U.S. patent application number 12/873248 was filed with the patent office on 2011-03-03 for use of cannabidiol prodrugs in topical and transdermal administration with microneedles.
This patent application is currently assigned to ALLTRANZ INC.. Invention is credited to Stan Lee Banks, Miroslaw Jerzy Golinski, Dana Carmel Hammell, Jeffery Lynn Howard, Audra Lynn Stinchcomb.
Application Number | 20110052694 12/873248 |
Document ID | / |
Family ID | 43469376 |
Filed Date | 2011-03-03 |
United States Patent
Application |
20110052694 |
Kind Code |
A1 |
Stinchcomb; Audra Lynn ; et
al. |
March 3, 2011 |
USE OF CANNABIDIOL PRODRUGS IN TOPICAL AND TRANSDERMAL
ADMINISTRATION WITH MICRONEEDLES
Abstract
Described herein are microneedle drug delivery systems
comprising a pharmaceutical compositions comprising
pharmaceutically active agents (e.g., cannabidiol and prodrugs of
cannabidiol) and microneedle arrays suitable for local and systemic
delivery of the active agent to a mammal. Also described herein are
methods of using a microneedle transdermal or topical drug delivery
systems comprising pharmaceutical compositions, comprising
cannabidiol and prodrugs of cannabidiol, and microneedle arrays in
the treatment disease, including pancreatitis and pancreatic
cancer.
Inventors: |
Stinchcomb; Audra Lynn;
(Lexington, KY) ; Banks; Stan Lee; (Frankfort,
KY) ; Golinski; Miroslaw Jerzy; (Lexington, KY)
; Howard; Jeffery Lynn; (Richmond, KY) ; Hammell;
Dana Carmel; (Georgetown, KY) |
Assignee: |
ALLTRANZ INC.
Lexington
KY
|
Family ID: |
43469376 |
Appl. No.: |
12/873248 |
Filed: |
August 31, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61238524 |
Aug 31, 2009 |
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Current U.S.
Class: |
424/484 ;
424/642; 424/643; 424/702; 514/150; 514/162; 514/163; 514/21.9;
514/226.5; 514/263.31; 514/334; 514/374; 514/378; 514/406; 514/411;
514/413; 514/420; 514/423; 514/440; 514/458; 514/473; 514/512;
514/546; 514/548 |
Current CPC
Class: |
A61K 9/7007 20130101;
A61P 17/06 20180101; A61K 31/265 20130101; A61P 31/22 20180101;
A61P 31/18 20180101; A61P 1/18 20180101; C07C 271/52 20130101; A61P
19/02 20180101; C07C 229/12 20130101; A61P 25/08 20180101; C07C
219/04 20130101; A61P 25/04 20180101; A61P 1/04 20180101; A61P
17/04 20180101; A61P 25/00 20180101; A61P 37/02 20180101; A61K
31/225 20130101; A61P 3/00 20180101; A61P 17/00 20180101; A61P
39/06 20180101; A61K 31/222 20130101; C07C 229/16 20130101; A61P
21/00 20180101; A61P 43/00 20180101; C07C 219/16 20130101; C07C
2601/16 20170501; A61K 9/0021 20130101; A61K 31/27 20130101; A61K
9/0014 20130101; A61P 35/00 20180101; A61P 25/18 20180101; A61P
29/00 20180101; A61P 17/02 20180101; A61K 45/06 20130101; A61P
17/14 20180101; A61P 1/08 20180101 |
Class at
Publication: |
424/484 ;
514/548; 514/512; 514/546; 514/162; 514/163; 514/420; 514/413;
514/226.5; 514/374; 514/150; 514/423; 514/378; 514/411; 514/406;
514/473; 514/334; 514/21.9; 514/458; 424/642; 424/643; 424/702;
514/263.31; 514/440 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/24 20060101 A61K031/24; A61K 31/265 20060101
A61K031/265; A61K 31/235 20060101 A61K031/235; A61K 31/616 20060101
A61K031/616; A61K 31/405 20060101 A61K031/405; A61K 31/407 20060101
A61K031/407; A61K 31/5415 20060101 A61K031/5415; A61K 31/421
20060101 A61K031/421; A61K 31/655 20060101 A61K031/655; A61K 31/40
20060101 A61K031/40; A61K 31/42 20060101 A61K031/42; A61K 31/415
20060101 A61K031/415; A61K 31/341 20060101 A61K031/341; A61K 31/444
20060101 A61K031/444; A61K 38/06 20060101 A61K038/06; A61K 31/355
20060101 A61K031/355; A61K 33/30 20060101 A61K033/30; A61K 33/04
20060101 A61K033/04; A61K 31/522 20060101 A61K031/522; A61K 31/385
20060101 A61K031/385; A61P 35/00 20060101 A61P035/00; A61P 29/00
20060101 A61P029/00; A61P 1/08 20060101 A61P001/08; A61P 3/00
20060101 A61P003/00; A61P 25/00 20060101 A61P025/00; A61P 19/02
20060101 A61P019/02; A61P 25/08 20060101 A61P025/08; A61P 25/18
20060101 A61P025/18; A61P 39/06 20060101 A61P039/06; A61P 37/02
20060101 A61P037/02; A61P 17/06 20060101 A61P017/06; A61P 17/04
20060101 A61P017/04; A61P 1/04 20060101 A61P001/04; A61P 17/02
20060101 A61P017/02 |
Claims
1. A microneedle drug delivery system for transdermal or topical
administration of a cannabidiol prodrug to a mammal comprising: a)
a pharmaceutical composition comprising a cannabidiol prodrug
having the formula: ##STR00012## wherein R.sub.1 and R.sub.2 can be
the same or different and are each independently selected from the
group consisting of: a hydrogen, an ester, an oxygenated ester, an
oxaester, pegylated ester, a hydroxylated ester, an alkyl ester, an
amino ester, an alkylamino ester, a dialkylamino ester, a
trialkylammonium ester, a carbonate, an alkyl carbonate, an amino
carbonate, an alkylamino carbonate, a dialkylamino carbonate, a
trialkylammonium carbonate, a carbamate, an alkyl carbamate, an
amino carbamate, an alkylamino carbamate, a dialkylamino carbamate,
a trialkylammonium carbamate, a substituted phosphate ester, an
unsubstituted phosphate ester, an unsubstituted diphosphate ester,
a substituted diphosphate ester, an unsubstituted triphosphate
ester, a substituted triphosphate ester, a phosphonate ester, a
substituted sulfate esters, an unsubstituted sulfate esters, a
sulphonate ester, an alpha-acyloxyalkyl, an
alpha-phosphoryloxyalkyl, an alpha-sulphonyloxyalkyl; and wherein
R.sub.1 and R.sub.2 cannot both be a hydrogen atom; and b) a
microneedle array.
2. The drug delivery system of claim 1, wherein the cannabidiol
prodrug is selected from the group consisting of: ##STR00013##
##STR00014## ##STR00015## ##STR00016## ##STR00017##
3. The drug delivery system of claim 1, wherein the cannabidiol
prodrug selected from the group consisting of: ##STR00018##
##STR00019## wherein X.sup.- is a counter ion derived from
pharmaceutically acceptable acids.
4. The drug delivery system of claim 1, wherein the cannabidiol
prodrug is present in an amount of about 0.1% to about 50% (wt/wt)
of the pharmaceutical composition.
5. The drug delivery system of claim 1, wherein the cannabidiol
prodrug is present in an amount of about 0.1% to about 40% (wt/wt)
of the pharmaceutical composition.
6. The drug delivery system of claim 1, wherein the cannabidiol
prodrug is present in an amount of about 5% to about 30% (wt/wt) of
the pharmaceutical composition.
7. The drug delivery system of claim 1, wherein the cannabidiol
prodrug is present in an amount of about 10% to about 20% (wt/wt)
of the pharmaceutical composition.
8. The drug delivery system of claim 1, wherein the pharmaceutical
composition is in a form of a hydrogel.
9. The drug delivery system of claim 8, wherein the hydrogel is
incorporated into a matrix- or reservoir-type patch.
10. The drug delivery system of claim 1, wherein the pharmaceutical
composition further comprises a COX inhibitor selected from the
group consisting of: a non-specific COX inhibitor, a COX-1
inhibitor and a COX-2 inhibitor.
11. The drug delivery system of claim 9, wherein the non-specific
COX inhibitor is selected from the group consisting of: aspirin,
diclofenac, diflunisal, fenoprofen, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam,
nabumetone, naproxen, olsalzine, oxaprozin, piroxicam, salsalate,
sulfasalazine, sulindac and tolmetin.
12. The drug delivery system of claim 9, wherein the COX-1
inhibitor is selected from the group consisting of: mofezolac,
SC-560 and FR122047.
13. The drug delivery system of claim 9, wherein the COX-2
inhibitor is selected from the group consisting of: etodolac,
celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib and
etoricoxib.
14. The drug delivery system of claim 1, wherein the pharmaceutical
composition further comprises is an antioxidant selected from the
group consisting of: citric acid, butylated hydroxytoluene,
ascorbic acid, glutathione, retinol, .alpha.-tocopherol,
.beta.-carotene, .alpha.-carotene, ubiquinone, butylated
hydroxyanisole, ethylenediaminetetraacetic acid, selenium, zinc,
lignan, uric acid, lipoic acid, and N-acetylcysteine.
15. The drug delivery system of claim 1, wherein the pharmaceutical
composition further comprises a penetration enhancer selected from
the group consisting of: isostearic acid, octanoic acid, oleic
acid, oleyl alcohol, lauryl alcohol, ethyl oleate, isopropyl
myristate, butyl stearate, methyl laurate, diisopropyl adipate,
glyceryl monolaurate, tetrahydrofurfuryl alcohol polyethylene
glycol ether, polyethylene glycol, propylene glycol,
2-(2-ethoxyethoxy)ethanol, diethylene glycol monomethyl ether,
alkylaryl ethers of polyethylene oxide, polyethylene oxide
monomethyl ethers, polyethylene oxide dimethyl ethers, dimethyl
sulfoxide, glycerol, acetoacetic ester, N-alkylpyrrolidone,
terpenes, n-octanol, sodium oleate, D-limonene, monoolein, cineol,
oleyl oleate, ethanol, propanol, butanol, 2-butanol, pentanol,
2-pentanol, hexanol, octanol, nonanol, decanol, benzyl alcohol,
Polyxamer 231, Polyxamer 182, Polyxamer 184, Polysorbate 20,
Polysorbate 60, Brij 30, Brij 93, Brij 96, Brij 99, Span 20, Span
40, Span 60, Span 80, Span 85, Tween 20, Tween 40, Tween 60, Tween
80), Myrj 45, Myrj 51, Myrj 52) and Miglyol 840.
16. The drug delivery system of claim 15, wherein the penetration
enhancer is present in an amount of about 0.1% to about 40% (wt/wt)
of the pharmaceutical composition.
17. The drug delivery system of claim 15, wherein the penetration
enhancer is present in an amount of about 0.1% to about 30% (wt/wt)
of the pharmaceutical composition.
18. The drug delivery system of claim 15, wherein the penetration
enhancer is present in an amount of about 1% to about 20% (wt/wt)
of the pharmaceutical composition.
19. The drug delivery system of claim 15, wherein the penetration
enhancer is present in an amount of about 1% to about 10% (wt/wt)
of the pharmaceutical composition.
20. The drug delivery system of claim 1, wherein the pharmaceutical
composition further comprises a lower alcohol selected from the
group consisting of: ethanol and isopropanol.
21. The drug delivery system of claim 1, wherein the pharmaceutical
composition delivers a therapeutically effective amount of the
cannabidiol prodrug over a period of time selected from the group
consisting of: about 1 hour, about 2 hours, about 3 hours, about 4
hours, about 6 hours, about 12 hours, about 24 hours, about 48
hours, about 72 hours, about 96 hours, about 5 days, about 6 days
or about 7 days.
22. A method of treating a disease state in a mammal in need
thereof, comprising the step of: (a) applying a microneedle drug
delivery system as described in any of claims 1 to 20; wherein the
disease state is selected from the group consisting of: acute
pancreatitis, chronic pancreatitis, pancreatic cancer, nausea,
emesis, pain, wasting syndrome, HIV-wasting, chemotherapy induced
nausea and vomiting, alcohol use disorders, dystonia, multiple
sclerosis, inflammatory bowel disorders, arthritis, dermatitis,
Rheumatoid arthritis, systemic lupus erythematosus, melanoma,
anti-inflammatory, anti-convulsant, anti-psychotic, antioxidant,
neuroprotective, anti-cancer, immunomodulatory effects, peripheral
neuropathic pain, neuropathic pain associated with post-herpetic
neuralgia, diabetic neuropathy, shingles, burns, actinic keratosis,
oral cavity sores and ulcers, post-episiotomy pain, psoriasis,
pruritis, contact dermatitis, eczema, bullous dermatitis
herpetiformis, exfoliative dermatitis, mycosis fungoides,
pemphigus, severe erythema multiforme (e.g., Stevens-Johnson
syndrome), seborrheic dermatitis, ankylosing spondylitis, psoriatic
arthritis, Reiter's syndrome, gout, chondrocalcinosis, joint pain
secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain,
neuropathic-postoperative complications, polymyositis, acute
nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic
osteoarthritis, osteoarthritis, rheumatoid arthritis, synovitis,
juvenile rheumatoid arthritis and inhibition of hair growth.
23. A microneedle drug delivery system for transdermal or topical
administration of a cannabidiol prodrug to a mammal comprising: (a)
a pharmaceutical composition comprising (i) about 0.1% to about 40%
of a cannabidiol prodrug having the formula: ##STR00020## wherein
R.sub.1 and R.sub.2 can be the same or different and are each
independently selected from the group consisting of: a hydrogen, an
ester, an oxygenated ester, an oxaester, pegylated ester, a
hydroxylated ester, an alkyl ester, an amino ester, an alkylamino
ester, a dialkylamino ester, a trialkylammonium ester, a carbonate,
an alkyl carbonate, an amino carbonate, an alkylamino carbonate, a
dialkylamino carbonate, a trialkylammonium carbonate, a carbamate,
an alkyl carbamate, an amino carbamate, an alkylamino carbamate, a
dialkylamino carbamate, a trialkylammonium carbamate, a substituted
phosphate ester, an unsubstituted phosphate ester, an unsubstituted
diphosphate ester, a substituted diphosphate ester, an
unsubstituted triphosphate ester, a substituted triphosphate ester,
a phosphonate ester, a substituted sulfate esters, an unsubstituted
sulfate esters, a sulphonate ester, an alpha-acyloxyalkyl, an
alpha-phosphoryloxyalkyl, an alpha-sulphonyloxyalkyl; and wherein
R.sub.1 and R.sub.2 cannot both be a hydrogen atom; and (ii) about
0.1% to about 20% of one or more co-solvents; (iii) about 15% to
about 95% a lower alcohol; and (iv) water in a quantity sufficient
for the composition to total 100% (wt/wt) (b) a microneedle
array.
24. The drug delivery system of claim 23, wherein the cannabidiol
prodrug is selected from the group consisting of: ##STR00021##
##STR00022## ##STR00023## ##STR00024## ##STR00025##
25. The drug delivery system of claim 23, wherein the cannabidiol
prodrug selected from the group consisting of: ##STR00026##
##STR00027## wherein X.sup.- is a counter ion derived from
pharmaceutically acceptable acids.
26. The drug delivery system of claim 23, wherein the cannabidiol
prodrug is present in an amount of about 5% to about 30% (wt/wt) of
the pharmaceutical composition.
27. The drug delivery system of claim 23, wherein the cannabidiol
prodrug is present in an amount of about 10% to about 20% (wt/wt)
of the pharmaceutical composition.
28. The drug delivery system of claim 23, wherein the co-solvents
is selected from the group consisting of: ethanol, benzyl alcohol
and mixtures of the foregoing.
29. The drug delivery system of claim 23, wherein the
pharmaceutical composition is in the form of a hydrogel.
30. The drug delivery system of claim 29, wherein the hydrogel is
incorporated into a matrix- or reservoir-type patch.
31. The drug delivery system of claim 23, wherein the
pharmaceutical composition further comprises a COX inhibitor
selected from the group consisting of: a non-specific COX
inhibitor, a COX-1 inhibitor and a COX-2 inhibitor.
32. A compound selected from the group consisting of: ##STR00028##
##STR00029## wherein X.sup.- is a counter ion derived from
pharmaceutically acceptable acids.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/238,524, filed on Aug. 31, 2009, which is hereby
incorporated by reference in its entirety to the extent permitted
by law.
FIELD
[0002] Described herein are microneedle drug delivery systems
comprising: a pharmaceutical composition comprising
pharmaceutically active agents (e.g., cannabinoids, such as
cannabidiol or prodrugs of cannabidiol) and microneedle arrays
suitable for local and systemic delivery to a mammal, including
systemic transdermal delivery and topical delivery. Also described
herein are methods of using a microneedle transdermal or topical
drug delivery system comprising a pharmaceutical composition,
comprising a cannabinoid (such as cannabidiol or prodrugs of
cannabidiol), and a microneedle array in the treatment of a disease
responsive to cannabinoid therapy
BACKGROUND
[0003] It has now been found that a pharmaceutical composition
comprising a cannabinoid, such as cannabidiol, or a cannabinoid
prodrug, such as a cannabidiol prodrug, can be transdermally
administered to a mammal in conjunction with a microneedle array to
treat a medical condition responsive to cannabinoids, such as
alcohol use disorders, pain, inflammation and pancreatic diseases,
such as pancreatic cancer and pancreatitis, via transdermal or
topical drug delivery systems. It has further been found that
microneedle transdermal or topical drug delivery systems comprising
a pharmaceutical composition, comprising a cannabinoid or
cannabinoid prodrug and a penetration enhancer (i.e., co-solvent),
and a microneedle array can be used to treat a medical condition
responsive to cannabinoids, such as alcohol use disorders, pain,
inflammation and pancreatic diseases, such as pancreatic cancer and
pancreatitis. It has further been found that microneedle
transdermal or topical drug delivery systems comprising a
pharmaceutical composition, comprising a cannabinoid or cannabinoid
prodrug, a microneedle array and a COX inhibitor, such that the
duration in which the microneedle created pore will remain open is
increased, can be administered to a mammal. Suitable COX inhibitors
include diclofenac and ibuprofen.
[0004] The pharmaceutical compositions described herein are
suitable for use with a COX inhibitor-containing gel or hydrogel
which has been optionally incorporated into a patch. In one
embodiment, the COX inhibitor-containing gel or hydrogel which has
been optionally incorporated into a patch is distinct from the
pharmaceutical composition containing a cannabinoid or a
cannabinoid prodrug and is applied to the skin surface either
before, during or after the skin has been treated with a
microneedle array. In another embodiment, the pharmaceutical
compositions comprising the cannabinoid or cannabinoid prodrug
further comprises a COX-inhibitor and is administered as a gel or
hydrogel which has been optionally incorporated into a patch that
is applied to the skin surface either before, during or after the
skin had been treated with a microneedle array.
