Drug preparations for treating sexual dysfunction

Topical gelled compositions comprising a drug for treating sexual dysfunction dispersed within a polymer matrix and methods and treatments using said compositions.

FIELD OF THE INVENTION 
This invention relates to the preparation of a transdermal delivery system. 
The preparation is designed to deliver therapeutic levels of a drug for 
treating sexual dysfunction to specific sites below the dermal level of 
the skin. Specifically, the preparations address sexual dysfunction caused 
by impotency in males and vaginal dryness in females. 
DESCRIPTION OF THE PRIOR ART 
Over the years, methods have been developed to achieve the efficient 
delivery of a therapeutic drug to a mammalian body part requiring 
pharmaceutical treatment. Use of an aqueous liquid which can be applied at 
room temperature as a liquid but which forms a semi-solid gel when warmed 
to body temperature has been utilized as a vehicle for some drug delivery 
since such a system combines ease of application with greater retention at 
the site requiring treatment than would be the case if the aqueous 
composition were not converted to a gel as it is warmed to mammalian body 
temperature. In U.S. Pat. No. 4,188,373, PLURONIC.RTM. polyols are used in 
aqueous compositions to provide thermally gelling aqueous systems. 
Adjusting the concentration of the polymer provides the desired sol-gel 
transition temperature, that is, the lower the concentration of polymer, 
the higher the sol-gel transition temperature, after crossing a critical 
concentration minimum, below which a gel will not form. 
In U.S. Pat. Nos. 4,474,751 and 4,478,822 drug delivery systems are 
described which utilize thermosetting gels; the unique feature of these 
systems is that both the gel transition temperature and/or the rigidity of 
the gel can be modified by adjusting the pH and/or the ionic strength, as 
well as by the concentration of the polymer. 
Other patents disclosing pharmaceutical compositions which rely upon an 
aqueous gel composition as a vehicle for the application of the drug are 
U.S. Pat. Nos. 4,883,660; 4,767,619; 4,511,563; 4,861,760; and 5,318,780. 
Thermosetting gel systems are also disclosed for application to injured 
mammalian tissues of the thoracic or peritoneal cavities in U.S. Pat. No. 
4,911,926. 
Ionic polysaccharides have been used in the application of drugs by 
controlled release. Such ionic polysaccharides as chitosan or sodium 
alginate are disclosed as useful in providing spherical agglomerates of 
water-insoluble drugs in the Journal of Pharmaceutical Sciences, Volume 
78, Number 11, November 1989, Bodmeier et al. Calcium alginate gel 
formulations have also found use as a matrix material for the controlled 
release of herbicides, as disclosed in the Journal of Controlled Release, 
(1986), pages 229-233, Pfister et al. 
In U.S. Pat. No. 3,640,741, a molded plastic mass composed of the reaction 
product of a hydrophilic colloid and a cross-linking agent such as a 
liquid polyol, also containing an organic liquid medium such as glycerin, 
is disclosed as useful in the controlled release of medication or other 
additives. The hydrophilic colloid can be carboxymethyl cellulose gum or a 
natural alginate gum which is cross-linked with a polyol. The 
cross-linking reaction is accelerated in the presence of aluminum and 
calcium salts. 
In U.S. Pat. No. 4,895,724, compositions are disclosed for the controlled 
release of pharmacological macromolecular compounds contained in a matrix 
of chitosan. Chitosan can be cross-linked utilizing aldehydes, 
epichlorohydrin and benzoquinone. 
In U.S. Pat. No. 4,795,642, there are disclosed gelatin-encapsulated, 
controlled-release compositions for release of pharmaceutical 
compositions, wherein the gelatin encloses a solid matrix formed by the 
cation-assisted gelation of a liquid filling composition incorporating a 
vegetable gum together with a pharmaceutically-active compound. The 
vegetable gums are disclosed as polysaccharide gums such as alginates 
which can be gelled utilizing a cationic gelling agent such as an alkaline 
earth metal cation. 
While the prior art is silent with respect to aqueous drug delivery 
vehicles and isotonicity thereof, osmotic drug delivery systems are 
disclosed in U.S. Pat. No. 4,439,196 which utilize a multi-chamber 
compartment for holding osmotic agents, adjuvants, enzymes, drugs, 
pro-drugs, pesticides, and the like. These materials are enclosed by 
semipermeable membranes so as to allow the fluids within the chambers to 
diffuse into the environment into which the osmotic drug delivery system 
is in contact. The drug delivery device can be sized for oral ingestion, 
implantation, rectal, vaginal, or ocular insertion for delivery of a drug 
or other beneficial substance. Since this drug delivery device relies on 
the permeability of the semipermeable membranes to control the rate of 
delivery of the drug, the drugs or other pharmaceutical preparations by 
definition, are not isotonic with mammalian blood. 
Pharmacological erection therapy is an effective method to treat male 
erectile dysfunction. The medications most commonly used have been 
papaverine hydrochloride, a smooth muscle relaxant, and phentolamine 
mesylate, an .alpha.-adrenergic blocker. Recent data have suggested that 
prostaglandin E.sub.1 either alone or in combination with papaverine 
produces an improved erectile response. To date, however, there have been 
little objective data comparing the relative efficacy of these medications 
either alone or in combination. Furthermore, the use of these drugs has 
required special applicators, which besides being cumbersome, are also 
painful to use. 
