Title: Alcohol-free transdermal
United States Patent: 7,291,591
Issued: November 6, 2007
Inventors: Fishman; Robert
(Pembroke Plnes, FL)
Assignee: All Natural FMG,
Inc. (North Palm Beach, FL)
Appl. No.: 11/407,387
Filed: April 18, 2006
Executive MBA in Pharmaceutical Management, U. Colorado
The instant invention is directed toward
a dermal delivery system composition comprising an aqueous base vehicle
including Emu oil, at least one fatty acid alkyl ester, polyethylene
glycol, and a gelling agent, in combination with a therapeutically
effective amount of at least one species of insulin, and to processes for
the manufacture and use thereof.
Description of the Invention
FIELD OF THE
This invention relates to an insulin
composition in combination with an alcohol-free dermal delivery system for
transdermal application and to processes for manufacture and use thereof.
BACKGROUND OF THE
Insulin is a naturally occurring hormone
secreted by the beta cells of the islands of Langerhans in the pancreas in
response to increased levels of glucose in the blood. The hormone acts to
regulate the metabolism of glucose and the processes associated with the
intermediary metabolism of fat, carbohydrates and proteins. Insulin lowers
blood glucose levels and promotes transport and entry of glucose into
muscle cells and other tissues. Due to the chemical nature of insulin
molecules, the traditional route of insulin administration in diabetic
patients, who require multiple daily doses of insulin, is intradermal or
Prior art efforts to develop a non-injectable transdermal insulin delivery
system for the treatment of diabetes have not been successful to date.
While insulin can be systemically delivered to a patient by the topical
application of an insulin-containing vehicle, the systemic blood levels of
insulin that are achievable using this delivery method have proven to be
generally inadequate for meeting the demands of the diabetic patient.
Various methods have been developed for enhancing the transdermal delivery
of insulin including improved passive diffusion carriers for increasing
the permeability of the epidermis, sonophoresis, iontophoresis and
ionosonic transport. Passive diffusion through the outer layer of skin has
been used successfully for the delivery of low molecular weight lipophilic
drugs such as scopolamine, estradiol and nitroglycerine, but has been
largely unsuccessful for the transdermal delivery of hydrophilic peptides
such as insulin due to the low skin permeability of such peptides. Thus,
mechanical vibrational energy and/or iontophoresis are employed to
increase skin permeability and facilitate transdermal insulin delivery.
Sibalis et al., in U.S. Pat. No. 4,940,456, teaches an apparatus and
method for the iontophoretically mediated transdermal delivery of insulin.
Henley, in U.S. Pat. Nos. 5,667,487 and 5,658,247 discloses an ionosonic
apparatus suitable for the ultrasonic-iontophoretically mediated transport
of therapeutic agents across the skin. Insulin has a tendency to form
dimers and hexamers in pharmacological compositions, which are considered
to be too large for transdermal delivery. Brange, in U.S. Pat. No.
5,597,796, suggests chemically modifying insulin to produce insulin
analogs that resist intermolecular association and enable improved
iontophoretic delivery. Jang et al., in U.S. Pat. No. 5,681,580, discloses
a patch containing insulin formulated in a gel for the iontophoretically
driven transdermal delivery of insulin. Notwithstanding the advances in
methods for the transdermal delivery of insulin described above, the
transdermal delivery of insulin in a quantity sufficient to attain a
therapeutic level in the blood of diabetic patients has heretofore not
Clinical use of transdermal drug delivery has been limited because very
few drugs are able, at least by passive diffusion alone, to penetrate the
skin at a sufficient rate to produce a useful systemic drug concentration
in the patient. The outer layer of the skin, the stratum corneum, is a
major barrier to diffusion of low and especially high molecular weight
drugs across the skin to the bloodstream. One drug for which an effective
transdermal delivery system has long been sought is insulin, a therapeutic
agent useful in the control of both Type I (juvenile onset) and Type II
(adult onset) diabetes. Insulin, unfortunately, constitutes an example of
molecules which do not readily diffuse through the stratum corneum at a
therapeutically useful rate.
While there have been attempts in the prior art to develop transdermal
"patches" which contain a particular amount of insulin, which may be
transferred at a particular rate, these patches have numerous limitations.
One specific limitation is that insulin users must often gauge their
requirements relative to physical activity and ingestion of carbohydrates.
Additionally, there are different types of insulin, e.g. long-acting and
short-acting, and the patient must develop skill in blending both the type
and quantity of insulin in order to adequately control their blood sugar
levels. The use of multiple patches having variable dosage strengths and
insulin response characteristics thus becomes problematic.
Thus there remains a longfelt need for a dermal delivery system for
insulin in a convenient format, e.g. a gel or cream, which can be
formulated with insulin compounds having varied release characteristics,
and whereby the dosage could be determined as a function of the volume
DESCRIPTION OF THE
U.S. Pat. No. 6,416,772 teaches a topical
dermal anesthetic composition for relief of pain comprising alcohol in an
amount by weight of about 57 to about 91 percent; glycerin in an amount by
weight of about 1 to about 12 percent; an analgesic agent in an amount by
weight of about 2 to about 28 percent, the analgesic agent comprising a
derivative of salicylic acid; methylsulfonylmethane (MSM) in an amount by
weight of about 0.02 to 5 percent; and Emu oil in an amount by weight of
about 0.01 to 3 percent. The composition provides transdermal pain when
the analgesic agent is applied directly to an area of pain.
