The present invention relates to the discovery of a transdermal delivery system that can deliver high molecular weight pharmaceuticals and cosmetic agents to skin cells. A novel transdermal delivery system with therapeutic and cosmetic application and methods of use of the foregoing is disclosed.

The present invention relates to the discovery of a transdermal delivery system that can deliver high molecular weight pharmaceuticals and cosmetic agents to skin cells. A novel transdermal delivery system with therapeutic and cosmetic application and methods of use of the foregoing is disclosed.
The skin provides a protective barrier against foreign materials and infection. In mammals this is accomplished by forming a highly insoluble protein and lipid structure on the surface of the corneocytes termed the cornified envelope (CE). (Downing et al., Dermatology in General Medicine, Fitzpatrick, et al., eds., pp. 210-221 (1993), Ponec, M., The Keratinocyte Handbook, Leigh, et al., eds., pp. 351-363 (1994)). The CE is composed of polar lipids, such as ceramides, sterols, and fatty acids, and a complicated network of cross-linked proteins; however, the cytoplasm of stratum corneum cells remains polar and aqueous. The CE is extremely thin (10 microns) but provides a substantial barrier. Because of the accessibility and large area of the skin, it has long been considered a promising route for the administration of drugs, whether dermal, regional, or systemic effects are desired.
A topical route of drug administration is sometimes desirable because the risks and inconvenience of parenteral treatment can be avoided; the variable absorption and metabolism associated with oral treatment can be circumvented; drug administration can be continuous, thereby permitting the use of pharmacologically active agents with short biological half-lives; the gastrointestinal irritation associated with many compounds can be avoided; and cutaneous manifestations of diseases can be treated more effectively than by systemic approaches. Most transdermal delivery systems achieve epidermal penetration by using a skin penetration enhancing vehicle. Such compounds or mixtures of compounds are known in the art as xe2x80x9cpenetration enhancersxe2x80x9d or xe2x80x9cskin enhancersxe2x80x9d. While many of the skin enhancers in the literature enhance transdermal absorption, several possess certain drawbacks in that (i) some are regarded as toxic; (ii) some irritate the skin; (iii) some on prolonged use have a thinning effect on the skin; (iv) some change the intactness of the skin structure, resulting in a change in the diffusability of the drug; and (v) all are incapable of delivering high molecular weight pharmaceuticals and cosmetic agents. Clearly there remains a need for safe and effective transdermal delivery systems that can administer a wide-range of pharmaceuticals and cosmetic agents to skin cells.
In aspects of the invention described below, transdermal delivery systems are provided that can be used to administer pharmaceuticals and cosmetic agents of various molecular weights. In several embodiments, the transdermal delivery system comprises a novel formulation of penetration enhancer and aqueous adjuvant that enables the delivery of a wide range of pharmaceuticals and cosmetic agents having molecular weights of less than 100 daltons to greater than 500,000 daltons. For example, embodiments of the transdermal delivery system described herein can be used to deliver a therapeutically effective amount of a non-steroidal anti-inflammatory drug (NSAID), a capsaicin or Boswellin containing pain-relief solution, or several different collagen preparations. Methods of making and using the transdermal delivery devices of the invention for the treatment and prevention of human disease and cosmetic condition are also provided.
Accordingly, in one embodiment a transdermal delivery system is provided that comprises an ethoxylated lipid, an alcohol mixed with the ethoxylated lipid so as to form a penetration enhancer, an aqueous adjuvant mixed with the penetration enhancer, wherein the aqueous adjuvant is a plant extract from the family of Liliaceae, and a delivery agent mixed with the aqueous adjuvant and the penetration enhancer. In some aspects of this embodiment, the ethoxylated lipid is a vegetable or animal oil having at least 20 ethoxylations per molecule. In other aspects of this embodiment, about 0.1% to 40.0% by weight or volume is ethoxylated lipid. Other embodiments of the invention include the transdermal delivery system described above wherein about 0.1% to 15% by weight or volume is alcohol or wherein about 0.1% to 85% by weight or volume is Aloe Vera. Still more embodiments of the invention have a ratio of ethoxylated lipid:alcohol:aqueous adjuvant selected from the group consisting of 1:1:4, 1:1:14, 3:4:3, and 1:10:25.
Desirably, the transdermal delivery systems described above have delivery agents that are molecules having a molecular weight of less than 6,000 daltons. In some embodiments, the transdermal delivery system described above has a delivery agent that is one or more of the compounds selected from the group consisting of capsaicin, Boswellin, non steroidal anti-inflammatory drug, and collagen. Preferably, however, the delivery agent is a molecule having a molecular weight of greater than 6,000 daltons. Additional embodiments include an apparatus comprising a vessel joined to an applicator and the transdermal delivery system described above incorporated in the vessel. Applicators in embodiments of the invention can be a roll-on or a sprayer.
In another aspect, a transdermal delivery system is provided which comprises an ethoxylated oil, an alcohol mixed with the ethoxylated oil so as to form a penetration enhancer, an Aloe extract mixed with the penetration enhancer, and a therapeutically effective amount of capsaicin or NSAID or both mixed with the penetration enhancer and Aloe extract. In some embodiments of this aspect, the therapeutically effective amount of capsaicin is by weight or volume 0.01% to 5.0% capsaicin or 1.0% to 13% oleoresin capsicum. In other embodiments of this aspect, the transdermal delivery system further includes by weight or volume 0.1% to 10% Boswellin. As above, an apparatus having a vessel joined to an applicator that houses the transdermal delivery system is also an embodiment and preferred applicators include a roll-on or a sprayer.
Several methods are also within the scope of aspects of the invention. For example, one approach involves a method of reducing pain or inflammation comprising the step of administering the transdermal delivery system described above to a subject in need and monitoring the reduction in pain or inflammation. Additional methods of the invention include approaches to treat cancer and Alzheimer""s disease. For example, a method of treating or preventing cancer and Alzheimer""s disease can comprise the step of identifying a subject in need of a COX enzyme inhibitor and administering the transdermal delivery system described above to the subject.
In addition to the delivery of low and medium molecular weight delivery agents, several compositions that have high molecular weight delivery agents (e.g., collagens) and methods of use of such compositions are embodiments of the invention. For example, one embodiment concerns a transdermal delivery system comprising an ethoxylated oil, an alcohol mixed with the ethoxylated oil so as to form a penetration enhancer, an Aloe extract mixed with the penetration enhancer, and a therapeutically effective amount of collagen mixed with the penetration enhancer and Aloe extract.
In different embodiments of this transdermal delivery system, the collagen has a molecular weight less than 6,000 daltons or greater than 6,000 daltons. Thus, in certain embodiments, the collagen can have an approximate molecular weight as low as 2,000 daltons or lower. In a certain embodiment, the molecular weight is from about 300,000 daltons to about 500,000 daltons. Further, these transdermal delivery systems can have a therapeutically effective amount of collagen by weight or volume that is 0.1% to 50.0% and the collagen can be Hydrocoll EN-55 when the therapeutically effective amount by weight or volume is 0.1% to 50.0%; the collagen can be Solu-Coll when the therapeutically effective amount is 0.1% to 2.0%; and the collagen can be Plantsol when the therapeutically effective amount by weight or volume is 0.1% to 4.0%. As above, an apparatus having a vessel joined to an applicator that houses the transdermal delivery system is also an embodiment and preferred applicators include a roll-on or a sprayer.
Methods of reducing wrinkles and delivery of high molecular weight molecules are also embodiments of the invention. For example, by one approach, a method of reducing wrinkles in the skin comprises identifying a subject in need of skin tone restoration, administering the transdermal delivery system, such as is described above, to the subject and monitoring the restoration of skin tone. Further, methods of making a transdermal delivery system are within the scope of the invention. Accordingly, a method of making a transdermal delivery system can involve providing an ethoxylated oil, mixing the ethoxylated oil with an alcohol, nonionic solubilizer, or emulsifier so as to form a penetration enhancer, mixing the penetration enhancer with an aqueous adjuvant, wherein the aqueous adjuvant is an extract from a plant of the Liliaceae family; and mixing the penetration enhancer and aqueous adjuvant with a delivery agent and thereby making the transdermal delivery system.
In some aspects of this method, the delivery agent is selected from the group consisting of capsaicin, Boswellin, non steroidal anti-inflammatory drug, and collagen. In another embodiment of this method, the delivery agent has a molecular weight greater than 6,000 daltons. As above, an apparatus having a vessel joined to an applicator that houses the transdermal delivery system is also an embodiment and preferred applicators include a roll-on or a sprayer.
