U.S. patent application number 11/334206 was filed with the patent office on 2006-05-18 for topical drug delivery using phosphatidylcholine.
Invention is credited to Nicholas V. Perricone.
Application Number | 20060105955 11/334206 |
Document ID | / |
Family ID | 29715338 |
Filed Date | 2006-05-18 |
United States Patent
Application |
20060105955 |
Kind Code |
A1 |
Perricone; Nicholas V. |
May 18, 2006 |
Topical drug delivery using phosphatidylcholine
Abstract
The present invention relates to compositions and methods for
transdermal drug delivery comprising formulating a
phosphatidylcholine carrier composition containing the drug and
applying the composition to the skin.
Inventors: |
Perricone; Nicholas V.;
(Meriden, CT) |
Correspondence
Address: |
ST. ONGE STEWARD JOHNSTON & REENS, LLC
986 BEDFORD STREET
STAMFORD
CT
06905-5619
US
|
Family ID: |
29715338 |
Appl. No.: |
11/334206 |
Filed: |
January 18, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10448632 |
May 30, 2003 |
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11334206 |
Jan 18, 2006 |
|
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60384597 |
May 31, 2002 |
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Current U.S.
Class: |
514/21.2 ;
514/10.3; 514/10.9; 514/11.1; 514/11.3; 514/11.6; 514/11.9;
514/5.9 |
Current CPC
Class: |
A61J 3/07 20130101; A61K
47/10 20130101; A61K 38/27 20130101; A61K 38/31 20130101; A61K
38/23 20130101; A61K 38/56 20130101; A61K 38/095 20190101; A61K
47/24 20130101; A61K 47/22 20130101; A61P 17/00 20180101; A61K
38/28 20130101; A61K 9/06 20130101; A61K 31/56 20130101; A61K
9/1277 20130101; A61K 9/02 20130101; Y10S 514/866 20130101; A61K
38/02 20130101; A61K 38/24 20130101; C07K 14/62 20130101; A61P 5/06
20180101; Y10S 514/806 20130101; A61P 3/10 20180101; A61K 47/14
20130101; A61K 9/0014 20130101; A61K 9/127 20130101; Y10S 514/97
20130101; Y10S 514/808 20130101; A61K 47/34 20130101; Y10S 514/807
20130101 |
Class at
Publication: |
514/012 ;
514/003 |
International
Class: |
A61K 38/28 20060101
A61K038/28; A61K 38/22 20060101 A61K038/22; A61K 38/27 20060101
A61K038/27 |
Claims
1. A composition comprising crystallized phosphatidylcholine and
polypeptide drug molecules entrapped within the phosphatidylcholine
for transdermal delivery of the polypeptide drug molecules into
dermal vasculature.
2. The composition of claim 1, wherein the polypeptide drug
molecules are selected from the group consisting of oxytocin,
vasopressin, insulin, somatotropin, calcitonin, chorionic
gonadotropin, menotropins, follitropins, somatostatins, progestins,
and combinations of any of these.
3. The composition of claim 1, wherein the phosphatidylcholine is
enriched with polyenylphosphatidylcholine.
4. The composition of claim 3, wherein the phosphatidylcholine is
pure polyenylphosphatidylcholine.
5. The composition of claim 1, wherein the composition contains
about 85% phosphatidylcholine.
6. The composition of claim 1, wherein the phosphatidylcholine is
soybean lecithin.
7. The composition of claims 1, further comprising one or more
adjunct ingredients to preserve integrity of the polypeptide drug
molecules, selected from the group consisting of ascorbyl
palmitate, lipoic acid, and combinations of these.
8. The composition of claim 2, wherein the phosphatidylcholine is
enriched with polyenylphosphatidylcholine.
9. The composition of claim 8, wherein the phosphatidylcholine is
pure polyenylphosphatidylcholine.
10. The composition of claim 2, wherein the composition contains
about 85% phosphatidylcholine.
11. The composition of claim 2, wherein the phosphatidylcholine is
soybean lecithin.
12. The composition of claims 2, further comprising one or more
adjunct ingredients to preserve integrity of the polypeptide drug
molecules, selected from the group consisting of ascorbyl
palmitate, lipoic acid, and combinations of these.
13. A topical composition for transdermal delivery of
macromolecular drugs, comprising: a carrier containing crystallized
phosphatidylcholine enriched with polyenylphosphatidylcholine; and
at least one macromolecular drug entrapped within the crystallized
phosphatidylcholine carrier for transdermal delivery into dermal
vasculature.
