WO2006055726A2 - Composition and method for facilitating the healing of non-healing and slow-healing wounds and ulcerations - Google Patents

Abstract

A composition for treatment of non-healing and slow-healing wounds and ulcerations, and for treating and preventing peripheral neuropathy. The composition is primarily characterized by a combination of nitroglycerin, arginine and curcumin. Preferred embodiments comprise emollient cream, mineral oil, and zinc oxide.

Description

APPLICATION UNDER THE PATENT

COOPERATION TREATY

TITLE: COMPOSITION AND METHOD FOR FACILITATING

THE HEALING OF NON-HEALING AND SLOW-

HEALING WOUNDS AND ULCERATIONS

CITATION TO PRIOR APPLICATION

This is a CONTINUATION-IN-PART with respect to U.S.

Application, Serial No. 10/992,636, filed 17 NOVEMBER

2004 (17.11. 2004) and of U.S. Application Serial No.

10/992,623, filed 17 November 2004 (17.11.2004) from both

of which priority is claimed under 35 U.S.C. §120 and

under provisions of the Paris Convention and of the

Patent Cooperation Treaty.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally relates to an

improved composition for treatment of a skin condition.

More specifically, the present invention relates to an

improved composition for treatment for common types of skin ulcers, including diabetic, stasis, and decubitus

ulcers.

2. . Background Information

Wound healing is a highly complex process, involving

multiple, co-ordinated interactions of multiple factors

and agents. Poor wound healing in diabetics, patients on

dialysis, elderly in nursing homes, paralyzed/confined

patients in wheel chairs, and patients on hospice is

believed to relate to circulatory impairment and its

sequlae.

Extensive research leads the present inventors to

believe that the most vital elements for successful wound

healing are:

1. Nitric Oxide;

2. Endothelial nitric oxide synthase (eNOS/iNOS)

(enzyme to make NO from arginine which is in sufficient

amounts in properly functioning endothelium and not in

diabetic and other compromised patients) ;

3. L-arginine (arginine is needed in sufficient

amounts in local tissues to be acted on by eNOS to make NO and is .often deficient in diabetic and other

compromised populations) ;

4. Peptide growth factors (especially transforming

growth factor beta- TGF-beta) ;

5. A healthy blood supply (local and systemic);

6. Ability to form new blood supply (angiogenesis) ;

7. Elimination or absence of microbes causing

infection/excessive inflammation;

8. Sufficient macrophages;

9. Normal levels of homocysteine;

In highly compromised populations, such as

diabetics, dialysis patients, confined patients, and the

chronically ill and elderly, many of these essential

factors are missing, or are deleteriously defficient.

The present inventors believe that, when all the

above factors are in proper balance, de facto debridement

occurs, new cell island matrix flourish, pernicious

microbes are minimized, and the three stages of wound

healing (a healthy amount of inflammation, proliferation

and remodeling) occur efficiently and rapidly.

Various treatments for ulcer-type skin conditions

are known in the art, yet none addresses the totality of 5 041708

4 factors needed to adequately and successfully facilitate

healing of that which would be described clinically as

"non-healing" or "slow-healing" wounds and ulcerations.

Facts and statistics relating to non-healing and

slow-healing wounds and ulcerations, and their underlying

origins or propensities, are sobering.

Type II diabetes is one such factor, and is the most

common form of the disease, accounting for 90 to 95

percent of all diabetes cases.

Throughout the world, the incidence of Type II

diabetes is nearing epidemic proportions. Examination of

current and expected diabetic trends (and the detrimental

effects therefrom) is helpful for grasping the tremendous

need for the present invention.

By way of example, the Center for Disease Control

and Prevention ("CDC") reports an increase in the cases

of diagnosed adult diabetes of 49% between 1990 and 2000.

Further, the CDC estimates the diabetes, both diagnosed

and undiagnosed, affects approximately seventeen million

Americans (or some 6.2% of the U.S. population) .

Diabetes is a prevalent disease and an ever-growing

domestic and international public health concern. The 005/041708

5 World Health organization estimates that approximately

150 million people are affected by diabetes; and, these

numbers are expected to only get worse (estimated 215

million people affected by 2010; estimated 300 million

people affected by 2025) . Worldwide, diabetes has a

relatively high mortality rate. Diabetes is reportedly

among the top five causes of death by disease in most

countries, though this may be a conservative ranking.

More likely, diabetes is even more deadly as it is

frequently under-reported on death certificates.