In the following disclosure, several transdermal delivery systems are described that can administer an effective amount of a pharmaceutical or cosmetic agent to the human body. Although embodiments of the invention can be used to administer low or high (or both low and high) molecular weight pharmaceuticals and cosmetic agents, preferable embodiments include transdermal delivery systems that can administer compounds having molecular weights greater than 6,000 daltons. One embodiment, for example, includes a transdermal delivery system that can administer a therapeutically effective amount of a non-steroidal anti-inflammatory drug (NSAID). Another embodiment concerns a transdermal delivery system having a novel pain-relief solution (e.g., a formulation comprising capsaicin or Boswellin or both). Another aspect of the invention involves a transdermal delivery system that can administer a collagen preparation (e.g., soluble collagens, hydrolyzed collagens, and plant collagens). These examples are provided to demonstrate that embodiments of the invention can be used to transdermally deliver both low and high molecular weight compounds and it should be understood that many other molecules can be effectively delivered to the body, using the embodiments described herein, in amounts that are therapeutically, prophylactically, or cosmetically beneficial.
A transdermal delivery system has three components, a delivery agent, a penetration enhancer, and an aqueous adjuvant. Accordingly, one component of the transdermal delivery system of the invention is a xe2x80x9cdelivery agentxe2x80x9d. A molecule or a mixture of molecules (e.g., a pharmaceutical or cosmetic agent) that are delivered to the body using an embodiment of a transdermal delivery system of the invention are termed xe2x80x9cdelivery agentsxe2x80x9d. A delivery agent that can be administered to the body using an embodiment of the invention can include, for example, a protein, a sugar, a nucleic acid, a chemical, or a lipid. Desirable delivery agents include, but are not limited to, glycoproteins, enzymes, genes, drugs, and ceramides. Preferred delivery agents include collagens, NSAIDS, capsaicin, and Boswellin. In some embodiments, a transdermal delivery system comprises a combination of the aforementioned delivery agents.
The second component of a transdermal delivery system is a penetration enhancer. Desirable penetration enhancers comprise both hydrophobic and hydrophilic components. The xe2x80x9chydrophobic componentxe2x80x9d includes one or more polyether compounds. One preferred polyether compound is an ethoxylated lipid. Although an ethoxylated lipid can be created in many ways, a preferred approach involves the reaction of ethylene oxide with a vegetable or animal oil. The xe2x80x9chydrophilic componentxe2x80x9d can be, for example, an alcohol, a nonionic solubilizer or an emulsifier. Suitable hydrophilic components include, but are not limited to, ethylene glycol, propylene glycol, dimethyl sulfoxide (DMSO), dimethyl polysiloxane (DMPX), oleic acid, caprylic acid, isopropyl alcohol, 1-octanol, ethanol (denatured or anhydrous), and other pharmaceutical grade or absolute alcohols with the exception of methanol.
Embodiments of the invention can also comprise a third component termed an xe2x80x9caqueous adjuvantxe2x80x9d. Aqueous adjuvants include, but are not limited to, water (distilled, deionized, filtered, or otherwise prepared), Aloe Vera juice, and other plant extracts. Thus, several embodiments of the invention have a penetration enhancer that includes a hydrophobic component comprising an ethoxylated oil (e.g., castor oil, glycerol, corn oil, jojoba oil, or emu oil) and a hydrophilic component comprising an alcohol, a nonionic solubilizer, or an emulsifier (e.g., isopropyl alcohol) and an aqueous adjuvant such as Aloe Vera extract. Other materials can also be components of a transdermal delivery system of the invention including fragrance, creams, ointments, colorings, and other compounds so long as the added component does not deleteriously affect transdermal delivery of the delivery agent. Unexpectedly, it has been found that compositions using extracts of plants of the Liliaceae family, such as Aloe Vera, provide superior benefits in transdermal delivery of high molecular weight delivery agents, including collagen having an average molecular weight greater than 6,000 daltons.
In addition to the aforementioned compositions, methods of making and using the embodiments of the invention are provided. In general, an embodiment of the invention is prepared by mixing a hydrophilic component with a hydrophobic component and an aqueous adjuvant. Depending on the solubility of the delivery agent, the delivery agent can be solubilized in either the hydrophobic, hydrophilic, or aqueous adjuvant components prior to mixing. In addition to physical mixing techniques (e.g., magnetic stirring or rocker stirring) heat can be applied to help coalesce the mixture. Desirably, the temperature is not raised above 40xc2x0 C.
Several formulations of transdermal delivery system are within the scope of aspects of the invention. One formulation comprises a ratio of hydrophilic component:hydrophobic component:aqueous adjuvant of 3:4:3. The amount of delivery agent that is incorporated into the penetration enhancer depends on the compound, desired dosage, and application. The amount of delivery agent in a particular formulation can be expressed in terms of percentage by weight, percentage by volume, or concentration. Several specific formulations of delivery systems are provided in the Examples described herein.
Methods of treatment and prevention of pain, inflammation, and human disease are also provided. In some embodiments, a transdermal delivery system comprising an NSAID, capsaicin, Boswellin or any combination thereof is provided to a patient in need of treatment, such as for relief of pain and/or inflammation. The use of transdermal delivery systems described herein which contain extracts of the Liliaecae family, such as Aloe Vera extract, are particularly beneficial in the delivery of these delivery agents. A patient can be contacted with the transdermal delivery system and treatment continued for a time sufficient to reduce pain or inflammation or inhibit the progress of disease.
Additionally, a method of reducing wrinkles and increasing skin tightness and flexibility is provided. By this approach, a transdermal delivery system comprising a collagen delivery agent is provided to a patient in need, the patient is contacted with the transdermal delivery system, and treatment is continued for a time sufficient to restore a desired skin tone (e.g., reduce wrinkles or restore skin tightness and flexibility). The transdermal delivery system described herein provides unexpectedly superior results in the delivery of collagen of all molecular weights.
In the disclosure below, there is provided a description of several of the delivery agents that can be incorporated into the transdermal delivery devices of the present invention.
Delivery Agents
Many different delivery agents can be incorporated into the various transdermal delivery systems of the invention and a non-exhaustive description of embodiments is provided in this section. While the transdermal delivery of molecules having a molecular weight in the vicinity of 6000 daltons has been reported, it has not been possible, until the present invention, to administer molecules of greater size transdermally. (U.S. Pat. No. 5,614,212 to D""Angelo et al.).
The described embodiments can be organized according to their ability to deliver a low or high molecular weight delivery agent. Low molecular weight molecules (e.g., a molecule having a molecular weight less than 6,000 daltons) can be effectively delivered using an embodiment of the invention and high molecular weight molecules (e.g., a molecule having a molecular weight greater than 6,000 daltons) can be effectively delivered using an embodiment of the invention. Desirably a delivery system of the invention can administer a therapeutically or cosmetically beneficial amount of a delivery agent having a molecular weight of 50 daltons to less than 6,000 daltons. Preferably, however, a delivery system of the invention can administer a therapeutically or cosmetically beneficial amount of a delivery agent having a molecular weight of 50 daltons to 2,000,000 daltons or less. That is, a preferred delivery system of the invention can administer a delivery agent having a molecular weight of less than or equal to 50, 100, 200, 500, 1,000, 1,500, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500, 5,000, 5,500, 6,000, 7,000, 8,000, 9,000, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, 35,000, 36,000, 37,000, 38,000, 39,000, 40,000, 41,000, 42,000, 43,000, 44,000, 45,000, 46,000, 47,000, 48,000, 49,000, 50,000, 51,000, 52,000, 53,000, 54,000, 55,000, 56,000, 57,000, 58,000, 59,000, 60,000, 61,000, 62,000, 63,000, 64,000, 65,000, 66,000, 67,000, 68,000, 69,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, 100,000, 125,000, 150,000, 175,000, 200,000, 225,000, 250,000, 275,000, 300,000, 350,000, 400,000, 450,000, 500,000, 600,000, 700,000, 800,000, 900,000, 1,000,000, 1,500,000, 1,750,000, and 2,000,000 daltons.
