the right upper neck
radiating to the right parietal region, the right eye, the
right temporal region. They are aching and stabbing with
a severity between 6-10/10. They are always present but
the severity varies. They have occurred since he had a
motor vehicle accident in August 1993.
Physical Examina p nn
Flexion normal, extension 800, rotation right 90o and
rotation left 900. He is tender at the cervical facets of
right 2-3, left 2-3 and the right lesser occipital nerve.
Diaano~i~
Cervicogenic headache.
This was confirmed by a positive response to
diagnostic facet blocks at the right 2-3 and 3-4 cervical
facets.
TreatmA"t- Wi h Di lof nac-
This was rubbed on the facet joint area on the right
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side of the neck and the patient noticed a marked decrease
in pain for the next 4 to 8 hours after use. When the gel
was used 2 or 3 times a day, the generalized neck ache was
markedly reduced. In addition, some of his headaches were
also decreased.
TEST PROCEDURE ITI
Her complaint is of severe bolo-cranial headaches.
Hi storm
She gave a history that one and one-half years ago she
fell flat on her back on concrete. She has had severe
headaches since then although earlier in her life she had
headaches that were attributed to migraine.
She is 37-years-old. The headaches are biparietal,
temporal, behind the eyes and alter in the day they become
bioccipital. They have an aching and throbbing character.
Sometimes she wakes up with headaches.
She has had some success with Fiorinal C'-~ in treating
her headaches.
Physical Examinati~n~
Neck: Flexion 305, extension 400, right rotation 800
and left rotation 700. Tenderness of the cervical facets,
right 2-3 and 3-4 and left 2-3, 3-4, 4-5 and 5-6, 1 + at
each.
Diaano is
Cervicogenic headache.
Possible pre-existing migraine.
Treatm n Wi h Di l nfPnar r'ol
This was rubbed on the facet joint areas bilaterally
in the neck region. The patient noticed a marked decrease
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in pain in the neck for 4 to 8 hours after use. When the
gel was used 2 to 3 times a day, the generalized neck pain
was markedly reduced. In addition, some of her headaches
were also decreased.
TEST PROCEDURE IV
This 52-year-old lady has a long history of occasional
headaches and occasional neck pain.
Histo_r
The patient had a long history of headaches of about
30 years duration. These were of a migrainous nature
usually on the right side. More recently, these have been
associated with neck pain.
Fh~sical Examina nom
This revealed a tilt of the head to the left, with the
right shoulder higher than the left.
The facet joints at C2-3, C3-4, C4-5 and C5-6
bilaterally were very tender. However, they were
particularly tender at C2-3 and C4-5 on the right.
Diaan-o is
Degenerative joint disease of the cervical spine
causing chronic headaches and occasional neck aches.
Resul of T a mPnt W9 t-h Di r-1 ~f na 1
This was used on three occasions for the neck pain.
In each case, it decreased the neck pain substantially. On
two occasions, it aborted a migraine headache in its early
stages.
TEST PROCEDURE V
This 47-year-old lady has a long history of:
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1. Constant headaches.
2. Constant neck aches.
History
The patient has a history of 7 motor vehicle
accidents. She underwent facet rhizolysis about three
years ago. This almost entirely relieved her headaches.
She still however continued to have neck aches with
physical activity particularly involving the neck.
~hvsical Examina , m
This showed some limitation of flexion and extension
to about 65o of normal. The facet joints from C2 to C6
were exquisitely tender more on the right than the left.
Diaano~iw
Degenerative joint disease of the cervical spine
causing occasional headaches and neck aches.
Treatment Wi h Di l~fPpa~
The diclofenac gel has successfully relieved her neck
ache on three different occasions. Each time the pain
relief was almost 1000. In addition, it stopped the
beginnings of a headache on each occasion.
TEST PROCEDURE VI
This 26-year-old lady has a long history of:
1. Constant neck ache.
2. Almost daily headaches.
History
The patient was thrown off a friend's shoulders while
playing at a party. She landed on her jaw and had her neck
thrust backwards violently.
She was thought to have actually broken her jaw at the
time of the fall.
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She has been investigated for TMJ disorder because
there is clearly some asymmetry in her face since the
accident. However, the TMJ specialist found that there was
no TMJ damage.
She also was found to have tender facet joints from C2
to C6 bilaterally, her neck was abnormally thrust forward
and she had difficulty in flexion and extension
particularly extension being only about 60o of normal.
Phvsical Examina
This revealed tenderness over the facet joints at C2-
3, C3-4, C4-5 and C5-6 bilaterally but especially on the
right. And the facet joints were more prominent on the
right.
The TMJ was not especially tender to palpation.