Importantly for present purposes - the occurrence of

diabetes and skin ulcers and non-healing wounds and

ulcerations is directly related. Accordingly, the sharp

increase in the number of diabetes cases has led to an

increase in the number of people affected by non-healing

and slow-healing wounds and ulcerations.

By way of example, diabetics have a fifteen percent

chance of developing a foot ulcer during their lifetime.

Of those diabetics that develop foot ulcers,

approximately twenty percent will require amputation.

(International J of Pharm Compounding 8 (4) July/August

2004, 269) . Such amputations are also increasing at an 08

6 alarming rate. Between 1990 and 2000, the number of

amputations resulting from foot ulcers increased by

twenty six percent. This trend is expected not only to

continue, but to worsen in the coming years. Foot ulcers

cause approximately eighty five percent of all diabetic

amputation of the lower extremities (Emergency Medicine

36(8) Au 2004, 14-23) . The number of such lower

extremity amputations (LEA' s) now exceeds 100,000 per

year!

Recurring foot ulcers, and the amputations that may

result, present a continuing problem on a national and

global scale. In the event that an ulcer is successfully

treated, it is more likely than not that the ulcer will

reoccur. Recurrence rates associated with diabetic foot

ulcers and resulting LEA's are commonly as high as fifty

percent to seventy percent over a period of three to five

years .

Those skilled in the art of wound treatment realize

that the accepted standard of care is simply not working.

Current medications and modes of treatment all too

commonly fail to heal wounds and ulcers in compromised patients, and thereby fail to prevent such complications

as infection and gangrene.

Overall, fifty to eighty percent of patients having

diabetic foot ulcers will heal within six months-

assuming optimal management from a multi-disciplinary

team. (Emergency Medicine 36(8) August, 2004, 14-23) .

However, all too common complications require

hospitalization, painful and expensive surgery, and a

prolonged rehabilitation regimen (if rehabilitation is

possible at all) . With the incidence of ulcer recurrence

as high as seventy percent, the healing of one ulcer is

often rapidly followed by the development of a new one.

In view of the serious, and often unconquerable

consequences of diabetic ulcers alone, and in further

view of the need to address non-healing and slow-healing

wounds and ulcerations in other compromised patient

populations, a great need exists for an improved

treatment for non-healing and slow-healing wounds and

ulcertations. There is more, however.

Another collateral, or even related condition which

afflicts many in the same patient populations as those

discussed above with respect to non-healing and slow- healing wounds and ulcerations is that of peripheral

neuropathy. Many of the same conditions and

circumstances that contribute to non-healing and slow-

healing wounds and ulcerations also contribute to, cause,

or exacerbate peripheral neuropathy.

Known treatment regimens rely heavily on the use of

debridement and washing (clearly involved in the present

standard of care) . In fact, with only conventional wound

treatment regimens available, such steps are necessary,

though debridement and washing typically results in

scarring, non-closure of the wound, and/or recurrence.

In summary, the present state of would care is

woefully deficient, and leaves many patients with"

unending pain, loss of extremities, general disability,

and even death.

SUMMARY OF THE INVENTION

In view of the above, the general purpose of the

present invention, which will be described subsequently

in greater detail, is to provide a uniquely efficacious

composition and associated method for the treatment of

non-healing and slow-healing wounds and ulcerations, as well as peripheral neuropathy, which composition and

method are neither anticipated, rendered obvious,

suggested, nor even implied by any of the known

compositions or methods of treatment, either alone or in

any combination thereof.

Therefore, it is an object of the present invention

to provide a composition for treatment of non-healing and

slow-healing wounds and ulcerations.

It is another object of the present invention to

provide a composition and method for treating (or

preventing) peripheral neuropathy.

It is another object of the present invention to

provide a compound and associated method of use thereof

in the treatment of wounds and ulcerations, which

composition and use thereof .obviates the need for

debridement in wound and ulcer treatment.

It is another object of the present invention to

provide a method for treatment of wounds and ulcerations,

with particular efficacy for previously non-healing and

slow-healing wounds and ulcerations.

It is another object of the present invention to

provide a composition and associated method for treatment of non-healing and slow-healing wounds and ulcerations,

at least in part, by effecting to an unprecedented level,

improvement of circulation at the wound site and

associated healing in otherwise non-responsive patients.

