| United States Patent |
6,458,841 |
| Fossel |
October 1, 2002 |
Topical and oral delivery of arginine to cause
beneficial effects
Abstract
The use of orally administered L-arginine in conjunction
with a topical preparation for producing enhanced blood flow
in tissue thus causing beneficial effects such as warming
cold tissue of the hands and feet, promoting hair growth on
bald scalp tissue, promoting healing of superficial Ilcers
such as leg ulcers in persons with diabetes, and overcoming
male erectile failure (impotence) is disclosed. Specifically,
use of orally administered L-arginine in conjunction with
this is topical preparation provides local delivery of the
amino acid L-arginine, an important biological precursor to
the main substance which is responsible for relaxation of
blood vessels permitting enhancement of blood flow. In the
preferred embodiments, the L-arginine is provided so that
it can be topically applied to the cold tissue. The preparation
also contains an agent which aids in the transfer of L-arginine
into the tissue. In the preferred embodiments this agent overcomes
the resistance to transfer caused by the high charge density
of L-arginine. In the preferred embodiments this means is
high ionic strength created by addition of sodium chloride.
This preparation, when topically applied to cold tissue, warming
begins within 10 to 45 minutes and is sustained for periods
as long as 2 to 18 hours. Further this preparation when applied
nightly to bald scalp tissue-for a period of time causes substantial
growth of hair on the bald scalp, causes the healing of superficial
ulcers such as leg ulcers and overcomes impotence.
| Inventors: |
Fossel; Eric T. (South
Hero, VT) |
| Assignee: |
New England Property Holdings,
LLC (Burlington, VT) |
| Appl. No.:
|
734096 |
| Filed: |
December 11, 2000 |
| Current U.S. Class: |
514/565; 424/401;
424/439; 424/450 |
| Intern'l Class:
|
A61K 031/195; A61K
006/00; A61K 047/00; A61K 009/127 |
| Field of Search:
|
514/565 424/401,450,439
|
References Cited [Referenced
By]
U.S. Patent Documents
| 5595753 |
Jan., 1997 |
Hechtman |
424/436. |
| 5629002 |
May., 1997 |
Weuffen et al. |
424/401. |
| 5925372 |
Jul., 1999 |
Berner et al. |
424/448. |
Other References
Cooper et al., "Transdermal Delivery of Drugs", vol. II,
editors Kydonieus and Berner, CRC Press, Inc., Boca Raton,
FL, 1987, pp. 57-52. (Library of Congress Card No. 86-2585).
|
Primary Examiner: Criares; Theodore J.
Attorney, Agent or Firm: Lorusso & Loud
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This is a Divisional application of U.S. Ser. No. 08/936,189,
filed Sep. 17, 1997, now U.S. Pat. No. 6,207,713 the contents
of which are incorporated herein by reference.
Claims
What is claimed is:
1. A method of promoting hair growth by delivering a nitric
oxide releasing substance selected from a member of the group
consisting of L-arginine, L-arginine salts and L-arginine derivatives
comprising the step of orally administering to the body a delivery
vehicle for the substance, said delivery vehicle containing
an effective amount of the substance and a concentration of
ionic salt sufficient to create a hostile biophysical environment
which causes the substance to migrate from said delivery vehicle
to the surrounding tissue where it is absorbed.
2. The method of claim 1 wherein the vehicle is selected from
a member of the group consisting of capsules, tablets, and liquids
containing the substance.
3. The method of claim 1 comprising the further step of topically
applying a delivery vehicle containing an effective amount of
the substance and a concentration of ionic salt sufficient to
create a hostile biophysical environment which causes the substance
to migrate from the vehicle to the selected area of skin where
hair growth is desired.
4. The method of claim 3 wherein the delivery vehicle that is
topically applied is selected from the group consisting of topical
creams, topical liquids, topical lotions and topical ointments.
5. The method of claim 3 wherein the delivery vehicle that is
topically applied is hydrophobic.
6. The method of claim 3 wherein a transdermal patch containing
the delivery vehicle that is topically applied is applied to
the selected area of the skin.
