THE TREATMENT OF VASCULAR DISEASE WITH PROSTAGLANDINS VIA A SUSTAINED-RELEASE DERMAL PATCH

Related Applications

This application claims priority from Provisional Application

60/01 8,828 filed May 30, 1 996.

Background of the Invention

Prostaglandins comprise a class of compounds denominated as

derivatives of the hypothetical prostanoic acid as shown below:

'prostanoic acid'

All naturally occurring prostaglandins have a double bond in the

trans configuration between C-1 3 and C-14; additional double bonds

occur in the cis configuration between C-1 7 and C-18. Prostaglandins are

a collection of short-lived chemical mediators within the body which

control numerous functions, including smooth muscle contraction (as in

peripheral resistance to blood flow through small arteries and degree of

muscular activity in the uterus and small intestines), exocrine gland

secretion (such as tear and saliva flow), and components of the immune

response. The starting material for biosynthesis of these specialized

mediators is a group of substances in the diet called essential fatty acids.

Here, the term "essential" means that the body cannot chemically produce

these starting materials and, like vitamins and certain amino acids, must

1/1

obtain them from the diet. Essential fatty acids are better known by the

term "polyunsaturated fats."

2

Investigational clinical studies of the effect of intravascular infusion

of prostaglandins have been carried out in various subjects, including

some with end-stage arteriosclerotic peripheral vascular disease. Some

studies have found a marked and often persistent clinical improvement in

end-stage arteriosclerotic peripheral vascular disease symptoms. This

effect is noted well beyond the time of prostaglandin infusion for a high

percentage of these patients with end-stage peripheral vascular disease.

The physiologic (or pharmacologic) mechanism by which this clinical

improvement occurs is currently a subject of debate. Furthermore, clinical

application of prostaglandin therapy has been minimal due to the extreme

biochemical instability of the natural prostaglandins and the consequent

difficulty of routinely parenterally administering such unstable compounds.

Attention is drawn to "Prostanoids Stimulate Fibrinolysis in the Rat,"

Arch, int. Pharmacodvn. 296: 155-1 62 (1988); "Effect of Prostacyclin on

Fibrinolytic Activity in Patients with Atherosclerosis Obliterans, "

Dembiήska-Kiec et al., Thromb Haemostas (Stuttgart.. 47(2):1 90 ( 1 982);

"Effect of Prostacyclin (PGI ₂ on Platelets and Fibrinolytic Activity in

Patients with Atherosclerosis Obliterans," Dembiήska-Kiec et al.,

Pharmacological Research Communications. 14(6):485-498(1 982); and

"Prostacyclin and the Fibrinolytic System in Ischemic Vascular Disease,"

Szczeklik et al., Thrombosis Research. 29:655-660 (1983), the teachings

of which are incorporated herein by reference.

The E ₂ prostaglandin analogue CL1 1 5,347 (Cyanamid International)

has been administered transdermally in a study directed to the treatment

3 of Raynaud's Disease. Blech βt al., "Double-Blind Trial of CL1 1 5,347, a

Transdermally Absorbed Prostaglandin E-, Analogue, in Treatment of

Raynaud's Phenomenon." The Lancet. 1 : 1 180-1 183 (1 985). The authors

particularly note that questions have been raised as to using

prostaglandins at vasodialatory levels or other vasodilator drugs in

atherosclerotic peripheral disease. Id., 1 183. The phenomenon of

generalized vasodilation "stealing" blood from maximally dilated ischemic

areas has been postulated. In clinical practice, stealing is not believed to

be a problem. Vasodilation occurs only at a range of prostaglandin doses

higher than those achieved with clinical intravenous infusion regimens.

Without being bound by any particular theory, it is believed that in the

method of this invention, misoprostol administered as described below

does not substantially dilate ischemic vessels. The data that indicate the

important therapeutic property of prostaglandins in this medical

phenomenon is their property of stimulating endogenous fibrinolysis.

