U.S. patent application number 10/141131 was filed with the patent office on 2002-11-28 for topical drug preparations.
This patent application is currently assigned to L.A.M. Pharmaceutical Corp.. Invention is credited to Drizen, Alan, Nath, Gary M., Rothbart, Peter.
Application Number | 20020176892 10/141131 |
Document ID | / |
Family ID | 46203578 |
Filed Date | 2002-11-28 |
United States Patent
Application |
20020176892 |
Kind Code |
A1 |
Drizen, Alan ; et
al. |
November 28, 2002 |
Topical drug preparations
Abstract
Topical gelled compositions comprising an optional drug
dispersed within a polymer matrix, methods of producing the same
and treatments with the complex.
Inventors: |
Drizen, Alan; (Ontario,
CA) ; Rothbart, Peter; (Ontario, CA) ; Nath,
Gary M.; (Bethesda, MD) |
Correspondence
Address: |
Gary M. Nath
NATH & ASSOCIATES PLLC
Sixth Floor
1030 Fifteenth Street, N.W.
Washington
DC
20005
US
|
Assignee: |
L.A.M. Pharmaceutical Corp.
North York
CA
|
Family ID: |
46203578 |
Appl. No.: |
10/141131 |
Filed: |
May 9, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10141131 |
May 9, 2002 |
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09280841 |
Mar 30, 1999 |
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6387407 |
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09280841 |
Mar 30, 1999 |
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08796578 |
Feb 6, 1997 |
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5897880 |
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08796578 |
Feb 6, 1997 |
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08536750 |
Sep 29, 1995 |
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Current U.S.
Class: |
424/488 ;
514/54 |
Current CPC
Class: |
Y10S 514/886 20130101;
A61K 9/0019 20130101; Y10S 514/825 20130101; A61K 31/196 20130101;
A61K 9/0014 20130101; A61K 9/06 20130101; A61K 47/36 20130101; A61K
9/08 20130101; Y10S 514/887 20130101; A61K 9/0034 20130101; A61K
47/38 20130101 |
Class at
Publication: |
424/488 ;
514/54 |
International
Class: |
A61K 009/14; A61K
031/737; A61K 031/728 |
Claims
What is claimed is:
1. A stable, sterile gelled composition which comprises: a matrix
containing a negative charged polymer having a mean average
molecular weight between about 650,000 and 800,000 blended with a
nonionic polymer, wherein the molar ratio of the charged polymer to
the nonionic polymer is 1:0.5 to 4 and the negative charged polymer
is present in amounts of about 2.0% to about 3.5% by weight.
2. The gelled composition of claim 1, wherein the negative charged
polymer is selected from the group consisting of polysulfated
glucosoglycans, glucosaminoglycans, mucopolysaccharides, and
derivatives thereof.
3. The gelled composition of claim 1, wherein the negative charged
polymer is a mucopolysaccharide polymer having an average molecular
weight between about 700,000 to about 775,000.
4. The gelled composition of claim 3, wherein the negative charged
polymer is chondroitin sulfate or the hyaluronate salt of sodium,
calcium, potassium or magnesium.
5. The gelled composition of claim 1, wherein the nonionic polymer
is selected from the group consisting of carboxymethylcellulose
sodium, hydroxyethyl cellulose, hydroxypropyl cellulose and
mixtures thereof.
6. The gelled composition of claim 1, wherein the molar ratio of
the polymers is 1:0.5 to 2.
7. The gelled composition of claim 1, wherein the molar ratio of
the polymers is 1:0.7 to 2.5.
8. The gelled composition of claim 1, wherein the negative charged
polymer is present in amounts of about 2.0% to about 3.0% by
weight.
9. The gelled composition of claim 1, wherein the nonionic polymers
are present in amounts of about 0.1 to about 1.5% by weight.
10. A method for the treatment of a condition in animals for a
sustained period of time, which comprises: topically applying a
therapeutically effective dose of a gelled composition comprising a
polymer matrix which is suspended in a liquid medium; wherein the
polymer matrix contains a negatively charged polymer blended with a
nonionic polymer.