Diaanosis~
Degenerative joint disease of the cervical spine
causing chronic neck aches and headaches.
Treatmen Wi h Di 1 nfPr~ar r-o~
1
This was used on three occasions for severe neck pain.
It decreased the neck pain by about 500. It did not
however relieve the headaches . The patient is now using
the gel daily because she does find that it cuts down her
neck pain, and she is hoping it will cut down the
headaches.
DERMP,TOI,OGI AI~ APPhI ATIONS
In addition to treating disorders associated with pain
below the dermal level of the skin, the preparations of
this invention may be used to treat a wide variety of
dermatologic disorders. Exemplary, non-limiting disorders
include dermatitis conditions such as: Contact Dermatitis:
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Atopic Dermatitis; Seborrheic Dermatitis; Nummular
Dermatitis; Chronic Dermatitis of Hands and Feet;
Generalized Exfoliative Dermatitis; Stasis Dermatitis; and
Localized Scratch Dermatitis; bacterial infections of the
skin, such as: Staphylococcal Diseases of the skin,
Staphylococcal Scalded Skin syndrome; Erysipelas;
Folliculitis; Furuncles; Carbuncles; Hidradenitis
Suppurativa; Paronychial Infections and Erythrasma;
superficial fungal infections such as: Dermatophyte
Infections; Yeast Infections; Candidiasis; and Tinea
Versicolor; parasitic infections of the skin such as
Scabies; Pediculosis; and Creeping Eruption; disorders of
hair follicles and sebaceous glands such as: Acne; Rosacea;
Perioral Dermatitis; Hypertrichosis; Alopecia;
Pseudofolliculitis Barbae; and Keratinous Cyst; scaling
papular diseases, such as: Psoriasis; Pityriasis Rosea; and
Lichen Planus; pressure sores; benign tumors and malignant
tumors.
WOUND AppI,I ATION
Additional disorders to be treated are pressure sores.
Factors that precipitate pressure sores include loss of
pain and pressure sensations (which ordinarily prompt the
patient to shift position and relieve the pressure) and the
'5 thinness of fat and muscle padding between bony weight
bearing prominences and the skin. Disuse atrophy,
malnutrition, anemia, and infection play contributory rate.
Spasticity, especially in patients with spinal cord
injuries, can place a shearing force on the blood vessels
0 to further compromise circulation.
The most important of the extrinsic factors is
pressure. Its force and duration directly determines the
extent of the ulcer. Pressure severe enough to impair
local circulation can occur within hours in an immobilized
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patient, causing local tissue anoxia that progresses, if
unrelieved, to necrosis of the skin and subcutaneous
tissues. The pressure is due to infrequent shifting of the
patient's position; friction and irrigation from ill-
s adjusted supports or wrinkled bedding or clothing may be
contributory. Moisture, which may result from perspiration
or from urinary or fecal incontinence, leads to tissue
maceration and predisposes to pressure sores.
The stages of decubitus ulcer formation correspond to
tissue layers. Stage 1 consists of skin redness that
blanches or disappears on pressure; the skin and underlying
tissues are still soft. Stage 2 shows redness, edema, and
induration, at times with epidermal blistering or
desquamation. In stage 3, the skin becomes necrotic with
exposure of fat and drainage from wound. In stage 4,
necrosis extends through the skin and fat to muscle;
further fat and muscle necrosis characterizes stage 5. In
stage 6, bone destruction begins, with periostitis and
osteitis, progressing finally to ostemyelitis, with the
possibility of septic arthritis, pathologic fraction and
septicemia.
The best known treatment for pressure sores is
prevention. Pressure on sensitive areas must be relieved.
Unless a full flotation bed (water bed) is used to provide
even distribution of the patient's weight through
hydrostatic buoyancy, the bedridden patient's position must
be changed at least once every 2 hours until tolerance for
longer periods can be demonstrated (by the absence of
redness). Air-filled alternating-pressure mattresses,
sponge-rubber "egg-crate" mattresses, and silicone gel or
water mattresses decrease pressure on sensitive areas but
do not negate the need for position changes. A turning
(Stryker) frame facilities turning patients with cord
injuries. Protective padding (e.g., sheepskin or a
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synthetic equivalent) at bony prominences should be used
under braces or plaster casts, and at potential pressure
sites a window should be cut out of the cast. A wheelchair
patient must be able to shift his position every 10 to 15
minutes even if he is using a pressure-relieving pillow.
Otherwise, patients in chairs may be more likely to have
pressure sores than those who are in bed.
The major problem in treating decubitus ulcer is that
the ulcer is like an iceberg, a small visible surface with
an extensive unknown base, and to date there is no good
method to determine the extent of tissue damage. Ulcers
that have not advanced beyond stage 3 may heal
spontaneously if the pressure is removed and the area is
small.