[0005] Cannabinoids and Cannabidiol
[0006] Cannabinoids, including cannabidiol ("CBD"), have recently
been found useful in treating pancreatic illnesses. For example, it
has been found that cannabidiol is useful in the treatment of acute
and chronic pancreatitis. Pancreatitis is widely known as a very
painful disease and can ultimately lead to pancreatic cancer. It
has been found that cannabidiol has anti-inflammatory activity that
results in a decrease of pain in pancreatitis cases. Pancreatic
cancer is the fourth most common fatal cancer in the United States
and fifth most prevalent worldwide. Cannabinoids, such as
tetrahydrocannabinol and the synthetic cannabinoid WIN 55, 212-2,
have been found to induce apoptosis of pancreatic tumor cells in
vitro and in vivo. Cannabidiol has the same potential to cause the
same cascade that results in tumor cell death and diminish
proliferation to lateral tumor formation.
[0007] In addition, the clinical usefulness of cannabinoids,
including cannabidiol, to provide analgesia and neuroprotection,
reduce inflammation, help alleviate nausea and emesis, as well as
treat epilepsy, anxiety disorders and glaucoma, has been
well-recognized. In addition, it is also well-known that
cannabidiol lacks the psychoactive effects seen in many of the
other cannabinoids, including .DELTA..sup.9-tetrahydrocannabinol,
which is currently available in an oral dosage form, sold under the
trade name Marinol.RTM..
[0008] Pain is the most frequently reported symptom and it is a
common clinical problem confronting all clinicians. Millions of
people in the United States suffer from severe pain that, according
to numerous recent reports, is chronically under-treated or
inappropriately managed. Similarly, millions of people also suffer
from severe nausea and/or frequent emesis. Moreover, all too
frequently, many patients suffering from chronic, under-treated or
irretraceable pain also suffer from lack of appetite, nausea and/or
frequent emesis. These patients present a greater clinical
challenge as they are unable to receive effective doses of oral
pain medications, thereby leaving their pain unalleviated.
Cannabinoids, including cannabidiol, are effective in alleviating
pain. Moreover, cannabinoids, including cannabidiol, can reduce a
patient's nausea and vomiting, independent of any pain relief
achieved. Thus, cannabinoids are particularly useful in patients
experiencing nausea and vomiting secondary to un- or under-treated
pain.
[0009] A notable percentage of the United States population satisfy
the diagnostic criteria for alcohol use disorders ("AUDs"). The
consumption of excessive amounts of alcohol results in a complex
array of pharmacological effects that directly impact the ability
to treat the condition. These effects directly impact the brain and
include progressive neurodegeneration, impaired executive function
and dependence leading to withdrawal-induced negative effects. It
is known that cannabinoids, including cannabidiol, have
neuroprotective, anxiolytic and anti-convulsant effects, which may
be effective in preventing additional brain damage in persons with
AUDs, while simultaneously decreasing the frequency of
relapses.
[0010] Chronic abusers of cannabis can develop dependence and
experience withdrawal symptoms when they attempt to discontinue use
of the drug. Collectively, cannabis dependence and withdrawal are
referred to herein as cannabis use disorders. It is known to those
of skill in the art that cannabinoids, including cannabidiol, are
useful in treating cannabis use disorders.
[0011] Dystonia is a neurological movement disorder, with many
known causes, and characterized by involuntary, continual muscular
contractions causing twisting and repetitive movements or abnormal
postures. Cannabinoids have been shown to reduce the muscular
contractions characteristic of this disorder.
[0012] The etiological pathology of many diseases relates to the
inflammatory processes that are regulated by an individual's immune
system. Inflammation may result from (1) an otherwise appropriate
immunoresponse to an outside trauma, such as brain swelling
secondary to a closed head injury; (2) an overactive
immunoresponse, such as an allergic reaction or dermatitis; or (3)
an inappropriate auto-immunoresponse, such as certain forms of
multiple sclerosis, inflammatory bowel disorders and arthritis.
Regardless of the underlying cause of the inflammation, it is
therapeutically desirable under these circumstances to regulate the
immune system and lessen the inflammatory response. Cannabinoids
have been shown to regulate various steps in the immune response
and could show some therapeutic benefit in the treatment of certain
inflammatory diseases such as psoriatic arthritis.
[0013] Rheumatoid arthritis affects approximately 0.5-1% of the
United States population, and autoimmune diseases in general affect
more than 20 million Americans. The pain associated with rheumatoid
arthritis can often be disabling. Cannabinoids have been found to
be useful as an adjunct treatment for rheumatoid arthritis and
joint pain secondary to other autoimmune diseases, such as
inflammatory bowel disease, multiple sclerosis and systemic lupus
erythematosus.
[0014] In addition, transdermally administered cannabinoids have
been found to be useful to alleviate pain and other conditions
associated with deeper tissues, such as peripheral nerves, muscles
and synovial tissues. Examples of conditions associated with deeper
tissues responsive to cannabinoids include: peripheral neuropathic
pain, including but not limited to, the peripheral neuropathic pain
associated with diabetic neuropathy, ankylosing spondylitis,
Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to
dysmenorrhea, fibromyalgia, musculoskeletal pain,
neuropathic-postoperative complications, polymyositis, acute
nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic
osteoarthritis, osteoarthritis, rheumatoid osteoarthritis,
synovitis and juvenile rheumatoid arthritis. When cannabinoids are
administered transdermally to treat pain and other conditions
associated with deeper tissues, including peripheral neuropathic
pain, it may be useful to have significant local tissue and
systemic levels of cannabinoids.
[0015] In addition to the above-discussed therapeutics benefits,
cannabinoids, such as cannabidiol and cannabidiol prodrugs, present
a variety of pharmacological benefits, including, but not limited
to, anti-inflammatory, anti-convulsant, anti-psychotic,
antioxidant, neuroprotective, anti-cancer, such as melanoma, and
immunomodulatory effects.
[0016] Given these systemic therapeutic benefits, it would be
advantageous to develop a composition in which a cannabinoid, such
as cannabidiol or a prodrug of cannabidiol, is delivered
systemically to achieve therapeutically effective plasma
concentrations in a patient. However, cannabinoid oral dosage
forms, including those comprising cannabidiol, must overcome
several obstacles in order to achieve a therapeutically-effective
systemic concentration. First, cannabinoids are generally highly
lipophilic. Their limited water solubility thereby restricts the
amount of cannabinoid available for absorption in the
gastrointestinal tract. Second, cannabidiol, as with the other
cannabinoids, undergoes substantial first-pass metabolism when
absorbed from the human gastrointestinal tract. Finally, the oral
bioavailability of any product is further diminished when a patient
suffers from nausea or emesis, as either the patient avoids taking
his oral medications or the oral dosage form does not remain in the
gastrointestinal tract for a sufficient period of time to release
the entire dose and achieve a therapeutic concentration.
[0017] Therefore, in view of the foregoing, it would be desirable
to systemically deliver therapeutically effective amounts of a
cannabinoid, such as cannabidiol or cannabidiol prodrug, to a
mammal in need thereof for the treatment of one or more medical
conditions responsive to cannabinoids, including pancreatic cancer,
pancreatitis, pain, nausea or appetite stimulation, by a route of
administration that does not depend upon absorption from the
gastrointestinal tract of the mammal. One non-oral route of
administration for the systemic delivery of cannabidiol is
transdermal administration.
[0018] In addition, the epidermis and dermis of many mammals, such
as humans and guinea pigs, contains enzymes which are capable of
metabolizing active pharmaceutical agents which pass through the
stratum corneum. The metabolic process occurring in the skin of
mammals, such as humans, can be utilized to deliver
pharmaceutically effective quantities of a cannabinoid, such as
cannabidiol, to the systemic circulation of a mammal in need
thereof. Described herein are prodrugs of cannabinoids, such as
cannabidiol prodrugs, and compositions comprising prodrugs of
cannabinoids that can be transdermally administered to a mammal,
such as a human, so that the metabolic product resulting from
metabolism in the skin is the cannabinoid which is systemically
available for the treatment of a medical condition responsive to
cannabinoid, for example pancreatic diseases, such as pancreatitis
and pancreatic cancer.
[0019] Unfortunately, due to its highly lipophilic nature,
cannabidiol is poorly absorbed through membranes such as the skin
of mammals, including humans. Therefore, the success of
transdermally administering therapeutically effective quantities of
cannabidiol to a mammal in need thereof within a reasonable time
frame and over a suitable surface area has been substantially
limited.
[0020] Microneedles and COX Inhibitors
[0021] Enhancing the transdermal delivery of an active
pharmaceutical agent by use of microneedle treatment has become an
important area of research in the field of transdermal drug
delivery. In addition, shorter microneedles may alternatively be
used to topically administer an active pharmaceutical agent for
local delivery to treat dermal conditions. It has further been
found that a pharmaceutical composition comprising a cannabinoid or
cannabinoid prodrug and a penetration enhancer can be administered
to a mammal in conjunction with a microneedle array to treat a
medical condition responsive to cannabinoids, including alcohol use
disorders and pancreatic diseases, such as pancreatic cancer and
pancreatitis. To enhance the transdermal or topical delivery of
cannabinoids when administered in conjunction with microneedles,
cannabinoid prodrugs (e.g., cannabidiol prodrugs) have been
designed which typically have a greater water solubility than the
parent cannabinoid molecule in order to take advantage of the
aqueous pores created by microneedle use.
[0022] Microneedles are generally considered to be structures that
are between about 20 .mu.m and about 1000 .mu.m in length capable
of puncturing the outermost layer of the epidermis (stratum
corneum) to create large-scale openings (relative to the size of
the active pharmaceutical agent to be delivered there through) or
pores through which one or more active pharmaceutical ingredients
can be delivered. The depth of microneedle penetration is
sufficient to enhance transdermal drug delivery but not sufficient
to stimulate nerve endings. Therefore, the use of microneedles is
pain-free. This aspect, as well as their economical and easy use,
makes a system incorporating microneedle technology an attractive
alternative for transdermal drug delivery.
[0023] The active pharmaceutical agents to be delivered in
conjunction with microneedle technology range from large
oligonucleotides to insulin, and highly water-soluble compounds.
Compared to other methods of physically altering the cutaneous
structure to aid in improving transdermal transport, microneedle
delivery is a relatively simple technique. Microneedles are
typically micromachined to increase permeability and decrease skin
sensation and come in various forms, such as biodegradable
polymers, silicon and stainless steel. Various researchers have
studied the effects of microneedle-treated skin on increased
permeation of mostly water soluble compounds through
microneedle-created aqueous pores. It has been shown that the use
of microneedles can enhance the permeation of many compounds
including non-viral gene therapy vectors, desmopressin, insulin and
naltrexone. Further, the application of microneedles has been shown
to be pain free in comparison to a 26-gauge hypodermic needle.
[0024] The effectiveness of microneedles is dependent on the
duration of time that the microneedle-created pores in the stratum
corneum remain sufficiently open and "un-healed." It is during this
time that the enhanced delivery of the active pharmaceutical agent
can continue. Recently there have been many determinations in pore
lifetime and viability via a number of experiments involving
transepidermal water loss, microscopic visualization and
pharmacokinetic analysis. Transepidermal water loss ("TEWL")
measures the rate at which water escapes from the skin. TEWL values
are commonly measured in damaged skin to determine water loss over
time as a function of skin repair. By using an evaporimeter, an
instrument that measures water loss, damage or changes in skin
morphology can be determined by an increase in rate of water loss
compared to "normal" skin. It has now been shown that TEWL readings
are a valid measurement to observe the status of the permeability
barrier.
[0025] Occlusive coverings, such as patches or hydrogels (which can
be optionally incorporated into a patch), can be used to maintain
microneedle-created pores. When a microneedle array was placed on
the skin and removed without having been treated with an occlusive
patch, the skin healed rapidly and TEWL readings returned to
baseline levels within 30 minutes. In contrast, it has been
demonstrated that under an occlusive environment,
microneedle-created pores remained open for at least 48-72 hours.
Likewise, microscopic visualization after staining has revealed
that pores were present up to 72 hours. In hairless guinea pigs
treated with 6-.beta.-naltrexol hydrochloride, significant
enhancement in microneedle pore viability was observed for 48 hours
after microneedle exposure and occlusion, compared to untreated
skin. It has also been shown that therapeutic levels of naltrexone
(2.5.+-.1.1 ng/mL) were achieved when a 16% naltrexone
hydrochloride gel was administered to 6 healthy human volunteers
after microneedle pretreatment. Further, it has been observed that
when used in conjunction with microneedles, steady state naltrexone
concentrations were achieved within two hours and remained for 48
hours. These results indicate that microneedle application to skin
provides an alternative delivery route to oral, injectables and
traditional passive transdermal delivery.
[0026] Even with the use of occlusive techniques (e.g., a patch
which may optionally have a hydrogel incorporated therein) in
conjunction with the microneedle-generated pores, it is,
nevertheless, desirable to further extend the lifetime of
microneedle-created pores. Such an increase in the duration of the
pore opening can correspond to an increase in the interval between
which doses are administered. Said differently, by increasing the
duration of the pore opening, it is possible to reduce the
frequency with which an active must be administered. Reductions in
the dosage frequency have a positive impact on patient acceptance
and compliance. Thus, it would be desirable to further enhance the
viability of the microneedle-created pores in order to increase the
rate, duration and extent of transdermal delivery of an active
pharmaceutical agent.
[0027] It has been found that the rate and extent of cannabinoid
transdermal absorption can be improved by administering a
cannabinoid (e.g. cannabidiol) or a cannabinoid prodrug (e.g., a
prodrug of cannabidiol) and optionally a penetration enhancer or
co-solvent and/or a COX inhibitor, in pharmaceutical compositions
in conjunction with microneedle arrays. It has further been
discovered that by optimizing the composition excipients, the
cannabinoid or cannabinoid prodrug can be administered, in
conjunction with a microneedle array, on a schedule that encourages
patient compliance, by reducing frequency of dosing to once or
twice daily or even once or twice weekly.
[0028] Accordingly, a significant advancement in the art would
occur with the development of a transdermal drug delivery system
comprising pharmaceutical compositions, comprising a cannabinoid
(e.g. cannabidiol) or a cannabinoid prodrug (e.g., a prodrug of
cannabidiol), and a microneedle array in treatment of conditions
responsive to cannabinoids. A further advancement would be the
development of a transdermal drug delivery system comprising a
pharmaceutical composition, comprising a cannabinoid (e.g.
cannabidiol) or a cannabinoid prodrug (e.g., a prodrug of
cannabidiol) and a microneedle array in treatment of (i) acute
pancreatitis; (ii) chronic pancreatitis; (iii) pancreatic cancer;
(iv) pain; (v) inflammation or (vi) alcohol use disorders.
[0029] Topical Delivery
[0030] In addition to the benefits of systemically administered
cannabinoid discussed above, cannabinoids, including cannabidiol
and prodrugs of cannabidiol, have been found to have localized
benefits from topical administration. For example, topically
administered cannabinoids have been found to be useful to alleviate
pain and other conditions originating at or near the surface of the
skin, including but not limited to, pain associated with
post-herpetic neuralgia, shingles, burns, actinic keratosis, oral
cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis,
contact dermatitis, eczema, bullous dermatitis herpetiformis,
exfoliative dermatitis, mycosis fungoides, pemphigus, severe
erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic
dermatitis, melanoma and psoriatic arthritis. Also, it has been
found that the topical administration of cannabinoids, including
cannabidiol, can inhibit the growth of hair.
[0031] In order to achieve these local benefits, it may be
advantageous for the cannabinoid, (e.g., cannabidiol) or a
cannabinoid prodrug (e.g., a cannabidiol prodrug) to penetrate the
stratum corneum but not be absorbed systemically. In such a case,
the cannabinoid (e.g., cannabidiol) or cannabinoid prodrug (e.g., a
prodrug of cannabidiol) would concentrate in the skin and/or
pilosebaceous unit, thus maximizing its local effect. Not only does
the localized effect increase the potential therapeutic benefit, it
lessens the frequency and severity of side-effects associated with
systemic cannabinoid administration because the amount of active
compound circulating in the patient is reduced. The cannabinoid
(e.g., cannabidiol) or cannabinoid prodrug (e.g., a cannabidiol
prodrug) can be incorporated into a composition with an additional
active moiety that is capable of improving the appearance and/or
hydration of the skin.
[0032] Accordingly, a significant advancement in the art would
occur with the development of a topical drug delivery system
comprising a pharmaceutical composition, comprising a cannabinoid
(e.g., cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol
prodrug) and a microneedle array in the treatment of condition
responsive to cannabinoid therapy.
SUMMARY
[0033] Described herein are microneedle drug delivery systems
suitable for transdermal and topical administration comprising a
pharmaceutical composition, comprising a cannabinoid (e.g.,
cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol prodrug)
and a microneedle array. Also described herein are methods of using
a microneedle transdermal or topical drug delivery system for
administering pharmaceutical compositions comprising a cannabinoid
(e.g., cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol
prodrug) and a microneedle array in the treatment of diseases in
mammals.
[0034] Some alternative embodiments also include the use of a
hydrogel as part of the drug delivery system.
[0035] Other embodiments, objects, features and advantages will be
set forth in the detailed description of the embodiments that
follows, and in part will be apparent from the description or may
be learned by practice of the claimed invention. These objects and
advantages will be realized and attained by the processes and
compositions described and claimed herein. The foregoing Summary
has been made with the understanding that it is to be considered as
a brief and general synopsis of some of the embodiments disclosed
herein, is provided solely for the benefit and convenience of the
reader, and is not intended to limit in any manner the scope, or
range of equivalents, to which the appended claims are lawfully
entitled.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 shows the cumulative permeation profile of total CBD
(total cannabidiol equivalents delivered in the form of cannabidiol
and/or prodrugs ALL00179 and ALL00180) from ALL00179 (n=5) in 100%
ddH.sub.2O donor solution through microneedle-treated Yucatan pig
skin.
DESCRIPTION
[0037] While the present invention is capable of being embodied in
various forms, the description below of several embodiments is made
with the understanding that the present disclosure is to be
considered as an exemplification of the claimed subject matter, and
is not intended to limit the appended claims to the specific
embodiments illustrated. The headings used throughout this
disclosure are provided for convenience only and are not to be
construed to limit the claims in any way. Embodiments illustrated
under any heading may be combined with embodiments illustrated
under any other heading. Embodiments disclosed herein are inclusive
and exclusive of other embodiments.
