U.S. patent application number 15/205833 was filed with the patent office on 2017-06-08 for compositions for transdermal delivery of active agents.
The applicant listed for this patent is NeuroDerm, Ltd.. Invention is credited to Mara Nemas, Oron Yacoby-Zeevi, Eduardo Zawoznik.
Application Number | 20170157076 15/205833 |
Document ID | / |
Family ID | 45464029 |
Filed Date | 2017-06-08 |
United States Patent
Application |
20170157076 |
Kind Code |
A1 |
Yacoby-Zeevi; Oron ; et
al. |
June 8, 2017 |
COMPOSITIONS FOR TRANSDERMAL DELIVERY OF ACTIVE AGENTS
Abstract
Disclosed herein are compositions that are useful in effecting
the transdermal delivery of therapeutic agents. More particularly,
the disclosed transdermal compositions may include a fatty alcohol
(for example, octanol), a terpene (for example, limonene), and an
active agent comprising an amine moiety.
Inventors: |
Yacoby-Zeevi; Oron; (Moshav
Bitsaron, IL) ; Nemas; Mara; (Gedera, IL) ;
Zawoznik; Eduardo; (Mazkeret Batya, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NeuroDerm, Ltd. |
Rehovot |
|
IL |
|
|
Family ID: |
45464029 |
Appl. No.: |
15/205833 |
Filed: |
July 8, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13885512 |
Aug 29, 2013 |
9415108 |
|
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PCT/IL2011/000880 |
Nov 15, 2011 |
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15205833 |
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61413608 |
Nov 15, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/439 20130101;
A61K 47/12 20130101; A61K 31/5377 20130101; A61K 31/4166 20130101;
A61K 31/554 20130101; A61K 31/137 20130101; A61K 47/183 20130101;
A61K 31/195 20130101; A61K 47/10 20130101; A61K 9/0014 20130101;
A61K 31/198 20130101; A61K 47/06 20130101; A61K 31/465 20130101;
A61K 31/407 20130101; A61K 31/167 20130101; A61K 47/14 20130101;
A61K 31/49 20130101; A61K 31/277 20130101; A61K 9/7023 20130101;
A61K 31/55 20130101; A61K 31/138 20130101; A61K 31/4402
20130101 |
International
Class: |
A61K 31/198 20060101
A61K031/198; A61K 31/195 20060101 A61K031/195; A61K 31/55 20060101
A61K031/55; A61K 31/407 20060101 A61K031/407; A61K 31/465 20060101
A61K031/465; A61K 31/4402 20060101 A61K031/4402; A61K 31/167
20060101 A61K031/167; A61K 31/138 20060101 A61K031/138; A61K
31/5377 20060101 A61K031/5377; A61K 31/554 20060101 A61K031/554;
A61K 31/439 20060101 A61K031/439; A61K 31/277 20060101 A61K031/277;
A61K 31/4166 20060101 A61K031/4166; A61K 47/10 20060101 A61K047/10;
A61K 47/12 20060101 A61K047/12; A61K 47/14 20060101 A61K047/14;
A61K 47/18 20060101 A61K047/18; A61K 47/06 20060101 A61K047/06;
A61K 9/70 20060101 A61K009/70 |
Claims
1. A pharmaceutically acceptable transdermal composition comprising
a fatty alcohol, a terpene, and an active agent.
2. The pharmaceutically acceptable transdermal composition of claim
1, wherein the active agent has at least one primary, secondary or
tertiary amine moiety.
3. The pharmaceutically acceptable transdermal composition of claim
1, wherein the active agent has a negatively charged carbonyl
moiety.
4. (canceled)
5. The pharmaceutically acceptable transdermal composition of claim
4, wherein the active agent is selected from the group consisting
of carbidopa, levodopa, and a pharmaceutically acceptable salt
thereof.
6. The pharmaceutically acceptable transdermal composition of claim
1, wherein the active agent is selected from the group consisting
of opipramol, physostigmine, chlorpheniramine, lidocaine,
metoprolol, nicotine, salbutmol, timolol, diltiazem, quinidine,
imipramine, quetiapine, venlafaxine, and a pharmaceutically
acceptable salt thereof.
7. The pharmaceutically acceptable transdermal composition of claim
1, wherein (i) the composition has about 1 to about 10 weight
percent active agent; and/or (ii) the composition has about 1 to
about 5 weight percent fatty alcohol; and/or (iii) the fatty
alcohol is octanol, preferably 1-octanol.
8. The pharmaceutically acceptable transdermal composition of claim
1, wherein the composition is about 0.25 to about 5 weight percent
terpene.
9. The pharmaceutically acceptable transdermal composition of claim
1, wherein the terpene is d-limonene.
10. The pharmaceutically acceptable transdermal composition of
claim 1, further comprising a fatty acid ester.
11. The pharmaceutically acceptable transdermal composition of
claim 10, wherein the fatty acid ester is lauroglycol.
12. The pharmaceutically acceptable transdermal composition of
claim 11, wherein the weight ratio of fatty alcohol to lauroglycol
is about 3:1 to about 1.5:1.
13. The pharmaceutically acceptable transdermal composition of
claim 10, wherein the composition is about 0.1 to about 5.0 weight
percent fatty acid ester.
14. The pharmaceutically acceptable transdermal composition of
claim 1, further comprising hydroxypropyl methyl cellulose.
15. The pharmaceutically acceptable transdermal composition of
claim 1, further comprising an organic acid, wherein the organic
acid is selected from the group consisting of ascorbic acid,
tartaric acid, malic acid, succinic acid, fumaric acid, citric
acid, lactic acid, glutamic acid, or aspartic acid, more preferably
glutamic acid, aspartic acid, and tartaric acid.
16. The pharmaceutically acceptable transdermal composition of
claim 1, further comprising a basic amino acid, wherein the basic
amino acid is selected from the group consisting of arginine,
lysine and histidine.
17. The pharmaceutically acceptable transdermal composition of
claim 1, further comprising propylene glycol.
18. A pharmaceutically acceptable transdermal composition
comprising octanol, limonene, organic acid, and an active agent
comprising an amine moiety.
19. The pharmaceutically acceptable transdermal composition of
claim 18, wherein the active agent is selected from the group
consisting of opipramol and a pharmaceutically acceptable salt
thereof.
20-24. (canceled)
25. The pharmaceutically acceptable transdermal composition of
claim 18, wherein (i) the composition has about 0.5 to about 7.5
weight percent octanol; and/or (ii) the composition has about 0.25
to about 5 weight percent limonene.
26. The pharmaceutically acceptable transdermal composition of
claim 18, further comprising lauroglycol.
27. The pharmaceutically acceptable transdermal composition of
claim 26, wherein the weight ratio of octanol to lauroglycol is
about 3:1 to about 1.5:1.
28. The pharmaceutically acceptable transdermal composition of
claim 18, further comprising arginine.
