U.S. patent application number 15/972625 was filed with the patent office on 2018-09-06 for pain relief compositions, manufacture and uses.
The applicant listed for this patent is VIZURI HEALTH SCIENCES LLC. Invention is credited to Philip J. BIRBARA, Daniel BUCKS.
Application Number | 20180250246 15/972625 |
Document ID | / |
Family ID | 46940596 |
Filed Date | 2018-09-06 |
United States Patent
Application |
20180250246 |
Kind Code |
A1 |
BUCKS; Daniel ; et
al. |
September 6, 2018 |
PAIN RELIEF COMPOSITIONS, MANUFACTURE AND USES
Abstract
The present invention relates to TRPV1 selective agonist topical
compositions including capsaicinoid and analgesic agent
compositions and methods of manufacture and methods of providing
pain relief as well as treating a variety of disorders with such
compositions.
Inventors: |
BUCKS; Daniel; (Millbrae,
CA) ; BIRBARA; Philip J.; (West Hartford,
CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VIZURI HEALTH SCIENCES LLC |
Fairfax |
VA |
US |
|
|
Family ID: |
46940596 |
Appl. No.: |
15/972625 |
Filed: |
May 7, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14482930 |
Sep 10, 2014 |
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15972625 |
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13609100 |
Sep 10, 2012 |
8889659 |
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14482930 |
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61533120 |
Sep 9, 2011 |
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61642942 |
May 4, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 15/00 20180101;
A61P 29/00 20180101; A61K 31/351 20130101; A61K 31/513 20130101;
A61K 31/045 20130101; A61K 31/196 20130101; A61K 31/60 20130101;
A61K 31/165 20130101; A61P 1/02 20180101; A61K 9/0014 20130101;
A61K 31/125 20130101; A61K 31/352 20130101; A61K 9/06 20130101;
A61P 17/00 20180101; A61P 13/10 20180101; A61P 17/06 20180101; A61P
17/04 20180101; A61K 31/618 20130101; A61K 45/06 20130101; A61K
47/10 20130101; A61K 31/35 20130101; A61K 31/05 20130101; A61P
43/00 20180101; A61P 31/22 20180101; A61P 25/04 20180101; A61P
25/06 20180101; A61P 11/02 20180101; A61P 19/02 20180101; A61K 9/08
20130101; A61K 31/60 20130101; A61K 2300/00 20130101; A61K 31/618
20130101; A61K 2300/00 20130101; A61K 31/165 20130101; A61K 2300/00
20130101; A61K 31/045 20130101; A61K 2300/00 20130101; A61K 31/513
20130101; A61K 2300/00 20130101; A61K 31/351 20130101; A61K 2300/00
20130101; A61K 31/125 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/165 20060101
A61K031/165; A61K 9/06 20060101 A61K009/06; A61K 31/045 20060101
A61K031/045; A61K 31/196 20060101 A61K031/196; A61K 31/05 20060101
A61K031/05; A61K 31/125 20060101 A61K031/125; A61K 31/618 20060101
A61K031/618; A61K 45/06 20060101 A61K045/06; A61K 31/35 20060101
A61K031/35; A61K 31/352 20060101 A61K031/352; A61K 31/513 20060101
A61K031/513; A61K 9/00 20060101 A61K009/00; A61K 47/10 20060101
A61K047/10; A61K 9/08 20060101 A61K009/08; A61K 31/351 20060101
A61K031/351; A61K 31/60 20060101 A61K031/60 |
Claims
1. A composition comprising: i) 0.2-30% by weight of a
capsaicinoid, and ii) 50-95% by weight of an analgesic agent
comprising a) a topical salicylate and b) a TRPM8 agonist or a
TRPV3 agonist, capable of solubilizing said capsaicinoid, wherein
said composition comprises an amount of capsaicinoid sufficient to
decrease the density of functional nociceptive nerve fibers when
said composition is applied topically to a mammal, and said
composition comprises an amount of analgesic agent sufficient to
eliminate or reduce the burning or stinging sensation or erythema
created by the topical administration of the capsaicinoid to a
mammal.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 14/482,930 filed Sep. 10, 2014, which is a divisional of U.S.
application Ser. No. 13/609,100 filed Sep. 10, 2012, now U.S. Pat.
No. 8,889,659, which claims priority from U.S. Provisional
Application No. 61/533,120 filed Sep. 9, 2011 and U.S. Provisional
Application No. 61/642,942 filed May 4, 2012, the entire contents
of each of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to compositions of transient
receptor potential vanilloid 1(TRPV1) selective agonists such as
capsaicin, and related compounds, methods of manufacture and
methods of providing pain relief, as well as methods of treating a
variety of medical conditions.
BACKGROUND OF THE INVENTION
##STR00001##
[0004] Capsaicin is the main capsaicinoid in capsicum plants
including chili peppers. It is a pungent substance that has long
been used for the relief of pain because of its selective action on
the small diameter afferent nerve fibers (C fibers and A-delta
fibers) that are believed to signal pain. From studies in animals,
capsaicin appears to trigger C fiber membrane depolarization by
opening cation channels permeable to calcium and sodium. Capsaicin
has been reported to work by depleting a compound called Substance
P, which is a neuropeptide that functions as a neurotransmitter and
promotes pain perception, from the nerve terminal fibers. However,
capsaicin also can elicit erythema and/or an intense burning or
stinging sensation upon application. The intense burning or
stinging can be intolerable for some. Additionally, it may take
more than a day or two for effectuating actual pain relief, and for
the intense burning to stop. Following the initial period of
intense burning pain that may be accompanied by erythema, topical
capsaicin application causes insensitivity to pain elicited by a
variety of noxious stimuli or disease states. In theory, neurons
shut down after they've been stimulated by capsaicin, so the
burning and other unrelated sensations--including pain--cease. The
results from studies testing the low concentrations of capsaicin
present in most over-the-counter products (0.075 percent or less)
haven't been impressive. Many people are bothered by the burning
sensation, so they don't stick with the treatment. Current
over-the-counter capsaicin products are not effective for many
people. High-dose capsaicin patches have been developed, but they
require local or regional anesthesia and therefore are only
appropriate for treatment for severe chronic pain under the
supervision of a physician.
[0005] Because of the ability of capsaicin to desensitize
nociceptors in peripheral tissues, their potential analgesic
effects have been assessed in various clinical trials. However,
since the application of capsaicin itself frequently causes burning
pain and hyperalgesia apart from the neuropathic pain being
treated, patient compliance has been poor and the dropout rates
during clinical trials have typically exceeded fifty percent. The
most frequently encountered adverse effect with capsaicin is
burning pain at the site of application, particularly in the first
week of application. This can make it impossible to blind trials
and can lead to dropout rates ranging from 33 to 67% (Watson C P et
al. "A randomized vehicle-controlled trial of topical capsaicin in
the treatment of postherpetic neuralgia." Clinical Therapeutics.
15.3 (1993):510-26.) Another factor in compliance is the time delay
before therapeutic effect is observed. Daily topical applications
for at least a week or two may be required.
[0006] Many individuals discontinue the prolonged treatment of
topical capsaicin prior to the anticipated analgesic effects of
capsaicin due to the intense stinging and burning pain. It was
reported that 26 out of 39 (66.7%) patients suffering from
post-herpetic neuralgia did not tolerate the treatment of a 0.025%
capsaicin preparation (Zostrix, Gen Derm, USA). With a 0.075%
preparation (Zostrix-HP, Gen Derm, USA), 5 out of 16 (31.3%) and 45
out of 74 (60.8%) patients with post-herpetic neuralgia did not
tolerate the long term topical treatment. (Peikert, A. et al.,
Topical 0.025% capsaicin in chronic post-herpetic neuralgia:
efficacy, predictors of response and long-term course, J. Neurol.
238:452-456, 1991; Watanabe, A. et al., Efficacy of capsaicin
ointment (Zostrix) in the treatment of herpetic pain and
postherpetic neuralgia, Pain Clinic 15:709-713, 1994; Bernstein J.
E. et al., Topical capsaicin treatment of chronic postherpetic
neuralgia, J. Am. Acad. Dermatol. 21: 265-270, 1989; and Watson C.
P. N. et al., A randomized vehicle-controlled trial of topical
capsaicin in the treatment of postherpetic neuralgia, Clin. Ther.
15:510-526, 1993.)
[0007] The spontaneous burning pain and hyperalgesia are believed
to be due to intense activation and temporary sensitization of the
peripheral nociceptors at the site of capsaicin application. This
activation and sensitization occurs prior to the desensitization
phase and is a barrier to topical capsaicin use because the burning
pain produced compromises patient's tolerability of treatment.
[0008] Capsaicin is believed to relieve pain by causing a localized
degradation of the C neuron endings. The activity of capsaicin
results from its binding to, and activating, an ion channel called
vanilloid receptor 1, or VR1. Under normal circumstances, when the
VR1 ion channel is activated, it opens for a short time, causing
the C neurons to transmit a pain signal toward the brain. When
capsaicin binds to, and activates VR1, it causes a series of events
within the cell that degrade the pain-sensing endings, or terminals
of the C neuron, thereby preventing the neuron from transmitting
pain signals.
[0009] In 1997, a research team led by David Julius of University
of California, San Francisco showed that capsaicin selectively
binds to a protein known as TRPV1 that resides on the membranes of
pain and heat sensing neurons TRPV1 is a heat activated calcium
channel, which opens between 37 and 45.degree. C. (98.6 and
113.degree. F., respectively). When capsaicin binds to TRPV1, it
causes the channel to open below 37.degree. C. (normal human body
temperature), which is why capsaicin is linked to the sensation of
heat. Prolonged activation of these neurons by capsaicin depletes
presynaptic substance P, one of the body's neurotransmitters for
pain and heat. Neurons that do not contain TRPV1 are unaffected.
The result appears to be that the chemical mimics a burning
sensation; the nerves are overwhelmed by the influx, and are unable
to report pain for an extended period of time. With chronic
exposure to capsaicin, neurons are depleted of neurotransmitters,
leading to reduction in sensation of pain and blockade of
neurogenic inflammation. If capsaicin is removed, the neurons
recover.
[0010] Although capsaicin's analgesic effect was thought to be due
to a depletion in the pain-causing substance P, recent evidence
suggests a process of "defunctionalization" of nociceptor fibers is
responsible for its analgesic effect. (Anand P, Bley K. Topical
capsaicin for pain management: therapeutic potential and mechanisms
of action of the new high-concentration capsaicin 8% patch. Br J
Anaesth. 2011; 107(4):490-502.)
[0011] Humans have long been exposed to dietary sources of
capsaicin-containing spices and to topical preparations used for a
variety of medical indications. This vast experience has not
revealed significant or lasting adverse effects of capsaicin
exposure. The recent determination of potential therapeutic effects
of capsaicin on unmyelinated sensory afferent nerve fibers requires
diligent consideration of this compound for further pharmaceutical
development.
[0012] Capsaicin is currently marketed for topical administration
in the form of over-the-counter, low dose, non-sterile creams and
patches, which tend to be poorly absorbed. There are more than
thirty brands of creams and patches, including Capzasin-P.RTM.
(Chattem) and Zostrix.RTM. (Rodlen Laboratories). These
over-the-counter preparations can be purchased widely without a
prescription and are used topically by consumers to relieve pain
with variable and often inadequate results in conditions such as
osteoarthritis, shingles (herpes zoster), psoriasis and diabetic
neuropathy.
[0013] In addition to relieving pain, capsaicin triggers the body
to increase blood flow to promote natural healing on the skin
surface and within the epidermal layers. This is especially
important for healing injuries and environmental damage from
pollution, sun and winter weather. Capsaicin is also a powerful
anti-microbial that destroys bacteria in clogged skin pores and
hair follicles.
[0014] Topical capsaicin has been used in skin and scalp care
products that target a variety of conditions including acne,
dermatitis, eczema, psoriasis and even dandruff. Capsaicin can stop
itching when topically applied. Known in the medical world as
pruritus, itching is both a symptom and a cause of many skin
ailments. The more a person itches, the more they scratch and the
worse their condition becomes. Unfortunately, many skin and scalp
conditions cause itching that leads to a chronic cycle of sick
skin. From bug bites to eczema, the key to fast healing is to stop
the itch so the condition can heal naturally, and capsaicin is a
known natural substance that can effectively do this.
[0015] Capsaicin mediated effects include: (i) activation of
nociceptors in peripheral tissues; (ii) eventual desensitization of
peripheral nociceptors to one or more stimulus modalities; (iii)
cellular degeneration of sensitive A-delta and C-fiber afferents;
(iv) activation of neuronal proteases; (v) blockage of axonal
transport; and (vi) the decrease of the absolute number of
nociceptive fibers without affecting the number of non-nociceptive
fibers.
[0016] The use of capsaicin is known for the treatment of a number
of pain disorders. Accordingly, topical preparations of capsaicin
find use as a topical therapy for a variety of skin disorders that
involve pain and itching, such as postherpetic neuralgia, diabetic
neuropathy, pruritus, psoriasis, cluster headache, postmastectomy
pain syndrome, rhinopathy, oral mucositis, cutaneous allergy,
detrusor hyperreflexia, loin pain/hematuria syndrome, neck pain,
amputation stump pain, reflex sympathetic dystrophy, pain due to
skin tumor and arthritis including rheumatoid arthritis,
osteoarthritis, diabetic neuropathy, psoriasis, pruritus (itching),
cluster, headache, post-surgical pain, oral pain, and pain caused
by injury, amongst others. (Martin Hautkappe et al., Review of the
Effectiveness of Capsaicin for Painful Cutaneous Disorders and
Neural Dysfunction, Clin. J. Pain, 14:97-106, 1998)
[0017] Capsaicin is used in topical ointments and creams to relieve
minor aches and pains of muscles and joints. Capsaicin is also
available in large adhesive bandages that can be applied to the
back. Concentrations of capsaicin are typically between 0.025 wt. %
and 0.075 wt. %. A partial listing of capsaicin products with their
capsaicin, methyl salicylate, camphor, and menthol contents is
shown below in Table 1.
TABLE-US-00001 TABLE 1 % % Methyl % % Product Name Capsaicin
Salicylate Camphor Menthol APANOL LINIMENTO OBRERO 10% 27% -- --
Axane* 0.025% 5% 2.5% 2.5% Axe Brand Red Flower Oil 0.25% 60% -- --
Capzasin-P and Capzasin-HP 0.035% -- -- -- CORALITE TOPICAL
ANALGESIC) liquid 0.025% Inactive Inactive -- DENDRACIN
NEURODENDRAXCIN lotion 0.025% 30% -- 10% DENDRACIN NEURODENDRAXCIN
lotion 0.0375% 30% -- 10% DR. OH BALM) cream 0.015% -- 3.5% 1%
EXOTEN-C lotion 0.002% 20% -- 10% Heet Pain Reliever with Hand's
Off Applicator 0.025% 18% 3.6% -- ICY HOT ARTHRITIS lotion Inactive
-- 4% 16% MEDI-DERM TOPICAL PAIN RELIEF cream 0.035% 20% -- 5%
MEDROX ointment 0.0375% 20% -- 5% MEDROX-RX ointment 0.050% 20% --
7% (Bordon/Eagle) MUSCULAR BALM ointment 0.15% 30% -- 13.5%
Myolaxin-D Gel 0.075% 20% 5% 10% ORTHO-NESIC WITH CAPSAICIN gel
0.01% -- 0.2% 3/5% OVERTIME lotion 0.0375% 30% -- 10% PAIN
RELIEFROLL ON ROLL ON 0.03% 30% 4% 10% TEROCIN lotion 0.025% 25% --
10% TOPICAL PAIN RELIEF cream 0.035% 20% -- 5% XOTEN-C lotion
0.002% 20% -- 10% ZIKS ARTHRITIS PAIN RELIEF cream 0.025% 12% -- 1%
Zostrix 0.025% -- -- -- Zostrix-HP 0.075% -- -- --
[0018] One approach toward potentially minimizing adverse effects
and accelerating the rate of analgesia has been to topically apply
a higher capsaicin concentration as practiced by the Qutenza.RTM.
(capsaicin) 8% patch under regional anesthesia. Application of the
Qutenza.RTM. (capsaicin) 8% patch provides for sustained analgesia
lasting 1 to 8 weeks in cases of complex regional pain syndrome and
neuropathic pain (Robbins et al. Treatment of intractable pain with
topical large-dose capsaicin: preliminary report. Anesth. Analg.
1998; 86:579-583). When topical local anesthetics were applied with
1% topical capsaicin, no alteration in pain produced by the
capsaicin was observed in healthy subjects indicating that this
co-treatment approach was not sufficient to block the pain induced
by capsaicin (Fuchs et al., Secondary hyperalgesia persists in
capsaicin desensitized skin. Pain 2000; 84: 141.)
Analgesics
[0019] The primary use of a topical analgesic is to relieve the
pain such as that associated with arthritis as well as muscle aches
and pains caused by sports injuries or physical work. One benefit
of topical pain relievers is that they can be applied directly to
the site of the pain, so there is minimal systemic distribution of
the pain reliever throughout the body. This localized application
and associated action minimizes the potential for systemic side
effects. In addition, the pain relieving action of topical
analgesics is faster than most oral forms because it is applied
directly onto the painful area whereas oral analgesics need to be
digested, absorbed in the gastrointestinal tract, survive
first-pass metabolism in the liver and then be transported
throughout the body.
Methyl Salicylate
[0020] Methyl salicylate (oil of wintergreen or wintergreen oil) is
a natural product of many species of plants. Some of the plants
which produce it are called wintergreens, hence the common name.
Methyl salicylate is an analgesic.
[0021] Methyl salicylate is an active ingredient in many
over-the-counter pain-relief ointments.
[0022] It is one of a group of anti-inflammatory chemicals known
collectively as salicylates because salicylic acid is their shared,
root compound. Aspirin--salicylic acid with an acetyl group
attached (thus its formal chemical name, acetylsalicylic acid)--is
the best known of the salicylates.
[0023] Topical analgesics containing methyl salicylate suppress
pain by blocking the enzymes involved in the production of
prostaglandins, which signal inflammation and cause pain. The
health benefits of wintergreen oil are in the analgesic, anti
rheumatic, anti spasmodic and astringent properties it contains.
The oil is said to relieve pain by way of the methyl salicylate
compound, which causes the treated, affected area of the body to
experience a feeling of numbness, to help with blood circulation
and to promote a warming in the affected area. The mechanism of
action by which methyl salicylate expresses topical analgesia is
not fully understood. Current literature indicates that methyl
salicylate has both stimulatory and inhibitory actions on TRPV1
channels and suggests that the latter action may partly underlie
the analgesic effects of methyl salicylate independent of
inhibition of cyclooxygenases in vivo. In addition, methyl
salicylate-induced human TRPV1 activation was mediated by distinct
channel regions from capsaicin. (Mol Pharmacol. 2009 February;
75(2):307-17. Epub 2008 Nov. 5.)
Menthol
[0024] Menthol is an organic compound made synthetically or
obtained from peppermint or other mint oils. The natural form of
menthol ((l)-menthol) exists as one pure stereoisomer and is the
preferred form for analgesic effects.
[0025] Menthol's ability to chemically trigger the cold-sensitive
TRPM8 receptors in the skin is responsible for the well-known
cooling sensation that it provokes when inhaled, eaten, or applied
to the skin. Menthol has analgesic properties that are mediated
through a selective activation of .kappa.-opioid receptors.
Typically, ice is applied to the skin to create a cold response in
order to reduce pain because cold reduces the pain threshold.
Menthol creates a chemical action on cold receptors rather than a
physical action, resulting in a cold response. Patel and colleagues
provide an excellent review of the mechanisms behind menthol.
(Patel T, Ishiuji Y, Yosipovitch G. Menthol: a refreshing look at
this ancient compound J Am Acad Dermatol. 2007; 57(5):
873-878.)
[0026] Similar to ice, topical application of menthol in a 3.5% gel
reduces blood flow by 35% within 60 seconds of application, and
remains .about.20% reduced at 10 minutes after application. (Olive
J L, Hollis B, Mattson E, Topp R. Vascular conductance is reduced
after menthol or cold application. Clin J Sport Med. 2010;
20(5):372-376). Recently, Topp and colleagues noted decreased blood
flow in both lower limbs after application to one limb, suggesting
a possible systemic mechanism of topical menthol. (Topp R,
Winchester L J, Schilero J, Jacks D. Effect of topical menthol on
ipsilateral and contralateral superficial blood flow following a
bout of maximum voluntary muscle contraction. Int J Sports Phys
Ther. 2011; 6(2):83-91.)
[0027] Studies have shown that (l)-menthol (natural menthol derived
from peppermint oil) was able to increase pain threshold whereas
(d)-menthol (synthetic menthol) was completely devoid of any
analgesic effect.
[0028] Menthol is an active ingredient in most of the traditional
rub-in products that elicit a cooling sensation.
Camphor
[0029] Camphor is a naturally occurring compound that is used as a
major active ingredient of balms and liniments supplied as topical
analgesics. Camphor is highly volatile and readily absorbed through
the skin. It produces a cool sensation and can under certain
circumstances act as a mild local anesthetic. Camphor is readily
absorbed through the skin and produces a feeling of cooling similar
to that of menthol, and can act as a local anesthetic substance.
There are anti-itch and cooling gels with camphor as the active
ingredient.
[0030] When applied externally, camphor can numb the nerve endings.
The nerve endings then no longer transmit the sensation of pain.
Camphor has recently been shown to activate TRPV3, and it has been
demonstrated that camphor also activates heterologous expressed
TRPV1, requiring higher concentrations than capsaicin. The
camphor-induced desensitization of TRPV1 and block of TRPA1 may
underlie the analgesic effects of camphor.
[0031] Camphor oil was traditionally massaged into sprains and sore
muscles and joints for pain relief, and most modern herbalists
agree that this is the best use for pure camphor oil. Camphor has
been shown to help ease inflammation. It is readily absorbed when
applied topically, making it a particularly effective treatment for
arthritic and rheumatic joint pain.
Phenol
[0032] Phenol is fairly widely used as a topical antiseptic agent
in sore throat lozenges and sprays and as well as a topically
applied skin exfoliant. Small amounts of phenol are present in many
consumer products that are commonly used, such as mouthwashes, sore
throat lozenges, ear or nose drops, cold sore lotions, analgesic
rubs and antiseptic lotions. Phenol is the active ingredient in the
marketed oral analgesics Chloraseptic spray and Carmex.