An aspect of this invention is to exploit a route of administration of

the prostaglandin or prostaglandin analog in non-vasodilatory

concentrations which will circumvent the gastrointestinal effects of oral

prostaglandin administration. This aspect is particularly distinct from the

presentation with regard to vasospastic disease (i.e. in Raynaud's

disease). Atherosclerotic disease has a distinct etiology from other

vascular disease. The present invention addresses delivery by the patch of

a stimulator of endogenous fibrinolytic activity.

4 In one embodiment, the practice of this invention is particularly

directed to transdermal delivery of an endogenous stimulator of fibrinolytic

activity, such as prostaglandins, and, more particularly, at non-

vasodilatory levels.

Chemical modifications have been made to the various

prostaglandins so as to allow a pharmacologically effective dose to be

given by oral administration. Orally administered prostaglandin analogs

have a very pronounced pharmacologic effect on the motility of the

gastrointestinal musculature (due to the high concentration of the drug in

the GI tract) resulting in a dose-dependent side effect of diarrhea. This

side effect markedly limits the dose that can be administered such that

the resulting dose entering the blood stream tends to be very small.

In 1 973, Carlson and Eriksson ( 1 ) conducted a study of the effect

of intra-arterial infusion of prostaglandin E, on the symptoms and outcome

of end-stage peripheral vascular disease. In this study, the term 'end-

stage' was defined as a clinical condition of existing or impending

extremity gangrene due to ischemia and/or extreme continuous pain at

rest. The study reports that all subjects noted pain at rest either to

disappear promptly or to improve markedly. Gangrene present in two of

the patients markedly improved. None of the patients required amputation

of the involved limb during the study period even though, during the prior

interval of conventional therapy, all had deteriorated to the point where

amputation was considered imminent. Subsequent studies (2-1 2) have

replicated these results and have shown that the beneficial effect can

5 occur with intravenous as well as intra-arterial infusion. Also of note is

the finding that substantial benefit can persist for more than four months

after the infusion period. Despite the significant clinical improvement that

occurs with the infusion of several prostaglandins (PGE,, PGI ₂

(prostacyclin), and iloprost (a prostacyclin analog)), this finding remains a

clinical curiosity. Hitherto, it has not been feasible to incorporate long

term prostaglandin administration into routine medical practice due to the

unstable nature of these compounds and the complexities of the infusion

procedure.

Chemical analogs of several of the native prostaglandins have been

developed to circumvent problems of clinical administration, but have

been unsuccessful. These analogs possess biological activity similar to

the native compound, but are biologically degraded much more slowly (on

the order of tens of minutes versus a few seconds ). Some are also

reasonably stable at the level of acidity found in the stomach and can thus

be effective if given orally. An example of this kind of chemical analog is

misoprostol, ( 1 1 ,1 3E)-( ±)-1 1 , 1 6-Dihydroxy-1 6-methyl-9-oxoprost-1 3-en-

1 -oic acid methyl ester, a compound with the biological activity of

prostaglandin E, (Cytotec ^® , G. D. Searle). Other suitable prostaglandins

are those of the E, and E ₂ series, as well as PGF _2α (semistable), PGD ₂ ,

PGI ₂ (prostacyclin). It is understood that analogues and derivatives of

these compounds with similar fibrinolytic bioactivity are also

contemplated.

6 Misoprostol is described in the literature as a prescription

medication which stimulates the production of mucous and bicarbonate

ions by the stomach and intestinal lining, thus protecting these areas from

gastric acid damage. Misoprostol mimics these effects and is helpful in

healing ulcers. However, both PGE, and misoprostol also increase

intestinal muscular activity and thus cause dose-dependent diarrhea,

which markedly limits the dose that can be given by mouth. As a result,

the amount of misoprostol that is absorbed into the blood steam is

reduced to the extent that the drug given orally cannot effectively

reproduce the benefits of i.v. infusion of PGE, .

To achieve a reasonable level of medication in the bloodstream,

without an unacceptable degree of gastrointestinal stimulation, an

alternative route of administration is required. This alternative method

must also avoid the complexities of direct intravascular infusion

procedures.