29. The pharmaceutically acceptable transdermal composition of
claim 18, wherein the transdermal composition, when transdermally
administered to a patient, delivers more than twice the amount of
active agent to said patient over 20 hours as compared to (i) a
formulation that does not include octanol; (ii) a formulation that
does not include limonene; or (iii) a formulation that does not
include an organic acid.
30-32. (canceled)
33. The pharmaceutically acceptable composition of claim 1, wherein
the active agent is selected from the group consisting of
atorvastatin, amoxicillin, fexofenadine, pravastatin, cefalexin,
furosemide, ibuprofen, naproxen, gemfibrozil, mupirocin, cefprozil,
methotrexate, tretinoin, cefuroxime, etodalac, penicillin, folic
acid, fosinopril, ursodiol, indometacin, falsartan, lisinopril,
diclofenac (Na salt), fluvoxamine, memantine, amlodipine, cefdinir,
lamotrigine, amphetamine, triamterene, minocycline, phentermine,
famciclovir, trimethoprim, aciclovir, hydralazine, doxazosin,
dextro-amphetamine, famotidine, desipramine, atomoxetine,
azathioprine, bromocriptine, burpropione, clonidine,
dexmethyl-phenidate, duloxetine, enalapril, Formoterol,
Hydrochloro-thiazide, Lornoxicam, Metoprolol, Sertraline
Paroxetine, Fluoxetine, Ramipril, Salbutamol, Bupropion,
Carvedilol, Atenolol, Nifedipine, Felodipine, Enalapril, Quinapril,
Tizanidine, Clonidine, Benzonatate, Propranolol HCl, Benazepril,
Paroxetine, Allopurinol, Labetalol HCl, Sotalol, Torasemide,
Bisoprolol, Pindolol, and Pseudo-ephedrine, Miconazole, Econazole,
Clotrimazole, Ketoconazole, Quinidine, Pargiline, Alprazolam,
Apomorphine, Bromazepam, Burenorphine, Chlorpheniramine, Diltiazem,
Dipyridamole, Domperidone, Galantamine (HBr), Haloperidol,
Hydromorphone, Levomepromazine, Methadone, Methazolamide, Metformin
HCl, Azithromycin, Omeprazol, Fentanyl, Oxycodone, Risperidone,
Tramadol, Citalopram, Ondansetro, Morphine, Dextropropoxyphene,
Cyclobenzaprine HCl, Ciprofloxacin, Ranitidine, Verapamil,
Baclofen, Oxybutynin, Venlafaxine HCl, Opipramol, Lidocaine,
Oxcarbazepine, Carisoprodol, Meloxicam, glibenclamide (glyburide),
phenytoin, glimepiride, barbital, metho-carbamol, modafinil,
methysergide, lisinopril, levosalbutamol, formotoerol,
arformoterol, ipratorium bromide, voriconazole, ciclopirox, and
entacapone.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/885,512, filed Aug. 29, 2013, which is the
National Stage filing under 35 U.S.C. .sctn.371 of International
Application No. PCT/IL2011/000880, filed Nov. 15, 2011, which
claims the benefit of and priority to U.S. Provisional Patent
Application No. 61/413,608, filed Nov. 15, 2010, the entire
contents of each of which are hereby incorporated by reference.
TECHNICAL FIELD
[0002] The present invention provides compositions that are useful
in effecting the transdermal delivery of therapeutic agents. More
particularly, these transdermal compositions may include a fatty
alcohol, e.g., octanol, a terpene, e.g., limonene, and an active
agent comprising an amine moiety.
BACKGROUND ART
[0003] Active agents (for example, therapeutic agents such as drugs
or immunologically active agents such as vaccines) are
conventionally administered either orally or by injection. However,
many active agents are completely ineffective or have radically
reduced efficacy when orally administered since they either are not
absorbed or are adversely affected before entering the bloodstream
and thus do not possess the desired activity. On the other hand,
the direct injection of active agents intravenously or
subcutaneously, while assuring no modification of the agents during
administration, can be invasive, painful, and often results in poor
patient compliance.
[0004] Transdermal delivery of active agents, however, result in
systemic circulation of the active agent and can provide an
alternative mode of administration. For example, transdermal
delivery can potentially provide better drug bioavailability than
oral administration, in part because such delivery bypasses not
only the initial metabolism of the drug by the liver and the
intestines but also the unpredictable absorption of the drug from
the gastrointestinal tract. Transdermal delivery also can result in
more stable blood serum level of the drug (e.g., leading to a
prolonged pharmacological effect that is similar to intravenous
infusion), and can allow for easily adjustable dosing rate. For
example, transdermal patches can be easily removed which results in
rapid cessation of dosing and elimination of the drug from
circulation. Finally, transdermal delivery typically results in
greater patient compliance because it is non-invasive and can be
easily administered.
[0005] The skin serves as a barrier to the penetration of many
foreign substances. The feasibility of using transdermal delivery
of active agents as a route of administration requires that a
therapeutic rate of drug delivery through the skin be achieved.
This can be accomplished if the skin can be made more permeable to
the drug. Factors which determine the permeability of the skin to a
particular drug can include drug diffusivity through the skin
membrane and/or drug concentration in the vehicle. In addition,
certain materials used as adjuvants in vehicles may affect the
characteristics of the skin membrane barrier and thus alter the
permeability of the skin to the drug. Permeation enhancers, for
example, can maximize penetration rates and/or minimize lag times
in drug penetration through the skin, and should be substantially
non-toxic, non-irritant and non-sensitizing on repeated
exposure.
[0006] However, it is often difficult to predict which compounds
will work as permeation enhancers and which permeation enhancers
will work for particular drugs. Consequently, there remains a need
for transdermal formulations that could deliver, at controlled
rates, an active agent or a mixture thereof, combined with
appropriate permeation enhancers.
SUMMARY OF INVENTION
[0007] Provided herein are pharmaceutically acceptable transdermal
compositions that include an active agent, and may include a fatty
alcohol and/or a terpene. Contemplated compositions provided herein
may include an active agent having at least one primary, secondary
or tertiary amine moiety, a negatively charged carbonyl moiety,
and/or an amide moiety. In other embodiments, a disclosed
composition may include an active agent that is an amino acid or
amino acid derivative, for example, may include an agent chosen
from: carbidopa, levodopa, and/or pharmaceutically acceptable salts
thereof. In other embodiments, a disclosed composition may include
an active agent selected from the group consisting of: opipramol,
physostigmine, chlorpheniramine, lidocaine, metoprolol, nicotine,
diltiazem, quinidine, imipramine, quetiapine, venlafaxine, and
pharmaceutically acceptable salts thereof.
