AU2013227981B2 - Excipient system for topical delivery of pharmaceutical agents - Google Patents

Abstract

EXCIPIENT SYSTEM FOR TOPICAL DELIVERY OF PHARMACEUTICAL AGENTS Abstract The subject invention is based upon the discovery that a wide variety of pharmaceutical agents can be delivered into the skin, fingernails, and toenails of patients by dissolving or dispersing the pharmaceutical agent in a solvent system which is comprised of 10 a combination of an alkyl lactate and Simmondsia chinesis seed oil. It is critical for the solvent system to contain both the alkyl lactate and Simmondsia chinesis seed oil to attain penetration through skin, fingernails and toenails. In other words, for effective delivery of the pharmaceutical agent through the skin or nail it is critical for the pharmaceutical agent to be dissolved or dispersed in a mixture of an alkyl lactate and Simmondsia chinesis seed oil. 15 The subject invention more specifically discloses a pharmaceutical serum which is comprised of (1) an alkyl lactate, wherein the alkyl group in the alkyl lactate contains from 2 to about 12 carbon atoms, (2) Simmondsia chinesis seed oil, and (3) a pharmaceutical agent. Some representative examples of pharmaceutical agent which can be incorporated into the pharmaceutical serums of this invention include, antifungal agents, hormones, growth 20 factors (cytokines), antimicrobials, antibacterials, antibiotics, non-steroidal anti inflammatory agents, immunodilators, anesthetics, plant extracts, vitamins, corticosteroids, hair growth stimulants, and the like.

Description

2013227981 10 Sep 2013 -1 -

EXCIPIENT SYSTEM FOR TOPICAL DELIVERY OF PHARMACEUTICAL AGENTS

Background of the Invention

The effectiveness of virtually all pharmaceutical compositions which are applied to 5 the skin of a patient is normally contingent upon delivery of the active ingredients of such composition through the stratum comeum and viable epidermis into the dermis layer of the skin structure. This is because the active ingredients in such compositions cannot be effective unless they penetrate through the dead layers of skin tissue and into the dermis layer of living skin cells. This is normally a difficult proposition for water soluble active 10 ingredients, such as ascorbic acid, because the stratum comeum is a good water barrier. The stratum comeum and viable epidermis act to protect the body by holding water therein to prevent dehydration and by keeping external water which is frequently contaminated with harmful microorganisms and toxic chemicals out of the body. By the same token, the skin is also a good barrier with respect to most organic solvents. Accordingly, only a few solvents 15 are capable of topically delivering pharmaceutical agents deeply into the skin.

Known solvents which are capable of penetrating through the stratum comeum and viable epidermis into the dermis layer of the skin stmcture cannot be beneficially used in many cases. This is because many pharmaceutical agents are not soluble in such solvents making effective topical delivery using them impossible. In other cases, the solvent may by 20 chemically or biologically incompatible with pharmaceutical agent by virtue of reacting with it or otherwise destroying its bioavailability. In still other cases, human or animal exposure to the solvent may to detrimental due to toxicity and/or undesirable side effects. For instance, the long term exposure of humans or animals to solvents, such as dimethylsulfoxide, would not be desirable and its use on a repeated basis would not 25 normally be warranted.

In many cases, by the topical administration of beneficial pharmaceutical agents to treat maladies in human patients and animals or to attain other desired beneficial results is simply not possible because a solvent system for the effective delivery of the pharmaceutical agent is simply not known. In other cases, pharmaceutical agents can be delivered topically 30 to attain beneficial results. However, the results attained could be dramatically improved if 2013227981 10 Sep 2013 -2- better topical delivery systems were available. For instance, hair growth stimulants, such as minoxidil, can be topically delivered with some degree of success. However, the level of beneficial hair growth attained could be significantly improved if a delivery system to transport the hair growth stimulant deeper into the skin structure at a higher concentration 5 was available.

There has been a long felt need for an excipient system which is capable of delivering a wide range of pharmaceutical compositions through the stratum comeum and viable epidermis into the dermis layer of the skin structure at high levels of concentration. Such an excipieint system should be chemically and biologically inert with respect to the 10 pharmaceutical agent. It should also be nontoxic and should not induce any undesirable side effects in the human patient or animal being treated. It is also of utmost importance for the excipient system to be a good solvent for the pharmaceutical agent or for the pharmaceutical agent to be highly dispersible in it.

These has been a long felt need for an excipient system for the delivery of anti-15 fungal agents. A fungus is a member of a large group of organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushroom. These organisms are classified as a Kingdom, Fungi, which is separate from plants, animals and bacteria. Before the introduction of molecular methods for phylogenetic analysis, taxonomists considered fungi to be members of the Plant Kingdom primarily because of the 20 similarities in lifestyle, as both fungi and plants are largely immobile, and have similarities in general morphology and growth habitat. Post molecular methods for phylogenetic analysis, the fungi have been a separate Kingdom distinct from both plants and animals, from which they appear to have diverged around one billion years ago. Advances in molecular genetics have opened the door for DNA analysis to be incorporated into 25 taxonomy, which has oftentimes challenged the historical groupings of fungi based on morphology and other traits. Phylogenetic studies published in the last decade have helped reshape the classification of the Kingdom Fungi, which is divided into one subkingdom, seven phyla, and ten subphyla.

The fungus kingdom encompasses an enormous diversity of taxa with varied 30 ecologies, life cycle strategies, and morphologies ranging from single-celled aquatic chytrids 2013227981 10 Sep 2013 -3 - to large mushrooms. However, little is known of the true diversity of Kingdom Fungi, which has been estimated at around 1.5 million species, with about 5% of these having been formally classified.

The English word fungus is directly adopted from the Latin Fungus (mushroom), 5 used in the writings of Florace and Pliny. This in turn is derived from the Greek word Sphongos (Sponge), which refers to the macroscopic structures and morphology of mushrooms and molds. The discipline of biology devoted to the study of fungi is known as mycology, which is regarded as a branch of botany, even though studies have shown that fungi are more closely related to animals than to plants. 10 The Kingdom Fungi includes some of the most important organisms, both in terms of their economic and ecological roles. For instance fungi by breaking down the dead organic material in the environment continue the cycle of nutrients through ecosystems. Furthermore, most vascular plants could not grow without the symbiotic fungi that inhabit their roots and supply essential nutrients. Fungi has been essential in providing many 15 breakthrough drug , such as penicillin and more sophisticated antibiotics. Other fungi have given us wonderful foods such as mushrooms, morels and the much desired truffle. From fungi we also obtain our breads, beers, and champagnes. However, with the Kingdom Fungi also comes the negative. Fungi are also responsible for a number of diseases of both plant (leaf, root and stem rot, rusts and smuts) and varied disease in animals and humans. 20 Precisely because fungi are more genetically and chemically similar to animals than any other organisms, this makes fungal diseases very difficult to treat.

Onychomycosis is a fungal infection of human fingernails or toenails. Onychomycosis is a progressive, recurring fungal infection that initially first occurs in the nail bed and progresses to the nail plate. The main structural components of the nail include 25 the lateral and proximal folds, cuticle, matrix, plate and hyponychium. The proximal nail fold is located at the proximal end of the visible nail plate where it folds over itself. The horny layer of the proximal nail fold is called the cuticle. The cuticle consists of modified stratum comeum that originates at the junction of the dorsal and ventral epithelial surfaces and proceeds along the nail surface. The cuticle protects the matrix from exposure to 30 foreign material, including infection from microorganisms. The matrix is the growth center 2013227981 10 Sep 2013 -4- of the nail and is located at the proximal end under the cuticle. This site contains basal cells that migrate into the nail plate, where they divide and differentiate, forming the hard, keratinized component of the nail plate. The nail plate is the largest structure of the nail unit and is attached to the top of the nail bed. This transparent structure is gradually replaced as 5 it grows out. The structure is completely renewed every 6 months on fingers and every 10 to 18 months on toes. The nail grows faster on longer digits, digits that are used most often and on traumatized nails. The nail bed is located under the nail plate and consists of epidermal grooves and ridges that contain small blood vessels. The dermis of the nail borders bone(the phalanx) rather than subcutaneous tissue. 10 Fungal infections usually invade the nail (between the nail plate and the nail bed ) through an opening in the subungual space of the hyponychium, near the distal groove. The infection starts distally, then progresses proximally. However, trauma to the cuticle may also permit entry of fungal organisms.

The types of microorganisms that cause onychomycosis can be broadly classified 15 into 2 groups: dermatophytes and nondermatophytes. Dermatophytes are fungi that infect keratinous tissue. Nondermatophytes that cause onochomycosis are either yeasts or molds. Dermatophytes are by far the most common causative pathogens of onychomycosis.

The nail provides the perfect place for the fungus and protects it while it grows, since fungi love damp, warm, dark places, the nails of our fingers and toes are very effective 20 barriers. This barrier makes it quite difficult for a superficial infection to invade the nail.

However, once an infection has invaded that same barrier that was so effective in protecting us against infection now works against us, making this type of fungal infection very difficult to treat.

Onychomycosis is not an uncommon disease. This type of infection accounts for 25 approximately half of all nail disorders and one third of cutaneous fungal infections in the United States. Studies suggest that the number of persons affected is apparently on the rise. This rise may be attributed to many factors among them the aging population. Some studies suggest that 48% of the population may be infected by age 70. The increasingly higher occurrence of onychomyosis may also be attributable to the greater use of 30 immunosuppressive drugs, the increasing number of people infected with HIV, the 2013227981 10 Sep 2013 -5 - increasing exposure to pathogens in public swimming pools and spas, and high heels and tight fitting shoes in fashion styles. The growth of low cost nail salons that may not always properly disinfect nail instruments thoroughly between clients is also attributing to the increasing occurrence of onychomycosis in many countries. 5 The problem with onychomycosis is aggravated by the fact that it is very contagious and easily passed from person to person. In fact, many infected people are under the impression that the infection will resolve spontaneously and go without any treatment while infecting other people. On the other hand, onychomycosis is notoriously difficult to treat and long treatment periods have typically been required to cure the infection using 10 conventional drugs and techniques. It is not uncommon for patients to simply give up before that infection has been eradicated.