In one aspect, a low molecular weight compound (e.g., a pain relieving substance or mixture of pain relieving substances) is transdermally delivered to cells of the body using an embodiment of a transdermal delivery system of the invention. The delivery agent can be, for example, any one or more of a number of compounds, including non-steroidal anti-inflammatory drugs (NSAIDs) that are frequently administered systemically. These include ibuprofen (2-(isobutylphenyl)-propionic acid); methotrexate (N-[4-(2,4 diamino 6-pteridinyl-methyl]methylamino]benzoyl)-L-glutamic acid); aspirin (acetylsalicylic acid); salicylic acid; diphenhydramine (2-(diphenylmethoxy)-NN-dimethylethylamine hydrochloride); naproxen (2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (xe2x88x92)); phenylbutazone (4-butyl-1,2-diphenyl-3,5-pyrazolidinedione); sulindac-(2)-5-fuoro-2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene-]-1H-indene-3-acetic acid; diflunisal (2xe2x80x2,4xe2x80x2, -difluoro-4-hydroxy-3-biphenylcarboxylic acid; piroxicam (4-hydroxy-2-methyl-N-2-pyridinyl-2H-1, 2-benzothiazine-2-carboxamide 1, 1-dioxide, an oxicam; indomethacin (1-(4-chlorobenzoyl)-5-methoxy-2-methyl-H-indole-3-acetic acid); meclofenamate sodium (N-(2,6-dichloro-m-tolyl) anthranilic acid, sodium salt, monohydrate); ketoprofen (2-(3-benzoylphenyl)-propionic acid; tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl-1H-pyrrole-2-acetate dihydrate); diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzeneatic acid, monosodium salt); hydroxychloroquine sulphate (2-{[4-[(7-chloro-4-quinolyl) amino]pentyl]ethylamino}ethanol sulfate (1:1); penicillamine (3-mercapto-D-valine); flurbiprofen ([1,1-biphenyl]-4-acetic acid, 2-fluoro-alphamethyl-, (+xe2x88x92.)); cetodolac (1-8-diethyl-13,4,9, tetra hydropyrano-[3-4-13]indole-1-acetic acid; mefenamic acid (N-(2,3-xylyl)anthranilic acid; and diphenhydramine hydrochloride (2-diphenyl methoxy-N, N-di-methylethamine hydrochloride).
The delivery systems of the invention having NSAIDs desirably comprise an amount of the compound that is therapeutically beneficial for the treatment or prevention of disease or inflammation. Several studies have determined an appropriate dose of an NSAID for a given treatment or condition. (See e.g., Woodin, R N, August: 26-33 (1993) and Amadio et al., Postgrduate Medicine, 93(4):73-97 (1993)). The maximum recommended daily dose for several NSAIDs is listed in Table 1. The amount of NSAID recommended in the literature and shown in Table 1 can be incorporated into a delivery system of the invention. Because the transdermal delivery system of the invention can administer a delivery agent in a site-specific manner, it is believed that a lower total dose of therapeutic agent, as compared to the amounts provided systemically, will provide therapeutic benefit. Additionally, greater therapeutic benefit can be gained by using a transdermal delivery system of the invention because a high dose of therapeutic agent (e.g., an NSAID) can be applied to the particular site of inflammation. That is, in contrast to systemic administration, which applies the same concentration of therapeutic to all regions of the body, a transdermal delivery system of the invention can site-specifically administer a therapeutic and, thereby, provides a much greater regional concentration of the agent than if the same amount of therapeutic were administered systemically.
Additionally, desirable embodiments include a delivery system that can administer a pain relieving mixture comprising capsaicin (e.g., oleoresin capsicum) or Boswellin or both. Capsaicin (8-methyl-N-vanillyl-6-nonenamide), the pungent component of paprika and peppers, is a potent analgesic. (See U.S. Pat. Nos. 5,318,960 to Toppo, 5,885,597 to Botknecht et al., and 5,665,378 to Davis et al.). Capsaicin produces a level of analgesia comparable to morphine, yet it is not antagonized by classical narcotic antagonists such as naloxone. Further, it effectively prevents the development of cutaneous hyperalgesia, but appears to have minimal effects on normal pain responses at moderate doses. At high doses capsaicin also exerts analgesic activity in classical models of deep pain, elevating the pain threshold above the normal value. Capsaicin can be readily obtained by the ethanol extraction of the fruit of Capsicum frutescens or Capsicum annum. Capsaicin and analogs of capsaicin are available commercially from a variety of suppliers, and can also be prepared synthetically by published methods. Aspects of the invention encompass the use of synthetic and natural capsaicin, capsaicin derivatives, and capsaicin analogs.
A form of capsaicin used in several desirable embodiments is oleoresin capsicum. Oleoresin capsicum contains primarily capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, and homodihydrocapsaicin. The term xe2x80x9ccapsaicinxe2x80x9d collectively refers to all forms of capsaicin, capsicum, and derivatives or modifications thereof. The pungency of these five compounds, expressed in Scoville units, are provided in Table 2.
The delivery systems of the invention having capsaicin desirably comprise by weight or volume 0.01% to 1.0% capsaicin or 1.0% to 10% oleoresin capsicum. Preferred amounts of this delivery agent include by weight or volume 0.02% to 0.75% capsaicin or 2.0% to 7.0% oleoresin capsicum. For example, the delivery systems of the invention having capsaicin can comprise by weight or volume less than or equal to 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 0.1%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.325%, 0.35%, 0.375%, 0.4%, 0.425%, 0.45%, 0.475%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, and 1.0% capsaicin. Although not a desirable embodiment, the delivery systems of the invention having capsaicin can comprise an amount of capsaicin by weight or volume that is greater than 1.0%, such as 1.2%, 1.5%, 1.8%, 2.0%, 2.2%, 2.5%, 2.8%, 3.0%, 3.5%, 4.0%, 4.5%, and 5.0%. Similarly, the delivery systems of the invention having oleoresin capsicum can comprise an amount of oleoresin capsicum less than 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 11.0%, 12.0%, and 13.0%.
Boswellin, also known as Frankincense, is an herbal extract of a tree of the Boswellia family. Boswellin can be obtained, for example, from Boswellia thurifera, Boswellia carteri, Boswellia sacra, and Boswellia serrata. There are many ways to extract Boswellin and Boswellin gum resin and boswellic acids are obtainable from several commercial suppliers (a 65% solution of Boswellic acid is obtainable from Nature""s Plus over the internet at http://www.natplus.com/products/productNumber=7124). Some suppliers also provide creams and pills having Boswellin with and without capsaicin and other ingredients. (See e.g., http://www.preventics.com). Embodiments of the invention comprise Boswellin and the term xe2x80x9cBoswellinxe2x80x9d collectively refers to Frankincense, an extract from one or more members of the Boswellia family, Boswellic acid, synthetic Boswellin, or modified or derivatized Boswellin.
The delivery systems of the invention having Boswellin desirably comprise 0.1% to 10% Boswellin by weight or volume. Preferred amounts of this delivery agent include 1.0% to 5.0% Boswellin by weight. For example, the delivery systems of the invention having Boswellin can comprise by weight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, and 2.0%, 2.1%, 2.15%, 2.2%, 2.25%, 2.3%, 2.35%, 2.4%, 2.45%, 2.5%, 2.55%, 2.6%, 2.65%, 2.7%, 2.75%, 2.8%, 2.85%, 2.9%, 2.95%, 3.0%, 3.1%, 3.15%, 3.2%, 3.25%, 3.3%, 3.35%, 3.4%, 3.45%, 3.5%, 3.55%, 3.6%, 3.65%, 3.7%, 3.75%, 3.8%, 3.85%, 3.9%, 3.95%, 4.0%,. 4.1%, 4.15%, 4.2%, 4.25%, 4.3%, 4.35%, 4.4%, 4.45%, 4.4%, 4.45%, 4.5%, 4.55%, 4.6%, 4.65%, 4.7%, 4.75%, 4.8%, 4.85%, 4.9%, 4.95%, and 5.0% Boswellin. Although not a desirable embodiment, the delivery systems of the invention having Boswellin can comprise amounts of Boswellin by weight that are greater than 5.0%, such as 5.5%, 5.7%, 6.0%, 6.5%%, 6.7%, 7.0%, 7.5%, 7.7%, 8.0%, 8.5%, 8.7%, 9.0%, 9.5%, 9.7%, and 10.0% or greater. Additionally, Boswellin from different sources can be combined to compose the Boswellin component of an embodiment. For example, in one embodiment an extract from Boswellia thurifera is combined with an extract from Boswellia serrata.
Additional embodiments of the invention comprise a transdermal delivery system that can administer a pain relieving solution comprising two or more members selected from the group consisting of NSAIDs, capsacin, and Boswellin. The delivery systems of the invention that include two or more members selected from the group consisting of NSAIDs, capsacin, and Boswellin desirably comprise an amount of delivery agent that can be included in a delivery agent having an NSAID, capsaicin, or Boswellin by itself. For example, if the delivery agent comprises an NSAID, the amount of NSAID that can be used can be an amount recommended in the literature (See e.g., Woodin, R N, August: 26-33 (1993) and Amadio, et al., Postgrduate Medicine, 93(4):73-97 (1993)), or an amount listed in Table 1. Similarly, if capsaicin is a component of the delivery agents then the delivery system can comprise by weight or volume less than or equal to 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 0.1%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.325%, 0.35%, 0.375%, 0.4%, 0.425%, 0.45%, 0.475%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, and 1.0% capsaicin or less than 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 11.0%, 12.0%, 13.0%, oleoresin capsicum. Further, if Boswellin is a component of the delivery agents, then the delivery system can comprise by weight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, 2.0%, 2.1%, 2.15%, 2.2%, 2.25%, 2.3%, 2.35%, 2.4%, 2.45%, 2.5%, 2.55%, 2.6%, 2.65%, 2.7%, 2.75%, 2.8%, 2.85%, 2.9%, 2.95%, 3.0%, 3.1%, 3.15%, 3.2%, 3.25%, 3.3%, 3.35%, 3.4%, 3.45%, 3.5%, 3.55%, 3.6%, 3.65%, 3.7%, 3.75%, 3.8%, 3.85%, 3.9%, 3.95%, 4.0%,. 4.1%, 4.15%, 4.2%, 4.25%, 4.3%, 4.35%, 4.4%, 4.45%, 4.4%, 4.45%, 4.5%, 4.55%, 4.6%, 4.65%, 4.7%, 4.75%, 4.8%, 4.85%, 4.9%, 4.95%, 5.0%, 5.5%, 5.7%, 6.0%, 6.5%%, 6.7%, 7.0%, 7.5%, 7.7%, 8.0%, 8.5%, 8.7%, 9.0%, 9.5%, 9.7%, and 10.0% Boswellin.