Stage 4 ulcers require debridement; some may also
require deeper surgery. When the ulcers are filled with
pus and necrotic debris, application of dextranomer beads
or other and newer hydrophilic polymers may hasten
debridement without surgery. Conservative debridement of
necrotic tissue with forceps and scissors should be
instituted. Some debridement may be done by cleansing the
wound with 1.5o hydrogen peroxide. Wet dressings of water
(especially whirlpool baths) will assist in debriding. The
granulation that follows removal of necrotic tissue may be
satisfactory for skin grafts to cover small areas.
More advanced ulcers with fat and muscle involvement
require surgical debridement and closure. Affected bone
tissue requires surgical removal; disarticulation of a
joint may be needed. A sliding full-thickness skin flap
graft is the closure of choice, especially over large bony
prominences (e. g., the trochanters, ischia, and sacrum),
since scar tissue cannot develop the tolerance to pressure
that is needed.
For spreading cellulitis, a penicillinase-resistant
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penicillin or a cephalosporin is necessary.
Peripheral vascular distress due to diabetes is also
treatable. The primary cause of ulceration in diabetic
patients is the occlusion of the blood supply to the
extremities, as well as sensory denervation. Both factors
contribute to the impaired ability of the patient to
perceive trauma which has occurred, thus possibly causing
a compounding of the damage due to lack of timely
treatment. However, even with prompt treatment, reduced
blood supply combined with decreased cellular immunity
greatly increase the risk of fungal and bacterial
infections.
Treatment of peripheral vascular distress due to
diabetes is complex, because management of the underlying
condition is primary. Further, stabilization of the
diabetic condition alone will not necessarily alleviate the
ulcerations. If possible, patients are advised to avoid
weight bearing activities and appropriate orthotic
protection applied. Production and application of a
cushioned layer of the matrix incorporating the appropriate
antiviral and/or antibiotic agent is an effective as well
as efficient treatment.
MOTION SICKNESS APPLICATIONS
Difficulties experienced in adaptation to various
forms of travel or movement are also treatable via
embodiments of the present invention. Motion sickness is
caused by excessive stimulation of the vestibular apparatus
during motion. While the complete physiological mechanism
is not fully understood, it is believed that a combination
of visual stimuli, poor ventilation and emotional factors
precipitate attacks of motion sickness.
It is generally believed that treating person susceptible
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to motion sickness prior to onset of symptoms produces a
greater reduction in the severity of distress than
treatment after symptoms have developed. Due to the
complexity and combined nature of the symptoms, a variety
of treatment options may be employed. Drugs such as
dimenhydrate, diphenhydramine, meclinzine, cyclizine,
promethazine, diazepam and scopolamine, as well as
phenobarbital, in the case of psychological distress, may
be employed.
Utilization of a dermal patch produced with an
effective motion sickness medicament applied approximately
one to four hours prior to exposure to precipitating
factors can deliver an effective and prolonged dosage. If
extended exposure to travel is anticipated, a dermal patch
produced with a more appropriate dosage amount may be
administered.
GENERAL APPhICATIONS
Many new dressings and topical agents are being tested
and made available for use. No one powder, gel, or
dressing is universally superior. The subject is complex;
i.e., some are wet and lead to Pseudomonas infection if
used too long, others are painful, all are expensive, and
some are of little value.
Use of the present formulations either alone or in
combination with various therapeutic agents overcomes all
of these prior deficiencies.
It has also been unexpectedly found that when the
system is administered in a repetitive manner, once the
effects of the active drug are reduced in intensity or
effectiveness, such repeat treatments may result in a
synergistic effect by enhancing the initial term of relief
to a period which exceeds the initial time of relief. This
is also experienced on subsequent treatments. In this way,
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the present formulations are able to extend relief or
treatment from normally several hours to at least several
days of relief. The use of repeat applications enhances
drug release which significantly reduces drug dependence.
It also results in the relief of continued tissue damage
and may even assist in tissue repair.
Regardless of the route of administration elected, the
formulations of the present invention are formulated into
pharmaceutically acceptable dosage forms by conventional
methods known in the pharmaceutical art.
As discussed above, an effective but nontoxic amount
of the system is employed in treatment. The dose regimen
for administering drugs or treating various conditions,
such as pain as described above, is selected in accordance
with a variety of factors including the type, age, weight,
sex, and medical condition of the subject, the severity of
the pain, the route of administration and the particular
complex or combination of drugs employed. Determination of
the proper dose for a particular situation is within the
skill of the art. Generally, treatment is initiated with
smaller dosages which are less than the optimum doses of
the compound. Thereafter, the dose is increased by small
increments until the optimum effect under the circumstances
is reached. For convenience, the total daily dosage may be
divided and administered in portions during the day if
desired. Generally, amounts of matrix with or without drug
may vary from O.OOOlo to about 75o by weight of the system
when using topically with 2 to 25 ml concentrations and
preferably in 3 to 10 ml amounts.