[0038] Transdermal and Topical Drug Delivery Systems
[0039] One embodiment described herein includes microneedle
transdermal or topical drug delivery systems comprising a
microneedle array and a pharmaceutical composition, wherein the
pharmaceutical composition comprises a cannabinoid (e.g.,
cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol
prodrug). In a further embodiment, the microneedle transdermal or
topical drug delivery system comprises a microneedle array and a
pharmaceutical composition, wherein the composition comprises a
cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a
cannabidiol prodrug) and a COX inhibitor. In yet a further
embodiment, the microneedle transdermal or topical drug delivery
system comprises a microneedle array and a pharmaceutical
composition, where in the composition comprises a cannabinoid
(e.g., cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol
prodrug) and a penetration enhancer or co-solvent. In yet a further
embodiment, the microneedle transdermal or topical drug delivery
system comprises a microneedle array and a pharmaceutical
composition, where in the composition comprises a cannabinoid
(e.g., cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol
prodrug), a COX inhibitor and a penetration enhancer or
co-solvent.
[0040] In one embodiment described herein, the microneedle
transdermal or topical drug delivery system comprises a
pharmaceutical composition and a microneedle array. In another
embodiment described herein, administration of the transdermal or
topical drug delivery system means that the pharmaceutical
composition is applied or administered to the skin of a mammal in
conjunction with the microneedle array. As used herein "in
conjunction with" means use before, use after or use
simultaneously. For example, administration of a transdermal or
topical drug delivery system comprising a pharmaceutical
composition in conjunction with a microneedle array means that the
pharmaceutical composition may be administered before the
administration of the microneedle array, after the administration
of the microneedle array or simultaneously with the administration
of the microneedle array.
[0041] In another embodiment described herein, the microneedle
transdermal or topical drug delivery system described herein
comprises a pharmaceutical composition comprising a cannabinoid
(e.g., cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol
prodrug) in conjunction with a microneedle array for the treatment
of a disease or condition responsive to a cannabinoid.
[0042] In another embodiment described herein, the microneedle
transdermal or topical drug delivery system described herein
comprises a pharmaceutical composition comprising a cannabinoid
(e.g., cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol
prodrug) incorporated into a hydrogel which is used in conjunction
with a microneedle array.
[0043] In another embodiment described herein, the microneedle
transdermal or topical drug delivery system described herein
comprises a pharmaceutical composition comprising a cannabinoid
(e.g., cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol
prodrug) incorporated into a hydrogel which is used in conjunction
with a microneedle array for the treatment of a disease or
condition responsive to a cannabinoid.
[0044] In another embodiment, the microneedle transdermal or
topical drug delivery system consists essentially of a microneedle
array and a pharmaceutical composition, wherein the pharmaceutical
composition consists essentially of a cannabinoid (e.g.,
cannabidiol) or a cannabidiol prodrug (e.g., a cannabidiol prodrug)
and optionally further consists essentially of a COX inhibitor
and/or a penetration enhancer (i.e., a co-solvent).
[0045] In another embodiment, the microneedle transdermal or
topical drug delivery system consists of a microneedle array and a
pharmaceutical composition, wherein the pharmaceutical composition
consists of a cannabinoid (e.g., cannabidiol) or a cannabidiol
prodrug (e.g., a cannabidiol prodrug) and optionally further
consists of a COX inhibitor and/or a penetration enhancer (i.e., a
co-solvent).
[0046] Cannabinoids, Cannabidiol and Cannabidiol Prodrugs
[0047] As used herein, "cannabinoid" includes any compound that
interacts with a cannabinoid receptor and various cannabinoid
mimetics, including, but not limited to certain tetrahydropyran
analogs (e.g., delta-9-tetrahydrocannabinol;
delta-8-tetrahydrocannabinol,
6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol;
3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9-
H-dibenzo[b,d]pyran-9-one;
(-)-(3S,4S)-7-hydroxy-delta-6-tetrahydrocannabinol-1,1-dimethylheptyl;
(+)-(3S,4S)-7-hydroxy-delta-6-tetrahydrocannabinol-1,1-dimethylheptyl;
11-hydroxy-delta-9-tetrahydrocannabinol and
delta-8-tetrahydrocannabinol-11-oic acid); certain piperidine
analogs (e.g.,
(-)-(6S,6aR,9R,10aR)-5,6,6a,7,8,9,10,10a-octahydro-6-methyl-1-3-[(-
R)-1-methyl-4-phenylbutoxy]-1,9-phenanthridinediol 1-acetate),
certain aminoalkylindole analogs (e.g.,
(R)-(+)[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,-
4-benzoxazin-6-yl]-1-naphthalenyl-methanone), certain open
pyran-ring analogs (e.g.,
2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenedi-
-ol and
4-(1,1-dimethylheptyl)-2,3'-dihydroxy-6'alpha-(3-hydroxypropyl)-1'-
,-2',3',4',5',6'-hexahydrobiphenyl), and their pharmaceutically
acceptable salts, solvates, metabolites (e.g., cutaneous
metabolites), and metabolic precursors (e.g., prodrugs).
[0048] As used herein, "cannabidiol" refers to cannabidiol;
cannabidiol prodrugs; pharmaceutically acceptable derivatives of
cannabidiol, including pharmaceutically acceptable salts of
cannabidiol; and cannabidiol derivatives. As used herein
"cannabidiol prodrug" means a compound that undergoes a chemical
conversion, through a metabolic process or otherwise within the
body of the mammal receiving the compound into cannabidiol. The
term "cannabidiol prodrug" also includes the free base, free acid,
salt, ester, hydrate, anhydrate, amide, enantiomer, isomer,
tautomer, polymorph, or derivative of a compound that undergoes a
chemical conversion, through a metabolic process or otherwise
within the body of the mammal receiving the compound into
cannabidiol.
[0049] In one embodiment described herein, the cannabinoid or
mixture of cannabinoids, is obtained from the extract from of a
natural source, such as plants from the cannabis genus (e.g.,
Cannabis sativa, Cannabis indicia and Cannabis ruderalis). In an
alternative embodiment, the cannabinoid or mixture of cannabinoids
results from synthetic chemical reactions. The synthesis of
cannabidiol can be found in Petilka et al., Helv. Chim. Acta,
52:1102 (1969) and in Mechoulam et al., J. Am. Chem. Soc., 87:3273
(1965), which are hereby incorporated by reference. In a further
embodiment, the cannabinoid or mixture of cannabinoids, is obtained
from the extract from of a natural source, such as plants from the
cannabis genus and not as a result of synthetic chemical reactions.
In yet another embodiment, the cannabinoid or mixture of
cannabinoids results from synthetic chemical reactions and not from
the extract of a natural source, such as plants from the cannabis
genus.
[0050] A cannabinoid may be in any suitable form for administration
to a mammal such as in the form of a free base, free acid, salt,
hydrate, anhydrate, enantiomer, isomer, tautomer, polymorph, or the
like, provided that the form of the cannabinoid is therapeutically
active or undergoes conversion within or outside of the body to a
therapeutically active form of the cannabinoid.
[0051] "Pharmaceutically acceptable salts," or "salts," include the
salt of the parent molecule, such as cannabinoid or a cannabinoid
prodrug, suitable for administration to a mammal and includes those
prepared from formic, acetic, propionic, succinic, glycolic,
gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic,
maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic,
mandelic, embonic, methanesulfonic, ethanesulfonic,
benzenesulfonic, pantothenic, toluenesulfonic,
2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic,
algenic, beta-hydroxybutyric, galactaric and galacturonic acids.
The following list of pharmaceutically acceptable salts is not
meant to be exhaustive but merely illustrative as a person of
ordinary skill in the art would appreciate that other
pharmaceutically acceptable salts of a cannabinoid and prodrugs of
a cannabinoid may be prepared.
[0052] In one embodiment, acid addition salts are prepared from the
free base forms using conventional methodologies involving reaction
of the free base with a suitable acid. Suitable acids for preparing
acid addition salts include both organic acids, e.g., formic acid,
acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, and the like, as well as
inorganic acids, e.g., hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. The
following list of organic and inorganic acids is not meant to be
exhaustive but merely illustrative as a person of ordinary skill in
the art would appreciate that other acids may be used to create
pharmaceutically acceptable salts of prodrugs of cannabidiol. In
still other embodiments, the basic salts are alkali metal salts,
e.g., sodium salt.
[0053] In a further embodiment, the cannabinoid is substantially
free from impurities. As used herein, "substantially free of
impurities" shall mean that impurities, including any cannabinoid
not intended to be administered in a therapeutically effective
quantity, are present in an amount by weight of the composition of
less than about 10%, less than about 5%, less than about 4%, less
than about 3%, less than about 2%, less than about 1%, or less than
about 0.1%.
[0054] As used herein "prodrug" refers to a compound that undergoes
a chemical conversion, through a metabolic process or otherwise
within the body of the mammal receiving the compound into its
active form that has therapeutic effects. As used herein, the terms
"cannabidiol" and "cannabidiol prodrug" are used interchangeably,
such that any embodiment in which cannabidiol is used, may also be
used with one or more cannabidiol prodrugs.
[0055] In one embodiment, illustrative cannabidiol prodrugs include
those compounds of Formula (I):
##STR00001##
wherein R.sub.1 and R.sub.2 can be the same or different and are
each independently comprised of a hydrogen and/or a bio-labile
linker (e.g., ester, oxygenated ester, oxaester, pegylated ester,
hydroxylated ester, alkyl ester, amino ester, alkylamino ester,
dialkylamino ester, trialkylammonium ester, carbonate, alkyl
carbonate, amino carbonate, alkylamino carbonate, dialkylamino
carbonate, trialkylammonium carbonate, carbamate, alkyl carbamate,
amino carbamate, alkylamino carbamate, dialkylamino carbamate,
trialkylammonium carbamate, substituted phosphate ester,
unsubstituted phosphate ester, unsubstituted diphosphate ester,
substituted diphosphate ester, unsubstituted triphosphate ester,
substituted triphosphate ester, phosphonate ester, substituted
sulfate esters, unsubstituted sulfate esters, sulphonate ester,
alpha-acyloxyalkyl, alpha-phosphoryloxyalkyl,
alpha-sulphonyloxyalkyl or other suitable bio-labile linking
structure) and further comprising moieties which can be selected in
order to control the rate and extent of absorption and metabolism,
including transdermal absorption and metabolism. However, R.sub.1
and R.sub.2 cannot both be a hydrogen atom. Several options for
R.sub.1 and R.sub.2 are disclosed herein. Also included herein is
the free base, free acid, salt, ester, hydrate, amide, enantiomer,
isomer, tautomer, polymorph, or derivative thereof of compounds of
Formula I.
[0056] In a further embodiment, the cannabidiol prodrug can be
selected from a group comprising:
##STR00002## ##STR00003## ##STR00004## ##STR00005##
##STR00006##
[0057] In an additional embodiment, cannabidiol prodrugs bearing an
alkylamino or dialkylamino substituent in the side chain are used
in the form of tetraalkylammonium salts. For example, dialkylamino
ester can be used in the form of trialkylammonium ester. These
separate chemical entities include a counter ion derived from
pharmaceutically acceptable acids.
[0058] In one embodiment of the quaternary ammonium derivatives
(tetraalkylammonium ammonium derivatives), the cannabidiol prodrug
can be selected from a group comprising:
##STR00007## ##STR00008##
wherein X.sup.- is a counter ion derived from pharmaceutically
acceptable acids.
[0059] In a further embodiment, one or more cannabidiol prodrugs
can be used with or instead of cannabidiol or other cannabinoids in
the pharmaceutical compositions and drug delivery systems described
herein. In an additional embodiment, a cannabidiol prodrug can be
used with or instead of cannabidiol or other cannabinoids in the
method of administering cannabidiol to mammal described herein.
[0060] Additional embodiments of cannabidiol prodrugs contemplated
by the present disclosure include, but are not limited to, those
described in U.S. patent application Ser. No. 12/182,974, published
as US 2009-0036523 A1 on Feb. 5, 2009, which is incorporated herein
by reference in its entirety.
[0061] In one embodiment, illustrative
.DELTA..sup.9-tetrahydrocannabidiol prodrugs suitable for use in
the compositions, drug delivery systems and methods described
herein include those compounds of Formula (II):
##STR00009##
wherein R.sub.1 is comprised of a bio-labile linker (e.g. ester,
oxygenated ester, oxaester, pegylated ester, hydroxylated ester,
branched hydroxylated ester, succinic acid monoester, oxalic acid
mixed pegylated ester, amino ester, cyclic amino ester, acylated
amino ester, carbonate, oxygenated carbonate, oxacarbonate,
pegylated carbonate, hydroxylated carbonate, branched hydroxylated
carbonate, aminoalkyl carbonate, cyclic aminoalkyl carbonate,
acylated aminoalkyl carbonate, hydroxycarbonylalkyl carbonate,
carbamate, alkyl carbamate, aminoalkyl carbamate, acylated
aminoalkyl carbamate, cyclic aminoalkyl carbamate, oxacarbamate,
pegylated carbamate, hydroxylated carbamate, branched hydroxylated
carbamate, hydroxycarbonylalkyl carbamate, phosphate, diphosphate,
triphosphate or other suitable bio-labile linking structure) and
further comprising moieties which can be selected in order to
control the rate and extent of absorption and metabolism, such as
transdermal absorption and metabolism. Several options for R.sub.1
are disclosed herein. Also included herein is the free acid, free
base, salt, ester, hydrated forms, anhydrous, amide, enantiomer,
isomer, tautomer, polymorph, or derivative thereof of compounds of
Formula II.
[0062] In one embodiment, the pharmaceutical compositions disclosed
herein comprise a cannabinoid, such as cannabidiol or cannabidiol
prodrug, in a total amount by weight of the composition of about
0.1% to about 95%. For example, the amount of a cannabinoid, such
as cannabidiol or a cannabidiol prodrug, by weight of the
pharmaceutical composition may be about 0.1%, about 0.2%, about
0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%,
about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about
1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%,
about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about
2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%,
about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about
3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%,
about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about
4.7%, about 4.8%, about 4.9%, about 5%, about 5.1%, about 5.2%,
about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about
5.8%, about 5.9%, about 6%, about 6.1%, about 6.2%, about 6.3%,
about 6.4%, about 6.5%, about 6.6%, about 6.7%, about 6.8%, about
6.9%, about 7%, about 7.1%, about 7.2%, about 7.3%, about 7.4%,
about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about
8%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%,
about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9%, about
9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%,
about 9.7%, about 9.8%, about 9.9%, about 10%, about 11%, about
12%, about 13%, about 14%, about 15%, about 16%, about 17%, about
18%, about 19%, about 20%, about 25%, about 30%, about 35%, about
40%, about 45%, about 50%, about 55%, about 60%, about 65%, about
70%, about 75%, about 80%, about 85%, about 90% or about 95%.
[0063] Illustratively, the pharmaceutical compositions disclosed
herein may comprise a total amount of a cannabinoid, such as
cannabidiol or a cannabidiol prodrug, by weight of about 1% to
about 10%; about 2% to about 10%; about 3% to about 10%; about 4%
to about 10%; about 5% to about 10%; about 6% to about 10%; about
7% to about 10%; about 8% to about 10%; about 9% to about 10%;
about 1% to about 9%; about 2% to about 9%; about 3% to about 9%;
about 4% to about 9%; about 5% to about 9%; about 6% to about 9%;
about 7% to about 9%; about 8% to about 9%; about 1% to about 8%;
about 2% to about 8%; about 3% to about 8%; about 4% to about 8%;
about 5% to about 8%; about 6% to about 8%; about 7% to about 8%;
about 1% to about 7%; about 2% to about 7%; about 3% to about 7%;
about 4% to about 7%; about 5% to about 7%; about 6% to about 7%;
about 1% to about 6%; about 2% to about 6%; about 3% to about 6%;
about 4% to about 6%; about 5% to about 6%; about 1% to about 5%;
about 2% to about 5%; about 3% to about 5%; about 4% to about 5%;
about 1% to about 4%; about 2% to about 4%; about 3% to about 4%;
about 1% to about 3%; about 2% to about 3%; or about 1% to about
2%.
[0064] In an alternative embodiment, the pharmaceutical
compositions disclosed herein comprise a cannabinoid (e.g.,
cannabidiol) or a prodrug of a cannabinoid (e.g., a prodrug of
cannabidiol) which may be incorporated into a hydrogel. Optionally,
a penetration enhancer (i.e., co-solvent) or COX inhibitor may also
be incorporated into the hydrogel as well. The cannabinoid or
prodrug thereof comprises about 0.1%, about 0.2%, about 0.3%, about
0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%,
about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about
1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%,
about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about
2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%,
about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about
3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%,
about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about
4.8%, about 4.9%, about 5%, about 5.1%, about 5.2%, about 5.3%,
about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about
5.9%, about 6%, about 6.1%, about 6.2%, about 6.3%, about 6.4%,
about 6.5%, about 6.6%, about 6.7%, about 6.8%, about 6.9%, about
7%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, about 7.5%,
about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8%, about
8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%,
about 8.7%, about 8.8%, about 8.9%, about 9%, about 9.1%, about
9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%,
about 9.8%, about 9.9%, about 10%, about 11%, about 12%, about 13%,
about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,
about 20%, about 21%, about 22%, about 23%, about 24%, about 25%,
about 26%, about 27%, about 28%, about 29%, about 30%, about 31%,
about 32%, about 33%, about 34%, about 35%, about 36%, about 37%,
about 38%, about 39%, about 40%, about 41%, about 42%, about 43%,
about 44%, about 45%, about 46%, about 47%, about 48%, about 49%,
about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,
about 80%, about 85%, about 90% or about 95% by weight of the
hydrogel.
[0065] Microneedle Arrays
[0066] As used herein, the term "pore viability" refers to pores,
holes or channels created by the entry of one or more microneedles
into the skin of a mammal in need of transdermal administration of
an active pharmaceutical agent and the duration of lifetime that
the resulting pores remain sufficiently open or "un-healed" thereby
allowing the transdermal delivery of an active pharmaceutical agent
to be systemically or locally delivered, whereby the dosing
interval between microneedle treatments can be extended.
[0067] As used herein the term "microneedle" or "microneedle array"
refers to any apparatus, construction, equipment, implement,
material, means or mechanism used to create micrometer-scale
transport pathways in the epidermis of a mammal. As used herein,
the terms "microneedle" and "microneedle array" are
interchangeable.
[0068] The pharmaceutical compositions described herein, and
optionally incorporated into a hydrogel, are suitable for use in a
transdermal or topical drug delivery system in conjunction with
microneedles which create micrometer-scale transport pathways.
Microneedles provide a minimally invasive means to transport
molecules into and/or through the skin for local or systemic
delivery of an active pharmaceutical agent. The channels or pores
created by a microneedle array are extremely small on a clinical
level. However, because the channels or pores are orders of
magnitude larger than even macromolecules, such channels or pores
have been shown to significantly increase skin permeability.
[0069] Microneedles can be can be solid or hollow and are made from
many bio-compatible materials, including silicon, biodegradable
polymers, and stainless steel. Solid microneedles can be used to
create channels or pores in the skin, followed by application of a
transdermal patch to the skin surface. Alternatively, solid
microneedles can be first coated with an active pharmaceutical
agent and then inserted into the skin. Hollow microneedles can also
be used to facilitate active permeation through the bore in the
microneedle and into the skin. See, e.g., Prausnitz, Microneedles
for transdermal drug delivery, Adv. 56 Drug. Deliv. Rev. 581-587
(2004), for a review of some of the microneedle technology suitable
for use with the various embodiments of the claimed invention
described herein.