11. The method of claim 10, wherein the negatively charged polymer
material is selected from the group consisting of
glucosminoglycans, mucopolysaccharides and mixtures thereof.
12. The method of claim 10, wherein the negative charged polymer
material is chondroitin sulfate or hyaluronate salt of sodium,
calcium, potassium or magnesium.
13. The method of claim 12, wherein the material has a mean average
molecular weight below about 800,000.
14. The method of claim 12, wherein the material has a mean average
molecular weight between 700,000 and 775,000.
15. The method of claim 12, wherein the hyaluronate salt is the
sodium salt and has a mean average molecular weight from about
650,000 to about 800,000, a sulphated ash content below about 15%,
a protein content below about 5% and purity of at least 98%.
16. The method of claim 10, wherein the nonionic polymer is
selected from the group consisting of carboyxmethylcellulose
sodium, hydroxyethyl cellulose, hydroxypropyl cellulose and
mixtures thereof.
17. The method of claim 10, wherein the gelled composition also
contains a therapeutically effective amount of drug in the gelled
composition which composition is administered to treat acute,
chronic or intractable diseases or conditions.
18. The method of claim 10, wherein the therapeutically effective
dose penetrates the skin layers to alleviate the pain without
significantly modifying motor or sensory functions.
19. The method of claim 10, wherein the condition treated is pain
associated with or caused by abnormal cell growth, cancer, tumor
mass, arthritis, degenerative joint disease (osteoarthritis),
sickle cell disease, hemophilia, pinched nerve, or damaged nerve
and muscle and dermatologic disorders.
20. The method of claim 19, wherein the pain is located in joints,
ligaments, tendons, cartilage or muscle.
21. A process for the use of a composition as a medical device, for
drug delivery, the application of a diagnostic agent, or the
prevention of post operative adhesions, said process comprises
topically administering to a mammal an aqueous based gelled
composition containing a polymer matrix composed of negatively
charged polymers blended with nonionic polymers.
22. The process of claim 21, wherein the negatively charged polymer
material is selected from the group consisting of
glucosminoglycans, mucopolysaccharides and mixtures thereof.
23. The process of claim 21, wherein the negative charged polymer
material is chondroitin sulfate or hyaluronate salt of sodium,
calcium, potassium or magnesium.
24. The process of claim 21, wherein the material has a mean
average molecular weight below about 800,000.
25. The process of claim 21, wherein the material has a mean
average molecular weight between 700,000 and 775,000.
26. The process of claim 21, wherein the hyaluronate salt is the
sodium salt and has a mean average molecular weight form about
650,000 to about 800,000, a sulphated ash content below about 15%,
a protein content below about 5% and purity of at least 98%.
27. The process of claim 21, wherein the nonionic polymer is
selected from the group consisting of carboyxmethylcellulose
sodium, hydroxyethyl cellulose, hydroxypropyl cellulose and
mixtures thereof.
28. The process of claim 21, wherein the composition also contains
an active therapeutic agent or drug.
29. An antiarthritic gelled composition, which comprises:
therapeutically effective amounts of an active NSAID drug dispersed
within a matrix containing a negative charged polymer having a mean
average molecular weight between about 650,000 and 800,000 blended
with a nonionic polymer, wherein the molar ratio of the charged
polymer to the nonionic polymer is 1:0.5 to 4 and the negative
charged polymer is present in amounts of about 2.0% to about 3.0%
by weight.
30. The gelled composition of claim 29, wherein the negative
charged polymer is a mucopolysaccharide polymer having an average
molecular weight between 700,000 to 750,000.
31. The gelled composition of claim 29, wherein the charged polymer
is the hyaluronate salt of sodium, calcium, potassium or
magnesium.
32. The gelled composition of claim 29, wherein the nonionic
polymers are selected from the group consisting of
carboxymethylcellulose sodium, hydroxyethyl cellulose,
hydroxypropyl cellulose and mixtures thereof.
33. The gelled composition of claim 29, wherein the molar ratio of
the polymers is 1:0.7 to 2.5.