It is another object of the present invention to

provide an improved composition for treatment of non¬

healing and slow-healing wounds and ulcerations that

effects a high degree of pernicious microbe eradication,

without requiring debridement or other pre-medication

would or ulcer manipulation or alteration.

It is another object of the present invention to

provide an improved composition for treatment for non¬

healing and slow-healing wounds and ulcerations that

facilitates peripheral nerve growth and regeneration.

It is yet another object of the present invention to

provide an improved composition for treatment for non¬

healing and slow-healing wounds and ulcerations that

effects and utilizes synergistic action of Arginine,

Nitroglycerin and Curcumin.

In satisfaction of these and other related objects,

the present invention provides a composition and

associated treatment method for the treatment of non- 08

11 healing and slow-healing wounds and ulcerations, as well

as the remediation or prevention of peripheral neuropathy-

associated with impaired circulation. The present

invention, by way of a novel composition and associated

methods of applying that composition, yields results that

simply are not possible with any other known treatments.

The composition of the present invention comprises,

principally as active ingredients, nitroglycerin,

arginine, and curcumin which have been found by the

present inventors to work synergistically to increase the

absorption and distribution of each other, as well as to

effect an unprecedented therapeutic result. In addition,

however, other ingredients (such as the recited zinc and

aloe vera constituents) are instrumental in maintaining

the medicament on-site for treatment of wounds and

ulcerations, such that the optimal therapeutic result is

achieved.

A few practical examples, experienced first hand by

the present inventors, will reveal the unique benefits of

the present invention:

Patient B has had diabetes for several years, the

last two of which he has been confined to a wheel chair. 005/041708

12

During this past year Patient B has been hospitalized for

non-healing pressure ulcers on his buttock region. Every

developed ulcer has caused a tremendous amount of pain an

suffering. Also, these ulcers have necessitated surgery

and costly medical bills. Complication of these ulcers

extended to the pelvic bone, which required removal of a

portion of the bone. The present composition was applied

to the wound one time per day for a period of three days .

By the third day of treatment the wound had decreased in

size by approximately twenty five percent. Also, the

wound was radically improved, where approximately thirty

percent of the wound had been covered with new white

granular tissue with obvious healing occurring throughout

the entire ulcer. During the next three days, the

composition was applied twice daily. After a total of

six days of treatment, the original wound was virtually

covered with new tissue growth.

Before application of the present composition,

Patient F had lost one finger tip to an ulcer and poor

circulation. Her entire hand was rigid and swollen.

Before treatment, several of Patient F's fingers were at

risk of amputation. After a week of application of the present composition, her hand was soft and mobile, had

better circulation, less pain, and a reduction of dark

areas marked by poor blood flow. A single lesion had

been open to the bone; however, after three days of

treatment the lesion went from oozing blood and pus to

being completely closed. According to standard treatment

protocols, Patient F's lesion would have been reopened

for further drainage. However, the present regimens

avoids such a necessity.

Patient F has an open scalp lesion of approximately

two centimeters in length. After three days of treatment

(where the patient continued to wash the wound against

Applicant's advise), the lesion had decreased by seventy

percent. From the fourth to sixth day, the patient did

not wash the wound. By the night of the forth day the

lesion has completely closed, By day six, the patient

reported a fifty percent reduction in pain such that she

could rest her head upon a pillow to sleep.

Patient G had a developing lesion between her

buttocks, which appeared to have a monilial infection.

Applicant fear the overlying yeast infection would block

entry of the present composition. After two days of treatment, the lesion had improved by some fifty percent.

After a week of treatment, the lesion had completely

healed and the patient reported a tremendous decrease in

pain and overall discomfort.

In its preferred form (as presently believed, though

variations in relative constituency will fall well within

the scope of the present invention) , the present

composition comprises: nitroglycerin (Nitrobid) 2%

ointment, an emollient cream base (PCCA emollient cream

formulation) , mineral oil (light 65-75 VIS liquid) ,

Curcumin Powder 95% (or a curcumin-containing ingredient,

such as a measure of tumeric sufficient to provide the

desired measure of curcumin, or even a synthetic

curcumin), Aloe Vera (freeze dried 200:1 powder), Zinc

Oxide USP, and Arginine (L) USP (HCL powder) . This

composition is formed as the triturate powders and wet

powders are combined with the mineral oil and then

thoroughly mixed with emollient cream, QS ' ed to the

desired volume.

Associated application of the present composition

are generally characterized by the topical application.