[0070] Numerous studies have demonstrated that solid microneedles
can increase skin permeability by up to four orders of magnitude
for compounds ranging in size from small molecules to proteins to
nanoparticles. Henry et al., Microfabricated microneedles: a novel
approach to transdermal drug delivery, 87 J. Pharm. Sci. 922-925
(1998); McAllister et al., Microfabricated needles for transdermal
delivery of macromolecules and nanoparticles: fabrication methods
and transport studies, 100 Proc. Nat'l Acad. Sci. 13755-13760
(2003); Lin et al., Transdermal delivery of antisense
oligonucleotides with microprojection patch (Macroflux) technology,
18(12) Pharm. Res. 1787-1793 (2001); and Cormier et al.,
Transdermal delivery of desmopressin using a coated microneedle
array patch system, 97 J. Control. Release. 503-511 (2004). Hollow
microneedles have also been shown to deliver macromolecules such as
insulin. See McAllister, Proc. Nat'l Acad. Sci. 13755-13760;
Martanto et al., Transdermal delivery of insulin using microneedles
in vivo, 21 Pharm. Res. 947-952 (2004). Microneedle insertion in
human volunteers resulted in a sensation described as that similar
to a smooth surface applied to the skin or the "sensation of a
piece of tape" applied to the skin. Kaushik et al., Lack of pain
associated with microfabricated microneedles, 92 Anesth. &
Analg. 502-504 (2001).
[0071] Suitable microneedle arrangements for use with the compounds
and compositions described herein can be found in the foregoing
references as well as in U.S. patent application Ser. No.
11/812,249, published as US 2008-0008745 A1 on Jan. 10, 2008, which
is incorporated by reference herein in its entirety.
[0072] In one embodiment, solid microneedle adhesive patches can be
fabricated for insertion into the skin. In another embodiment,
fixed microneedle geometries can be cut into 75 .mu.m thick
stainless steel sheets (Trinity Brand Industries, SS 304;
McMaster-Carr, Atlanta, Ga., USA) using an infrared laser
(Resonetics Maestro, Nashua, N.H., USA) and then can be manually
bent perpendicular to the plane of their metal substrate. For
better insertion and adhesion of patches to the skin, microneedle
arrays can be assembled into adhesive patches. The adhesive would
serve to hold the microneedles firmly against the skin by
compensating for the mechanical mismatch between the flexible skin
tissue and the rigid microneedle substrate. The microneedle patches
can be assembled in a laminar flow hood for cleanliness and then
sterilized using ethylene oxide (AN 74j, Andersen Sterilizers, Haw
River, N.C., USA) before use.
[0073] In another embodiment, microneedle arrays can be fabricated
to produce patches containing 50 microneedles arranged in a
5.times.10 array of microneedles. In one embodiment, suitable
individual microneedles can be about 620 .mu.m in length, about 160
.mu.m in width at the base, and less than about 1 .mu.m in radius
of curvature at the tip.
[0074] Pharmaceutical Compositions
[0075] As used herein, "pharmaceutical composition" includes any
ointment, cream, solution, suspension, lotion, paste, gel,
hydrogel, spray, foam, solid or oil which may be created or formed
and used to administer a cannabinoid (e.g., cannabidiol) or
cannabinoid prodrug (e.g., a cannabidiol prodrug) to a mammal,
alone, or in conjunction with microneedles.
[0076] As used herein, the terms "gel" or "gel-like" can be used
interchangeably.
[0077] The term "excipient" herein means any substance, not itself
a therapeutic agent, which may be used in a composition for
delivery of an active therapeutic agent to a subject or combined
with an active therapeutic agent (e.g., to create a pharmaceutical
composition) to improve its handling or storage properties or to
permit or facilitate formation of a dose unit of the composition
(e.g., formation of a hydrogel which may then be optionally
incorporated into a patch). Excipients include, by way of
illustration and not limitation, binders, disintegrants, taste
enhancers, solvents, thickening or gelling agents (and any
neutralizing agents, if necessary), penetration enhancers,
solubilizing agents, wetting agents, antioxidants, lubricants,
emollients, substances added to mask or counteract a disagreeable
odor, fragrances or taste, substances added to improve appearance
or texture of the composition and substances used to form
hydrogels. Any such excipients can be used in any dosage forms
according to the present disclosure. The foregoing classes of
excipients are not meant to be exhaustive but merely illustrative
as a person of ordinary skill in the art would recognize that
additional types and combinations of excipients could be used to
achieve the desired goals for delivery of the cannabinoid (e.g.,
cannabidiol) or cannabinoid prodrug (e.g., a cannabidiol
prodrug).
[0078] The pharmaceutical compositions described herein are
suitable for transdermal or topical administration. In one
embodiment, the microneedle transdermal or topical drug delivery
system comprises a microneedle array and a pharmaceutical
composition, wherein the pharmaceutical composition comprises a
cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a
cannabidiol prodrug) which has been optionally incorporated into a
hydrogel. In further embodiments, the pharmaceutical composition
may comprise a COX inhibitor which has been optionally incorporated
into a hydrogel. In further embodiments, the pharmaceutical
composition may optionally further comprise on or more
pharmaceutically acceptable excipients such as solvents,
co-solvents, thickening agents, neutralizers, solubilizing agents,
wetting agents, penetration enhancers, lubricants, emollients,
antioxidants, substances added to mask or counteract a disagreeable
odor, fragrances or tastes, and substances added to improve
appearance or texture of the composition. In a further embodiment,
the pharmaceutical composition can be part of, or incorporated
into, a hydrogel.
[0079] COX Inhibitors
[0080] It has been found that certain compounds can be administered
to mammals to prevent or reduce prostaglandin biosynthesis in
mammals by inhibiting the production of prostaglandin G/H synthase
which is also known as cyclooxygenase or COX. There are two forms
of cyclooxygenase, cyclooxygenase-1 (COX-1) and cyclooxygenase-2
(COX-2). As used herein, the term "COX inhibitor" includes those
compounds which (i) primarily or exclusively inhibit the COX-1
enzyme; (ii) primarily or exclusively inhibit the COX-2 enzyme; and
(iii) those compounds which inhibit both the COX-1 and COX-2
enzymes (i.e., non-specific inhibitors). COX-1, COX-2 and
non-specific COX inhibitors are each suitable for use in the
compositions, drug delivery systems and methods described
herein.
[0081] Examples of COX inhibitors suitable for use in the various
embodiments described herein include: aspirin, diflunisal,
olsalazine, salsalate, sulfasalazine, acetaminophen, indomethacin,
sulindac, etodolac, mefenamic acid, meclofenamate, flufenamic acid,
tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen,
ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam,
nabumetone, celecoxib, valdecoxib, rofecoxib, parecoxib,
etoricoxib, lumiracoxib, valdecoxib, nimesulide, mofezolac, SC-560,
FR122047, and DuP-697. Additional COX inhibitors can be found in
Merck Index, Thirteenth Ed., The Physicians Desk Reference,
58.sup.th Ed., and Goodman and Gilmans, "The Pharmacological Basis
of Therapeutics, 11th Ed.
[0082] Pharmaceutically acceptable forms of a COX inhibitor include
those which are suitable for transdermal or topical administration
to a mammal. The COX inhibitors described herein may be in any form
suitable for administration to a mammal, such as in the form of a
free base, free acid, salt, ester, hydrate, anhydrate, enantiomer,
isomer, tautomer, polymorph, derivative, or the like.
[0083] Pharmaceutically acceptable salts of a COX inhibitor include
salts suitable for administration to a mammal and includes those
prepared from formic, acetic, propionic, succinic, glycolic,
gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic,
maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic,
mandelic, embonic, methanesulfonic, ethanesulfonic,
benzenesulfonic, pantothenic, toluenesulfonic,
2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic,
beta-hydroxybutyric, galactaric and galacturonic acids. The
following list of pharmaceutically acceptable salts is not meant to
be exhaustive but merely illustrative as a person of ordinary skill
in the art would appreciate that other pharmaceutically acceptable
salts of a COX inhibitor may be prepared.
[0084] In one embodiment, acid addition salts can be prepared from
the free base forms through a reaction of the free base with a
suitable acid. Suitable acids for preparing acid addition salts of
COX inhibitors include both organic acids, e.g., acetic acid,
propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic
acid, malonic acid, succinic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid, and the like, as well as inorganic acids,
e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like. The following list of organic
and inorganic acids is not meant to be exhaustive but merely
illustrative as a person of ordinary skill in the art would
appreciate that other acids may be used to create pharmaceutically
acceptable salts of a COX inhibitor. In other embodiments, an acid
addition salt is reconverted to the free base by treatment with a
suitable base. In still other embodiments, the basic salts are
alkali metal salts, e.g., sodium salt.
[0085] One embodiment described herein is a microneedle transdermal
or topical drug delivery system, which includes a pharmaceutical
composition comprising a cannabinoid (e.g., cannabidiol) or a
cannabinoid prodrug (e.g., a prodrug of cannabidiol), and a first
COX inhibitor, and a microneedle array which is arranged to
penetrate the skin of a mammal in need of for transdermal or
topical delivery of the cannabinoid to treat a medical condition.
In other embodiments, the COX inhibitor is a COX-1 inhibitor. In a
further embodiment, the COX inhibitor is a COX-2 inhibitor. In
another embodiment, the COX inhibitor is both a COX-1 and a COX-2
inhibitor (i.e., a non-specific COX inhibitor). In a further
embodiment, the COX inhibitor can be in any pharmaceutically
acceptable form (e.g., salts, esters, prodrugs, etc.). The use of a
COX inhibitor in conjunction with microneedles is described in U.S.
patent application Ser. No. 12/325,919 which is incorporated by
reference in its entirety.
[0086] Penetration Enhancers and Co-Solvents
[0087] In one embodiment, the pharmaceutical composition may
comprise one or more penetration enhancing agent or co-solvent for
transdermal or topical delivery. A penetration enhancer is an
excipient that aids in the diffusion of the active through the
stratum corneum. Many penetration enhancers also function as
co-solvents which are thought to increase the thermodynamic
activity or solubility of the cannabinoid in the composition and
enhance drug delivery through the microneedle-created holes or
pores. Penetration enhancers are also known as accelerants,
adjuvants or sorption promoters. A suitable penetration enhancer
for use in the pharmaceutical compositions and methods described
herein should: (i) be highly potent, with a specific mechanism of
action; (ii) exhibit a rapid onset upon administration; (iii) have
a predictable duration of action; (iv) have only non-permanent or
reversible effects on the skin; (v) be chemically stable; (vi) have
no or minimal pharmacological effects; (vii) be physically and
chemically compatible with other composition components; (viii) be
odorless; (ix) be colorless; (x) be hypoallergenic; (xi) be
non-irritating; (xii) be non-phototoxic; (xiii) be non-comedogenic;
(xiv) have a solubility parameter approximating that of the skin
(10.5 cal/cm3); (xv) be readily available; (xvi) be inexpensive;
and (xvii) be able to formulated in pharmaceutical compositions for
topical or transdermal delivery of an active pharmaceutical
agent.
[0088] Several classes of chemical compounds, with various
mechanisms of action, can be used as penetration enhancers. Set
forth below are non-limiting examples of penetration enhancing
agents, many of which are also suitable co-solvents. Sulfoxides,
such as dimethylsulfoxide and decylmethylsulfoxide can be used as
penetration enhancing agents. Dimethylsulfoxide enhances
penetration in part by increasing lipid fluidity and promoting drug
partitioning. In contrast, decylmethylsulfoxide enhances
penetration by reacting with proteins in the skin that change the
conformation of the proteins, which results in the creation of
aqueous channels.
[0089] Another class of a penetration enhancers are alkanones, such
as N-heptane, N-octane, N-nonane, N-decane, N-undecane, N-dodecane,
N-tridecane, N-tetradecane and N-hexadecane. Alkanones are thought
to enhance the penetration of an active agent by altering the
stratum corneum. A further class of penetration enhancers are
alkanol alcohols, such as ethanol, propanol, butanol, 2-butanol,
pentanol, 2-pentanol, hexanol, octanol, nonanol, decanol and benzyl
alcohol. Low molecular weight alkanol alcohols, i.e., those with 6
or less carbons, may enhance penetration in part by acting as
solubilizing agents, while more hydrophobic alcohols may increase
diffusion by extracting lipids from the stratum corneum. A further
class of penetration enhancers are fatty alcohols, such as oleyl
alcohol, caprylic alcohol, decyl alcohol, lauryl alcohol, 2-lauryl
alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl
alcohol, linoleyl alcohol and linolenyl alcohol. Polyols, including
propylene glycol, polyethylene glycol, ethylene glycol, diethylene
glycol, triethylene glycol, dipropylene glycol, glycerol,
propanediol, butanediol, pentanediol, hexanetriol, propylene glycol
monolaurate and diethylene glycol monomethyl ether (transcutol),
can also enhance penetration. Some polyols, such as propylene
glycol, may function as a penetration enhancer by solvating
alpha-kertin and occupying hydrogen bonding sites, thereby reducing
the amount of active-tissue binding.
[0090] Another class of penetration enhancers are amides, including
urea, dimethylacetamide, diethyltoluamide, dimethylformamide,
dimethyloctamide, dimethyldecamide and biodegradable cyclic urea
(e.g., 1-alkyl-4-imidazolin-2-one). Amides have various mechanisms
of enhancing penetration. For example, some amides, such as urea
increase the hydration of the stratum corneum, act as a keratolytic
and create hydrophilic diffusion channels. In contrast, other
amides, such as dimethylacetamide and dimethylformamide, increase
the partition to keratin at low concentrations, while increasing
lipid fluidity and disrupting lipid packaging at higher
concentrations. Another class of penetration enhancing agents are
pyrrolidone derivatives, such as 1-methyl-2-pyrrolidone,
2-pyrrolidone, 1-lauryl-2-pyrrolidone,
1-methyl-4-carboxy-2-pyrrolidone, 1-hexyl-4-carboxy-2-pyrrolidone,
1-lauryl-4-carboxy-2-pyrrolidone,
1-methyl-4-methoxycarbonyl-2-pyrrolidone,
1-hexyl-4-methoxycarbonyl-2-pyrrolidone,
1-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-methyl-pyrrolidone,
N-cyclohexylpyrrolidone, N-dimethylaminopropyl-pyrrolidone,
N-cocoalkypyrrolidone and N-tallowalkypyrrolidone, as well as
biodegradable pyrrolidone derivatives, including fatty acid esters
of N-(2-hydroxyethyl)-2-pyrrolidone. In part, pyrrolidone
derivatives enhance penetration through interactions with the
keratin in the stratum corneum and lipids in the skin structure. An
additional class of penetration enhancers are cyclic amides,
including 1-dodecylazacycloheptane-2-one ("Azone"),
1-geranylazacycloheptan-2-one, 1-farnesylazacycloheptan-2-one,
1-geranylgeranylazacycloheptan-2-one,
1-(3,7-dimethyloctyl)-azacycloheptan-2-one,
1-(3,7,11-trimethyldodecyl)azacyclohaptan-2-one,
1-geranylazacyclohexane-2-one, 1-geranylazacyclopentan-2,5-dione
and 1-farnesylazacyclopentan-2-one. Cyclic amides, such as Azone,
enhance the penetration of active agents in part by affecting the
stratum corneum's lipid structure, increasing partitioning and
increasing membrane fluidity. Additional classes of penetration
enhancers include diethanolamine, triethanolamine and
hexamethylenlauramide and its derivatives.
[0091] Additional penetration enhancers include linear fatty acids,
such as octanoic acid, linoleic acid, valeric acid, heptanoic acid,
pelagonic acid, caproic acid, capric acid, lauric acid, myristric
acid, stearic acid, oleic acid and caprylic acid. Linear fatty
acids enhance penetration in part via selective perturbation of the
intercellular lipid bilayers. In addition, some linear fatty acids,
such as oleic acid, enhance penetration by decreasing the phase
transition temperatures of the lipid, thereby increasing motional
freedom or fluidity of the lipids. Branched fatty acids, including
isovaleric acid, neopentanoic acid, neoheptanoic acid, nonanoic
acid, trimethyl hexaonic acid, neodecanoic acid and isostearic
acid, are a further class of penetration enhancers. An additional
class of penetration enhancers are aliphatic fatty acid esters,
such as ethyl oleate, isopropyl n-butyrate, isopropyl n-hexanoate,
isopropyl n-decanoate, isopropyl myristate ("IPM"), isopropyl
palmitate and octyldodecyl myristate. Aliphatic fatty acid esters
enhance penetration by increasing diffusivity in the stratum
corneum and/or the partition coefficient. In addition, certain
aliphatic fatty acid esters, such as IPM, enhance penetration by
directly acting on the stratum corneum and permeating into the
liposome bilayers thereby increasing fluidity. Alkyl fatty acid
esters, such as ethyl acetate, butyl acetate, methyl acetate,
methyl valerate, methyl propionate, diethyl sebacate, ethyl oleate,
butyl stearate and methyl laurate, can act as penetration
enhancers. Alkyl fatty acid esters enhance penetration in part by
increasing the lipid fluidity.
[0092] An additional class of penetration enhancers are anionic
surfactants, including sodium laurate, sodium lauryl sulfate and
sodium octyl sulfate. Anionic surfactants enhance penetration of
active agents by altering the barrier function of the stratum
corneum and allowing removal of water-soluble agents that normally
act as plasticizers. A further class of penetration enhancers are
cationic surfactants, such as cetyltrimethylammonium bromide,
tetradecyltrimethylammonium, octyltrimethyl ammonium bromide,
benzalkonium chloride, octadecyltrimethylammonium chloride,
cetylpyridinium chloride, dodecyltrimethylammonium chloride and
hexadecyltrimethylammonium chloride. Cationic surfactants enhance
penetration by adsorbing at, and interacting with, interfaces of
biological membranes, resulting in skin damage. A further class of
penetration enhancers are zwitterionic surfactants, such as
hexadecyl trimethyl ammoniopropane sulfonate, oleyl betaine,
cocamidopropyl hydroxysultaine and cocamidopropyl betaine. Nonionic
surfactants, including Polyxamer (231, 182, 184), Polysorbate (20,
60), Brij (30, 93, 96, 99), Span (20, 40, 60, 80, 85), Tween (20,
40, 60, 80), Myrj (45, 51, 52) and Miglyol 840, are yet another
class of penetration enhancing agents. Nonionic surfactants enhance
penetration in part by emulsifying the sebum and enhancing the
thermodynamic activity or solubility of the active.
[0093] Another class of penetration enhancer increase the
thermodynamic activity or solubility of the active, which include,
but are not limited to, n-octanol, sodium oleate, D-limonene,
monoolein, cineol, oleyl oleate, and isopropryl myristate.