Many women, particularly menopausal women, women suffering from an 
autoimmune disease and women undergoing radiation therapy, experience 
vaginal dryness caused by loss of normal vulval and vaginal secretions, 
particularly during sexual activity, resulting in difficulty with or an 
inability to achieve intercourse. Currently, there are only a limited 
number of available therapies which address the problem of vaginal 
dryness. Though in mild cases, local hygiene and antipruritic ointments 
and creams may be beneficial, typically additional therapy will be 
necessary. Some currently available therapies involve treatment with 
hormone-based formulas containing either testosterone or glucocorticoids. 
Parnell, U.S. Pat. No. 5,380,757, discloses a therapy involving treatments 
with gamma-linolenic acid (GLA) and dihomo-gamma-linolenic acid (DGLA). 
U.S. Pat. No. 4,347,237 discloses a vaginal suppository composed of a 
variety of different types of water soluble polyoxy alkylene polyol 
components. 
However, the formulations disclosed in the prior art are all deficient in 
that the delivery systems which they employ do not carefully control the 
delivery of the active therapeutic agent thus leading to adverse effects. 
For example, currently used testosterone treatments can produce clitoral 
enlargement or other masculinization, and glucocorticoids when used for 
long periods of time carry a serious risk of producing atrophy and 
thinning of the epithelium. 
A need thus exists for the administration of active therapeutic agents that 
can be applied topically and transported through the skin or administered 
by injection without the concomitant presence of pain or side effects. 
SUMMARY OF THE INVENTION 
The present invention relates to the formation of gelled compositions and 
methods for using said gelled compositions in treating sexual dysfunction, 
including impotency or erectile dysfunction in males, and sexual 
dysfunction in females caused by vaginal dryness. The methods of the 
invention comprise topically applying to a specific site on the surface of 
an animal a therapeutically effective amount of a drug for treating sexual 
dysfunction dispersed within a gelled composition comprising a polymer 
matrix which is suspended in a liquid medium, wherein the polymer matrix 
contains a negative charged polymer blended with a nonionic polymer, and 
wherein the molar ratio of the negative charged polymer to the nonionic 
polymer is 1:4 to 0.09, and the negative charged polymer is present in 
amounts of about 1.0% to about 3.5% by weight. 
In a further embodiment of the invention, a method for the treatment of 
erectile dysfunction in a male animal comprises topically applying to the 
surface of a penis a therapeutically effective amount of a drug for 
treating impotency dispersed within a gelled composition comprising a 
polymer matrix which is suspended in a liquid medium; wherein the polymer 
matrix contains a negative charged polymer blended with a nonionic 
polymer; and wherein the molar ratio of the negative charged polymer to 
the nonionic polymer is 1:0.5 to 0.09 and the negative charged polymer is 
present in amounts of about 2.0% to about 3.5% by weight. 
In another embodiment of the invention, a gelled composition for treating 
impotency comprises therapeutically effective amounts of a drug for 
treating impotency dispersed within a matrix containing a negative charged 
polymer blended with a nonionic polymer, wherein the molar ratio of the 
negative charged polymer to the nonionic polymer is 1:4 to 0.09 and the 
negative charged polymer is present in amounts of about 1.0% to about 3.5% 
by weight. 
In yet another embodiment of the invention, a method for the treatment of 
erectile dysfunction in male animals comprises injecting into the corpora 
cavernosa a therapeutically effective amount of a drug dispersed within a 
gelled composition comprising a polymer matrix which is suspended in a 
liquid medium; wherein the polymer matrix contains a negative charged 
polymer blended with a nonionic polymer; and wherein the molar ratio of 
the negative charged polymer to the nonionic polymer is 1:4 to 0.09 and 
the negative charged polymer is present in amounts of about 1.0% to about 
3.5% by weight. 
In a further embodiment of the invention, a method for the treatment of 
sexual dysfunction or vaginal dryness in a female animal comprises 
topically applying to the surface of a vagina a therapeutically effective 
amount of a drug for treating female sexual dysfunction or vaginal dryness 
dispersed within a gelled composition comprising a polymer matrix which is 
suspended in a liquid medium, and wherein the polymer matrix contains a 
negatively charged polymer blended with a nonionic polymer, and wherein 
the molar ratio of the negative charged polymer to the nonionic polymer is 
1:4 to 0.09 and the negative charged polymer is present in amounts of 
about 1.0% to about 3.5% by weight. 
In a still further embodiment of the invention, a gelled composition for 
treating vaginal dryness comprises therapeutically effective amounts of a 
drug for treating impotency dispersed within a matrix containing a 
negative charged polymer having a mean average molecular weight between 
about 650,000 and 800,000 blended with a nonionic polymer, wherein the 
molar ratio of the negative charged polymer to the nonionic polymer is 1:4 
to 0.09 and the negative charged polymer is present in amounts of about 
1.0% to about 3.5% by weight. 