Alcohol, preferably ethyl or isopropyl alcohol, is taught as being
necessary to effectively dissolve the analgesic so that it can be absorbed
through the skin. Glycerin, in turn, is required to act as a stabilizer
for the acetylsalicylic acid, triethanolamine salicylate, or other
analgesic agent, such that the alcohol does not significantly affect the
marketable shelf life of the composition. Glycerin is also taught as being
necessary to sufficiently disperse the analgesic agent such that the
composition does not need to be shaken or stirred before topical use.
Methylsulfonylmethane (MSM) and Emu oil are taught as being included to
help facilitate the absorption of the composition into the skin and also,
due to the pain relieving characteristics in and of themselves, potentiate
the analgesic to increase the efficacy of the composition.
This patent fails to teach a composition which is effective in alleviating
pain when applied to various trigger points, distal from the actual
perceived area of discomfort. Furthermore, the '772 patent requires the
use of alcohol for transdermal delivery, which causes degradation of the
analgesic, and subsequently requires glycerin as a stabilizer to retard
the alcohol degradation.
U.S. Pat. No. 6,346,278 teaches a lipid extract of Perna canaliculus or
Mytilus edulis as an active component, in a composition suitable for
transdermal administration comprising an ointment or lotion base or
vehicle, which may include a skin penetration enhancing agent to assist in
administration of the active component. Suitable bases or vehicles are
oils such as olive or Emu oil, administered alone or with a penetrant such
as cineole or limonene.
U.S. Pat. No. 6,444,234 teaches an alcohol containing pharmaceutical
compositions for the transdermal administration of a medicament or other
active agent by topical application of the composition to the skin of
humans or other animals. Methodology for formulating such compositions
which provide for very rapid uptake of the medicament and transmigration
into and through the skin to either fatty tissues or the vascular system,
while minimizing irritation to the skin and/or immunological response, is
based on a transdermal delivery system (TDS) wherein the medicament is
modified to form a true solution in a complex formed from particular
solvents and solvent and solute modifiers in combination with skin
stabilizers. Analgesics such as ibuprofen and the like, MSM and Emu oil
are taught as useful in combination with the transdermal delivery system.
U.S. Pat. No. 6,528,040 teaches an Emu oil-based formulation for use as an
analgesic, anesthetic and antipruritic. The formulation contains 0.01 to
13 wt % alkyl esters; and 20 to 70 wt % Emu oil; 10 to 33 wt % benzyl
alcohol; 10 to 33 wt % benzoin; 0.2 to 2 wt % allantoin; 0.25 to 1.25 wt %
methylparaben and 0.01 to 0.30 wt % propylparaben. The formulation may be
formulated as a spray or transdermal formula and may be used for treatment
of chronic cutaneous ulcers and burn wounds.
U.S. Pat. No. 5,885,597 teaches a topical composition for relieving pain
in a person in need of such relief, consisting essentially of an effective
amount of a combination of at least one corticoid analgesic, at least one
arylpropionic acid type analgesic, and at least one p-aminobenzoic acid
ester type local anesthetic; an amount effective in enhancing the
effectiveness in relieving pain of the combination of capsaicin, and an
amount effective to increase the transmission thereof through the skin of
at least one phospholipid and at least one polyoxyethylenepolyoxypropylene
U.S. Patent Application 20030031724 teaches compositions that may be
cost-effectively derived or processed from the Emu, Dromiceius
novaehollandiae, and used as anti-inflammatory agents in patients. The
application does not contemplate the use of MSM or insulin compositions in
a transdermal delivery environment.
U.S. Patent Application 20010033838 teaches the use of Emu oil and its
various fractions as a carrier for antifungal, antibacterial, and
antiviral medications and preparations. The use of MSM in combination with
Emu oil is taught, however when transdermal application is desired the Emu
oil is replaced with a liposomal or oil-based transdermal component.
U.S. Pat. No. 6,024,975 is directed toward a high molecular weight drug
which is transdermally administered by applying a polymer skin enhancer
and a drug active to the skin of the patient. The drug may be encapsulated
or the drug solution may be partly encapsulated and partly free. The skin
enhancer which is required is polyvinylpyrrolidone (PVP)and it is mixed at
between 7 and 35% of the drug. A gelling agent may be optionally added at
up to 20% by volume. The chemical system is preferably administered via a
multidose transdermal drug patch assembly which includes a drug-impervious
support impressed to form a series of compartments. Each compartment is a
reservoir for a unit dose of an active drug designed to be transdermally
administered. The support is adhesively secured to the skin of a patient.