In addition to low molecular weight delivery agents, many medium molecular weight delivery agents (eg., humates) can be delivered to cells in the body by using an embodiment of the transdermal delivery system. Synthetic humates (xe2x80x9cHepsylsxe2x80x9d) are medium molecular weight compounds (1,000 to 100,000 daltons), which are known to be strong antiviral and antimicrobial medicaments (International Application Publication No. WO 9834629 to Laub). Hepsyls are generally characterized as polymeric phenolic materials comprised of conjugated aromatic systems to which are attached hydroxyl, carboxyl, and other covalently bound functional groups. A delivery system that can administer Hepsyls to cells of the body has several pharmaceutical uses, including but not limited to, treatment of topical bacterial and viral infections.
Accordingly, in another aspect of the invention, a transdermal. delivery system that can administer a medium molecular weight compound (e.g., a form of Hepsyl) to cells of the body is provided. As described above, many different medium molecular weight compounds can be administered by using an embodiment of a transdermal delivery system of the invention and the use of a medium molecular weight Hepsyl as a delivery agent is intended to demonstrate that embodiments of the invention can deliver many medium molecular weight compounds to calls of the body.
In addition to low molecular weight delivery agents and medium molecular weight delivery agents, several high molecular weight delivery agents (e.g., glycoproteins) can be delivered to cells in the body by using an embodiment of the transdermal delivery system. Glycoproteins are high molecular weight compounds, which are generally characterized as conjugated proteins containing one or more heterosaccharides as prosthetic groups. The heterosaccharides are usually branched but have a relatively low number of sugar residues, lack a serially repeating unit, and are covalently bound to a polypeptide chain. Several forms of glycoproteins are found in the body. For example, many membrane bound proteins are glycoproteins, the substances that fill the intercellular spaces (e.g., extracellular matrix proteins) are glycoproteins, and the compounds that compose collagens, proteoglycans, mucopolysaccharides, glycosaminoglycans, and ground substance are glycoproteins. A delivery system that can administer glycoproteins to cells of the body has several pharmaceutical and cosmetic uses, including but not limited to, the restoration of skin elasticity and firmness (e.g., the removal of wrinkles by transdermal delivery of collagen) and the restoration of flexible and strong joints (e.g., water retention in joints can be increased by transdermal delivery of proteoglycans).
Accordingly, in another aspect of the invention, a transdermal delivery system that can administer a high molecular weight compound (e.g., a form of collagen) to cells of the body is provided. As described above, many different high molecular weight compounds can be administered by using an embodiment of a transdermal delivery system of the invention and the use of a high molecular weight collagen as a delivery agent is intended to demonstrate that embodiments of the invention can deliver many high molecular weight compounds to cells of the body.
Collagens exist in many forms and can be isolated from a number of sources. Additionally, several forms of collagen can be obtained commercially (e.g., Brooks Industries Inc., New Jersey). Many low molecular weight collagens can be made, for example, by hydrolysis. Several transdermal delivery systems of the invention can deliver collagens having molecular weights below 6,000 daltons. Additionally, several high molecular weight collagens exist. Some are isolated from animal or plant sources and some are synthesized or produced through techniques common in molecular biology. Several transdermal delivery systems of the invention can deliver collagens having molecular weights of 1,000 daltons to greater than 2,000,000 daltons. That is, embodiments of the transdermal delivery systems can deliver collagens having molecular weights of less than or equal to 1,000, 1,500, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500, 5,000, 5,500, 6,000, 7,000, 8,000, 9,000, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, 35,000, 36,000, 37,000, 38,000, 39,000, 40,000, 41,000, 42,000, 43,000, 44,000, 45,000, 46,000, 47,000, 48,000, 49,000, 50,000, 51,000, 52,000, 53,000, 54,000, 55,000, 56,000, 57,000, 58,000, 59,000, 60,000, 61,000, 62,000, 63,000, 64,000, 65,000, 66,000, 67,000, 68,000, 69,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, 100,000, 125,000, 150,000, 175,000, 200,000, 225,000, 250,000, 275,000, 300,000, 350,000, 400,000, 450,000, 500,000, 600,000, 700,000, 800,000, 900,000, 1,000,000, 1,500,000, 1,750,000, and 2,000,000 daltons.
In some embodiments, the commercially available collagen xe2x80x9cHydrocoll EN-55xe2x80x9d was provided as the delivery agent and was delivered to cells of a test subject. This form of collagen is hydrolyzed collagen and has a molecular weight of 2,000 daltons. In another embodiment, the commercially available collagen xe2x80x9cSolu-Collxe2x80x9d was provided as the delivery agent and was delivered to cells of a test subject. This form of collagen is a soluble collagen having a molecular weight of 300,000 daltons. An additional embodiment includes the commercially available collagen xe2x80x9cPlantsolxe2x80x9d, which is obtained from yeast and has a molecular weight of 500,000 daltons. This collagen was also provided as a delivery agent and was delivered to cells of a test subject.
The delivery systems of the invention having a form of collagen as a delivery agent desirably comprise by weight or volume between 0.1% to 50.0% collagen depending on the type of collagen, its solubility, and the intended application. That is, some transdermal delivery systems of the invention comprise by weight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%,. 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0% 8.25%, 8.5%, 8.75%, 9.0%, 9.25%, 9.5%, 9.75%, 10.0%, 10.25%, 10.5%, 10.75%, 11.0%,. 11.25%, 11.5%, 11.75%, 12.0%, 12.25%, 12.5%, 12.75%, 13.0%, 13.25%, 13.5%, 13.75%, 14.0%, 14.25%, 14.5%, 14.75%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%, 28.0%, 28.5%, 29.0%, 29.5%, 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%, 33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%, 40.0%, 41.0%, 42.0%, 43.0%, 44.0%, 45.0%, 46.0%, 47.0%, 48.0%, 49.0%, or 50.0% collagen.
For example, embodiments having Hydrocoll-EN55 can comprise by weight or volume less than or equal to 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%,. 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0% 8.25%, 8.5%, 8.75%, 9.0%, 9.25%, 9.5%, 9.75%, 10.0%, 10.25%, 10.5%, 10.75%, 11.0%,. 11.25%, 11.5%, 11.75%, 12.0%, 12.25%, 12.5%, 12.75%, 13.0%, 13.25%, 13.5%, 13.75%, 14.0%, 14.25%, 14.5%, 14.75%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%, 28.0%, 28.5%, 29.0%, 29.5%, 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%, 33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%, 40.0%, 41.0%, 42.0%, 43.0%, 44.0%, 45.0%, 46.0%, 47.0%, 48.0%, 49.0%, or 50.0% Hydrocoll-EN-55. Further, delivery systems of the invention having Solu-Coll can comprise by weight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, or 2.0% Solu-Coll. Additionally, delivery systems of the invention having Plantsol can comprise by weight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, 2.0%, 2.1%, 2.15%, 2.2%, 2.25%, 2.3%, 2.35%, 2.4%, 2.45%, 2.5%, 2.55%, 2.6%, 2.65%, 2.7%, 2.75%, 2.8%, 2.85%, 2.9%, 2.95%, 3.0%, 3.1%, 3.15%, 3.2%, 3.25%, 3.3%, 3.35%, 3.4%, 3.45%, 3.5%, 3.55%, 3.6%, 3.65%, 3.7%, 3.75%, 3.8%, 3.85%, 3.9%, 3.95%, or 4.0% Plantsol.