[0033] Campho-Phenique, a commonly used topical OTC product,
contains the active ingredients 10.8% camphor, 4.7% phenol blended
with the eucalyptus and mineral oil. ingredients. The combination
of camphor with phenol has been cited for its anesthetic and
antiseptic properties.
Other Natural Analgesic Ingredients
[0034] In addition to methyl salicylate, menthol, camphor and
phenol, ingredients with analgesic properties possessing analgesic
and other desirable therapeutic properties include eugenol, thymol
and several essential oils.
[0035] Eugenol, a component of clove oil and some essential oils,
has analgesic, anti-inflammatory, and antibacterial effects. It is
also used as a flavoring agent and is used in oral hygiene
preparations e.g. mouthwash. Eugenol can also be mixed with other
pain reducing products to increase the pain relief.
[0036] Thymol is an essential oil found in several species of thyme
and oregano plants that contains significant antibacterial,
antifungal, antiseptic, analgesic and antioxidant properties.
[0037] There are many analgesic compositions on the market for
topical application and the specific compositions of several of
them are presented in Table II. The molecular structures of several
of the analgesic ingredients are shown in FIG. 5.
TABLE-US-00002 TABLE II EXTERNAL ANALGESIC COMPOSITIONS Koong Eagle
White Po Sum on Yic Wood Brand Kwan Flower Medicated (Hong Lock
Shilling Medicated Loong Oil Oil Hoa Oil) Oil Oil Oil Oil Camphor 6
16 5 Menthol Oil 15 10 16 14.5 16 Methyl Salicylate 40 66 50 47 30
35 Lavender Oil 6 -- 7 Eucalyptus Oil 18 -- 3 Peppermint Oil 15
57.3 Tea Oil 38.7 Dragon Blood 2.07 Cinnamon Oil 0.96 -- Licorice
-- Turpentine Oil 22 Clove Oil -- EtOH 13 Chlorophyll -- Dill Oil
-- Mineral Oil -- 39
NSAIDs
[0038] NSAIDs decrease pain, inflammation, and fever by blocking
cyclooxygenase (COX) enzymes. Understanding of the pharmacology of
NSAIDs continues to evolve, but it is now thought that most NSAIDs
block three different COX isoenzymes, known as COX-1, COX-2, and
COX-3. COX-1 protects the lining of the stomach from acid. COX-2 is
found in joint and muscle, and mediates effects on pain and
inflammation. By blocking COX-2, NSAIDs reduce pain compared to
placebo in patients with arthritis, low back pain, minor injuries,
and soft tissue rheumatism. However, NSAIDs that also block the
COX-1 enzyme (also called "nonselective NSAIDs") can cause
gastrointestinal bleeding.
[0039] Clinical trials have demonstrated that topical NSAIDs have a
better safety profile than oral NSAIDs. Adverse effects secondary
to topical NSAID use occurs in about 10 to 15% of patients and are
primarily cutaneous (rash and pruritus where the topical NSAID was
applied). Gastrointestinal adverse drug reactions are rare with
topical NSAIDs, compared with a 15% incidence reported for oral
NSAIDs. Hayneman, C. et al, Oral versus topical NSAIDs in rheumatic
diseases: a comparison, Drugs, pgs. 555-74, September, 2000.
[0040] Several topical formulations combine NSAIDS, primarily
diclofenac salts, with capsaicin. The Table below contains a
listing of several of these formulations.
TABLE-US-00003 Topical Formulations Containing Capsaicin &
Diclofenac Salts ITEM TRADE NO. NAME ACTIVE INGREDIENTS COMPANY 1
Topac Fast Gel; Topical; Capsaicin 0.025%; Diclofenac Sodium 1%;
Menthol 5%; Abbott Methyl Salicylate 5% 2 Voveran Gel; Topical;
Capsaicin 0.025%; Diclofenac Sodium 1%; Menthol 5%; Novartis
Thermagel Methyl Salicylate 5% 3 Xidol Gel Gel; Topical; Capsaicin
0.025%; Diclofenac Diethylamine 1.16%; Dewcare Linseed Oil 3%;
Menthol 5%; Methyl Salicylate 10% Concept 4 Diclomax Gel; Topical;
Capsaicin 0.025%; Diclofenac Diethylamine 1.16%; Torrent Power
Linseed Oil 3%; Menthol 5%; Methyl Salicylate 10% Pharmaceuticals 5
Divexx Gel Gel; topical; Capsaicin 0.022%; Diclofenac Sodium 1%;
Menthol 5%; Zuventus Methyl Salicylate 10% Healthcare
[0041] U.S. Pat. No. 4,424,205 discloses a variety of
hydroxyphenylacetamides having analgesic and anti-irritant
properties.
[0042] U.S. Pat. No. 4,486,450 discloses a method and composition
of treating psoriatic skin in which capsaicin is applied topically
to the psoriatic skin in a pharmaceutically acceptable carrier
wherein capsaicin is present in therapeutically acceptable
concentrations of between about 0.01 and about 1 percent by weight.
Subsequent exposure of the treated psoriatic skin to ultraviolet
light in small doses aids treatment.
[0043] U.S. Pat. No. 4,997,853 discloses a method and composition
for treating superficial pain syndromes, which incorporates
capsaicin into a pharmaceutically acceptable carrier, and adding to
this composition a local anesthetic such as lidocaine or
benzocaine. The composition containing the anesthetic is then
applied to the site of the pain. A variation on the treatment
includes initial treatment with the composition containing the
local anesthetic until the patient has become desensitized to the
presence of capsaicin and subsequent treatment with a composition
omitting the local anesthetic.
[0044] U.S. Pat. No. 5,134,166 discloses methods and compositions
for treating certain allergy related condition and headaches using
capsaicin in solution or suspension combined with a selected
anesthetic, topical steroid or antihistamine.
[0045] U.S. Pat. No. 5,178,879 discloses clear, water-washable,
non-greasy gels useful for topical pain relief containing
capsaicin, water, alcohol and a carboxypoly-methylene emulsifier. A
method of preparing the gels is also disclosed.
[0046] U.S. Pat. No. 5,560,910 discloses compositions and methods
that are useful for topically treating inflammation caused by a
wide variety of diseases. The compositions comprise an effective
amount of a proteolytic enzyme, such as bromelain, in combination
with capsaicin in a pharmaceutically acceptable carrier.
[0047] U.S. Pat. No. 5,910,512 discloses a water-based topical
analgesic and method of application wherein the analgesic contains
capsicum, capsicum oleoresin and/or capsaicin. This analgesic is
applied to the skin to provide relief for rheumatoid arthritis,
osteoarthritis, and the like.
[0048] U.S. Pat. No. 5,962,532 discloses a method of providing pain
relief comprising administering an anesthetic along with injecting
a composition of capsaicin.
[0049] U.S. Pat. No. 6,239,180 discloses a transdermal application
of capsaicin in a concentration from greater than about 5 wt. % to
about 10 wt. % for treating neuropathic pain. An anesthetic is
initially administered to minimize the burning side effects from
subsequent capsaicin application.
[0050] U.S. Pat. No. 6,348,501 discloses a lotion for treating the
symptoms of arthritis using capsaicin and an analgesic along with a
method for making such formulations.
[0051] U.S. Pat. No. 6,573,302 discloses a cream comprising: a
topical carrier wherein the topical carrier comprises a member
selected from the group comprising lavender oil, myristal
myristate, and other preservatives in addition to hypericum
perforatum arnica montana capric acid; and 0.01 to 1.0 wt. %
capsaicin; 2 to 10 wt. % of an encapsulation agent selected from
the group comprising colloidal oatmeal hydrogenated lecithin,
dipotassium glycyrlhizinate and combinations thereof; esters of
amino acid; a light scattering element having a particle size up to
100 nm.; and a histidine.
[0052] U.S. Pat. No. 6,593,370 discloses a topical capsaicin
preparation for the treatment of painful cutaneous disorders and
neural dysfunction. The preparation contains a nonionic, amphoteric
or cationic surfactant in an amount effective to eliminate or
substantially ameliorate burning pain caused by capsaicin.
[0053] US Patent Application 2005/0090557 relates to compositions
of a TRPV1 agonist such as capsaicin, and a solvent system such as
a penetration enhancer.
[0054] U.S. Patent Application 2006/0100272 discloses compositions
and methods for the treatment of pain, and neuropathic pain in
particular. The formulations are eutectic mixtures of a
capsaicinoid and a local anesthetic agent and/or an anti-pruritic
agent.
[0055] US Patent Application 2006/0148903 relates to a method of
treating post surgical pain comprising administering at the
surgical site, a dose of capsaicinoid gel.
[0056] U.S. Pat. No. 7,282,224 discloses a pain relief composition
comprising an effective amount of a nerve inhibiting component,
including capsaicin, a capsaicinoid or a capsaicin analogue, which
numbs or inhibits the nerve endings that signal pain, in
combination with at least one of the following: an effective amount
of an inflammation control component which is designed to reduce
immediate pain and discourage future pain in the joints and
muscles; an effective amount of a cooling component; an effective
amount of a heat minimizing or blocking component; an effective
amount of a circulation increasing component which effectuates
better penetration of the actives to the skin and nerves; and an
effective amount of a soothing and anti-inflammatory complex for
the joints and/or muscles comprising glucosamine sulfate or HCl,
zingiber officiniale (ginger root) extract, methyl sulfonylmethane
(MSM), polygonum cuspidatum.
[0057] U.S. Pat. No. 7,632,519 discloses a variety of TRPV1 agonist
compounds (capsaicinoids and their related esters) and formulations
thereof.
[0058] U.S. Pat. No. 7,771,760 discloses topical oils of
capsacinoids comprising a capsaicinoid, a solvent capable of
solubilizing the capsaicinoid, and a capsaicinoid crystallization
inhibitor.
[0059] U.S. Pat. No. 7,943,166 relates to a method and liquid
solvent system of penetration enhancers from 10% (w/v) to about 30%
(w/v) of a TRPV1 agonist, such as capsaicin, where a single topical
application of the liquid formulation results in pain relief for at
least two weeks.
[0060] U.S. Pat. No. 7,943,666 discloses formulations of ester
derivatives of capsaicin and ester derivatives of myristoleic acid.
These derivatives are capable of reverting to the active parent
compound following enzymatic or chemical hydrolysis. These
derivatives have a higher lipophilicity, lipid solubility and less
irritation to the skin than the parent compound, and hence are
better able to be incorporated into certain pharmaceutical
formulations, including cream and ointment pharmaceutical
formulations. The disclosed pharmaceutical compositions are useful
for pain management in mammals in vivo and have been contemplated
to be used in the treatment of various pains in humans.
[0061] Despite the advancements in the art, there remains a need
for more effective pain-relieving capsaicin formulations.
OBJECTS OF THE INVENTION
[0062] It is an object of the invention to provide a topical pain
relief composition that provides long-term pain relief without loss
of sensation in the area treated.
[0063] It is an object of the invention to provide topical
compositions of TRPV1 selective agonists such as capsaicin and
other related compounds in preparations which eliminate or
substantially ameliorates initial burning/stinging pain caused by
the TRPV1 selective agonist compound observed following topical
administration thereby making the preparation tolerable following
initial and long-term use.
[0064] It is an object of the invention to provide topical TRPV1
selective agonist containing compositions such as capsaicin
formulations for use in the treatment of joint pain, tendonitis,
and for certain forms of localized neuropathic pains that are not
amenable to treatment with currently marketed topical preparations,
and do not have the side effects of systemic treatments.
[0065] It would be advantageous to provide methods and compositions
containing compositions such as capsaicin or analogues thereof, at
therapeutically effective concentrations to cause an analgesic
effect without the side effects normally associated with the use of
capsaicin.
[0066] It is therefore an object of the present invention to
provide methods for administering capsaicin or capsaicin analogues
topically at high concentrations to achieve a prolonged pain
reduction effect but without the severe burning sensation that
occurs following topical application.
[0067] It is yet another object of the present invention to provide
compositions containing analgesic/anti-inflammatory agents to
complement the remedial properties of capsaicin, or related
compounds, for the treatment of pain of the joints and muscles and
other medical conditions, where the analgesic agents are
conveniently administered with the capsaicin.
[0068] It is yet another object of the present invention to provide
a composition and method for topically treating pain and
inflammation that is safe and effective and does not have the side
effects of conventional NSAIDS.
[0069] It is another object of this invention to provide solvent
systems that solubilize appreciable concentrations of the
relatively aqueous insoluble TRPV1 selective agonists (such as
capsaicin and capsaicin derivatives) to produce compositions such
that solvent systems contains analgesic and anti-inflammatory
ingredients that rapidly penetrate the skin's layers to mitigate
the stinging and burning pain resulting from the topical
application of the significant capsaicin concentrations.
[0070] Other objects and advantages of the present invention will
be apparent from a review of the following specification.
SUMMARY OF THE INVENTION
[0071] The invention relates to liquid solution compositions
comprising a TRPV1 selective agonist, and an analgesic agent
capable of solubilizing said TRPV1 selective agonist, wherein said
composition has an amount of TRPV1 selective agonist sufficient to
decrease the density of functional nociceptive nerve fibers when
said composition is applied topically, and said composition has an
amount of analgesic agent sufficient to eliminate or reduce the
burning sensation or erythema created by the topical administration
of the TRPV1 specific agonist. In one embodiment, the amount of
TRPV1 selective agonist sufficient to decrease the density of
functional nociceptive nerve fibers by at least 20%, or at least
50%, after topical application.
[0072] In another embodiment the composition is 0.20-30% by weight
of the TRPV1 selective agonist which can be a vanilloid, or in an
advantageous embodiment, a capsaicinoid. The analgesic agent is one
or more components selected from the group consisting of methyl
salicylate, a TRPM8 agonist (e.g., menthol, icilin or eucalyptol),
and a TRPV3 agonist (e.g. camphor). In one embodiment, the
analgesic agent is greater than 50% by weight of the composition
and is capable of solubilizing said TRPV1 selective agonist. In
another embodiment, the methyl salicylate is replaced in whole or
part by an alcohol such as ethanol.
[0073] In an advantageous embodiment the invention discloses a
composition comprising: [0074] i) 0.075-30% by weight of a TRPV1
selective agonist, and [0075] ii) 50-95% by weight of an analgesic
agent comprising a) a topical salicylate and b) a TRPM8 agonist or
a TRPV3 agonist, capable of solubilizing said TRPV1 selective
agonist,
[0076] wherein said composition has an amount of TRPV1 selective
agonist sufficient to decrease the density of functional
nociceptive nerve fibers when said composition is applied
topically, and said composition has an amount of analgesic agent
sufficient to eliminate or reduce the burning and/or stinging
sensation or erythema created by the topical administration of the
TRPV1 selective agonist.
[0077] In another embodiment the invention discloses a composition
comprising: [0078] 0.075-30% by weight of a TRPV1 selective
agonist, and [0079] 70-95% by weight of an analgesic agent capable
of solubilizing said TRPV1 selective agonist,
[0080] wherein said composition has an amount of TRPV1 selective
agonist sufficient to decrease the density of functional
nociceptive nerve fibers when said composition is applied
topically, and said composition has an amount of analgesic agent
sufficient to eliminate or reduce the burning and/or stinging
sensation or erythema created by the topical administration of the
TRPV1 selective agonist, and wherein said composition does not
include turpentine oil.
[0081] In a further advantageous embodiment, the composition
comprises: [0082] 0.075-30% by weight of a capsaicinoid, [0083]
30-75% by weight methyl salicylate and/or ethanol, [0084] 1-20% by
weight menthol, and [0085] 1-20% by weight camphor. [0086]
Advantageously, 0.2-30%, or 5-20 by weight of a capsaicinoid
compound, 30-70% by weight methyl salicylate and/or ethanol, or
40-60% by wt. methyl salicylate and 10-25% by wt. ethanol; 1-20% by
weight menthol, more advantageously 10-20%; and 1-20% by weight
camphor, more advantageously 5-15%.
[0087] In a still further embodiment, the composition comprises
[0088] a capsaicinoid,
[0089] methyl salicylate and/or ethanol, and
[0090] phenol.
[0091] Advantageously, the composition comprises 0.20-30% by weight
of a capsaicinoid compound; 30-75% by weight methyl salicylate
and/or ethanol; 1-20% by weight menthol; 1-20% by weight camphor;
and 0.5-5% phenol.
[0092] In another embodiment (not involving capsaicin or related
compound), the composition comprises: [0093] 70-95% by weight
methyl salicylate and/or an alcohol such as ethyl alcohol, [0094]
10-20% by weight menthol, [0095] 10-20% by weight camphor, and
optionally [0096] 0.5-5% phenol.
[0097] The invention also relates to methods of making and using
compositions for the treatment of pain as well as treating a
variety of other medical conditions. Methods of treating pain in a
mammal (e.g. human) comprise topically administering the
compositions of the invention, and include methods of reducing the
density of nociceptor nerve fibers in the dermis and epidermis of a
selected region of a mammal, comprising administering the
composition of the invention to said region, e.g. where the density
of functional nociceptive nerve fibers is decreased by at least
20%, 30%, 40% or 50% after topically administering the
composition.
[0098] The invention includes methods of treating a capsaicin
responsive condition such as pain including neuropathic pain,
inflammatory hyperalgia, vulvodynia, interstitial cystitis,
rhinitis, burning mouth syndrome, oral mucositis, herpes,
dermatitis, pruritis, tinnitus, psoriasis, or headaches, with the
compositions of the invention. The invention also includes treating
arthritis pain in a mammal, and a method of treating itching in a
mammal. Typically, administration is topical application to the
affected area.
[0099] Also included are methods of formulating a capsaicinoid
liquid comprising the capsaicinoid dissolving in methyl salicylate
to form a solution, and adding camphor and/or menthol to the
solution, and methods of producing a topical formulation of
capsaicin comprising mixing capsaicin and methyl salicylate, and
adding one or more of menthol, camphor and phenol.
[0100] The invention also relates to kits comprising the liquid
formulation of the invention and a non occlusive applicator device.
In another embodiment the kit further comprises a cleaning solution
for removal of residual agonist.
BRIEF DESCRIPTION OF THE DRAWINGS
[0101] FIG. 1 shows the tolerability of API-CAPS (0%, 2%, 5%, 10%
or 20% capsaicin) following once daily, 60 minute exposure,
treatment of osteoarthritic knees for 4 consecutive days. Subjects
rated tolerability (burning & stinging sensation) at 15, 30,
45, and 60 minutes after API-CAPS application on a 0-10 numeric
rating scale (0=no pain; 10=worst pain imaginable) in conjunction
with the Wong-Baker Faces Rating Scale as a guide.
[0102] FIG. 2 is a plot of the tolerability of API-CAPS (0%, 2%,
5%, 10% or 20% capsaicin) following once daily, 60 minute exposure,
treatment of osteoarthritic knees for 4 consecutive days. Subjects
rated tolerability (burning & stinging sensation) at 15, 30,
45, and 60 minutes after API-CAPS application on a 0-10 numeric
rating scale (0=no pain; 10=worst pain imaginable) in conjunction
with the Wong-Baker Faces Rating Scale as a guide.
[0103] FIG. 3 shows the end of study percent pain reduction from
initial osteoarthritic pain level prior to initiation of short-term
API-CAPS, 0.25% capsaicin, therapy (two weeks of treatment applied
three times per day, five days per week).
[0104] FIG. 4 is a bar chart graph displaying the tolerability of
API-CAPS, 0.25% capsaicin, treatment following each application
over the course of two weeks of treatment applied three times per
day, five days per week. Subjects rated tolerability (burning
sensation) on a 0-10 numeric rating scale (0=no pain; 10=worst pain
imaginable) in conjunction with the Wong-Baker Faces Rating Scale
as a guide.
[0105] FIG. 5 shows the molecular structures of selected analgesic
ingredients: menthol, camphor, methyl salicylate, eucalyptol,
lavender oil, and phenol.
DETAILED DESCRIPTION OF THE INVENTION
[0106] The invention relates to compositions, typically liquid
solution pharmaceutical formulations, of a TRPV1 selective agonist
(i.e. acting as specific agonist for TRPV1 such as does capsaicin)
agonist such as capsaicin or a capsaicin derivative/analogue,
primarily for the treatment of pain. The compositions include one
or more analgesics which reduce or eliminate the burning or
stinging pain caused by administration of the TRPV1 selective
agonist, thereby making the TRPV1 selective agonist formulation
administration tolerable, including in long-term administration.
The present application discloses the discovery that a TRPV1
selective agonist containing topical composition is very effective
in treating pain in humans, and causes significantly less burning
pain at the site of the application, when administered with one or
more topical analgesics at high concentration(s) such as methyl
salicylate, camphor, menthol and phenol, than the same composition
without an analgesic. Unlike conventional formulating where a base
vehicle is selected and the actives are added thereto, in the
formulations of the subject invention, the actives, the analgesics,
are the vehicle or are the primary vehicle. The analgesic
components of the formulations of the invention together make up
typically greater than 50%, or 60%, 70% or greater than 75% by
weight of the formulations.
[0107] The present invention provides immediate pain relief from
the analgesic agent along with the long lasting pain relief
afforded by the TRPV1 selective agonist, e.g. capsaicin, without
the same severity of concentration-dependent capsaicin side effects
(e.g. stinging and burning) associated with prior art capsaicin
formulations. The formulations can provide pain relief for periods
of weeks to months dependent upon disease state and severity.
Importantly, the formulations of the present invention maintain
sensation in the skin onto which the formulation has been topically
applied.
[0108] The topical formulations, particularly for the treatment of
pain, contain higher levels of TRPV1 selective agonists such as
capsaicin, than normally used. The subject formulations do not have
the discomfort and burning associated with capsaicin formulations
of the prior art. The formulations of the TRPV1 selective agonist
can include anti-inflammatory, antioxidant and other additives that
contribute to pain relief and the therapeutic treatment of
pathological conditions such as arthritis pain, osteoarthritis,
joint disorders, muscular pain, neuropathic pain, neck and back
pain, shingles, cluster headaches and other disease or
health-related conditions.
[0109] The subject invention relates to pharmaceutical topical
compositions for delivery of significant quantities of a TRPV1
selective agonist compound such as capsaicin or related compounds
via the skin. The components of the composition other than the
TRPV1 selective agonist compound are included to reduce or
eliminate the burning sensation associated with administration of
the TRPV1 selective agonist compound as well as to enhance skin
penetration of said TRPV1 selective agonist compound. The
additional components are typically camphor, methyl salicylate
and/or alcohol, and menthol, and optionally phenol, which are
generally accepted as safe and effective for the temporary relief
of minor aches and pains of muscles and joints associated with
simple backache, arthritis, strains, bruises and sprains.