34. The gelled composition of claim 29, wherein the negative
charged polymer is present in amounts of about 2.0% to about 3.0%
by weight.
35. The gelled composition of claim 29, wherein the nonionic
polymers are present in amounts of about 0.2 to 1.0% by weight.
36. The gelled composition of claim 29, wherein the NSAID is
selected from the group consisting of naproxen, acetaminophen,
ibuprofen, flurbiprofen, ketoprofen, phenacetin, salicylamide,
indomethacin and mixtures thereof.
37. A method for treating an arthritic condition, which comprises:
topically administering to a mammal an aqueous based gelled
composition containing therapeutically effective amounts of an
NSAID drug dispersed within a polymer matrix composed of negatively
charged polymers blended with nonionic polymers, wherein the molar
ratio of the negatively charged polymer to nonionic polymer is
1:0.5 to 4.
38. The method of claim 37, wherein the negative charged polymer is
selected from the group consisting of polysulfated glucosoglycans,
glucosaminoglycans, mucopolysaccharides, and derivatives
thereof.
39. The method of claim 37, wherein the negative charged polymer is
a mucopolysaccharide polymer having an average molecular weight
between about 700,000 to about 775,000.
40. The method of claim 37, wherein the negative charged polymer is
chondroitin sulfate or the hyaluronate salt of sodium, calcium,
potassium or magnesium.
41. The method of claim 37, wherein the nonionic polymer is
selected from the group consisting of carboxymethylcellulose
sodium, hydroxyethyl cellulose, hydroxypropyl cellulose and
mixtures thereof.
42. The method of claim 37, wherein the molar ratio of the polymers
is 1:0.7 to 2.5.
43. The method of claim 37, wherein the negative charged polymer is
present in amounts of about 2.0% to about 3.0% by weight.
44. The method of claim 37, wherein the nonionic polymers are
present in amounts of about 0.1% to about 1.5% by weight.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 08/536,750 filed Sep. 29, 1995, the entire
contents of which are incorporated herein in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to the preparation of a transdermal
delivery system. The preparation 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.
DESCRIPTION OF THE PRIOR ART
[0003] 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 U.S. Pat. No. 4,188,373, PLURONIC.RTM. 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.
[0004] In U.S. Pat. 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.
[0005] Other patents disclosing pharmaceutical compositions which
rely upon an aqueous gel composition as a vehicle for the
application of the drug are U.S. Pat. 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 tissues of the
thoracic or peritoneal cavities in U.S. Pat. No. 4,911,926.
[0006] 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 Sciences, 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.
[0007] In U.S. Pat. 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.
[0008] In U.S. Pat. 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.
[0009] In U.S. Pat. No. 4,795,642, there are disclosed
gelatin-encapsulated, controlled-release compositions for release
of pharmaceutical 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.
[0010] 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. Pat. 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 con-tact. The drug
delivery device 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.
[0011] To date prescription pain and antiinflammatory medications
which have been formulated for topical use have not been approved
for sale in the United States. This is due 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 not been successful.
[0012] In contrast, over-the-counter drugs which include
counter-irritants such as menthol, eucalyptus, and camphor are sold
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.
[0013] A need thus exists for the administration of active
therapeutic agents that can be applied topically and transported
through the skin.
SUMMARY OF THE INVENTION
[0014] The present invention relates to the formation of a stable,
sterile gelled composition and its use in treating acute or chronic
conditions. More particularly, this invention relates to a stable,
sterilized composition, optionally containing a therapeutic drug,
which comprises: a polymer matrix composed of a highly negative
charged polymer material which may be selected from the group
consisting of polysulfated glucosoglycans, glycosaminoglycans,
mucopolysaccharides and mixtures thereof, and a nonionic polymer
which may be selected from the group consisting of
carboxymethylcellulose sodium, hydroxyethyl cellulose,
hydroxypropyl cellulose, and mixtures thereof.