However, application by injection of the aforementioned composition may be appropriate under certain

circumstances. When injected, the medication is

typically delivered by syringe in amount depending on the

size and depth of the particular lesion. Generally,

syringes between % CC and 2CC are sufficient.

The treatment protocol essentially involves leaving

the wound alone to heal on its own. That is, the wound

is not to be interfered with and use of anti-bacterial or

anti-microbial soaps is to be avoided. Debridement and

washing of the wound are to be avoided (such has been

discovered to promote scarring, non closure, and

recurrence of the ulcer) . After application of the

composition (usually b.i.d.), the wound is typically

covered with a tefla pad (or some equivalent) and

breathable tape. This allows the wound to remain fairly

dry (substantially free of any undue moisture) and open

to the surrounding air.

While the characteristics unique to this treatment

protocol may at some point, at first appear to be subtle

distinctions vis a vis existing prior art, these

distinctions self-evidently yield a regimen that is

different from any such known in the art and produces unexpected (and previously unachievable) results. For

instance, the present method increases blood flow to

nerves thereby increasing nerve growth. This expedites

the growth of new island cells and allows skin to take

root and grow. This appears to be a primary reason for

the improved results not seen in any of the known

treatment regimen for wound, ulcer or neutopathy

consitions.

Further, Applicant has devised a compound that

creates effective vasodilation of the underlying-

capillary bed in patients with compromised vascular

function The present invention eliminates the need for

debridement while acting as an agent or substantially

eradicating pernicious microbes.

While the synergistic action of the three primary

constituents are likely not fully understood or explained

at this time, the individual actions of the

nitroglycerine, arginine and curcumin, and some aspects

of their complimentary actions have been revealed, at

least in part, through the present inventors' research

and experimentation,

Nitroglycerine Nitroglycerin is a nitrate that has been approved by

the FDA since 1938 to dilate blood vessels. It is

frequently used in the management of angina pectoris. It

was first synthesized in 1846 and first used in cardiac

therapeutics by physicians since 1879.

Nitroglycerin is a nitric oxide (NO) donor. NO is a

small radical that is pivotal for wound healing. Nitrates

preferentially dilate blood vessels that are compromised.

Nitroglycerin acts by donating nitric oxide, which

relaxes the walls of blood vessels, especially large

microvessels .

Non healing wounds especially in diabetic and

dialysis patients are notoriously deficient in nitric

oxide, as well as the specific enzymes that are involved

in nitric oxide local production and in the substrate

needed to make NO (the amino acid L-arginine) .

Why is NO essential to enhance healing at the wound

site?

1. NO improves angiogenesis (Angiogenesis is the

process by which new blood vessels form by sprouting from

pre-existing vessels) ; 2. NO improves inflammation (healthy inflammation is

stage one of wound healing, but then it must be

contained. NO does not allow it to intensify) ;

3. NO promotes cell proliferation;

4. N0 enhances matrix deposition;

5. NO helps speeds up remodeling;

6. NO promotes re-eptithlialization (Journal of

Investigative Dermatology 1999 Dec;113 (6) :1090-8) which

enhances closure of the wound.

7. NO decrease viscosity by inhibiting platelet

aggregation (diabetics and dialysis patients, and often

ill and elderly, have excessive clotting of platelets

which reduces circulation and healing) (Biological

Pharmacology Bulletin 2003 Aug;26 (8) :1135-43) ; and

8. Nitrates enhance circulation by increasing red

blood cell (erythrocyte) deformability. (International

Journal of Clinical Pharmacologic Therapeutics 1998

Jul;36 (7) :398-402. )

Therefore, nitroglycerin:

1. Enhances arterial and venous vasodilation/

circulation in large microvessels by donating NO; 2. Enhances erythrocyte deformability (enhances

local circulation) ;

3. Decreases blood viscosity (improving local

circulation) ; and

4. Improves tissue -oxygen tension (tcpO2) (improving

circulation and distribution of vital factors to all

cells) .

In the past, a problem with the use of nitroglycerin

is that of headaches occurring in a significant number of

patients. Among its many other positive attributes, the

present composition, though utilizing nitroglycerin,

produces no reported problems with headaches . The

present inventors believe that this somehow relates to

the presence of curcumin in the composition.

Another feature of nitroglycerine, as revealed

through prior investigations for use in wound care,

relates to the rapidity of its physiological reactions

and ultimate dissipation. This characteristic has greatly

limited nitroglycerine's efficacy, when used alone, in

wound care, because, to put it plainly, it did not stick

around long enough to effect significant would healing.