[0110] It has been discovered that incorporation of a sufficient
quantity of these ingredients into the capsaicin preparations forms
a mixture for the topical treatment of pain such that the initial
burning/stinging pain resulting from capsaicin is eliminated or
ameliorated.
[0111] It has been demonstrated that the analgesic properties of
these ingredients reduce the burning/stinging sensation produced
following topical application of a TRPV1 selective agonist
compounds such as capsaicin. The compositions of the invention
include appreciable quantities of menthol, camphor, and methyl
salicylate, and optionally phenol which also enhances the analgesic
properties that minimize the burning/stinging sensation produced
following topical application capsaicin. Other suitable/compatible
analgesic oils such as peppermint oil (which also contains
menthol), eucalyptus oil, lavender oil and other analgesic oils can
be added to the topical mixture. Components can also be added which
enhance the penetration of the capsaicin into the viable layers of
the skin and into subcutaneous tissues.
[0112] Accordingly, the present invention provides topical
preparations comprising an amount of a TRPV1 selective agonist such
as capsaicin effective in initial and long-term or repeated
administration to reduce pain associated with certain cutaneous
disorders and neural dysfunctions.
COMPOUNDS OF THE INVENTION
[0113] The components of the formulations of the invention are
discussed below.
TRPV1 Selective Compounds including Capsaicinoids, Capsaicin and
its Analogues
[0114] According to the present invention, the pain relief
composition comprises a therapeutically effective amount of a
nerve-inhibiting component--a TRPV1 selective agonist, which
inhibits the nerve endings that signal pain. The TRPV1 selective
agonist component is typically a vanilloid, a capsaicinoid, more
specifically capsaicin, nonivamide or other capsaicin analogue, or
a mixture thereof.
[0115] TRPV1 selective agonist compounds of the subject invention
include the natural capsaicinoids (Capsaicin Oleoresin), and
synthetic (Nonivamide) forms, as well as derivatives (analogues) of
capsaicin. Capsaicin is known by the chemical name
N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-trans-6-enamide.
Capsaicin is the main capsaicinoid (typically 69%) in chili
peppers, followed by dihydrocapsaicin (typically 22%) and
norihydrocapsaicin (typically 7%). Nonivamide is found in trace
amounts in chili peppers.
TABLE-US-00004 CAPSAICIN & CAPSAICINOID PROPERTIES Natural
Scoville Capsaicinoid Relative Heat Molecular Name Abbr. MW Amount
Units Formula Chemical Structure Capsaicin C 305 .sup. 69% 16
.times. 10.sup.6 C.sub.18H.sub.27NO.sub.3 ##STR00002## Dihydro-
capsaicin DHC 307 .sup. 22% 15 .times. 10.sup.6
C.sub.18H.sub.29NO.sub.3 ##STR00003## Nordihydro- capsaicin NDHC
293 .sup. 7% 9.1 .times. 10.sup.6 C.sub.17H.sub.27NO.sub.3
##STR00004## Homodihydro- capsaicin HDHC 321 .sup. 1% 8.6 .times.
10.sup.6 C.sub.19H.sub.31NO.sub.3 ##STR00005## Homo- capsaicin HC
319 .sup. 1% 8.6 .times. 10.sup.6 C.sub.19H.sub.29NO.sub.3
##STR00006## Nonivamide PAVA 293 .sup.(1)0.25% 16 .times. 10.sup.6
C.sub.17H.sub.27NO.sub.3 .sup.(1)Constant et al, J. Nat. Prod.
1996, 59, 425-426 As noted above, capsaicin and several related
compounds are called capsaicinoids. Nonivamide, the vanillylamide
of n-nonanoic acid (also PAVA) is used as a reference substance for
determining the relative pungency of capsaicinoids as well as being
used as a food additive to add pungency.
[0116] Capsaicin and dihydrocapsaicin together make up 80-90% of
the capsaicinoids found in chili peppers. The different
capsaicinoid compounds have slight structural variations in the
hydrocarbon tail, changing their ability to bind to the nerve
receptors and their ability to penetrate layers of receptors on the
tongue, mouth, and throat.
[0117] Capsaicinoids are very similar in structure, varying only by
the length of a long hydrocarbon portion (that is, a portion
containing only carbon and hydrogen atoms), and by the presence or
absence of one carbon-to-carbon double bond in that hydrocarbon
portion (carbon-carbon double bonds).
[0118] Nonivamide is present in chili peppers but is commonly
manufactured synthetically. It is more heat-stable than capsaicin.
Ointments sold to relieve arthritis and muscle pain often contain
nonivamide. Application of the ointment on the skin is claimed to
result in a warm to burning sensation and pain relief for several
hours.
[0119] Both the naturally occurring capsaicin and the synthetic
capsaicin analogues that differ slightly in their alkyl chain, have
similar pharmacological effects.
[0120] Capsaicin is practically insoluble in water, but freely
soluble in alcohol, methyl salicylate, ether, benzene and
chloroform. Capsaicin is a lipophilic white crystalline powder;
melting point 60-65 degrees C.
[0121] Therapeutically, capsaicin has been used as a topical
analgesic. Both the natural and synthetic (forms of capsaicin are
available commercially.
[0122] Capsaicinoids in addition to capsaicin are applicable to
this invention.
[0123] Resiniferatoxin (RTX) is a very potent capsaicin analogue.
Other TRPV1 selective agonists include anandamide, and NADA. Many
additional agonists are disclosed in U.S. Pat. No. 7,943,166 and
U.S. Pat. No. 7,632,519, each of which is hereby incorporated by
reference in its entirety. Some capsaicin analogues are described
in U.S. Pat. No. 5,962,532, hereby incorporated by reference in its
entirety.
[0124] The formulations of the invention typically include
0.075-30% by weight, 0.2-30%, or 2-20%, 2-10% or 5-15% of
capsaicin, or related compounds. When the TRPV1 selective agonist
is other than capsaicin, since potency can vary, the amount of
agonist in the formulation is that amount which achieves the same
results achieved by the weight percent ranges noted herein for
capsaicin.
Analgesics and Other Components
[0125] The compositions of the subject invention also include an
analgesic agent--one or more analgesics. As used herein, an
"analgesic agent" is a compound or compounds which, when topically
applied, reduces pain or burning sensation without loss of
sensation. The analgesics agents of the invention do not include a
capsaicinoid and do not include an opioid. Further, the analgesic
agents do not include a topical local anesthetic, such as lidocaine
(or procaine, amethocaine, cocaine lidocaine (also known as
Lignocaine), prilocaine, bupivacaine, levobupivacaine, ropivacaine,
mepivacaine, dibucaine) in the TRPV1 specific agonist containing
formulations. These caine local anesthetics have not been effective
in sufficiently moderating the burning effect of capsaicin when
administered concomitantly with capsaicin topically; they have a
slower onset of action relative to capsaicin. To reduce the burning
sensation, these caine local anesthetics are typically administered
in advance of capsaicin attempting to elicit sufficient anesthetic
action prior to the burning sensation associated with capsaicin. In
one embodiment, the analgesic agent does not include turpentine
oil.
[0126] Accordingly, it was discovered that a system of analgesic
compounds can function to: (1), solubilize appreciable
concentrations of the relatively aqueous insoluble capsaicin and
related capsaicinoids and TRPV1 selective agonists; (2), rapidly
penetrate the skin surface and underlying dermis and epidermis; and
(3) reduce or eliminate the burning and stinging sensation and
erythema associated with the topical administration of the TRPV1
(e.g. capsaicin), including reducing thermal hyperalgesia (enhanced
sensitivity to heat) associated with the topical administration of
the TRPV1 selective agonist (e.g. capsaicin) which can occur hours
to days after administration of the TRPV1 selective agonist. The
subject invention includes the use of specific topical analgesics
that have a fast "onset of action" relative to capsaicin (such as
methyl salicylate, menthol, camphor, and phenol) to effectively
moderate the burning effect of capsaicin when concomitantly
administered with capsaicin topically. Onset of action of a
compound is linked to its physicochemical properties; some of which
are summarized below.
TABLE-US-00005 Oil Aqueous Log MP Onset of Ingredients MW Soluble
Soluble. O/W (.degree. C.) Action Capsaicin 305.41 soluble
insoluble 3.327 62-65 moderate Methyl 152.15 Alcohol sparingly 2.23
-9 fast Salicylate miscible Ethyl 46.07 soluble miscible -0.18 -114
fast Alcohol Phenol 94.11 soluble soluble 10 43 fast Menthol 156.26
soluble slightly 2.66 42 fast soluble Camphor 152.23 soluble
Slightly 2.089 176 fast soluble Lidocaine 234.34 soluble insoluble
2.359 68 slow Prilocaine 220.31 soluble sparingly 2.11 137 slow
Benzocaine 165.19 Soluble sparingly 1.95 90 moderate
[0127] The use of these selected topical analgesics with a fast
onset of action effectively moderates the burning effect of
capsaicin when concomitantly administered topically, but also
provides more immediate pain relief relative to capsaicin. In one
embodiment of the invention, the topical analgesic agent has a
molecular weight of 160 or less. Capsaicin provides more long
term/long lasting pain relief relative to these fast onset of
action topical analgesics.
[0128] The present application includes the discovery that topical
TRPV1 selective agonist containing compositions have significantly
less burning pain at the site of the application when combined with
topical analgesics such as methyl salicylate, camphor, menthol, and
phenol (when compared to the same composition without analgesic),
and are extremely effective in treating pain in mammals including
humans. As used herein, "topical" refers to administration of the
composition to a defined area of the body such as a defined area of
skin surface or mucous membrane.
[0129] The analgesic agent of the invention is one or more agents
selected from the group consisting of methyl salicylate and/or
alcohol (30-75% by weight), a TRPM8 agonist (e.g. menthol, icilin
or eucalyptol), and a TRPV3 agonist (e.g. camphor). The analgesic
agent (which can be multiple compounds) is capable of solubilizing
the TRPV1 selective agonist. The analgesic components of the
formulations of the invention are typically greater than 50% by
weight of the formulations.
Topical Salicylates Including Methyl Salicylate
[0130] Methyl salicylate can act as an analgesic and
anti-inflammatory agent. Some of the plants which produce it are
called wintergreens, hence the common name. Trolamine salicylate,
the active ingredient in Aspercreme.TM. is another salicylate which
can be used in topical pain compositions. Esters of methyl
salicylate have also been made. It has been found that methyl
salicylate can be used advantageously as a solvent to dissolve
capsaicinoids.
[0131] The formulations of the invention typically include 30-70%
or 40-60% by weight methyl salicylate.
Menthol
[0132] Menthol is an organic compound made synthetically or
obtained from peppermint or other mint oils that produces a feeling
of cooling. Advantageously, (l)-menthol (natural menthol derived
from peppermint oil) is used in the subject invention for analgesic
effects. Alternatively, another transient receptor potential
subfamilyM8 (TRPM8) agonist such as icilin or eucalyptol can be
used.
[0133] The formulations of the invention include 1-20%, 10-20% by
weight menthol.
Camphor
[0134] Camphor is readily absorbed through the skin and produces a
feeling of cooling similar to that of menthol, and acts as slight
local anesthetic. Camphor is a naturally occurring compound.
Alternatively, another transient receptor potential vanilloid 3
(TRPV3) agonist such as icilin or eucalyptol can be used.
[0135] The formulations of the invention include 1-20%, 10-20%, or
5-15% by weight camphor.
Phenol
[0136] Phenol cools and numbs skin on contact, making it an
effective topical analgesic ingredient. It also kills germs, and
reduces the risk for infection in minor skin irritations. It has
been used medically for over 100 years, for these and other
applications. Because it can improve the effectiveness of a
preparation at relieving itching, phenol is added to formulations
meant for the relief of insect bites and stings, sunburn, and other
painful and itchy skin conditions.
[0137] The formulations of the invention can include 0-4.6%,
advantageously 1-3% phenol.
[0138] Eugenol/clove oil and thymol/thyme oil or an Essential Oil
(see Table II or Table below) can be added in addition to, or as
alternative to phenol. Below is a listing of natural analgesic
ingredients together with some of their properties.
TABLE-US-00006 NATURAL FUNCTION ANALGESIC Anti- Anti- Rube-
Anti-in- Anti- INGREDIENTS Analgesic Anesthetic Antiseptic Fungal
Bacterial facient flammatory Pruritic Menthol X X X X X X (Mint
Oils) Camphor X X X X X X Wintergreen Oil X X X X X (methyl
salicylate) Phenol X X X X X X X Eugenol/Clove oil X X X X X X
Thymol/Thyme Oil X X X X X X X X Eucalyptus Oil X X X X X X
Peppermint Oil X X X X X X Lavender Oil X X X X X Tea Tree Oil X X
X X X X Turpentine Oil X X X X X X
Alcohol
[0139] In another embodiment of the invention, the methyl
salicylate is replaced with, or supplemented with an alcohol such
as ethyl alcohol or benzyl alcohol, which like methyl salicylate,
can solubilize capsaicinoids as well as menthol and camphor. This
results in compositions with lower viscosity and shorter drying
times. In one embodiment where the methyl salicylate is replaced
with ethanol, glycerol can be added to the composition.
Surfactants and Other Agents that Enhance Skin Penetration
[0140] One or more surfactant(s), advantageously non ionic (e.g.
polysorbates such as PS80, sorbitan esters (Spans), poloxamers,
etc.), can be also be added to the compositions of the invention to
enhance the skin penetration of the analgesic and capsaicin
compounds. They can ameliorate the initial stinging pain caused by
capsaicin (or related compounds) in admixture with the
pharmaceutically acceptable carrier ingredients for topical
administration. Fatty acid ester non-ionic surfactants which are
utilized in pharmaceutical, cosmetics and food stuffs are
especially advantageous because of the compatibility with
biological tissues.
[0141] Other penetrating agents include propylene glycol,
.alpha.Bisabolol, and other oil soluble organic compounds known in
the art of topical formulation development which can enhance skin
penetration.
Anti-Inflammatory Agents
[0142] Apigenin & .alpha.Bisabolol
[0143] An effective amount of an inflammation control component,
which reduces or relieves inflammation, swelling, redness, and/or
pain in the joints and muscles associated with inflammation, can be
added (e.g. apigenin and .alpha.bisabolol).
[0144] Apigenin offers some of nature's most potent and effective
anti-inflammatory and antioxidant properties. It can be included in
the formulation to further enhance therapeutic efficacy. Apigenin
has a broad range of anti-inflammatory properties and has been
cited for the ability to block the production of compounds that
cause pain; e.g., the arthritis causing substance cyclooxygenase
(COX). The addition of apigenin to a mixture of capsaicin in the
constituents of the subject pain relieving formulations can be
accomplished using the high temperature surfactant technology where
apigenin is first dissolved in PS80 at elevated temperatures to
form a concentrate that is then added to the mixture (see US
Application US 2011/0311592 A1).
[0145] .alpha.Bisabolol is another potent anti-inflammatory
sesquiterpene which is known to also have anesthetic,
anti-irritant, anti-inflammatory, anti-fungal and anti-microbial
properties. .alpha.Bisabolol is also demonstrated to enhance the
percutaneous absorption of certain molecules. .alpha.Bisabolol
helps transport active ingredients transdermally by enhancing skin
penetration. (R. Kadir and B. W. Barry. Alpha-Bisabolol, a Possible
Safe Penetration Enhancer for Dermal and Transdermal Therapeutics.
Int. J. Phann. 70:87-94 (1991).)
[0146] NSAIDs/Diclofenac Sodium
[0147] In further embodiments of the invention, a Non-Steroidal
Anti-Inflammatory Agent (NSAID) is co-administered with the TRPV-1
selective agonist formulations. The NSAID and the TRPV-1 selective
agonist can be administered together as a single composition (where
a topical NSAID is used) or administered as separate compositions
(where a topical or not topical NSAID is used). The NSAID can be
administered before, after or at the same time as the TRPV-1
selective agonist by the same or different routes of
administration. For example, the TRPV-1 selective agonist can be
administered topically while the NSAID agent can be administered
orally, topically or parentally.
[0148] NSAIDs useful as adjunctive agents in the formulations of
the present invention include aspirin (acetylsalicylic acid),
ibuprofen, naproxen, diclofenac, benoxaprofen, ketoprofen,
indomethacin etc., and mixtures thereof. As used herein, "NSAID"
does not include methyl salicylate.
[0149] Combining an NSAID such as a Diclofenac Salt with capsaicin
in a topical formulation combines two established pain relieving
agents which function via two different mechanisms of action
(MOAs); i.e., TRPV1 nerve defunctionalizer and a potent COX-2
inhibitor. Solubility studies were conducted (see below) and
formulations were prepared containing the NSAID, diclofenac sodium,
together with the TRPV1 selective agonist, capsaicin, utilizing the
subject invention.
Odor Reduction Components
[0150] Many topically applied analgesic formulations contain a
blend of volatile aromatic compounds and essential oils which are
used for the temporary relief of minor aches and pains of muscles
and joints associated with simple backache, arthritis, sprains,
bruises and strains. For example: White Flower Analgesic Balm
consists of the active ingredients: Methyl Salicylate (Wintergreen
Oil) 40%, Menthol 15%, Camphor 6% and other ingredients; Eucalyptus
Oil 18%, Peppermint Oil 15%, and Lavender Oil 6%. However, all the
components of White Flower Analgesic Balm are known for their
distinctive odors such that these combined ingredients do
contribute to a strong, penetrating pungent, odor that is
objectionable for many users and to many individuals who come in
contact with the users. Further, the magnitude of the perceived
odor of these volatile aromatic compounds and essential oils often
increases within closed spaces such as in automobiles, buses,
planes, and poorly ventilated rooms, etc. The teachings of this
invention are particularly advantageous in the reduction of the
severity of these perceived odors from the aforementioned topical
analgesic compounds whose combined concentration often exceeds more
than 35% by weight of a formulation.
[0151] Inclusion of relatively non-odiferous oils with low ambient
vapor pressures such as Aloe Vera, Coconut, Borage and/or Macadamia
Nut Oils to formulations containing significant quantities of
volatile topical analgesic compounds such as methyl salicylate,
camphor and menthol results in a significant reduction in the
perception of these strongly penetrating pungent aromatic odors.
This effect is particularly useful with formulations having
relatively high capsaicin concentrations.
Aloe Vera Oil
[0152] Aloe Vera in Aloe Vera Oil is a nutrient rich ingredient
used in skin preparations as it contains Vitamin C, E,
Beta-Carotene, and B12, minerals such as magnesium, copper,
chromium, calcium, iron and potassium, essential amino acids, plant
sterols and lignin.
[0153] Aloe Vera is rich in anti-inflammatory, emollient,
anti-fungal, anti-bacterial and anti-viral properties, making it a
potent remedy for many skin ailments. The various enzymes in Aloe
Vera reduce the itching, swelling and inflammation that often
accompany common skin ailments. Aloe Vera has been used to treat
wounds, burns, scalds and even sunburn. The plant extract counters
bacterial infection while improving circulation and expediting the
healing process. Aloe Vera is useful for cell regeneration.
Coconut Oil
[0154] Coconut Oil is useful in the treatment of skin conditions
such as eczema, psoriasis, rosacea and various other skin
infections; and helps to reduce or eliminate itching and flaking of
the skin due to dryness. Coconut Oil contains vitamin E, which is
necessary for healthy skin, as well as the medium-chain fatty acids
Capric Acid, Caprylic Acid, Caproic Acid and Lauric Acid.
[0155] It moisturizes the skin, either alone or in combination with
other oils, and is an exceptional base oil for moisturizing creams
and oils and aromatherapy blends. Coconut Oil's antioxidant
properties can help delay wrinkles and sagging skin related to
aging by preventing the formation of free radicals and
strengthening the skin's underlying connective tissues, as well as
by limiting the damage caused by excessive sun exposure.
Borage Oil
[0156] Topical application of borage oil has been shown to be
effective in preventing and treating inflammatory conditions and
skin disorders, such as eczema and dermatitis, in both animals and
humans. Although essential fatty acids are important in diet, they
can also play an important role when applied topically to the skin.
Borage Oil is the richest known source (24%) of an essential fatty
acid called gamma-linolenic acid (GLA). These polyunsaturated
essential fatty acids are essential for the structure and
flexibility of the cell membranes and also play an important role
in the construction of the epidermal lipid barrier. They therefore
can help normalize trans-epidermal water loss. Borage oil is
extremely high in mucilage and also contains pyrrolizdine
alkaloids. The main constituents of the oil are vitamin C,
saponins, tannins and minerals. The tannins in the oil have a
slight tightening effect on the skin and the oil helps to restore
moisture and smoothness to dry skin, soothing irritated and damaged
skin. Borage oil also helps provide relief to people who suffer
from chronic skin disorders, such as eczema and atopic
dermatitis.
Macadamia Nut Oil
[0157] This hypoallergenic "oil" contains a high concentration of
palmitoleic Acid, 18%, in addition to 60% oleic acid, 2.7% linoleic
acid, 3% omega-3 and omega-6. Macadamia Nut Oil indeed is an
effective emollient that gives a rich skin feel. The oil has
several natural healing properties as well. Many are finding great
success using it to help with irritated skin, small wounds, and to
reduce the coloration in scars.
[0158] The stability of Macadamia Nut Oil makes it an ideal
ingredient for an array of cosmetic applications. Macadamia Nut Oil
is known to be a protective oil with a respectable and reasonably
quick absorption rate. Macadamia Nut Oil acts in a similar way as
does the human sebum that naturally protects and lubricates the
skin. The oils regenerative properties make it a quality ingredient
for products targeting damaged skin.
Compositions of the Invention
[0159] The invention relates to a compositions, advantageously a
liquid solution, comprising a TRPV1 selective agonist, and an
analgesic agent capable of solubilizing said TRPV1 selective
agonist, wherein said composition has an amount of TRPV1 selective
agonist sufficient to decrease the density of functional
nociceptive nerve fibers when said composition is applied
topically, and said composition has an amount of analgesic agent
sufficient to eliminate or reduce the burning and/or stinging
sensation or erythema created by the topical administration of the
TRPV1 selective agonist. The liquid solution of the invention is
advantageously a non aqueous solution. If ethanol is in the
solution, water can be included. Typically, the water is less than
5%, or advantageously less than 2% by wt. In the compositions of
the subject invention, inert ingredients (i.e. other than the TRPV1
selective agonist, and the analgesics) typically comprise less than
25%, 10% or 5% by weight, of the composition.