[0094] Further penetration enhancers are bile salts, such as sodium
cholate, sodium salts of taurocholic acid, glycolic acids and
desoxycholic acids. Lecithin also has been found to have
penetration enhancing characteristics. An additional class of
penetration enhancers are terpenes, which include hydrocarbons,
such as d-limonene, alpha-pinene and beta-carene; alcohols, such
as, alpha-terpineol, terpinen-4-ol and carvol; ketones, such
ascarvone, pulegone, piperitone and menthone; oxides, such as
cyclohexene oxide, limonene oxide, alpha-pinene oxide, cyclopentene
oxide and 1,8-cineole; and oils such as ylang ylang, anise,
chenopodium and eucalyptus. Terpenes enhance penetration in part by
disrupting the intercellular lipid bilayer to increase diffusivity
of the active and opening polar pathways within and across the
stratum corneum. Organic acids, such as salicylic acid and
salicylates (including their methyl, ethyl and propyl glycol
derivates), citric acid and succinic acid, are penetration
enhancers. Another class of penetration enhancers are
cyclodextrins, including 2-hydroxypropyl-beta-cyclodextrin and
2,6-dimethyl-beta-cyclodextrin. Cyclodextrins enhance the
permeation of active agents by forming inclusion complexes with
lipophilic actives and increasing their solubility in aqueous
solutions.
[0095] Additional penetrations enhancers include, but are not
limited to: alkyl-2-(N,N-disubstituted amino)-alkanoate ester
(NexAct.RTM.); 2-(n-nonyl)-1,3-dioxolane (SEPA.RTM.);
di(lower)alkyl esters of diacids (e.g., diisopropyl adipate);
monoglyceride fatty acids (e.g., glyceryl monolaurate);
tetrahydrofurfuryl alcohol; 2-(2-ethoxyethoxy)ethanol; alkylaryl
ethers of polyethylene oxide; polyethylene oxide monomethyl ethers;
polyethylene oxide dimethyl ethers; acetoacetic ester; oleoyl
macrogolglyceride; caprylocaproyl macrogolylyceride;
polyoxyethylene 6 caprylic triglyceride; polyoxyethylene glyceride;
PPG-5 ceteth-20; lauroyl macroglyceride oleic acid. Additional
penetration enhancers suitable for use can also be found in U.S.
patent application Ser. No. 10/032,163, which is incorporated by
reference herein.
[0096] In one embodiment, the penetration enhancer would be (i) one
or more co-solvents that increase the solubility of the cannabinoid
(e.g., cannabidiol) or cannabinoid prodrug (e.g., a cannabidiol
prodrug) but do not increase viscosity and/or (ii) compounds that
increase blood flow to the microneedle treatment site
(vasodilators).
[0097] Co-solvents include the penetration enhancers as described
above. Further, co-solvent suitable for use include, but are not
limited to, surfactants which can be found in U.S. Pat. No.
6,248,363, which is incorporated herein by reference in its
entirety.
[0098] The penetration enhancing agent(s) and/or co-solvent(s)
is/are present in an amount sufficient to provide the desired level
of drug transport through the stratum corneum and epidermis or to
increase the thermodynamic activity or solubility of the
cannabinoid. Illustratively, one or more pharmaceutically
acceptable penetration enhancer and/or co-solvent is present in a
total amount by weight of about 0.1%, about 0.2%, about 0.3%, about
0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%,
about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about
1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%,
about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about
2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%,
about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about
3.7%, about 3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%,
about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about
4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%,
about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about
5.9%, about 6.0%, about 6.1%, about 6.2%, about 6.3%, about 6.4%,
about 6.5%, about 6.6%, about 6.7%, about 6.8%, about 6.9%, about
7.0%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, about 7.5%,
about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8.0%, about
8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%,
about 8.7%, about 8.8%, about 8.9%, about 9.0%, about 9.1%, about
9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%,
about 9.8%, about 9.9% or about 10%, about 11%, about 12%, about
13%, about 14%, about 15%, about 16%, about 17%, about 18%, about
19%, about 20%, about 21%, about 22%, about 23%, about 24%, about
25%, about 26%, about 27%, about 28%, about 29%, about 30%, about
31%, about 32%, about 33%, about 34%, about 35%, about 36%, about
37%, about 38%, about 39%, about 40%, about 41%, about 42%, about
43%, about 44%, about 45%, about 46%, about 47%, about 48%, about
49%, about 50%, about 51%, about 52%, about 53%, about 54%, about
55%, about 56%, about 57%, about 58%, about 59%, about 60%, about
61%, about 62%, about 63%, about 64%, about 65%, about 66%, about
67%, about 68%, about 69%, about 70%, about 71%, about 72%, about
73%, about 74%, about 75%, about 76%, about 77%, about 78%, about
79%, about 80%, about 81%, about 82%, about 83%, about 84%, about
85%, about 86%, about 87%, about 88%, about 89%, about 90%, about
91%, about 92%, about 93%, about 94%, or about 95%.
[0099] As a further illustration, one or more pharmaceutically
acceptable penetration enhancer and/or co-solvent is present in a
total amount by weight of about 1% to about 95%; about 5% to about
95%; about 10% to about 95%; about 15% to about 95%; about 20% to
about 95%; about 25% to about 95%; about 30% to about 95%; about
35% to about 95%; about 40% to about 95%; about 45% to about 95%;
about 50% to about 95%; about 55% to about 95%; about 60% to about
95%; about 65% to about 95%; about 70% to about 95%; about 75% to
about 95%; about 80% to about 95%; about 85% to about 95%; about
90% to about 95%; about 1% to about 90%; about 5% to about 90%;
about 10% to about 90%; about 15% to about 90%; about 20% to about
90%; about 25% to about 90%; about 30% to about 90%; about 35% to
about 90%; about 40% to about 90%; about 45% to about 90%; about
50% to about 90%; about 55% to about 90%; about 60% to about 90%;
about 65% to about 90%; about 70% to about 90%; about 75% to about
90%; about 80% to about 90%; about 85% to about 90%; about 1% to
about 85%; about 5% to about 85%; about 10% to about 85%; about 15%
to about 85%; about 20% to about 85%; about 25% to about 85%; about
30% to about 85%; about 35% to about 85%; about 40% to about 85%;
about 45% to about 85%; about 50% to about 85%; about 55% to about
85%; about 60% to about 85%; about 65% to about 85%; about 70% to
about 85%; about 75% to about 85%; about 80% to about 85%; about 1%
to about 80%; about 5% to about 80%; about 10% to about 80%; about
15% to about 80%; about 20% to about 80%; about 25% to about 80%;
about 30% to about 80%; about 35% to about 80%; about 40% to about
80%; about 45% to about 80%; about 50% to about 80%; about 55% to
about 80%; about 60% to about 80%; about 65% to about 80%; about
70% to about 80%; about 75% to about 80%; about 1% to about 75%;
about 5% to about 75%; about 10% to about 75%; about 15% to about
75%; about 20% to about 75%; about 25% to about 75%; about 30% to
about 75%; about 35% to about 75%; about 40% to about 75%; about
45% to about 75%; about 50% to about 75%; about 55% to about 75%;
about 60% to about 75%; about 65% to about 75%; about 70% to about
75%; about 1% to about 70%; about 5% to about 70%; about 10% to
about 70%; about 15% to about 70%; about 20% to about 70%; about
25% to about 70%; about 30% to about 70%; about 35% to about 70%;
about 40% to about 70%; about 45% to about 70%; about 50% to about
70%; about 55% to about 70%; about 60% to about 70%; about 65% to
about 70%; about 1% to about 65%; about 5% to about 65%; about 10%
to about 65%; about 15% to about 65%; about 20% to about 65%; about
25% to about 65%; about 30% to about 65%; about 35% to about 65%;
about 40% to about 65%; about 45% to about 65%; about 50% to about
65%; about 55% to about 65%; about 60% to about 65%; about 1% to
about 60%; about 5% to about 60%; about 10% to about 60%; about 15%
to about 60%; about 20% to about 60%; about 25% to about 60%; about
30% to about 60%; about 35% to about 60%; about 40% to about 60%;
about 45% to about 60%; about 50% to about 60%; about 55% to about
60%; about 1% to about 55%; about 5% to about 55%; about 10% to
about 55%; about 15% to about 55%; about 20% to about 55%; about
25% to about 55%; about 30% to about 55%; about 35% to about 55%;
about 40% to about 55%; about 45% to about 55%; about 50% to about
55%; about 1% to about 50%; about 5% to about 50%; about 10% to
about 50%; about 15% to about 50%; about 20% to about 50%; about
25% to about 50%; about 30% to about 50%; about 35% to about 50%;
about 40% to about 50%; about 45% to about 50%; about 1% to about
45%; about 5% to about 45%; about 10% to about 45%; about 15% to
about 45%; about 20% to about 45%; about 25% to about 45%; about
30% to about 45%; about 35% to about 45%; about 40% to about 45%;
about 1% to about 40%; about 5% to about 40%; about 10% to about
40%; about 15% to about 40%; about 20% to about 40%; about 25% to
about 40%; about 30% to about 40%; about 35% to about 40%; about 1%
to about 35%; about 5% to about 35%; about 10% to about 35%; about
15% to about 35%; about 20% to about 35%; about 25% to about 35%;
about 30% to about 35%; about 1% to about 30%; about 5% to about
30%; about 10% to about 30%; about 15% to about 30%; about 20% to
about 30%; about 25% to about 30%; about 1% to about 25%; about 5%
to about 25%; about 10% to about 25%; about 15% to about 25%; about
20% to about 25%; about 1% to about 20%; about 5% to about 20%;
about 10% to about 20%; about 15% to about 20%; about 1% to about
15%; about 5% to about 15%; or about 10% to about 15%; about 1% to
about 10%; about 2% to about 10%; about 3% to about 10%; about 4%
to about 10%; about 5% to about 10%; about 6% to about 10%; about
7% to about 10%; about 8% to about 10%; about 9% to about 10%;
about 1% to about 9%; about 2% to about 9%; about 3% to about 9%;
about 4% to about 9%; about 5% to about 9%; about 6% to about 9%;
about 7% to about 9%; about 8% to about 9%; about 1% to about 8%;
about 2% to about 8%; about 3% to about 8%; about 4% to about 8%;
about 5% to about 8%; about 6% to about 8%; about 7% to about 8%;
about 1% to about 7%; about 2% to about 7%; about 3% to about 7%;
about 4% to about 7%; about 5% to about 7%; about 6% to about 7%;
about 1% to about 6%; about 2% to about 6%; about 3% to about 6%;
about 4% to about 6%; about 5% to about 6%; about 1% to about 5%;
about 2% to about 5%; about 3% to about 5%; about 4% to about 5%;
about 1% to about 4%; about 2% to about 4%; about 3% to about 4%;
about 1% to about 3%; about 2% to about 3%; or about 1% to about
2%.
[0100] In an alternate embodiment, the weight percentage or weight
percent range of penetration enhancer (i.e., co-solvent) is
determined as a percentage of the total weight of the hydrogel.
[0101] Thickening or Gelling Agents and Related Excipients
[0102] In one embodiment, the pharmaceutical composition may
comprise a thickening or gelling agent suitable for use in the
compositions and methods described herein to increase the viscosity
of the composition. Non-limiting examples of thickening agents (aka
gelling agents), which may be used to create the composition or be
present in the composition herein include neutralized anionic
polymers or neutralized carbomers, such as polyacrylic acid
(CARBOPOL.RTM. by Noveon, Inc., Cleveland, Ohio) (see information
at http://www.nuven.com, incorporated by reference herein),
carboxypolymethylene, carboxymethylcellulose and the like,
including derivatives of Carbopol.RTM. polymers, such as
Carbopol.RTM. Ultrez 10, Carbopol.RTM. 940, Carbopol.RTM. 941,
Carbopol.RTM. 954, Carbopol.RTM. 980, Carbopol.RTM. 981,
Carbopol.RTM. ETD 2001, Carbopol.RTM. EZ-2 and Carbopol.RTM. EZ-3.
As used herein, a "neutralized carbomer" is a synthetic, high
molecular weight polymer, composed primarily of a neutralized
polyacrylic acid. Further, when a base is added to neutralize a
carbomer solution, the viscosity of the solution increases. Also
suitable are other known polymeric thickening agents, such as
Pemulen.RTM. polymeric emulsifiers, Noveon.RTM. polycarbophils, and
Klucel.RTM.. Additional thickening agents, enhancers and adjuvants
may generally be found in Remington's The Science and Practice of
Pharmacy as well as the Handbook of Pharmaceutical Excipients,
Arthur H. Kibbe ed. 2000. Thickening agents or gelling agents are
present in an amount sufficient to provide the desired rheological
properties of the composition, which include having a sufficient
viscosity for forming a gel or gel-like composition that can be
applied to the skin of a mammal.
[0103] Illustratively, one or more pharmaceutically acceptable
thickening agent or gelling agent is present in a total amount by
weight of about 0.1%, about 0.25%, about 0.5%, about 0.75%, about
1%, about 1.25%, about 1.5%, about 1.75%, about 2.0%, about 2.25%,
about 2.5%, about 2.75%, about 3.0%, about 3.25%, about 3.5%, about
3.75%, about 4.0%, about 4.25%, about 4.5%, about 4.75%, about
5.0%, about 5.25%, about 5.5%, about 5.75%, about 6.0%, about
6.25%, about 6.5%, about 6.75%, about 7.0%, about 7.25%, about
7.5%, about 7.75%, about 8.0%, about 8.25%, about 8.5%, about
8.75%, about 9.0%, about 9.25%, about 9.5%, about 9.75%, about 10%,
about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about
13.5%, about 14%, about 14.5% or about 15%. As a further
illustration, one or more pharmaceutically acceptable thickening or
gelling agent is present in a total amount by weight of about 0.1%
to about 15.0%; about 0.5% to about 5.0%; or about 1.0% to about
3.0%.
[0104] In another embodiment, the pharmaceutical composition
contains an anionic polymer thickening agent precursor, such as a
carbomer, which has been combined with a neutralizer in an amount
sufficient to form a gel or gel-like composition with a viscosity
greater than 1000 cps as measured by a Brookfield RV DVII+
Viscometer with spindle CPE-52, torque greater than 10% and the
temperature maintained at 25.degree. C.
[0105] In yet a further embodiment, the pharmaceutical composition
contains an anionic polymer thickening agent precursor, such as a
carbomer, which has been combined with a neutralizer selected from
the group consisting of: sodium hydroxide, ammonium hydroxide,
potassium hydroxide, arginine, aminomethyl propanol,
tetrahydroxypropyl ethylenediamine, triethanolamine ("TEA"),
tromethamine, PEG-15 cocamine, diisopropanolamine, and
triisopropanolamine, or combinations thereof in an amount
sufficient to neutralize the anionic polymer thickening agent
precursor to form a gel or gel-like composition in the course of
forming the composition. Suitable neutralizing agents and their use
with selected anionic polymer thickening agent precursors are
disclosed in "Neutralizing Carbopol.RTM. and Pemulen.RTM. Polymers
in Aqueous and Hydroalcoholic Systems," Commercial Brochure TDS-237
(October 1998) by Noveon Inc. of Cleveland, Ohio, incorporated by
reference herein.
[0106] In yet a further embodiment, the pharmaceutical composition
contains an anionic polymer thickening agent precursor, such as a
carbomer, which has been combined with a neutralizer which is an
aqueous solution of sodium hydroxide, such as 0.01 N, 0.02 N, 0.025
N, 0.05 N, 0.075 N, 0.1 N sodium hydroxide, or 1.5 N sodium
hydroxide, or 2.0 N sodium hydroxide or any other convenient
strength aqueous solution in an amount sufficient to adequately
neutralize the polyacrylic acid and form a gel or gel-like
composition. In one embodiment, the composition was prepared using
from about 1.0% to about 10.0% 0.025N sodium hydroxide.
Accordingly, embodiments employing any percentage from about 1.0%
to about 10.0% 0.025 N NaOH may be used, such as, e.g., 1.0%, 2.0%,
3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0% or 10% 0.025 N NaOH.
[0107] In an embodiment, the viscosity of a pharmaceutical
composition described herein is about 1,000 cps to about 100,000
cps. Accordingly, the viscosity of the compositions described and
disclosed herein may be any amount from about 1,000 cps to about
100,000 cps, such as, e.g., about 1,000, about 2,000, about 3,000,
about 4,000, about 5,000, about 6,000, about 7,000, about 8,000,
about 9,000, about 10,000, about 11,000, about 12,000, about
13,000, about 14,000, about 15,000, about 16,000, about 17,000,
about 18,000, about 19,000, about 20,000, about 21,000, about
22,000, about 23,000, about 24,000, about 25,000, about 26,000,
about 27,000, about 28,000, about 29,000, about 30,000, about
31,000, about 32,000, about 33,000, about 34,000, about 35,000,
about 36,000, about 37,000, about 38,000, about 39,000, about
40,000, about 41,000, about 42,000, about 43,000, about 44,000,
about 45,000, about 46,000, about 47,000, about 48,000, about
49,000, about 50,000, about 51,000, about 52,000, about 53,000,
about 54,000, about 55,000, about 56,000, about 57,000, about
58,000, about 59,000, about 60,000, about 61,000, about 62,000,
about 63,000, about 64,000, about 65,000, about 66,000, about
67,000, about 68,000, about 69,000, about 70,000, about 71,000,
about 72,000, about 73,000, about 74,000, about 75,000, about
76,000, about 77,000, about 78,000, about 79,000, about 80,000,
about 81,000, about 82,000, about 83,000, about 84,000, about
85,000, about 86,000, about 87,000, about 88,000, about 89,000,
about 90,000, about 91,000, about 92,000, about 93,000, about
94,000, about 95,000, about 96,000, about 97,000, about 98,000,
about 99,000, about 100,000 cps.
[0108] In one embodiment, a neutralizing agent is optionally used
to assist in forming a pharmaceutical composition. Suitable
neutralizing agents include sodium hydroxide (e.g., as an aqueous
mixture), potassium hydroxide (e.g., as an aqueous mixture),
ammonium hydroxide (e.g., as an aqueous mixture), triethanolamine,
tromethamine(2-amino 2-hydroxymethyl-1, 3 propanediol), aminomethyl
propanol (AMP), tetrahydroxypropyl ethylene diamine,
diisopropanolamine, Ethomeen C-25 (Armac Industrial Division), Di-2
(ethylhexyl)amine (BASF-Wyandotte Corp., Intermediate Chemicals
Division), triamylamine, Jeffamine D-1000 (Jefferson Chemical Co.),
b-Dimethylaminopropionitrite (American Cyanamid Co.), Armeen CD
(Armac Industrial Division), Alamine 7D (Henkel Corporation),
dodecylamine and morpholine. The neutralizing agent is present in
an amount sufficient to increase viscosity and form a gel or
gel-like composition which is suitable for contact with the skin of
a mammal. Illustratively, one or more pharmaceutically acceptable
neutralizing agent is present in a total amount by weight of about
0.001%, about 0.0015%, about 0.01%, about 0.015%, about 0.1%, about
0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%,
about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about
1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%,
about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about
2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%,
about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about
3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4.0%,
about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about
4.6%, about 4.7%, about 4.8%, about 4.9%, about 5.0%, about 5.1%,
about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about
5.7%, about 5.8%, about 5.9%, about 6.0%, about 6.1%, about 6.2%,
about 6.3%, about 6.4%, about 6.5%, about 6.6%, about 6.7%, about
6.8%, about 6.9%, about 7.0%. As a further illustration, one or
more pharmaceutically acceptable neutralizing agent is present in a
total amount by weight of about 0.1% to about 7.0% or about 1.0% to
about 5.0%.