DETAILED DESCRIPTION OF THE INVENTION 
It has been unexpectedly discovered that an effective therapeutic level of 
a drug may be administered topically and transdermally delivered through 
the skin into various sites where the drug is therapeutically effective. 
In order for this to be accomplished, it has been discovered that the 
active drug must be suspended or entrapped in a specially designed polymer 
matrix containing a specific molar ratio of negatively charged polymers 
and a non-ionic polymer suspended or dissolved in water and solubilizers. 
This system is believed to form a matrix which microencapsulates, suspends, 
and/or entraps the active drug entity such that when it is administered, 
it is slowly released into the systemic circulatory system or muscular 
tissue providing a method of delivering an active drug to an affected site 
in the body through the skin. 
The molar ratio of the polymers present in the matrix is critical in this 
invention. It has been found that molar ratios of the negative charged 
polymer to the non-ionic polymer must be from 1:4 to 0.09, and preferably 
from 1:2.5 to 0.1, and most preferably from 1:0.4 to 0.2. For transdermal 
delivery of drugs, it has been found that ratios either higher or lower 
than these levels will result in a polymer shearing effect which produces 
unacceptable turbulence and air pockets in the composition with resulting 
loss of potency and efficacy. Furthermore, the solutions tend to separate 
and form distinct polymer layers when ionic molarity is not appropriate. 
At least one of the polymers used to form the matrix of this invention must 
be sufficiently negatively charged to aid in the dispersion, encapsulation 
or solubilization of the drug. The viscosity and molecular weight of the 
negative charged polymer is also critical to the invention. Further, at 
least one of the polymers of the invention must be a nonionic polymer. The 
viscosity and molecular weight of the nonionic polymer is also critical to 
the invention. Particularly preferred nonionic polymers which have a 
viscosity of about 1,500 for a 5% solution to about 5,500 for a 1% 
solution have been found to be suitable for forming a polymer matrix 
capable of transdermal drug delivery. For drug delivery, using nonionic 
polymers with viscosities below these ranges will result in an excessive 
rate of release leading to drug dispersion into fatty tissue, causing 
reduced efficacy, while requiring higher levels of drug with accompanying 
side effects. Using nonionic polymers with a viscosity above these ranges 
will result in solid materials which are unsuitable for transdermal drug 
delivery. 
As discussed herein, viscosity, or solution viscosity, refers to the 
intrinsic viscosity of a polymer in solution (the viscosity which the 
unassociated polymer molecules give to the solution) and is a function of 
the molecular weight and very easily measured. Intrinsic viscosity is 
commonly used for control purposes, and the values can be converted into 
molecular weight by calibration with osmotic pressure, light scattering, 
or sedimentation measurements. The viscosity measurements and ranges used 
herein were provided by Aqualon, a division of Hercules, Inc., in its 
product specifications for Natrosol.RTM. (hydroxyethyl-cellulose), and all 
were Brookfield viscosities measured at 25.degree. C. It is well within 
the capabilities of an ordinarily skilled artisan to obtain and/or 
identify polymers within the ranges specified by the invention. 
Particularly preferred negative charged polymers which have mean average 
molecular weights below about 800,000 and preferably molecular weights 
between 650,000 to 800,000 have been found acceptable to form usable 
polymer matrixes for transdermal delivery. Polymers with average molecular 
weights between 700,000 and 775,000 are most preferred. Polymers having 
molecular weights above about 800,000 form solid gels in solution and are 
unable to serve as part of a transdermal delivery system. Furthermore, the 
polymers must be sterilizable and be stable during sterilization so that 
the polymer does not lose molecular weight once formulated into the final 
transdermal delivery form. 
Exemplary, non-limiting examples of compounds that may be used as a source 
of this molecular weight polymer include polysulfated glucosoglycans, 
glucosaminoglycans, and mucopolysaccharides, derivatives thereof and 
mixtures thereof. Particularly preferred mucopolysaccharides are 
chondroitin sulfate and hyaluronic acid salts. Exemplary hyaluronate salts 
include sodium, calcium, potassium and magnesium salts with hyaluronate 
sodium being most preferred. 
Hyaluronic acid (HA) occurs naturally in joint synovial fluid, where it 
plays a lubricating role, and may have biological activity was well. HA is 
a mucopolysaccharide, and may alternatively be referred to as 
glucosaminoglycan. The repeating unit of the hyaluronic acid molecule is a 
disaccharide consisting of D-glucuronic acid and N-acetyl-D-glucosamine. 
Because hyaluronic acid possesses a negative charge at neutral pH, it is 
soluble in water, where it forms highly viscous solutions. The 
D-glucuronic acid unit and N-acetyl-D-glucosamine unit are bonded through 
a glycosidic, beta (1-3) linkage, while each disaccharide unit is bonded 
to the next disaccharide unit through a beta (1-5) linkage. The (beta 1-4) 
linkages may be broken through hydrolysis with the enzyme hyaluronidase. 
A variety of substances, commonly referred to as hyaluronic acid, have been 
isolated by numerous methods from various tissue sources including 
umbilical cords, skin, vitreous humor, synovial fluid, tumors, hemolytic 
streptocci pigskin, rooster combs, and the walls of veins and arteries. It 
is also being synthesized artificially and by recombinant technology. 