[0160] The TRPV1 selective agonists, analgesic agents and
excipients suitable for use in the pharmaceutical compositions of
the present invention, are those which are pharmaceutically
acceptable when applied to human skin, ie having acceptable
toxicity at the levels used. All components of the formulations of
the invention are USP grade. In a preferred embodiment of the
invention, the compositions are manufactured in full compliance
with GMP regulations of the U.S. FDA.
[0161] In one embodiment, the amount of TRPV1 selective agonist
sufficient to decrease the density of functional nociceptive nerve
fibers by at least 20%, or at least 50%, after topical application.
In another embodiment the composition is 0.20-30% by weight of the
TRPV1 selective agonist.
[0162] The TRPV1 selective agonist can be a vanilloid, or in an
advantageous embodiment, a capsaicinoid such as capsaicin.
[0163] The analgesic agent that solubilizes the TRPV1 selective
agonist, is one or more agent selected from the group consisting of
methyl salicylate (30-70% by weight), a TRPM8 agonist (e.g.
menthol, icilin or eucalyptol), and a TRPV3 agonist (e.g. camphor).
The analgesic agent is typically greater than 50% by weight of the
composition and is capable of solubilizing said TRPV1 selective
agonist. [0164] Advantageous components of the compositions of the
invention are:
[0165] capsaicin or a related compound,
[0166] methyl salicylate and/or ethanol,
[0167] menthol,
[0168] camphor, and optionally
[0169] phenol.
[0170] When combined with analgesic/desensitizing ingredients, the
amount of capsaicin (e.g. trans-capsaicin) in the topical
preparation can be from 0.075-30 wt. %, 0.2 wt. % to 30 wt. %,
between 1 wt. % and 20 wt. %, e.g. 1 wt. %, 5 wt. %, 10 wt. %, and
20 wt. %.
[0171] The amount of analgesic ingredients to achieve the above
effect is greater than 50 wt. %, or in the range of 60 wt. % to 95
wt. % of the preparation.
[0172] Advantageous formulations of the invention include (by
weight):
[0173] methyl salicylate and/or ethanol .about.30-75 wt. %,
advantageously 40-60 wt. %
[0174] menthol, .about.1-20 wt. %, advantageously 10-20 wt. %
[0175] camphor .about.1-20 wt. %, advantageously 5-15 wt. %, and
optionally
[0176] phenol .about.0-4.6 wt. %, advantageously 0.5-2 wt. %.
[0177] Advantageous embodiment of the invention without a TRPV1
selective agonist includes: a composition comprising: [0178] 30-75%
by weight methyl salicylate and/or ethanol, [0179] 1-20% by weight
menthol, [0180] 1-20% by weight camphor, and [0181] optionally
phenol, [0182] wherein the percentage by weight of the methyl
salicylate, menthol, and camphor is greater than 50% of the
composition;
[0183] In another embodiment, the invention includes
[0184] a composition comprising:
[0185] a capsaicinoid,
[0186] methyl salicylate and/or ethyl alcohol, and
[0187] phenol,
[0188] wherein the percentage by weight of the methyl salicylate
and phenol is greater than 50% of the composition. More
specifically in this embodiment the composition can comprise:
[0189] 0.075-30% by weight of a capsaicinoid compound,
[0190] 30-75% by weight methyl salicylate and/or ethyl alcohol,
[0191] and
[0192] 0.5-5% phenol.
[0193] Table III, IIIA, and IIIB contain a listing of the
compositions of several prepared Nonivamide and Capsaicin
formulations.
TABLE-US-00007 TABLE III INGREDIENTS OF PREPARED NONIVAMIDE
FORMULATIONS Form Form Form Form Form .sup.(16) Form .sup.(16) Form
Form Form 1 2 3 4 5 6 7 8 9 INGREDIENTS Wt % Wt % Wt % Wt % Wt % Wt
% Wt % Wt % Wt % .sup.(1) NONIVAMIDE 0.2 1.8 4 1.8 1.8 1.8 1.8 1.8
1.8 .sup.(2) METHYL SALICYLATE 20 35 45 35 49.2 55 55 55 55
.sup.(3) MENTHOL 6 13 15 13 15 15 0 15 0 .sup.(4) CAMPHOR 3 6 8 9
11 0 10 0 10 .sup.(5) PHENOL 0 0 0 1.5 2 0 0 0 0 .sup.(6)
.alpha.BISABOLOL NATURAL 0 0 0 1 1 0 0 0 0 .sup.(7)HYDROCORTISONE 1
1 1 0 0 0 0 0 0 .sup.(8) POLYSORBATE 80 9.25 9.25 9.25 9.25 9.25 0
0 0 0 .sup.(9) APIGENIN 0.75 0.75 0.75 0.75 0.75 0 0 0 0 .sup.(10)
ETHYL ALCOHOL 0 0 0 0 10 20 20 20 20 .sup.(11) GLYCEROL 0 0 0 0 0
8.2 9 0 0 .sup.(12) PROPYLENE GLYCOL 0 0 0 0 0 0 4.2 0 0 Balance
Including: .sup.(13) 59.8 .sup.(13) 33.2 .sup.(13) 17.0 .sup.(13)
28.7 0 0 0 .sup.(14) 8.2 .sup.(14) 13.2 Aloe Vera, Coconut &
Macadamia Nut Oils TOTAL 100 100 100 100 100 100 100 100 100 Form
Form Form Form Form Form Form 10 11 12 13 14 15 16 INGREDIENTS Wt %
Wt % Wt % Wt % Wt % Wt % Wt % .sup.(1) NONIVAMIDE 1.8 0.25 0.25 5
10 15 1.8 .sup.(2) METHYL SALICYLATE 55 45 45 50 50 50 50 .sup.(3)
MENTHOL 0 15 15 15 15 15 15 .sup.(4) CAMPHOR 0 10 10 11 11 10.5 11
.sup.(5) PHENOL 0 2 2 2 2 1.5 2 .sup.(6) .alpha.BISABOLOL NATURAL 0
0 0 1 1 1 0 .sup.(7)HYDROCORTISONE 0 0 0 0 0 0 0 .sup.(8)
POLYSORBATE 80 0 0 9.25 9.25 9.25 7.4 0 .sup.(9) APIGENIN 0 0 0.75
0.75 0.75 0.60 0 .sup.(10) ETHYL ALCOHOL 20 10 10 0 0 0 0 .sup.(11)
GLYCEROL 0 0 0 0 0 0 0 .sup.(12) PROPYLENE GLYCOL 0 0 0 0 0 0 0
Balance Including: .sup.(14) 23.2 .sup.(14) 17.75 .sup.(14) 7.75
.sup.(15) 6 .sup. .sup.(15) 1 .sup. 0 .sup.(15) 20.2 Aloe Vera,
Coconut & Macadamia Nut Oils TOTAL 100 100 100 100 100 100 100
NOTE: .sup.(1) Nonivamide, Aversion Technologies Inc., CAS #
2444-46-4 .sup.(2) Methyl Salicylate, Spectrum Chemical, NF, CAS #
119-36-8 .sup.(3) L-Menthol, Crystal, Spectrum Chemical, USP, CAS #
2216-51-5 .sup.(4) Camphor, Synthetic, Spectrum Chemical, USP, CAS
# 76-22-2 .sup.(5) Phenol, Liquefied (Carbolic Acid), USP, Spectrum
Chemical, CAS # 108-95-2 .sup.(6) Alpha Bisabolol Natural (96%)
from Alpha Aesar, CAS # 515-69-5 .sup.(7)Hydrocortisone, USP,
Spectrum CAS 50-23-7 .sup.(8) Polysorbate 80, Super refined, Croda
Inc., CAS # 9005-65-6 .sup.(9) Apigenin 98.sup.+%, Skyherb
Technologies Co., Ltd, Lot # 0000418019 .sup.(10) Ethyl Alcohol,
Graves Grain Alcohol, 190 Proof .sup.(11) Glycerin, Lotioncrafters,
USP, CAS # 56-81-5 .sup.(12) Propylene Glycol, .sup.(13) Aloe Vera
Oil obtained from Spectrum Chemical, Product # A1612, CAS #
85507-69 .sup.(14) Coconut Oil, Nature's Way EfaGold Coconut Oil,
Pure Extra Virgin .sup.(15) Macadamia Nut Oil, CAS #128497-20-1,
Lotioncrafters Lot # 1506-3187 .sup.(16) The shaded highlighted
columns, Form 6 & 7, experienced phase separation
TABLE-US-00008 TABLE IIIA INGREDIENTS OF PREPARED CAPSAICIN
FORMULATIONS Form Form Form Form Form Form Form Form Form Form 1A
2A 3A 4A 5A 6A 7A 8A 9A 10A INGREDIENTS Wt % Wt % Wt % Wt % Wt % Wt
% Wt % Wt % Wt % Wt % .sup.(1) CAPSAICIN, NATURAL 0.25 1.8 0 0 0 0
0 0 0 0 .sup.(2) TRANS-CAPSAICIN 0 0 0.25 0.25 2.0 2.0 5.0 10.0
15.0 20 .sup.(3) METHYL SALICYLATE 0 0 50 50 50 50 50 50 50 50
.sup.(4) MENTHOL 0 0 15 15 15 15 15 15 15 15 .sup.(5) CAMPHOR 0 0
11 11 11 11 11 11 11 11 .sup.(6) PHENOL 0 0 1.5 1.5 1.5 1.5 1.5 1.5
1.5 1.5 .sup.(7) POLYSORBATE 80 9.25 9.25 0 9.25 0 9.25 0 0 0 0
.sup.(8)APIGENIN 0.75 0.75 0 0.75 0 0.75 0 0 0 0 .sup.(9) WHITE
FLOWER 89.75 88.2 0 0 0 0 0 0 0 0 ANALGESIC BALM .sup.(10)
MACADAMEA NUT OIL 0 0 22.25 12.25 20.50 10.50 17.50 12.50 7.50 2.50
TOTAL 100 100 100 100 100 100 100 100 100 100 NOTE: .sup.(1)
Natural Capsaicin, Sigma Aldrich, Product # 360376, CAS # 404-86-4,
65% Capsaicin & 35% Dihydrocapsaicin .sup.(2) Trans-Capsaicin,
Aversion Technologies Inc., 95.7% Trans-Capsaicin, Balance
Cis-Capsaicin, Batch # 30111007N, USP 30 .sup.(3) Methyl
Salicylate, Spectrum Chemical, (NF, CAS # 119-36-8) .sup.(4)
L-Menthol, Crystal, Spectrum Chemical, USP, CAS # 2216-51-5
.sup.(5) Camphor, Synthetic, Spectrum Chemical, USP, CAS # 76-22-2
.sup.(6) Phenol, Liquefied, USP, Spectrum Chemical, CAS # 108-95-2
.sup.(7) Polysorbate 80, Super refined, Croda Inc., CAS # 9005-65-6
.sup.(8)Apigenin 98.sup.+%, Skyherb Technologies Co., Ltd, Lot #
0000418019 .sup.(9) White Flower Analgesic Balm, Contains 40%
Methyl Salicylate, 15% Menthol, 6% Camphor, 18% Eucalyptus Oil, 15%
Peppermint Oil, & 6% Lavender Oil .sup.(10) Macadamia Nut Oil,
Lotioncrafters Lot # 1506-3187
TABLE-US-00009 TABLE IIIB INGREDIENTS OF PREPARED ESSENTIAL
OIL-FREE CAPSAICIN FORMULATIONS Form Form Form Form .sup.(9) Form
.sup.(9) Form Form Form Form Form Form Form 1B 2B 3B 4B 5B 6B 7B 8B
9B 10B 11B 12B INGREDIENTS Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt %
Wt % Wt % Wt % Wt % .sup.(2) TRANS-CAPSAICIN 0 0.25 2.0 5.0 0 5.0 0
0.25 2.0 5.0 10 0 .sup.(2) ETHYL ALCOHOL 50 50 50 50 0 0 22.5 22.25
20.5 17.5 12.5 0 .sup.(3) METHYL SALICYLATE 0 0 0 0 50 50 50 50 50
50 50 50 .sup.(4) MENTHOL 15 15 15 15 15 15 15 15 15 15 15 15
.sup.(5) CAMPHOR 11 11 11 11 11 11 11 11 11 11 11 11 .sup.(6)
PHENOL 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 .sup.(7)
GLYCERIN, USP 22.5 22.25 20.5 17.5 22.5 17.5 0 0 0 0 0 0 .sup.(8)
MINERAL OIL, USP 0 0 0 0 0 0 0 0 0 0 0 22.5 TOTAL 100 100 100 100
100 100 100 100 100 100 100 100 NOTE: .sup.(1) Trans-Capsaicin,
Aversion Technologies Inc., 95.7% Trans-Capsaicin, Balance
Cis-Capsaicin, USP 30 .sup.(2) Ethyl Alcohol, Graves Grain Alcohol,
190 Proof .sup.(3) Methyl Salicylate, Spectrum Chemical, NF, CAS #
119-36-8 .sup.(4) L-Menthol, Crystal, Spectrum Chemical, USP, CAS #
2216-51-5 .sup.(5) Camphor, Synthetic, Spectrum Chemical, USP, CAS
# 76-22-2 .sup.(6) Phenol, Liquefied (Carbolic Acid), USP, Spectrum
Chemical, CA 108-95-2 .sup.(7) Glycerin, Lotioncrafters, USP, CAS #
56-81-5 .sup.(8) Mineral Oil, USP Grade, CVS .sup.(9) The shaded
highlighted columns, Form 5B & 6B, experienced phase
separation
[0194] In other embodiments, the formulation can be a spray or gel.
Topical compositions of the present invention can be formulated as
an emulsion using water and a surfactant or emulsifying system,
along with the liquid formulations discussed above.
Methods of Making the Formulations
[0195] Capsaicin, nonivamide, camphor and menthol are solids at
room temperatures with melting points of 60-62.degree. C.,
54.degree. C., 175-177.degree. C., and 42-45.degree. C.,
respectively. Significantly, methyl salicylate functions as the
prime solubilizing agent for the relatively aqueous insoluble solid
capsaicin, camphor and menthol ingredients. Methyl salicylate is a
liquid at room temperature (with a melting point of -9.degree. C.)
and with concentration levels up to 75 wt. %, is the formulation's
most concentrated ingredient. (As noted in Table III, the analgesic
agent concentration exceeded >50% for several of the
formulations.)
[0196] A series of solubility experiments verified that the
solubility levels of nonivamide in methyl salicylate exceeded 25
wt. %. The addition of nonivamide powder to the 30 wt. %
nonivamide/methyl salicylate solution at ambient temperature and
also cooling the 30 wt. % nonivamide/methyl salicylate solution to
-10.degree. C. for 10 hours did not result in the precipitation of
nonivamide thereby indicating the utility of the methyl salicylate
as a solvent. Further, there was no evidence of any precipitation
of nonivamide from the concentrated 30 wt. % nonivamide solution
after 2 weeks of storage at 5.degree. C. Similar results were
obtained with capsaicin.
[0197] Consequently, methyl salicylate functions as a primary
component in a mixture of compounds to: (1), solubilize appreciable
concentrations of the relatively aqueous insoluble capsaicin,
related capsaicinoids and other solid ingredients including menthol
and camphor; (2), penetrate the skin surface and underlying dermis
and epidermis; and (3), reduce or eliminate the burning and
stinging (B&S) sensation associated with the topical
administration of a capsaicinoid.
[0198] Initial capsaicin formulations with concentrations ranging
from 0.25-10.0 wt. % were prepared with White Flower Analgesic Balm
and apigenin/Polysorbate 80 concentrate as detailed in Example 1
below. White Flower Analgesic Balm consists of the ingredients:
Methyl Salicylate (Wintergreen Oil) 40%, Menthol 15%, Camphor 6%
and Eucalyptus Oil 18%, Peppermint Oil 15%, and Lavender Oil
6%.
[0199] Example 1 describes the preparation Formulation 2A (Table
IIIA) of a 1.8 wt. % Capsaicin, 0.75 wt. % Apigenin & White
Flower Analgesic Balm Formulation.
[0200] Example 2 describes the preparation of Formulation 9 (Table
III) containing a Nonivamide concentration of 1.8 wt. %.
[0201] Example 3 describes the preparation of Formulation 4 (Table
III) containing a Nonivamide concentration of 1.8 wt. %.
[0202] Example 4 describes the preparation of Formulation 11 (Table
III) containing a Nonivamide concentration of 0.25 wt. %.
[0203] Example 5 describes the preparation of Formulation 7A (Table
IIIA) containing a Trans-Capsaicin concentration of 5 wt. %.
[0204] Example 6 describes the preparation of Formulation 6A (Table
IIIA) containing a Trans-Capsaicin concentration of 2.0 wt. %.
[0205] Example 7 describes the preparation of Formulation 3B (Table
IIIB), an alcohol based formulation, containing a Trans-Capsaicin
concentration of 2.0 wt. %.
[0206] Example 8 describes the preparation of Formulation 9B (Table
IIIB) containing ethyl alcohol and a Trans-Capsaicin concentration
of 2.0 wt. %.
[0207] Example 9 describes methods of using the formulations.
[0208] Example 10 describes human skin tests of nonivamide and
trans-capsaicin formulations.
[0209] Example 11 describes treatment of shoulder pain with
trans-capsaicin 0.25% and 2.0% formulations.
[0210] Example 12 describes API-CAPS-001: a randomized,
single-blind, multiple dose study of the safety and tolerability of
API-CAPS in subjects with osteoarthritis of the knee.
[0211] Example 13 describes API-CAPS-004: 0.25% API-CAPS topical
treatment for osteoarthritis pain in hands and knees of adult
patients.
[0212] Example 14 describes API-CAPS-005: multiple dose case
studies of treatment with API-CAPS for pain from osteoarthritis in
the elderly.
[0213] Example 15 describes components elimination comparison.
[0214] Example 16 describes API-CAPS-002, cohort 1: 0.25% API-CAPS
(0.25% w/w trans-capsaicin, USP) & capzasin HP arthritis pain
relief analgesic cream (0.1% capsaicin).
[0215] Example 17 describes diclofenac solubility studies.
Methods of Using the Formulations
Pain
[0216] The compositions of the present invention discussed above
can be used for treating various conditions associated with pain by
attenuating pain at a specific site. The components of the
formulations are typically administered concomitantly. Examples of
conditions to be treated include, but are not limited to,
nociceptive pain (pain transmitted across intact neuronal
pathways), neuropathic pain (pain caused by damage to neural
structures), pain from nerve injury (neuromas and neuromas in
continuity), pain from neuralgia (pain originating from disease
and/or inflammation of nerves), pain from myalgias (pain
originating from disease and/or inflammation of muscle), pain
associated with painful trigger points, pain from tumors in soft
tissues, pain associated with neurotransmitter-dysregulation
syndromes (disruptions in quantity/quality of neurotransmitter
molecules associated with signal transmission in normal nerves) and
pain associated with orthopedic disorders such as conditions of the
foot, knee, hip, spine, shoulders, elbow, hand, head and neck.
[0217] Neuropathic pain generally involves abnormalities in the
nerve itself, such as degeneration of the axon or sheath. For
example, in certain neuropathies the cells of the myelin sheath
and/or Schwann cells may be dysfunctional, degenerative and may
die, while the axon remains unaffected. Alternatively, in certain
neuropathies just the axon is disturbed, and in certain
neuropathies the axons and cells of the myelin sheath and/or
Schwann cells are involved. Neuropathies may also be distinguished
by the process by which they occur and their location (e.g. arising
in the spinal cord and extending outward or vice versa). Direct
injury to the nerves as well as many systemic diseases can produce
this condition including AIDS/HIV, Herpes Zoster, syphilis,
diabetes, and various autoimmune diseases. Neuropathic pain is
often described as burning, or shooting type of pain, or tingling
or itching pain and may be unrelenting in its intensity and even
more debilitating than the initial injury or the disease process
that induced it.
[0218] The receptors involved in pain detection are aptly enough
referred to as nociceptor-receptors for noxious stimuli. These
nociceptors are free nerve endings that terminate just below the
skin as to detect cutaneous pain. Nociceptors are also located in
tendons and joints, for detection of somatic pain and in body
organs to detect visceral pain. Pain receptors are very numerous in
the skin, hence pain detection here is well defined and the source
of pain can be easily localized. In tendons, joints, and body
organs the pain receptors are fewer. The source of pain therefore
is not readily localized. Apparently, the number of nociceptors
also influences the duration of the pain felt. Cutaneous pain
typically is of short duration, but may be reactivated upon new
impacts, while somatic and visceral pain is of longer duration. It
is important to note that almost all body tissue is equipped with
nociceptors. As explained above, this is an important fact, as pain
has primary warning functions. Nociceptive pain preferably
includes, but is not limited to post-operative pain, cluster
headaches, dental pain, surgical pain, pain resulting from severe
burns, postpartum pain, angina, genitor-urinary tract pain, pain
associated with sports injuries (tendonitis, bursitis, etc.) and
pain associated with joint degeneration and cystitis.
[0219] Topical preparations of the compositions of the present
invention find use as a topical therapy for a variety of skin
disorders that involve pain and itching, such as postherpetic
neuralgia, diabetic neuropathy, psoriasis, cluster headache,
postmastectomy pain syndrome, rhinopathy, oral mucositis, cutaneous
allergy, detrusor hyperreflexia, loin pain/hematuria syndrome, neck
pain, amputation stump pain, reflex sympathetic dystrophy, pain due
to skin tumor and arthritis, including rheumatoid arthritis,
osteoarthritis, diabetic neuropathy, psoriasis, pruritus (itching),
cluster, headache, post-surgical pain, oral pain, and pain caused
by injury, amongst others. The formulations can be used to relieve
aches and pains of muscles and joints.
[0220] As used herein, a "therapeutically effective amount" refers
to the quantity or dose of an agent to produce a clinically desired
result such as a biological or chemical response, or reduction or
elimination of a symptom of a disease or condition, e.g. reduction
in or elimination of pain.
Administration
Topical
[0221] The composition of the present invention can be used
topically by rubbing over an area to be treated. A typical method
of use is to rub the formulation over the entire area, until the
formulation disappears, and use about 1 to 3 or 4 times daily.
Additionally, the amount of formulation used can be gradually
increased with each successive application. Topical administration
can continue for 1-7 days, weeks, or months.