[0008] Disclosed compositions may have about 1 to about 10 weight
percent active agent. In other embodiments, disclosed compositions
may include about 0.5 to about 7.5, or about 2 to about 5 weight
percent fatty alcohol, such as octanol, e.g., 1-octanol. Disclosed
compositions may further include a fatty acid ester, e.g.;
lauroglycol. In some embodiments, a disclosed composition may have
a weight ratio of fatty alcohol to lauroglycol of about 3:1 to
about 1.5:1, and/or may have about 0.1 to about 5.0 weight percent
fatty acid ester. Disclosed compositions may further comprise a
cellulose ester such as hydroxypropyl methyl cellulose, and/or
propylene glycol.
[0009] In other embodiments, a disclosed composition may further
comprise an organic acid, such as an organic acid selected from the
group consisting of ascorbic acid, tartaric acid, malic acid,
succinic acid, fumaric acid, citric acid, lactic acid, glutamic
acid, and aspartic acid. An organic acid may be selected from the
group consisting of arginine, lysine or histidine.
[0010] For example, provided herein is a pharmaceutically
acceptable transdermal composition comprising octanol, limonene,
and an active agent comprising an amine moiety, such as an active
agent selected from the group consisting of opipramol and
pharmaceutically acceptable salts thereof. Also provided herein is
a pharmaceutically acceptable transdermal composition comprising
octanol, limonene, and an active agent comprising an amine moiety,
e.g., carbidopa, levodopa, and pharmaceutically acceptable salts
thereof. A pharmaceutically acceptable transdermal composition
comprising octanol, limonene, and an active agent comprising an
amide moiety, e.g. entacapone, and pharmaceutically acceptable
salts thereof, is also contemplated.
[0011] Disclosed compositions may include about 0.5 to about 7.5
weight percent octanol and/or about 0.5 to about 5 weight percent
limonene; and optionally may further include lauroglycol. In some
embodiments, if lauroglycol is present, the ratio of octanol to
lauroglycol may be about 3:1 to about 1.5:1. Contemplated
pharmaceutically acceptable transdermal compositions may further
include arginine.
[0012] Provided herein, in some embodiments, is a disclosed
pharmaceutically acceptable transdermal composition wherein the
transdermal composition comprises an active agent, optionally an
organic acid, octanol, and lauroglycol and/or limonene, when
transdermally administered to a patient, delivers more than twice
the amount of active agent to said patient over 20 hours as
compared to a formulation that does not include octanol.
[0013] Also provided herein is a pharmaceutically acceptable
transdermal composition comprising an active agent, optionally an
organic acid, octanol, and limonene, wherein the transdermal
composition, when transdermally administered to a patient, delivers
more than twice the amount of active agent to said patient over 20
hours as compared to a formulation that does not include limonene.
Provided herein, in some embodiments, is transdermal composition
having an active agent and an organic acid, when transdermally
administered to a patient, delivers more than twice the amount of
active agent a to said patient over 20 hours as compared to a
formulation that does not include an organic acid.
[0014] A pharmaceutically acceptable transdermal composition
contemplated herein also includes an active agent, optionally an
organic acid, octanol, and lauroglycol, wherein the transdermal
composition, when transdermally administered to a patient, delivers
more than twice the amount of active agent to the patient over 20
hours as compared to a formulation that does not include
lauroglycol.
[0015] Provided herein, in some embodiments, is a transdermal
composition having an active agent, and organic acid, octanol, and
laoroglycol and/or limonene. Such a composition, when transdermally
administered to a patient, may deliver more than twice the amount
of active agent to said patient over 20 hours as compared to a
formulation that does not include an organic acid.
[0016] Also provided herein is pharmaceutically acceptable
transdermal composition comprising octanol tartaric acid; and an
active agent, and limonene and/or lauroglycol.
[0017] In some embodiments, provided herein is a pharmaceutically
acceptable transdermal composition comprising: octanol,
lauroglycol, organic acid, optionally a basic amino acid, and an
active agent comprising an amine moiety or an amide moiety.
BRIEF DESCRIPTION OF DRAWINGS
[0018] FIG. 1 depicts the effects of limonene, octanol and
lauroglycol on the transdermal delivery of carbidopa/arginine salt
through porcine skin ex vivo.
[0019] FIG. 2 depicts the effects of octanol and limonene on
transdermal delivery of carbidopa/arginine salt through porcine
skin ex vivo.
[0020] FIG. 3 depicts the effect of lactic acid and/or pH on the
transdermal delivery of carbidopa/arginine salt through porcine
skin ex vivo.
[0021] FIG. 4 depicts the effects of hydroxypropylcellulose on the
transdermal delivery of carbidopa/arginine salt through porcine
skin ex vivo.
[0022] FIG. 5 depicts the effects of carbidopa and water
concentration on the transdermal delivery of carbidopa through
porcine skin ex vivo.
[0023] FIG. 6 depicts the transdermal delivery of
carbidopa/arginine and levodopa/arginine through porcine skin ex
vivo.
[0024] FIGS. 7A and 7B depict the effects organic acids on the
transdermal delivery of opipramol through porcine skin ex vivo.
[0025] FIG. 8 depicts the effects of octanol, limonene and
lauroglycol on the transdermal delivery of opipramol through
porcine skin ex vivo.
[0026] FIG. 9 depicts the effects of glutamic acid on the
transdermal delivery of opipramol through porcine skin ex vivo.
[0027] FIG. 10 depicts the effects of hydroxypropylcellulose on the
transdermal delivery of opipramol through porcine skin ex vivo.
[0028] FIG. 11 depicts the effects of organic and non-organic acids
on the transdermal delivery of opipramol through porcine skin ex
vivo.
[0029] FIG. 12 depicts the dependence of transdermal delivery on
the concentration of opipramol in a disclosed formulation.
[0030] FIG. 13 depicts the transdermal delivery of physostigmine
through porcine skin ex vivo.
[0031] FIG. 14 depicts the transdermal delivery of chlorpheniramine
through porcine skin ex vivo.
[0032] FIG. 15 depicts the transdermal delivery of lidocaine
through porcine skin ex vivo.
[0033] FIG. 16 depicts the transdermal delivery of metoprolol
through porcine skin ex vivo.
[0034] FIG. 17 depicts the transdermal delivery of nicotine through
porcine skin ex vivo.
[0035] FIG. 18 depicts the transdermal delivery of diltiazem
through porcine skin ex vivo.
[0036] FIG. 19 depicts the transdermal delivery of quinidine
through porcine skin ex vivo.
[0037] FIG. 20 depicts the transdermal delivery of imipramine
through porcine skin ex vivo.
[0038] FIG. 21 depicts the transdermal delivery of quetiapine
through porcine skin ex vivo.
[0039] FIG. 22 depicts the effects of limonene on the lag time of
the transdermal delivery of quetiapine through porcine skin ex
vivo.
[0040] FIG. 23 depicts the effects of limonene on the lag time of
the transdermal delivery of venlafaxine through porcine skin ex
vivo.
[0041] FIG. 24 depicts the transdermal delivery of timolol through
porcine skin ex vivo.
[0042] FIG. 25 depicts the transdermal delivery of albuterol
through porcine skin ex vivo.