Further still, prior attempts to use nitroglycerin alone, or in other combinations, revealed some patients'

tendency to develop tolerance for the drug, with reduced

efficacious results (such as were, to a limited degree,

achieved in the first instance) .

The combination of L-arginine and curcumin with

nitroglycerine, as later detailed, provides a therapeutic

compound which is more long acting, overcomes the

tolerance issue, and also eliminates the headache side

effects .

Curcumin

Curcumin (diferuloylmethane) , is a natural product

and the most active isolated substance obtained from the

plant Curcuma longa (tumeric) . Curcumin promotes wound

healing by a number of mechanisms.

Curcumin significantly accelerates wound healing as

it enhances "expression of TGF-betal and TGF-beta tllrc,

both in normal and impaired healing wounds as

demonstrated by immunohistochemistry (Biofactors

2002;16 (1-2) :29-43) .

Curcumin increases eNos/iNOS within a wound.

As discussed above, NO is a vital factor in wound healing

and its production is regulated by inducible nitric oxide synthetase (iNOS) or also called endothelial NO (eNOS)

During cutaneous wound repair, iNOS is induced in large

quantities, in a normal non compromised patient.

Decreased circulation, poor nutrition, deficient local

enzymes, excess sugar within cells, insufficient arginine

levels, all decrease the inducibility of iNOS. The

presence of a functionally active iNOS is a crucial

prerequisite for normal wound reeptithelialization (J

Investigative Dermatology 1999 Dec;113 (6) :1090-8)

Curcumin enhances macrophage production (white

blood cells that function to engulfs and kill foreign

pathogens and microbes)

Curcumin augments vasodilation (Biological

Pharmaceutical Bulletin 2003 Aug;26 (8) :1135-43) .

Curcumin demonstrates anti-inflammatory action

against mediators of inflammation (Phytomedicine 2005

Jun;12 (6-7) :445-52. Purified curcumin (More than other

curcutninoids in tumeric: demethoxy- or

bisdemethoxycurcumin) was found to reduce inflammatory

mediators in vitro study.

In experimental animals curcumin has been shown to

be anti-diabetic, anti-inflammatory, cytotoxic and have anitoxidant properties (Medical Science Monitor 2005

JuI¹¹Il (7) :BR228-234) .

Curcumin helps fight off pathogens acting as a

natural antibiotic.

Curcumin has been found to be effective against

bacteria, viruses and fungi.

Curcumin reduced mediators of inflammation from

Neisseria gonorrhoeae-induced NF-kappaB signaling.

Curcumin abolished the adherence of bacteria to cells in

infection, emphasizing the high potential of curcumin as

an anti-microbial compound without cytotoxic side effects

(Biological Chemistry 2005 May;386 (5) :481-90) .

Curcumin has antimicrobial action (Journal of

Ethnopharmacology 2005 May 13,-99 (1) :147-51 (Letters of

Applied Microbiology 2004;39 (5) :401-6) .

Curcumin has antifungal properties - 100% phytotoxic

against Lemma minor, Fitoterapia 2005 Mar;76 (2) :254-7.

Curcumin is anti-inflammatory, antioxidant,

anticarcinogenic, antiviral and antiinfectious activities

(Critical Reviews for Food Science and Nutrition

2004;44 (2) :97-lll) .

Curcumin shows antibacterial, anti-inflammatory, and antineoplastic activity (J Pharmacologic Pharmacology

2000 May:55 (5) :593-601. Study assessed curcumin in vitro,

and with skin absorption of Wistar rats.

Curcumin enhances angiogenesis (Journal of

Physiologic Pharmacology 2005 Mar;56 Suppl 1:51-69.

Angiogenesis is a prerequisiste for wound healing.

Curcumin is frequently studied for it's role in enhancing

angiogenesis) .

Curcumin has been shown in many animal studies to

accelerate the repair of excision wounds in mice whole

body exposed to various doses of gamma radiation (Journal

of Surgical Research 2004 JuI;120 (1) :127-38.

Radiation disrupts normal response to injury and

inhibits normal wound healing and increasing the time of

healing. Rats pretreated with curcumin and then exposed

to radiation, enhanced wound contraction, decreased

healing time, increased synthesis of collagen,

hexosamine, DNA, and NO, and improved fibroblast and

vascular densities. (Surgical Research 2004

JuI;120 (1) :127-38) /

Topical curcumin enhances cutaneous wound healing in

rats and guinea pigs. Curcumin was effective both orally and topically in diabetic rats and mice. (Wound Repair

Regeneration 1998 Mar-Apr' 6 (2) :167-77.