The formulations of this invention are particularly
useful in the administration of drugs that could be
previously administered only orally.
Particularly preferred nonionic polymers are cellulose
derivatives and particularly those selected from the group
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consisting of carboxymethylcellulose sodium, hydroxyethyl
cellulose, hydroxypropyl cellulose and mixtures thereof.
These particular polymers have been found to possess
exceptional ability to form sustained release matrix
formulations when used in combination with a negatively
charged polymer. Such polymers are generally employed in
amounts of about 0.1o to about 1.0o and preferably about
0.5o to about 1.0o. Amounts above about 1.0o result in the
formation of a solid gel when used with the negatively
charged polymer. Amounts below about O.lo have not been
found suitable to prepare a storage stable product that has
sustained drug release.
A particularly preferred HEC concentration is about
0.2o to about 1.0o by weight of the matrix.
A wide variety of medicaments which may be
administered topically may be used in the delivery system
according to this invention. These include drugs from all
major categories, and without limitation, for example,
anesthetics including benzocaine, tetracaine, mepivacaine,
prilocaine, etidocaine, bupivacaine and lidocaine;
analgesics, such as acetaminophen, ibuprofen, fluriprofen,
ketoprofen, voltaren (U. S. Patent No. 3,652,762),
phenacetin and salicylamide; nonsteroidal anti-
inflammatories (NSAIDS) selected from the group consisting
of naproxen, acetaminophen, ibuprofen, flurbiprofen,
ketoprofen, phenacetin, salicylamide, and indomethacin;
antibiotics including amebicides, broad and medium spectrum
antibiotics, fungal medications, and anti-viral agents and
specifically including erythromycin, penicillin and
cephalosporins and their derivatives; central nervous
system drugs such as thioridazine, diazepam, meclizine,
ergoloid mesylates, chlorpromazine, carbidopa and levodopa;
metal salts such as a potassium chloride and lithium
carbonate; minerals selected from the group consisting of
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iron, chromium, molybdenum and potassium; immunomodulators;
immunosuppressives; thyroid preparations such as synthetic
thyroid hormone, and thyroxine sodium; steroids and
hormones including ACTH, anabolics, androgen and estrogen
combinations, androgens, corticoids and analgesics,
estrogens, glucocorticoid, gonadotropin, gonadotropin
releasing, human growth hormone, hypocalcemic, menotropins,
parathyroid, progesterone, progestogen, progestogen and
estrogen combinations, somatostatis-like compounds,
urofollitropin, vasopressin, and others; and vitamins
selected from water-soluble vitamins such as B complex,
vitamin C, vitamin B12 and folic acid and veterinary
formulations.
Chemotherapeutics such as Actinomycin D, adriamycin,
altretamine, asparaginase, bleomycin, busulphan,
capecitabine, carboplatin, carmustine, chlorambucil,
cisplatin, cyclophosphamide, cytarabine, dacarbazine,
daunorubicin, doxorubicin, epirubicin, etoposide,
fludarabine, fluorouracil, gemcitabine, hydroxyurea,
idarubicin, ifosfamide, irinotecan, liposomal doxorubicin,
lomustine, melphalan, mercaptopurine, methotrexate,
mitomycin, mitozantrone, oxaliplatin, procarbazine,
steroids, streptozocin, taxol, taxotere, tamozolomide,
thioguanine, thiotepa, tomudex, topotecan, treosulfan,
vinblastine, vincristine, vindesine, vinorelbine, and the
like may be empolyed. Other chemotherapeutics useful in
combination and within the scope of the present invention
are buserelin, chlorotranisene, chromic phosphate,
dexamethasone, estradiol, estradiol valerate, estrogens
conjugated and esterified, estrone, ethinyl estradiol,
floxuridine, goserelin, and prednisone.
One particular criteria of the drug is that they must
be solubilized in the polymer matrix solution in order to
be topically administered.
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A particularly preferred additional use of the
compositions of this invention include their uses as 1) a
medical device, 2) for drug delivery, 3) the application of
a diagnostic agent or 4) the prevention of post operative
adhesions.
CONCENTRATION POTENTIALS
One useful aspect of the present invention is
that of concentrating the matrix to various degrees
depending upon intended usage. The step of concentrating,
must be practiced under conditions that avoid degradation
of the hyaluronic acid and its salts. These conditions can
be determined without undue experimentation by a person of
ordinary skill in the art. Concentrating is generally
practiced until between about 10 percent by weight and
about 70 percent by weight, and preferably until between
about 20 percent by weight and about 50 percent by weight,
of the water is removed from the first aqueous solution.