[0015] Another embodiment of this invention involves a method for
the treatment of a condition in animals, which comprises topically
applying therapeutically effective doses of a gelled suspension of
a composition comprising an optional drug within a polymer matrix
which is suspended in a liquid medium. Preferably, one of the
polymer materials has a mean average molecular weight below about
800,000, and the other polymer is a nonionic cellulose derivative.
The present invention utilizes a novel combination of polymers each
having a specific ionicity. More specifically, the polymers used in
the formulation are of two basic types: those which have a strong
negative charge, and those which are non-ionic or have no charge
attached to them.
[0016] An alternative embodiment of the invention involves a
process for the use of a composition as a medical device, for drug
delivery, the application of a diagnostic agent, or the prevention
of post operative adhesions. This process involves topically
administering to a mammal an aqueous gelled composition containing
a polymer matrix composed of negatively charged polymers blended
with nonionic polymers.
[0017] An additional embodiment involves the preparation of an
antiarthritic gelled composition which comprises an active NSAID
drug dispersed within a matrix containing a negative charged
polymer having a mean average molecular weight between about
650,000 and 800,000 blended with a nonionic polymer, wherein the
molar ratio of the charged polymer to the nonionic polymer is 1:0.5
to 4 and the negative charged polymer is present in amounts of
about 2.0% to about 3.0% by weight.
DETAILED DESCRIPTION OF THE INVENTION
[0018] It has been unexpectedly discovered that an effective
therapeutic 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.
[0019] 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 system or muscular tissue providing a method
of delivering an active drug to an affected site in the body
through the skin.
[0020] 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 with
resulting loss of potency and efficacy. Furthermore, the solutions
tend to separate and form distinct polymer layers when ionic
molarity is not appropriate.
[0021] 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 of the drug.
Particularly preferred polymers which have mean 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. Polymers with
mean average molecular weights between 700,000 and 775,000 are most
preferred. Polymers having molecular weights above 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.
[0022] 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.
[0023] 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 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 through a beta (1-5) linkage.
The (beta 1-4) linkages may be broken through hydrolysis with the
enzyme hyaluronidase.
[0024] 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 is also being synthesized
artificially and by recombinant technology.
[0025] Conventional methods for obtaining hyaluronic acid results
with a product having differing properties and a wide range of
viscosities. U.S. Pat. No. 2,585,546 to Hadian, discloses an
example of a method for obtaining hyaluronic acid and which
involves extracting acetone-washed umbilical cords with a dilute
salt solution, acidifying the resulting extract, removing the clot
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 umbilical cords
with alcohol and ammonium sulfate. Alcohol is added to the acidic
salt extract, and the 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.
[0026] U.S. Pat. No. 4,517,296 to Bracke et al. is directed to the
preparation of hyaluronic acid in high yield from Streptococcus
bacteria by fermenting the bacteria under anaerobic conditions in a
CO.sub.2 enriched growth medium, separating the bacteria from the
resulting broth and isolating the 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 purified
by precipitation, resuspension and reprecipitation.
[0027] One particular fraction of hyaluronic acid (HA) that
exhibits excellent matrix formation according to the present
invention is hyaluronate sodium having a mean or average molecular
weight between 650,000-800,000, preferably 700,000-775,000 with a
high degree of purity, 95-105% free, and preferably at least 98%
pure, from contamination of related mucopolysaccharides.
Furthermore, this hyaluronic acid has a sulphated ash content of
less than 15% and a protein content of less than 5%. Examples of
usable base salts include those safe from animal and human use,
such as sodium, potassium, calcium, and magnesium salts or the
like.
[0028] 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.
[0029] The negative charged polymers are generally present in the
system in amounts which enable a solid gel to be formed. Generally,
gels are formed using amounts of about 2.0 to about 3.0 by weight
with amounts of about 2.1 to about 2.5% by weight being preferred
for use as a topical gel.
[0030] The solutions used to prepare the gels of the present
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.
[0031] A particularly preferred procedure involves separately
dissolving the nonionic polymer in water and centrifuging the
material to form a solution and remove impurities. This may be
conveniently done at rotation speeds of 2000 rpm for times of about
30 minutes to about two hours.