In other embodiments of the invention, a transdermal delivery system that can administer a collagen solution comprising two or more forms of collagen (e.g., Hydro-Coll EN-55, Solu-coll, or Plantsol) is provided. The delivery systems of the invention that include two or more forms of collagen desirably comprise an amount of delivery agent that can be included in a delivery agent having the specific type of collagen by itself. For example, if the mixture of delivery agents comprises Hydro-Coll EN55, the amount of Hydro-Coll EN55 in the transdermal delivery system can comprise by weight or volume less than or equal to 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%,. 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0% 8.25%, 8.5%, 8.75%, 9.0%, 9.25%, 9.5%, 9.75%, 10.0%, 10.25%, 10.5%, 10.75%, 11.0%,. 11.25%, 11.5%, 11.75%, 12.0%, 12.25%, 12.5%, 12.75%, 13.0%, 13.25%, 13.5%, 13.75%, 14.0%, 14.25%, 14.5%, 14.75%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%, 28.0%, 28.5%, 29.0%, 29.5%, 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%, 33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%, 40.0%, 41.0%, 42.0%, 43.0%, 44.0%, 45.0%, 46.0%, 47.0%, 48.0%, 49.0%, or 50.0% Hydrocoll-EN-55. Similarly if the mixture of delivery agents have Solu-coll, then the amount of Solu-coll in the delivery device can comprise by weight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, or 2.0% or Solu-Coll. Further, if the mixture of delivery agents have Plantsol, then the amount of Plantsol in the delivery system can comprise by weight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, 2.0%, 2.1%, 2.15%, 2.2%, 2.25%, 2.3%, 2.35%, 2.4%, 2.45%, 2.5%, 2.55%, 2.6%, 2.65%, 2.7%, 2.75%, 2.8%, 2.85%, 2.9%, 2.95%, 3.0%, 3.1%, 3.15%, 3.2%, 3.25%, 3.3%, 3.35%, 3.4%, 3.45%, 3.5%, 3.55%, 3.6%, 3.65%, 3.7%, 3.75%, 3.8%, 3.85%, 3.9%, 3.95%, or 4.0% Plantsol.
In the section below, there is a description of the manufacture and use of a penetration enhancer that enables the delivery of both low and high molecular weight molecules to the skin cells of the body.
Penetration Enhancers
A penetration enhancer included in many embodiments of the invention is comprised of two componentsxe2x80x94a hydrophobic component and a hydrophilic component. Desirably, the hydrophobic component comprises a polyether compound, such as an ethoxylated vegetable or animal oil, that has the ability to reduce the surface tension of materials that are dissolved into it. Preferable ethoxylated oils can be obtained or created from, for example, castor oil, jojoba oil, corn oil, and emu oil. Desirably, the ethoxylated compound comprises at least 20-25 ethoxylations per molecule and preferably the ethoxylated compound comprises at least 30-35 ethoxylations per molecule. Thus, in a preferred embodiment, an ethoxylated oil comprises a molar ratio of ethylene oxide:oil of 35:1. A 99% pure ethylene oxide/castor oil having such characteristics can be obtained commercially (BASF) or such an ethoxylated compound can be synthesized using conventional techniques. Desirable compounds often found in ethoxylated oils that are beneficial for some embodiments and methods of the invention are glycerol-polyethylene glycol ricinoleate, the fatty esters of polyethylene glycol, polyethylene glycol, and ethoxylated glycerol. Some of these desirable compounds exhibit hydrophilic properties and the hydrophilic-lipophilic balance (HLB) is preferably maintained between 10 and 18. In some embodiments, more than one ethoxylated compound is added or another hydrophobic compound is added (e.g., Y-Ling-Y-Lang oil; Young Living Essential Oils, Lehl, Utah)) to balance or enhance the penetration enhancer.
Depending on the type of delivery agent and the intended application, the amount of ethoxylated lipid(s) in the delivery system can vary. For example, delivery systems of the invention can comprise between 0.1% and 40% by weight or volume ethoxylated compound(s). That is, embodiments of the invention can comprise by weight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%,. 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0% 8.25%, 8.5%, 8.75%, 9.0%, 9.25%, 9.5%, 9.75%, 10.0%, 10.25%, 10.5%, 10.75%, 11.0%,. 11.25%, 11.5%, 11.75%, 12.0%, 12.25%, 12.5%, 12.75%, 13.0%, 13.25%, 13.5%, 13.75%, 14.0%, 14.25%, 14.5%, 14.75%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%, 28.0%, 28.5%, 29.0%, 29.5%, 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%, 33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%, and 40.0% ethoxylated lipid(s).
The hydrophilic component of the penetration enhancers of the invention desirably comprise an alcohol, a non-ionic solubilizer, or an emulsifier. Compounds such as ethylene glycol, propylene glycol, dimethyl sulfoxide (DMSO), dimethyl polysiloxane (DMPX), oleic acid, caprylic acid, isopropyl alcohol, 1-octanol, ethanol (denatured or anhydrous), and other pharmaceutical grade or absolute alcohols with the exception of methanol can be used. Preferred embodiments comprise an alcohol (e.g., absolute isopropyl alcohol), which is commercially available. As above, the amount of hydrophilic component in the penetration enhancer depends on the type of the delivery agent and the intended application. The hydrophilic component of a penetration enhancer of the invention can comprise between 0.1% and 50% by weight or volume. That is, a delivery system of the invention can comprise by weight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%,. 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0% 8.25%, 8.5%, 8.75%, 9.0%, 9.25%, 9.5%, 9.75%, 10.0%, 10.25%, 10.5%, 10.75%, 11.0%,. 11.25%, 11.5%, 11.75%, 12.0%, 12.25%, 12.5%, 12.75%, 13.0%, 13.25%, 13.5%, 13.75%, 14.0%, 14.25%, 14.5%, 14.75%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%, 28.0%, 28.5%, 29.0%, 29.5%, 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%, 33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%, 40.0%, 41.0%, 42.0%, 43.0%, 44.0%, 45.0%, 46.0%, 47.0%, 48.0%, 49.0%, or 50.0% hydrophilic component.
In addition to the delivery agent and penetration enhancer, desirable transdermal delivery devices comprise a third componentxe2x80x94an aqueous adjuvant. In the section below, there is described the manufacture and use of a preferred aqueous adjuvant, Aloe Vera, that enhances the delivery of both low and high molecular weight molecules to the skin cells of the body.
Aqueous Adjuvants
The term xe2x80x9cAloexe2x80x9d refers to the genus of South African plants of the Liliaceae family, of which the Aloe barbadensis plant is a species. Aloe is an intricate plant, which contains many biologically active substances. (Cohen, et al. in Wound Healing/Biochemical and Clinical Aspects, 1st ed. W B Saunders, Philadelphia (1992)). Over 300 species of Aloe are known, most of which are indigenous to Africa. Studies have shown that the biologically active substances are located in three separate sections of the Aloe leafxe2x80x94a clear gel fillet located in the center of the leaf, in the leaf rind or cortex of the leaf and in a yellow fluid contained in the pericyclic cells of the vascular bundles, located between the leaf rind and the internal gel fillet, referred to as the latex. Historically, Aloe products have been used in dermatological applications for the treatment of burns, sores and other wounds. These uses have stimulated a great deal of research in identifying compounds from Aloe plants that have clinical activity, especially anti-inflammatory activity. (See, e.g., Grindlay and Reynolds (1986) J. of Ethnopharmacology 16:117-151; Hart, et al. (1988) J. of Ethnopharmacology 23:61-71). As a result of these studies there have been numerous reports of Aloe compounds having diverse biological activities, including anti-tumor activity, anti-gastric ulcer, anti-diabetic, anti-tyrosinase activity, (See e.g., Yagi, et al. (1977) Z. Naturforsch. 32c:731-734), and antioxidant activity (International Application Serial No. PCT/US95/07404). Recent research has also shown that Aloe Vera, a term used to describe the extract obtained from processing the entire leaf, isolated from the Aloe Vera species of Aloe, can be used as a vehicle for delivering hydrocortisone, xcex2-estradiol, and testosterone propionate. (Davis, et al, JAPMA 81:1 (1991) and U.S. Pat. No. 5,708,038 to Davis)). As set forth in Davis (U.S. Pat. No. 5,708,308), one embodiment of xe2x80x9cAloe Veraxe2x80x9d can be prepared by xe2x80x9cwhole-leaf processingxe2x80x9d of the whole leaf of the Aloe barbadensis plant. Briefly, whole leaves obtained from the Aloe barbadensis plant are ground, filtered, treated with cellulase (optional) and activated carbon and lyophilized. The lyophilized powder is then reconstituted with water prior to use.
In some embodiments, Aloe Vera is commercially available and obtained through Aloe Laboratories. In some embodiments, the Aloe Vera is manufactured by manually harvesting the Aloe leaves. Next, the leaves are washed with water and the thorns on both ends are cut. The leaves are then hand-filleted so as to extract the inner part of the leaf. The inner gel is passed through a grinder and separator to remove fiber from the gel. Next, the gel is put into a pasteurizing tank where L-Ascorbic Acid (Vitamin C) and preservatives are added. The gel is pasteurized at 85xc2x0 C. for 30 minutes. After pasteurization, the gel is put into a holding tank for about one or two days, after which the gel is sent through a xc2xd micron filter. Finally, the gel is cooled down through a heat exchanger and stored in a steamed, sanitized and clean 55 gallon drum.