Transdermal drug administration is known in the pharmaceutical art.

Examples of transdermal drug administration include clonidine

administration in hypertension (Catapres Transdermal Therapeutic System,

Boehinger Ingelhiem), estridiol administration in estrogen replacement

therapy (Estraderm Transdermal System, Ciba Pharmaceutical),

nitroglycerin administration for the treatment of coronary artery disease

(Nitro-Dur, Key Pharmaceuticals), nicotine administration for smoking

cessation (Habitrol Nicotine Transdermal, Basel; Nicoderm Nicotine

Transdermal System, Marion Merrell Dow), scopolamine administration for

7 motion sickness (Transderm Scop Transdermal Therapeutic System, Ciba

Consumer), and fentanyl administration for pain control (Duragesic

Transdermal System, Janssen Pharmaceutica.

Summary of the Invention

Administration of either native prostaglandins or prostaglandin

analogs by an extended release dermal patch circumvents problems

associated with other routes of prostaglandin administration. This method

allows much higher levels of medication to be absorbed into the skin and,

subsequently, directly into the parenteral circulation without undesirable

gastrointestinal side effects.

This invention comprises a method of treating arteriosclerosis by

chronically augmenting peripheral fibrinolytic function comprising:

transdermally administering to a subject in need of such treatment a

non-vasodilating fibrinolysis augmenting dosage of a prostaglandin.

Particular note is made of the use of administration by at least a long term

regimen. In particular cases, administration of a non-vasodilating

fibrinolysis augmenting dosage of a prostaglandin every day, or every

other day for a period of at least about 1 2 months are contemplated. In

specific applications where peripheral ulcers are a presenting clinical

problem, treatment may be extended until healing of the ulcers.

In some embodiments of the invention the prostaglandin is selected from the group consisting of misoprostol, prostacyclin, E, and E ₂ series

8 prostaglandins, as well as PGF _2α and PGD _2< Particular note is made of

the prostaglandin misoprostol, and further of misoprostol in the ( ± )-S-

form and in the ( ± )-R-form.

In some embodiments, misoprostol is administered from about 2μg

to about 25μg/day, and particularly from about 5μg to about 10μg/day.

Also noted is the administration of misoprostol from about 0.5μg/kg/day

to about 3.5μg/kg/day, and also from about 0.7μg/kg/day to about

1 .5μg/kg/day. Specifically contemplated is the method of this invention

wherein the misoprostol dosage is at least about 0.006μg/hr as well as at

least about 0.83μg/liter of blood/day.

In the broad embodiments, the method includes a dosage of

prostaglandin from about 2μg to about 25μg/day, and particularly from

about 5μg to about 10μg/day. Also contemplated is a dosage from about

0.5μg/kg/day to about 3.5μg/kg/day.

Also contemplated in the method is infusion of prostaglandin and

especially misoprostol at a rate of about 1 to about 6ng/hr, and

particularly from about 2 to about 5 ng/hr.

A particular embodiment of this invention includes a method of

treating arteriosclerosis by chronically augmenting peripheral fibrinolytic

function comprising administration to a subject in need of such treatment

a non-vasodilating fibrinolysis augmenting dosage of a prostaglandin by

buccal or sublingual administration, or by nasal administration (such as by

spray or by inhalation such as via a nebulizer generated prostaglandin

containing mist).

Detailed Description of the Invention

This invention is best understood with resort to the following

definitions:

A and B. "Chronically" maintaining as non-vasodilating peripheral levels

of augmented fibrinolysis over at least about 1 0 hours. In contrast, the

term "long term regimen" shall refer to repeated chronic daily maintaining

of drug levels over periods of at least about 1 5 days in a 60 day period.

C. "Peripheral," as to augmented fibrinolysis, shall mean limbs, including

digits, ears, and nose.