[0043] FIG. 26 depicts the transdermal delivery of phenytoin
through porcine skin ex vivo.
[0044] FIGS. 27A, 27B, and 27C depict the transdermal delivery of
entacapone through porcine skin ex vivo.
[0045] FIG. 28 depicts the effects of limonene on the lag time of
the transdermal delivery of entacapone through porcine skin ex
vivo.
[0046] FIGS. 29A and 29B show the mean.+-.SD of carbidopa
concentrations (ng/ml) as detected in the plasma of female
landrace.times.large white swine (15.+-.2 kg) following the
application of 2 transdermal carbidopa patches (28
cm.sup.2/patch).
[0047] FIG. 30 shows the mean.+-.SD of metoprolol concentrations
(ng/ml) as detected in the plasma of female landrace.times.large
white swine (15.+-.2 kg) following the application of 2 transdermal
metoprolol patches (28 cm.sup.2/patch).
[0048] Unless indicated otherwise, all amounts indicated in the
above figures are weight percent.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0049] For convenience, certain terms used in the specification,
examples, and appended claims are collected in this section.
[0050] The term "therapeutically effective amount" refers to the
amount of an active ingredient, or combination of active
ingredients, that will elicit the biological or medical response
that is being sought by the researcher, veterinarian, medical
doctor or other clinician. Alternatively, a therapeutically
effective amount of an active ingredient is the quantity of the
compound required to achieve a desired therapeutic and/or
prophylactic effect, such as the amount of the active ingredient
that results in the prevention of or a decrease in the symptoms
associated with the condition (for example, to meet an
end-point).
[0051] The terms "pharmaceutically acceptable" or
"pharmacologically acceptable" refer to molecular entities and
compositions that do not produce an adverse, allergic or other
untoward reaction when administered to an animal, or to a human, as
appropriate. The term, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents and the like. The use of such media and agents with
pharmaceutical active agents is well known in the art. In some
embodiments, supplementary active ingredients can also be
incorporated into the compositions.
[0052] The terms "carriers" or "vehicles" as used herein refer to
carrier materials suitable for transdermal drug administration.
Contemplated carriers and/or vehicles include any such materials
known in the art, which are substantially nontoxic and/or do not
interact with other components of a pharmaceutical formulation or
drug delivery system in a deleterious manner. Examples of specific
suitable carriers and vehicles for use herein include water,
propylene glycol, mineral oil, silicone, inorganic gels, aqueous
emulsions, liquid sugars, waxes, petroleum jelly, and/or other oils
and polymeric materials.
[0053] The term "transdermal" refers generally to passage of an
agent across the skin layers. For example, the term "transdermal"
may refer to delivery of an agent (e.g., a vaccine or a drug)
through the skin to the local tissue or systemic circulatory system
without substantial cutting or penetration of the skin, such as
cutting with a surgical knife or piercing the skin with a
hypodermic needle. Transdermal agent delivery includes delivery via
passive diffusion.
[0054] The terms "penetration enhancement" or "permeation
enhancement" as used herein refer to an increase in the
permeability of skin to a pharmacologically active agent, i.e., so
as to increase the rate at which the active agent permeates through
the skin and enters the bloodstream. The enhanced permeation
effected through the use of skin permeation enhancers, for example,
through the use of a composition disclosed herein, can be observed
by e.g., measuring the rate of diffusion of drug ex-vivo, i.e.,
through animal or human skin using a diffusion cell apparatus, or
in-vivo, as described in the examples herein.
[0055] The terms, "individual," "patient," or "subject" are used
interchangeably herein and include any mammal, including animals,
for example, primates, for example, humans, and other animals, for
example, dogs, cats, swine, cattle, sheep, and horses. The
compositions disclosed herein can be administered to a mammal, such
as a human, but can also be other mammals, for example, an animal
in need of veterinary treatment, for example, domestic animals (for
example, dogs, cats, and the like), farm animals (for example,
cows, sheep, pigs, horses, and the like) and laboratory animals
(for example, rats, mice, guinea pigs, and the like). The subject
may be in need of treatment by delivery of a therapeutic agent, for
example, transcutaneous delivery of a vaccine or transdermal
delivery of a drug.
[0056] Disclosed herein are transdermal compositions that may be
part of, for example, a transdermal patch, ointment, cream, gel,
lotion or other transdermal solution or suspension. For example,
for transdermal delivery, a transdermal patch that includes a
disclosed composition is contemplated, and may include a single
layer adhesive patch, a multi-layer and adhesive patch, a reservoir
patch, a matrix patch, a microneedle patch or an iontophoretic
patch, which typically requires applying a direct current. In some
embodiments, contemplated transdermal patches may be adapted for
sustained release.
[0057] Contemplated transdermal drug delivery systems can, in some
embodiments, rely on passive, chemical diffusion as opposed to
physical, electrical, or mechanical based approaches. For example,
passive transdermal systems may have a drug reservoir containing a
high concentration of drug adapted to contact the skin where the
drug diffuses through the skin and into the body tissues or
bloodstream of a patient.
Compositions
[0058] In one aspect, the present invention relates to a
pharmaceutically acceptable transdermal composition comprising one
or more skin permeation enhancers. For example, the transdermal
composition may comprise a skin permeation enhancer such as one or
more fatty alcohols, fatty acids, and/or fatty acid esters, and an
active agent, and/or may comprise a terpene and an active agent.
Contemplated transdermal compositions may include, for example, one
or more fatty alcohols, fatty acids, and/or fatty acid esters, a
terpene, and an active agent.
[0059] For example, contemplated herein, in part, are transdermal
compositions with two or more skin permeation enhancers, wherein
the two or more skin permeation enhancers provide an additive or
even a synergistic effect on the transdermal delivery of active
agents. It is contemplated that the use of two or more disclosed
skin permeation enhancers, each increasing skin permeability via a
different mechanism, may be additive in their enhancing effects. In
an embodiment, a disclosed combination of enhancers may even have a
synergistic effect on skin penetration, i.e. an effect that is
greater than the sum of the individual effects of the enhancers
alone.
[0060] For example, in a transdermal composition that includes
octanol and limonene, the octanol and limonene may act to provide
enhanced transdermal delivery of active agents e.g., may provide
for a larger transdermal delivery amount of an active agent that is
more than the sum transdermal delivery amount of a composition that
included the active agent and limonene and transdermal delivery
amount of a composition that included an active agent and octanol,
e.g., a synergistic transdermal composition. In another embodiment,
such a composition that includes octanol and limonene, optionally
may include lauroglycol and/or an inorganic or organic acid.
[0061] In some embodiments, compositions contemplated herein may be
a gel, gel-like, or liquid at room temperature.