The above described sources and manufacturing methods of Aloe Vera are given as examples and not intended to limit the scope of the invention. One of ordinary skill in the art will recognize that Aloe Vera is a well known term of art, and that Aloe Vera is available from various sources and manufactured according to various methods.
Several embodiments of the invention are comprised of aqueous adjuvants such as Aloe Vera juice or water or both. Absolute Aloe Vera (100% pure) can be obtained from commercial suppliers (Lily of the Desert, Irving, Tex.). Aloe Vera juice, prepared from gel fillet, has an approximate molecular weight of 200,000 to 1,400,000 daltons. Whole leaf Aloe Vera gel has a molecular weight of 200,000 to 3,000,000 depending on the purity of the preparation. Although, preferably, the embodiments of the invention having Aloe Vera comprise Aloe Vera juice, other extracts from a member of the Liliaceae family can be used (e.g., an extract from another Aloe species).
Transdermal delivery systems of the invention having Aloe Vera can comprise between 0.1% to 85.0% by weight or volume Aloe Vera. That is, embodiments of the invention can comprise by weight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%,. 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0% 8.25%, 8.5%, 8.75%, 9.0%, 9.25%, 9.5%, 9.75%, 10.0%, 10.25%, 10.5%, 10.75%, 11.0%,. 11.25%, 11.5%, 11.75%, 12.0%, 12.25%, 12.5%, 12.75%, 13.0%, 13.25%, 13.5%, 13.75%, 14.0%, 14.25%, 14.5%, 14.75%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%, 28.0%, 28.5%, 29.0%, 29.5%, 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%, 33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%, 40.0%, 40.25%, 40.5%, 40.75%, 41.0%, 41.25%, 41.5%, 41.75%, 42.0%, 42.25%, 42.5%, 42.75%, 43.0%,. 43.25%, 43.5%, 43.75%, 44.0%, 44.25%, 44.5%, 44.75%, 45.0%, 45.25%, 45.5%, 45.75%, 46.0%, 46.25%, 46.5%, 46.75%, 47.0% 47.25%, 47.5%, 47.75%, 48.0%, 48.25%, 48.5%, 48.75%, 49.0%, 49.25%, 49.5%, 49.75%, 50.0%,. 50.25%, 50.5%, 50.75%, 51.0%, 51.25%, 51.5%, 51.75%, 52.0%, 52.25%, 52.5%, 52.75%, 53.0%, 53.25%, 53.5%, 53.75%, 54.0%, 54.5%, 54.0%, 54.5%, 55.0%, 55.5%, 56.0%, 56.5%, 57.0%, 57.5%, 58.0%, 58.5%, 59.0%, 59.5%, 60.0%, 60.5%, 61.0%, 61.5%, 62.0%, 62.5%, 63.0%, 63.5%, 64.0%, 64.5%, 65.0%, 65.5%, 66.0%, 66.5%, 67.0%, 67.5%, 68.0%, 68.5%, 69.0%, 69.5%, 70.0%, 70.5%, 71.0%, 71.5%, 72.0%, 72.5%, 73.0%, 73.5%, 74.0%, 74.5%, 75.0%, 75.5%, 76.0%, 76.5%, 77.0%, 77.5%, 78.0%, 78.5%, 79.0%, 79.5%, 80.0%, 80.5%, 81%, 81.5%, 82%, 82.5%, 83%, 83.5%, 84%, 84.5%, and 85% Aloe Vera.
The amount of water in the delivery system generally depends on the amount of other reagents (e.g., delivery agent, penetration enhancer, and other aqueous adjuvants or fillers). Although water is used as the sole aqueous adjuvant in some embodiments, preferred embodiments use enough water to make the total volume of a particular preparation of a delivery system such that the desired concentrations of reagents in the penetration enhancer, aqueous adjuvant, and delivery agent are achieved. Suitable forms of water are deionized, distilled, filtered or otherwise purified. Clearly, however, any form of water can be used as an aqueous adjuvant.
In addition to the aforementioned compositions, methods of making and using the transdermal delivery systems of the invention are provided below.
Preparing Transdermal Delivery Systems
In general, an embodiment of the invention is prepared by combining a penetration enhancer with an aqueous adjuvant and a delivery agent. Depending on the solubility of the delivery agent, the delivery agent can be solubilized in either the hydrophobic or hydrophilic components of the penetration enhancer. Additionally, some delivery agents can be solubilized in the aqueous adjuvant prior to mixing with the penetration enhancer. Desirably, the pH of the mixture is maintained between 3 and 11 and preferably between 5 and 9. That is, during preparation and after preparation the pH of the solution is desirably maintained at less than or equal to 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5.0, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7.0, 7.25, 7.5, 7.75, 8.0, 8.25, 8.5, 8.75, 9.0, 9.25, 9.5, 9.75, 10.0, 10.25, 10.5, 10.75, or 11.0. Several physical mixing techniques can be employed to help the delivery system coalesce. For example, a magnetic stir plate and bar can be used, however, the speed of stirring is preferably minimized so as not to drive air into the mixture. Additionally, a rocker can be used to bring components of the delivery system together. Heat can also be applied to help coalesce the mixture but desirably, the temperature is not raised above 40xc2x0 C. so that labile aqueous adjuvants or labile delivery agents are not degraded. Preferably, once the delivery system has coalesced, other components such as fragrances and colors are added or the delivery system is incorporated into a cream or ointment or a device for applying the delivery system.
Several formulations of delivery system are within the scope of aspects of the invention. Desirably, the ratio of hydrophilic component:hydrophobic component:aqueous adjuvant is 3:4:3, but preferred formulations comprise 1:1:4, 1:1:14, and 1:10:25. As described above, a sufficient amount of delivery agent to suit the intended purpose is incorporated into the delivery system. The amount of delivery agent that is incorporated into the penetration enhancer depends on the compound, desired dosage, and application.
Typically, a preferable transdermal delivery system is made by providing an ethoxylated oil, mixing the ethoxylated oil with an alcohol, non-ionic solubilizer, or emulsifier so as to form a penetration enhancer, mixing the penetration enhancer with an aqueous adjuvant (e.g., an extract from a plant of the Liliaeacae family), and mixing the penetration enhancer and aqueous adjuvant with a delivery agent and thereby making the transdermal delivery system. For example, an embodiment of a transdermal delivery system comprising a pain relief solution is manufactured as follows. A solution of 2.0% to 7.0% oleoresin capsicum, 2.5 grams of Boswellin, and 1.5 mls of a 65% solution of Frankensence is mixed with 400 ml of absolute carpilic alcohol or isopropyl alcohol, 300 ml of ethylene oxide admixed and reacted with castor oil, and 300 ml of a 100% solution of Aloe Vera. This transdermal delivery system has been observed to alleviate pain when rubbed on a targeted area.
The delivery systems of the invention having a form of Hepsyl as a delivery agent desirably are comprised by weight or volume of between 0.005% to 12.0% Hepsyl, depending on the type of Hepsyl, its solubility, and the intended application. For example, embodiments having Hepsyl CA 1501C. Hepsyl CGA 1501K., and Hepsyl RA 150K can be comprised by weight or volume of 0.01-2 grams of Hepsyl delivery agent, 0-50 mL of hydrophobic penetration enhancers (e.g., ethoxylated castor oil, jojoba oil, etc.), 0-50 mL of hydrophilic penetration enhancers, nonionic solubilizers, or emulsifiers (e.g., isopropyl. alcohol, DMSO, etc.), and 0-50 mL of aqueous adjuvant (e.g., water, Aloe Vera extract, etc.). A particularly desirable embodiment of the invention is comprised of 0.1-0.5 gram of Hepsyl, 5-10 mL of ethoxylated castor oil, 5-10 mL of isopropyl alcohol, and 5-10 mL of Aloe Vera extract.
By using these formulations, other delivery agents can incorporated into a transdermal delivery system. Formulations of transdermal delivery systems having collagens are described in Example 2.
In the disclosure below, several therapeutic, prophylactic and cosmetic applications are provided.
Therapeutic, Prophylactic, and Cosmetic Applications
Many embodiments are suitable for treatment of subjects either as a preventive measure (e.g., to avoid pain or skin disorders) or as a therapeutic to treat subjects already afflicted with skin disorders or who are suffering pain. In one embodiment, a method of treatment or prevention of inflammation, pain, or human diseases, such as cancer, arthritis, and Alzheimer""s disease, comprises using a transdermal delivery system of the invention. Because delivery agents such as NSAIDs, capsaicin, and Boswellin interfere and/or inhibit cyclooxygenase enzymes (COX-1 and COX-2), they will provide a therapeutically beneficial treatment for cancer and Alzheimer""s disease when administered by a transdermal delivery system of the invention. (U.S. Pat. No. 5,840,746 to Ducharme et al., and U.S. Pat. No. 5,861,268 to Tang et al.).