The dermatophyte fungus that causes the onychomycosis infection is ubiquitous. It rarely remits spontaneously and typically spreads to involve the entire nail anatomy. Unfortunately, onychomycosis frequently spreads to other digits, and sometimes spreads to 15 other sites and to other family members as well as others that come in contact with the infected person or infected articles which are contaminated by the infected person.

Participants in numerous athletic activities of varied nature are much more susceptible to onychomycosis. Some of these athletic activities include: long distance running, ballet dancing, golf, and soccer. A wide array of preexisting medical conditions 20 also leads to a higher level of susceptibility to being infected with onychomycosis. Some of these medical conditions include: diabetes mellitus, blood circulation disorders (including varicose veins in the legs, pallor of fingers and toes, and poor peripheral circulation), and genetic susceptibility associated with Down’s Syndrome, Raynaud Syndrome, and Cushing’s Syndrome. Cancer patients that are being treated with chemotherapy and organ 25 transplant recipients on anti-rejection drugs are also in a high risk group.

Nail trauma is a frequent cause of onychomycosis. Individuals in trades and professions that involve the wearing of sports or safety shoes are also at higher risk. Men are more prone to onychomycosis than women. The reasons for this gender difference are not clear but may involve higher occurrence of nail trauma that results from professional and 30 athletic activities. Social and/or genetic factors may also play a role. 2013227981 10 Sep 2013 -6-

Nail fungus is more than just a cosmetic problem. Many people complain of discomfort in walking, pain, or limitation of their work or other activities. Gross distortion and dystrophy of the nail may cause trauma to adjacent skin and may lead to secondary bacterial infection. In several studies, patients with onochomycosis reported significantly 5 poorer general health, mental health, social functioning, and body pain than did people without this nail infection. Psychosocial limitations included fear of social situations that exposed on infected fingernail or toenail.

In immuno-compromised people, there is a great risk that this infection will disseminate. Although onychomycosis causes some degree of morbidity for healthy 10 individuals it is especially pronounced in high risk patients such as diabetics, patients with HIV, AIDS or other types of immunosuppressant, including transplant recipients, and patients on long term corticosteroid therapy.

Onychomycosis poses a greater risk to diabetic patients because of the possible sequelae. In particular, high risk diabetic patients with compromised lower extremities and 15 severe neuropathy are at increased risk of developing complications from onychomycosis. Most notably impaired sensation can make many diabetics less aware of minor abrasions and ulcerations on their feet that may be caused by trauma, from poor nail grooming or by the sharp brittle or infected nails characteristic of onychomyosis. These lesions in turn may develop into serious paronychia, cellulites or bacterial infections, and contribute to the 20 severity of the diabetic foot. Osteomyelitis can also result from neglected, infected nail bed erosion in diabetic patients because of the close proximity of the nail bed to the underlying bone. Nearly 18% of gangrene and 10% of foot ulcers in people can be attributed to onychomycosis. Thus, diabetics with onychomycosis should treat it quickly as it may lead to much greater, catastrophic results. 25 Everyone should seek treatment of a nail fungus as soon as one is suspected.

Symptoms of nail fungus can include nail changes such as, brittleness, change in nail shape, crumbling of the outside edges of the nail, debris trapped under the nail, loosening or lifting up of the nail, loss of luster or shine, white spots, thickening of the nail or white or yellow streaks on the side of the nail. Much more rarely, a black strip or spot is present. 30 Current treatment for ocychomycosis include mechanical debridement, oral drugs, 2013227981 10 Sep 2013 -7- topical drugs, removal of nail and laser treatments. Mechanical debridement is a traditional podiatric approach that requires time, specialized instruments, and experience. The goal of this approach is to reduce pressure and fungal load by mechanically reducing nail thickness. Since mechanical debridement removes a large portion of fungal material it has potential to 5 enhance the effectiveness of other therapies. However, it does have its limitations. It does not eradicate the infectious pathogens, and it must be repeated as the nail grows until the infection is gone.

Oral antifungal medications are often prescribed as first -line treatments for nail fungus. These systemic drugs reach the infected nail via the peripheral circulation. Though 10 antifungal medications have improved it has been suggested that as many as 25% to 40% of onychomycosis cases are classified as treatment failures in clinical practice. In addition these oral drugs have many adverse side affects including headache, gastrointestinal symptoms such as diarrhea, dyspepsia, abdominal pain, constipation, nausea and flatulence; dermatological symptoms such as rash, pruritus and urticaria. Additionally these oral 15 antifungal drugs may effect the liver, therefore liver function and white cell counts should be assessed at baseline and periodically during treatment. Neutropenia and transient taste disturbance may also result. Another downside to oral antifungal medication is the financial impact for the patient as these oral antifungal drugs can be quite expensive.

Current topical antifungal therapy is effective for the treatment of onochomycossis in 20 some cases. This approach involves the direct application of an antifungal drug to the infected nail. These drugs are thought to diffuse through the nail plate to reach the site of infection, where they eradicate fungal organisms. These over the counter creams and ointments generally do not help treat this condition.

Removal of the nail involves the removal of the affected nail plate, this may be 25 performed surgically or chemically. This approach allows growth of a new nail but can traumatize the nail bed, which may affect the appearance of the new nail. Total nail removal causes great discomfort to the patient and therefore is discouraged. Only in the most severe cases should this method be recommended.

Practitioners have been using lasers for toenail fungus since 2009. However, 30 podiatrists using this method disagree greatly on its effectiveness both medically and from 2013227981 10 Sep 2013 -8- the standpoint of cost. The treatment consists of the practitioner aiming a laser beam at the patient’s toenail to kill the organisms that cause the fungus. The nails are not immediately clear after the treatment, which takes up to an hour and the patient must wait for the fungus free nail to grow out which cat take up to about 18 months. Multiple laser treatments are 5 frequently required and the total cost of such treatments can preclude them from being a possibility for many patients. In addition to this the high cost of laser treatments is generally not covered by insurance because it is considered to be an aesthetic procedure.

Considering the problems associated with the current methods of treatment for nail fungus something more ideal needs to be found. Georgeanne Botek, DPM Department of 10 Orthopedic Surgery at The Cleveland Clinic, suggests that the ideal anti fungal treatment would be broad spectrum, taken up and incorporated into the nail matrix, diffusing through the epithelium of the nail bed to reach the nail bed hyperkeratosis, and penetrating into the ventral surface of the plate. Additionally, it would be effective, with high rates of clinical cure (ascertained by laboratory testing, fungal culture) and a low rate of relapse and 15 effective when used short term (the duration of new nail re-growth) and have few in any adverse effects and adverse drug interactions. It should also, of course, be cost effective.

Summary of the Invention

The subject invention is based upon the discovery that a wide variety of 20 pharmaceutical agents can be delivered into the skin, fingernails, and toenails of patients by dissolving or dispersing the pharmaceutical agent in a solvent system which is comprised of a combination of an alkyl lactate and Simmondsia chinesis seed oil. It is critical for the solvent system to contain both the alkyl lactate and Simmondsia chinesis seed oil to attain penetration through skin, fingernails and toenails. In other words, for effective delivery of 25 the pharmaceutical agent through the skin or nail it is critical for the pharmaceutical agent to be dissolved or dispersed in a mixture of an alkyl lactate and Simmondsia chinesis seed oil. The subject invention more specifically discloses a pharmaceutical serum which is comprised of (1) an alkyl lactate, wherein the alkyl group in the alkyl lactate contains from 2 to about 12 carbon atoms, (2) Simmondsia chinesis seed oil, and (3) a pharmaceutical agent. 30 Some representative examples of pharmaceutical agent which can be incorporated into the 9 2013227981 31 Aug 2017 pharmaceutical serums of this invention include, antifungal agents, hormones, growth factors (cytokines), antimicrobials, antibacterials, antibiotics, non-steroidal anti inflammatory agents, immunodilators, anesthetics, plant extracts, vitamins, corticosteroids, hair growth stimulants, and the like.

The subject invention more specifically discloses a pharmaceutical serum which is comprised of (1) an alkyl lactate, wherein the alkyl group in the alkyl lactate contains from 2 to about 12 carbon atoms, (2) Simmondsia chinesis seed oil, and (3) a pharmaceutical agent.

The subject invention further discloses a pharmaceutical serum which is comprised of (1) an alkyl lactate, wherein the alkyl group in the alkyl lactate contains from 2 to about 12 carbon atoms, (2) Simmondsia chinesis seed oil, and (3) a pharmaceutical agent, wherein the pharmaceutical agent is selected from the group consisting of antifungal agents, hormones, growth factors, antimicrobials, antibacterials, antibiotics, non-steroidal anti inflammatory agents, immunodilators, anesthetics, plant extracts, vitamins, corticosteroids, hair growth stimulants, and the like.

In one embodiment of this invention a hair growth stimulant is included in the pharmaceutical serum of this invention as the pharmaceutical agent. In most cases the hair growth stimulant will be a antihypertensive vasodilator medication, such as minoxidil (6-(1 piperidinyl)-2,4-pyrimidinedia mine 3-oxide) which is included in the serum at a level which is within the range of about 0.5 weight percent to about 12 weight percent. The hair growth stimulant will more typically be included in the serum at a level which is within the range of about 1 weight percent to about 8 weight percent. The hair growth stimulant will most typically be included in the serum at a level which is within the range of about 2 weight percent to about 5 weight percent.

The present invention also reveals a method for treating hair loss, the method comprising topically applying the pharmaceutical serum comprising a hair growth stimulant to an area of skin where hair growth is desired.