[0062] Fatty alcohols contemplated for use in disclosed
compositions, include, but are not limited to, 1-octanol,
2-octanol, 3-octanol, 4-octanol, hexanol, heptanol, nonanol,
decanol (capric alcohol), undecanol, dodecanol (lauryl alcohol),
2-ethyl hexanol, pelargonic alcohol, myristyl alcohol, cetyl
alcohol, palmitoleyl alcohol, octadeconal (stearyl alcohol),
isostearyl alcohol, isolauryl alcohol, isomyristyl alcohol,
isopalmityl alcohol, isostearyl alcohol, elaidyl alcohol, oleyl
alcohol, linoleyl alcohol, elaidolinoleyl alcohol, linoleynyl
alcohol, elaidolinolenyl alcohol, ricinoleyl alcohol, arachidyl
alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, ceryl
alcohol, montanyl alcohol, myricyl alcohol, geddyl alcohol,
cetearyl alcohol, and mixtures thereof. For example, a disclosed
composition may comprise about 0.1 to about 10 weight percent, for
example, about 0.2 to 10 weight percent or about 0.5 to about 7.5
weight percent fatty alcohol. In an exemplary embodiment, a
transdermal composition may include octanol (for example,
1-octanol).
[0063] Contemplated fatty acid esters include, but are not limited
to, lauroglycol, methyl laurate, ethyl oleate, propylene glycol
monolaurate, propylene glycerol dilaurate, glycerol monolaurate,
glycerol monooleate, sorbitan monooleate, isopropyl palmitate,
methyl propionate, monoglycerides, sorbitan monolaurate, isopropyl
n-decanoate, and oetyldodecyl myristate, and mixtures thereof. For
example, a disclosed composition may comprise about 0.1 to about 10
weight percent, for example, about 0.1 to 7 weight percent or about
0.1 to about 5 weight percent (e.g., 2 weight percent) fatty acid
ester, e.g., lauroglycol. In some embodiments, compositions are
provided that include a fatty alcohol (e.g., octanol) and a fatty
acid ester (e.g., lauroglycol) in a weight ratio of about 3:1 to
about 1.5:1, or about 5:1 to about 1:1.
[0064] Contemplated fatty acids include, but are not limited to,
oleic acid, alkanoic acids, capric acid, hexanoic acid, lactic
acid, lauric acid, linoleic acid and mixtures thereof.
[0065] Contemplated transdermal compositions may include a terpene,
i.e., a nonaromatic compound found in essential oils, which may be
extracted from flowers, fruits, and other natural products.
Exemplary terpenes include, but are not limited to, d-limonene,
dipentene (d/l-limonene), .alpha.-pinene, .gamma.-terpinene,
.beta.-mircene, p-cimene, .alpha.-pinene, .alpha.-phellandrene,
citronellolio, geraniale (citrale), nerol, beta-carotene, menthol,
geraniol, farnesol, phytol, their homologs, derivatives,
enantiomers, isomers including constitutional isomers,
stereoisomerisms, regioisomers, and geometric isomers, and any
combinations thereof. For example, provided herein is a transdermal
composition comprising 0.1 to about 10 weight percent, or about 0.2
to about 8 weight percent, or about 0.5 to about 5 weight percent
terpene, e.g., d-limonene.
[0066] Contemplated transdermal compositions may further include a
pharmaceutically acceptable excipient such as e.g.,
N-methylpyrrolidone, polyvinylpyrrolidone, propylene glycol, or
polyethylene glycol, or a combination of one or more such
excipients. For example, disclosed compositions may include polyols
and esters thereof, such as propylene glycol, ethylene glycol,
glycerol, butanediol, polyethylene glycol, polyethylene glycol
monolaurate, and mixtures thereof. In some embodiments, the effect
of the skin permeation enhancer in a disclosed composition may be
dependent on the solvent in which they are dissolved, e.g dependent
on the concentration of water and/or propylene glycol. For example,
compositions that include a fatty alcohol and a terpene are
provided that may further include about 0% to about 5%, or about 1%
to about 10%, or about 0 to about 50%, by weight, water. Also
provided herein are compositions that may include about 20 to about
98%, or about 50 to about 98%, by weight propylene glycol.
Contemplated compositions may additionally include one or more
antioxidants or preservatives such as, for example, N-acetyl
cysteine, sodium bisulfite, sodium metabisulfite, EDTA,
glutathione, and ascorbic acid.
[0067] In other embodiments, disclosed compositions may include an
organic acid such as ascorbic acid, tartaric acid, malic acid,
succinic acid, fumaric acid, citric acid, or lactic acid. In some
embodiments, the organic acid may be an amino acid, for example, an
amino acid having a pI (isoelectric point) of less than 4, such as
glutamic acid or aspartic acid. In other embodiments, the organic
acid may be a basic amino acid such as arginine, lysine, or
histidine. Disclosed transdermal compositions, in some embodiments,
may comprise about 0.1% to about 20 weight percent, for example,
about 0.2 to about 15 weight percent, or about 0.5 to about 15
weight percent organic acid. In other embodiments, disclosed
compositions may include an inorganic acid, e.g., hydrochloric
acid.
[0068] Disclosed transdermal compositions of the present invention
may further include thickening agents including cellulose ethers
such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose,
ethylcellulose, hydroxyethyl cellulose, and carboxymethyl
cellulose. For example, in one embodiment, a transdermal
composition may comprise about 0.1 to about 10 weight percent, for
example, about 0.1 to about 9 weight percent, or about 0.1 to about
8 weight percent of cellulose ether such as hydroxypropyl methyl
cellulose and/or hydroxypropyl cellulose, for example, Klucel.RTM.
hydroxypropyl cellulose.
[0069] A disclosed transdermal composition may have a
physiologically acceptable pH. The term "physiologically acceptable
pH" is understood to mean a pH that facilitates administration of
the composition to a patient without significant adverse effects,
e.g. a pH of about 4 to about 10.
[0070] Also provided herein are transdermal compositions that allow
for enhanced delivery of active agents over an extended period of
time. For example, a contemplated transdermal composition that
includes a terpene and octanol may deliver more than two times,
three times, or more of the active agent than compositions that do
not include a terpene and/or octanol. In another example, a
contemplated transdermal composition that includes an organic acid
may deliver more than two times, three times, or more of the active
agent than compositions that do not include an organic acid. In
another example, a contemplated composition that includes a terpene
and octanol, and an active agent, may deliver more of the active
agent over a period of 1 hour, 2 hours, 5, hours, 10 hours, 20
hours, 1 day, two days, three days, or more, than compositions that
include the active agent but do not include a terpene and/or
octanol. In a specific embodiment, the transdermal composition when
administered to a patient, may deliver more than twice of amount of
carbidopa to the patient over 20 hours as compared to a transdermal
formulation of carbidopa that do not include octanol. In another
embodiment, a disclosed composition, when administered to a
patient, may deliver more than twice of amount of opipramol,
diltiazem, phenytoin, imipramine or entacapone to the patient over
about 42 hours as compared to a transdermal formulation of
opipramol, diltiazem, phenytoin, imipramine or entacapone that does
not include limonene. For example, provided herein are compositions
having opipramol or quinidine, when administered to a patient, may
deliver even more than ten times of amount of e.g., opipramol or
quinidine, as compared to a transdermal composition having e.g.
opipramol that does not include tartaric acid. In another
embodiment, compositions disclosed herein may provide more than 4
times of amount of diltiazem or quetiapine over 42 hours as
compared to a trandermal formulation of one of those actives but
that do not include tartaric acid.