By one approach, a transdermal delivery system comprising a delivery agent that is effective at reducing pain or inflammation (e.g., NSAIDS, capsaicin, Boswellin, or any combination thereof) is administered to a subject in need and the reduction in pain or inflammation is monitored. An additional approach involves identifying a subject in need of a COX enzyme inhibitor (e.g., a subject suffering from cancer or Alzheimer""s disease) and administering a transdermal delivery system comprising a delivery agent that inhibits a COX enzyme (e.g., NSAIDS, capsaicin, Boswellin, or any combination thereof). Although many individuals can be at risk for contracting cancer or Alzheimer""s disease, those with a family history or a genetic marker associated with these maladies are preferably identified. Several diagnostic approaches to identify persons at risk of developing these diseases have been reported. (See e.g., U.S. Pat. Nos., 5,891,857; 5,744,368; 5,891,651; 5,837,853; and 5,571,671). The transdermal delivery system is preferably applied to the skin at a region of inflammation or an area associated with pain or the particular condition and treatment is continued for a sufficient time to reduce inflammation, pain, or inhibit the progress of the disease. Typically, pain and inflammation will be reduced in 5-20 minutes after application. Cancer and Alzheimer""s disease can be inhibited or prevented with prolonged use.
In another method of the invention, an approach to reduce wrinkles and increase skin tightness and flexibility (collectively referred to as xe2x80x9crestoring skin tonexe2x80x9d) is provided. Accordingly, a transdermal delivery system comprising a form of collagen as a delivery agent is provided and contacted with the skin of a subject in need of treatment. By one approach, a subject in need of skin tone restoration is identified, a transdermal delivery system comprising collagen is administered to the subject, and the restoration of the skin tone is monitored. Identification of a person in need of skin restoration can be based solely on visible inspection and the desire to have tight, smooth, and flexible skin. Treatment with the delivery system is continued until a desired skin tone is achieved. Typically a change in skin tone will be visibly apparent in 15 days but prolonged use may be required to retain skin tightness and flexibility. The form of collagen in the delivery agent can be from various sources and can have many different molecular weights, as detailed above. Preferably, high molecular weight collagens are used.
The transdermal delivery systems of this invention can be processed in accordance with conventional pharmacological and cosmetological methods to produce medicinal agents and cosmetics for administration to patients, e.g., mammals including humans. The transdermal delivery systems described herein can be incorporated into a pharmaceutical or cosmetic product with or without modification. The compositions of the invention can be employed in admixture with conventional excipients, e.g., pharmaceutically acceptable organic or inorganic carrier substances suitable for topical application that do not deleteriously react with the molecules that assemble the delivery system. The preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, coloring, aromatic substances and the like that do not deleteriously react with the active compounds. They can also be combined where desired with other active agents.
The effective dose and method of administration of a carrier system formulation can vary based on the individual patient and the stage of the disease, as well as other factors known to those of skill in the art. Although several doses of delivery agents have been indicated above, the therapeutic efficacy and toxicity of such compounds in a delivery system of the invention can be determined by standard pharmaceutical or cosmetological procedures with experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical and cosmetological compositions that exhibit large therapeutic indices are preferred. The data obtained from animal studies is used in formulating a range of dosages for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
The exact dosage is chosen by the individual physician in view of the patient to be treated. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Additional factors that may be taken into account include the severity of the disease state, age, weight and gender of the patient; diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Short acting compositions are administered daily whereas long acting pharmaceutical compositions are administered every 2, 3 to 4 days, every week, or once every two weeks. Depending on half-life and clearance rate of the particular formulation, the pharmaceutical compositions of the invention are administered once, twice, three, four, five, six, seven, eight, nine, ten or more times per day.
Routes of administration of the delivery systems of the invention are primarily topical, although it is desired to administer some embodiments to cells that reside in deep skin layers. Topical administration is accomplished via a topically applied cream, gel, rinse, etc. containing a delivery system of the invention. Compositions of delivery system-containing compounds suitable for topical application include, but are not limited to, physiologically acceptable ointments, creams, rinses, and gels.
In some embodiments, the mixture of penetration enhancer, aqueous adjuvant, and delivery agent is incorporated into a device that facilitates application. These apparatus generally have a vessel joined to an applicator, wherein a transdermal delivery system of the invention is incorporated in the vessel. Some devices, for example, facilitate delivery by encouraging vaporization of the mixture. These apparatus have a transdermal delivery system of the invention incorporated in a vessel that is joined to an applicator such as a sprayer (e.g., a pump-driven sprayer). These embodiments can also comprise a propellant for driving the incorporated transdermal delivery system out of the vessel. Other apparatus can be designed to allow for a more focused application. A device that facilitates a focused application of a transdermal delivery system of the invention can have a roll-on or swab-like applicator joined to the vessel that houses the transdermal delivery system. Several devices that facilitate the administration of a delivery system of the invention have a wide range of cosmetic or therapeutic applications.
In the example below a clinical study is described that was performed to evaluate the efficacy of a transdermal delivery system that administered a low molecular weight pain relief solution comprising capsaicin.

Mixture for transdermal delivery of low and high molecular weight compounds


At least one compound selected from among ellagic acid, its salts, its metal complexes, its monoether or polyether, monoacylated or polyacylated derivatives and its carbonate or carbamate derivatives deriving from hydroxyl groups and mixtures thereof, and admixtures thereof with other active agents selected from among active agents for combating desquamative conditions of the scalp, plant extracts having propigmenting activity and active agents that slow hair loss and/or promote hair regrowth, are useful for preventing and/or limiting and/or stopping the development of canities.

1. Technical Field of the Invention
The present invention relates to the cosmetic administration of ellagic acid, its salts, its metal complexes, its monoether or polyether, monoacylated or polyacylated derivatives and its carbonate or carbamate derivatives deriving from hydroxyl groups for treating canities.
2. Description of Background and/or Related and/or Prior Art
The hair follicle is a tubular invagination of the epidermis which extends to the deep layers of the dermis. The lower part, or hair bulb, itself comprises an invagination in which the dermal papilla is located. The lower part of the bulb is an area of cell proliferation where the precursors of keratinized cells that make up hair are found. The ascending cells derived from these precursors become gradually keratinized in the upper part of the bulb, and this assembly of keratinized cells will form the hair shaft.
The color of head hair and of body hair depends, in particular, on the presence, in variable amounts and ratios, of two groups of melanins: eumelanins (brown and black pigments) and pheomelanins (red and yellow pigments). The pigmentation of head hair and body hair requires the presence of melanocytes in the bulb of the hair follicle. These melanocytes are in an active state, that is to say that they synthesize melanins. These pigments are transmitted to the keratinocytes intended to form the hair shaft, which will result in the growth of a pigmented head hair or body hair. This structure is hereinafter called "follicular pigmentation unit".
In mammals, melanogenesis involves at least three enzymes: tyrosinase, DOPAchrome tautomerase (TRP-2, for Tyrosinase Related Protein 2) and DHICA oxidase (TRP-1, for Tyrosinase Related Protein 1).
Tyrosinase is the enzyme that initiates the biosynthesis of melanins. It is also described as being the limiting enzyme of melanogenesis.
TRP-2 catalyzes the tautomerization of DOPAchrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA). In the absence of TRP-2, DOPAchrome undergoes a spontaneous decarboxylation to form 5,6-dihydroxyindole (DHI).
DHICA and DHI are both pigment precursors, TRP-1 oxidizes the DHICA molecules to form quinone derivatives (Pawelek, J. M. and Chakraborty, A. K., "The Enzymology of Melanogenesis", In: "The Pigmentary System: Physiology and Pathophysiology", by Nordlund, J. J., Boissy, R. E., Hearing, V. J., King, R. A., and Ortonne, J-P., New York, Oxford University Press, 1998, p. 391-400).
The three enzymes, tyrosinase, TRP-2 and TRP-1, appear to be specifically involved in melanogenesis. In addition, the activity of these three enzymes has been described as being necessary to the maximum activity of biosynthesis of eumelanins.
Head hair and body hair undergo a cycle. This cycle comprises a growth phase (anagen phase), a degenerative phase (catagen phase) and a rest phase (telogen phase) following which a new anagen phase will develop. Due to this hair cycle, and unlike the epidermal pigmentation unit, the follicular pigmentation unit must also be cyclically renewed.
Canities (natural hair whitening) is linked to a specific and gradual depletion of the hair melanocytes which affects both the melanocytes of the hair bulb and the precursor cells for melanocytes (Commo, et al., Br. J. Dermatol., 2004, 150, 435-443). Other cell types present in the hair follicles are not affected. In addition, this depletion of melanocytes is not observed in the epidermis. The cause of this gradual and specific depletion of melanocytes and melanocyte precursors in the hair follicle has not been identified to date.
It therefore appears necessary to combat the disappearance of melanocytes from human hair follicles, a process which affects both the active melanocytes of the bulbs and the quiescent melanocytes of the upper region of the hair follicles, in order to combat canities.