[0109] In one embodiment, a solution of sodium hydroxide is used,
such as, e.g., 0.01 N, 0.02 N, 0.025 N, 0.05 N, 0.075 N, 0.1 N
sodium hydroxide solution, 0.2 N sodium hydroxide solution, 0.5 N
sodium hydroxide solution, 1.0 N sodium hydroxide solution, 1.5 N
sodium hydroxide solution, 2.0 N sodium hydroxide solution, 10.0 N
sodium hydroxide solution, or any other suitable solution for
providing a sufficient amount of the aqueous sodium hydroxide to
form the desired gel or gel-like composition. In one embodiment,
the pharmaceutically acceptable composition results from combining
a gelling agent with a neutralizing agent such as about 1% to about
10% (wt/wt) 0.025 N sodium hydroxide, while in another embodiment
about 0.1% to about 1% (wt/wt) 0.25 N sodium hydroxide is used. Of
course, other suitable neutralizing agents can be used as can other
concentrations and amounts of aqueous sodium hydroxide so long as
there is a sufficient amount of OH.sup.- ions to assist in the
formation of a gel or gel-like composition.
[0110] Additional Excipients
[0111] The pharmaceutical compositions described herein optionally
comprise one or more pharmaceutically acceptable wetting agents as
excipients. Non-limiting examples of surfactants that can be used
as wetting agents in compositions of the disclosure include
quaternary ammonium compounds, for example benzalkonium chloride,
benzethonium chloride and cetylpyridinium chloride; dioctyl sodium
sulfosuccinate; polyoxyethylene alkylphenyl ethers, for example
nonoxynol 9, nonoxynol 10, and octoxynol 9; poloxamers
(polyoxyethylene and polyoxypropylene block copolymers);
polyoxyethylene fatty acid glycerides and oils, for example
polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,
Labrasol.TM. of Gattefosse), polyoxyethylene (35) castor oil and
polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl
ethers, for example polyoxyethylene (20) cetostearyl ether;
polyoxyethylene fatty acid esters, for example polyoxyethylene (40)
stearate; polyoxyethylene sorbitan esters, for example polysorbate
20 and polysorbate 80 (e.g., Tween.TM. 80 of ICI); propylene glycol
fatty acid esters, for example propylene glycol laurate (e.g.,
Lauroglycol.TM. of Gattefosse); sodium lauryl sulfate, fatty acids
and salts thereof, for example oleic acid, sodium oleate and
triethanolamine oleate; glyceryl fatty acid esters, for example
glyceryl monostearate; sorbitan esters (e.g., sorbitan monolaurate,
sorbitan monooleate, sorbitan monopalmitate and sorbitan
monostearate); tyloxapol and mixtures thereof. Such wetting agents,
if present, constitute in total about 0.25% to about 15%, about
0.4% to about 10%, or about 0.5% to about 5%, of the total weight
of the composition. Illustratively, one or more pharmaceutically
acceptable wetting agents are present in a total amount by weight
of about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%,
about 1.5%, about 1.75%, about 2.0%, about 2.25%, about 2.5%, about
2.75%, about 3.0%, about 3.25%, about 3.5%, about 3.75%, about
4.0%, about 4.25%, about 4.5%, about 4.75%, about 5.0%, about
5.25%, about 5.5%, about 5.75%, about 6.0%, about 6.25%, about
6.5%, about 6.75%, about 7.0%, about 7.25%, about 7.5%, about
7.75%, about 8.0%, about 8.25%, about 8.5%, about 8.75%, about
9.0%, about 9.25%, about 9.5%, about 9.75% or about 10%.
[0112] As used herein, a "solubility agent" or "solubilizing agent"
is any excipient which is added to a pharmaceutical composition to
increase the solubility of a solute.
[0113] The pharmaceutical compositions described herein optionally
comprise one or more pharmaceutically acceptable lubricant,
including an anti-adherent and/or a glidant. Suitable lubricants
include, either individually or in combination, glyceryl behapate
(e.g., Compritol.TM. 888); stearic acid and salts thereof,
including magnesium (magnesium stearate), calcium and sodium
stearates; hydrogenated vegetable oils (e.g., Sterotex.TM.);
colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium
acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene
glycol ("PEG") (e.g., Carbowax.TM. 4000 and Carbowax.TM. 6000);
sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate.
Such lubricants, if present, constitute about 0.1% to about 10%,
about 0.2% to about 8%, or about 0.25% to about 5%, of the total
weight of the composition. Illustratively, one or more
pharmaceutically acceptable lubricant is present in a total amount
by weight of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about
0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%,
about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about
1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%,
about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about
2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%,
about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about
3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3%,
about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about
4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%,
about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about
6.0%, about 6.1%, about 6.2%, about 6.3%, about 6.4%, about 6.5%,
about 6.6%, about 6.7%, about 6.8%, about 6.9%, about 7.0%, about
7.1%, about 7.2%, about 7.3%, about 7.4%, about 7.5%, about 7.6%,
about 7.7%, about 7.8%, about 7.9%, about 8.0%, about 8.1%, about
8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%,
about 8.8%, about 8.9%, about 9.0%, about 9.1%, about 9.2%, about
9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%,
about 9.9% or about 10%.
[0114] In another embodiment, the pharmaceutical compositions
described herein optionally comprise an emollient. Illustrative
emollients include mineral oil, mixtures of mineral oil and lanolin
alcohols, cetyl alcohol, cetostearyl alcohol, petrolatum,
petrolatum and lanolin alcohols, cetyl esters wax, cholesterol,
glycerin, glyceryl monostearate, isopropyl myristate, isopropyl
palmitate, lecithin, allyl caproate, althea officinalis extract,
arachidyl alcohol, argobase EUC, butylene glycol,
dicaprylate/dicaprate, acacia, allantoin, carrageenan, cetyl
dimethicone, cyclomethicone, diethyl succinate, dihydroabietyl
behenate, dioctyl adipate, ethyl laurate, ethyl palmitate, ethyl
stearate, isoamyl laurate, octanoate, PEG-75, lanolin, sorbitan
laurate, walnut oil, wheat germ oil, super refined almond, super
refined sesame, super refined soyabean, octyl palmitate,
caprylic/capric triglyceride and glyceryl cocoate. An emollient, if
present, is present in the compositions described herein in an
amount by weight of the composition of about 1% to about 30%, about
3% to about 25%, or about 5% to about 15%. Illustratively, one or
more emollients are present in a total amount of about 1%, about
2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%,
about 9%, about 10%, about 11%, about 12%, about 13%, about 14%,
about 15%, about 16%, about 17%, about 18%, about 19%, about 20%,
about 21%, about 22%, about 23%, about 24%, about 25%, about 26%,
about 27%, about 28%, about 29%, or about 30%, by weight.
[0115] In one embodiment, the pharmaceutical compositions described
herein comprise an antioxidant. Illustrative antioxidants include
citric acid, butylated hydroxytoluene (BHT), ascorbic acid,
glutathione, retinol, .alpha.-tocopherol, .beta.-carotene,
.alpha.-carotene, ubiquinone, butylated hydroxyanisole,
ethylenediaminetetraacetic acid, selenium, zinc, lignan, uric acid,
lipoic acid, and N-acetylcysteine. An antioxidant, if present, is
present in the compositions described herein in the amount of about
less than 1% by weight. Illustratively, one or more antioxidants
are present in the total amount of about 0.025%, about 0.05%, about
0.075%, about 0.1%, about 0.125%, about 0.15%, about 0.175%, about
0.2%, about 0.225%, about 0.25%, about 0.275%, about 0.3%, 0.325%,
about 0.35%, about 0.375%, about 0.4%, about 0.425%, about 0.45%,
about 0.475%, about 0.5%, about 0.525%, about 0.55%, about 0.575%,
about 0.6%, about 0.625%, about 0.65%, about 0.675%, about 0.7%,
about 0.725%, about 0.75%, about 0.775%, about 0.8%, about 0.825%,
about 0.85%, about 0.875%, about 0.9%, about 0.925%, about 0.95%,
about 0.975%, or about 1.0%, by weight. As a further illustration,
one or more antioxidants are present in the total amount by weight
of about 0.01% to about 1.0%; about 0.05% to about 0.5% or about
0.05% to about 0.2%.
[0116] In one embodiment, the pharmaceutical compositions described
herein comprise an antimicrobial preservative. Illustrative
anti-microbial preservatives include acids, including but not
limited to, benzoic acid, phenolic acid, sorbic acids, alcohols,
benzethonium chloride, bronopol, butylparaben, cetrimide,
chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben,
imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl
alcohol, phenylmercuric acetate, phenylmercuric borate,
phenylmercuric nitrate, potassium sorbate, propylparaben, sodium
propionate or thimerosal. The anti-microbial preservative, if
present, is present in an amount by weight of the composition of
about 0.1% to about 5%, about 0.2% to about 3%, or about 0.3% to
about 2%, for example about 0.2%, about 0.4%, about 0.6%, about
0.8%, about 1%, about 1.2%, about 1.4%, about 1.6%, about 1.8%,
about 2%, about 2.2%, about 2.4%, about 2.6%, about 2.8%, about
3.0%, about 3.2%, about 3.4%, about 3.6%, about 3.8%, about 4%,
about 4.2%, about 4.4%, about 4.6%, about 4.8%, or about 5%.
[0117] The pharmaceutical composition described herein optionally
comprises one or more emulsifying agents. The term "emulsifying
agent" refers to an agent capable of lowering surface tension
between a non-polar and polar phase and includes self emulsifying
agents. Suitable emulsifying agents can come from any class of
pharmaceutically acceptable emulsifying agents including
carbohydrates, proteins, high molecular weight alcohols, wetting
agents, waxes and finely divided solids. The optional emulsifying
agent, if present, is present in a composition in a total amount of
about 1% to about 25%, about 1% to about 20%, or about 1% to about
15% by weight of the composition. Illustratively, one or more
emulsifying agents are present in a total amount by weight of about
1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,
about 8%, about 9%, about 10%, about 11%, about 12%, about 13%,
about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,
about 20%, about 21%, about 22%, about 23%, about 24%, or about
25%.
[0118] In another embodiment, the pharmaceutical composition
optionally comprises a water miscible solvent, such as propylene
glycol. A suitable water miscible solvent refers to any solvent
that is acceptable for use in a pharmaceutical composition and is
miscible with water. If present, the water miscible solvent is
present in a composition in a total amount of about 1% to about
95%, about 2% to about 75%, about 3% to about 50%, about 4% to
about 40%, or about 5% to about 25% by weight of the composition.
In a further embodiment, the water miscible solvent is present in a
composition in an amount of about 1% to about 99%, by weight of the
composition, for example about 1%, about 5%, about 10%, about 15%,
about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,
about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,
about 80%, about 85%, about 90%, about 95% or about 99%.
[0119] The pharmaceutical compositions described herein may
optionally comprise one or more alcohols. In a further embodiment,
the alcohol is a lower alcohol. As used herein, the term "lower
alcohol," alone or in combination, means a straight-chain or
branched-chain alcohol moiety containing one to about six carbon
atoms. In one embodiment, the lower alcohol contains one to about
four carbon atoms, and in another embodiment the lower alcohol
contains two or three carbon atoms. Examples of such alcohol
moieties include methanol, ethanol, ethanol USP (i.e., 95% v/v),
n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and
tert-butanol. As used herein, the term "ethanol" refers to
C.sub.2H.sub.5OH. It may be used as dehydrated alcohol USP, alcohol
USP or in any common form including in combination with various
amounts of water. If present, the alcohol is present in an amount
sufficient to form a composition which is suitable for contact with
a mammal. Illustratively, one or more pharmaceutically acceptable
alcohol is present in a total amount by weight of about 1%, about
2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%,
about 9%, about 10%, about 11%, about 12%, about 13%, about 14%,
about 15%, about 16%, about 17%, about 18%, about 19%, about 20%,
about 21%, about 22%, about 23%, about 24%, about 25%, about 26%,
about 27%, about 28%, about 29%, about 30%, about 31%, about 32%,
about 33%, about 34%, about 35%, about 36%, about 37%, about 38%,
about 39%, about 40%, about 41%, about 42%, about 43%, about 44%,
about 45%, about 46%, about 47%, about 48%, about 49%, about 50%,
about 51%, about 52%, about 53%, about 54%, about 55%, about 56%,
about 57%, about 58%, about 59%, about 60%, about 61%, about 62%,
about 63%, about 64%, about 65%, about 66%, about 67%, about 68%,
about 69%, about 70%, about 71%, about 72%, about 73%, about 74%,
about 75%, about 76%, about 77%, about 78%, about 79%, about 80%,
about 81%, about 82%, about 83%, about 84%, about 85%, about 86%,
about 87%, about 88%, about 89%, about 90%, about 91%, about 92%,
about 93%, about 94%, about 95%, about 96%, about 97%, or about
98%. As a further illustration, one or more pharmaceutically
acceptable alcohol is present in a total amount by weight of about
1% to about 98%; about 10% to about 95%; about 25% to about 75%;
about 35% to about 70%; or about 40% to about 50%.
[0120] In a further embodiment, water is separately added to the
pharmaceutical composition. The amount of water separately added to
a pharmaceutical composition is exclusive of the amount of water
independently present in the composition from any other component
(e.g., alcohol, neutralizing agent). Water is present in an amount
sufficient to form a composition which is suitable for
administration to a mammal. Illustratively, water can be separately
added by weight in an amount of about 1%, about 2%, about 3%, about
4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%,
about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,
about 17%, about 18%, about 19%, about 20%, about 21%, about 22%,
about 23%, about 24%, about 25%, about 26%, about 27%, about 28%,
about 29%, about 30%, about 31%, about 32%, about 33%, about 34%,
about 35%, about 36%, about 37%, about 38%, about 39%, about 40%,
about 41%, about 42%, about 43%, about 44%, about 45%, about 46%,
about 47%, about 48%, about 49%, about 50%, about 51%, about 52%,
about 53%, about 54%, about 55%, about 56%, about 57%, about 58%,
about 59%, about 60%, about 61%, about 62%, about 63%, about 64%,
about 65%, about 66%, about 67%, about 68%, about 69%, about 70%,
about 71%, about 72%, about 73%, about 74%, about 75%, about 76%,
about 77%, about 78%, about 79%, about 80%, about 81%, about 82%,
about 83%, about 84%, about 85%, about 86%, about 87%, about 88%,
about 89%, about 90%, about 91%, about 92%, about 93%, about 94%,
about 95%, about 96%, about 97%, or about 98%. As a further
illustration, water can be separately added by weight in an amount
of about 1% to about 98%; about 10% to about 70%; about 10% to
about 40%; about 10% to about 30%; about 20% to about 30%; or about
25% to about 30%.
[0121] In a further embodiment, water is separately added to the
pharmaceutical composition in a quantity or amount sufficient to
achieve the desired weight of the pharmaceutical composition. In an
additional embodiment, water is separately added in a quantity
sufficient to obtain 100% weight of the composition.
[0122] In one embodiment, the pH of the pharmaceutical composition
is suitable for administration to a mammal. In a further
embodiment, the pH of the pharmaceutical composition is suitable
for administration to the skin of a mammal. In additional
embodiments, the pH of the pharmaceutical composition is suitable
for buccal, sublingual, injection, rectal, vaginal, ocular, nasal
or oral administration to a mammal. In one embodiment, the pH of
the pharmaceutical composition is about 3, about 3.1, about 3.2,
about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8,
about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4,
about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5,
about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6,
about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2,
about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8,
about 6.9, about 7, about 7.1, about 7.2, about 7.3, about 7.4,
about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8,
about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6,
about 8.7, about 8.8, about 8.9, about 9, about 9.1, about 9.2,
about 9.3, about 9.4, about 9.5, about 9.6, about 9.7, about 9.8,
about 9.9 or about 10. Illustratively, the pH of the pharmaceutical
composition may be from about 3 to about 10, about 4 to about 8,
about 4.5 to about 6.5, or about 5 to about 6.
[0123] Therapeutic Uses
[0124] The term "therapeutically effective amount" or
"therapeutically and/or prophylactically effective amount" as used
herein refers to an amount of compound or agent that is sufficient
to elicit the required or desired therapeutic and/or prophylactic
response, as the particular treatment context may require.
[0125] It will be understood that a therapeutically and/or
prophylactically effective amount of a drug for a subject is
dependent inter alia on the body weight of the subject as well as
other factors known to a person of ordinary skill in the art. A
"subject" herein to which a therapeutic agent or composition
thereof can be administered includes mammals, such as a human
subject of either sex and of any age, and also includes any
nonhuman animal, particularly a domestic or companion animal;
illustratively a cat, dog or a horse as well as laboratory animals
such as guinea pigs.
[0126] The terms "treat", "treated", "treating" and "treatment" are
to be broadly understood as referring to any response to, or
anticipation of, a medical condition in a mammal, particularly a
human, and includes but is not limited to: [0127] i. preventing the
medical condition from occurring in a subject, which may or may not
be predisposed to the condition, but has not yet been diagnosed
with the condition and, accordingly, the treatment constitutes
prophylactic treatment for the medical condition; [0128] ii.
inhibiting the medical condition, e.g., arresting, slowing or
delaying the onset, development or progression of the medical
condition; or [0129] iii. relieving the medical condition, e.g.,
causing regression of the medical condition or reducing the
symptoms of the medical condition.
[0130] In one embodiment, a therapeutically effective amount of a
cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a
cannabidiol prodrug) is administered to treat alcohol use disorders
and/or pancreatic illness, such as pancreatitis, acute
pancreatitis, chronic pancreatitis or pancreatic cancer.