[0032] 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 400-3000 rpm for durations of 16-24 hours
have been found acceptable to produce stable solutions or gels of
the charged polymer.
[0033] Conventional pharmaceutically acceptable emulsifiers,
suspending agents, antioxidants (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 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.
[0034] 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 methoxypolyethylene glycol
(MPEG). Once all the components are blended together, for 400-3000
rpm for 1 to 4 hours, the system is filled into tubes and
sterilized. The resulting system is storage stable for several
years.
[0035] The formulations may be used topically and also contain
conventional pharmaceutically 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.
[0036] 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.
[0037] 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 house.
[0038] In this regard, it should be noted that reference to
therapeutically effective dose 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.
[0039] Doses may vary from patient to patient depending on 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.
[0040] The formulations of this invention may be used to treat a
variety of mammal and animal conditions and physical states. These
systems have particular application to pain management, namely the
treatment and alleviation of pain associated with any disease,
condition or physical state.
[0041] Without being limited to the specific pain being 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.
[0042] 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; 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 Kerati-nous Cyst; scalina
napular diseases, such as: Psoriasis; Pityriasis Rosea; and Lichen
Planus; pressure sores; benign tumors and malignant tumors.
[0043] A particularly preferred disorder 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 thinness of fat
and muscle padding between bony weight-bearing prominences and the
skin. Disuse atrophy, malnutrition, anemia, and infection play
contributory roles. In a paralyzed extremity, loss of vasomotor
control leads to a lowering of tone in the vascular bed and a
lowered circulatory rate. Spasticity, especially in patients with
spinal cord injuries, can place a shearing force on the blood
vessels to further compromise circulation.
[0044] The most important of the extrinsic factors is pressure. Its
force and duration directly determine the extent of the ulcer.
Pressure severe enough to impair local circulation can occur within
hours in an immobilized 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 irritation from ill-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.
[0045] 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 the 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 osteomyelitis, with the possibility of septic arthritis,
pathologic fraction and septicemia.
[0046] 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 ever 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 facilitates turning
patients with cord injuries. Protective padding (eg, sheepskin or a
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.
[0047] 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.
[0048] 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 1.5% 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.
[0049] 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 (eg, the trochanters,
ischia, and sacrum), since scar tissue cannot develop the tolerance
to pressure that is needed.
[0050] For spreading cellulitis, a penicillinase-resistant
penicillin or a cephalosporin is necessary.
[0051] 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; ie, some are wet and
lead to Pseudomonas infection if used too long, others are painful,
all are expensive, and some are of little value.
[0052] Use of the present formulations either alone or in
combination with various therapeutic agents overcomes all of these
prior art deficiencies.
[0053] 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, 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.
[0054] 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.
[0055] 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 drug
may vary from 0.0001% to about 75% by weight of the system when
using topically with 2 to 25 ml concentrations and preferably in 3
to 10 ml amounts.
[0056] The formulations of this invention are particularly useful
in the administration of drugs that could be previously
administered only orally.
[0057] 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.
[0058] Typically, NSAIDs have been known to produce gastric and
intestinal irritation. In addition, scarring and ulceration of the
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 market place, each one, however, with
the same potential to cause unpleasant and often serious
side-effects.
[0059] The transdermal applications of NSAIDs and particularly
diclofenac described herein, are a much safer way of treating
inflammatory disorders including those related to osteoarthritis
also known as Degenerative Joint Disease (DJD).
[0060] 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 antiinflammatory effect at the
joint level. At therapeutic dosages for diclofenac which are
usually between 100 mg and 200 mg per day, more than 50% of all
treated patients will experience some form of GI (gastrointestinal)
distress.
[0061] 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 a common practice of
rheumatologists and other specialists treating osteoarthritic 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 regimens "(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 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.
[0062] 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:
[0063] 1. Measurable blood levels of diclofenac.
[0064] 2. Diclofenac presence in the urine of patients treated with
the transdermal drug.
[0065] 3. The presence of diclofenac in synovial fluid where joints
with synovial fluid are the target sites for treatment.
[0066] 4. Rapid absorption following topical administration.