A number of techniques may be employed to dehydrate
the solution ranging from the use of solvents and rotary
evaporation to heating the solution. Preferably, the water
removal step is affected by controlling of the temperature
of the solution. Widely varying temperatures can be
employed for the concentrating step, however, the
temperature is generally maintained from about 10°C to about
80°C and preferably from about 30°C to about 60°C.
subatmospheric pressure may also be used. While,
superatmospheric pressure is suitable, this step is
preferably practiced at atmospheric pressure, namely about
760 mmHg.
Generally, the concentrated solutions of the
present invention may be prepared by slowly adding
hyaluronic acid to sterilized water being stirred at
approximately 200-600 rpms. The molecular weight and
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purity of the hyaluronic acid as described previously are
of the utmost importance and must not be significantly
changed during processing, therefore mild processing
conditions are required. Stirring is continued until the
HA has completely dissolved into the water and a crystal
clear viscous solution has formed. Next, a quantity of the
solution is removed and placed in a clean vessel, where
constant stirring is continued. The vessel is then placed
in a warm environment and is monitored. The water content
is removed by evaporation without causing the molecular
degradation of the HA. The amount of water removal may be
determined by the weight reduction of the solution. If
weighing the solution does not indicate the desired amount
of water either present or removed, the vessel may be
returned to the warm environment for further water removal.
According to another aspect of the present invention
the composition further comprises an active therapeutic
agent. Any active therapeutic agent which is compatible
with hyaluronic acid and its salts can be employed in the
present invention. A wide variety of medicaments which are
administered may be used in the delivery system according
to this invention.
DRESSING PREPARATIONS
Sodium hyaluronate (NAHA) is a major carbohydrate
component of the extracellular matrix and can be found in
skin, joints, eyes and most other organs and tissues. It
has a linear co-polymer structure that it is completely
conserved throughout a large span of the evolutionary tree,
indicating a fundamental biological importance. Amongst
extracellular matrix molecules, it has unique hydroscopic,
rheological and viscoelastic properties. Sodium
hyaluronate binds to many other extracellular matrix
molecules through its complex interaction with matrix
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components and cells.
Furthermore it is believed that sodium hyaluronate has
an important biological role in skin wound healing, by
virtue of the fact that during wound healing levels of
sodium hyaluronate are elevated temporarily in granulation
tissue. It has been determined that there is a specific
binding interaction between fibrin, the major clot protein,
and sodium hyaluronate which is a constituent of the wound
extracellular matrix. The binding interaction may provide
the driving force to organize a three-dimensional NAHA
matrix which attaches to the fibrin matrix.
Sodium hyaluronate-fibrin matrix plays a major role in
the subsequent tissue reconstruction processes. Traumatic
wounds, such as those caused by surgical procedures, often
produce irregular patterns on NAHA-fibrin matrix and the
biological functioning of the system wounds is often
compromised.
One purpose of providing hyaluronate acid derived
matrix, which is unique to the polymer matrix, is to
facilitate wound healing and to prevent complications such
as those found when scarring and adhesions are formed. In
other words, the prime purpose of providing an impregnated
web or padded web with a stable, transdermal sodium
hyaluronate matrix in the form of the polymer matrix
complex is important in regulating the molecules which
control cellular function and which are involved in the
inflammatory response and new blood vessel formulation
amongst other factors which are involved in wound healing.
Matrices of the present invention, alone or incorporating
a drug, have been found to be effective in the treatment
and healing of wounds. Therefore, the matrices of the
present invention may be utilized without incorporating an
additional drug.
In addition, the same rationale can be applied to
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wounds of a long-standing nature where the natural
biological components including the extracellular matrix
have been compromised as in slow healing diabetic ulcers
and bed sores.
The thrust of the current experimental work is to
examine the compatibility of the components used for the
construction of the bandage material, such as bandage
products manufactured by those well known in the art and
conventionally available, with those of typical matrices
used for various products. A matrix was formulated to
serve as a prototype polymer matrix which would be suitable
for the prevention of adhesions and scarring when
impregnated or otherwise combined with the Web bandage.
Experiments to Examine Compatibility
Various matrices, including Diclofenac Matrix and
Eczema Matrix, produced by the process of Example 1, were
placed directly on the surface of the web. Various methods
were used to dry the matrix including direct heat, infra
red heat and room temperature (3-5 minutes).