7. The method of claim 3 wherein the delivery vehicle that is
orally administered further comprises L-arginine from 0.5-30
g/day and the delivery vehicle that is topically administered
further comprises water from 20-80%, mineral oil from 3-18%,
glyceryl stearate from 0.5-12%, squalene from 0.2-12%, cetyl
alcohol from 0.1-11%, propylene glycol stearate from 0.1-11%,
wheat germ oil from 0.1-6%, glyceryl stereate from 0.1-6%, isopropyl
myristate from 0.1-6%, stearyl stearate from 0.1-6%, polysorbate
from 60 0.1-5%, propylene glycol from 0.05-5%, tocopherol acetate
from 0.05-5%, collagen from 0.05-5%, sorbitan stearate from
0.05-5%, vitamin A&D from 0.02-4%, triethanolamine from
0.01-4%, methylparaben from 0.01-4%, aloe vera extract from
0.01-4%, imidazolidinyl urea from 0.01-4%, propylparaben from
0.01-4%, bha from 0.01-4%, L-arginine hydrocholide from 0.25-25%,
sodium chloride from 0.25-25%, and magnesium chloride from 0.25-25%.
8. The method of claim 7 wherein the delivery vehicle that is
topically applied further includes choline chloride from 0.25-25%.
9. The method of claim 7 wherein the delivery vehicle that is
topically applied further comprises L-arginine glutamate (0.25-25%).
10. A method of promoting hair growth by delivering a nitric
oxide releasing substance selected from a member of the group
consisting of L-arginine, L-arginine salts and L-arginine derivatives
comprising the step of orally administering to the body a delivery
vehicle for the substance, said delivery vehicle containing
an effective amount of the substance and a concentration of
ionic salt sufficient to create a hostile biophysical environment
which causes the substance to migrate from said delivery vehicle
to the surrounding tissue where it is absorbed, in conjunction
with the step of topically applying to a selected area of skin
a topical delivery vehicle containing an effective amount of
the substance within a liposome, so that the liposome containing
the substance migrates from the delivery vehicle into the skin
where the substance is absorbed by tissue.
Description
BACKGROUND
1. Field of the Invention
This invention relates to the use of L-arginine orally alone
or in conjunction with topical application of a cream, gel,
or other vehicle which contains substances such as L-arginine
which delivers these substances into tissue for the purpose
of producing beneficial effects such as warming of cold or cool
tissues, growth of hair on the scalp, healing of leg ulcers
secondary to diabetes or confinement to bed, relief of impotence,
as well as beneficial effects through restoration of natural
mechanisms based on improvement of local blood supply.
2. Prior Art
Approaches to improving local blood flow have been many and
consist of both systemic and topical approaches. Many beneficial
effects could be obtained should improvement in local blood
flow be achieved since impairment of local blood flow causes
a variety of negative consequences. Among these are cold hands
and feet, baldness, leg ulcers, certain forms of impotence,
as well as a variety of other things. Approaches to warming
cold tissue including cold hands, fingers, feet and toes constitute
one section of the prior art. Many persons suffer from cold
hands, feet or other body parts. This is often caused by insufficient
blood flow in the cold tissue. Previously cold hands or feet
have been treated by wearing warm socks or gloves, sometimes
even socks or gloves which are mechanically heated. The use
of hot packs and glove or shoe inserts which generate heat through
chemical reactions has also been a potential solution. Certain
liniments which are essentially irritants, such as those containing
the red pepper derived substance, capsicum fall into this category.
More recently, topical creams containing nitroglycerine have
been used. See H. Natsuda et al., Ryumachi 34, 849 (1994). All
of these approaches work at one level or another though are
often extremely transient in nature. Nitroglycerine creams also
have the disadvantage that nitroglycerine is a cardioactive
drug, raising concerns of effects on the heart.
It has been recognized that deficiencies in blood flow in the
scalp occur in male pattern baldness. See G. Duplechain et al.,
J. Lousiana State Med Soc. 146, 7 (1994); P Klemp et al., J
Invests Dermatol 95, 725 (1989); S Toshitani et al., J Dermatol
17, 240 (1990). Topical minoxidil has been used as an agent
for hair growth in male pattern baldness with varying results.
Though the suggestion has been made that minoxidil operates
through increase in the blood supply to the scalp, many investigators
have failed to show such an effect. See E de Boer et al., Acta
Dermato- Venereoligica 68, 271 (1988); C Bunker et al., British
J Derm 117, 668 (1987).