Conventional methods for obtaining hyaluronic acid results with a product 
having differing properties and a wide range of viscosities. U.S. Pat. No. 
2,585,546 to Hadian, discloses an example of a method for obtaining 
hyaluronic acid and which involves extracting acetone-washed umbilical 
cords with a dilute salt solution, acidifying the resulting extract, 
removing the clot so formed, precipitating some hyaluronic acid with 
protein from the acidified extract with ammonium sulfate, agitating the 
liquid with pyridine, precipitating another fraction highly contaminated 
with protein, followed by more ammonium sulfate which forces some pyridine 
out of solution along with the high viscosity hyaluronic acid. The 
hyaluronic acid collects at the interface between the two liquid phases 
and may be separated by filtration, centrifugation or another usual 
procedure. A modification of this process involves the fractionation of 
the acidic salt extract from umbilical cords with alcohol and ammonium 
sulfate. Alcohol is added to the acidic salt extract, and the resulting 
precipitate is removed. Solid ammonium sulfate is added to the liquid 
until saturation and the solution forms two phases with a precipitate of 
hyaluronic acid at the interface. 
Bracke et al., U.S. Pat. No. 4,517,296, is directed to the preparation of 
hyaluronic acid in high yield from Streptococcus bacteria by fermenting 
the bacteria under anaerobic conditions in a CO.sub.2 enriched growth 
medium, separating the bacteria from the resulting broth and isolating the 
hyaluronic acid from the remaining constituents of the broth. Separation 
of the microorganisms from the hyaluronic acid is facilitated by killing 
the bacteria with trichloroacetic acid. After removal of the bacteria 
cells and concentration of the higher molecular weight fermentation 
products, the hyaluronic acid is isolated and purified by precipitation, 
resuspension and reprecipitation. 
One particular fraction of hyaluronic acid (HA) that exhibits excellent 
matrix formation according to the present invention is hyaluronate sodium 
having a mean or average molecular weight between 650,000-800,000, 
preferably 700,000-775,000 with a high degree of purity, 95-105% free, and 
preferably at least 98% pure, from contamination of related 
mucopolysaccharides. Furthermore, this hyaluronic acid has a sulphated ash 
content of less than 15% and a protein content of less than 5%. Examples 
of usable base salts include those safe from animal and human use, such as 
sodium, potassium, calcium, and magnesium salts or the like. 
In contrast to HA, chondroitins are mucopolysaccharides comprising 
repeating units of D-glucuronic acid and N-acetyl-D-galactosamine. 
Chondroitin sulphates are important components of cartilage and bone and 
are excellent for preparing the polymer matrix herein. 
The negative charged polymers are generally present in the system in 
amounts which enable a semi-solid gel to be formed. Generally, gels are 
formed using amounts of about 1.0 to about 3.5% by weight with amounts of 
about 2.1 to about 2.5% by weight being preferred for use as a topical 
gel. Concentrations of negative charged polymer greater than 3.5% result 
in solids which are not suitable for pharmaceutical use. 
The solutions used to prepare the gels of the present invention may be 
prepared in a variety of ways. For example, the polymers may be dissolved 
in water and purified either separately or jointly and then the optional 
active drug added to the system. 
A particularly preferred procedure involves separately dissolving the 
nonionic polymer in water and centrifuging the material to form a solution 
and remove impurities. This may be conveniently done at rotation speeds of 
2000 rpm for times of about 30 minutes to about two hours. 
In contrast, the negative charged polymer may be blended and stirred in 
water until it is dissolved. This process must be done while avoiding the 
formation of bubbles and while freeing the polymer of its electrostatic 
activity. Furthermore, the molecular weight of the polymer must not be 
significantly changed during processing and as such mild process 
conditions are required. Processing conditions of 400-3000 rpm for 
durations of 16-24 hours have been found acceptable to produce stable 
solutions or gels of the charged polymer. 
Conventional pharmaceutically acceptable emulsifiers, suspending agents, 
antioxidants (such as sodium meta-bisulfate) and preservatives (such as 
benzyl alcohol) may then be added to this system. Once all the components 
are blended together, such as by mixing 400-3000 rpm for one to four 
hours, the system is filled into tubes and sterilized. The resulting 
system is a clear gel which is storage stable for several years. 
The drug may be added to the homogenous solution or gel separately once 
dissolved or disbursed in water. Emulsifiers, suspending agents and 
preservatives may then be added to this system. One particularly 
nonlimiting effective material for solubilizing water insoluble drugs is 
methoxypolyethylene glycol (MPEG). Once all the components are blended 
together, for 400-3000 rpm for 1 to 4 hours, the system is filled into 
tubes and sterilized. The resulting system is storage stable for several 
years. 
The formulations may be used topically and also contain conventional 
pharmaceutically acceptable excipients well known to those skilled in the 
art, such as surfactants, suspending agents, emulsifiers osmotic 
enhancers, extenders and dilutants, pH modifiers as well as fragrances, 
colors, flavors and other additives. 