Once dry, the Web with matrix film was subjected to a
variety of experiments. These included boiling, heating
and otherwise using extreme adverse conditions to produce
deterioration and destruction of the Web/Matrix combination
material. The results of these experiments show that heat
did not adversely affect the inherent qualities of the
Web/Matrix; that is, by heating with forced heat through a
blower or with ultra-violet heat. The adhesive properties
of the web are not reduced or otherwise compromised by the
addition of polymer matrix.
Removing the matrix film produced no significant
change in the adhesive qualities of the Web bandaid
material. In addition, the polymer matrices when applied
directly to the padded portion of the Web/bandaid material
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absorb totally either when dried by the methods described
above or when left for approximately 3-5 minutes on the
surface of the padded portion at room temperature.
Description of Experiments and Results
A pro-forma wound healing matrix was manufactured
using the process of Example 1. The formula was a follows:
Sodium Hyaluronate (NAHA) 2.50
Hydroxyethylcellulose (HEC low weight) 156
Methoxyhydroxypolyethylene glycol (MPEG) l00
Sodium D-Pantothenate 1.50
Water q.s.
It was determined that the pro-forma wound healing
matrix produced a film when heat was applied to the
bandaid-type pad (Large Water Block Plus) which has a
padded area of 2.5 x 5 cm. The heat method used was forced
air drying or UV light. When the matrix was applied to the
pad alone and left for 3-5 minutes at room temperature, it
dried and was integrated into the pad without producing a
film. This method has several advantages: the integrated
padded portion does not need moisture for rehydration, the
material is active immediately when placed on the skin, and
the cover for the bandaid keeps the skin dry.
Experiments with Niacin Matrix
In order to assess the transdermal activity associated
with Web impregnated matrix, experiments were performed
with a Niacin Matrix produced according to the procedures
set forth above. The Niacin Matrix produces peripheral
vasodilation with resulting redness, in a few minutes, at
the site to which it is applied. Heat, at the site is also
generated. These effects generally last for 15-20 minutes.
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The experimental procedure described above was
conducted using the large Bandaid-type: Large Water Block
Plus with a useful area of 2.5 x 5 cm. All samples were
dried at room temperature for 3-5 minutes and the gel was
completely absorbed throughout the patch. The gel was
applied carefully with a fine syringe and spread with a
spatula. After applying the gel, the active area was
sealed by pressing down the paper type (material covering
the bandaid) on the four sides of the bandaid where the
adhesive is located.
TESTING RESULTS
0.5 ml of Niacin Matrix was applied to the patch
portion of the bandaid and was placed on the left arm of a
subject and left in place for half-an-hour. The result was
that reddening of the skin on the patch area was evident
after the bandaid was removed.
In the second experiment, 0.75 ml of Niacin Matrix was
applied, using similar techniques to the patch. The patch
was placed on the subject's right arm and was left in place
for half-an-hour. There was increased reddening of the
skin which radiated about 1 inch outward.
In the fourth experiment, 1.5 ml of Niacin gel was
applied to the patch. However this was too much matrix for
the area, and the patch could not be successfully applied
to the subject's skin.
Comments and Observations
There is a definite compatibility of the polymer
matrix with bandaid (web material) either on the web itself
or more successfully on the padded portion of the bandaid.
The Matrix appears to be very effective when used on the
Web and allowed to integrate by room temperature air drying
for 3-5minutes.
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Conclusions
From the experiments conducted, it would appear that
a number of presentations can be developed using the
Web/Matrix technology. Ultimately the objective would be
to impregnate or coat the covering to be applied to the
skin with an appropriate amount of matrix. The material
covering the patch following matrix impregnation may be of
the Teflon coated variety to avoid interaction or contact,
or be made of any other suitably approved polymer material
generally used for medical applications. Such materials
should remain inert or non-reactive with the matrix
material.
The design and shape of the wound healing product will
depend on the nature of the wound to be dressed. Obviously
the length is determined again by the length of the wound
itself. When treating ulcerated wounds which occur through
illness or a deficiency, as in the case of bed sores,
circular designs may work well.
Another factor that would appear to be favorable is
the ability of the health care professional treating the
patient or the patient themselves, to use additional
matrix, where necessary, to heal stubborn conditions such
as diabetic or slow healing ulcers. This would appear to
be able to be accomplished simply by adding additional
matrix to the already impregnated product at the time of
application.
The Matrix can also be presented in individual
dispensing cartridges containing an appropriate amount of
product. Such single dose cartridges are available through
several sources. One possible source is Confab in Quebec,
even though other sources well known in the art can be
used. The use of these cartridges may be customized for
polymer matrix formulations and could be used to provide
additional matrix for application to Web/pad materials in
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the treatment of difficult cases.