The fundamental fact that cold tissue of the hands, fingers,
feet and toes as well as other cold tissue is caused by insufficient
blood flow to the tissue has been suggested. It has further
been suggested by some that the use of increased blood flow
through relaxation of blood vessels, particularly small and
very small vessels may be of use in warming cold tissue. However
reasonable this suggestion, many attempts to demonstrate warming
by use of agents which produce vasodilation and therefore increased
blood flow have produced negative results. See N Dietz et al.,
J Appl Physiol 76, 2047 (1994); S Whitmore et al., J Rheumatol
22, 50 (1995); S Singh et al., Eur J Clin Invest 25, 182 (1995).
The only report of modest temporary success involved the use
of nitroglycerine. See H Natsuda et al., Ryumachi 34, 849 (1994).
The use of the nitric oxide precursors such as L-arginine to
produce warming secondary to vasodilation has been suggested.
And a variety of indirect and non-definitive experiments have
been conducted using oral administration. See M. Sonntag et
al., Pflugers Arch 420, 194 (1992); A. Agostoi et al., Int J
Clin Lab Res 21, 202 (1991). Thus, while the literature contains
suggestions that vasodilation by administration of oral L-arginine,
the precursor of nitric oxide (endothelium ependent relaxing
factor), no reports exist of success in producing warming of
tissue using this agent. In fact Dietz (see N Dietz et al.,
J Appl Physiol 76, 2047 (1994)) concludes from his data that
"These data suggest that NO (nitric oxide) does not play a major
role in cutaneous vasodilation during body heating in humans."
Further Singh (see S Singh et al., Eur J of Clin Invest 25,
182 (1995)) in a study of patients with Raynaud's phenomenon
(severely cold hands and/or feet) concludes that L-arginine
failed to cause vasodilation (and therefore warming) in patients
with Raynaud's phenomenon.
The literature contains no suggestions or examples of the use
of L-arginine in any mode of administration for the growth of
hair in male pattern baldness, healing of ulcers of the skin,
impotence or for any other purpose.
It has long been recognized that impaired blood flow to the
penis is a major cause of erectile failure (impotence) in men.
See A Moradian et al. Am J. Med 85, 748, (1988); T Hwang et
al. J Formosan MedAssoc 89, 992 (1990). Further it has been
recognized by using isolated tissue in vitro and in animal experiments
that nitric oxide is an important mediator of relaxation of
the vessels in penile cavernous tissue. See H Kirkeby et al.
Acta Physiol Scand 149, 385 (1993). Topical nitroglycerine has
been used in the treatment of impotence because of its ability
to dilate vessels. The results were inconclusive and the treatment
not well tolerated because of the cardiac response to nitroglycerine.
See S Negelev J Urology 143, 586 (1990).
It was discovered that topical application of the nitric oxide
precursor, L-arginine, in its various forms including orally
alone or in conjunction with a variety of topical preparations,
either by themselves or with other agents to aid in penetration
such as a high ionic strength environment, neutralization of
its charge in a complex or by other means, or included in a
liposome or other biological carrier, when administered to cold
or cool tissue causes a substantial and prolonged warming effect
in the tissue, grow hair on bald scalp, facilitate healing of
superficial ulcers such as leg ulcers and overcome impotence
in many subjects.
In accordance with that invention, oral arginine by itself or
in combination with a penetrating cream containing L-arginine
at a concentration sufficient to produce an effect and sodium
chloride or other salt at a concentration sufficient to create
a hostile biophysical environment for the L-arginine in the
cream is applied to the cold or cool tissue alone and/or in
conjunction with oral arginine, exerts a warming effect which
is prolonged, often lasting from 2-18 hours. In persons with
very cold tissue (for example 22.degree. C.) this warming effect
can have a magnitude of 10.degree. C. or more.
Further, in accordance with this invention, oral L-arginine
alone or in conjunction with a penetrating cream containing
L-arginine in a concentration sufficient to produce the desired
effect along with sodium chloride or other salts at a concentration
sufficient to produce a hostile biophysical environment when
applied to bald areas of the scalp nightly either alone and/or
in conjunction with oral arginine, produced growth of new hair
within one month and substantial growth of hair within 3-4 months.
Yet further, in accordance with this invention, oral arginine
alone or in conjunction with a penetrating cream containing
L-arginine in a concentration sufficient to produce the desired
effect along with sodium chloride or other salts at a concentration
sufficient to produce a hostile biophysical environment when
applied locally as the cream directly to the penis either alone
and/or in conjunction with oral arginine, was effective in overcoming
impotence.