As indicated above, the active drug agents may be blended with the aqueous 
polymer matrix at the time of manufacture. As such, the drug when in the 
form of a water-soluble solid is simply diluted with sterilized water or 
polymer matrix solution and prepared in gel form. 
The dosage system can be formed with or without the use of pharmaceutically 
acceptable preservatives. A significant advantage of the dosage form of 
the present system relates to its ability to allow the drug to slowly 
diffuse through tissue when administered thus allowing for an effective 
therapeutic dose to be present for long periods of time, i.e., 15 minutes 
to several hours. 
In this regard, it should be noted that reference to therapeutically 
effective dose does not necessarily relate to conventional dosage levels, 
but does relate to drug levels that achieve an effective therapeutic level 
at the dose employed, which may be the same level but not at the same 
frequency of administration previously required for drugs taken orally or 
by injection. This not only significantly reduces the number of doses 
required to achieve the same effect, but it also reduces costs, 
maintenance and health hazards associated with conventional treatment 
therapies. 
Doses may vary from patient to patient depending on the type and severity 
of the condition being treated and the drug being administered. Generally, 
doses of 150 mcg to 1000 mcg may be administered with preferred doses 
using 200 to 500 mcg of drug disbursed in the gelled matrix system. The 
total dosage of the gelled matrix with drug is usually 0.5 ml to 5 ml in 
volume. 
There is a physiological basis for the treatment of both male and female 
sexual dysfunctions together since they have physiological responses in 
common. See Foreman, U.S. Pat. No. 4,521,421. With regard to male sexual 
dysfunction, it is generally recognized that primary erectile dysfunction 
is almost always due to intrapsychic factors. In rare cases, biogenic 
factors, usually associated with low testosterone levels and reflecting 
disorders of the hypothalamic-pituitary-gonadal axis, provide the major 
etiology. Occasionally, vascular abnormalities are found. Physical factors 
include systemic diseases (e.g., diabetes mellitus [the most common], 
syphilis, alcoholism, drug dependency, hypopituitarism, and 
hypothyroidism); local disorders (e.g., congenital abnormalities na 
inflammatory diseases of the genitalia); vascular disturbances such as 
aortic aneurysm and atherosclerosis (e.g., Leriche's syndrome); neurogenic 
disorders (e.g., multiple sclerosis, spinal cord lesions, pituitary 
mifcroadenoma with hyperprolactinemia, and cardiovascular accident); drugs 
such as hypertensives, sedatives, tranquilizers, and amphetamines; and 
surgical procedures such as sympathectomy. prostatectomy and castration 
produce varying effects. Impotence is usually not induced by transurethral 
prostatectomy, whereas it almost always occurs after perineal 
prostatectomy. However, retrograde ejaculation is produced in the vast 
majority of men, irrespective of the type of prostatectomy. 
Pharmacological erection therapy is an effective method to treat male 
erectile dysfunction. The medications most commonly used have been 
papaverine hydrochloride, a smooth muscle relaxant, and phentolamine 
mesylate, an .alpha.-adrenergic blocker. Recent data have suggested that 
prostaglandin E.sub.1 either alone or in combination with papaverine 
produces an improved erectile response. 
There currently is increasing evidence that prostaglandin E.sub.1 is 
presently the single most effective agent for pharmacological erection 
therapy. Prostaglandin E.sub.1 is a physiological agent that is 
metabolized locally within the cavernous tissue and there appears to be a 
low incidence of corporeal fibrosis, priapism or systemic reactions 
associated with its use. Several studies using subjective evaluation have 
shown that prostaglandin E.sub.1 is more effective than a combination of 
papaverine and phentolamine. Lee et al. found that two-thirds of the men 
who failed prior intracavernous therapy with papaverine and phentolamine 
achieved adequate erections with prostaglandin E.sub.1. Prostaglandin 
E.sub.1 has also been found to be extremely effective as a single agent in 
several other studies. Liu et al. recently reported that prostaglandin 
E.sub.1 is at least as effective as papaverine in increasing penile blood 
flow measured by duplex sonography. Prostaglandin E.sub.1 has the 
advantage over papaverine of a slower onset, longer maintenance and less 
chance of priapism. 
Despite these advantages, however, prostaglandin E.sub.1 is associated with 
a significant incidence of penile discomfort. 
Prostaglandin E.sub.1 is a naturally occurring acidic lipid that is 
synthesized from fatty acid precursors by most mammalian tissues and has a 
variety of pharmacologic effects. Human seminal fluid is a rich source of 
prostaglandins, including PGE.sub.1 and PGE.sub.2, and the total 
concentration of prostaglandins in ejaculate has been estimated to be 
approximately 100-200 mcg/mL. In vitro, alprostadil (PGE.sub.1) has been 
shown to cause dose-dependent smooth muscle relaxation in isolated corpus 
cavernosum and corpus spongiosum preparations. Additionally, vasodilation 
has been demonstrated in isolated cavernosal artery segments that were 
pre-contracted with either norepinephrine or prostaglandin E.sub.2 
.alpha.. The vasodilatory effects of alprostadil on the cavernosal 
arteries and the trabecular smooth muscle of the corpora cavernosa result 
in rapid arterial inflow and expansion of the lacunar spaces within the 
corpora. As the expanded corporal sinusoids are compressed against the 
tunica albuginea, venous outflow through subtunical vessels is impeded and 
penile rigidity develops. This process is referred to as the corporal 
veno-occlusive mechanism. 