The following examples are illustrative of
preferred embodiments of the invention and are not to be
construed as limiting the invention thereto. All polymer
molecular weights are mean average molecular weights. All
percentages are based on the percent by weight of the final
delivery system or formulation prepared unless otherwise
indicated and all totals equal 1000 by weight.
Example 1
This example illustrates the synthesis of a
composition of the present invention. The following
ingredients are combined as indicated.
~naredient Quantity crams)
Hyaluronate Sodium (HA) 13.7
Sterile Water 900
Into a sterilized glass vessel is added 500 ml of the
sterile water which is stirred at 400-600 rpms. Slowly add
13.7 grams of HA having an average molecular weight of
around 700,000 to 775,000.
Allow stirring for 10 to 20 hours until all the HA has
dissolved into the water and a crystal clear viscous
solution has formed.
A quantity (500 grams) of the above viscous solution
is placed in a clean beaker of known weight. A magnetic
stirrer of known weight is placed in the beaker. The
beaker containing the viscous solution and the stirrer is
placed in a laboratory hood where the beaker and its
contents are maintained in a warm location at 40°C while
being constantly stirred. Under these conditions water is
removed from the viscous solution without any molecular
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degradation of the HA. At the end of one hour the beaker
is weighed. If the weight reduction does not indicate
removal of the desired amount of water, the beaker, with
its contents, is returned to the warm location in the hood
for further water removal.
In this example removal of 37 weight percent of
the water is deemed sufficient to prepare a semi-solid
material.
Example 2
This example illustrates the synthesis of a
composition of the present invention employing
hydroxyethylcellulose (HEC) as a nonionic polymer. The
following ingredients are combined as indicated.
Ingredient Quantity (crams)
Hydroxyethylcellulose (HEC) 12.5
Hyaluronate Sodium (HA) 13.7
Sterile Water 900
Into a sterilized glass vessel is added 500 ml of
the sterile water which is stirred at 400-600 rpms. Slowly
add 13.7 grams of HA having an average molecular weight of
around 700,000 to 775,000 and a purity described
previously.
Allow to stir for 10 to 20 hours until all the HA
has dissolved into the water and a crystal clear viscous
solution has formed.
Prepare a 1. 25 o solution of HEC by adding 12 . 5
grams of the solid material under aseptic conditions to 275
ml of sterile water. Allow to dissolve for 1 to 2 hours
while stirring thereby forming an HEC solution. Add the
HEC solution to the HA solution and mix until a homogenous
clear viscous solution is produced.
A quantity (500 grams) of the above viscous
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solution is placed in a clean beaker of known weight. A
magnetic stirrer of known weight is placed in the beaker.
The beaker containing the viscous solution and the stirrer
is placed in a laboratory hood where the beaker and its
contents are maintained in a warm location at 40°C while
being constantly stirred. Under these conditions water is
removed from the viscous solution without any molecular
degradation of the HA. At the end of one hour the beaker
is weighed. If the weight reduction does not indicate
removal of the desired amount of water, the beaker, with
its contents, is returned to the warm location in the hood
for further water removal.
In this example removal of 68 weight percent of
the water is deemed sufficient to prepare a semi-solid
sodium hyaluronate polymer matrix delivery system.
Example 3
This example demonstrates the formation of a
transdermal nonsteroidal anti-inflammatory preparation
known as diclofenac which produces relief of osteoarthritic
and associated pain in areas affected by the disease. Such
areas include, but are not limited to, knees, ankles, feet,
back, neck, elbows, and hips.
The present example also demonstrates the formation of
a transdermal preparation containing the NSAID drug which
when administered topically to sites affected by rheumatic
or osteoarthritic disease will have an analgesic and
beneficial effect. The onset of this beneficial effect in
the form of pain relief and reduction of inflammation
occurs between 10 and 20 minutes following topical
administration and lasts for up to 6 hours.
The dosage range for the drug is between 2-4 ml ( 60
mg-120 mg) depending on the severity and site of the
affected area.
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MATERIAL
Diclofenac sodium 30
Sodium hyaluronate (HA) 2.30
Hydroxyethyl cellulose (HEC) 0.70
Methoxypolyethylene glycol (MPEG) 10%
Benzyl alcohol 2.50
Water Remainder
BATCH SIZE 1500 ml
Into a sterilized glass vessel is added 1062.5 ml of
sterile water which is stirred at 1500 to 2000 rpm. Slowly
add 34.5 grams of HA, having an average molecular weight of
around 700,000 to 775,000 and a purity described above.
Allow to stir for 16 to 20 hours until all of the HA
polymer has dissolved into the water and a crystal-clear
viscous solution has formed.