Consequently, with the discovery of the present invention, a
means to warm cold and cool tissue, a problem shared by many,
was developed for improving this uncomfortable and often painful
problem in human health has been found. Further with the discovery
of the present invention, a means to restore hair growth on
a bald portion of scalp has been found. Still further, with
the discovery of the present invention, a means effect healing
of superficial ulcers such as leg ulcers has been found. Yet
further, with the discovery of the present invention, a means
to overcome impotence in many men has been found.
These and other objects and features of the present invention
will become apparent to those skilled in the art from reading
the description of the invention, which follows.
SUMMARY OF THE INVENTION
Accordingly, several objects and advantages of the instant invention
are to warm cold tissue in hands, feet or other tissue by increasing
blood flow in the tissue means of enhancement of the body's
natural mechanisms. It is further an object and advantage of
the instant invention to prophylactically prevent tissue from
becoming cold by use prior to entering into situations which
induce cold hands and feet such as skiing or other winter outdoors
activities. It is further an object and advantage of the instant
invention to induce the growth of hair on bald portions of human
scalp by means of enhancement of the body's natural mechanisms.
It is yet another object of the instant invention to induce
healing of superficial ulcers of the limbs by means of enhancement
of the bodys natural mechanisms. It is still further another
object of the instant invention to provide a means for overcoming
impotence in many men.
In preferred embodiments, the delivery vehicles are capsules
or tablets containing L-arginine used alone or in conjunction
with a penetrating cream. In the cream the L-arginine is present
as L-arginine hydrochloride in a concentration sufficient to
produce the desired effect and the agent which creates the hostile
biophysical environment is sodium chloride at a concentration
sufficient to aid in tissue absorption.
PREFERRED EMBODIMENTS
The preferred embodiment consists tablets or capsules containing
200-500 mg of L-arginine to be used alone or in conjunction
with a base cream with the properties of excellent absorption
into the skin which also contains L-arginine hydrochloride (15%
w/v) and sodium chloride (10% w/v). The components of the base
cream may be those commonly found in hand creams. The purpose
of L-arginine hydrochloride is to provide a precursor to the
molecule, nitric oxide, NO. The purpose of the sodium chloride
is to provide a high ionic strength environment for the highly
charged molecule, L-arginine. The base cream containing L-arginine
and sodium chloride is the agent which is applied to the hands
and/or feet to produce to produce a warming effect in the tissue,
to produce hair growth or to effect healing of ulcers such as
leg ulcers, or directly to the penis in order to aid in overcoming
impotence.
The treatment consisting of oral administration of capsules
or tablets containing Larginine used alone or in conjunction
with the cream acts effectively to warm cold tissue such as
hands, fingers, feet, toes or other tissue when applied to the
tissue and rubbed into the tissue to assure maximal absorption.
The warming effect, caused by increased blood flow in the tissue
is not instant but begins within 5 to 20 minutes. The effect
is long lasting. Often the tissue remains warm for more than
2 to 18 hours. The treatment consisting of oral administration
of capsules or tablets containing L-arginine used alone or in
conjunction with the cream acts effectively to induce hair growth
on bald human scalp when applied nightly to the bald area each
night for several months. Hair growth is naturally a slow process.
However, substantial hair growth is achieved over large areas
of scalp with results becoming evident in a few weeks and substantial
within several months. The cream further acts to promote healing
of superficial ulcers such as those sometimes found on the legs
of persons with severe diabetes. Application twice daily for
a period. of two weeks causes substantial healing and in many
cases complete healing is achieved within this time period or
slightly longer (3-4 weeks). Further the treatment consisting
of oral administration of L-arginine used alone or in conjunction
with the cream when carried out daily for a period of 7-10 days
and then maintained with daily administration causes substantial
relief from impotence in many men.
Other Embodiments
Other Active Agents
While L-arginine hydrochloride is the preferred active agent
because it is the agent in nature itself, it is non-toxic, is
highly soluble and it is inexpensive, other agents could be
used which are also precursors or donors of nitric oxide. These
include the salt, arginine glutamate, the salt, arginine butyrate,
and esters of arginine such as arginine ethyl ester or arginine
butyl ester as well as other donors of nitric oxide. In the
case an alternative active agent were used it would be simply
substituted for L-arginine in a delivery preparation and the
preparation used as in the case of the L-arginine preparation.