[0222] In certain embodiments, the administration of a TRPV1
selective agonist, such as capsaicin, formulations at the discrete
site provides pain attenuation or pain relief for at least about 48
hours to about 16 weeks.
[0223] Several methods are available for the dispensing of the
capsaicin formulations on the skin's surface. TRPV1 selective
agonist containing formulation can be applied by physical means
including applicator pads, swabs, or other devices intended to
apply the formulations in a thin film such as roller bottles, felt
tip or sponge tip applicators.
Roller Bottles
[0224] For liquids formulations, dispensers can include bottles
with a constriction to facilitate fluid droplet application to the
skin. Especially advantageous for capsaicin containing liquid
formulations are tubes and/or bottles with a sponge or a `roll on`
applicator.
[0225] Roll on bottles (also referred to as roller bottles) are
especially advantageous. The roll on bottle greatly simplifies the
dispensing of the fluid on the skin's surface. No finger rubbing or
Q-tip application is required. The movement of the roller ball on
the skin massages the fluid into the skin.
[0226] The roll on bottle has a plastic, glass or metal roll on
ball and glass or suitable plastic housing. As the ball rolls it
picks up the solution and applies it to the skin's surface. The
caps of roll on bottles may contain a special ring on the inner
side. This ring presses on the ball when the cap is tightly shut.
The pressure on the ball prevents leakage of the product.
[0227] After filling the bottles, the roll on housing and ball are
fitted into the mouth of the bottle. The roll on housing and ball
is fitted by pushing the housing into the mouth of the bottle.
[0228] Precise control over where the formulation is applied
important. The roller-ball provides a more precise control where
the formulation is to be applied, to avoid contact with eyes,
contact lenses, tender skin, clothing, etc. The "roll on bottle"
minimizes the likelihood of causing lip and/or eye burning since
finger application is not required to spread a film of the
capsaicin solution on the body.
[0229] The roll on bottle configuration allows the TRPV1 selective
agonist compositions to be applied as a thin homogeneous film.
Generally, the application of a thin film formulation is rapidly
absorbed into the skin's surface following application. In several
embodiments, substantially complete disappearance of the film is
complete within 15 minutes following application, and more usually
within 10 minutes, or with some embodiments, even less than 5
minutes after application.
Intranasal
[0230] When used intranasally, capsaicin irritates the nasonasal
area. However, the area becomes desensitized to the irritation
after repeated use. Nerve endings responsible for rhinorrhea,
sneezing, and congestion become desensitized when capsaicin is
applied to the nasal mucosa. Capsaicin use has been targeted at
patients presenting congestion, rhinorrhea, sneezing, or a
combination of these symptoms. Clinical studies revealed a 60%
reduction in nasal airway resistance. In most patients,
effectiveness continued for more than 4 months.
Kits
[0231] The invention also includes kits comprising a liquid TRPV1
selective agonist composition, and
[0232] a non-occlusive applicator device. The kit can also include
a cleaning solution for removal of residual TRPV1 selective agonist
such as polyethylene glycol.
[0233] The present invention will be further understood after
careful consideration is given to the following non-limiting
examples thereof.
EXAMPLES
Example 1
Preparation of 100 Grams of the 1.8 wt. % Capsaicin, 0.75 wt. %
Apigenin & White Flower Analgesic Balm Formulation
Form 2A, TABLE IIIA
Step I--Preparation of the Apigenin/Polysorbate 80 (PS80)
Concentrate
Ingredients Include:
[0234] 9.25 grams of Super Refined PS80, CRODA, Inc. CAS #9005-65-6
[0235] 0.75 grams of Apigenin powder, Skyherbs Technologies Co.,
Lot #0000418019
Procedure:
[0235] [0236] 1. Add 9.25 grams of the Super Refined PS80 to a 50
cc "Pyrex" beaker. [0237] 2. Add 0.75 grams of Apigenin powder to
the PS80. [0238] 3. Heat the PS80/Apigenin mixture to a temperature
slightly in excess of .about.275.degree. C. At about 200.degree.
C., it will be observed that the mixture will take on a light
brown/reddish color which will darken when the Apigenin is
completely solubilized at .about.275.degree. C. [0239] 4. The
Apigenin/PS80 solution is set aside and allowed to cool to
<100.degree. C.
Step II--the Preparation of a Liquid Solution of Selected
Ingredients
Ingredients:
[0239] [0240] 88.2 grams of While Flower Analgesic Balm [0241] 1.8
grams of Capsaicin, Natural, Sigma Aldrich, CAS #404-86-4
Procedure:
[0241] [0242] 1. Obtain the "tare weight" of a .about.200 cc beaker
& add 88.2 grams of White Flower Analgesic Balm. [0243] 2. Add
1.8 grams of Capsaicin, Natural to the mixture from Step 1. Heat
the mixture to about 40 to 50.degree. C. to hasten the dissolving
of the Capsaicin powder. (Note: Adhere to safety precautions in the
handling of the powder. [0244] 3. Heat the above mixture to
.about.40.degree. C. to 50.degree. C. while stirring to hasten the
solution of the capsaicin. [0245] 4. Allow the solution mixture
from Step 3 to cool to room temperature.
Step III--the Combining of the Step I & II Solutions Mixtures
& Subsequent Centrifuging
Ingredients Include:
[0245] [0246] The solution mixture from STEP I [0247] The solution
mixture from STEP II.
Procedure:
[0247] [0248] 1. The Apigenin/PS80 solution from STEP I is added to
the solution mixture from STEP II and the combined mixture is
thoroughly stirred. [0249] 2. The solution mixture from Step 1 is
now ready to be centrifuged for 30 minutes in a MicroCentrifuge
with a fixed speed of 3,100 RPM for 30 minutes (A Thermo Fischer
Model 004480 F Microcentrifuge with slots for 6 15 ml centrifuge
tubes). The solution mixture from Step 1 is evenly divided amongst
the 15 ml centrifuge tubes which are placed within the centrifuge.
The centrifuge's timer is then set for 30 minutes which then
activates the spinning process. [0250] 3. At the conclusion of the
centrifugation process from Step 2, the supernatant liquid from
each of the centrifuge tubes is decanted into a 200 ml Pyrex
beaker. [0251] 4. The mixture from Step 3 is now ready for
subsequent packaging.
Example 2
Preparation of 100 Grams of the 1.8% Nonivamide/Apigenin
Formulation
Form 9, TABLE III
Step I--the Preparation of a Liquid Solution of Selected
Ingredients & Capsaicin
Ingredients:
[0251] [0252] 55 grams of NF grade Methyl Salicylate, Spectrum
Chemical, CAS #119-36-8 [0253] 10 grams of USP grade Camphor,
Spectrum Chemical, CAS #76-22-2 [0254] 1.8 grams of Nonivamide
obtained from Aversion Technologies CO.; Bowie, Md., CAS #2444-46-4
[0255] 20 grams of Ethyl Alcohol, Graves grain alcohol, 190
Proof
Procedure:
[0255] [0256] 1. Obtain the "tare weight" of a .about.200 cc beaker
& add 55 grams of NF grade Methyl Salicylate. [0257] 2. Add 10
grams of USP grade Camphor flakes to the mixture of Step 1. Heat
the mixture to .about.40.degree. C. to hasten the dissolving of the
Camphor flakes while stirring. [0258] 3. Add 1.8 grams of
Nonivamide to the mixture from Step 2. Heat the mixture to 40 to
50.degree. C. to hasten the dissolving of the Nonivamide powder.
(Note: Adhere to safety precautions in the handling of the powder.)
[0259] 4. Allow the solution mixture from Step 3 to cool to room
temperature and add 20 grams of Ethyl Alcohol.
Step II--the Addition of Other Ingredients to the Liquid Solution
from Step I
Ingredients Include:
[0259] [0260] The solution mixture from STEP I [0261] 13.2 grams of
Coconut Oil, Nature's Way EfaGold Coconut Oil, Pure Extra
Virgin
Procedure:
[0261] [0262] 1. Add 13.2 grams of the Aloe Vera Oil to the mixture
from Step I and thoroughly stir the resulting solution mixture. The
mixture is now ready for subsequent packaging.
Example 3
Preparation of 100 Grams of the 1.8% Nonivamide/Apigenin
Formulation
Form, 4 TABLE III
Step I--Preparation of the Apigenin/Polysorbate 80 (PS80)
Concentrate
Ingredients Include:
[0262] [0263] 9.25 grams of Super Refined PS80, CRODA, Inc. CAS
#9005-65-6 [0264] 0.75 grams of Apigenin powder, Skyherbs
Technologies Co., Lot #0000418019
Procedure:
[0264] [0265] 1. Add 9.25 grams of the Super Refined PS80 to a 50
cc "Pyrex" beaker. [0266] 2. Add 0.75 grams of Apigenin powder to
the PS80. [0267] 3. Heat the PS80/Apigenin mixture to a temperature
slightly in excess of .about.275.degree. C. At about 200.degree.
C., the it will be observed that the mixture will take on a light
brown/reddish color which will darken when the Apigenin is
completely solubilized at .about.275.degree. C. [0268] 4. The
Apigenin/PS80 solution is set aside and allowed to cool to
<100.degree. C.
Step II--the Preparation of the Selected Ingredients &
Nonivamide Mixture
Ingredients:
[0268] [0269] 35 grams of NF grade Methyl Salicylate, Spectrum
Chemical, CAS #119-36-8 [0270] 13 grams of USP grade Menthol,
Spectrum Chemical, CAS #2216-51-5 [0271] 9 grams of USP grade
Camphor, Spectrum Chemical, CAS #76-22-2 [0272] 1.8 grams of
Nonivamide obtained from Aversion Technologies Co.; Bowie, Md., CAS
#2444-46-4
Procedure:
[0272] [0273] 1. Obtain the "tare weight" of a .about.200 cc beaker
& add 35 grams of NF grade Methyl Salicylate [0274] 2. Add 13
grams of USP grade menthol crystals to the Methyl Salicylate (Step
1). [0275] 3. Add 9 grams of USP grade Camphor flakes to the
mixture of Step 2. Heat the mixture to .about.40.degree. C. to
hasten the dissolving of the menthol & Camphor while stirring.
[0276] 4. Add 1.8 grams of Nonivamide to the mixture from Step 3.
Heat the mixture to 40 to 50.degree. C. to hasten the dissolving of
the Nonivamide powder. (Note: Adhere to safety precautions in the
handling of the powder.)
Step III--the Combining of the Step I & II Solutions Mixtures
& Subsequent Centrifuging
Ingredients Include:
[0276] [0277] The solution mixture from STEP I [0278] The solution
mixture from STEP II.
Procedure:
[0278] [0279] 1. The Apigenin/PS80 solution from STEP I is added to
the solution mixture from STEP II and the combined mixture is
thoroughly stirred. [0280] 2. The solution mixture from Step 1 is
now ready to be centrifuged for 30 minutes in a MicroCentrifuge
with a fixed speed of 3,100 RPM for 30 minutes (A Thermo Fischer
Model 004480 F Microcentrifuge with slots for 6 15 ml centrifuge
tubes). The solution mixture from Step 1 is evenly divided amongst
the 15 ml centrifuge tubes which are placed within the centrifuge.
The centrifuge's timer is then set for 30 minutes which then
activates the spinning process. [0281] 3. At the conclusion of the
centrifugation process from Step 2, the supernatant liquid from
each of the centrifuge tubes is decanted into a 200 ml Pyrex
beaker.
Step IV--the Addition of Other Ingredients to the Supernatant
Liquid from Step III
Ingredients Include:
[0281] [0282] The solution mixture from STEP III [0283] 1 gram of
Apha Bisabolol Natural, Aloha Aesar, CAS #515-69-5 [0284] 1.5 grams
of Liquefied Phenol USP grade, Spectrum Chemical, CAS #108-95-2
[0285] 28.7 grams of Aloe Vera Oil, Spectrum Chemical, Product #
A1612, CAS #85507-69
Procedure:
[0285] [0286] 1. Add 1 gram of Alpha Bisabolol Natural to the
solution mixture from STEP III. [0287] 2. Add 1.5 grams of
Liquefied Phenol USP grade to the solution mixture from Step 1 and
stir the resulting solution mixture. [0288] 3. Add 28.7 grams of
Aloe Vera Oil to the mixture from Step 2 and thoroughly stir the
resulting solution mixture. [0289] 4. The mixture from Step 3 is
now ready for subsequent packaging.
Example 4
Preparation of 100 Grams of the 0.25% Nonivamide/Apigenin
Formulation
Form 11, TABLE III
Step I--the Preparation of a Liquid Solution of Selected
Ingredients & Capsaicin
Ingredients:
[0289] [0290] 45 grams of NF grade Methyl Salicylate, Spectrum
Chemical, CAS #119-36-8 [0291] 15 grams of USP grade Menthol,
Spectrum Chemical, CAS #2216-51-5 [0292] 10 grams of USP grade
Camphor, Spectrum Chemical, CAS #76-22-2 [0293] 2 grams of
Liquefied Phenol U.S.P., Spectrum Chemical, CAS #108-95-2 [0294]
1.8 grams of Nonivamide, Aversion Technologies Co.; Bowie, Md., CAS
#2444-46-4 [0295] 10 grams of Ethyl Alcohol, Graves grain alcohol,
190 Proof
Procedure:
[0295] [0296] 1. Obtain the "tare weight" of a .about.200 cc beaker
& add 45 grams of NF Methyl Salicylate. [0297] 2. Add 15 grams
of USP grade Menthol flakes to the mixture of Step 1. [0298] 3. Add
10 grams of USP grade Camphor flakes to the mixture of Step 2. Heat
the mixture to .about.40.degree. C. to hasten the dissolving of the
Camphor flakes while stirring. [0299] 4. Add 2 grams of USP grade
Liquefied Phenol to the mixture of Step 3. [0300] 5. Add 1.8 grams
of Nonivamide to the mixture from Step 4. Heat the mixture to 40 to
50.degree. C. to hasten the dissolving of the Nonivamide powder.
(Note: Adhere to safety precautions in the handling of the powder.)
[0301] 6. Allow the solution mixture from Step 5 to cool to room
temperature and add 20 grams of Ethyl Alcohol.
Step II--the Addition of Other Ingredients to the Liquid Solution
from Step I
Ingredients Include:
[0301] [0302] The solution mixture from STEP I [0303] 17.75 grams
of Coconut Oil, Nature's Way EfaGold Coconut Oil, Pure Extra
Virgin
Procedure:
[0303] [0304] 1. Add 17.75 grams of Aloe Vera Oil to the mixture
from Step I and thoroughly stir the resulting solution mixture. The
mixture is now ready for subsequent packaging.
Example 5
Preparation of 100 Grams of the 5.0% Trans-Capsaicin
Formulation
Form 7A, TABLE IIIA
STEP I--The Blending of the Ingredients to Produce the 5.0%
Capsaicin Formulation
Ingredients:
[0304] [0305] 50.0 grams of Methyl Salicylate, Spectrum Chemical,
NF, CAS #119-36-8 [0306] 15.0 grams of Menthol, Crystal, Spectrum
Chemical, USP, CAS #2216-51-5 [0307] 11.0 grams of Camphor,
Spectrum Chemical, USP, CAS #76-22-2 [0308] 1.5 grams of Liquefied
Phenol, Spectrum Chemical, CAS #108-95-2 [0309] 5.0 grams of
Trans-Capsaicin Powder, Aversion Technologies, Bowie, Md., USP 30
[0310] 17.5 grams of Macadamia Nut Oil, Lotioncrafters Lot
#1506-3187
Procedure:
[0310] [0311] 1. Add 50.0 grams of NF grade Methyl Salicylate to
250 cc "Pyrex" beaker. [0312] 2. Add 15.0 grams of USP grade
Menthol Crystals to the Methyl Salicylate in Step 1. [0313] 3. Add
11.0 grams of Camphor flakes to the mixture in Step 2. [0314] 4.
Heat the above mixture to .about.50.degree. C. to 60.degree. C.
while stirring to hasten the solution of the solid Menthol &
Camphor. [0315] 5. Add 5.0 grams of Trans-Capsaicin to the heated
mixture from Step 5 while gently stirring to solubilize the
Trans-Capsaicin. [0316] 6. Allow the solution from Step 5 to cool
to .about.30.degree. C. to 35.degree. C. & then add 1.5 grams
of Liquefied Phenol to the solution. [0317] 7. Add 17.5 grams of
Macadamia Nut Oil to the solution from Step 6 & thoroughly
stir. [0318] 8. Set aside the mixture & allow it to cool to
ambient temperatures. [0319] 9. The mixture from Step 8 is now
ready for subsequent packaging.
Example 6
Preparation of 100 Grams of the 2.0% Trans-Capsaicin/Apigenin
Form 6A, TABLE IIIA
Ingredients Include:
[0319] [0320] 9.25 grams of a Super Refined PS80, CRODA, Inc., CAS
#9005-65-6 [0321] 0.75 grams of Apigenin powder, Skyherbs
Technologies Co., Lot #0000418019
Procedure:
[0321] [0322] 1. Add 9.25 grams of the highly purified PS80 to a 50
cc "Pyrex" beaker. [0323] 2. Add 0.75 grams of Apigenin powder to
the PS80. [0324] 3. Heat the PS80/Apigenin mixture to a temperature
slightly in excess of .about.275.degree. C. At about 200.degree.
C., the it will be observed that the mixture will take on a light
brown/reddish color which will darken when the Apigenin is
completely solubilized at .about.275.degree. C. [0325] 4. The
Apigenin/PS80 solution is set aside and allowed to cool to
<100.degree. C.
STEP II--the Blending of the Ingredients to Produce the 5.0%
Capsaicin Formulation
Ingredients:
[0325] [0326] 50.0 grams of Methyl Salicylate, Spectrum Chemical,
NF, CAS #119-36-8 [0327] 15.0 grams of Menthol, Crystal, Spectrum
Chemical, USP, CAS #2216-51-5 [0328] 11.0 grams of Camphor,
Spectrum Chemical, USP, CAS #76-22-2 [0329] 1.5 grams of Liquefied
Phenol, Spectrum Chemical, CAS #108-95-2 [0330] 5.0 grams of
Trans-Capsaicin Powder, Powder, Aversion Technologies, Bowie, Md.,
USP 30 [0331] 17.5 grams of Macadamia Nut Oil, Lotioncrafters Lot
#1506-3187 [0332] 10.0 grams of Apigenin/Polysorbate 80 Concentrate
from STEP I.
Procedure:
[0332] [0333] 1. Add 50.0 grams of NF grade Methyl Salicylate to
250 cc "Pyrex" beaker. [0334] 2. Add 15.0 grams of USP grade
Menthol Crystals to the Methyl Salicylate in Step 1. [0335] 3. Add
11.0 grams of Camphor flakes to the mixture in Step 2. [0336] 4.
Heat the above mixture to .about.50.degree. C. to 60.degree. C.
while stirring to hasten the solution of the solid Menthol &
Camphor. [0337] 5. Add 5.0 grams of Trans-Capsaicin to the heated
mixture from Step 4 while gently stirring to solubilize the
Trans-Capsaicin. [0338] 6. Allow the solution from Step 5 to cool
to .about.30.degree. C. to 35.degree. C. & then add 1.5 grams
of Liquefied Phenol to the solution. [0339] 7. Add 17.5 grams of
Macadamia Nut Oil to the solution from Step 6 & thoroughly
stir. [0340] 8. Add the 10 grams of the Apigenin/Polysorbate
Concentrate from STEP I to the solution from Step 7 and thoroughly
stir. [0341] 9. Set aside the mixture from Step 8 & allow it to
cool to ambient temperatures. [0342] 10. The mixture from Step 9 is
now ready for subsequent packaging.
Example 7
Preparation of 100 Grams of the 2.0% Trans-Capsaicin/50% Ethyl
Alcohol/20.5% Glycerin Formulation
Form 3B, TABLE IIIB
STEP I--The Blending of the Ingredients to Produce the 5.0%
Capsaicin Formulation
Ingredients:
[0342] [0343] 50.0 grams of Ethyl Alcohol, Graves Grain Alcohol,
190 Proof [0344] 15.0 grams of Menthol, Crystal, Spectrum Chemical,
USP, CAS #2216-51-5 [0345] 11.0 grams of Camphor, Spectrum
Chemical, USP, CAS #76-22-2 [0346] 1.5 grams of Liquefied Phenol,
Spectrum Chemical, CAS #108-95-2 [0347] 2.0 grams of
Trans-Capsaicin Powder, Powder, Aversion Technologies, Bowie, Md.,
USP 30 [0348] 20.5 grams of Glycerin, Lotioncrafters, USP CAS
#56-81-5
Procedure:
[0348] [0349] 1. Add 50.0 grams of Ethyl Alcohol to 250 cc "Pyrex"
beaker. [0350] 2. Add 15.0 grams of USP grade Menthol Crystals to
the Methyl Salicylate in Step 1. [0351] 3. Add 11.0 grams of
Camphor flakes to the mixture in Step 2. [0352] 4. Heat the above
mixture to .about.40.degree. C. to 50.degree. C. while stirring to
hasten the solution of the solid Menthol & Camphor. [0353] 5.
Add 2.0 grams of Trans-Capsaicin to the heated mixture from Step 5
while gently stirring to solubilize the Trans-Capsaicin. [0354] 6.
Allow the solution from Step 5 to cool to .about.30.degree. C. to
35.degree. C. & then add 1.5 grams of Phenol to the solution.
[0355] 7. Add 20.5 grams of Glycerin to the solution from Step 6
& thoroughly stir. [0356] 8. Set aside the mixture & allow
it to cool to ambient temperatures. [0357] 9. The mixture from Step
8 is now ready for subsequent packaging.
Example 8
Preparation of 100 Grams of the 2.0% Trans-Capsaicin/50% Methyl
Salicylate/20.5% Ethyl Alcohol Formulation
Form 9B, TABLE IIIB
STEP I--The Blending of the Ingredients to Produce the 5.0%
Capsaicin Formulation
Ingredients:
[0357] [0358] 50.0 grams of Methyl Salicylate, Spectrum Chemical,
NF, CAS #119-36-8 [0359] 15.0 grams of Menthol, Crystal, Spectrum
Chemical, USP, CAS #2216-51-5 [0360] 11.0 grams of Camphor,
Spectrum Chemical, USP, CAS #76-22-2 [0361] 1.5 grams of Liquefied
Phenol, Spectrum Chemical, CAS #108-95-2 [0362] 2.0 grams of
Trans-Capsaicin Powder, Powder, Aversion Technologies, Bowie, Md.,
USP 30 [0363] 20.5 grams of Ethyl Alcohol, Graves Grain Alcohol,
190 Proof
Procedure:
[0363] [0364] 1. Add 50.0 grams of Methyl Salicylate to 250 cc
"Pyrex" beaker. [0365] 2. Add 15.0 grams of USP grade Menthol
Crystals to the Methyl Salicylate in Step 1. [0366] 3. Add 11.0
grams of Camphor flakes to the mixture in Step 2. [0367] 4. Heat
the above mixture to .about.40.degree. C. to 50.degree. C. while
stirring to hasten the solution of the solid Menthol & Camphor.