Active Agents
[0071] Provided herein are pharmaceutically acceptable transdermal
compositions that include one or more active agents. Contemplated
active agents include active agents having an amine moiety (e.g. at
least one primary, secondary or tertiary amine) or an active agent
having a negatively charged carbonyl moiety (e.g. an amide and/or
carboxyl moiety).
[0072] For example, disclosed active agents may include, but are
not limited to, alkaloids (e.g., nicotine, amphetamine, lidocaine
(and other caine analgesics), carbamates (e.g., pyridostigmine
bromide, physostigmine), barbiturates, carbamazepines,
benzodiazepines, phenothiazines, thioxanthenes, butyrophenones
(e.g., haloperidol), benzamides, dibenzodiazepines, phenylindoles,
benzisoxazoles (e.g., risperidone, ziprasidone), GABA-T inhibitors
(e.g., vigabatrin), thienobenzaodiazepines, phenylethylamines
(e.g., deprenyl HCl), SNRIs (e.g., venlafaxine HCl), SSRIs,
tertiary amines (e.g., opipramol), aromatic amino acids (e.g.,
levodopa, carbidopa, and derivatives), DNA (e.g. supercoiled
plasmid DNA), oligonucleotides (e.g., DNA, RNAi, siRNA, saRNA,
pRNA), low molecular weight heparin (e.g., ardeparin), peptides
(e.g., decapeptide LHRH analogues, copolymer-1, pentapeptide
enkephalin), and proteins (e.g., PTH, insulin). In an embodiment,
the active agent comprises an amine moiety, for example, at least
one primary, secondary or tertiary amine groups. For example, the
active agent may be chosen from: opipramol, diltiazem, quetiapine,
quinidine, imipramine, venlafaxine, physostigmine,
chlorpheniramine, metoprolol, lidocaine, apomorphine, memantine,
ziprasidone, atomoxetine, sibutramine, salbutamol, phenytoin,
galantamine, timolol, nicotine, methysergide, lisinopril,
levosalbutamol, formotoerol, arformoterol, ipratorium bromide,
voriconazole, and/or ciclopirox.
[0073] In some embodiments, the active agent may be an amino acid
or amino acid derivative. For example, the active agent may be
levodopa or carbidopa. In a further embodiment, the active agent
comprises negatively charged carbonyl groups, e.g. amide or
carboxyl groups. For example, the active agent may be entacapone,
phenytoin, or carbamazepine.
[0074] Other contemplated agents include agents having a carboxylic
acid group such as an agent chosen from atorvastatin, amoxicillin,
fexofenadine, pravastatin, cefalexin, furosemide, ibuprofen,
naproxen, gemfibrozil, mupirocin, cefprozil, methotrexate,
tretinoin, cefuroxime, etodalac, penicillin, folic acid,
fosinopril, ursodiol, indometacin, falsartan, lisinopril, and
diclofenac (Na salt). Contemplated agents include those having
primary amines (fluvoxamine, Memantine, Amlodipine, Cefdinir,
Lamotrigine, Amphetamine, Triamterene, Minocycline, Phentermine,
Famciclovir, Trimethoprim, Aciclovir, Hydralazine, Doxazo sin,
Dextro-amphetamine or Famotidine); secondary amines (such as
Desipramine, Atomoxetine, Azathioprine, Bromocriptine, Burpropione,
Clonidine, Dexmethyl-phenidate, Duloxetine, Enalapril, Formoterol,
Hydrochloro-thiazide, Lornoxicam, Metoprolol, Sertraline
Paroxetine, Fluoxetine, Ramipril, Salbutamol, Bupropion,
Carvedilol, Atenolol, Nifedipine, Felodipine, Enalapril, Quinapril,
Tizanidine, Clonidine, Benzonatate, Propranolol HCl, Benazepril,
Paroxetine, Allopurinol, Labetalol HCl, Sotalol, Torasemide,
Bisoprolol, Pindolol, and Pseudo-ephedrine), tertiary amines
(including for example, agents such as Miconazole, Econazole,
Clotrimazole, Ketoconazole, Quinidine, Pargiline, Alprazolam,
Apomorphine, Bromazepam, Burenorphine, Chlorpheniramine, Diltiazem,
Dipyridamole, Domperidone, Galantamine (HBr), Haloperidol,
Hydromorphone, Levomepromazine, Methadone, Methazolamide, Metformin
HCl, Azithromycin, Omeprazol, Fentanyl, Oxycodone, Risperidone,
Tramadol, Citalopram, Ondansetro, Morphine, Dextropropoxyphene,
Cyclobenzaprine HCl, Ciprofloxacin, Ranitidine, Verapamil,
Baclofen, Oxybutynin, Venlafaxine HCl, Opipramol, Lidocaine; or
amido agents such as: Oxcarbazepine, Carisoprodol, Meloxicam,
Glibenclamide (glyburide), Phenytoin, Glimepiride, Barbital,
Metho-carbamol, Modafinil and Entacapone.
[0075] Also contemplated are pharmaceutically acceptable salts of
the disclosed active agents. Pharmaceutically acceptable salts of
the disclosed therapeutic or active agents can be synthesized by
conventional chemical methods. Generally, such salts can be
prepared by reacting the free acid or base forms of the agents with
a stoichiometric amount of the appropriate base or acid in water or
in an organic solvent, or in a mixture of the two; generally,
non-aqueous media like propylene glycol, ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile. Lists of suitable salts are
found in Remington's Pharmaceutical Sciences, 20th ed., Lippincott
Williams & Wilkins, Baltimore, Md., 2000, p. 704.
[0076] In some embodiments, a provided transdermal composition
includes an amino acid salt of an active agent, e.g., carbidopa,
levodopa, or entacapone salt with a basic amino acid selected from
arginine, lysine, or histidine. In one embodiment, the salt of an
active agent is the carbidopa arginine salt.
[0077] Active agents may be present in the disclosed compositions
in varying amounts, e.g. a disclosed composition may include for
example about 0.5 to about 10 weight percent active agent, about 1
to about 7 weight percent active agent, about 1 to 3 weight
percent, about 2 to about 4 weight percent, e.g., about 2, 2.5, 3,
4, 5, or 6 weight percent. For example, contemplated herein are
compositions that include about 3-8 weight percent carbidopa and/or
levodopa, and about 3 to about 7 weight percent arginine, or about
3 to about 15 weight percent arginine (e.g. about 6 to about 12
weight percent carbidopa-arginine salt or levodopa-arginine
salt).