The present invention also reveals a method for treating human hair loss which comprised topically applying a hair growth serum to an area of skin where hair growth is desired, wherein the hair growth serum is comprised of (1) an alkyl lactate, wherein the alkyl group in the alkyl lactate contains from 2 to about 12 carbon atoms, (2) Simmondsia chinesis seed oil, and (3) from about 0.5 weight percent to about 12 weight percent of a hair growth stimulant.

In another embodiment of this invention an antioxidant is included in the (13554927_1):GGG 2013227981 10 Sep 2013 30 -10- pharmaceutical serum of this invention as the pharmaceutical agent. In most cases the antioxidant, such as carnosic acid, will be included in the pharmaceutical serum at a level which is within the range of about 0.01 weight percent to about 15 weight percent. The antioxidant will more typically be included in the serum at a level which is within the range 5 of about 0.1 weight percent to about 12 weight percent. The antioxidant will most typically be included in the serum at a level which is within the range of about 0.5 weight percent weight percent to about 10 weight percent.

In another embodiment of this invention (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-l-enyl)nona-2,4,6,8-tetraen-l-ol, commonly known as retinol, or retinoic 10 acid, commonly known as Retin-A, is included in the pharmaceutical serum of this invention as the pharmaceutical agent. Retinol and Retin-A are known to increase the production of cells in the top layer of skin, helping to rejuvenate the skin. As a result, the skin gradually looks younger in appearance. Retinol and Retin-A also induce higher levels of collagen production which makes to skin firmer and accordingly gives it a younger appearance. 15 These agents may also reduce pigmentation issues that stem from sun damage. In any case retinol and Retin-A are known to help improve the overall appearance of the skin and to reduce the visible signs of aging. These agents are also highly effective antioxidants that can help prevent harmful carcinogens from breaking down skin cells. They also stimulate the production of healthy skin cells, which is essential in healing skin damage caused by 20 aging and environmental exposure. Retinol and Retin-A also stimulates collagen production, which can help fill in the fine lines and wrinkles caused by age, shrink pores, and soften the skin.

By virtue of their ability to unclog pores and remove dead skin cells retinol and Retin-A are often used in treating patients suffering with acne. The healing properties of 25 retinol can also help to reverse sun damage and relieve sunburn. Retinol and Retin-A are both derivatives of vitamin A and are sometimes used interchangeably due to confusion. However, Retin-A is much stronger and has a much more aggressive effect on the skin. As a consequence of Retin-A being significantly harsher and causing a higher incidence of side effects, such as skin redness, itchiness and rashes, retinol is much better for sensitive skin.

In most cases the retinol will be included in the pharmaceutical serum at a level 2013227981 10 Sep 2013 -11 - which is within the range of about 0.1 weight percent to about 15 weight percent. On the other hand, retinoic acid will typically be included in such pharmaceutical serums at levels which are in the range of about 0.005 weight percent to about 0.5 weight percent. In any case, this invention further discloses a pharmaceutical serum which is comprised of (1) an 5 alkyl lactate, wherein the alkyl group in the alkyl lactate contains from 2 to about 12 carbon atoms, (2) Simmondsia chinesis seed oil, and (3) a pharmaceutical agent which is selected from the group consisting of retinol and retinoic acid.

The present invention also reveals a method for skin rejuvenation which comprised topically applying a skin rejuvenation serum to an area of skin where skin rejuvenation is 10 desired, wherein the skin rejuvenation serum is comprised of (1) an alkyl lactate, wherein the alkyl group in the alkyl lactate contains from 2 to about 12 carbon atoms, (2) Simmondsia chinesis seed oil, and (3) an effective amount of a vitamin A derivative selected from the group consisting of retinol and retinoic acid.

The subject invention is based upon the discovery that an antifungal agent can be 15 delivered through the fingernail or the toenail of an infected human to treat onychomycosis by dissolving or dispersing the antifungal agent in a solvent system which is comprised of a combination of an alkyl lactate and Simmondsia chinesis seed oil. It is critical for the solvent system to contain both the alkyl lactate and Simmondsia chinesis seed oil to attain penetration through the fingernail or the toenail. In other words, for effective delivery of the 20 antifungal agent through the nail to reach the fungus under the nail it is critical for the antifungal agent to be dissolved or dispersed in a mixture of an alkyl lactate and Simmondsia chinesis seed oil. Accordingly, in accordance with this invention the antifungal agent is absorbed by and incorporated into the nail matrix by diffusing through the epithelium of the nail bed to reach the nail bed hyperkeratosis. The antifungal agent 25 additionally penetrates into the ventral surface of the nail plate.

The antifungal serum of this invention has been determined to be highly effective (offers a high rate of clinical cure) and offers a low rate of relapse. It is also effective when used short term (the duration of new nail re-growth) and is not believed to have any adverse effects or to cause adverse drug interactions. Additionally, the antifungal serum of this 30 invention is highly cost effective in treating onychomycosis. 2013227981 10 Sep 2013 - 12-

The subject invention more specifically discloses an antifungal serum which is comprised of (1) an alkyl lactate, wherein the alkyl group in the alkyl lactate contains from 2 to about 12 carbon atoms, (2) Simmondsia chinesis seed oil, and (3) an antifungal agent.

The present invention also reveals a method for treating a human fingernail or toenail 5 which is infected with onychomycosis which comprised applying an antifungal serum to the infected nail, wherein the antifungal serum is comprised of (1) an alkyl lactate, wherein the alkyl group in the alkyl lactate contains from 2 to about 12 carbon atoms, (2) Simmondsia chinesis seed oil, and (3) an antifungal agent. 10 Detailed Description of the Invention

The pharmaceutical serum of this invention is comprised of (1) an alkyl lactate, (2) Simmondsia chinesis seed oil, and (3) a pharmaceutical agent. The alkyl lactate utilized will typically have an alkyl group that contains from 2 to about 12 carbon atoms and will accordingly be of the structural formula:

15 OH O

I II

H3C-CH-C—O-R wherein R represents an straight chained or a branched alkyl group that contains from 2 to 12 carbon atoms. The alkyl group (R) of the alkyl lactate will typically contain from 2 to 20 about 8 carbon atoms and will more typically contain from 3 to 6 carbon atoms. In many cases the alkyl group of the alkyl lactate will contain from 4 to 6 carbon atoms. For instance, the alkyl group of the alkyl lactate can contain 4, 5, or 6 carbon atoms. Some representative examples of alkyl lactates that can be used include: ethyl lactate, n-propyl lactate, iso-propyl lactate, n-butyl lactate, iso-butyl lactate, t-butyl lactate, isoamyl lactate, n-25 pentyl lactate, t-pentyl lactate, n-hexyl lactate, iso-hexyl lactate, t-hexyl lactate, n-heptyl lactate, iso-heptyl lactate, t-heptyl lactate, n-octyl lactate, iso-octyl lactate, and t-octyl lactate.

Isoamyl lactate is preferred for utilization as the alkyl lactate because it is not a volatile as the lower molecular weight alkyl lactates, but is still a low viscosity liquid at 30 room temperature. Isoamyl lactate is of the structural formula: 2013227981 10 Sep 2013 - 13- OH O CH3

I II I H3C-CH-C—O-CH2-CH2-CH-CH3 and is also a colorless liquid having a pleasant mild odor. Isoamyl lactate is preferred for 5 utilization in conjunction with oil soluble antifungal agents, such as undecylenic acid.

Mixtures of various alkyl lactates can be utilized in the pharmaceutical serum of this invention. For instance, a mixture of ethyl lactate and isoamyl lactate can be employed. Ethyl lactate is a colorless liquid of the structural formula:

OH O 10 I || H3C-CH-C—O-CH2-CH3 which is preferred for utilization in conjunction with antifungal agents which are water soluble. However, ethyl lactate has a strong odor. Accordingly, it is preferred to utilize ethyl lactate in mixtures with a higher molecular weight alkyl lactate to reduce volatility and 15 the level of odor. It is desirable to utilize ethyl lactate in mixtures with isoamyl lactate in some cases. The weight ratio of ethyl lactate to isoamyl lactate will typically be within the range of about 1:10 to about 20:1. The weight ratio of ethyl lactate to isoamyl lactate will more typically be within the range of about 1:5 to about 10:1. Such mixtures of ethyl lactate and isoamyl lactate will preferably contain from about 30 weight percent to 70 weight 20 percent ethyl lactate and from about 30 weight percent to about 70 weight percent isoamyl lactate. Such mixtures of ethyl lactate and isoamyl lactate will more preferably contain from about 40 weight percent to 60 weight percent ethyl lactate and from about 40 weight percent to about 60 weight percent isoamyl lactate. Such mixtures of ethyl lactate and isoamyl lactate will most preferably contain from about 45 weight percent to 55 weight percent ethyl 25 lactate and from about 45 weight percent to about 55 weight percent isoamyl lactate.

The Simmondsia chinesis seed oil used in the antifungal serums of this invention is commonly known as jojoba oil or goat-nut oil. The Simmondsia chinesis seed oil can be expeller processed or it can be cold pressed at a temperature which does not exceed 150°F (66°C) and which preferably does not exceed 120°F (49°C). The Simmondsia chinesis seed 30 oil is preferably golden Simmondsia chinesis seed oil which is filtered, but which is not 2013227981 10 Sep 2013 - 14- refined. Accordingly, the Simmondsia chinesis seed oil will normally be filtered to remove undesired particulate matter. In some cases refined Simmondsia chinesis seed oil can by used in the pharmaceutical serums of this invention with good results. Such refined Simmondsia chinesis seed oil is clear, rather than being golden in color, and offers the 5 advantage of having an extended shelf-life without becoming rancid. However, in the practice of the subject invention color is not of importance and oil stabilization can be achieved by adding a small amount of a soluble antioxidant, such as Vitamin E to the antifungal serum. In any case, the Simmondsia chinesis seed oil can be refined by extracting it from unrefined material with an organic solvent, such as n-hexane or cyclohexane, and 10 then fractionally distilling the extract to remove the organic solvent.