[0368] 5. Add 2.0 grams of Trans-Capsaicin to the heated mixture
from Step 5 while gently stirring to solubilize the
Trans-Capsaicin. [0369] 6. Allow the solution from Step 5 to cool
to .about.30.degree. C. to 35.degree. C. & then add 1.5 grams
of Phenol to the solution. [0370] 7. Add 17.5 grams of Ethyl
Alcohol to the solution from Step 6 & thoroughly stir. [0371]
8. Set aside the mixture & allow it to cool to ambient
temperatures. [0372] 9. The mixture from Step 8 is now ready for
subsequent packaging.
Example 9
Human Skin Test of Natural Capsaicin, Nonivamide and
Trans-Capsaicin Formulations
First Test--OTC "CapZasin" and Nonivamide
[0373] Adult male and female of normal health tested the following
formulations:
[0374] Formulation #1. OTC "CAPZASIN" containing 0.15% natural
capsaicin (in roll-on dispenser)
[0375] Formulation #2. OTC "CAPZASIN" 0.10 natural capsaicin
(cream)
[0376] Formulation #3. 0.25% Nonivamide concentration, Formulation
12, TABLE III (45% methyl salicylate, 15% menthol, 10% camphor,
9.25% PS80, 0.75% apigenin, 10% ethyl alcohol, 7.75% coconut
oil)
[0377] Formulation #4. 1.8% Nonivamide concentration, Formulation
4, TABLE III, (35% methyl salicylate, 13% menthol, 9% camphor,
9.25% PS80, 0.75% apigenin, 1.5% phenol, 1% alpha bisabolol, 28.7%
aloe vera oil)
[0378] Subjects applied the above formulations to the topside
(dorsal) of the right forearm.
[0379] After 30 minutes Subject A reported most S&B from
Formulation #1 while Subject B reported most S&B from
formulation #2. Subjects A & B reported no S&B, during the
first 30 minute period for Formulations #3 & #4.
[0380] After 60 minutes Subject A reported most S&B from
Formulation #1 while Subject B reported most S&B from
formulation #2. Subjects A & B reported no S&B, during the
first 60 minute period for Formulations #3 & #4.
[0381] After 90 minutes Subject A reported most S&B from
Formulation #1 while Subject B reported most S&B from
formulation #2. After 90 minutes Subject A reported redness of skin
along with S&B from Formulation #1 and redness of skin without
S&B from Formulation #4. After 90 minutes Subject B did not
report any redness of skin.
[0382] After 90 minutes Subject A washed off all formulations with
rubbing alcohol. While showering 24 hours later, Subject A still
felt some S&B from formulation #1.
[0383] Both Subjects A & B, using a scale of 1-10 with 10 being
the most S&B, reported a maximum level of 2-3 for the above
trial during the first 90 minute period for Formulations #1 &
#2. Both Subjects A & B reported no S&B, during the first
90 minute period for Formulations #3 & #4.
[0384] Subject B did NOT wash off the formulations at all and 12
hours later, still felt some S&B from Formulations #1 & #2.
Subject B 12 hours later still felt some S&B from Formulations
#1 & #2 at level 3.
[0385] After 24 hours, Subject A still felt some S&B from
formulations #1 & at level 2. After 24 hours, both Subjects A
& B reported no S&B for formulations #3 & #4.
Second Test--Trans-Capsaicin at 5%, 10% and 15% (Formulations 7A,
8A & 9A TABLE IIIA)
[0386] Same adult male and female subjects of normal health (A and
B) also tested the following Trans-Capsaicin formulations (referred
to here as "Capsaicin"):
[0387] 1. 5% Capsaicin concentration (50% methyl salicylate, 15%
menthol, 11% camphor, 17.5% macadamia nut oil, 1.5% phenol)
[0388] 2. 10% Capsaicin concentration (50% methyl salicylate, 15%
menthol, 11% camphor, 12.5% macadamia nut oil, 1.5% phenol)
[0389] 3. 15% Capsaicin concentration (50% methyl salicylate, 15%
menthol, 11% camphor, 7.5% macadamia nut oil, 1.5% phenol)
[0390] Each subject applied the above formulations to the topside
(dorsal) of the left forearm. "Stinging & Burning" sensations
(S&B) were rated on a scale of 0 to 10. Erythema (reddening)
observations were rated on a scale of 0 to 5 (0 being no
erythema):
After 10 Minutes:
[0391] Subject A reported:
[0392] S&B (stinging and burning) of 1 with a 5% Capsaicin
concentration
[0393] S&B of 2 with a 10% Capsaicin concentration
[0394] S&B of 1 with a 15% Capsaicin concentration
[0395] Erythema of 0 (zero) with all three Capsaicin
concentrations
[0396] Subject B reported:
[0397] S&B of 2 with a 5% Capsaicin concentration
[0398] S&B of 2 with a 10% Capsaicin concentration
[0399] S&B of 2 with a 15% Capsaicin concentration
[0400] Erythema of 0 (zero) with all three Capsaicin
concentrations
After 20 Minutes:
[0401] Subject A reported:
[0402] S&B of 1 with a 5% Capsaicin concentration
[0403] S&B of 2 with a 10% Capsaicin concentration
[0404] S&B of 1 with a 15% Capsaicin concentration
[0405] Erythema of 0 (zero) with 5% Capsaicin concentration
[0406] Erythema of 1 with both 10% & 15% Capsaicin
concentrations
[0407] Subject B reported:
[0408] S&B of 2 with a 5% Capsaicin concentration
[0409] S&B of 2 with a 10% Capsaicin concentration
[0410] S&B of 2 with a 15% Capsaicin concentration
[0411] Erythema of 0 (zero) with all three Capsaicin
concentrations
After 30 Minutes:
[0412] Subject A reported:
[0413] S&B of 0 (zero) with a 5% Capsaicin concentration
[0414] S&B of 2 with a 10% Capsaicin concentration
[0415] S&B of 1 with a 15% Capsaicin concentration
[0416] Erythema of 0 (zero) with 5% Capsaicin concentration
[0417] Erythema of 2 with both 10 & 15% Capsaicin
concentrations
[0418] Subject B reported:
[0419] S&B of 2 with a 5% Capsaicin concentration
[0420] S&B of 2 with a 10% Capsaicin concentration
[0421] S&B of 2 with a 15% Capsaicin concentration
[0422] Erythema of 0 (zero) with all three Capsaicin
concentrations
After 40 Minutes:
[0423] Subject A reported:
[0424] S&B of 0 (zero) with a 5% Capsaicin concentration
[0425] S&B of 1 with a 10% Capsaicin concentration
[0426] S&B of 1 with a 15% Capsaicin concentration
[0427] Erythema of 0 (zero) with 5% Capsaicin concentration
[0428] Erythema of 2 with both 10 & 15% Capsaicin
concentrations
[0429] Subject B reported:
[0430] S&B of 1 with a 5% Capsaicin concentration
[0431] S&B of 1 with a 10% Capsaicin concentration
[0432] S&B of 1 with a 15% Capsaicin concentration
[0433] Erythema of 0 (zero) with all three Capsaicin
concentrations
After 50 Minutes:
[0434] Subject A reported:
[0435] S&B of 0 (zero) with a 5% Capsaicin concentration
[0436] S&B of 0 (zero) with a 10% Capsaicin concentration
[0437] S&B of 0 (zero) with a 15% Capsaicin concentration
[0438] Erythema of 0 (zero) with 5% Capsaicin concentration
[0439] Erythema of 1 with both 10% & 15% Capsaicin
concentrations
[0440] Subject B reported:
[0441] S&B of 0 (zero) with a 5% Capsaicin concentration
[0442] S&B of 0 (zero) with a 10% Capsaicin concentration
[0443] S&B of 0 (zero) with a 15% Capsaicin concentration
[0444] Erythema 0 (zero) with all three Capsaicin
concentrations
After 90 Minutes:
[0445] Subject A reported:
[0446] S&B of 0 (zero) with a 5% Capsaicin concentration
[0447] S&B of 1 with a 10% Capsaicin concentration
[0448] S&B 0 (zero) with a 15% Capsaicin concentration
[0449] Erythema of 0 (zero) with 5% Capsaicin concentration
[0450] Erythema of 1 with both 10% & 15% Capsaicin
concentrations
[0451] Subject B reported:
[0452] S&B of 0 (zero) with a 5% Capsaicin concentration
[0453] S&B of 0 (zero) with a 10% Capsaicin concentration
[0454] S&B of 0 (zero) with a 15% Capsaicin concentration
[0455] Erythema 0 (zero) with all three Capsaicin
concentrations
After 150 minutes:
[0456] Subject A reported:
[0457] S&B of 1 with a 5% Capsaicin concentration
[0458] S&B of 2 with a 10% Capsaicin concentration
[0459] S&B of 2 with a 15% Capsaicin concentration
[0460] Erythema of 0 (zero) with 5% Capsaicin concentration
[0461] Erythema 1 with both 10% & 15% Capsaicin
concentrations
[0462] Subject B reported:
[0463] S&B of 2 with a 5% Capsaicin concentration
[0464] S&B of 2 with a 10% Capsaicin concentration
[0465] S&B of 2 with a 15% Capsaicin concentration
[0466] Erythema of 0 (zero) with all three Capsaicin
concentrations
[0467] After 150 minutes: residual formulations were washed-off the
skin using soap and cold water.
Example 10
Human Skin Tests of Nonivamide and Trans-Capsaicin Formulations
Nonivamide Formulation (Formulation 13, TABLE III)
5% Nonivamide
[0468] 50-year old male of normal health applied single topical
application of 5.0% nonivamide solution (50% methyl salicylate, 15%
menthol, 11% camphor, 9.25% PS80, 0.75% apigenin, 6% macadamia nut
oil, 2% phenol, 1% alpha bisabolol) for 90 minutes prior to washing
off with soap and water.
[0469] A single application of formulation via several passes from
a roller-ball bottle was made to a 50 cm.sup.2 area (7 cm.times.7
cm) of skin on subject's arm, 20 cm above the elbow joint on the
top side of subject's left arm. Stinging and Burning sensations
(S&B) were rated on a scale of 0-10. Erythema (reddening) was
rates on a scale of 0-5 (0 no erythema).
[0470] Subject observed a gradual onset of a slight, but tolerable,
burning sensation over the first 20 minutes following application.
Maximum irritation (S&B) rated at 2.5 (on a scale of 0 to 10)
was observed after 20 minutes. This 2.5 irritation level continued
for 20 minutes until the 40-minute mark. From the 40 minute mark to
the 60 minute mark, the subject observed a gradual reduction of
irritation such that as of the 60 minute mark the irritation level
was a 1.5 rating (on a scale of 0 to 10). Complete cessation of
irritation had occurred by the 80-minute mark. All levels of
irritation were considered to be well within a "tolerable" level
for topical use in subject's opinion.
[0471] In addition, reddening (erythema) and subsequent cessation
of reddening of the entire 50 cm.sup.2 application area was
observed over the initial 90 minute period of application. Subject
observed a reddening rated of a 1 (on a scale of 0 to 5) after 5
minutes, to a rating of 2 after 10 minutes, and a rating of 3 after
15 minutes. The 3 rating was the maximum observed and continued at
this level for 25 minutes until the 40 minute mark. Reddening
gradually lessened beginning after the 40-minute mark and was
completely gone after 70 minutes following application. Reddening
was uniform and no blotching or other form of inconsistent effect
was observed. By the 20-minute mark, the area of reddening had
expanded beyond the 50 cm.sup.2 application area by 1.5 cm in all
directions to encompass a total area of reddening of 72 cm.sup.2.
This was deemed due to the spreading of the formulation over the
surface of the skin outside the original application site.
Finalgon--European OTC Product (0.4% Nonivamide)
[0472] For comparison purposes, subject applied a European OTC
Nonivamide product called Finalgon which contains a Nonivamide
concentration of 0.4%. In this application of 0.4% Finalgon subject
(50 year old male of normal health) observed a relatively intense
burning sensation which was significantly greater than that which
occurred with the application of 5.0% Nonivamide of the invention,
Subject rated the Finalgon-induced burning sensation at a 5 to 6
(on the same scale of 0 to 10) 30 minutes after application. In
addition, a more severe form of erythema was experienced on the
Finalgon area of application relative to the 5.0% Nonivamide
formulation of the invention. Subject rated the Finalgon-induced
erythema at a 4 (on the same scale of 0 to 5 used to estimate
erythema) 30 minutes after application. Subject believed the
S&B and erythema were "intolerable" 30 minutes following
application and Finalgon was washed off at that point.
Trans-Capsaicin Formulations
5% Trans-Capsaicin Formulation 7A, Table IIIA
[0473] A 50-year old male of normal health applied a single topical
application of 5% trans-capsaicin (50% methyl salicylate, 15%
menthol, 11% camphor, 17.5% macadamia nut oil, 1.5% phenol)
solution for 120 minutes prior to washing off.
[0474] Application of the formulation via a 10 ml roller-ball
bottle on a 50 cm.sup.2 (7 cm.times.7 cm) area of skin arm, 20 cm
below the elbow joint on the underside (ventral) of subject's right
forearm (a relatively sensitive area of skin). Several passes of
the roller-ball were undertaken to cover the entire 50 cm.sup.2
application area.
[0475] Subject observed a gradual onset of a mild, but tolerable,
burning sensation over the first 20 minutes following application.
This irritation was observed and rated (on a scale of 0-10) to be a
1 after 2 minutes, a 2 after 5 minutes and a 3 after 20 minutes.
Maximum irritation rated at a 3 was observed after 20 minutes. This
irritation rating of a 3 irritation continued for only 10 minutes
until the 30-minute mark. The irritation level had decreased to a
rating of 2 by the 40 minute mark. From the 40-minute mark to the
80-minute mark, the subject observed a gradual reduction of
irritation, which was observed to be reduced from a 2 rating to a
0.5 rating (on a scale of 0-10) over this period. Complete
cessation of irritation occurred at the 120 minute mark. All levels
of irritation were considered to be well within a "tolerable" level
for topical use in subject's opinion.
[0476] In addition, reddening (erythema) and the subsequent
cessation of reddening of the entire 50 cm.sup.2 application area
was observed over the initial 90 minute period following
application. Subject observed a reddening rated at a 1 (on a scale
of 0-5) after 10 minutes, to a rating of 1.5 after 20 minutes, and
a rating of 2 after 30 minutes. This reddening rating of 2 was the
maximum level observed and lasted from the 30 minute mark until the
60 minute mark. Reddening gradually lessened after the 60-minute
mark and was completely gone after 120 minutes following
application. Reddening was uniform and no blotching or other form
of inconsistent effect was observed. By the 20-minute mark, the
area of reddening had expanded beyond the 50 cm.sup.2 application
area by 1.5 cm in all directions to encompass a total area of
reddening of 72 cm.sup.2 due to the spreading of the formulation
over the surface of the skin outside of the original application
site.
[0477] After 20 minutes, the skin area of application became more
sensitive to touch. Sensitivity to touch decreased after 60
minutes.
0.1% and 0.15% OTC Product Trans-Capsaicin Formulations
First Test:
[0478] For comparison purposes, subject (50 year old male) had
previously applied two U.S. OTC products which each contain
capsaicin as its active ingredient. These two OTC products were
CAPZASIN-HP (containing 0.1% capsaicin) and GELLERT Joint Care
(containing 0.17% capsaicin). Products were both creams and were
applied to the inner (ventral) side of subject's left arm (a
relatively sensitive area of skin). The application of 0.1%
CAPZASIN-HP and 0.17% GELLERT Joint Care caused subject a burning
sensation which was about the same as that observed for application
of 5.0% Trans-Capsaicin. For 0.1% CAPZASIN-HP and GELLERT Joint
Care the burning sensation was rated at a 2.5 and a 3 respectively
(on the same scale of 0 to 10 used to estimate burning/S&B in
5% Trans-Capsaicin formulation) 30 minutes after application.
Subject considered the burning irritation from both U.S. OTC
products to be "intense" yet still within a "tolerable" level for
topical use. A slight erythema was observed for both U.S. OTC
products. Subject rated erythema in both cases at a 1 (on the same
scale of 0 to 5 used to estimate erythema) 30 minutes after
application.
Second Test:
[0479] Subject applied the same two OTC products tested above a
second time, but this time on a different area of the skin.
CAPZASIN-HP (containing 0.1% capsaicin) and GELLERT Joint Care
(containing 0.17% capsaicin) are both creams and were applied to
the inner (ventral) side of subject's lower left leg. After 20
minutes CAPZASIN-HP and GELLERT Joint Care had a burning sensation
rating of a 1 and a 2, respectively (on the same scale of 0 to 10
used to estimate burning/S&B in 5% Trans-Capsaicin
formulation). After 30 minutes each had a burning rating of a 1.5
and 2.5 respectively (the maximum observed for each). From the 30
minute mark to the 90 minute mark both OTC products showed a
gradual lessening of the burning sensation such that none was
observed by the 90 minute mark in both products. Leg was tanned and
no erythema (rating 0) was observed.
10% Trans-Capsaicin Formulation 8A, TABLE IIIA
[0480] A 50-year old male of normal health applied a single topical
application of 10% trans-capsaicin ((50% methyl salicylate, 15%
menthol, 11% camphor, 12.5% macadamia nut oil, 1.5% phenol))
solution for 120 minutes prior to washing off.
[0481] Application of formulation via 10 mg roller-ball bottle was
undertaken to achieve an initial dosing on a 50 cm.sup.2 (7
cm.times.7 cm) area of skin on his arm, 20 cm below the elbow joint
on the underside of his left arm. Several passes of the roller-ball
were undertaken to the entire 20 cm.sup.2 application area.
[0482] Subject observed a slight itching a minute after
application. Subject noticed a gradual increase in burning
sensation over the first 20 minutes until a burning level of 2 (on
a scale of 0-10) was observed at the 20 minute mark. The burning
sensation remained at a 2 level for 10 minutes until the 30 minute
mark. At the 40 minute mark, the burning sensation level had
increased to a 2.5, where it remained for 20 minutes until the 60
minute mark. Maximum irritation was rated at a 2.5 (on a scale of
0-10). At the 90-minute mark the burning sensation had dropped to a
2 level. From that point forward subject observed a gradual
reduction of irritation. The burning sensation level had decreased
to a rating of 1 (on a scale of 0-10) by the 120-minute mark. By
the 180-minute mark, the subject noted that the irritation was no
more than a 0.5 rating. All levels of irritation were considered to
be well within a "tolerable" level for topical use in subject's
opinion.
[0483] In addition, reddening (erythema) and cessation of reddening
of the entire 50 cm.sup.2 application area was observed over a 180
minute period following application. Subject observed a reddening
rated at 0.5 (on a scale of 0-5) after 10 minutes, to a rating of
1.5 after 20 minutes, a rating of 2.5 after 30 minutes and a rating
of 3 after 60 minutes. This reddening rating of 3 was the maximum
level. After the 60 minute mark, the reddening gradually lessened
and was completely gone after 180 minutes following application.
Reddening was uniform and no blotching or other form of
inconsistent effect was observed.
[0484] By the 20 minute mark, the area of reddening had expanded
beyond the 50 cm.sup.2 application area by 1.5 cm in all directions
to encompass a total area of reddening of 72 cm.sup.2.
[0485] The area became sensitive to the touch after the 15 minute
mark. This sensitivity increased and eventually subsided over time
and intensity in a manner that was consistent with the observation
of erythema.
10% Trans-Capsaicin Formulation with Ethanol and Methyl Salicylate
Formulation 11B, TABLE IIIB
[0486] A normally healthy 50-year old male applied a single topical
application of a 10% Trans-Capsaicin (50% methyl salicylate, 15%
menthol, 11% camphor, 1.5% phenol, 12.5% ethyl alcohol) solution
for 80 minutes prior washing off the residual formulation from the
application area.
[0487] The liquid formulation was applied to a 50 cm.sup.2 (7
cm.times.7 cm) area of skin on the left shoulder via all) ml
roller-ball bottle. Absorption of the formulation was almost
immediate and the area of skin to which formulation was applied was
almost dry after one minute, and completely dry after two
minutes.
[0488] A minute after application, subject noted a slight itching
on the application area. Subject noticed a gradual increase in
burning sensation over the first 10 minutes. On a scale of (0-10),
the subject indicated a burning (S&B) level of 1 at the 10
minute mark. The burning sensation remained relatively constant at
a 1 level for the next 40 minutes (i.e., from the 10 to 50 minute
mark. At the 60 minute mark the burning sensation had dropped to a
0.5 level. By the 80-minute mark, the subject noted that the
irritation was gone, and the recordation was ended. The subject
indicated that the maximum irritation (S&B) was rated at a 1.0
(on a scale of 0-10) and that all levels of irritation were
considered to be well within a "tolerable" level for topical use in
subject's opinion, and in fact hardly noticeable.
[0489] Additionally, minimal reddening (erythema) of the entire 50
cm.sup.2 application area was observed over the 80 minute duration
following application. The subject indicated a reddening level at
0.5 (on a scale of 0-5) after 5 minutes, which gradually increased
to a 1.0 after 10 minutes, a 1.5 after 20 minutes. This reddening
rating of 1.5 was the maximum level observed. At the 60 minute
mark, the reddening had gradually decreased to a level of 0.5, and
remained constant at 0.5 when recordation was ended 80 minutes
following application. Reddening was uniform and no blotching was
observed, The subject observed that the area of erythema did not
spread beyond the application area.
Example 11
Treatment of Shoulder Pain with Trans-Capsaicin 0.25% and 2.0%
Formulations
Formulations 3A & 5A, TABLE IIIA
[0490] A 57-year old male of normal health applied multiple topical
applications of 0.25% trans-capsaicin (50% methyl salicylate, 15%
menthol, 11% camphor, 22.25% macadamia nut oil, 1.5% phenol)
solution followed by 2.0% trans-capsaicin solution (50% methyl
salicylate, 15% menthol, 11% camphor, 20.5% macadamia nut oil, 1.5%
phenol) for the treatment of shoulder pain. Applications of
formulation via a 10 ml roller-ball bottle were applied twice daily
to the right shoulder. The area of application was .about.40
cm.sup.2 (5 cm.times.8 cm) of skin.