[0078] In some embodiments, the disclosed transdermal composition
includes biologics as active agent such as DNA, RNA, or proteins,
and/or may be used for the transfection of foreign materials (e.g.
supercoiled plasmid DNA, siRNA, polynucleotides, peptides, and/or
proteins) into cells. For example, the disclosed transdermal
composition may be used for the transfection of plasmid DNA into
eukaryotic cells resulting in either transient or stable expression
of the DNA. In another example, the disclosed transdermal
composition may be used for the delivery peptides into eukaryotic
cells. In some instances, the disclosed transdermal composition may
be used for the transfection of a protein e.g. an antibody into
cells.
[0079] Disclosed transdermal compositions may be used in a method
of treatment for a disease in a patient in need thereof, for
example a method of treatment of a disease associated with
treatment by an active agent that forms part of a disclosed
composition, comprising transdermally administering a disclosed
composition to the patient.
EXAMPLES
[0080] The invention now being generally described, it will be more
readily understood by reference to the following examples which are
included merely for purposes of illustration of certain aspects and
embodiments of the present invention, and are not intended to limit
the invention in any way.
Example 1: Transdermal Delivery of Carbidopa Ex Vivo
[0081] The effects of octanol, limonene and/or lauroglycol on the
transdermal delivery of carbidopa through full thickness pig skin
are evaluated using the Franz Cell delivery system. Formulations
containing carbidopa, octanol, limonene, and/or lauroglycol are
prepared (formulations 1-8). Samples are collected from the receive
cell at 24 and 41 hours after application of the formulation to the
skin. The amount of carbidopa compounds in the receiver cell fluid
is determined using a spectrophotometer and/or UV-HPLC at 280
nm.
[0082] FIGS. 1 and 2, and Table 1 (corresponding to FIG. 1) and
Table 2 (corresponding to FIG. 2) indicate that the combination of
octanol and limonene provides an additive and/or synergistic effect
on the delivery of carbidopa through pig skin, ex vivo. For
example, as depicted in FIG. 1, application of formulation 6 which
includes a combination of octanol, limonene, and lauroglycol
results in greater carbidopa penetration through the skin than the
combination of octanol and lauroglycol (formulation 7) or limonene
(Lim) and lauroglycol (LG) (formulation 8). In Table 1 and FIG. 1,
the formulations each contain 14.5% (by weight) carbidopa-arginine
salt.
TABLE-US-00001 TABLE 1 Transdermal delivery of Carbidopa
(mg/cm.sup.2) through full thickness pig skin, ex vivo Formulation
# 1 2 3 4 5 6 7 8 Octanol 0 2.5 0 4 4 2.5 2.5 0 Limonene 1.5 0 1 0
1 1 0 1 Lauroglycol 0 2.5 2.5 2 2 1.5 1.5 1.5 24 h 1.0 3.6 2.2 6.6
11.1 5.3 2.4 1.9 41 h 1.2 5.4 3.3 17.5 21.8 13.4 9.4 2.7
Formulation #3 + 4 Formulation Formulation Formulation (calculated)
# 3 #4 #5 (Lim + LG) + Limonene + Octanol + Lim + Oct + (Octanol +
LG LG LG LG) 41 h 3.3 17.5 21.8 20.8 24 h 2.2 6.6 11.1 8.8
Formulation #7 + 8 Formulation Formulation Formulation (calculated)
# 8 #7 #6 (Lim + LG) + Limonene + Octanol + Lim + Oct + (Octanol +
LG LG LG LG) 41 h 2.7 9.4 13.4 12.1 24 h 1.9 2.4 5.3 4.3
[0083] In Table 2 the formulations each contain 8.85% (by weight)
carbidopa-arginine salt.
TABLE-US-00002 TABLE 2 Transdermal delivery of Carbidopa
(mg/cm.sup.2) through full thickness pig skin, ex vivo Octanol 0 4
0 Limonene 1.5 1.5 1.5 Oleic Acid 0 0 2 24 h 1.0 6.4 1.0
[0084] FIG. 1 also indicates that the combination of octanol and
lauroglycol enhances the delivery of carbidopa through pig skin, ex
vivo. This effect, however, depends on the ratio between the
octanol and lauroglycol in the formulation.
[0085] FIG. 3 depicts the effect of lactic acid on the transdermal
delivery of carbidopa through pig skin, ex vivo. The addition of
lactic acid into a carbidopa formulation containing octanol and
limonene results in a reduction in pH and reduces the lag time of
carbidopa penetration through the skin.
[0086] FIG. 4 depicts the effect of Klucel.RTM. hydroxypropyl
cellulose on the transdermal delivery of carbidopa. The inclusion
of Klucel.RTM. into a carbidopa formulation containing octanol and
limonene not only reduces the rate of carbidopa penetration through
the skin but also increases the lag time of carbidopa
penetration.
[0087] FIG. 5 depicts the effect of carbidopa concentration and
water on the transdermal delivery of carbidopa. Increasing the
amount of carbidopa in a formulation by 50% enhances the
penetration of the drug through the skin by 25%.
Example 2: Transdermal Delivery of Carbidopa or Levodopa Ex
Vivo
[0088] The transdermal delivery of levodopa through full thickness
pig skin is evaluated using the Franz Cell delivery system.
Formulations containing carbidopa or levodopa, octanol, limonene,
and lauroglycol are prepared. Samples are collected from the
receiver cells at 24 hours at 18 and 222 hours after application of
the formulation to the skin. The amount of carbidopa or levodopa
compounds in the receiver cell fluid is determined using a
spectrophotometer and/or UV-HPLC at 280 nm.
[0089] As depicted in FIG. 6, a gel formulation containing a
carbidopa+arginine or levodopa+arginine with octanol (4%), limonene
(1.1-1.2%), lauroglycol (2%), water (5.2%), [all weight percent],
propylene glycol and antioxidants can deliver, ex vivo, at least 6
mg/cm.sup.2 carbidopa or levodopa through pig skin within 22
hours.
Example 3: Transdermal Delivery of Opipramol with Organic
Hydrophilic Acids Ex Vivo
[0090] FIGS. 7A and 7B depict the effect of organic acids on the
transdermal delivery of opipramol through full thickness pig skin.
Formulations containing opipramol, various organic acids (succinic
acid, citric acid, lactic acid, ascorbic acid, malic acid, or
tartaric acid), octanol, lauroglycol, and/or Klucel.RTM. are
prepared. Samples are collected from the receive cell at 22 and 46
hours after application of the formulations to the skin. The amount
of opipramol compounds in the receiver cell fluid is determined
using a spectrophotometer and/or UV-HPLC at 280 nm.
[0091] Results indicate that the addition of organic acids
significantly increases the transdermal delivery of opipramol.
Tartaric acid has the highest enhancing effect on opipramol
delivery followed by ascorbic acid, succinic acid, and malic acid.
Lactic acid and citric acid appear to have minimal effect on
opipramol penetration through the skin.