The most notable systemic effects of alprostadil are vasodilation, 
inhibition of platelet aggregation, and stimulation of intestinal and 
uterine smooth muscle. Intravenous doses of 1 to 10 micrograms per 
kilogram of body weight lower blood pressure in mammals by decreasing 
peripheral resistance. Reflex increases in cardiac output and heart rate 
may accompany these effects. 
Alprostadil is rapidly metabolized locally by enzymatic oxidation of the 
15-hydroxyl group to 15-keto-PGE.sub.1. The enzyme catalyzing this process 
has been isolated from many tissues in the lower genitourinary tract 
including the urethra, prostate, and corpus cavernosum. 15-keto-PGE.sub.1 
retains little (1-2%) of the biological activity of PGE.sub.1. 
15-keto-PGE.sub.1 is rapidly reduced at the C.sub.13 -C.sub.14 position to 
form the most abundant metabolite in plasma, 13,14-dihydro,15-keto 
PGE.sub.1 (DKH-PGE.sub.1), which is biologically inactive. The majority of 
DKH-PGE.sub.1 is further metabolized to smaller prostaglandin remnants 
that are cleared primarily by the kidney and liver. Between 60% and 90% of 
PGE.sub.1 has been shown to be metabolized after one pass through the 
pulmonary capillary beds. 
Use of the present formulations either alone or in combination with various 
therapeutic agents overcomes all of these prior art deficiencies. 
Regardless of the route of administration elected, the formulations of the 
present invention are formulated into pharmaceutically acceptable dosage 
forms by conventional methods known in the pharmaceutical art. 
As discussed above, an effective but nontoxic amount of the system is 
employed in treatment. The dose regimen for administering drugs or 
treating various conditions, such as pain as described above, is selected 
in accordance with a variety of factors including the type, age, weight, 
sex, and medical condition of the subject, the severity of the pain, the 
route of administration and the particular complex or combination of drugs 
employed. Determination of the proper dose for a particular situation is 
within the skill of the art. Generally, treatment is initiated with 
smaller dosages which are less than the optimum doses of the compound. 
Thereafter, the dose is increased by small increments until the optimum 
effect under the circumstances is reached. For convenience, the total 
daily dosage may be divided and administered in portions during the day if 
desired. Generally, amounts of drug may vary from 0.0001% to about 75% by 
weight of the system when using topically with 0.5 to 5 ml concentrations 
and preferably in 1 to 3 ml amounts. 
The formulations of this invention are particularly useful in the 
administration of drugs that could be previously administered only by 
injection. 
The transdermal delivery system described herein offers a major alternative 
especially for those individuals who have a history of undesirable 
side-effects associated with irritation and/or pain from the injection. 
Also for those patients who have already suffered damage, the transdermal 
preparations described herein present a new way of providing effective 
treatment and relief of painful symptoms. 
Female sexual dysfunction is generally caused by vaginal dryness. Women 
most susceptible to vaginal dryness include menopausal women, women 
undergoing radiation therapy, and women suffering from an autoimmune 
disease. However, vaginal dryness is not limited to such women, and may be 
caused by numerous factors, many of which may be as yet unidentified. 
Because female sexual dysfunction has traditionally received significantly 
less attention than male sexual dysfunction, there is little literature 
available on the subject. 
In many cases vaginal dryness is directly caused by vulvar dystrophy. The 
vulvar dystrophies are a common group of disorders in which various parts 
of the vulva atrophy or become dystrophic. While the vulvar dystrophies 
are common after menopause, they can occur at any time of life, even 
during childhood. Treatment is often unsatisfactory. See Horrobin, U.S. 
Pat. No. 5,380,757. Local hygiene and antipruritic ointments and creams 
may be beneficial but topical preparations containing either 
glucocorticoids or testosterone, the male sex hormone, are usually 
required. While these hormone based preparations are often effective, the 
glucocorticoids when used for long periods carry a serious risk of 
producing atrophy and thinning of the epithelium, while the testosterone 
preparations can produce clitoral enlargement or other masculinization. 
Vaginal dryness can also be caused by pharmacological influences, for 
example, as a common side effect of many medications, including diuretics, 
antiarthritics and antidepressants. Generally, synthetic lubricants or 
synthetic moisturizers are prescribed for such situations, with limited 
effectiveness. 
The methods and compositions of the present invention contemplate the 
treatment of female sexual dysfunction in its broadest manifestations. The 
drug delivery system which the present invention embodies is ideally 
suited for the topical application of formulations capable of containing 
an active agent and releasing said agent in a controlled manner to achieve 
efficacious transdermal drug delivery without the side effects which may 
accompany the same agent when used with delivery systems disclosed in the 
prior art. The formulations of the invention may be applied to the surface 
of the vagina, so that a therapeutically effective amount of the drug for 
treating vaginal dryness is released in a controlled manner, and thus the 
drug penetrates the exterior layers of the vagina to relieve said vaginal 
dryness. 