[0067] 5. Rapid relief of painful symptoms in a significant number
of patients already being treated with the products.
[0068] 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 proven ability for
the cream to be transdermally absorbed. Amounts of diclofenac
delivered by the cream are considered to be minimal at best.
[0069] It should be pointed out that diclofenac, as the sodium or
potassium salt, is a benzeneacetic acid 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.RTM. and Calaflam.RTM., 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 known;
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.
[0070] 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.
[0071] 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 in animals natural absorption of
the negatively charged polymer.
[0072] 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 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.
[0073] Particularly preferred nonionic polymers are cellulose
derivatives and particularly those selected from the group
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 0.1% to about 1.5% and
preferably about 0.5 to about 1.4%. Amounts above about 1.5% result
in the formation of a solid gel when used with the negatively
charged polymer. Amounts below about 0.1% have not been found
suitable to prepare a storage stable product that has sustained
drug release.
[0074] A particularly preferred HEC concentration is about 0.2% to
about 1.0% by weight of the matrix.
[0075] 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,
fluriproten, ketoprofen, voltaren (U.S. Pat. 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, fungal medications, monobactams and
viral agents and specifically including such as 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 potassium chloride and lithium carbonate; minerals
selected from the group consisting of 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.
[0076] One particular criteria of the drug is that they must be
solubilized in the polymer matrix solution in order to be topically
administered.
[0077] 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.
[0078] 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 100% by
weight.
EXAMPLE 1
[0079] This example demonstrates the formation of a transdermal
nonsteroidal antiinflammatory 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.
[0080] Example 1 also demonstrates the formation of a transdermal
preparation containing the NSAID drug 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.
[0081] 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.
1 MATERIALS Diclofenac sodium 3% Sodium hyaluronate (HA) 2.3%
Hydroxyethyl cellulose (HEC) 0.7% Methoxypolyethylene glycol (MPEG)
10% Benzyl alcohol 2.5% Water Remainder
Batch Size 1500 ml
[0082] 1. 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 a 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.
[0083] 2. Prepare a 0.7% 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.
[0084] 3. Carefully measure 150 ml of methoxypolyethylene glycol
(MPEG) 10% into the mixture. RPM speeds should be increased for the
mixture while this step is being performed to 2500 rpm. The
resulting mixture thus formed should be allowed to mix at 2000 rpm
for an additional 3 to 4 hours.
[0085] 4. At this point 2.5% 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 should be allowed to mix for
3 to 5 hours at 2000 rpm.
[0086] 5. Using safe techniques, 45 grams (3%) of the diclofenac
should be 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.
[0087] 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 technics, to 25 ml
borasylicate glass jars with a lined cap.
EXAMPLE 2
[0088] The formula and method of manufacture of Example 1 is
repeated for diclofenac potassium. The only difference is that MPEG
is not used.
2 MATERIALS Diclofenac potassium 3% Sodium hyaluronate (HA) 2.3%
Hydroxyethyl cellulose (HEC) 0.7% Benzyl alcohol 2.5%
Batch Size 15000 ml
[0089] 1. 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 a 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.
[0090] 2. Prepare a 0.7w 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.
[0091] 3. At this point 2.5% 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 should be allowed to mix for
3 to 5 hours at 2000 rpm.
[0092] 4. As described above, using safe techniques, 45 grams (3%)
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.
[0093] The final mixture is clear with a slight green tint
following 15 to 20 house of further mixing at 2000 rpm.
[0094] The final product should be transferred, using aseptic
technic, to 25 ml borasylicate glass jars with a lined cap.
EXAMPLE 3
[0095] The general manufacturing procedure of Example 1 is repeated
for a topical dermalogical preparation. The main difference in
composition is the use of methylparabin as a preservative.
3 MATERIALS Sodium hyaluronate (HA) 2.5% Hydroxyethyl cellulose
(HEC) 1.25% Benzyl alcohol 1% Methyl parabin 0.2% Water Q.S.
[0096] 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.
[0097] 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.
Test Procedure I
[0098] Patient LHN's complaint is of headache and pain in the back
of the neck.