Individual devices are provided for resealably enclosing the drug in each
of the reservoirs. The individual enclosing devices are removable to
release the unit dose into contact with the skin of the patient and are
actuable to control the transdermal absorption of the drug actives. The
patent disclosure is largely directed toward trans-dermal medication
assemblies and more particularly to such assemblies consisting of multiple
unit-dose reservoirs with each reservoir having individual tear and
release resealable closure means for initiation and administration of the
medication. However, it is suggested that the drug may also be
administered in a creme. All formulations would nevertheless require
U.S. Pat No. 6,444,240 is directed toward compositions containing insulin
formulated for topical application and a method for using the compositions
for the cosmetic treatment of wrinkles.
SUMMARY OF THE
The instant invention discloses a dermal
delivery system composition comprising an aqueous base vehicle including
at least one fatty acid alkyl ester having thirteen to thirty six carbon
atoms, polyethylene glycol-8 (PEG-8), Emu oil, and a gelling agent. For
enhanced skin penetration methylsulfonylmethane (MSM) may be added to the
composition. One or more active insulin ingredients are added to this
aqueous base vehicle.
Examples of suitable fatty acid alkyl esters include, albeit not limited
to, methyl laurate, methyl myristate, methyl palmitate, methyl stearate,
methyl behenate, ethyl oleate, ethyl linoleate, butyl oleate, butyl
stearate, isopropyl myristate, isopropyl palmitate, dodecyl acetate,
tetradecyl octanote, cetyl palmitate, and stearyl stearate.
The aforementioned fatty acid alkyl esters facilitate compounding and can
be added to the formulation from about 0.001 to about 31.0 wt % of the
composition, preferably about 3 wt %.
Examples of idoneous gelling/emulsifying agents that can be used in the
present invention include guar gums, xanthan gums, carrageenan, cellulose,
hydroxyalkyl celluloses, sodium carboxycelluloses, SEPIGEL 305, gelatin,
agar, starch, or the like. SEPIGEL 305 is a trademark and manufactured by
Seppic (Fairfield, N.J.). SEPIGEL 305 is a gelling/emulsifying agent
comprising about 40% polyacrylamide, about 15% C.sub.13-C.sub.14
Isoparaffin and about 5% laureth-7, and q.s. water.
The gelling/emulsifying agent is added to the formulation to achieve the
desired viscosity and can range from about 0.001 to about 31.0 wt %,
preferably about 3 wt %.
The preferred polyethylene glycol used herein is PEG-8 (tradename
PROTACHEM 400, manufacture by Protameen Chemical, Inc. Totawa, N.J.) and
can be added to the formulation in amounts from about 0.001 to about 31.0
wt % of the composition, preferably about 3 wt %. Emu oil is added to the
formulation to facilitate the absorption of the composition into the skin.
Emu oil can be added to the instant formulation in amounts from about
0.001 to about 31.0 wt %.
In a preferred embodiment, the instant invention discloses a dermal
delivery system composition comprising an aqueous base vehicle including
Emu oil (American), isopropyl palmitate (tradename PROTACHEM IPP, sold by
Protameen Chemical, Inc. Totawa, N.J.), PEG-8, and SEPIGEL 305 (sold by
Seppic). Methylsulfonylmethane (MSM) may also be included to help
facilitate the absorption of the composition into the skin.
To this base vehicle, one or more active insulin ingredients are added,
As opposed to the use of injected insulin, topical creams of the instant
invention have the advantage of not requiring the patient or a caregiver
to give an injection; nor must the patient carry and/or transport the
necessary paraphernalia required for giving an injection.
The dermal delivery system, as illustrated herein, is alcohol free and
therefore does not suffer from the problems of decreased shelf-life
associated with alcohol containing prior art formulations. Since alcohol
is not utilized, the presence of glycerin is likewise not required. Thus,
a unique alcohol-free dermal delivery system is provided which provides
enhanced penetration via the dermal layers thereby enabling a safer,
quick-acting, and easier-to-comply alternative to capsules and tablets.
Accordingly, it is an objective of the instant invention to provide an
alcohol-free, cream base rapid dermal delivery system for transdermal
dosing of insulin compositions effective for the therapeutic treatment of
It is another objective of the instant invention to provide a process for
manufacture of said dermal delivery system.
OF THE INVENTION
In order to reduce to practice a dermal
delivery system which provides enhanced skin penetration, it is necessary
to understand the parameters which affect this phenomenon.
Various Factors Affecting Skin Penetration:
1) Oil solubility (J Pharm Sci "Linear relationships between lipophilic
character and biological activity of drugs." 1972 Jan;61(1):1-19) the more
oil soluble [lipophilic] the substance, the greater the skin penetration;
2) Molecular weight (the smaller the molecule, the easier penetration);
3) Creams, gels and liquids penetrate better than solids;
4) Penetration enhancers improve topical absorption of lipophilic
substances (Targeted drug delivery to the skin and deeper tissues: role of
physiology, solute structure and disease; Clin Exp Pharmacol Physiol 1997
Claim 1 of 6 Claims
1. An alcohol-free composition effective
for transdermal delivery of insulin comprising in combination: an
effective amount of Emu Oil, an effective amount of at least one fatty
acid alkyl ester, an effective amount of polyethylene glycol, a gelling
agent in an amount effective for gelling, a therapeutically effective
amount of insulin, and sterile water sufficient to make 100% W/W.
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