Other Means of Effecting Absorption
A variety of means for effecting absorption of the active agent
from the topical cream might be envisioned. One principle behind
the absorption of a highly charged molecule such as L-arginine
into tissue is to either create a biophysically hostile environment
in the delivery vehicle such that L-arginine would prefer to
be in tissue, or to package L-arginine in such a way that it
is carried into tissue or neutralize its charge by derivitization
or forming a neutral salt. Examples of biophysically hostile
environments, include but are not limited to, high ionic strength,
high or low pH, and highly hydrophobic environments. Examples
of packaging which would be carried into tissue includes liposomes
or emulsions of collagen, collagen peptides or other components
of skin or basement membrane. Examples of neutralization of
charge include the salt, arginine glutamate which is electronically
neutral.
In each case of creating a hostile biophysical environment for
the active agent, the agent was added to an appropriate preparation.
In the case of creating a high ionic strength ions such as but
not limited to sodium chloride, potassium chloride, choline
chloride, lithium chloride, alone or in combination were added
in high concentration. Other highly charged molecules such as
polylysine, polyglutamine, polyaspartate or copolymers of such
charged amino acids may be used to create the hostile biophysical
environment. Alternatively a hostile biophysical environment
may be created by placing the highly charged L-arginine in an
hydrophobic, oily environment such as in an oil-based cream
containing little or no water.
EXAMPLE 1
In this example a person with very cold fingers was provided
with the above warming cream consisting of a delivery vehicle
of penetrating cream, L-arginine hydrochloride (15% w/v), and
sodium chloride (10% w/v). The surface temperature of the subject
fingers of the left hand varied from 21 to 24.degree. C. The
warming cream was applied through rubbing into the skin. Surface
temperatures of each finger were measured each 15 minutes for
the initial hour. At 15 minutes following administration of
the warming cream the effect had begun to occur with surface
temperatures or various fingers rising to 26 to 29.degree. C.
The maximal effect was reached by 45 minutes with surface temperatures
of various fingers becoming 31 to 34.degree. C. The effect was
sustained at least 4 hours.
EXAMPLE 2
In this example a 53 year old man with baldness consisting of
a severely receding hairline as well as large "bald spot" on
the top rear of his head was provided with a penetrating cream
containing L-arginine hydrochloride (15% w/v) and sodium chloride
(10% w/v). The cream was applied to the bald areas each night
before going to bed and was rubbed in extensively for maximal
absorption. New hair growth was noted within 2-3 weeks. Within
4 months the receding hairline (previously 4 cm of bald skin)
had returned to normal and the "bald spot" previously more than
7 cm in diameter had been reduced to an area of less than 2
cm with even this area showing some new hair growth.
EXAMPLE 3
In a 54 year old man with a history of impotence administration
of 1.5 g L-arginine daily in the form of oral capsules combined
with twice daily administration of a penetrating cream containing
L-arginine hydrochloride (15% w/v) and sodium chloride (10%
w/v) directly to the penis for 7 days brought initial relief
from the symptoms of impotence and allowed the subject to resume
normal sexual activity.
This relief of symptoms was maintained by continuation of the
treatment daily.
Accordingly, it can be seen that in the present invention I
have provided a method and agents, which when applied to cold,
and often painful tissue, an increase in skin temperature results
through utilization of one of the body's own mechanisms for
producing warmth. This effect is achieved by providing the biochemical
substrate at the local site from which the controlling substance,
nitric oxide, is produced. Nitric oxide causes increases in
local blood flow which results in warming. Further, it can be
seen that in the present invention I have provided a method
and agents which when applied to bald scalp causes hair growth
through utilization of one of the body's own mechanisms. This
effect is achieved by providing the biochemical substrate at
the local site from which the controlling substance, nitric
oxide is produced. Nitric oxide causes increases in local blood
flow which enables the growth of hair. Still further it can
be seen that in the present invention I have provided a method
and agents which when applied to leg ulcers cause healing through
use of the body's own mechanisms. Yet still further, it can
be seen that in the present invention I have provided a method
and agents which when applied to a person with impotence causes
overcoming of impotence by use of the body's own mechanisms.
This effect is achieved by providing the biochemical substrate
at the local site from which the controlling substance, nitric
oxide is produced. Nitric oxide causes increases in local blood
flow allowing the body's own healing cells and substances to
reach the ulcer site.
Although the description above contains many specificities,
these should not be construed as limiting the scope of the invention
but as merely providing illustrations of some of the presently
preferred embodiments of this invention. Various other embodiments
and ramifications are possible within this scope. Thus the scope
of the invention should be determined by the appended claims
and their legal equivalents, rather than by the examples given.
* * * * *
|