In cases where Vitamin E (α-tocopherol, β -tocopherol, γ-tocopherol, and/or 5-tocopherol) is utilized in the pharmaceutical serum it is typically present at a level which is within the range of about 0.01 weight percent to about 2 weight percent, based upon the total weight of the antifungal serum. In cases where Vitamin E is utilized in the pharmaceutical 15 serum it is more typically added at a level which is within the range of 0.05 weight percent to about 1 weight percent, and is generally employed at a level which is within the range of 0.1 weight percent to 0.5 weight percent, based upon the total weight of the pharmaceutical serum. A wide variety of pharmaceutical agents can be utilized in the pharmaceutical 20 serums of this invention. For instance, the pharmaceutical agent can be selected from antifungal agents, hormones, growth factors, antimicrobials, antibacterials, antibiotics, nonsteroidal anti-inflammatory agents, immunodilators, anesthetics, plant extracts, vitamins, vitamin derivatives, corticosteroids, hair growth stimulants, and the like.

In one embodiment of this invention the pharmaceutical agent is an antifungal agent. 25 A wide variety of antifungal agents can be utilized in the antifungal serums of this invention. For instance, the antifungal agent can be selected from azoles or imidazoles, including but not limited to, miconazole, econazole, terconazole, saperconazole, itraconazole, butaconazole, clotrimazole, tioconazole, fluconazole and ketoconazole, vericonazole, fenticonazole, sertaconazole, posaconazole, bifonazole, oxiconazole, sulconazole, elubiol, 30 vorconazole, isoconazole, flutrimazole, tioconazole and their pharmaceutically acceptable 2013227981 10 Sep 2013 - 15- salts and the like. The antifungal agent can also be an allylamine or it can be selected from other chemical families, including but not limited to, ternafine, naftifine, amorolfine, butenafine, ciclopirox, griseofulvin, undecyclenic acid, haloprogin, tolnaftate, nystatin, iodine, rilopirox, BAY 108888, purpuromycin and their pharmaceutically acceptable salts. 5 However, the preferred antifungal agents for utilization in conjunction with this invention include clioquinol, haloprogin, miconazole nitrate, poridone-iodine, tolnaftate, undecylenic acid, calcium undecylenate, cobalt undecylenate, zinc undecylenate, and clotrimazole. Undecylenic acid is a highly preferred antifungal agent for utilization in the practice of this invention. 10 The alkyl lactate will typically be present in the antifungal serums of this invention at a level which is within the range of about 5 weight percent to about 80 weight percent and will more typically be present at a level which is within the range of about 10 weight percent to about 70 weight percent. The alkyl lactate will commonly be present in the antifungal serums of this invention at a level which is within the range of about 10 weight percent to 15 about 60 weight percent and will more commonly be present at a level which is within the range of about 15 weight percent to about 60 weight percent. In most cases, the alkyl lactate will typically be present in the antifungal serums of this invention at a level which is within the range of about 15 weight percent to about 50 weight percent.

The Simmondsia chinesis seed oil will typically be present in the antifungal serums 20 of this invention at a level which is within the range of f about 5 weight percent to about 80 percent and more typically be present at a level which is within the range of about 10 weight percent to about 70 percent. The Simmondsia chinesis seed oil will commonly be present in the antifungal serums of this invention at a level which is within the range of about 10 weight percent to about 60 percent and more typically will be present at a level which is 25 within the range of about 15 weight percent to about 50 percent. In most cases, the

Simmondsia chinesis seed oil will be present in the antifungal serums of this invention at a level which is within the range of about 15 weight percent to about 45 percent and in many cases will preferably be present at a level which is within the range of about 15 weight percent to about 40 percent. 30 The antifungal agent will typically be present at a level of about 0.25 weight percent 2013227981 10 Sep 2013 - 16- to about 40 weight percent and will more typically be present at a level which is within the range of about 0.5 weight percent to about 35 weight percent. The antifungal agent will commonly be present at a level of about 0.75 weight percent to about 30 weight percent and will more commonly be present at a level which is within the range of about 1 weight 5 percent to about 30 weight percent. However, the level of antifungal agent utilized is highly dependant upon the identity of the antifungal agent employed in the antifungal serum. For instance, undecylenic acid, calcium undecylenate, cobalt undecylenate, zinc undecylenate will typically be utilized alone or in a mixture at a level which is within the range of about 5 weight percent to about 30 weight percent. Undecylenic acid, calcium undecylenate, cobalt 10 undecylenate, zinc undecylenate will more typically be utilized alone or in a mixture at a level which is within the range of about 10 weight percent to about 25 weight percent. Undecylenic acid, calcium undecylenate, cobalt undecylenate, zinc undecylenate will most typically be utilized alone or in a mixture at a level which is within the range of about 15 weight percent to about 25 weight percent. Undecylenic acid, calcium undecylenate, cobalt 15 undecylenate, zinc undecylenate will preferably be utilized alone or in a mixture at a level which is within the range of about 20 weight percent to about 25 weight percent.

In cases where haloprogin, tolnaftate, or clotrimazole are utilized as the antifungal agent in the antifungal serums of this invention they will typically be incorporated at a level which is within the range of about 0.25 weight percent to about 2 weight percent. 20 Haloprogin, tolnaftate, or clotrimazole will more typically be incorporated into the antifungal serums of this invention at a level which is within the range of about 0.5 weight percent to about 1.5 weight percent and will preferably be included at a level of which is within the range of about 0.75 weight percent to about 1.25 weight percent. It is normally most preferred for haloprogin, tolnaftate, or clotrimazole to be included in the antifungal 25 serums of this invention at a level of 1 weight percent.

In cases where poridone-iodine is utilized as the antifungal agent in the antifungal serums of this invention it will typically be incorporated at a level which is within the range of about 4 weight percent to about 20 weight percent. Poridone-iodine will more typically be incorporated into the antifungal serums of this invention at a level which is within the 30 range of about 6 weight percent to about 14 weight percent and will preferably be included 2013227981 10 Sep 2013 - 17- at a level of which is within the range of about 8 weight percent to about 12 weight percent. It is normally most preferred for poridone-iodine to be included in the antifungal serums of this invention at a level of 10 weight percent.

In cases where miconazole nitrate is utilized as the antifungal agent in the antifungal 5 serums of this invention it will typically be incorporated at a level which is within the range of about 05 weight percent to about 8 weight percent. Miconazole nitrate will more typically be incorporated into the antifungal serums of this invention at a level which is within the range of about 1 weight percent to about 4 weight percent and will preferably be included at a level of which is within the range of about 1.5 weight percent to about 3 weight 10 percent. It is normally most preferred for miconazole nitrate to be included in the antifungal serums of this invention at a level of 2 weight percent.

In cases where clioquinol is utilized as the antifungal agent in the antifungal serums of this invention it will typically be incorporated at a level which is within the range of about 1 weight percent to about 10 weight percent. Clioquinol will more typically be incorporated 15 into the antifungal serums of this invention at a level which is within the range of about 2 weight percent to about 4 weight percent and will preferably be included at a level of which is within the range of about 2.5 weight percent to about 3.5 weight percent. It is normally most preferred for clioquinol to be included in the antifungal serums of this invention at a level of 3 weight percent. 20 In one embodiment of this invention the alkyl lactate is present in the antifungal serum of this invention at a level which is within the range of about 15 weight percent to about 40 weight percent, wherein the Simmondsia chinesis seed oil is present at a level of about 15 weight percent to about 40 percent, wherein the an antifungal agent is at least one member selected from the group consisting of undecylenic acid, calcium undecylenate, 25 cobalt undecylenate, zinc undecylenate present, and wherein the antifungal agent is present at a level of about 20 weight percent to about 25 weight percent.

In another embodiment of this invention the alkyl lactate is present in the antifungal serum of this invention at a level which is within the range of about 15 weight percent to about 40 weight percent, wherein the Simmondsia chinesis seed oil is present at a level of 30 about 15 weight percent to about 40 percent, wherein the an antifungal agent is at least one 2013227981 10 Sep 2013 - 18- member selected from the group consisting of undecylenic acid, calcium undecylenate, cobalt undecylenate, zinc undecylenate present, and wherein the antifungal agent is present at a level of about 20 weight percent to about 25 weight percent.

In a further embodiment of this invention the alkyl lactate is present in the antifungal 5 serum of this invention at a level which is within the range of about 15 weight percent to about 35 weight percent, wherein the Simmondsia chinesis seed oil is present at a level of about 15 weight percent to about 35 percent, wherein the an antifungal agent is at least one member selected from the group consisting of undecylenic acid, calcium undecylenate, cobalt undecylenate, zinc undecylenate present, and wherein the antifungal agent is present 10 at a level of about 20 weight percent to about 25 weight percent.

In a further embodiment of this invention the alkyl lactate is present in the antifungal serum of this invention at a level which is within the range of about 15 weight percent to about 30 weight percent, wherein the Simmondsia chinesis seed oil is present at a level of about 15 weight percent to about 30 percent, wherein the an antifungal agent is at least one 15 member selected from the group consisting of undecylenic acid, calcium undecylenate, cobalt undecylenate, zinc undecylenate present, and wherein the antifungal agent is present at a level of about 20 weight percent to about 25 weight percent.