14. The composition of claim 13, wherein the polypeptide drug
molecules are selected from the group consisting of oxytocin,
vasopressin, insulin, somatotropin, calcitonin, chorionic
gonadotropin, menotropins, follitropins, somatostatins, progestins,
and combinations of any of these.
15. The composition of claim 13, further comprising at least one
adjunct ingredient selected from the group consisting of ascorbyl
palmitate, lipoic acid, and combinations of these, to preserve
integrity of the macromolecular drug during delivery.
16. The composition of claim 13, wherein the phosphatidylcholine
carrier is pure polyenylphosphatidylcholine.
17. The composition of claim 13, wherein the composition contains
about 85% phosphatidylcholine.
18. The composition of claim 13, wherein the phosphatidylcholine
carrier is soybean lecithin.
Description
PRIOR APPLICATION
[0001] This application is a divisional patent application of
copending U.S. patent application Ser. No. 10/448,632 for "Topical
Drug Delivery Using Phosphatidylcholine," filed May 30, 2003, which
claims priority benefits under 35 U.S.C. .sctn.119(e) of U.S.
Provisional Patent Application Ser. No. 60/384,597 filed May 31,
2002.
FIELD OF THE INVENTION
[0002] The present invention relates to a topical drug delivery
composition and method. More specifically, this invention relates
to topical drug delivery compositions and methods using
phosphatidylcholine.
BACKGROUND OF THE INVENTION
[0003] Transdermal drug delivery systems may be designed to act
locally at the point of application or to act systemically by
entering the body's blood circulation. In these systems, delivery
may be achieved by direct topical application of a substance or
drug in the form of an ointment or the like, or by adhesion of a
patch with a reservoir that holds the drug and releases it to the
skin in a time-controlled fashion.
[0004] Transdermal delivery systems for agents such as drugs, pain
relieving compounds, vitamins, and skin improving compounds have
been in use for a number of years. However, these systems have
typically only been useful for transdermal delivery of relatively
small molecules. The skin's porous structure permits such small
molecules to pass from the epidermis to the dermis via diffusion.
These transdermal delivery systems such as creams have been
developed for use with analgesics and skin refining compounds.
Transdermal systems using a patch have been developed for nicotine
and estrogen therapies. Estradiol technologies are described in
U.S. Pat. No. 6,521,250 to Meconi, et al. However, large molecules,
such as insulin, are not able to diffuse through the skin. To date
there has not been an effective and economical method to transport
such molecules through the epidermis to enter the bloodstream via
the dermal vasculature.
[0005] It has been proposed that molecules, potentially including
larger molecules, can be transported through the skin when such
molecules are contained within spherical vesicles, variously called
microparticles, microspheres, liposomes, lipid vesicles,
transfersomes, formed by hydrating a phospholipid. The resulting
vessels are water-insoluble and are dispersed and suspended in a
liquid base material which is applied to the skin to deliver the
drug. U.S. Pat. No. 6,165,500 to Cevc discloses "transfersomes,"
which are vesicles containing both a lipid and surfactant, to
achieve transdermal delivery, based on a theory that osmotic
pressure will drive the transfersomes through the dermis. Other
solutions have been proposed, including the use of ultrasound
devices to generating shock waves to enlarge pores, use of electric
current to drive substances across skin, and the use of
microneedles to pierce skin and deliver drugs into bloodstream.
(See More Than the Patch: New Ways to Take Medicine Via Skin, New
York Times, Jul. 2, 2002, page F5.
[0006] There remains a need for a transdermal drug delivery system
with the improved skin permeability and ability to transport a
wider range of substances or drugs. This problem is particularly
apparent in the transdermal delivery of substances composed of
large molecules, such as polypeptides or proteins, which do not
readily pass through the pores of the skin. Absent such a
transdermal drug delivery system, the use of injections to deliver
these substances will remain the conventional dosage method,
despite the pain, complicated administration and general
invasiveness involved therein.
SUMMARY OF THE INVENTION
[0007] The present invention relates to compositions and methods of
transdermal drug delivery comprising formulating a composition
containing the drug in a crystallized phosphatidylcholine carrier
and applying the composition to the skin.
DETAILED DESCRIPTION OF THE INVENTION
[0008] Phosphatidylcholine is used as a carrier for the topical
drug delivery of macromolecules in the practice of this invention.
Phosphatidylcholine is a basic component of cell membrane bilayers
and the main phospholipid circulating in the plasma.