[0092] FIG. 8 depicts the effects of octanol, limonene and/or
lauroglycol on the transdermal delivery of opipramol (5% by weight)
through full thickness pig skin. Results indicate that the
combination of octanol and limonene provides an additive and/or
synergistic effect on the delivery of opipramol through pig skin,
ex vivo. The presence of lauroglycol in the formulation reduces the
additive and/or synergistic effect of octanol and limonene on
opipramol delivery, as shown in Table 3:
TABLE-US-00003 TABLE 3 Synergistic Effect between Octanol (O) and
Limonene (L) or Lauroglycol (LG) and the Inhibitory Effect between
Lauroglycol and Limonene Calculated Experimental LG + O LG LG/O
LG/L L/O L/LG/O L + O LG + O F #3 F #4 F #1 F #6 F #5 F #2 F#1 + 6
F#4 + 3 24 h 0.3 0.2 0.6 0.3 5.5 3.1 0.9 0.5 42 h 0.9 0.3 1.7 0.7
9.7 5.9 2.4 1.2
[0093] FIG. 9 depicts the effect of glutamic acid on the
transdermal delivery of opipramol through full thickness pig skin.
Results indicate that glutamic acid significantly increases the
opipramol penetration through the skin. In addition, the lag time
of opipramol penetration through the skin is shortened in the
presence of 5% water. However, the rate of penetration is reduced
in the presence of 1% limonene.
[0094] FIG. 10 depicts the effect of Klucel.RTM. hydroxypropyl
cellulose on the transdermal delivery of opipramol. Increasing
concentration of Klucel.RTM. within an opipramol formulation
reduces the penetration of opipramol through the skin.
[0095] FIG. 11 compares the effect of tartaric acid and
hydrochloric, non-organic acid on the transdermal delivery of
opipramol through full thickness pig skin. Results indicate that
tartaric acid significantly increases opipramol penetration through
the skin as compared to opipramol base, and that tartaric acid was
significantly superior to hydrochloric acid.
[0096] FIG. 12 depicts the effect of octanol concentration in the
formulation on the transdermal delivery of opipramol through full
thickness pig skin. The figure shows that there is a positive
correlation between the rate and total amount of opipramol
transdermal delivery and opipramol concentration, i.e., formulation
containing 2.5% (wt) opipramol concentration delivers more
opipramol than the 1% formulation. The correlation is inversed when
the concentration of opipramol in the formulation is 5%, i.e., the
transdermal delivery of opipramol may be inhibited with higher
concentration.
Example 4: Transdermal Delivery of Other Drug Compounds with an
Amine Group Ex Vivo
[0097] FIGS. 13-26 depict the transdermal delivery of various drug
compounds with an amine group through full thickness pig skin, ex
vivo. The drug compounds are administered with organic acids. The
concentrations of the tested compounds in the receiver cell are
measured using a spectrophotometer as follows:
TABLE-US-00004 Absorption Molecular Transdermal Delivery Compound
(nm) Weight (Figure #) Opipramol 254 364 8-12 Physostigmine 230 275
13 Chlorphiniramine 262 275 14 Lidocanine 263 234 15 Metoprolol 275
267 16 Nicotine 261 162 17 Diltiazem 237 415 18 Quinidine 331 324
19 Imipramine 250 280 20 Quetiapine 291 384 21-22 Venlafaxine 225
277 23 Timolol 293 316 24 Albuterol 276 239 25
[0098] The results indicate that formulations containing octanol,
limonene, with or without lauroglycol significantly enhance the
penetration of all amine compounds tested (with MW ranging between
162 and 415). Penetration was significantly increased in the
presence of an organic acid as compared to the base form of the
active compound. There was no correlation between the size of the
compound and the extent of its penetration through the skin. For
example, the penetration of chlorpheniramine (MW 275) was similar
to that of diltiazem (MW 415).
Example 5: Transdermal Delivery of Drug Compounds with a Negatively
Charged Carbonyl Group Ex Vivo
[0099] FIGS. 26-28 depict the transdermal delivery of various drug
compounds, all having a negatively charged carbonyl group, through
full thickness pig skin, ex vivo. The concentrations of the tested
compounds in the receiver cell are measured using a
spectrophotometer as follows:
TABLE-US-00005 Compound Absorption (nm) Molecular Weight TDD
(Figure #) Entacapone 315 305 27, 28 Phenytoin 230 252 26
[0100] The results indicate that formulations containing octanol,
limonene, with or without lauroglycol significantly enhance the
penetration of the amine compounds tested.
Example 6: Transdermal Delivery of Carbidopa In Vivo
[0101] In this experiment, the purpose is to determine the
transdermal delivery of carbidopa in pigs. Test Formulations, TF-2
and TF-4, each containing 14.5% carbidopa/arginine salt, octanol
(4%), lauroglycol (2%), hydroxypropyl cellulose (4%), propylene
glycol and water (5 and 10%, respectively) are applied to the back
of pigs (12-15 kg). Blood samples are collected at pre-determined
time points and plasma levels of carbidopa are analyzed by
HPLC-ECD. FIGS. 29A and 29B show the mean.+-.SD carbidopa plasma
concentrations (ng/ml) following application of 2 transdermal
patches (28 cm.sup.2/patch).
[0102] Results show that both formulations are effective in the
transdermal administration of carbidopa. Application of TF-2, which
contains less water, results in a shorter lag time and higher
steady state concentration of plasma carbidopa. TF-2 exhibits a 24
hour lag time and a steady state plasma concentration of carbidopa
ranging between 600-900 ng/ml for a period of 20 hour, until patch
removal. TF-4 exhibits a lag time of 30 hours and a steady state
plasma concentrations of 300-400 ng/ml. Both formulations cause
mild irritation after 48-52 hours of application.
Example 7: Transdermal Delivery of Metoprolol In Vivo
[0103] In this experiment, the purpose is to determine the
transdermal delivery of metoprolol in pigs. Test Formulations
containing 10% metoprolol and 2.8% tartaric acid, octanol (4%),
limonene (1%), hydroxypropyl cellulose (3%), water (3%) and
propylene glycol were applied to the back of pigs (12-15 kg). Blood
samples were collected at pre-determined time points and plasma
levels of metoprolol were analyzed by HPLC-UV. FIG. 30 shows the
metoprolol plasma concentrations (ng/ml) following application of 2
transdermal patches (28 cm.sup.2/patch).
[0104] Results show that the formulation was effective in the
transdermal administration of metoprolol. Application of the
metoprolol formulation results in a lag time of 5-13 hours and a
steady state concentration of plasma metoprolol. The formulation
caused mild and transient irritation after 24 hours of
application.
EQUIVALENTS
[0105] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
INCORPORATION BY REFERENCE
[0106] The entire contents of all patents, published patent
applications, websites, and other references cited herein are
hereby expressly incorporated herein in their entireties by
reference.
* * * * *