In still another embodiment of this invention the alkyl lactate is present in the antifungal serum of this invention at a level which is within the range of about 15 weight 20 percent to about 25 weight percent, wherein the Simmondsia chinesis seed oil is present at a level of about 15 weight percent to about 25 percent, wherein the an antifungal agent is at least one member selected from the group consisting of undecylenic acid, calcium undecylenate, cobalt undecylenate, zinc undecylenate present, and wherein the antifungal agent is present at a level of about 20 weight percent to about 25 weight percent. 25 In another embodiment of this invention the alkyl lactate is present in the antifungal serum of this invention at a level which is within the range of about 20 weight percent to about 80 weight percent, the Simmondsia chinesis seed oil is present at a level of about 20 weight percent to about 80 percent, and the antifungal agent is selected from the group consisting of haloprogin, tolnaftate, or clotrimazoleand is present at a level which is within 30 the range of about 0.25 weight percent to about 2 weight percent. In such compositions it is 2013227981 10 Sep 2013 - 19- typically preferred for the alkyl lactate to be present in the antifungal serum at a level which is within the range of about 20 weight percent to about 80 weight percent, for the Simmondsia chinesis seed oil to be present at a level of about 20 weight percent to about 80 percent, and for the antifungal selected from the group consisting of haloprogin, tolnaftate, 5 or clotrimazoleand to be present at a level which is within the range of about 0.5 weight percent to about 1.5 weight. In such compositions it is typically more preferred for the alkyl lactate to be present in the antifungal serum at a level which is within the range of about 20 weight percent to about 80 weight percent, for the Simmondsia chinesis seed oil to be present at a level of about 20 weight percent to about 80 percent, and for the antifungal 10 selected from the group consisting of haloprogin, tolnaftate, or clotrimazoleand to be present at a level which is within the range of about 0.75 weight percent to about 1.75 weight. In such compositions it is typically most preferred for the alkyl lactate to be present in the antifungal serum at a level which is within the range of about 20 weight percent to about 80 weight percent, for the Simmondsia chinesis seed oil to be present at a level of about 20 15 weight percent to about 80 percent, and for the antifungal selected from the group consisting of haloprogin, tolnaftate, or clotrimazoleand to be present at a level of about 1 weight percent. The antifungal agent use in such antifungal serums will typically consist solely of tolnaftate at a level of 1 weight percent.

The antifungal serum can also include a wide variety of other oils. These additional 20 oils are typically vegetable oils, such as peppermint oil and/or tea tree oil. Peppermint oil can optionally be included at a level which is within the range of about 5 weight percent to about 45 weight percent and is typically included at a level which is within the range of about 5 weight percent to about 40 weight percent. Peppermint oil is commonly included at a level which is within the range of about 10 weight percent to about 35 weight percent and 25 is more commonly included at a level which is within the range of about 15 weight percent to about 30 weight percent. Peppermint oil is preferably included in the antifungal serums of this invention at a level which is within the range of about 15 weight percent to about 25 weight percent.

Tea tree oil can optionally be included at a level which is within the range of about 5 30 weight percent to about 45 weight percent and is typically included at a level which is within 2013227981 10 Sep 2013 -20- the range of about 5 weight percent to about 40 weight percent. Tea tree oil is commonly included at a level which is within the range of about 10 weight percent to about 35 weight percent and is more commonly included at a level which is within the range of about 15 weight percent to about 30 weight percent. Tea tree oill is preferably included in the 5 antifungal serums of this invention at a level which is within the range of about 15 weight percent to about 25 weight percent.

In one embodiment of this invention the additional oil in the antifungal serum is a combination of peppermint oil and tea tree oil, wherein the peppermint oil is present at a level which is within the range of about 5 weight percent to about 45 weight percent, and 10 wherein the peppermint oil is present at a level which is within the range of about 5 weight percent to about 45 weight percent. In another embodiment of this invention the additional oil is a combination of peppermint oil and tea tree oil, wherein the peppermint oil is present at a level which is within the range of about 5 weight percent to about 40 weight percent, and wherein the peppermint oil is present at a level which is within the range of about 5 15 weight percent to about 40 weight percent.

In a further embodiment of this invention the additional oil is a combination of peppermint oil and tea tree oil, wherein the peppermint oil is present at a level which is within the range of about 10 weight percent to about 35 weight percent, and wherein the peppermint oil is present at a level which is within the range of about 10 weight percent to 20 about 35 weight percent. In still another embodiment of this invention the additional oil is a combination of peppermint oil and tea tree oil, wherein the peppermint oil is present at a level which is within the range of about 15 weight percent to about 30 weight percent, and wherein the peppermint oil is present at a level which is within the range of about 15 weight percent to about 30 weight percent. In a preferred embodiment of this invention the 25 additional oil additional oil is a combination of peppermint oil and tea tree oil, wherein the peppermint oil is present at a level which is within the range of about 15 weight percent to about 25 weight percent, and wherein the peppermint oil is present at a level which is within the range of about 15 weight percent to about 25 weight percent. A highly preferred antifungal serum which utilizes undecylenic acid as its antifungal 30 agent is comprised of isoamyl lactate which is present at a level which is within the range of 2013227981 10 Sep 2013 -21 - about 15 weight percent to about 30 weight percent, Simmondsia chinesis seed oil which is present at a level of about 15 weight percent to about 30 weight percent, undecylenic acid which is present at a level with is within the range of about 15 weight percent to about 30 weight percent, the peppermint oil which is present at a level which is within the range of 5 about 15 weight percent to about 30 weight percent, and tea tree oil which is present in the at a level which is within the range of about 15 weight percent to about 30 weight percent. In such formulations the the isoamyl lactate will typically be present at a level which is within the range of about 15 weight percent to about 25 weight percent, the Simmondsia chinesis seed oil will typically be present at a level of about 15 weight percent to about 25 weight 10 percent, the undecylenic acid will typically be present at a level with is within the range of about 20 weight percent to about 30 weight percent, the peppermint oil will typically be present at a level which is within the range of about 15 weight percent to about 25 weight percent, and the tea tree oil will typically be present in the at a level which is within the range of about 15 weight percent to about 25 weight percent. In such formulations the 15 isoamyl lactate will more typically be present at a level which is within the range of about 18 weight percent to about 22 weight percent, the Simmondsia chinesis seed oil will more typically be present at a level of about 18 weight percent to about 22 weight percent, the undecylenic acid will more typically be present at a level with is within the range of about 23 weight percent to about 27 weight percent, the peppermint oil will more typically be 20 present at a level which is within the range of about 18 weight percent to about 22 weight percent, and the tea tree oil will more typically be present in the at a level which is within the range of about 18 weight percent to about 22 weight percent. In such formulations the isoamyl lactate will generally be present at a level which is within the range of about 18 weight percent to about 20 weight percent, the Simmondsia chinesis seed oil will generally 25 be present at a level of about 18 weight percent to about 20 weight percent, the undecylenic acid will generally be present at a level with is within the range of about 24 weight percent to about 26 weight percent, the peppermint oil will generally be present at a level which is within the range of about 18 weight percent to about 20 weight percent, and the tea tree oil will generally be present in the at a level which is within the range of about 18 weight 30 percent to about 20 weight percent. 2013227981 10 Sep 2013 -22-

Another preferred antifungal serum which utilizes tolnaftate as its antifungal agent is comprised of isoamyl lactate which is present at a level which is within the range of about 15 weight percent to about 40 weight percent, Simmondsia chinesis seed oil which is present at a level of about 15 weight percent to about 40 weight percent, tolnaftate which is present 5 at a level with is within the range of about 0.25 weight percent to about 2 weight percent, peppermint oil which is present at a level which is within the range of about 15 weight percent to about 40 weight percent, and tea tree oil which is present in the at a level which is within the range of about 15 weight percent to about 40 weight percent. In such formulations the isoamyl lactate is typically present at a level which is within the range of 10 about 15 weight percent to about 30 weight percent, the Simmondsia chinesis seed oil is typically present at a level of about 15 weight percent to about 30 weight percent, the tolnaftate is typically present at a level with is within the range of about 0.5 weight percent to about 1.5 weight percent, the peppermint oil is typically present at a level which is within the range of about 15 weight percent to about 30 weight percent, and the tea tree oil is 15 present is typically present the at a level which is within the range of about 15 weight percent to about 30 weight percent. In such formulations the isoamyl lactate is more typically present at a level which is within the range of about 20 weight percent to about 35 weight percent, the Simmondsia chinesis seed oil is more typically present at a level of about 20 weight percent to about 35 weight percent, the tolnaftate is more typically present 20 at a level with is within the range of about 0.75 weight percent to about 1.25 weight percent, the peppermint oil is more typically present at a level which is within the range of about 20 weight percent to about 35 weight percent, and the tea tree oil is more typically present in the at a level which is within the range of about 20 weight percent to about 35 weight percent. In such formulations the isoamyl lactate is normally present at a level which is 25 within the range of about 20 weight percent to about 30 weight percent, the Simmondsia chinesis seed oil is normally present at a level of about 20 weight percent to about 30 weight percent, the tolnaftate is normally present at a level with is within the range of about 0.75 weight percent to about 1.25 weight percent, the peppermint oil is normally present at a level which is within the range of about 20 weight percent to about 30 weight percent, and the tea 30 tree oil is normally present in the at a level which is within the range of about 20 weight 2013227981 10 Sep 2013 -23- percent to about 30 weight percent. In such antifungal serum formulations the isoamyl lactate is generally present at a level which is within the range of about 22 weight percent to about 28 weight percent, the Simmondsia chinesis seed oil is generally present at a level of about 22 weight percent to about 28 weight percent, the tolnaftate is generally present at a 5 level with is within the range of about 0.75 weight percent to about 1.25 weight percent, the peppermint oil is generally present at a level which is within the range of about 22 weight percent to about 28 weight percent, and the tea tree oil is generally present in the at a level which is within the range of about 22 weight percent to about 28 weight percent.