[0131] In other embodiments, a therapeutically effective amount of
a cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a
cannabidiol prodrug) is administered to treat alcohol use disorders
and/or a medical condition selected from the group consisting of:
nausea, emesis, pain, wasting syndrome, HIV-wasting, chemotherapy
induced nausea and vomiting, alcohol use disorders, dystonia,
multiple sclerosis, inflammatory bowel disorders, arthritis,
dermatitis, Rheumatoid arthritis, systemic lupus erythematosus,
anti-inflammatory, anti-convulsant, anti-psychotic, antioxidant,
neuroprotective, anti-cancer, immunomodulatory effects, peripheral
neuropathic pain, neuropathic pain associated with post-herpetic
neuralgia, diabetic neuropathy, shingles, burns, actinic keratosis,
oral cavity sores and ulcers, post-episiotomy pain, psoriasis,
pruritic, contact dermatitis, eczema, bullous dermatitis
herpetiformis, exfoliative dermatitis, mycosis fungoides,
pemphigus, severe erythema multiforme (e.g., Stevens-Johnson
syndrome), seborrheic dermatitis, ankylosing spondylitis, psoriatic
arthritis, Reiter's syndrome, gout, chondrocalcinosis, joint pain
secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain,
neuropathic-postoperative complications, polymyositis, acute
nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic
osteoarthritis, osteoarthritis, rheumatoid arthritis, synovitis,
juvenile rheumatoid arthritis and inhibition of hair growth.
[0132] In a further embodiment, the cannabinoid gels, including
hydrogels (which can be optionally incorporated into a patch
system) and hydroalcoholic gels, described herein are used in
conjunction with microneedles and are suitable for use for the
relief of the pain of osteoarthritis of the joints, such as the
hands, feet, ankles, wrists, shoulders, back, elbows and knees as
well as the acute pain due to minor sprains, strains and
contusions.
[0133] In one embodiment, the pharmaceutical composition containing
a cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a
cannabidiol prodrug) is administered with the use of microneedles
once daily to a subject in need thereof. In a further embodiment,
the pharmaceutical composition containing a cannabinoid, such as
cannabidiol, or a cannabinoid prodrug, such as a cannabidiol
prodrug, is administered with the use of microneedles twice daily
to a subject in need thereof. In a further embodiment, the
pharmaceutical composition is administered with the use of
microneedles more than twice daily, such as three, four, five, six,
seven or eight times daily or once, twice, three, four, five or six
times per week. In a further embodiment, the pharmaceutical
composition is administered weekly, every two weeks, every three
weeks, every four weeks, every five weeks, or every six weeks.
[0134] Pharmaceutical Dosage Forms
[0135] The pharmaceutical compositions described herein are used in
a "pharmacologically effective amount." A "pharmacologically
effective amount" is the amount of the active pharmaceutical agent
in the composition which is sufficient to deliver a therapeutic
amount of the active agent during the dosing interval in which the
pharmaceutical composition is administered.
[0136] In one embodiment, the amount of the pharmaceutical
composition (e.g., the total weight of the hydrogel) administered
to deliver a therapeutically effective amount of the cannabinoid,
such as cannabidiol or cannabidiol prodrug, is about 0.01 g, about
0.05 g, about 0.1 g, about 0.2 g, about 0.3 g, about 0.4 g, about
0.5 g, about 0.6 g, about 0.7 g, about 0.8 g, about 0.9 g, about 1
g, about 1.1 g, about 1.2 g, about 1.3 g, about 1.4 g, about 1.5 g,
about 1.6 g, about 1.7 g, about 1.8 g, about 1.9 g, about 2 g,
about 2.1 g, about 2.2 g, about 2.3 g, about 2.4 g, about 2.5 g,
about 2.6 g, about 2.7 g, about 2.8 g, about 2.9 g, about 3 g,
about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g,
about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4 g,
about 4.1 g, about 4.2 g, about 4.3 g, about 4.4 g, about 4.5 g,
about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, about 5 g,
about 5.1 g, about 5.2 g, about 5.3 g, about 5.4 g, about 5.5 g,
about 5.6 g, about 5.7 g, about 5.8 g, about 5.9 g, about 6 g,
about 6.1 g, about 6.2 g, about 6.3 g, about 6.4 g, about 6.5 g,
about 6.6 g, about 6.7 g, about 6.8 g, about 6.9 g, about 7 g,
about 7.1 g, about 7.2 g, about 7.3 g, about 7.4 g, about 7.5 g,
about 7.6 g, about 7.7 g, about 7.8 g, about 7.9 g, about 8 g,
about 8.1 g, about 8.2 g, about 8.3 g, about 8.4 g, about 8.5 g,
about 8.6 g, about 8.7 g, about 8.8 g, about 8.9 g, about 9 g,
about 9.1 g, about 9.2 g, about 9.3 g, about 9.4 g, about 9.5 g,
about 9.6 g, about 9.7 g, about 9.8 g, about 9.9 g or about 10
g.
[0137] Illustratively, the amount of the pharmaceutical composition
administered to deliver a therapeutically effective amount of a
cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a
cannabidiol prodrug) is about 0.01 g to about 10 g, about 0.01 g to
about 6 g, about 0.01 g to about 4 g, or about 0.01 g to about 2
g.
[0138] In one embodiment, a single dosage unit of any
pharmaceutical composition described herein comprises a
therapeutically effective amount or a therapeutically and/or
prophylactically effective amount of a cannabinoid, such as
cannabidiol or a prodrug of cannabidiol.
[0139] In one embodiment, the pharmaceutical compositions described
herein are suitable for transdermal administration, in conjunction
with a microneedle array, comprising the microneedle transdermal
drug delivery system. In another embodiment, microneedle
transdermal drug delivery systems are adapted for administration in
and/or around the abdomen, back, chest, legs, arms, scalp or other
suitable skin surface and may include compositions in which the
cannabinoid or cannabinoid prodrug is administered in patches
(which can optionally contain a hydrogel), ointments, creams,
suspensions, lotions, pastes, gels, hydrogels (which can be
optionally incorporated into a patch), sprays, foams or oils. In
another embodiment, the pharmaceutical compositions described
herein comprise a cannabinoid, such as cannabidiol or a cannabidiol
prodrug, in a pharmaceutical gel or gel-like composition, which are
transdermally administrable, in conjunction with a microneedle
array, as part of a microneedle transdermal drug delivery
system.
[0140] In one embodiment, the pharmaceutical compositions described
herein are suitable for topical administration, in conjunction with
a microneedle array, comprising the microneedle topical drug
delivery system. In another embodiment, microneedle topical drug
delivery systems are adapted for administration in and/or around
the abdomen, back, chest, legs, arms, scalp or other suitable skin
surface and may include compositions in which the a cannabinoid,
such as cannabidiol or prodrug of cannabidiol, is administered in
patches (which can optionally contain a hydrogel), ointments,
creams, suspensions, lotions, pastes, gels, hydrogels (which can be
optionally incorporated into a patch), sprays, foams or oils. In
another embodiment, the pharmaceutical compositions described
herein comprise a cannabinoid, such as cannabidiol or a prodrug of
cannabidiol, in a pharmaceutical gel or gel-like composition which
are transdermally administrable, in conjunction with a microneedle
array, as part of a microneedle topical drug delivery system.
[0141] In one embodiment, the pharmaceutical compositions described
herein are administered via a membrane-modulated transdermal
delivery system used in conjunction with a microneedle array.
Together, the pharmaceutical composition and the microneedle array
comprise a "microneedle drug delivery system." In one embodiment of
the microneedle drug delivery system, this membrane-modulated
transdermal delivery system comprises a reservoir containing a
cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a
cannabidiol prodrug) to be transdermally administered to the
patient can be encapsulated in a shallow compartment molded from a
drug impermeable backing and a rate controlling polymeric membrane
through which the cannabinoid passes in a controlled manner in
conjunction with a microneedle array. In another embodiment, the
external surface of the membrane has a thin layer of a
drug-compatible, hypoallergenic adhesive polymer (e.g., silicone or
polyacrylate adhesive) which is applied to achieve intimate contact
with the skin of a mammal.
[0142] In another embodiment, the pharmaceutical compositions
described herein are administered via an adhesive-diffusion
controlled transdermal system used in conjunction with a
microneedle array. Together, the pharmaceutical composition and the
microneedle array comprise a "microneedle drug delivery system." In
these embodiments, the pharmaceutical composition acts as a
reservoir by directly dispersing a cannabinoid (e.g., cannabidiol)
or a cannabinoid prodrug (e.g., a cannabidiol prodrug) to be
delivered in an adhesive polymer and then spreading the medicated
adhesive onto a flat sheet of drug-impermeable backing membrane to
form a thin active pharmaceutical agent reservoir layer.
Optionally, additional layers of non-medicated rate controlling
adhesive polymer with a constant thickness are placed on top of the
drug reservoir layer to produce an adhesive diffusion-controlled
drug-delivery system. The resulting adhesive-diffusion controlled
transdermal system is then applied to the desired area of the skin
of a mammal in conjunction with a microneedle array.
[0143] In a further embodiment, the pharmaceutical compositions
described herein are administered via matrix dispersion-type
systems in conjunction with microneedle arrays. Together, the
pharmaceutical composition and the microneedle array comprise a
"microneedle drug delivery system." The dispersion-type system
comprises a reservoir containing a cannabinoid (e.g., cannabidiol)
or a cannabinoid prodrug (e.g., a cannabidiol prodrug) which can be
formed by homogeneously dispersing the cannabinoid or cannabinoid
prodrug in a hydrophilic or lipophilic polymer matrix. The
medicated polymer is then molded into a medicated disc with a
defined surface area and controlled thickness which is glued onto
an occlusive baseplate in a compartment fabricated from a
drug-impermeable backing. The adhesive polymer is spread along the
circumference to form a strip of adhesive rim around the medicated
disc. The resulting dispersion-type system is then applied to the
desired area of the skin in conjunction with a microneedle
array.
[0144] In still another embodiment, the pharmaceutical compositions
described herein are administered via microreservoir systems in
conjunction with microneedle arrays. Together, the pharmaceutical
composition and the microneedle array comprise a "microneedle drug
delivery system." The microreservoir system comprises a drug
reservoir which is formed by first suspending particles of a
cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a
cannabidiol prodrug) in an aqueous solution of water-soluble
polymer and then dispersing it homogeneously in a lipophilic
polymer by high-shear mechanical force to form a large number of
unleachable, microscopic spheres reservoirs of the cannabinoid or
cannabinoid prodrug. This unstable dispersion is quickly stabilized
by immediately cross-linking the polymer which produces a medicated
polymer disc with a constant surface area and fixed thickness. A
microreservoir system is produced in which the medicated disc is
positioned at the center and surrounded by an adhesive rim. The
resulting microreservoir system is then applied to the desired area
of the skin in conjunction with a microneedle array.
[0145] In another embodiment, the pharmaceutical compositions
described herein are administered via one monolithic layer,
comprising a cannabinoid (e.g., cannabidiol) or a cannabinoid
prodrug (e.g., a cannabidiol prodrug) and an adhesive, in
conjunction with a microneedle array. Together, the pharmaceutical
composition and the microneedle array comprise a "microneedle drug
delivery system." The cannabinoid can be mixed with an adhesive
(e.g., silicone type, available from Dow Corning and other
manufacturers) in a solvent (e.g., methylene chloride or ethyl
acetate). This resulting mixture would then be extruded onto a
polyester backing film to a uniform thickness of about 100 microns
or greater with a precision wet-film applicator. The solvent is
allowed to evaporate in a drying oven and the resulting "patch" is
trimmed to the appropriate size. Various patch compositions will be
made until the desired steady-state flux rate and adhesive
properties are obtained. Different adhesives can be tried, as well
as varying the amount of adhesive in the composition (Nalluri,
Milligan et al. 2005). Suitable results have been obtained by
making monolithic patches with DURO-TAK 387-2051, which is an
acrylate-vinyl acetate non-curing pressure sensitive adhesive from
the National Starch Chemical Company. Different solvents (e.g.,
isopropyl myristate, propylene glycol) can optionally be
incorporated into the composition in an attempt to optimize the
delivery rate of the active pharmaceutical agent. In a further
embodiment, the pharmaceutical compositions described herein are
administered via the reservoir system in conjunction with a
microneedle array. Together, the pharmaceutical composition and the
microneedle array comprise a "microneedle drug delivery system."
The cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g.,
a cannabidiol prodrug) and any excipient(s) could be formulated
into a gel and sealed between a release layer and an impermeable
backing material such as polyester or other suitable material known
to a person of skill in the art. Ethyl vinyl acetate membranes with
acrylic adhesives have been found to be suitable. In each of the
foregoing embodiments, the patch would then be applied to the
desired area of the skin in conjunction with a microneedle
array.
[0146] Adhesive patch compositions can be prepared containing
different loadings of a pharmaceutical composition comprising a
cannabinoid (e.g., cannabidiol) or a cannabinoid prodrug (e.g., a
cannabidiol prodrug) to be delivered transdermally by using
DURO-TAK adhesives (National Starch and Chemical Company, USA).
Appropriate amounts of adhesive and drug can be sonicated for ten
minutes, cast onto the release liner (9742 Scotchpak, 3M, St. Paul,
Minn.) with a wet film applicator (Paul N. Gardner Company, Inc.,
Pompano Beach, Fla.) set at a 40 mil thickness, and kept at room
temperature for one hour and then at 70.degree. C. in an oven for
ten minutes (to remove any residual solvent). The patches would
then be covered with backing membrane (CoTran 9722, 3M, St. Paul,
Minn.), will be cut into appropriate sizes, and then can be stored
in a desiccator for further study. The resulting patches would then
be applied to the desired area of the skin in conjunction with a
microneedle array.
[0147] In further embodiments, a combination of two or more types
of adhesives may be used, such as DURO-TAK 900A and a silicon
adhesive such as one produced by DOW, in a ratio from 1:99 to 99:1
in order to optimize release rates and drug solubility.
[0148] In further embodiments, additional adhesives which are
suitable for preparing patch transdermal delivery systems, such as
patches include polyisobutylenes, acrylates, silicone and
combinations of the foregoing, may be used. Additional adhesives
can be found in U.S. patent application Ser. No. 11/860,432,
published as US 2008/0076789 on Mar. 27, 2008.
[0149] In another illustrative embodiment, the transdermal patch
incorporating a cannabinoid (e.g., cannabidiol) or a cannabinoid
prodrug (e.g., a cannabidiol prodrug) is applied to the desired
area of the skin in conjunction with a microneedle array and is
capable of controlling the release of the active pharmaceutical
agent such that transdermal delivery of the active pharmaceutical
agent to the subject is substantially uniform and sustained over a
period of about 1 hour, about 2 hours, about 3 hours, about 4
hours, about 6 hours, about 12 hours, about 24 hours, about 48
hours, about 72 hours, about 96 hours, about 5 days, about 6 days
or about 7 days. In an alternative embodiment, the patch further
incorporates a penetration enhancer and/or a COX inhibitor and
optionally includes a hydrogel. Such a transdermal patch, which can
be used in the practice of the methods described herein, can take
the form of an occlusive body. In practice, the occlusive body,
which includes the pharmaceutical composition comprising a COX
inhibitor, a penetration enhancer and a cannabinoid (e.g.,
cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol prodrug)
is applied to the desired area of the skin in conjunction with a
microneedle array to transdermally or topically deliver the active
pharmaceutical agent.
[0150] In another embodiment, the pharmaceutical compositions
described herein are administered via a hydrogel in conjunction
with microneedle arrays. Together, the pharmaceutical composition
and the microneedle array comprise a "microneedle drug delivery
system." In one embodiment, the hydrogel is trimmed to an
appropriate size and shape, and allowed to equilibrate with a
cannabinoid- or cannabinoid prodrug-containing loading solution. In
one embodiment, the loading solution comprises a cannabinoid or a
cannabinoid prodrug (e.g. cannabidiol or a prodrug of cannabidiol),
polyethylene glycol, ethanol, benzyl alcohol and water. In another
embodiment, the hydrogel comprises a cannabinoid (e.g.,
cannabidiol) or a cannabinoid prodrug (e.g., a cannabidiol
prodrug). The hydrogel would then be applied to the desired area of
the skin in conjunction with a microneedle array. Optionally, the
hydrogel can be incorporated into a patch which can be applied to
the desired area of the skin in conjunction with a microneedle
array. Examples of suitable hydrogels include AquaSite.RTM. (Derma
Science, Inc., Princeton, N.J.), AquaFlo.RTM. Hydrogel Wound
Dressing (The Kendall Company, Mansfield, Mass.), AquaClear.RTM.
(Hartmann-Conco Inc., Rock Hill, S.C.) and 3M.TM. Tegaderm.TM.
Hydrocolloid Dressing (3M, St. Paul, Minn.).
[0151] A "hydrogel" (aka aquagel) is a hydrocolloidal polymer gel
comprising a hydrophilic natural or synthetic gel-forming polymer
dispersed in water. Hydrophilic polymers include natural gums, such
as gum karaya, guar gum, locust bean gum, gum arabic, gum
tragacanth, agarm alginic acid, carrageenan or other
polysaccharides; synthetically modified polysaccharides, such as
carboxymethyl cellulose, carboxypropyl cellulose and maltodextrin;
and synthetic polymers, such as polyacrylamide, polyacrylic acid,
polyquaternary amine and polysulfonate. Hydrogels are highly
absorbent, flexible, and similar to natural tissue.
[0152] One embodiment described herein employs a packet having a
polyethylene liner compatible with a pharmaceutical composition
comprising a cannabinoid, such as cannabidiol or a prodrug of
cannabidiol. The packet may hold a unit dose or multiple dose.
EXAMPLES
Example 1
[0153] A pharmaceutical composition, comprising cannabidiol or a
cannabidiol prodrug and optionally a penetration enhancer and/or
COX inhibitor, is administered via a membrane-modulated transdermal
delivery system in conjunction with the microneedle array.
Together, the pharmaceutical composition and the microneedle array
comprise a "microneedle drug delivery system." The composition
reservoir is encapsulated in a shallow compartment molded from a
drug impermeable backing and a rate controlling polymeric membrane
through which the cannabidiol or cannabidiol prodrug passes in a
controlled manner. The external surface of the membrane has a thin
layer of a drug-compatible, hypoallergenic adhesive polymer (e.g.,
silicone, polyisobutylene or polyacrylate adhesive) which is
applied to achieve intimate contact of the transdermal system with
the skin of a mammal in conjunction with a microneedle array to
treat a disease or condition responsive to cannabinoid therapy,
such as acute or chronic pancreatitis, pancreatic cancer, pain,
inflammation or alcohol use disorders.
Example 2
[0154] A pharmaceutical composition, comprising cannabidiol or a
cannabidiol prodrug and optionally a penetration enhancer and/or
COX inhibitor, is administered via an adhesive-diffusion controlled
transdermal system in conjunction with the microneedle array.
Together, the pharmaceutical composition and the microneedle array
comprise a "microneedle drug delivery system." The pharmaceutical
composition is formulated to act as an adhesive polymer containing
cannabidiol or a cannabidiol prodrug. The medicated adhesive
composition is spread onto a flat sheet of drug-impermeable backing
membrane and forms a thin active pharmaceutical agent reservoir
layer. The pharmaceutical composition is then administered to the
skin of a mammal in conjunction with a microneedle array to treat a
disease or condition responsive to cannabinoid therapy, such as
acute or chronic pancreatitis, pancreatic cancer, pain,
inflammation or alcohol use disorders.