D. "Augmented, " as to fibrinolytic activity, shall mean at least a 30%

increase over the non-treated state for a given subject averaged over the

time of daily administration.

E. "Non-vasodilating" shall mean not greater that 20% increase in blood

flow increase averaged over the time of daily administration

F. "Transdermal" is used to encompass patch-type delivery. While

buccal, intranasal, inhalation and other delivery of drugs are also

contemplated, the use of such routes will be specifically addressed when

these routes are intended.

G. "Subjects" is used expansively to include animals, mammals and,

particularly, humans.

The present invention enables sustained effective levels of a

prostaglandin or a prostaglandin analog to be absorbed into the blood

while avoiding undesirable gastrointestinal adverse effects by way of a

10 dermally applied patch. This invention specifically addresses the use of

prostaglandins or their analogs for the therapy of arteriosclerosis including

microvascular disease often seen in diabetes mellitus.

While particular doses are set forth, it is specifically to be

understood that specific subjects and specific prostaglandins will present

unique sensitivity to prostaglandin therapy. A non-vasodilating dose can

be determined by administering increasing or decreasing doses of a

particular prostaglandin to a subject to determine when vasodilation is

encountered. A skilled practitioner in the art will appreciate that ambient

temperature will have an effect on testing and should be accounted for.

However, a peripheral color change or temperature increase or pulse

amplitude discloses vasodilation.

Similarly, increased fibrinolytic activity may be easily determined by

any of a number of tests for fibrinolysis/fibrinolytic activity. Several tests

of fibrinolytic are presented in "Fibrinolysis induced by Streptokinase in

Man," Nilsson et al., Acta Chir Scand. 1 23:247-266 ( 1 962) the teachings

of which are incorporated herein by reference.

Articles of interest include:

Carlson LA, Eriksson I. Femoral-artery infusion of prostaglandin E,

in severe peripheral vascular disease. Lancet. 1973; 1 :1 55-1 56.

Carlson LA, Olsson AG. Intravenous prostaglandin E, in severe

peripheral vascular disease. Lancet. 1 976;2:810.

Sakaguchi S, Kusaba A, Mishima Y, Kamiya K, Nishimura A,

Furukawa K, Shionoya S, Kawashima M, Katsumura T, Sakuma A. A

1 1 multi-clinical double blind study with PGE, { -cyclodextrin clathrate) in

patients with ischemic ulcer of the extremities. Vasa. 1 978;7:263-266.

Szczeklik A, Nizankowski R, Skawinski S, Szczeklik J, Gluszko P,

Gryglewski RJ. Successful therapy of advanced arteriosclerosis obliterans

with prostacyclin. Lancet. 1979;1 : 1 1 1 1 -1 1 14.

Olsson AG. Intravenous prostacyclin for ischemic ulcers in

peripheral artery disease. Lancet. 1980;2:1076.

Sethi GK, Scott SM, Takaro T. Effect of intra-arterial infusion of

PGE, in patients with severe ischemia of lower extremity. J Cardiovas.

Sure. 1 980;21 : 1 85-192.

Pardy BJ, Lewis JD, Eastcott HHG. Preliminary experience with

prostaglandins E, and l ₂ in peripheral vascular disease. Surgery.

1 980;88:826-832.

Kyle V, Hazleman B. Prostaglandin E, and peripheral vascular

disease. Lancet. 1 983;2:282.

Siegel RJ, Shah PK, Nathan M, Rodriguez L, Shell, WE.

Prostaglandin E, infusion in unstable angina: effects on anginal frequency

and cardiac function. Am Heart J. 1 984; 108:863-868.

Balzer K, Rogatti W, Ruttgerodt K. Efficacy and tolerability of intra-

arterial and intravenous prostaglandin E, infusions in occlusive arterial

disease stage lll/IV. Vasa Suppl. 1989;28:31 -38.

Virgolini I, Fitscha P, Linet Ol, O'Grady J, Sinzinger H. A double

blind placebo controlled trial of intravenous prostacyclin (PGI ₂ ) in 108