In addition to the negative charged polymers, the transdermal polymer 
matrix must contain a non-ionic polymer which facilitates in retarding the 
absorption of the active drug through the skin and delays or slows down in 
animals natural absorption of the negatively charged polymer. 
Without the presence of this component, the active drug would not be 
delivered transdermally into the site targeted for treatment at levels 
which are therapeutically effective. In addition to the non-ionic polymers 
described in this system, these materials are necessary to provide 
thorough penetration of skin layers including the epidermis, dermis and 
fatty tissue layers. 
Particularly preferred nonionic polymers are cellulose derivatives and 
particularly those selected from the group consisting of 
carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl 
cellulose and mixtures thereof. These particular polymers have been found 
to possess exceptional ability to form sustained release matrix 
formulations when used in combination with a negative charged polymer. 
Such polymers are generally employed in amounts of about 0.1% to about 
1.5% and preferably about 0.5 to about 1.4%. Amounts above about 1.5% 
result in the formation of a solid gel when used with the negative charged 
polymer. Amounts below about 0.1% have not been found suitable to prepare 
a storage stable product that has sustained drug release. 
A particularly preferred HEC concentration is about 0.2% to about 1.0% by 
weight of the matrix. 
A wide variety of medicaments which may be administered topically may be 
used in the delivery system according to this invention. These drugs 
include, without limitation, papaverine hydrochloride, phentolamine 
mesylate and prostaglandin E.sub.1, nicotinic acid, glycerol, propylene 
glycol, testosterone, testosterone propionate, glucocorticoids, 
hydrocortisone, gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid 
(DGLA), Yerba Santa extract and mixtures thereof. 
One particular criteria of the drug is that they must be solubilized in the 
polymer matrix solution in order to be topically administered. 
The following examples are illustrative of preferred embodiments of the 
invention and are not to be construed as limiting the invention thereto. 
All polymer molecular weights are average molecular weights. All 
percentages are based on the percent by weight of the final delivery 
system or formulation prepared unless otherwise indicated and all totals 
equal 100% by weight.

EXAMPLE 1 
This example demonstrates the formation of a transdermal preparation of 
alprostadil. 
The dosage range for the drug is between 2-3 ml. 
Materials 
______________________________________ 
Alprostadil 250 mcg 
Sodium hyaluronate (HA) 2.5% 
Hydroxyethyl cellulose (HEC) 0.7% 
Methoxypolyethylene glycol (MPEG) 10% 
Benzyl alcohol 1% 
Water Remainder 
______________________________________ 
Batch Size 1000 ml 
1. Into a sterilized glass vessel is added 1062.5 ml of sterile water which 
is stirred at 1500 to 2000 rpm. Slowly add 34.5 grams of HA, having a 
molecular weight of around 700,000 to 775,000 and a purity described 
above. Allow to stir for 16 to 20 hours until all of the HA polymer has 
dissolved into the water and a crystal-clear viscous solution has formed. 
2. Prepare a 0.7% solution of HEC by adding 10.5 grams of the solid 
material under aseptic conditions to 250 ml of sterile water. Allow to 
dissolve for 1 to 2 hours while stirring at 1500 to 2000 rpm. Add the HEC 
solution to a sufficient amount of the HA solution and mix for 10 to 15 
hours until a homogeneous solution is produced. 
3. Carefully measure 100 ml of methoxypolyethylene glycol (MPEG) 10% into 
the mixture. RPM speeds should be increased for the mixture while this 
step is being performed to 2500 rpm. The resulting mixture thus formed 
should be allowed to mix at 2000 rpm for an additional 3 to 4 hours. 
4. At this point 1% of benzyl alcohol or 10 ml is added to the mixture. 
Again, the rpm speed is increased during this part of the procedure to 
2500. The mixture should be allowed to mix for 3 to 5 hours at 2000 rpm. 
5. Using safe techniques, 250 mg of alprostadil should be slowly added to 
the mixture. Again the rpm speed for the purpose of addition of drug 
should be increased to 2500, and the entire drug should be completed 
within 15 minutes. 
The final mixture is clear with a slight tint following 15 to 20 hours of 
further mixing at 2000 rpm. The final product should be transferred, using 
aseptic techniques, to 1-5 ml tubes. 
When used, approximately 2 ml of matrix is applied to the exterior surface 
of the penis 10 to 15 minutes before intercourse. Alternatively, 
approximately 2 ml may be infused into the urethra 10 to 15 minutes before 
intercourse. Either technique results in the formation of an erection. 
EXAMPLE 2 
A transdermal preparation of Alprostadil is prepared in the manner of 
Example 1 with the following components: 
______________________________________ 
Alprostadil 0.15% 
Sodium hyaluronate (HA) 2.6% 
Hydroxyethyl cellulose (HEC) 0.3% 
Methoxypolyethylene glycol (MPEG) 5% 
Benzyl alcohol 1.5 
Water Remainder 
______________________________________ 
The dosage range for the drug is between 2-3 ml. 