Example 3
[0155] A pharmaceutical composition, comprising cannabidiol or a
cannabidiol prodrug and optionally a penetration enhancer and/or
COX inhibitor, is administered via an adhesive-diffusion controlled
transdermal system in conjunction with the microneedle array.
Together, the pharmaceutical composition and the microneedle array
comprise a "microneedle drug delivery system." At least one layer
of a non-medicated, rate-controlling adhesive polymer, with a
constant thickness, is placed on top of the pharmaceutical
composition to produce an adhesive diffusion-controlled
drug-delivery system. The resulting adhesive-diffusion controlled
transdermal system is then applied to the desired area of the skin
of a mammal in conjunction with a microneedle array to treat a
disease or condition responsive to cannabinoid therapy, such as
acute or chronic pancreatitis, pancreatic cancer, pain,
inflammation or alcohol use disorders.
Example 4
[0156] A pharmaceutical composition, comprising cannabidiol or a
cannabidiol prodrug and optionally a penetration enhancer and/or
COX inhibitor, is administered via matrix dispersion-type system in
conjunction with the microneedle array. Together, the
pharmaceutical composition and the microneedle array comprise a
"microneedle drug delivery system." The composition is formed by
homogeneously dispersing cannabidiol or a cannabidiol prodrug in a
polymer matrix. The medicated polymer composition then is molded
into a disc with a defined surface area and controlled thickness.
The disc then is glued onto an occlusive baseplate in a compartment
fabricated from a drug-impermeable backing. An adhesive polymer is
spread along the circumference of the composition disc to form a
strip of adhesive rim around disc. The resulting dispersion-type
transdermal system is then applied to the desired area of the skin
of a mammal in conjunction with a microneedle array to treat a
disease or condition responsive to cannabinoid therapy, such as
acute or chronic pancreatitis, pancreatic cancer, pain,
inflammation or alcohol use disorders.
Example 5
[0157] A pharmaceutical composition, comprising cannabidiol or a
cannabidiol prodrug and optionally a penetration enhancer and/or
COX inhibitor, is administered via microreservoir systems in
conjunction with the microneedle array. Together, the
pharmaceutical composition and the microneedle array comprise a
"microneedle drug delivery system." The composition reservoir is
formed by first suspending cannabidiol or cannabidiol prodrug
particles in an aqueous solution of water-soluble polymer. The
suspension is then dispersed homogeneously in a lipophilic polymer
by high-shear mechanical force to form a large number of
unleachable, microscopic spheres reservoirs. This unstable
dispersion is quickly stabilized by immediately cross-linking the
polymer which produces a medicated polymer disc with a constant
surface area and fixed thickness. The medicated disc is positioned
at the center and surrounded by an adhesive rim. The resulting
microreservoir transdermal system is then administered to the
desired area of the skin of a mammal in conjunction with a
microneedle array for the treatment of a disease or condition
responsive to cannabinoid therapy, such as acute or chronic
pancreatitis, pancreatic cancer, pain, inflammation or alcohol use
disorders.
Example 6
[0158] A pharmaceutical composition, comprising cannabidiol or a
cannabidiol prodrug and optionally a penetration enhancer and/or
COX inhibitor, is administered via one monolithic layer and an
adhesive, in conjunction with the microneedle array. Together, the
pharmaceutical composition and the microneedle array comprise a
"microneedle drug delivery system." The composition is mixed with
an adhesive (e.g., silicone type, available from Dow Corning and
other manufacturers) in a solvent (e.g., methylene chloride or
ethyl acetate). This resulting mixture is then extruded onto a
polyester backing film to a uniform thickness of about 100 microns
or greater with a precision wet-film applicator. The solvent is
allowed to evaporate in a drying oven and the resulting "patch" is
trimmed to the appropriate size. The pharmaceutical composition is
then administered to the skin of mammal in conjunction with a
microneedle array to treat a disease or condition responsive to
cannabinoid therapy, such as pancreatitis, pancreatic cancer, pain,
inflammation or alcohol use disorders.
Example 7
[0159] A pharmaceutical composition, comprising cannabidiol or a
cannabidiol prodrug and optionally a penetration enhancer and/or
COX inhibitor, is administered as a reservoir patch in conjunction
with the microneedle array. Together, the pharmaceutical
composition and the microneedle array comprise a "microneedle drug
delivery system." The composition is a gel that is sealed between a
release layer and an impermeable backing material, such as
polyester. The patch is then administered to the desired area of
the skin of a mammal in conjunction with a microneedle array to
treat a disease or condition responsive to cannabinoid therapy,
such as acute or chronic pancreatitis, pancreatic cancer, pain,
inflammation or alcohol use disorders.
Example 8
[0160] A pharmaceutical composition, comprising cannabidiol or a
cannabidiol prodrug and optionally a penetration enhancer and/or
COX inhibitor in a gel composition, is administered in conjunction
with the microneedle array. Together, the pharmaceutical
composition and the microneedle array comprise a "microneedle drug
delivery system." The gel composition is prepared and stored in a
packet having a polyethylene liner compatible with the
pharmaceutical composition. The packet may hold a unit dose or
multiple doses. The composition is administered by opening the
packet, removing a dose of the composition, and applying it to the
skin of a mammal in conjunction with a microneedle array to treat a
disease or condition responsive to cannabinoid therapy, such as
acute or chronic pancreatitis, pancreatic cancer, pain,
inflammation or alcohol use disorders. In one embodiment, the
treated skin is occluded with an occlusive dressing for long-term
wear. In another embodiment, the treated skin is occluded with an
occlusive dressing for short-term wear.
Example 9
[0161] A pharmaceutical composition, comprising cannabidiol or a
cannabidiol prodrug and optionally a penetration enhancer and/or
COX inhibitor in a gel composition, is administered in conjunction
with a microneedle array. Together, the pharmaceutical composition
and the microneedle array comprise a "microneedle drug delivery
system." The gel composition is prepared and stored in rigid
multi-dose container (for example, with a hand pump) having a
larger foil packet insert. The larger packet comprises a
polyethylene liner. The composition is then administered to the
skin of the mammal in conjunction with a microneedle array to treat
a disease or condition responsive to cannabinoid therapy, such as
acute or chronic pancreatitis, pancreatic cancer, pain,
inflammation or alcohol use disorders. In one embodiment, the
treated skin is occluded with an occlusive dressing for long-term
wear. In another embodiment, the treated skin is occluded with an
occlusive dressing for short-term wear.
Example 10
[0162] A pharmaceutical composition, comprising cannabidiol or a
cannabidiol prodrug and optionally a penetration enhancer and/or
COX inhibitor in a hydrogel, is administered in conjunction with a
microneedle array. Together, the pharmaceutical composition and the
microneedle array comprise a "microneedle drug delivery system."
The hydrogel comprising the cannabidiol or cannabidiol prodrug is
applied to the desired area of the skin of the mammal in
conjunction with a microneedle array to treat a disease or
condition responsive to cannabinoid therapy, such as acute or
chronic pancreatitis, pancreatic cancer, pain, inflammation or
alcohol use disorders. In one embodiment, the treated skin is
occluded with an occlusive dressing for long-term wear. In another
embodiment, the treated skin is occluded with an occlusive dressing
for short-term wear.
Example 11
Solution Permeation Results for a Cannabidiol Prodrug with
Microneedles
[0163] a) Synthesis of a Cannabidiol Prodrug (ALL00179)
[0164] Anhydrous betaine was converted to the acyl chloride using
thionyl chloride. Cannabidiol (CBD) (273.23 mg, 0.00087 mol),
triethylamine (263.6 mg, 0.00261 mol) and the converted betaine
(374.2 mg, 0.00218 mol) were combined in 5 mL dry dichloromethane
under argon. The reaction mixture was stirred at room temperature
(RT) for two hours. Additional triethylamine (175.7 mg, 0.00174
mol) and betaine acyl chloride (149.7 mg, 0.00087 mol) were added
to the reaction mixture while flushing with argon. The mixture was
stirred for another hour at RT.
[0165] The reaction mixture was transferred to a separatory funnel
containing 50 mL each of acetonitrile and water saturated with
sodium chloride. The contents of the flask were shaken well and the
layers allowed to separate. The acetonitrile layer was collected
and most of the residual water was removed by stirring for one hour
with anhydrous sodium sulfate. The sodium sulfate was removed by
filtration and the acetonitrile transferred to a round bottom
flask. The volume of acetonitrile was reduced by rotary evaporation
until a small amount of water remained. The remaining water was
transferred to an Erlenmeyer flask containing acetonitrile and
again the residual water was removed with anhydrous sodium sulfate.
The mixture was again filtered and the filtrate was collected in a
round bottom flask. The acetonitrile was completely removed by
rotary evaporation and high vacuum. The tan powder obtained was
transferred to a vial, sealed and stored at -20.degree. C.
[0166] ALL00179 was analyzed by LC/MS using electrospray in the
positive ion mode. The mass spectrum of the compound was observed
as follows: m/z=513.426 (M.sup.+, no chloride counter ions, 6%
abundance), m/z=414.358 (M.sup.+-one betaine chain, no chloride
counter ion, 8%), m/z=257.357 (90%), m/z=223.363, (100%).
[0167] For ALL00179, the .sup.1H NMR (400 MHz, CD3OD) was as
follows: .delta.=7.04 (2H, s, ArH); 5.16 (1H, s, H-2); 4.70-4.84
(4H, m, CH.sub.2CO.sub.2); 3.56-3.65 (1H, m, H-3); 3.42 (18H, s,
N(CH.sub.3).sub.3); 2.60-2.70 (1H, m); 2.60-2.66 (2H, m, benzylic
CH.sub.2); 2.32-2.44 (1H, m); 2.04-2.13 (1H, m); 1.79-1.88 (2H, m);
1.70 (3H, br s, 7-Me); 1.59-1.68 (2H, m); 1.56 (3H, s, 10-Me); 0.90
(3H, t, J=7.0, CH.sub.2CH.sub.3).
[0168] Illustratively, the molecular structure of ALL00179 as shown
below:
##STR00010##
[0169] b) Stability of the Cannabidiol Prodrug
[0170] Stability of the prodrug in human plasma was performed to
monitor the conversion of ALL00179 to the mono-substituted form,
ALL00180, and CBD. The molecular structure of ALL00180 and CBD are
shown below:
##STR00011##
TABLE-US-00001 TABLE 1 Cannabidiol and Cannabidiol Prodrugs
Molecular Weight Compound Molecular weight Cannabidiol 314.4
ALL00179 585.65 ALL00180 450.05
[0171] ALL00179 was placed in 100% ddH.sub.2O donor solution to
check chemical stability. The initial purity of ALL00179 was 94.7%
ALL00179, 5.3% ALL00180, and 0% CBD. After 72 hr in ddH.sub.2O at
RT, the purity level was determined to be 86.8% ALL00179, 13.2%
ALL00180 and 0% CBD.
TABLE-US-00002 TABLE 2 Stability of ALL00179 in Human Plasma
Percent Prodrug and CBD at time (min) Prodrug 0* 5 10 20 30 60 120
CBD 4.7 30.2 55.1 77.1 89.4 97.6 100 ALL00179 9.2 3.0 0.0 0.0 0.0
0.0 0.0 ALL00180 86.1 66.8 44.9 22.9 10.6 2.4 0.0 *Time point 0
required approximately 1 minute of mixing and withdrawal time after
addition of ALL00179 to the human plasma and before the sample was
placed into acetonitrile for extraction and analysis. The spiking
solution was shown to contain at least 88% ALL00179. ALL00179
rapidly hydrolyzed to the mono-substituted prodrug form, ALL0180,
which further hydrolyzed to CBD.
[0172] c) Diffusion Study
[0173] The purpose of the diffusion study was to determine whether
microneedle (MN) treated skin would allow the rapid permeation of a
water-soluble prodrug of CBD (ALL00179) compared to CBD.
[0174] Briefly, full thickness Yucatan pig (YP) skin was used to
perform the microneedle studies. The average thickness of the YP
skin was approximately 1.0.+-.0.1 mm. A PermeGear flow-through
(In-Line, Hellertown, Pa.) diffusion cell system was used for the
skin permeation studies. One hundred microneedle insertions were
made into the skin before mounting in the flow-through diffusion
cell by treating the skin 20 times with an array containing 5
microneedles. Each cell was charged with 250 .mu.l of either 318 mM
CBD (n=4) or ALL00179 (n=5) and occluded with rubber stoppers. Ten
percent ethanol in water was used as a receiver solution. Samples
were collected at six-hour intervals for a total of 48 hours. (See
FIG. 1 for the permeation profile.)
TABLE-US-00003 TABLE 3 HPLC Conditions of CBD and CBD Prodrugs,
ALL00179 and ALL00180, for Microneedle in vitro Diffusion Studies
and Plasma Stability Studies. Column Brownlee .RTM. C.sub.18
reversed-phase Spheri VL, 5 .mu.m, (4.6 .times. 220 mm) column with
a Brownlee .RTM. C.sub.18 reversed-phase, 5 .mu.m, (3.2 .times. 150
mm) guard column Mobile phase 85:15 acetonitrile:0.05%
trifluoroacetic acid, pH 3 with triethylamine, with 5%
acetonitrile, Flow rate 1.5 mL/min Wavelength 210 nm Injection
volume 100 .mu.L (diffusion samples and respective standards) 20
.mu.L (skin samples, donor samples, and respective standards) Run
time 9.5 min Retention times Cannabidiol (CBD) = 3.6 min ALL00179 =
8.2 min ALL00180 = 5.6 min
TABLE-US-00004 TABLE 4 Permeation Data for Cannabidiol (n = 4) and
Total CBD from ALL00179 (n = 5) in a 100% ddH.sub.2O Donor Solution
through Yucatan Pig Skin after Microneedle Treatment. 48 h skin
conc 48 h cumulative Flux Lag time Compound (.mu.mol/g) amt (nmol)
(nmol/cm.sup.2/h) (h) Cannabidiol (CBD) (MN treated) 0.12 .+-. 0.09
0.0 .+-. 0.0 0.0 .+-. 0.0 ND Total CBD* from ALL00179 (MN 2.4 .+-.
2.8 3110.7 .+-. 686.0 63.2 .+-. 11.4 2.5 .+-. 3.0 treated) *total
CBD = total cannabidiol equivalents delivered in the form of
cannabidiol and/or prodrugs ALL00179 and ALL00180
[0175] As can be seen in the table above, high cumulative
permeation and flux values were achieved using a water soluble form
of CBD (ALL00179). Likewise, short lag times were observed
throughout the study for the ALL00179-treated skin. Previous
studies showed that ALL00179 and CBD permeation through intact skin
(non-MN treated, 100% ddH.sub.2O donor solution) gave no flux and
drug was detected in the skin in very small amounts (0.09.+-.0.03
.mu.mol/g skin CBD equivalents for ALL00179 and none for CBD). In
this study, the total amount of CBD delivered from a 25 mg
ALL00179-containing donor solution was 0.2.+-.0.1 mg total CBD
equivalents in the skin and 1.0.+-.0.2 mg total CBD equivalents in
the receiver solution after 48 hr. This accounts for approximately
4.8% of the total ALL00179 in the donor solution. Analysis of the
donor solutions at the end of the study showed 84.3.+-.2.6%
ALL00179, 15.7.+-.2.6% ALL00180 and 0% CBD.
[0176] As a comparison, permeation from an optimized gel system of
cannabidiol (2.5% w/w) through intact dermatomed human skin, dosed
every 12 hr, gave a flux of 5.2 nmol/cm.sup.2/h. The total CBD flux
from ALLL00179 after MN treatment of full thickness Yucatan pig
skin was 63.2.+-.11.4 nmol/cm.sup.2/h, resulting in a 12.2 fold
enhancement of flux.
[0177] The use of the terms "a" and "an" and "the" and similar
references in the context of this disclosure (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. All methods and individual method
steps described herein can be performed in any suitable order or
simultaneously unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., such as, preferred, preferably)
provided herein, is intended merely to further illustrate the
content of the disclosure and does not pose a limitation on the
scope, or range of equivalents, to which the appended claims are
entitled. No language in the specification should be construed as
indicating any non-claimed element as essential to the practice of
the present disclosure.
[0178] All references, including printed publications, patent
applications, and patents, cited herein are hereby incorporated by
reference to the same extent as if each reference were individually
and specifically indicated to be incorporated by reference and were
set forth in its entirety herein.
[0179] Alternative embodiments of the claimed disclosure are
described herein, including the best mode known to the inventors
for practicing the claimed invention. Of these, variations of the
disclosed embodiments will become apparent to those of ordinary
skill in the art upon reading the foregoing disclosure. The
inventors expect skilled artisans to employ such variations as
appropriate (e.g., altering or combining features or embodiments),
and the inventors intend for the invention to be practiced
otherwise than as specifically described herein.
[0180] Accordingly, this invention includes all modifications and
equivalents of the subject matter recited in the claims appended
hereto as permitted by applicable law. Moreover, any combination of
the above described elements in all possible variations thereof is
encompassed by the invention unless otherwise indicated herein or
otherwise clearly contradicted by context.
[0181] The use of individual numerical values are stated as
approximations as though the values were preceded by the word
"about" or "approximately." Similarly, the numerical values in the
various ranges specified in this application, unless expressly
indicated otherwise, are stated as approximations as though the
minimum and maximum values within the stated ranges were both
preceded by the word "about" or "approximately." In this manner,
variations above and below the stated ranges can be used to achieve
substantially the same results as values within the ranges. As used
herein, the terms "about" and "approximately" when referring to a
numerical value shall have their plain and ordinary meanings to a
person of ordinary skill in the art to which the disclosed subject
matter is most closely related or the art relevant to the range or
element at issue. The amount of broadening from the strict
numerical boundary depends upon many factors. For example, some of
the factors which may be considered include the criticality of the
element and/or the effect a given amount of variation will have on
the performance of the claimed subject matter, as well as other
considerations known to those of skill in the art. As used herein,
the use of differing amounts of significant digits for different
numerical values is not meant to limit how the use of the words
"about" or "approximately" will serve to broaden a particular
numerical value or range. Thus, as a general matter, "about" or
"approximately" broaden the numerical value. Also, the disclosure
of ranges is intended as a continuous range including every value
between the minimum and maximum values plus the broadening of the
range afforded by the use of the term "about" or "approximately."
Thus, recitation of ranges of values herein are merely intended to
serve as a shorthand method of referring individually to each
separate value falling within the range, unless otherwise indicated
herein, and each separate value is incorporated into the
specification as if it were individually recited herein.
[0182] It is to be understood that any ranges, ratios and ranges of
ratios that can be formed by, or derived from, any of the data
disclosed herein represents further embodiments of the present
disclosure and are included as a part of the disclosure as though
they were explicitly set forth. This includes ranges that can be
formed that do or do not include a finite upper and/or lower
boundary. Accordingly, a person of ordinary skill in the art most
closely related to a particular range, ratio or range of ratios
will appreciate that such values are unambiguously derivable from
the data presented herein.
* * * * *
References