Prepare a 0.7o solution of HEC by adding 10.5 grams of
the solid material under aseptic conditions to 250 ml of
sterile water. Allow to dissolve for 1 to 2 hours while
stirring at 1500 to 2000 rpm. Add the HEC solution to the
HA solution and mix for 10 to 15 hours until a homogeneous
solution is produced.
Carefully measure 150 ml of methoxypolyethylene glycol
(MPEG) loo into the mixture. RPM speeds should be
increased to 2500 rpm for the mixture while this step is
being performed. The resulting mixture thus formed should
be allowed to mix at 2000 rpm for an additional 3 to 4
hours.
At this point 2.50 of benzol alcohol or 37.5 ml is
added to the mixture. Again, the rpm speed is increased
during this part of the procedure to 2500 rpm. The mixture
should be allowed to mix for 3 to 5 hours at 2000 rpm.
Using safe techniques, 45 grams (30) of the diclofenac
should be slowly added to the mixture. Again the rpm speed
for the purpose of addition of diclofenac should be
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increased to 2500, and the entire 45 grams of diclofenac
should be completed within 15 minutes.
The final mixture is clear with a slight green tint
following 15 to 20 hours of further mixing at 2000 rpm.
The final product should be transferred, using aseptic
techniques, to 25 ml borasylicate glass jars with a lined
cap.
Example 4
The formula and method of manufacture of Example 3 are
repeated for diclofenac potassium. The only difference is
that MPEG is not used.
MATERIALS
Diclofenac potassium 30
Sodium hyaluronate (HA) 2.30
Hydroxyethyl cellulose (HEC) 0.70
Benzyl alcohol 2.50
BATCH SIZE 1500 ml
Into a sterilized glass vessel is added 1062.5 ml of
sterile water which is stirred at 1500 to 2000 rpm. Slowly
add 34.5 grams of HA, having an average molecular weight of
around 700,000 to 775,000 and a purity described
previously. Allow to stir for 16 to 20 hours until all of
the HA polymer has dissolved into the water and a crystal-
clear viscous solution has formed.
Prepare a 0.70 of HEC by adding 10.5 grams of the
solid material under aseptic conditions to 250 ml of
sterile water. Allow to dissolve for 1 to 2 hours while
stirring at 1500 to 2000 rpm. Add the HEC solution to the
HA solution and mix for 10 to 15 hours until a homogeneous
solution is produced.
At this point 2.5 0 of benzol alcohol or 37.5 ml is
added to the mixture. Again, the rpm speed is increased
during this part of the procedure to 2500. The mixture
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should be allowed to mix for 3 to 5 hours at 2000 rpm.
As described above, using safe techniques, 45 grams
(30) of the diclofenac is slowly added to the mixture.
Again the rpm speed for the purpose of addition of
diclofenac should be increased to 2500, and the entire 45
grams of diclofenac should be completed within 15 minutes.
The final mixture is clear with a slight green tint
following 15 to 20 hours of further mixing at 2000 rpm.
The final product should be transferred, using aseptic
techniques, to 25 ml borasylicate glass jars with a lined
cap.
Example 5
The general manufacturing procedure of Example 3 is
repeated for a topical dermalogical preparation. The main
difference in composition is the use of methylparabin as a
preservative.
MATERIALS
Sodium hyaluronate (HA) 2.50
Hydroxyethyl cellulose (HEC) 1.250
Benzyl alcohol to
Methyl parabin 0.20
Water Q.S.
Prior to dissolving the HA into the water, methyl
parabin is dissolved and then HA added thereto. The
remaining process steps of Example 1 were then repeated.
When 3 to 5 milliliters of this formulation was
applied to pressure sores 3 to 4 times daily, the tissue
healed and returned to a normal condition within 4 to 7
days.
Example 6
The following describes experiments with respect to a
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pro-forma wound healing dressing. The formula was as
follows:
Sodium Hyaluronate (NAHA) 2.5%
Hydroxyelthylcellulose (HEC low weight) 1.560
Mthooxyhydroxypolyethylene glycol (MPEG)l0o
Sodium D-Pantothenate 1.50
Water q.s.
It was determined that the pro-forma wound healing
matrix produced a sheet or film when heat was applied to
the mixture. The heat method used was force air drying or
ultraviolet light. When the wound healing matrix was
poured into a petri dish to the depth of 0.2 inches and
left for 30 minutes at room temperature the same sheet was
produced. This method has several advantages: the sheet
does not require rehydration for treatment purposes, the
sheet is immediately active when placed on the skin and the
sheet is easily protectable by a gauze or the type of
dressing fixative material.
The invention being thus described, it will be obvious
that the same may be varied in many ways. Such variations
are not to be regarded as a departure from the spirit and
scope of the invention and all such modifications are
intended to be included within the scope of the following
claims.
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