Phosphatidylcholine is highly absorbable and supplies choline which
is needed to facilitate movement of fats and oils across and
maintain cell membranes in animals.
[0009] Phosphatidylcholine compositions (herein abbreviated "PC
compositions") of the present invention are formulated to contain
macromolecules soluble in PC, which are then applied to skin for
transdermal delivery of the macromolecule. PC compositions of the
invention are efficacious in the delivery of macromolecular drugs
that are conventionally administered intramuscularly, intravenously
or orally, including, but not limited to polypeptides such as
insulin and somatropin, prostaglandins, glucocorticoids, estrogens,
androgens, and the like.
[0010] It is an advantage of the invention that topical delivery is
easier and pleasanter as an administration route than injections,
particularly for drugs such as insulin that must be given to
patients over a period of time, or for a lifetime. Furthermore,
unlike oral administration where a substantial amount of the drug
can be destroyed in the digestive process, the drugs in a topical
application are not wasted. Topical application allows a steady
diffusion of the drug to the desired target area without the cyclic
dosages typical of orally or parenterally administered drugs.
[0011] Typical phosphatidylcholine compositions of the present
invention are nonpolar and contain about 85% phosphatidylcholine.
By "phosphatidylcholine" is meant a mixture of stearic, palmitic,
and oleic acid diglycerides linked to the choline ester of
phosphoric acid, commonly called lecithin. Many commercial lecithin
products are available, such as, for example, Lecithol.RTM.,
Vitellin.RTM., Kelecin.RTM., and Granulestin.RTM. because lecithin
is widely used in the food industry. Compositions of the invention
can contain synthetic or natural lecithin, or mixtures thereof.
Natural preparations are preferred because they exhibit desirable
physical characteristics and are both economical and nontoxic.
[0012] The macromolecular drugs are mixed with the PC composition
under conditions to become entrapped in a phosphatidylcholine
bilayer. Phosphatidylcholine forms a bilayer entrapping the
macromolecular drug, which may be a polypeptide, contributing to
the stability of the active molecule and enhancing penetration. The
PC composition therein comprises a carrier-drug combination to be
applied topically.
[0013] While not wishing to be bound by any particular theory, it
is believed that the following mechanism illustrates how the PC
composition acts to efficiently transport the drug across the
epidermis, maximizing penetration of the drug. The PC composition,
in liquid crystal phase, is loosely arranged in multilamellar
fashion, with the drug being bonded and entrapped within the lipid
bilayers formed by the PC composition. This forms a loosely
arranged, yet stable, PC composition carrier-drug complex. When
placed on the epidermis, the carrier-drug complex begins to diffuse
through the epidermis. The phosphatidylcholine molecular chain
remains loosely linked with the drug molecular chain and the
diffusing phosphatidylcholine molecules "drag" the drug molecules
along as they pass through the skin layers. Moreover, the
phosphatidylcholine molecules may begin to separate from the
loosely arranged carrier-drug complex and become integrated into
the dermis. As the phosphatidylcholine molecules separate from the
crystallized phophoslipid bilayer structure of the carrier-drug
complex the drug molecules are released. As these drug molecules
are released, they are now within into the dermis and may enter the
dermal vasculature so they may act accordingly in the bloodstream.
Drug molecules which were once too large to diffuse, by themselves,
into the pores of the epidermis, have instead been forced through
the epidermis by phosphatidylcholine carriers which naturally enter
and integrate into lipid bilayer structures within the cells of the
epidermis and/or dermis and resultantly are required to release
their bonds to the drug molecules and set them free within the
dermis.
[0014] Preferred PC compositions comprise phosphatidylcholine in
crystal phase to increase fluidity of the lipid bilayer formed. By
reducing rigidity and loosening the phospholipid bilayer of the PC
composition, larger molecules may embed therein and penetration of
the carrier-drug composition by the cell membrane is facilitated.
The skin is more permeable to the fluid, less structured lipid
bilayer of the PC/carrier-drug composition applied thereon than to
the drug by itself, or entrapped in an organized, arranged vesicle
such as a liposome. The loosely packed lipid bilayer of the
crystallized carrier-drug composition integrates into the cell
membrane, and as a result, has transported the drug so it can enter
the bloodstream to act upon the body. The PC composition may be a
multilamellar liquid crystal phase or a liquid crystal phase
suspension in water which may be converted to multilamellar liquid
lipid vesicles.