In another embodiment of this invention the pharmaceutical agent is carnosic acid 10 which is a naturally occurring antioxidant. Carnosic acid can be included in the formulations of this invention to provide a serum which can be topically applied to skin to provide it with a higher level of protection against photo-induced and other types of oxidative attack. The carnosic acid will typically be included in the skin cream formulation at a level which is within the range of 0.01 weight percent to 3 weight percent. It is 15 normally preferred to include the carnosic acid at a level which is within the range of 0.05 weight percent to 1.5 weight percent with levels of 0.1 weight percent to 1 weight percent being most preferred. The carnosic acid is naturally found in Libiatae plants, such as rosemary, marjoram, and sage. United States Patent 5,859,293 and United States Patent 5,256,700 disclose techniques for extracting high purity carnosic acid from rosemary and 20 sage. For example, United States Patent 5,256,700 discloses a process for obtaining carnosic acid comprising extracting a vegetable material selected from the group consisting of sage and rosemary with an apolar solvent to obtain an extract containing apolar compounds including carnosic acid, contacting the extract with an adsorbent material having an affinity for polar compounds for adsorbing the carnosic acid to separate the carnosic acid 25 from the apolar compounds of the extract, desorbing the adsorbent material with a polar solvent to obtain the carnosic acid in the solvent and then evaporating the polar solvent from the carnosic acid to obtain a residue containing the carnosic acid.

Some methods for the preparation of carnosic acid by chemical synthesis have also been proposed in the literature by W. L. Meyer et al. [Tetrahedron Letters 1966, 4261; 1968, 30 2963; J. Org. Chem. 41, 1005 (1976)]. However, the syntheses involved are long and 2013227981 10 Sep 2013 -24- complex and, for economic reasons, cannot be applied to an industrial process. In addition, these syntheses lead to racemic mixtures of camosic acid precursors and not to the pure enantiomers. It should also be pointed out that these works stop at the preparation of camosic acid precursors and omit to describe the final preparation step(s). Another method 5 of obtaining camosic acid has been described in the literature by Brieskom and Domling [Arch. Pharm. 302, 641 (1969)], comprising the catalytic reduction of camosol. Once again, the application of this process on a large scale is not be envisaged because camosol is not readily available on a commercial basis. For these reasons the camosic acid used in the skin creams formulations of this invention will normally be obtained by extraction from a 10 Libiatae plant, such as rosemary or marjoram. Accordingly, rosemary or marjoram extract will typically be used in the practice of this invention as the source of camosic acid. However, to reduce the possibility of allergic reactions to the skin cream formulation the skin cream formulation will preferably be free of rosemary, sage, marjoram and other Libiatae plants. 15 Camosic acid will typically be incorporated into the pharmaceutical serums of this invention as the extract of a Libiatae plant, such as rosemary or marjoram. In most cases the extract of the Libiatae plant will be included in the pharmaceutical serum at a level of about 0.5 weight percent to about 30 weight percent. The extract of the Libiatae plant will typically be included in the pharmaceutical serum at a level of about 1 weight percent to 20 about 15 weight percent, and will more typically be included at a level of about 2 weight percent to about 10 weight percent. It is normally preferred to include the extract of the Libiatae plant in the pharmaceutical serum at a level of about 3 weight percent to about 8 weight percent. Such a sink rejuvenation serum can optionally contain up to about 5 weight percent glycerin and up to about 5 weight percent propylene glycol. It is typically preferred 25 for such compositions to contain from about 0.05 weight percent to about 3 weight percent glycerin and from about 0.01 weight percent to about 3 weight percent propylene glycol. It is typically more preferred for such compositions to contain from about 0.1 weight percent to about 1 weight percent glycerin and from about 0.05 weight percent to about 0.5 weight percent propylene glycol. 30 In another embodiment of this invention idebenone is included in the pharmaceutical 2013227981 10 Sep 2013 -25- serums of this invention as an antioxidant. Idebenone will typically be present in such pharmaceutical serums at a level which is within the range of about 0.01 weight percent to about 5 weight percent. The idebenone will preferably be present in such pharmaceutical serums formulation at a level which is within the range of about 0.05 weight percent to 5 about 3 weight percent and will more preferably be present at a level which is within the range of about 0.1 weight percent to about 1 weight percent.

Palmitoyl pentapeptide stimulates human fibroblasts to produce collagen and elastin which fight wrinkle formation and can reduce or eliminate existing wrinkles. However, as with all active ingredients in antiwrinkle formulations palmitoyl pentapeptide needs to be 10 delivered deep into the dermis of the skin structure to attain a maximum level of effectiveness. In still another embodiment of this invention pharmaceutical serums can be compounded with palmitoyl pentapeptide to facilitate its topical delivery deep into the dermis of human patients. In such an embodiment of this invention the palmitoyl pentapeptide can accordingly be included in the pharmaceutical serum at a level which is 15 within the range of about 0.05 weight percent to about 8 weight percent. In such pharmaceutical serums the palmitoyl pentapeptide will more typically be included at a level which is within the range of about 0.5 weight percent to about 6 weight percent, and will preferably be include at a level which is within the range of about 1 weight percent to about 5 weight percent. The palmitoyl pentapeptide will more preferably be included in the 20 pharmaceutical serums of this invention at a level which is within the range of 2 weight percent to 4 weight percent.

In a further embodiment of this invention a hair growth stimulant is included in the pharmaceutical serum of this invention as the pharmaceutical agent. In most cases the hair growth stimulant will be a antihypertensive vasodilator medication, such as minoxidil (6-(1-25 piperidinyl)-2,4-pyrimidinedia mine 3-oxide) which is included in the serum at a level which is within the range of about 0.5 weight percent to about 12 weight percent. The hair growth stimulant will more typically be included in the serum at a level which is within the range of about 1 weight percent to about 8 weight percent. The hair growth stimulant will most typically be included in the serum at a level which is within the range of about 2 weight 30 percent to about 5 weight percent. Such hair growth serums can be topically applied to an 2013227981 10 Sep 2013 -26- area of skin where hair growth is desired to facilitate such hair growth. In most cases the hair growth serum will be applied repeatedly to the area of skin over an extended period of time during which hair growth and hair maintenance in the area is desired. In most cases the hair growth serum will be applied at least once a day and can optionally be multiple times 5 each day, such as twice a day. For instance, the hair growth serum can be applied every morning and in the evening during the treatment period which can extend over many years.

In another embodiment of this invention a vitamin A derivative selected from the group consisting of retinol and retinoic acid is included in a skin rejuvenation serum.

Retinol based skin rejuvenation serums will typically contain retinol a level which is within 10 the range of about 0.1 weight percent to about 15 weight percent. Such serums will more typically contain from about 0.5 weight percent to about 12 weight percent retinol and will more typically contain from 1 weight percent to 10 weight percent retinol. It is preferred for such skin rejuvenation serums to contain from about 3 weight percent to about 8 weight percent retinol. On the other hand, retinoic acid based skin rejuvenation serums will 15 typically contain from about 0.005 weight percent to about 0.5 weight percent retinoic acid. Such skin rejuvenation serums will more typically contain from about 0.01 weight percent to about 0.4 weight percent retinoic acid and will preferably contain from about 0.02 weight percent to about 0.3 weight percent retinoic acid. Such skin rejuvenation serums will more preferably contain from about 0.03 weight percent to about 0.2 weight percent retinoic acid 20 and will most preferably contain from about 0.04 weight percent to about 0.1 weight percent retinoic acid.

In a further embodiment of this invention an antimicrobial agent is included in the pharmaceutical serum of this invention. Some representative examples of antimicrobial agents that can be use include 2,4,4'-trichloro-2'-hydroxydiphenyl ether (or triclosan), 3,4,4'25 trichlorobanilide, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, hexamidine isethionate, metronidazole and its salts, miconazole and its salts, itraconazole, terconazole, econazole, ketoconazole, saperconazole, fluconazole, clotrimazole, butoconazole, oxiconazole, sulfaconazole, sulconazole, terbinafine, ciclopirox, ciclopiroxolamine, undecylenic acid and its salts, benzoyl peroxide, 3-hydroxybenzoic acid, 4-hydroxybenzoic 30 acid, phytic acid, N-acetyl-L-cysteine acid, lipoic acid, azelaic acid and its salts, arachidonic 2013227981 10 Sep 2013 -27- acid, resorcinol, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorocarbanilide, octopirox, octoxyglycerine, octanoylglycine, caprylyl glycol, 10-hydroxy-2-decanoic acid, dichlorophenyl imidazole dioxolane and its derivatives, described in patent WO 93/18743, famesol and phytosphingosines, and mixtures thereof. The preferred antibacterial agents are 5 triclosan, phenoxyethanol, octoxyglycerine, octanoylglycine, 10-hydroxy-2-decanoic acid, caprylyl glycol, famesol and azelaic acid. Such antimicrobial agents will typically be included at a level which is within the range of 0.1 weight percent to 20 weight percent and will more typically be included at a level which is within the range of preferably from 0.2 weight percent to 10 weight percent relative to the total weight of the pharmaceutical serum. 10 In still another embodiment of this invention the pharmaceutical serum can include an agent for stimulating the synthesis of dermal or epidermal macromolecules and/or for preventing their degradation as the pharmaceutical agent. Among the active agents for stimulating dermal macromolecules or for preventing their degradation, mention may be made of those that act: either on collagen synthesis, such as extracts of Centella asiatica; 15 asiaticosides and derivatives; ascorbic acid or vitamin C and its derivatives; synthetic peptides such as lamin, biopeptide CL or the palmitoyloligopeptide sold by the company Sederma; peptides extracted from plants, such as the soybean hydrolysate sold by the company Coletica under the trade name Phytokine®; and plant hormones such as auxins and lignans; or on elastin synthesis, such as the extract of Saccharomyces cerivisiae sold by the 20 company LSN under the trade name Cytovitin®; and the extract of the alga Macrocystis pyrifera sold by the company Secma under the trade name Kelpadelie®; or on glycosaminoglycan synthesis, such as the product of fermentation of milk with Lactobacillus vulgaris, sold by the company Brooks under the trade name Biomin yogourth®; the extract of the brown alga Padina pavonica sold by the company Alban Muller under the trade name 25 HSP3; and the extract of Saccharomyces cerevisiae available especially from the company Silab under the trade name Firmalift® or from the company LSN under the trade name Cytovitin®; or on fibronectin synthesis, such as the extract of the zooplankton Salina sold by the company Seporga under the trade name GP4G®; the yeast extract available especially from the company Alban Muller under the trade name Drieline®; and the 30 palmitoyl pentapeptide sold by the company Sederma under the trade name Matrixil®; or on 2013227981 10 Sep 2013 -28- the inhibition of metalloproteases (MMPs), such as, more particularly, MMP 1, 2, 3 or 9. Mention may be made of: retinoids and derivatives, oligopeptides and lipopeptides, lipoamino acids, the malt extract sold by the company Coletica under the trade name Collalift®; extracts of blueberry or of rosemary; lycopene; isoflavones, their derivatives or 5 plant extracts containing them, in particular extracts of soybean (sold, for example, by the company Ichimaru Pharcos under the trade name Flavosterone SB®), of red clover, of flax, of kakkon, or of sage; or on the inhibition of serine proteases such as leukocyte elastase or cathepsin G. Mention may be made of: the peptide extract of Leguminosa seeds (Pisum sativum) sold by the company LSN under the trade name Parelastyl®; heparinoids; and 10 pseudodipeptides such as {2-[acetyl-(3-trifluoromethylphenyl)amino]-3-methylbutynylamino}acetic acid.