Wounds of animals treated with curcumin showed

earlier re-epithelialization, improved

hneovascularization, increased mmigratioh of various

cells including dermal myodfibroblasts, fibroblasts, and

macrophages into the wound bed, higher collagen content,

and increase in transforming growth factor-betal

confirmed by in situ hybridization and laser scan

cytometry.

Transforming growth factor-betal enhances wound

healing and curcumin increases the mRNA transcripts for

this growth factor, demonstrating that it enhances the

bodies own production of this growth factor, in a natural

manner, which may be one mechanism of enhanced wound

healing by curcumin (Wound Repair and Regeneration 1998

Mar-Apr;6(2) .167-77) .

With respect to safety, curcumin has been used in

Phase 1 clinical trials. There was no treatment-related

toxicity up to 8,000 mg/day and beyond that the only real

problem being the bulky volume was unacceptable to the

patients. This was taken orally, and our new drug is via the skin, which reduces systemic exposure significantly.

(Anticancer Research 2001 Jul-Aug;21 (4B) :2895-900)

With respect to the contribution of Arginine to the

efficacy of the present composition, NO is generated in

the local endothelium through the oxidation of the amino

acid L-arginine. This occurs due to the action of the

enzyme eNOS/iNOS.

NO casues vascular smooth muscle to relax causing

vasodilation. In addition to being the substrate for

eNOS, L-arginie facilitates the dimerization of two

identical subunits (Diabetes Care. 2004

Jan;27 (1) :284-5) , forming a homodimer. The enzyme is only

active in the dimeric form. Under proper conditions,

dimerization occurs rapidly, on a timescale of minutes.

Once formed, the dimmer is stable (Journal of Biological

Chemistry 2002 277:310200-31010)

Arginine

Arginine is a substrate to make NO, a particular

benefit in use for diabetic and dialysis patients, both

who have impaired wound healing, in part, because of a

reduction in nitric oxide at wound sites, as is a

characteristic of their conditions. The amino acid L-arginine is the only substrate for nitric oxide

synthesis.

Treatment in diabetically rendered mice with

L-arginine injections significantly increased wound fluid

nitrite/nitrate levels. The data demonstrated that the

impaired wound healing of diabetic rats can be partially

corrected by L-arginine supplementation, and that this

effect is accompanied by enhance wound nitric oxide

synthesis. Wound Repair Regeneration 2003

May-Jun;11 (3) :198-203) .

NO is a small radical, formed directly from the

amino acid L-arginine by three distinct isoforms of the

enzyme nitric oxide synthase. The inducible isoform

(iNOS) is synthesized in the early phase of wound healing

by inflammatory cells, mainly macrophages. Curcumin

enhances this production.

During the next proliferative phase, many cells

participate in NO synthesis.

NO released through iNOS regulates collagen

formation, cell proliferation (new growth of cells to

fill in the wound) , and wound contraction (for the wound

to start growing smaller in the healing process) . Arginine together with NO and curcumin administration

promotes these aspects of wound healing.

Arginine regulates dimerization locally, and

enhances wound strength and collagen deposition in

rodents and humans (Wound Repair Regeneration 2003

May-Jun_;ll(3) :198-203) .

Synergy between Arginine and Nitroglycerin

Arginine dilates small microvessels. The present

inventors believe that L-arginine and nitroglycerin

compliment each other, in part, because nitroglycerine

rapidly dilates relatively larger vessels than optimally

does arginine, whereas arginine tends to reside longer at

the wound site (or any other tissue site of

administration) . Thus, nitroglycerine "opens the door"

for arginine to get where it needs to be to effect wound

healing, after which, though the nitroglycerine (and its

effects) have passed, the arginine remains to effect

wound healing.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

In the preferred embodiment of the present

medicament, and in the medicament upon which an

associated method of treatment is based, the primary active ingredients are Nitroglycerin, Arginine, and

Curcumin. In this preferred embodiment, the

Nitroglycerin is in the form of two percent ointment

(NITROBID) ; the arginine is in the form of Arginine (L)

USP, and the Curcumin is in 95% powder form.