[0015] In preferred embodiments, nonpolar preparations of
phosphatidylcholine are formulated to contain adjunct ingredients,
e.g., lipoic acid and ascorbyl palmitate, in addition to the
macromolecular drug. The adjunct ingredients act synergistically to
help to minimize degradation and thus preserve the integrity of the
insulin polypeptide chains, and to enhance transdermal penetration
of active insulin so that it can be absorbed by the dermal
vasculature.
[0016] Preferred PC compositions of the invention contain some
polyenylphosphatidylcholine (herein abbreviated "PPC") to enhance
epidermal penetration. By "polyenylphosphatidylcholine" is meant
any phosphatidylcholine bearing two fatty acid substituents,
wherein at least one is an unsaturated fatty acid with at least two
double bonds such as linoleic acid. Preferred PPCs contain a
mixture of substitutents such as those found in natural products
such as soybean lecithin, which contains 11.7% palmitic, 4.0%
stearic, 8.6% palmitoleic, 9.8% oleic, 55.0% linoleic, and 4.0%
linolenic acid substituents and is a by-product of soybean oil
manufacture.
[0017] Certain types of soybean lecithin, for example, contain
higher levels of polyenylphosphatidylcholine, with
dilinoleoylphosphatidylcholine (18:2-18:2 phosphatidylcholine) as
the most abundant phosphatidylcholine species, than conventional
food grade lecithin, and are useful in formulating
phosphatidylcholine insulin compositions of the invention.
Alternatively, conventional soybean lecithin is enriched with PPC
by adding soybean extracts containing high levels of PPC. As used
herein, this type of phosphatidylcholine is called "PPC-enriched"
phosphatidylcholine, even where the term encompasses lecithin
obtained from natural sources exhibiting PPC levels higher than
ordinary soybean varieties. These products are commercially
available from American Lecithin, Rhone-Poulenc and other lecithin
vendors. American Lecithin markets its products with a "U"
designation, indicating high levels of unsaturation;
Rhone-Poulenc's product is a soybean extract containing about 42%
dilinoleoylphosphatidylcholine and about 24%
palmitoyllinoleylphosphatidylcholine (16:0-18:2 PC) as the major PC
components.
[0018] PC compositions are used for transdermal polypeptide
delivery in some preferred embodiments. Polypeptide drugs that are
delivered transdermally using formulations can be small, e.g.,
ocytocin and vasopressin nonapeptides or large, e.g., insulin,
gonadotropin, and somatropin. PC compositions of the invention
deliver drugs including, but are not limited to, oxytocin,
vasopressin, insulin, somatotropin, calcitonin, chorionic
gonadotropin, menotropins, follitropins, somatostatins, progestins,
and combinations of any of these. These drugs are readily available
from a variety of commercial sources. Insulin, for example, is
marketed under the tradenames Humulin.RTM., Novolin.RTM.,
Humalog.RTM., and Inutral.RTM.. Somatotropin is marketed under the
tradenames Gentropin.RTM., Humatrope.RTM., Nutropin.RTM., and
Serostim.RTM.. Some of these products and other polypeptides
contain porcine sequences. Preferable compositions of the invention
are preferably formulated with recombinant human polypeptides. It
is an advantage of the invention that PC insulin compositions are
formulated with commercially available ingredients.
[0019] One, non-limiting, example of an insulin topical preparation
was formulated by combining 0.75% methyl paraben with a commercial
phosphatidylcholine preparation marketed as a solution denoted
NAT-8729 (containing PEG-400 at 40% and P.G. at 5%) by mixing for
an hour or more to emulsify. To this is slowly added Dow Corning
Fluid 200-5 or 10 cst (1% by weight), the formulation is mixed, and
then Dow Corning Fluid 190 (1% by weight) is slowly added, and the
formulation is further mixed to provide a stock insulin carrier.
Prior to topical administration, insulin is added at a level of
about 3.8 mg/ml to provide about 100 insulin units per ml.
[0020] Another, non-limiting, example of a pituitary growth hormone
(somatotropin) composition was formulated with 85%
phosphatidylcholine to which lipoic acid and ascorbyl palmitate was
added as antioxidants. Somatotropin readily dispersed in
phosphatidylcholine and remained stable in it. Growth hormone
appeared to penetrate the skin well when the composition was
topically applied.
[0021] It is appreciated that the foregoing is illustrative and not
limiting of the invention, and that various changes and
modifications to the preferred embodiments described above will be
apparent to those skilled in the art. Such changes and
modifications can be made without departing from the spirit and
scope of the present invention, and it is therefore intended that
such changes and modification be covered by the following
claims.
* * * * *