Among the active agents that stimulate epidermal macromolecules, such as fillagrin and keratins, mention may be made especially of the extract of lupin sold by the company Silab under the trade name Structurine®; the extract of beech Fagus sylvatica buds sold by 15 the company Gattefosse under the trade name Gatuline®; and the extract of the zooplankton Salina sold by the company Seporga under the trade name GP4G®.

The pharmaceutical serum of this invention can optionally contain an agent for stimulating the proliferation of fibroblasts or keratinocytes and/or keratinocyte differentiation as the pharmaceutical agent. The agents for stimulating the proliferation of 20 fibroblasts that may be used in the composition according to the invention may be chosen, for example, from plant proteins or polypeptides, extracts, especially of soybean (for example an extract of soybean sold by the company LSN under the name Eleseryl SH-VEG 8 or sold by the company Silab under the trade name Raffermine®); and plant hormones such as giberrellins and cytokinins. 25 The agents for stimulating the proliferation of keratinocytes that may be used in the composition according to the invention especially comprise retinoids, such as retinol and its esters, including retinyl palmitate; phloroglucinol; extracts of nut cakes sold by the company Gattefosse; and extracts of Solanum tuberosum sold by the company Sederma.

The agents for stimulating keratinocyte differentiation comprise, for example, 30 minerals such as calcium; the extract of lupin sold by the company Silab under the trade 2013227981 10 Sep 2013 -29- name Photopreventine®; sodium beta-sitosteryl sulphate sold by the company Seporga under the trade name Phytocohesine®; and the extract of com sold by the company Solabia under the trade name Phytovityl®; and lignans such as secoisolariciresinol. The composition according to the invention comprising these compounds is preferably intended 5 to be used for preventing or treating signs of ageing of the skin.

The pharmaceutical serum of this invention can optionally further contain a dermo-decontracting agent as the pharmaceutical agent. The dermo-decontracting agents that may be used in the pharmaceutical serum of this invention include alverine and its salts, manganese gluconate, Diazepam, the hexapeptide argireline R sold by the company Lipotec, 10 certain carbonylated secondary and tertiary amines, adenosine, and also sapogenins and the natural extracts, in particular of Wild Yam, containing them.

The pharmaceutical serum of this invention can optionally further contain agents for acting on the capillary circulation as their pharmaceutical agent. The active agents acting on the capillary circulation (vasoprotective or vasodilating agents) may be chosen from 15 flavonoids, ruscogenins, esculosides, escin extracted from common horse chestnut, nicotinates, heperidine methyl chalcone, essential oils of lavender or of rosemary, and extracts of Ammi visnaga. The amount of these active agents may vary within a wide range. In general, these active agents are present in a concentration ranging from 0.01% to 15% and preferably from 0.05% to 10% by weight relative to the total weight of the pharmaceutical 20 serum.

The pharmaceutical serum of this invention can optionally further contain agents acting on the energy metabolism of cells as their pharmaceutical serum. The active agents concerned are those acting on the energy metabolism of the skin, for instance, and in a nonlimiting manner, ATP synthesis, and also those involved in the respiratory chain of the cell 25 or in the energy reserves. Mention may be made of coenzyme Q10 (ubiquinone), cytochrome C, creatine or phosphocreatine.

The alkyl lactate will typically be present in the pharmaceutical serums of this invention at a level which is within the range of about 5 weight percent to about 80 weight percent and will more typically be present at a level which is within the range of about 10 30 weight percent to about 70 weight percent. The alkyl lactate will commonly be present in 2013227981 10 Sep 2013 -30- the pharmaceutical serum of this invention at a level which is within the range of about 10 weight percent to about 60 weight percent and will more commonly be present at a level which is within the range of about 15 weight percent to about 60 weight percent. In most cases, the alkyl lactate will typically be present in the pharmaceutical serum of this invention 5 at a level which is within the range of about 15 weight percent to about 50 weight percent.

The Simmondsia chinesis seed oil will typically be present in the pharmaceutical serum of this invention at a level which is within the range of f about 5 weight percent to about 80 percent and more typically be present at a level which is within the range of about 10 weight percent to about 70 percent. The Simmondsia chinesis seed oil will commonly be 10 present in the pharmaceutical serum of this invention at a level which is within the range of about 10 weight percent to about 60 percent and more typically will be present at a level which is within the range of about 15 weight percent to about 50 percent. In most cases, the Simmondsia chinesis seed oil will be present in the pharmaceutical serum of this invention at a level which is within the range of about 15 weight percent to about 45 percent and in 15 many cases will preferably be present at a level which is within the range of about 15 weight percent to about 40 percent.

The level of pharmaceutical agent which is present in the pharmaceutical serums of this invention will very greatly with the nature of the pharmaceutical agent and the therapeutic result which is desired. However, the pharmaceutical agent will typically be 20 present in the pharmaceutical serums of this invention at a level which is within the range of 0.001 weight percent to 40 weight percent and will more typically be present at a level which is within the range of about 0.01 weight percent to 35 weight percent. The pharmaceutical agent will commonly be present in the pharmaceutical serums of this invention at a level which is within the range of 0.02 weight percent to 30 weight percent 25 and can be present at a level which is within the range of about 0.025 weight percent to 25 weight percent. For instance, the pharmaceutical agent can be present in the pharmaceutical serums of this invention at a level which is within the range of 0.05 weight percent to 25 weight percent. In some cases the pharmaceutical agent will be present at a relatively low level which is within the range of 0.01 weight percent to 0.5 weight percent or which is 30 within the range of 0.02 weight percent to 0.3 weight percent. In other cases the 2013227981 10 Sep 2013 -31 - pharmaceutical agent will be present at a relatively level which is within the range of 0.1 weight percent to 25 weight percent or which is within the range of 5 weight percent to 25 weight percent or which is within the range of 10 weight percent to 25 weight percent or which is within the range of 15 weight percent to 25 weight percent. 5 The pharmaceutical serum of this invention can also include a wide variety of other oils. These additional oils are typically vegetable oils (oils of plant origin), mineral oils (liquid petroleum jelly), oils of animal origin (such as lanolin), synthetic oils (perhydrosqualene), or a silicone oils (cyclomethicone). The vegetable oils that can be included in the pharmaceutical serum of this invention include avocado oil, soybean oil, 10 coconut oil, shea butter, almond oil, eucalyptus essential oil, olive oil, hazelnut oil, walnut oil, peanut oil, com oil, caster oil, soy oil, canola oil, rapeseed oil, cottonseed oil, palm oil, sesame oil, sunflower oil, safflower oil, rice bran oil, borage seed oil, syzigium aromaticum oil, hempseed oil, flaxseed oil, rape seed oil, evening primrose oil, rosehip oil, and melaleuca oil. Some representative examples of animal based oils that can optionally be 15 utilized include lanolin, various fish oils, such as herring oil, cod-liver oil, and salmon oil. Typically, the pharmaceutical serum of this invention will be void of these additional oils since they are not believed to serve any beneficial purpose and dilute the levels of the more desirable components of the serum, such as the Simmondsia chinesis seed oil and the alkyl lactate which facilitate the delivery of the pharmaceutical agent into the skin. Accordingly, 20 in cases where such oisl are included in the pharmaceutical serum their total level will normally be limited to be within the range of 0 weight percent to about 25 weight percent and will more typically be limited to be within the range of 0 weight percent to 10 weight percent, based upon the total weight of the pharmaceutical serum. In cases where such additional oils are included they will normally be present in a total amount which is within 25 the range of about 1 weight percent to about 5 weight percent.

Fatty alcohols (cetyl alcohol), fatty acids, petrolatum, and waxes (carnauba wax or ozokerite) can also optionally be included in the pharmaceutical serum of this invention. Petrolatum or mineral oil components, which when selected will generally be USP or NF grade. The petrolatum may be white or yellow. The viscosity or consistency grade of 30 petrolatum is not narrowly critical. Petrolatum can be partially replaced with mixtures of 2013227981 10 Sep 2013 -32- hydrocarbon materials, which can be formulated to resemble petrolatum in appearance and consistency. For example, mixtures of petrolatum or mineral oil with different waxes and the like may be combined. Preferred waxes include bayberry wax, candelilla wax, ceresin, jojoba butter, lanolin wax, montan wax, ozokerite, polyglyceryl-3-beeswax, polyglyceryl-6-5 pentastearate, microcrystalline wax, paraffin wax, isoparaffin, vaseline solid paraffin, squalene, oligomer olefins, beeswax, synthetic candelilla wax, synthetic carnauba, synthetic beeswax and the like may be blended together. Typically, the pharmaceutical serum of this invention will be void of petrolatum and waxes since they are not believed to serve any beneficial purpose and dilute the levels of more desirable ingredients. Accordingly, in cases 10 where petrolatum and/or waxes are included in the pharmaceutical serum their total level will normally be limited to be within the range of 0 weight percent to about 25 weight percent and will more typically be limited to be within the range of 0 weight percent to 10 weight percent, based upon the total weight of the pharmaceutical serum. In cases where petrolatum and/or such waxes are included they will normally be present in a total amount 15 which is within the range of about 1 weight percent to about 5 weight percent.