[0491] The 0.25% trans-capsaicin solution was applied initially
twice-a-day for 2 days. The subject experienced no redness
(erythema) and no stinging or burning at any time following the
four topical applications of the formulation. The subject reported
significant relief of shoulder pain but elected to go to a higher
concentration of trans-capsaicin for potential increased
efficacy.
[0492] The 2.0% trans-capsaicin solution was applied twice-a-day
for 3 days. The subject experienced no redness (erythema) at any
time following the six topical applications of the formulation.
Levels of burning and stinging were reported as tolerable. No
burning and stinging were experienced immediately (first hours)
following application. Two events of moderate burning were
experienced: first, on the second day while showering with hot
water and then during the third night while sleeping. In both cases
the level of burning was tolerable. The subject reported
significant relief of shoulder pain and increased mobility and
ability to use his right arm.
Example 12
[0493] API-CAPS-001: A Randomized, Single-Blind, Multiple Dose
Study of the Safety and Tolerability of API-CAPS in Subjects with
Osteoarthritis of the Knee
Hypothesis/Study Objective
[0494] The effect of the novel API-CAPS composition is expected to
minimize the burning effect of capsaicin following topical
application to tolerable levels while the formulation provides pain
relief and enhanced joint mobility in the topical treatment of pain
associated with osteoarthritis. The objective was to evaluate the
efficacy, mobility improvement and tolerability of API-CAPS when
applied topically for the treatment of pain from osteoarthritis of
the knee. Five concentrations of API-CAPS (0%, 2%, 5%, 10% and 20%
w/w trans-capsaicin, USP) were used in this study.
API-CAPS Formulation Compositions
TABLE-US-00010 [0495] 0% 2% 5% 10% 20% INGREDIENTS (Wt. %) (Wt. %)
(Wt. %) (Wt. %) (Wt. %) TRANS-CAPSAICIN 0.0 2.0 5.0 10 20 ETHYL
ALCOHOL 22.5 20.5 17.5 12.5 2.5 METHYL 50 50 50 50 50 SALICYLATE
MENTHOL 15 15 15 15 15 CAMPHOR 11 11 11 11 11 PHENOL 1.5 1.5 1.5
1.5 1.5 TOTAL 100 100 100 100 100
Study Design
[0496] Chronic pain relief resulting from capsaicin is known to be
dose dependent and temporary. Topical capsaicin is well tolerated
except for a potential acute skin sensation of burning in the area
of administration that diminishes over time and with multiple
applications. Capsaicin products currently on the market are
limited by this acute side effect. API-CAPS formulations were
created to minimize potential capsaicin skin burning sensation and
efficacious in topical pain treatment.
[0497] This was a phase 1, randomized, single-blind, multiple-dose,
study of adult subjects with pain from osteoarthritis of the knee,
conducted at two investigational centers. Each of the subject's
knees (two knees per subject) was separately and randomly assigned
in a 1:5 ratio to receive one of five concentrations (0%, 2%, 5%,
10% or 20% capsaicin) of API-CAPS and each knee was individually
treated. Study medication was applied once daily to the skin of
each knee independently by trained site staff at the
investigational study centers for 4 consecutive days. The skin
associated with the application site remained uncovered for 60
minutes after API-CAPS was applied. After 60 minutes, the area was
cleansed by trained personnel to remove any residual formulation
from the surface of the skin. Subjects were not allowed to apply
the solution themselves or take the medication home. Subjects were
instructed to avoid exposing the treated skin to any form of heat
(hot water, vigorous exercise, direct sunlight, heating pad, etc.)
until 24 hours after their final API-CAPS treatment. Subjects were
also told not to apply any topical substances to the treated skin
area and to avoid wearing tight clothing at the site of application
during this time. If the subject experienced intolerable pain or
severe irritation from the study medication after they left the
clinic, they were allowed to apply cold water, ice, or a cold pack,
and they were allowed to also take oral pain medications to ease
the pain. All evaluations were performed at the study sites. Each
subject signed an Informed Consent Form and had all questions
answered before any study procedures were performed.
Study Data
[0498] Thirty subjects were enrolled and treated in this study. Of
the 30 enrolled subjects, nine did not complete the full 4
applications per the protocol. Of these nine subjects: five
discontinued the study in connection with Adverse Events and four
did not return for unnamed reasons. Adverse events consisted of
coughing deemed "possibly" or "probably" related to the study,
resulting from multiple subjects treated with formulations on both
knees utilizing the same small poorly ventilated waiting room at
one or both sites. One subject, MTR, reported using oral medication
for pain of burning. All Adverse Events were resolved.
[0499] Rating of Osteoarthritis (OA) Pain: the level of
Osteoarthritis (OA) Pain was assessed (rated) by all subjects prior
to each application and recorded by trained professionals. Data
utilized here were those Osteoarthritis (OA) Pain ratings recorded
prior to initiation of treatment and those prior to the fourth
application of one of five API-CAPS formulations to both knees of
each subject. Ratings utilized included those from all 21 patients
receiving 4 applications and two receiving 2 and 3 applications
respectively (23 total subjects). Subjects rated the current
Osteoarthritis (OA) Pain in their joints on a 0-10 numeric pain
rating scale (0=no pain; 10=worst pain imaginable) in conjunction
with the Wong-Baker Faces Rating Scale as a guide. Additionally,
subjects were asked whether their Osteoarthritis (OA) Pain was
"Better", "Same" or "Worse" than prior to the 2.sup.nd, 3.sup.rd
and 4.sup.th applications.
[0500] Tolerability Assessment (current burning skin sensation):
the burning ensation on the skin was assessed (rated) by all
subjects following each application and recorded by trained
professionals. Data utilized here were those burning sensation
ratings recorded at 15, 30, 45, and 60 minutes following each
application of one of the five API-CAPS formulations to both knees
of each subject. Tolerability ratings utilized included all 21
patients receiving 4 applications and two receiving 2 and 3
applications respectively (23 total subjects). At each time
interval subjects rated the current burning sensation on a 0-10
numeric rating scale (0=no pain; 10=worst pain imaginable) in
conjunction with the Wong-Baker Faces Rating Scale as a guide.
[0501] Mobility Assessment (enhanced joint mobility): mobility in
the treated joints was assessed by all subjects prior to each
application and recorded by trained professionals. Data utilized
here were those mobility assessments recorded prior to each
application of one of five API-CAPS formulations to both knees of
each subject. Assessments utilized included those from all 21
patients receiving 4 applications and two receiving 2 and 3
applications respectively (23 total subjects). Subjects were asked
whether their "ability to use the joint" was "Better", "Same" or
"Worse" than pre-treatment levels prior to the 2.sup.nd, 3.sup.rd
and 4.sup.th applications.
Results
[0502] Efficacy of API-CAPS Treatment
[0503] The summary of percent improvement in Osteoarthritic (OA)
Pain prior to initiation of short-term treatment are shown in the
following Table.
Pain Reduction as a Function of Capsaicin Concentration
Based on the Pain Reduction from the 1.sup.st Visit to the
Follow-Up Visit at End of Study
TABLE-US-00011 [0504] CAPSAICIN PAIN CONCENTRATION NUMBER OF
REDUCTION (Wt. %) KNEES TREATED (%) 0 12 100 2 8 100 5 8 100 10 10
88.sup.(1) 20 8 100 Note: .sup.(1)One subject experienced a 40%
pain reduction level for both knees
[0505] Tolerability of API-CAPS Treatment
[0506] The combined API-CAPS tolerability for the right and left
kness for capsaicin concentrations of 0%, 2%, 5%, 10%, and 20% are
shown in FIG. 1. The tolerability readings are considered well
within the range of what would be considered "tolerable" therapy
for the treatment of osteoarthritis pain.
The Summary of the Tolerability of API-CAPS Treatment Over the
Course of the Four Days of Treatment at 15, 30, 45 and 60 Minutes
Following Each Application are Shown in FIG. 2.
Conclusions
[0507] Topical API-CAPS treatment of osteoarthritis pain was very
effective. The reduction in Osteoarthritis (OA) Pain was dramatic.
The percent improvement in osteoarthritis pain prior to the
4.sup.th dose ranged from >45% to 100% from initial
osteoarthritis pain levels prior to initiation of this short-term
course of therapy. At the follow-up visit at the end of study the
percent improvement in osteoarthritis pain ranged from 88% to 100%.
There was a trend for greater efficacy in mitigation of
osteoarthritis pain with increasing capsaicin concentration when
comparing responses to treatment of left versus right contralateral
knees with different capsaicin concentrations in the same patient.
When asked whether their Osteoarthritis (OA) Pain was "Better",
"Same" or "Worse" prior to the 2.sup.nd, 3.sup.rd and 4.sup.th
applications, subjects replied "better" in 122 out of 123 replies,
with one recording "worse".
[0508] Topical API-CAPS treatment in this study was demonstrated to
be highly tolerable as evidenced in the graphics above. At each
concentration level of one of five API-CAPS formulations, subjects
rated their burning sensations to be overwhelmingly either
non-existent or well within a range of tolerability. Tolerability
ratings averaged 2.2 upon the first application, 1.3 after the
fourth application and trended down over time. The literature on
topical capsaicin tolerability clearly teaches that different
people sense a potential transient burning sensation to capsaicin
to different degrees and that this sensation can vary from one
exposure to the next. This is evident in our findings. In this
study, capsaicin tolerability was, in general, found to be dose
(capsaicin-concentration) dependent; with the 20% capsaicin
concentration having the greater incidence of tolerability values
ranging above 6 and the frequency of burning and stinging
sensations decreased following repetitive treatments. At capsaicin
concentrations below 20% tolerability readings typically ranged
from 0 to 6 and are considered well within the range of what would
be considered "tolerable" therapy for the treatment of
osteoarthritis pain.
Example 13
API-CAPS-004: 0.25% API-CAPS Topical Treatment for Osteoarthritis
Pain in Hands and Knees of Adult Patients
Hypothesis/Study Objective
[0509] The effect of the novel API-CAPS composition is expected to
minimize the burning effect of capsaicin following topical
application to tolerable levels while the formulation provides pain
relief and enhanced joint mobility in the topical treatment of pain
associated with osteoarthritis. The objective was to evaluate the
efficacy, mobility improvement and tolerability of 0.25% API-CAPS
when applied topically for the treatment of pain from
osteoarthritis of the hand and knee.
API-CAPS Formulation Composition
TABLE-US-00012 [0510] 0.25% INGREDIENTS (Wt. %) TRANS-CAPSAICIN
0.25 ETHYL ALCOHOL 22.25 METHYL SALICYLATE 50 MENTHOL 15 CAMPHOR 11
PHENOL 1.5 TOTAL 100
Study Design
[0511] Chronic pain relief resulting from capsaicin is known to be
dose dependent and temporary. Topical capsaicin is well tolerated
except for a potential acute skin sensation of burning in the area
of administration which diminishes over time and with multiple
applications. Capsaicin products currently on the market are
limited by this acute side effect. API-CAPS was created to minimize
potential capsaicin skin burning sensation and be efficacious in
topical pain treatment.
[0512] This was a multiple-dose study of adult subjects with pain
from osteoarthritis of the hand and knee, conducted at two
investigational sites API-CAPS was applied three times per day,
five days per week, for two weeks to the skin of the afflicted hand
or knee by trained site staff. The skin associated with the
application site remained uncovered for 60 minutes after API-CAPS
was applied. After 60 minutes, the area was cleansed by trained
personnel to remove any residual formulation from the surface of
the skin. Subjects were then instructed to avoid exposing the
treated skin to any form of heat (hot water, vigorous exercise,
direct sunlight, etc.) for 24 hours. Subjects were also told not to
apply any topical substances to the treated skin area and to avoid
wearing tight clothing at the site of application during this time.
If the subject experienced intolerable pain or severe irritation
from the study medication after they left the clinic, they were
allowed to apply cold water, ice, or a cold pack. All evaluations
were performed at the study sites. Each subject signed an Informed
Consent Form and had all questions answered before any study
procedures were performed. Subjects were not allowed to apply the
solution themselves or take the medication home.
Study Data
[0513] Sixty-one subjects were enrolled in this study. Fifty-seven
subjects completed the study. Of the 61 enrolled subjects, four did
not return for personal reasons. No treatment related adverse
events were reported.
[0514] Rating of Osteoarthritis (OA) Pain: the level of
Osteoarthritis (OA) Pain was assessed (rated) by all subjects prior
to each application and recorded by trained professionals.
Arthritis pain was rated on a 0-10 numeric scale (0=no pain;
10=worst pain imaginable) using the Wong-Baker Faces Rating Scale
as a guide. If the patient had bilateral pain and both sides were
treated and data for each side (right and left) was collected
independently. Initial OA pain level data were collected at either
day 1 or day 2. The first value recorded for pain level was used in
the subsequent analysis of percent pain reduction achieved at the
end of study.
[0515] Tolerability Assessment (current burning skin sensation):
the burning sensation on the skin was assessed (rated) by all
subjects before treatment with API-CAPS and just prior to washing
the skin area (60 minutes after medication application) and
recorded by trained professionals. The subjects rated the current
burning sensation on a 0-10 numeric rating scale (0=no pain;
10=worst pain imaginable) in conjunction with the Wong-Baker Faces
Rating Scale as a guide.
[0516] Mobility Assessment (enhanced joint mobility): mobility in
the treated joints was assessed by all subjects prior to each
application and recorded by trained professionals. Subjects were
asked whether their "ability to use the joint" was "Better", "Same"
or "Worse" than pre-treatment levels prior to the starting
treatment.
Results
[0517] Efficacy of API-CAPS Treatment
[0518] FIG. 3 shows the summary of end of study percent improvement
in Osteoarthritic (OA) Pain with short-term treatment (two weeks of
treatment applied three times per day, five days per week).
[0519] Tolerability of API-CAPS Treatment
[0520] A summary of the tolerability of API-CAPS treatment
following each application over the course of two weeks of
treatment applied three times per day, five days per week is shown
in FIG. 4.
Conclusions
[0521] Topical API-CAPS treatment of osteoarthritis pain was very
effective as evidenced by the graphics above. The percent
improvement in osteoarthritis pain at the end of study ranged from
0% to 100% from initial osteoarthritis pain levels prior to
initiation of this short-term course of therapy; with almost all
subjects achieving >40% reduction in pain.
[0522] Topical API-CAPS treatment in this study was demonstrated to
be highly tolerable as evidenced in the graphics above. The
literature on topical capsaicin tolerability clearly teaches that
different people sense a potential transient burning sensation to
capsaicin to different degrees and that this sensation can vary
from one exposure to the next. This is evident in our findings. In
this study, capsaicin tolerability was, in general, found to be
excellent; with most subjects reporting no burning and the
preponderance tolerability values well below 6. These tolerability
values are considered well within the range of what would be
considered "tolerable" therapy for the treatment of osteoarthritis
pain.
[0523] Topical API-CAPS treatment in this study was also
demonstrated to enhance mobility, presumably due to the dramatic
decrease in Osteoarthritis (OA) Pain. When asked whether their
mobility was "Better", "Same" or "Worse" prior to each
applications, subjects replied "better" in 2313 cases, the "same"
in 50 cases, and "worse" in only one case.
Example 14
[0524] API-CAPS-005: Multiple Dose Case Studies of Treatment with
API-CAPS for Pain from Osteoarthritis in the Elderly
Hypothesis/Study Objective
[0525] The effect of the novel API-CAPS composition is expected to
minimize the burning effect of capsaicin following topical
application to tolerable levels while the formulation provides
efficacy in the topical treatment of pain associated with
osteoarthritis. The objective was to evaluate the efficacy and
tolerability of API-CAPS when applied topically for the treatment
of pain from osteoarthritis in the elderly. Three concentrations of
API-CAPS (2%, 5%, and 10% w/w trans-capsaicin, USP) were available
to the Investigators for use in this study.
API-CAPS Formulation Compositions
TABLE-US-00013 [0526] 2% 5% 10% INGREDIENTS (Wt. %) (Wt. %) (Wt. %)
TRANS-CAPSAICIN 2.0 5.0 10 ETHYL ALCOHOL 20.5 17.5 12.5 METHYL 50
50 50 SALICYLATE MENTHOL 15 15 15 CAMPHOR 11 11 11 PHENOL 1.5 1.5
1.5 TOTAL 100 100 100
Study Design
[0527] Chronic pain relief resulting from capsaicin is known to be
dose dependent and temporary. Topical capsaicin is well tolerated
except for a potential acute skin sensation of burning in the area
of administration which diminishes over time and with multiple
applications. Capsaicin products currently on the market are
limited by this acute side effect. API-CAPS was created to minimize
this burning skin sensation.
[0528] The Investigators identified eight subjects who could
benefit from treatment with API-CAPS and who meet standard
eligibility criteria. Each subject signed an Informed Consent Form
(ICF) prior to treatment with API-CAPS. For each subject, one joint
was topically treated 5 times with the same strength of API-CAPS,
with one application each day. API-CAPS was applied to the same
joint each time, and the concentration was not increased or
decreased. The clinician administered API-CAPS. The skin associated
with the application site remained uncovered for 60 minutes after
API-CAPS was applied. After 60 minutes, the area was cleansed by
trained personnel to remove any residual formulation from the
surface of the skin. Subjects were not allowed to apply the
solution themselves or take the medication home. Subjects were
instructed to avoid exposing the treated skin to any form of heat
(hot water, vigorous exercise, direct sunlight, heating pad, etc.)
until 24 hours after their final API-CAPS treatment. Subjects were
also told not to apply any topical substances to the treated skin
area and to avoid wearing tight clothing at the site of application
during this time. If the subject experienced intolerable pain or
severe irritation from the study medication after they left the
clinic, they may apply cold water, ice, or a cold pack, and they
may also take oral pain medications to ease the pain.
[0529] The Investigator consulted with each of the eight subjects
to determine the proper concentration for treatment (2%, 5%, and
10% API-CAPS). The Investigator considered the severity of
osteoarthritis pain, the subject's capacity for tolerating a
burning skin sensation (potential side effect), and the area of
skin where the medication would be applied (target skin area). The
10% concentration was considered most appropriate for subjects with
chronic osteoarthritis of long duration who have exhausted other
options. Rating of Osteoarthritis (OA) Pain: Prior to each
medication treatment, subjects rated the current pain in their
joint from osteoarthritis on a 0-10 numeric pain rating scale (0=no
pain; 10=worst pain imaginable) in conjunction with the Wong-Baker
Faces Rating Scale as a guide.
[0530] Tolerability Assessment (current burning skin sensation):
Burning skin sensation was assessed by the patient just prior to
treatment, at 30 minutes after API-CAPS application, and at 60
minutes post-application on a 0-10 numeric rating scale (0=no pain;
10=worst pain imaginable) in conjunction with the Wong-Baker Faces
Rating Scale as a guide.
Results
[0531] Efficacy of API-CAPS Treatment
[0532] A measure of osteoarthritic pain at the start of the study
(prior to first treatment) and at the end of the study for each of
the eight subjects is summarized in the following Tables.
TABLE-US-00014 % PAIN LEVEL REDUCTION DOSING WITH API-CAPS
Capsaicin Concentration (%) 2 2 5 5 5 5 10 10 Subject Initials M D
C V E A V D J E S M R A A R C D Start Pain Level 3 4 6 7 7 10 6 10
(0-10 Scale) End Pain Level 2 0 4 0 4 4 0 3 (0-10 Scale) Pain Level
Change 1 4 2 7 3 6 6 7 Pain Level 33 100 33 100 43 60 100 70
Reduction (%)
TABLE-US-00015 AVERAGE TOLERABILITY SCORE (0-10 Scale) Patient
Group Treatment Times - (Minutes) (All Patients) 0 30 60 All Visits
NA 3.35 3.07 Days 2-6 1.24 3.41 3.31 Day 1 0.00 3.00 2.38 Day 2
0.50 0.25 0.75 Day 4 3.00 3.50 4.13 Day 5 0.67 6.25 5.14 Day 6 0.00
4.00 2.00
Conclusions
[0533] Topical API-CAPS treatment of osteoarthritis pain was very
effective; percent improvement in osteoarthritis pain at the end of
study ranged from 33% to 100% from initial osteoarthritis pain
levels prior to initiation of this short-term course of
therapy.
[0534] The literature on topical capsaicin tolerability clearly
teaches that different people sense a potential transient burning
sensation to capsaicin to different degrees and that this sensation
can vary from one exposure to the next. This is evident in our
findings. Six out of eight subjects (75%) participating in this
study generally encountered burning sensations at levels considered
to be "tolerable" (6 and below). However, two of the eight subjects
(25%) experienced individual tolerability readings as high as 9 or
10 at several reading points during the study. Both subjects of
these extreme cases occurred with the application of the 5%
concentration. Averaging tolerability ratings of these two highly
sensitive subjects into the tolerability data set raises the
overall tolerability averages significantly. The median values of
the tolerability readings ranged from 0 to 6 and are considered
well within the range of what would be considered "tolerable"
therapy for the treatment of osteoarthritis pain.
Example 15
Components Elimination Comparison
[0535] Two individuals took place in a trial designed to explore
the differences in the capsaicin burning sensation caused by the
elimination of one or more individual components from the
embodiment of the invention including menthol camphor and phenol.
Subject #1 (50 year old healthy male) applied six (6) distinct
capsaicin formulations on six (6) separate areas of skin on his
thighs (3 per leg). Each application site was approximately 20
cm.sup.2 (5 cm.times.4 cm) in area.