The preferred nitroglycerin-arginine-curcumin-based

compositions of the present invention may be prepared

according to the following disclosure and protocol, with

variations appropriate to a desired scale or production

as will be apparent to person skilled in the production

of pharmaceutical preparations:

A. Constituents of Preferred Embodiment of

Composition for remediation of dermal anomalies

Ingredients Quantity

Nitroglycerin (Nitrobid) 2% ointment 10 GM

Arginine (L) HCL Powder 10 GM

PCCA Emollient cream base 100 GM

Mineral Oil, Light 65-75 VIS liquid 8.33 ML

Curcumin 95% Powder .07 GM

Aloe Vera freeze dried 200:1 powder .2 GM

Zinc Oxide USP 1 GM

Total: 124.5 GM B. General Mixing Procedure of Preferred

Embodiment of the Composition of the present invention:

1. Triturate powders and wet powders with mineral

oil and mix thoroughly with emollient cream.

2. Q.S. to desired volume.

The formed composition may then be applied topically

to any wound or ulceration (without debridement or

washing) , usually b.i.d. A treatment period between

three and ten days is thought to be sufficient to heal

the large majority of treated wounds. Extremely specific

dosage is not now believed to be critical, and a "general

coverage" of the wound site, generally such as one would

apply a sun screen or other lotion, will produce the

therapeutic result.

As with any multi-constituent composition, the

recited, relative measures of constituent ingredients may

be varied to some degree, without noticeably affecting

the therapeutic effect of the present composition.

For example, the present .2% Nitroglycerin

formulation described above (2mg per gram of medicament)

is believed optimal, but.lmg per gram to 50mg per gram is believed still safe (non-toxic) and efficacious, and,

even if not optimal, still within the scope of the

present invention, when used in combination with arginine

and curcumin.

Likewise, the present formulation of arginine (0.1%

or lOOmg per gram at 10%) is believed variable between

lmg per gram up to lOOOmg per gram, with retained safety

and efficacy. Curcumin is presently shown at an.08%

strength ( .8mg per gram) , and a range of .1 mg per gram

up to 50 mg per gram of medicament is believe efficacious

and safe (and clearly within the scope of the present

invention if efficaciously used as described, with the

other active ingredients) ..

Furthermore, no evidence presently available would

indicate that variations of relative constituency would

defeat efficacy or safety. For example, even a 1:2 ratio

(in either direction) of nitroglycerine and arginine

would not, it is presently believed, defeat the essential

therapeutic effects of the present composition, though

the recited formulation appears to be roughly a center

point of the efficacious mixture. Therefore, although the invention has been described

with reference to specific embodiments, this description

is not meant to be construed in a limited sense. Various

modifications of the disclosed embodiments, as well as

alternative embodiments of the inventions will become

apparent to persons skilled in the art upon the reference

to the description of the invention. It is, therefore,

contemplated that the appended claims will cover such

modifications that fall within the scope of the

invention.

Claims

CLAIMSI claim:

1. A topical, medicinal composition comprising:

nitroglycerin; and

arginine.

2. A topical, medicinal composition comprising:

nitroglycerin;

arginine; and curcumin.

3. A topical viscous medicament for topical

application to wounds and ulcerations

comprising:

nitroglycerin;

arginine; and

curcumin;

said nitroglycerin, arginine; and said

curcumin being suspended in a viscous

carrier medium.

4. The medicament of Claim 3 wherein said

nitroglycerin, arginine; and curcumin are present in

approximately ten parts nitroglycerin, approximately ten

parts arginine, and approximately 1 part curcumin.

5. The composition of claim 3 wherein said viscous

carrier medium comprises an emollient cream and a zinc-

containing ingredient.

6. The composition of claim 3 wherein said viscous

carrier medium comprises an emollient cream and a quantum

of mineral oil.

7. A topical medicament for treatment of wounds

and ulcerations comprising:

Nitroglycerin (Nitrobid) 2% ointment;

Arginine (L) HCL Powder;

an emollient cream base;

a first measure of an oil;

curcumin powder;

a first measure of aloe vera approximately; and

a zinc-based compound.

8. A topical medicament for treatment of wounds

and ulcerations comprising: Nitroglycerin (Nitrobid) 2% ointment,

approximately 20 parts by weight;

Arginine (L) HCL Powder, approximately 20 parts

by weight;

an emollient cream base;

a first measure of an oil;

curcumin powder, approximately 2 part by

weight;

a first measure of aloe vera approximately 1

part by weight; and

a zinc-based compound, approximately 2 part by

weight.