The pharmaceutical serum of this invention can be made by simply mixing the desired constituents under conditions that are adequate to attain an essentially homogeneous mixture at a temperature which is typically within the range of about 10°C to about 100°C.

In most cases this can be accomplished by mixing the constituents at room temperature 20 (18°C to 23°C). However, in some cases it is desirable to heat the components being mixed to a slightly elevated temperature which is within the range of about 30°C to 60°C to facilitate mixing.

This invention is illustrated by the following examples that are merely for the purpose of illustration and are not to be regarded as limiting the scope of the invention or the 25 manner in which it can be practiced. Unless specifically indicated otherwise, parts and percentages are given by weight.

Example 1

In this experiment an antifungal serum of this invention was prepared by adding 25 30 ml of jojoba oil (filtered and unrefined), 25 ml of peppermint oil, 25 ml of tea tree oil, 25 ml 2013227981 10 Sep 2013 -33- of isoamyl lactate, and 25 ml of undecylenic acid to a 250 ml beaker. Then, the mixture of liquids were well mixed with a stirring rod to make the antifungal serum.

The antifungal serum was subsequently used to treat the toenail of a 59 year old male who was suffering from onychomycosis. The onychomycosis was the result of trauma 5 caused by stubbing the big toe of the patient on a bed post. In this case, the onychomycosis was black in appearance and was located under the toenail. The antifungal serum was brushed onto the infected toe of the patient every morning, in the early afternoon, and in the evening every day.

After about one week of treatment the black color of the fungus lightened and the 10 toenail returned to a relatively normal appearance. The application of the antifungal serum was continued in the morning and in the evening for about 6 months to allow the infected toenail to completely grow out leaving only a normal nail structure. There was no reoccurrence of the onychomycosis after another 6 months. In other words, the patient remained free of fungus for 6 months after discontinuing treatment with the antifungal 15 serum.

Example 2

An antifungal serum was made as described in Example 1 and was subsequently used to treat a patient with Down’s Syndrome who had been suffering from onychomycosis 20 for many years. All ten of toes of this 30 year old male subject were severely infected with onychomycosis. In any case, the antifungal serum was applied to the toenails of the patient at least twice every day. After about 6 months of treatment the onychomycosis was completely eliminated from all of the toes of this patient. However, onychomycosis did reoccur and treatment was resumed on the infected toes. The subsequent treatment again 25 eliminated the onychomycosis after several months of further treatment.

Example 3

An antifungal serum was made as described in Example 1 and was subsequently used to treat a patient with diabetes mellitus who had been suffering from onychomycosis 30 for many years. All ten of toes of this 65 year old male subject were severely infected with 2013227981 10 Sep 2013 -34- onychomycosis. In any case, the antifungal serum was applied to the toenails of the patient at least twice every day. After about 6 months of treatment the onychomycosis was completely eliminated from all of the toes of this patient. There was no reoccurrence of the onychomycosis after another 2 months. In other words, the patient remained free of fungus 5 for 2 months after discontinuing treatment with the antifungal serum.

Example 4

An antifungal serum was made as described in Example 1 and was subsequently used to treat a 75 year old female patient that was otherwise healthy who had been suffering 10 from onychomycosis for about 6 months. She had previously treated the onychomycosis which several over the counter products without success. Most of her toes were severely infected with the onychomycosis. In any case, the antifungal serum was applied to the toenails of the patient at least twice every day. After about 6 months of treatment the onychomycosis was completely eliminated from all of the toes of this patient. There was no 15 reoccurrence of the onychomycosis after another 6 months. In other words, the patient remained free of fungus for 6 months after discontinuing treatment with the antifungal serum.

Example 5 20 An antifungal serum was made as described in Example 1 and was subsequently used to treat a 55 year old female patient that was otherwise healthy who had been suffering from onychomycosis for over 2 years. She had previously treated the onychomycosis which several over the counter products without success. Most of her toes were severely infected with the onychomycosis. In any case, the antifungal serum was applied to the toenails of the 25 patient at least twice every day. After about 6 months of treatment the onychomycosis was completely eliminated from all of the toes of this patient. There was no reoccurrence of the onychomycosis after another 6 months. In other words, the patient remained free of fungus for 6 months after discontinuing treatment with the antifungal serum. 2013227981 10 Sep 2013 -35-

Example 6

In this experiment a skin rejuvenation serum of this invention was prepared by adding 90 ml of jojoba oil (filtered and unrefined), 5 ml of rosemary extract, and 5 ml of 5 isoamyl lactate to a 150 ml beaker. Then, the mixture of liquids was then well mixed with a stirring rod to make a skin rejuvenation serum.

Example 7

In this experiment a skin rejuvenation serum of this invention was prepared by 10 adding 88 ml of jojoba oil (filtered and unrefined), 5 ml of rosemary extract, 5 ml of isoamyl lactate, 1 ml of glycerin, and 1 ml of propylene glycol to a 150 ml beaker. Then, the mixture of liquids was then well mixed with a stirring rod to make a skin rejuvenation serum.

Example 8 15 In this experiment a skin rejuvenation serum of this invention was prepared by adding about 50 ml of jojoba oil (filtered and unrefined), 5 ml of rosemary extract, and 50 ml of isoamyl lactate to a 150 ml beaker. Then, the mixture of liquids was then well mixed with a stirring rod to make a skin rejuvenation serum.

While certain representative embodiments and details have been shown for the 20 purpose of illustrating the subject invention, it will be apparent to those skilled in this art that various changes and modifications can be made therein without departing from the scope of the subject invention.

Claims (21)

1. A pharmaceutical serum which is comprised of (1) an alkyl lactate, wherein the alkyl group in the alkyl lactate contains from 2 to about 12 carbon atoms, (2) Simmondsia chinesis seed oil, and (3) a pharmaceutical agent.

2. The pharmaceutical serum as specified in claim 1 wherein the alkyl lactate is isoamyl lactate.

3. The pharmaceutical serum as specified in claim 1 or claim 2 wherein the Simmondsia chinesis seed oil is golden Simmondsia chinesis seed oil.

4. The pharmaceutical serum as specified in claim 1 or claim 2 wherein the Simmondsia chinesis seed oil is filtered.

5. The pharmaceutical serum as specified in claim 1 or claim 2 wherein the Simmondsia chinesis seed oil is refined.

6. The pharmaceutical serum as specified in any one of claims 1 to 5 wherein the alkyl lactate is present at a level which is within the range of about 5 weight percent to about 90 weight percent, wherein the Simmondsia chinesis seed oil is present at a level of about 5 weight percent to about 90 weight percent, and wherein the pharmaceutical agent is present at a level of about 0.01 weight percent to about 40 weight percent.

7. The pharmaceutical serum as specified in any one of claims 1 to 6 wherein the pharmaceutical agent is selected from the group consisting of antifungal agents, hormones, growth factors, antimicrobials, antibacterials, antibiotics, non-steroidal anti inflammatory agents, immunodilators, anesthetics, plant extracts, vitamins, corticosteroids, and hair growth stimulants.

8. The pharmaceutical serum as specified in claim 7 wherein the pharmaceutical agent is minoxidil.

9. The pharmaceutical serum as specified in claim 7 wherein the pharmaceutical agent is an antihypertensive vasodilator.

10. The pharmaceutical serum as specified in any one of claims 1 to 6 wherein the pharmaceutical agent is a vitamin A derivative selected from the group consisting of retinol and retinoic acid.

11. The pharmaceutical serum as specified in any one of claims 1 to 6 wherein the pharmaceutical agent is a growth factor.

12. The pharmaceutical serum as specified in any one of claims 1 to 6 wherein the pharmaceutical agent is an antifungal agent.

13. The pharmaceutical serum as specified in claim 12 wherein the antifungal agent is selected from the group consisting of clioquinol, haloprogin, miconazole nitrate, poridone-iodine, tolnaftate, undecylenic acid, calcium undecylenate, cobalt undecylenate, zinc undecylenate, and clotrimazole.

14. The pharmaceutical serum as specified in claim 12 wherein the antifungal agent is tolnaftate.

15. The pharmaceutical serum as specified in claim 12 wherein the antifungal agent is undecylenic acid.

16. The pharmaceutical serum as specified in any one of claims 13 to 15, wherein the alkyl lactate is present at a level which is within the range of about 15 weight percent to about 50 weight percent, wherein the Simmondsia chinesis seed oil is present at a level of about 15 weight percent to about 50 weight percent, and wherein the an antifungal agent is present at a level of about 1 weight percent to about 30 weight percent.

17. The pharmaceutical serum as specified in claim 12 wherein the alkyl lactate is present at a level which is within the range of about 15 weight percent to about 40 weight percent, wherein the Simmondsia chinesis seed oil is present at a level of about 15 weight percent to about 40 weight percent, wherein the an antifungal agent is at least one member selected from the group consisting of undecylenic acid, calcium undecylenate, cobalt undecylenate, zinc undecylenate present, and wherein the antifungal agent is present at a level of about 20 weight percent to about 25 weight percent.

18. The pharmaceutical serum as specified in any one of claims 12 to 17 wherein the pharmaceutical serum is further comprised of peppermint oil.

19. The pharmaceutical serum as specified in any one of claims 12 to 18 wherein the pharmaceutical serum is further comprised of tea tree oil.

20. A method for treating a human fingernail or toenail which is infected with onychomycosis, the method comprising applying the pharmaceutical serum specified in any one of claims 12 to 19 to the infected nail.

21. A method for treating hair loss, the method comprising topically applying the pharmaceutical serum as specified in claim 8 or 9 to an area of skin where hair growth is desired.