EXAMPLE 3 
A transdermal preparation of Alprostadil is prepared in the manner of 
Example 1 with the following components: 
______________________________________ 
Alprostadil 0.3 
Sodium hyaluronate (HA) 3.3% 
Hydroxyethyl cellulose (HEC) 0.5% 
Methoxypolyethylene glycol (MPEG) 10% 
Benzyl alcohol 2.5 
Water Remainder 
______________________________________ 
The dosage range for the drug is between 2-3 ml. 
EXAMPLE 4 
A transdermal preparation of Alprostadil, prostaglandin-E.sub.1 
-.gamma.-cyclodextrin complex (a water-soluble source of prostaglandin 
E.sub.1), formula is prepared in the following manner. 
First, into a sterilized glass vessel is added 1062.5 ml of sterile water 
which is stirred at 1500 to 2000 rpm. To that solution, 34.5 grams of HA, 
having a molecular weight of around 700,000 to 775,000 and a purity 
described above, is slowly added. The resulting solution is then stirred 
for 16 to 20 hours until all of the HA polymer dissolves into the water 
and a crystal-clear viscous solution is formed. 
Next, a 0.7% solution of HEC is prepared by adding 10.5 grams of the solid 
material under aseptic conditions to 250 ml of sterile water. The HEC 
solution is then allowed to dissolve for 1 to 2 hours while stirring at 
1500 to 2000 rpm. 
Then, the HEC solution is added to a sufficient amount of the HA solution 
and mixed for 10 to 15 hours until a homogeneous solution is produced. 100 
ml of carefully measured methoxypolyethylene glycol (MPEG) 10% is added 
into the mixture. The stirring speed should be increased for the mixture, 
while this step is being performed, to 2500 rpm. The resulting mixture 
thus formed should be allowed to mix at 2000 rpm for an additional 3 to 4 
hours. Next, 10 ml of benzyl alcohol (1%) is added to the mixture. Again, 
the stirring speed is increased during this part of the procedure to 2500 
rpm. Then, the mixture is stirred for 3 to 5 hours at 2000 rpm. 
Finally, to 6.6 ml of the HA/HEC polymer matrix thus formed, 20 mg of 
powdered Alprostadil (prostaglandin-E.sub.1 -.gamma.-cyclodextrin) complex 
is added. The resulting mixture is then mixed by hand for thirty minutes 
so as to insure that the Alprostadil is in solution, and that the gel is 
clear. This mixture is then refrigerated to allow air bubbles to come to 
the surface and dissipate. 1 ml of the gel thus formed is then charged 
into 3 ml syringes giving 1200 mcg of Alprostadil per dose. 
EXAMPLE 5 
A transdermal preparation of Alprostadil (prostaglandin E.sub.1) formula 
was prepared in the following manner. 
First, 20 ml of prostaglandin E.sub.1 was dissolved in 1.5 ml of propylene 
glycol. The resulting solution was mixed by hand until the prostaglandin 
E.sub.1 appears to be totally dissolved. Next, 5 ml of an HA/HEC polymer 
gel, prepared as described in Example 4, was added to the solution. The 
substance was then mixed by an electric stirrer for 2 hours. A 0.5 ml 
sample was removed from the resulting mixture. Slight separation in the 
mixture was observed. An additional 1 ml of propylene glycol was added to 
the mixture followed by mixing for an additional hour. The resulting 
mixture is observed to be very opaque. 
EXAMPLE 6 
A transdermal preparation of Alprostadil (0.4%) formula is prepared in the 
following manner. 
First, a mixture is prepared by dissolving 14.7 grams of Sodium Hyaluronate 
(HA) in 350 ml of water, then stirring the resulting solution at 1800 rpm 
initially, reducing to 800 rpm and stirring for 2 hours, and then stirring 
at a low speed overnight. To the resulting mixture is added a mixture of 
75 ml MPEG, and then 12.5 ml of benzyl alcohol, stirred for 30 minutes, is 
added. The resulting mixture is then stirred for 2 hours. 
Next, a solution is prepared by adding 3.5 g (0.7)% HEC to 75 ml of water 
and stirring for 35 minutes. The resulting solution is then added to the 
above formed mixture and stirred at a moderate speed overnight to form an 
HA/HEC polymer matrix. 
Then, 40 mg of prostaglandin E.sub.1 is added to 10 ml of the HA/HEC 
polymer matrix. The mixture is stirred for 2 hours. 0.5 to 0.75 ml of the 
resulting gel is loaded into syringes and stored in a refrigerator. 
EXAMPLE 7 
A topical gel formula for treating vaginal dryness is prepared in the 
manner of Example 6 by using a mixture of nicotinic acid and glycerol in 
place of prostaglandin E.sub.1. 
EXAMPLE 8 
A topical gel formula for treating vaginal dryness is prepared in the 
manner of Example 6 by using a steroid, such as testosterone, in place of 
prostaglandin E.sub.1. 
The invention being thus described, it will be obvious that the same may be 
varied in many ways. Such variations are not to be regarded as a departure 
from the spirit and scope of the invention and all such modifications are 
intended to be included within the scope of the following claims.