[0099] History
[0100] She has been getting headaches for 30 years since she was
5-years-old. She has had several injuries in the past including
being thrown down the stairs.
[0101] 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.
[0102] 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.
[0103] Physical Examination
[0104] 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
[0105] Diagnosis
[0106] Cervicogenic headaches.
[0107] This was confirmed by diagnostic blocks bilaterally at 2-3,
3-4 and 4-5 which reduced her head and neck pain respectively of
6/10 and 10/10 to 0/10.
[0108] Treatment With Diclofenac Gel
[0109] 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.
[0110] 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
[0111] This is a 32-year-old man who complains of headaches.
[0112] History
[0113] 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.
[0114] Physical Examination
[0115] Flexion normal, extension 80%, rotation right 90% and
rotation left 90%. He is tender at the cervical facets of right
2-3, left 2-3 and the right lesser occipital nerve.
[0116] Diagnosis
[0117] Cervicogenic headache.
[0118] This was confirmed by a positive response to diagnostic
facet blocks at the right 2-3 and 3-4 cervical facets.
[0119] Treatment With Diclofenac Gel
[0120] This was rubbed on the facet joint area on the right 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 III
[0121] Her complaint is of severe holo-cranial headaches.
[0122] History
[0123] 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.
[0124] 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
a headache.
[0125] She has had some success with Fiorinal C1/2 in treating her
headaches.
[0126] Physical Examination
[0127] Neck: Flexion 30%, extension 40%, right rotation 80% and
left rotation 70%. 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.
[0128] Diagnosis
[0129] 1. Cervicogenic headache.
[0130] 2. Possible pre-existing migraine.
[0131] Treatment With Diclofenac Gel
[0132] This was rubbed on the facet joint areas bilaterally in the
neck region. The patient noticed a marked decrease 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
[0133] This 52-year-old lady had a long history of:
[0134] 1. Occasional headaches.
[0135] 2. Occasional neck pain.
[0136] History
[0137] 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.
[0138] Physical Examination
[0139] This revealed a tilt of the head to the left. With the right
shoulder higher than the left.
[0140] 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.
[0141] Diagnosis
[0142] Degenerative joint disease of the cervical spine causing
chronic headaches and occasional neck aches.
[0143] Results of Treatment With Diclofenac Gel
[0144] 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
[0145] This 47-year-old lady has a long history of:
[0146] 1. Constant headaches.
[0147] 2. Constant neck aches.
[0148] History
[0149] 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.
[0150] Physical Examination
[0151] This showed some limitation of flexion and extension to
about 65% of normal. The facet joints from C2 to C6 were
exquisitely tender more on the right than the left.
[0152] Diagnosis
[0153] Degenerative joint disease of the cervical spine causing
occasional headaches and neck aches.
[0154] Treatment With Diclofenac Gel
[0155] The diclofenac gel has successfully relieved her neck ache
on three different occasions. Each time the pain relief was almost
100%. In addition, it stopped the beginnings of a headache on each
occasion.
Test Procedure VI
[0156] This 26-year-old lady has a long history of:
[0157] 1. Constant neck ache.
[0158] 2. Almost daily headaches.
[0159] History
[0160] 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.
[0161] She was thought to have actually broken her jaw at the time
of the fall.
[0162] She has been investigated for TMJ disorder because there is
clearly some asymmetry in her face since the accident. However, the
TMJ specialist felt that there was no TMJ damage that could be
found.
[0163] She also was found to have tender facet joints from C2 to C6
bilaterally, and she said with her neck thrust forward and with
difficulty in flexion and extension particularly extension being
only about 60% of normal.
[0164] Physical Examination
[0165] 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.
[0166] The TMJ was not especially tender to palpation.
[0167] Diagnosis
[0168] Degenerative joint disease of the cervical spine causing
chronic neck aches and headaches.
[0169] Treatment With Diclofenac Gel
[0170] This was used on three occasions for severe neck pain. It
decreased the neck pain by about 50%. 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.
[0171] 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.
* * * * *