[0536] Subject #2 (39 year old healthy female) applied the same six
(6) distinct capsaicin formulations simultaneously on six (6)
separate areas of skin on her inner left arm (above and below the
inside crease of the elbow joint). Each application site was
approximately 8 cm.sup.2 (2 cm.times.4 cm) in area. Both areas are
considered to be relatively sensitive areas of skin and as such
were chosen in order to distinguish differences in burning
sensations as much as possible. The formulations applied are
presented below:
TABLE-US-00016 APPLIED FORMULATIONS No Phenol, No Phenol, Camphor,
Camphor, No No No Menthol Menthol 10% MA Menthol Camphor Phenol
w/Mac Oil w/EtOH Subj1 Subj2 Subj1 Subj2 Subj1 Subj2 Subj1 Subj2
Subj1 Subj2 Subj1 Subj2 Capsaicin 10 10 5 5 5 5 5 5 5 5 5 5 Methyl
50 50 50 50 50 50 50 50 50 50 50 50 Salicate Ethyl 12.5 12.5 32.5
32.5 28.5 28.5 19 19 0 0 45 45 Alcohol Menthol 15 15 0 0 15 15 0 0
0 0 0 0 Camphor 11 11 11 11 0 0 15 15 0 0 0 0 Phenol 1.5 1.5 1.5
1.5 1.5 1.5 11 11 0 0 0 0 Macadamia 0 0 0 0 0 0 0 0 45 45 0 0 Nut
Oil
[0537] Note that three of the six formulations eliminates one
single compound respectively (menthol, camphor or phenol) amongst
the various combinations of compounds comprising the inventive
compositions. The other two formulations are variations which
exclude all three of these compounds: menthol, camphor and phenol.
The 6.sup.th formulation applied is 10% capsaicin formulation with
none of the active components removed. The six (6) formulations
were all applied upon each subject within 2 minutes of one another.
At the time increments of 5, 10, 15, 20, 30, 45, 60, 90 and 120 the
levels of the burning sensation were taken for all application
sites and rated on a scale of 1-10. Relative comparisons between
application sites were facilitated dramatically by the simultaneous
application of formulations. Each application site was rated on a
scale of 1-10 for the burning sensation at each time interval.
[0538] Erythema reddening was also rated (measured by eye) at the
same time increments for all six (6) application sites. Relative
comparisons between applications sites were facilitated by the
simultaneous application of formulations. At each time increment,
erythema was rated on a scale of (1-5).
Burning Sensation Results
TABLE-US-00017 [0539] Subject #1 TIME FORMULATIONS AFTER 5% CAP 5%
CAP 5% CAP 5% CAP 5% CAP DOSING 10% Cap MA no MA no MA No No PhCaMe
No PhCaMe (minutes) MA Menthol Camphor Phenol w/Mac Nut Oil w/EtOH
5 0.5 1.0 1.0 1.0 1.5 1.5 10 0.5 1.0 1.0 1.5 1.5 1.5 15 0.5 1.0 1.5
1.5 2.0 2.0 20 1.0 1.5 1.5 2.0 2.5 3.0 30 1.5 2.0 1.5 2.0 3.0 3.5
45 1.5 2.5 2.0 2.0 3.5 3.5 60 1.0 2.5 2.0 2.0 3.0 3.0 75 1.0 2.5
2.0 2.5 2.5 2.5 90 1.0 2.5 2.0 2.5 2.5 2.5 120 1.0 2.5 2.0 2.5 2.5
2.0
TABLE-US-00018 Subject #2 TIME FORMULATIONS AFTER 5% CAP 5% CAP 5%
CAP 5% CAP 5% CAP DOSING 10% Cap MA no MA no MA No No PhCaMe No
PhCaMe (minutes) MA Menthol Camphor Phenol w/Mac Nut Oil w/EtOH 5
0.0 0.5 0.0 0.5 0.0 0.0 10 0.0 1.0 0.0 2.0 0.0 0.5 15 0.0 2.0 1.0
2.0 0.0 1.0 20 0.0 2.0 1.0 1.0 1.0 1.5 30 0.0 2.0 1.0 1.0 1.0 1.5
45 0.0 2.5 0.0 1.0 1.0 1.0 60 0.0 2.5 0.0 1.0 1.0 0.0 75 0.0 2.5
0.0 0.0 2.0 0.0 90 0.0 2.5 0.0 0.0 2.0 0.0 120 0.0 2.5 0.0 0.0 1.0
0.0
Erythema Results
TABLE-US-00019 [0540] Subject #1 TIME FORMULATIONS AFTER 5% CAP 5%
CAP 5% CAP 5% CAP 5% CAP DOSING 10% Cap MA no MA no MA No No PhCaMe
No PhCaMe (minutes) MA Menthol Camphor Phenol w/Mac Nut Oil w/EtOH
5 0.5 1.0 1.0 1.0 1.5 1.5 10 0.5 1.0 1.0 1.5 1.5 1.5 15 0.5 1.0 1.5
1.5 2.0 2.0 20 1.0 1.5 1.5 2.0 2.5 3.0 30 1.5 2.0 1.5 2.0 3.0 3.5
45 1.5 2.5 2.0 2.0 3.5 3.5 60 1.0 2.5 2.0 2.0 3.0 3.0 75 1.0 2.5
2.0 2.5 2.5 2.5 90 1.0 2.5 2.0 2.5 2.5 2.5 120 1.0 2.5 2.0 2.5 2.5
2.0
TABLE-US-00020 Subject #2 TIME FORMULATIONS AFTER 5% CAP 5% CAP 5%
CAP 5% CAP 5% CAP DOSING 10% Cap MA no MA no MA No No PhCaMe No
PhCaMe (minutes) MA Menthol Camphor Phenol w/Mac Nut Oil w/EtOH 5
0.0 0.0 0.0 0.0 0.0 0.0 10 0.5 2.0 0.5 1.0 0.5 0.5 15 0.5 2.5 0.5
1.0 0.5 1.0 20 0.0 2.5 0.5 2.0 1.0 1.0 30 0.0 2.5 0.5 2.0 1.0 0.5
45 0.0 2.5 1.0 2.0 2.0 0.0 60 0.0 2.5 1.0 2.0 2.0 0.0 75 0.0 2.5
0.0 1.0 2.0 0.0 90 0.0 2.5 0.0 0.0 2.0 0.0 120 0.0 2.5 0.0 0.0 1.0
0.0
Example 16
API-CAPS-002, Cohort 1: 0.25% API-CAPS (0.25% w/w Trans-Capsaicin,
USP) & Capzasin HP Arthritis Pain Relief Analgesic Cream (0.1%
Capsaicin)
Hypothesis/Study Objective
[0541] The effect of the novel API-CAPS composition is expected to
minimize the burning effect of capsaicin following topical
application to tolerable levels. The objective of this study was to
assess the tolerability of 0.25% API-CAPS (0.25% w/w
Trans-Capsaicin, USP) compared to Capzasin HP Arthritis Pain Relief
Analgesic Cream (0.1% Capsaicin).
TABLE-US-00021 API-CAPS Formulation Composition 0.25 INGREDIENTS
(Wt. %) TRANS-CAPSAICIN 0.25 ETHYL ALCOHOL 22.25 METHYL SALICYLATE
50 MENTHOL 15 CAMPHOR 11 PHENOL 1.5 TOTAL 100
Study Design
[0542] This was a single-blind, single dose, over-the-counter (OTC)
product marketing study in 12 adult healthy volunteers, conducted
at a single study center. Test Materials consist of 0.25% API-CAPS
(0.25% w/w Trans-Capsaicin, USP) compared to Capzasin HP Arthritis
Pain Relief Analgesic Cream (0.1% Capsaicin). These two Test
Materials were applied to contralateral sites on the subject's back
by the site staff following subject's signed Informed Consent Form
after having all questions answered before any study procedures may
be performed. The screening procedures established eligibility for
study participation, and included demographics, height, weight,
vital signs, medical history, brief physical exam (optional), and
evaluation of inclusion and exclusion criteria.
[0543] Subjects were instructed to shower or bathe the evening
before or morning of Treatment. Each of the two contralateral areas
of Test Material application were 49 square centimeters (7.times.7
cm); just below the right and left shoulder blades on the subject's
back. The Test Materials were applied randomly to one side or the
other of the back (right or left).
[0544] The subjects evaluated tolerability prior to dosing, one
minute after dosing, and every 15 minutes post-dose for 2 hours.
Tolerability was measured by the subject's evaluation of a skin
sensation of burning on a 0-10 Numeric Rating Scale (where 0 is no
sensation and 10 is very severe burning, i.e., worst pain
imaginable) using the Wong-Baker faces as a guide.
[0545] Skin irritation (dermatologic evaluation) was assessed by a
trained clinical evaluator prior to dosing, and at 30 minutes, 1
hour, and 2 hours post-dose using a standard 0 to 7 rating scale
(where 0 is no evidence of irritation and 7 is a strong reaction
spreading beyond test site). The same evaluator performed all
assessments for a subject.
[0546] After completion of the 2-hour post-dose evaluations, the
site staff cleansed the subject's back to remove any residual
product and subjects were instructed to avoid exposing their back
to any form of heat (hot water, vigorous exercise, direct sunlight,
etc.) for 24 hours.
[0547] Subjects were released from the clinic and instructed to
contact the study staff if they had any adverse experiences that
are potentially related to the Test Materials.
Results
TABLE-US-00022 [0548] Subjective Assessments (Burning) 0.25%
API-CAPS Capzasin HP Arthritis Pain Relief (0.25% w/w Trans-
Analgesic Cream Capsaicin, USP) (0.1% Capsaicin) N = 12 12 Mean
0.11 0.10 Std Dev 0.21 0.20 Median 0.00 0.00 Range 0.00-0.70
0.00-0.50 Paired t-test P = 0.9279
TABLE-US-00023 Dermatologic Evaluations 0.25% API-CAPS Capzasin HP
Arthritis Pain Relief (0.25% w/w Trans- Analgesic Cream Capsaicin,
USP) (0.1% Capsaicin) N = 12 12 Mean 0.33 0.31 Std Dev 0.22 0.50
Median 0.25 0.00 Range 0.00-0.75 0.00-1.5 Paired t-test P =
0.8977
Conclusions
[0549] Both 0.25% API-CAPS (0.25% w/w Trans-Capsaicin, USP) and
Capzasin HP Arthritis Pain Relief Analgesic Cream (0.1% Capsaicin)
are comparable (p.gtoreq.0.05) and very tolerable with respect to
potential capsaicin-induced burning as well as comparable
(p.gtoreq.0.05) and very tolerable in potential skin
irritation.
API-CAPS-002, Cohort 2: 0.25% API-CAPS (0.25% w/w Trans-Capsaicin,
USP) & Capzasin No-Mess Applicator (0.15% Capsaicin)
Hypothesis/Study Objective
[0550] The effect of the novel API-CAPS vehicle is expected to
minimize the burning effect of 0.25% capsaicin following topical
application to tolerable levels. The objective of this study was to
assess the tolerability of 0.25% API-CAPS (0.25% w/w
Trans-Capsaicin, USP) compared to Capzasin No-Mess Applicator
(0.15% Capsaicin).
TABLE-US-00024 API-CAPS Formulation Composition 0.25 INGREDIENTS
(Wt. %) TRANS-CAPSAICIN 0.25 ETHYL ALCOHOL 22.25 METHYL SALICYLATE
50 MENTHOL 15 CAMPHOR 11 PHENOL 1.5 TOTAL 100
Study Design
[0551] This was a single-blind, single dose, over-the-counter (OTC)
product marketing study in 12 adult healthy volunteers, conducted
at a single study center. Test Materials consist of 0.25% API-CAPS
(0.25% w/w Trans-Capsaicin, USP) compared to Capzasin No-Mess
Applicator (0.15% Capsaicin). These two Test Materials were applied
to contralateral sites on the subject's back by the site staff
following subject's signed Informed Consent Form after having all
questions answered before any study procedures may be performed.
The screening procedures established eligibility for study
participation, and included demographics, height, weight, vital
signs, medical history, brief physical exam (optional), and
evaluation of inclusion and exclusion criteria.
[0552] Subjects were instructed to shower or bathe the evening
before or morning of Treatment. Each of the two contralateral areas
of Test Material application were 49 square centimeters (7.times.7
cm); just below the right and left shoulder blades on the subject's
back. The Test Materials were applied randomly to one side or the
other of the back (right or left).
[0553] The subjects evaluated tolerability prior to dosing, one
minute after dosing, and every 15 minutes post-dose for 2 hours.
Tolerability was measured by the subject's evaluation of a skin
sensation of burning on a 0-10 Numeric Rating Scale (where 0 is no
sensation and 10 is very severe burning, i.e., worst pain
imaginable) using the Wong-Baker faces as a guide.
[0554] Skin irritation (dermatologic evaluation) was assessed by a
trained clinical evaluator prior to dosing, and at 30 minutes, 1
hour, and 2 hours post-dose using a standard 0 to 7 rating scale
(where 0 is no evidence of irritation and 7 is a strong reaction
spreading beyond test site). The same evaluator performed all
assessments for a subject.
[0555] After completion of the 2-hour post-dose evaluations, the
site staff cleansed the subject's back to remove any residual
product and subjects were instructed to avoid exposing their back
to any form of heat (hot water, vigorous exercise, direct sunlight,
etc.) for 24 hours. Subjects were released from the clinic and
instructed to contact the study staff if they had any adverse
experiences that are potentially related to the Test Materials.
Results
TABLE-US-00025 [0556] Subjective Assessments (Burning) 0.25%
API-CAPS Capzasin HP Arthritis Pain Relief (0.25% w/w Trans-
Analgesic Cream Capsaicin, USP) (0.1% Capsaicin) N = 12 12 Mean
0.55 0.01 Std Dev 0.94 0.03 Median 0.2 0.00 Range 0.00-3.40
0.00-0.10 Paired t-test P = 0.0739
TABLE-US-00026 Dermatologic Evaluations 0.25% API-CAPS Capzasin HP
Arthritis Pain Relief (0.25% w/w Trans- Analgesic Cream Capsaicin,
USP) (0.1% Capsaicin) N = 12 12 Mean 0.21 0.00 Std Dev 0.28 0.00
Median 0.13 0.00 Range 0.00-0.75 0.00-0.00 Paired t-test P =
0.0172
Conclusions
[0557] Both 0.25% API-CAPS (0.25% w/w Trans-Capsaicin, USP) and
Capzasin No-Mess Applicator (0.15% Capsaicin) are comparable
(p.gtoreq.0.05) and very tolerable with respect to potential
capsaicin-induced burning as well as very tolerable in potential
skin irritation.
Example 17
Diclofenac Solubility Studies
[0558] Experimental Solubility Procedures and Results
[0559] All solubility samples were prepared in 20 gram sample size.
The ingredients of each test samples were weighed to the nearest
0.01 grams. The 20 gram samples were mixed in 50 cc Pyrex glass
beakers.
[0560] All solubility studies were performed with "Diclofenac
Sodium Salt" obtained from Sigma Aldrich, St. Louis, Mo. (CAS
#15307-79-6; Sigma-Aldrich Catalog No. D6899; Lot # BCBB7312; M.P.
275-277.degree. C.)
[0561] The molecular structure of Diclofenac Sodium is shown
below:
##STR00007##
[0562] The ingredients were thoroughly mixed at ambient
temperatures ranging from 75.degree. F. to 80.degree. F.
[0563] The solvents that indicated little or negligible solubility
levels of diclofenac sodium at room temperature were heated to
about 35.degree. C. to determine if the increased temperature would
impact the solubility of the diclofenac sodium. However, the
elevated temperature level of .about.35.degree. C. did not have a
significant impact in increasing the diclofenac sodium in those
mixtures where the diclofenac solubility levels were "sparingly
soluble to insoluble".
TABLE-US-00027 SAMPLE DICLOFENAC SODIUM NUMBER SOLVENT/SOLVENT
MIXTURES SOLUBILITY 1 98 wt. % .sup.(1)Methyl Salicylate, 2 wt. %
.sup.(9)Diclofenac Sodium Sparingly Soluble/ Insoluble 2 50 wt. %
.sup.(1)Methyl Salicylate, 15 wt. % .sup.(2)Menthol, 11 wt. %
Sparingly Soluble/ .sup.(3)Camphor, 1.5 wt. % .sup.(4)Phenol, 20.5
wt. % .sup.(5)Macadamia Nut Insoluble Oil, 2 wt. %
.sup.(9)Diclofenac Sodium 3 98 wt. % .sup.(6)Ethyl Alcohol, 2 wt. %
.sup.(9)Diclofenac Sodium .sup.(10)Completely Soluble 4 98 wt. %
.sup.(7)Transcutol, 2 wt. % Diclofenac Sodium .sup.(10)Completely
Soluble 5 88 wt. % Methyl Salicylate, 10 wt. % Ethyl Alcohol,
.sup.(10)Completely 2 wt. % .sup.(9)Diclofenac Sodium Soluble 6 50
wt. % Methyl Salicylate, 15 wt. % Menthol, 11 wt. % Sparingly
Soluble/ Camphor, 1.5 wt. % Phenol, 18.5 wt. % Macadamia Nut Oil,
Insoluble 2 wt. % .sup.(9)Diclofenac Sodium 7 50 wt. % Methyl
Salicylate, 15 wt. % Menthol, 11 wt. % .sup.(10)Completely Camphor,
1.5 wt. % Phenol, 18.5 wt. % Ethyl Alcohol, Soluble 2 wt. %
.sup.(8)Capsaicin, 2 wt. % .sup.(9)Diclofenac Sodium 8 50 wt. %
Methyl Salicylate, 15 wt. % Menthol, 11 wt. % .sup.(10)Completely
Camphor, 1.5 wt. % Phenol, 10.5 wt. % Ethyl Alcohol, Soluble 2 wt.
% .sup.(8)Capsaicin, 2 wt. % .sup.(9)Diclofenac Sodium NOTE:
.sup.(1)Methyl Salicylate, Spectrum Chemical, NF, CAS # 119-36-8
.sup.(2)L-Menthol, Crystal, Spectrum Chemical, USP, CAS # 2216-51-5
.sup.(3)Camphor, Synthetic, Spectrum Chemical, USP, CAS # 76-22-2
.sup.(4)Phenol, Liquefied (Carbolic Acid), USP, Spectrum Chemical,
CA 108-95-2 .sup.(5)Macadamia Nut Oil, Lotioncrafters Lot #
1506-3187, CAS #128497-20-1 .sup.(6)Ethyl Alcohol, Graves Grain
Alcohol, 190 Proof .sup.(7)Transcutol .TM., (Ethoxydiglycol),
Lotioncrafters, Lot# CAS # 111-90-0 .sup.(8)Trans-Capsaicin,
Aversion Technologies Inc., 95.7% Trans-Capsaicin, Balance
Cis-Capsaicin, USP 30, CAS # 404-86-4 .sup.(9)Diclofenac Sodium,
Lot # BCBB7312, Sigma-Aldrich Catalog No. D6899, CAS # 15307-79-6
.sup.(10)Samples 3, 4, 5 & 7 were placed in sealed 16 cc Pyrex
vials and placed in a freezer maintained at ~5.degree. F. for 48
hours. There was no visible evidence of any precipitates formed.
Further, no visible evidence of precipitation. was observed after
>5 days at ambient conditions. All solutions were totally
transparent & all mixtures completely miscible.
[0564] The table below includes the compositions of 7 completely
miscible and transparent diclofenac sodium and capsaicin liquid
solutions that were prepared.
TABLE-US-00028 The Composition of the Miscible Liquid Solution
SAMPLE NUMBER 1 2 3 4 5 6 7 INGREDIENTS (wt. %) (wt. %) (wt. %)
(wt. %) (wt. %) (wt. %) (wt. %) .sup.(1)CAPSAICIN 0 2 2 0.25 2 5 10
.sup.(2)DICLOFENAC SODIUM 2 2 2 1.5 1.5 1.5 1.5 .sup.(3)METHYL
SALICYATE 0 50 50 50 50 50 50 .sup.(4)MENTHOL 0 15 15 15 15 15 15
.sup.(5)CAMPHOR 0 11 11 11 11 11 11 .sup.(6)PHENOL 0 1.5 1.5 1.5
1.5 1.5 1.5 .sup.(7)ETHYL ALCOHOL 20 0 18.5 20.75 19 16 11
.sup.(8)MACADAMIA NUT OIL 78 10.5 0 0 0 0 0 .sup.(9) TRANSCUTOL 0 8
0 0 0 0 0 NOTE: .sup.(1)Trans-Capsaicin, Aversion Technologies
Inc., 95.7% Trans-Capsaicin, Balance Cis-Capsaicin, USP 30, CAS #
404-86-4 .sup.(2)Diclofenac Sodium, Sigma-Aldrich Catalog No.
D6899; Lot # BCBB7312, CAS # 15307-79-6 .sup.(3)Methyl Salicylate,
Spectrum Chemical, NF, CAS # 119-36-8 .sup.(4)L-Menthol, Crystal,
Spectrum Chemical, USP, CAS # 2216-51-5 .sup.(5)Camphor, Synthetic,
Spectrum Chemical, USP, CAS # 76-22-2 .sup.(6)Phenol, Liquefied
(Carbolic Acid), USP, Spectrum Chemical, CA 108-95-2 .sup.(7)Ethyl
Alcohol, Graves Grain Alcohol, 190 Proof .sup.(8)Macadamia Nut
Oil,, Lotioncrafters Lot # 1506-3187, CAS # 128497-20-1 .sup.(9)
Transcutol, (Ethoxydiglycol), Lotioncrafters, Lot# Lot#
034A00429324-3426, CAS #111-90-0.sup.)
[0565] It is evident that alcohols (ethyl alcohol and/or
ethoxydiglycol) are required to effect the solubility of Diclofenac
salts within the oil based ingredients of the capsaicin vehicles.
Significantly, as noted in Sample 5 of the table above, an ethyl
alcohol content of 10% results in the complete solution of 2%
Diclofenac Sodium within in a liquid solution containing 88% methyl
salicylate. Total solubility/miscibility of this 2% Diclofenac
sodium solution was observed after exposure to 5.degree. F.
(.about.15.degree. C.) for 48 hours. Formulations with ethyl
alcohol concentration >10 wt. % will result in the solubility of
higher diclofenac salt concentrations.
[0566] Based on the results of the aforementioned solubility
experiments, it was concluded that the ethyl alcohol capsaicin
vehicle was capable of maintaining complete solubility/miscibility
with concentrations of <2 wt. % Diclofenac Sodium salts.
[0567] While the invention has been described with reference to an
exemplary embodiment, it will be understood by those skilled in the
art that various changes may be made and equivalents may be
substituted for elements thereof without departing from the scope
of the invention. In addition, many modifications may be made to
adapt a particular situation or material to the teachings of the
invention without departing from the essential scope thereof.
Therefore, it is intended that the invention not be limited to the
particular embodiment disclosed as the best mode contemplated for
carrying out this invention, but that the invention will include
all embodiments falling within the scope of the appended
claims.
[0568] All documents and other information sources cited herein are
hereby incorporated in their entirety by reference.
* * * * *