The assignee hereof has identified a means of combating hair whitening by acting on the TRP-2 enzyme (WO 03/103568) especially by increasing the level of GSH. Indeed, it has been demonstrated that the expression of the TRP-2 enzyme is correlated with a higher level of GSH in the melanocytes, the expression of TRP-2 induces an increase of the level of GSH in the melanocytes. Thus, in the melanocytes which do not express TRP-2 (for example, the melanocyte precursors of hair), there is a low level of GSH in comparison with melanocytes that express the TRP-2 enzyme (for example, all the skin melanocytes).
The assignee hereof has therefore identified a novel target for the treatment of canities, more particularly, it has been demonstrated that the compounds capable of increasing the GSH level in the melanocytes that are deficient in TRP-2 increase the viability of these melanocytes, decrease hair whitening and lead, unlike their depigmenting effect described in the literature, to the restoring of hair pigmentation (FR 04/13756).

Administation of ellagic acid for the treatment of canities


A power door operator for multi-passenger mass transit vehicles, typically buses, features electric actuation of dual swinging doors. A manual activator having an ergonometrically correct actuating plunger, for emergency door opening, operates a sleeved clutch. Fixed to the sleeve clutch is a drive bar with arms having individually adjustable lengths. The drive arms actuate outboard door shaft levers on individual door leaf through door drive rods intermediate the door arms and drive arms. Each rod incorporates spherical rod ends. The drive arms also actuate limit switches establishing door opened and door closed circuitry for energizing the electric drive system. The adjustable length clutch door drive arms provide a convenient device for controlling door leaf closing sequence and residual or door holding force when the doors are in a closed position.

This invention relates generally to power door operators for multi-passenger mass transit vehicles, more particularly to an overhead electrically driven door operator mounted for opening and closing dual leaf swing doors such as used in multiple passenger vehicles including, airport utility transports, school, and small transit buses.
Operators of the type disclosed herein are at present largely pneumatically actuated since in most large vehicles use of air brake systems provides a reliable and convenient source of operating air at controlled pressures. However, the vehicles described above incorporate hydraulic brake systems. Therefore, no air supply is available, and hydraulic door drives are high in cost and involve excessive maintenance in order to prevent leaks and loss of brake system integrity. A growing need for a reliable low cost electric bus door operator now exists.
An electric operator for transit vehicles disclosed in U.S. Pat. No. 4,375,140, the specification of which is hereby incorporated by reference. While presenting a required alternate approach to door equipment for certain vehicles, operators of the type disclosed in U.S. Pat. No. 4,375,140 have substantial shortcomings, including, among others, limited force for holding a door closed, lack of provision for controlling individual door leaf phasing (i.e., opening/closing relationship) in operation, and an attendant lack of adjustment of the hold-closed force. Further, the emergency release clutch employed is automatically reset on subsequent powered operation, and utilizes an actuating lever having a substantial protrusion into the passenger space.
The operator disclosed herein overcomes many of these problems through provision of adjustable length door drive lever arms, and an emergency door opening clutch having an actuating plunger incorporating improved and ergonometrically correct actuation. The clutch actuating plunger greatly reduces protrusion into passenger space.

Power door operator for multi-passenger mass transit vehicles


A golf club (2) comprising a shaft (20), a head and a damping device (1, 100). The damping device (1, 100) includes an anchor element (3, 103) and a damping element (4, 104) interconnected by a rigid rod (5, 105). The anchor element (3, 103) is anchored within the lower section of the shaft (20) that has a substantially constant diameter such that the damping element (4, 104) is in contact with an internal surface of the shaft (20) to dampen vibrations therein.

1. Field of the Invention
This invention relates generally to a damping device, particularly for golf clubs. More specifically, although not exclusively, this invention relates to a damping device for a golf putter.
2. Description of the Background
It is known that the impact of a golf club hitting a golf ball causes vibrations through the shaft of the club. The frequency of these vibrations will generally indicate whether the ball has been struck using the correct portion of the club head, the so-called 'sweet spot', or whether contact has been made off the center of the sweet spot. The frequency of the vibrations that result from an off-center strike is generally unpleasant to the golfer and several attempts have been made to control and/or mitigate such frequencies through the use of damping devices.
A number of damping devices, for example that which is disclosed in EP0531233, were developed to be fitted to the exterior of the shaft of the golf club to dampen these vibrations. Later developments include shaft inserts that incorporate a damping material, for example those which are disclosed in U.S. Pat. No. 5,788,586 and WO0062873. However, none of these devices have been found to provide satisfactory results.


A method and a vehicle cruise control system performing the steps of driving with the cruise control active and set to maintain a set target speed, registering a first position when driving in an uphill slope of a hill where vehicle retardation has decreased vehicle speed to a first speed below the set target speed and where the retardation has decreased to zero or acceleration has just started in order to increase speed to the set target speed, registering a desired speed in a second position downhill of the crest at a first distance after the crest, based on the desired speed calculating a minimum speed at the crest with which the vehicle has to pass the crest in order to be able to reach the desired speed with zero fuel consumption during the first distance, controlling speed between the first position and the crest so that the vehicle reaches the minimum speed when passing the crest.

The present invention relates to a method for controlling a cruise control in a vehicle. The invention also relates to a vehicle cruise control system intended for such method for controlling said cruise control.
The present invention also relates to a computer program, computer program product and a storage medium for a computer all to be used with a computer for executing said method.
Motor vehicles, such as cars, lorries, towing vehicles and buses, are often provided with a so-called cruise control system, also denominated speed control system, for automatically controlling the vehicle speed. Such a cruise control system comprises means, such as a speed sensor, for monitoring the actual vehicle speed. The cruise control system compares the actual vehicle speed with a set target speed. The target speed may for instance be entered into the cruise control system as the prevailing actual vehicle speed when a set switch is actuated by the driver. The cruise control system generates an error signal by comparing the actual vehicle speed with the target speed. The error signal is then for instance used to control an actuator coupled to the fuel pump or to the vehicle throttle in order to change the engine speed until the error signal is substantially zero, i.e. until the actual vehicle speed is equal to the target speed.
EP1439976 and U.S. Pat. No. 6,990,401 disclose two examples of prior art where the cruise control system has been further developed. Here the cruise control system is a predictive cruise control system utilizing information about current vehicle position and upcoming road topography, that is for example gradients or elevation values for the coming road, in order to control throttle opening in such a way as to increase fuel efficiency.
It is desirable to further develop such a cruise control system where information about current vehicle position and upcoming road topography is used by the cruise control for controlling vehicle speed.
The method according to an aspect of the invention is a method for controlling a cruise control during driving of a vehicle. Said method comprising the steps of:                driving said vehicle with said cruise control active and set to maintain a vehicle set target speed;        registering a first vehicle position when driving in an uphill slope of a hill where vehicle retardation has decreased vehicle speed to a first vehicle speed below said vehicle set target speed and where said retardation has decreased to zero or the vehicle has just started to accelerate in order to increase vehicle speed to said vehicle set target speed;        registering a desired vehicle speed in a second position downhill of said crest at a first distance after said crest;        based on said desired vehicle speed calculating a minimum vehicle speed at said crest with which said vehicle has to pass said crest in order to be able to reach said desired vehicle speed with a minimized or zero fuel consumption during said first distance;        controlling vehicle speed during a second distance between said first vehicle position and said crest so that said vehicle reaches said minimum vehicle speed when passing said crest, and where a vehicle speed is maintained below said vehicle set target speed during said second distance.
According to a first alternative embodiment of said invention said second vehicle position is one of;                a predetermined vehicle traveling time from said crest,        a predetermined distance from said crest,        at the end of said downhill,        at a distance from said crest where a vehicle traveling resistance is estimated to change from negative to positive.
According to a further embodiment of said invention said method is characterized in further comprising the step of calculating a needed vehicle acceleration or retardation during said second distance in order to reach said minimum vehicle speed at said crest with a minimized fuel consumption during said second distance.
According to another embodiment of said invention said method is characterized in further comprising the steps of:                registering said first vehicle speed being just below a direct gear engagement vehicle speed;        when having registered a predetermined vehicle condition setting said minimum vehicle speed to equal said direct gear engagement vehicle speed and accelerating the vehicle up to said minimum vehicle speed and engaging a direct gear;        driving said vehicle with said direct gear engaged during remaining of said second distance.
According to a further embodiment of the invention said predetermined vehicle condition comprises at least one of:                said just below a direct gear engagement vehicle speed meaning a speed difference below 5 km/h between said direct gear engagement vehicle speed and said first vehicle speed;        said second distance is greater than a predetermined value;        an estimated time interval for driving said vehicle with said direct gear engaged during said second distance is greater than a predetermined value.
In another embodiment of the invention a maximum vehicle over speed is set for said vehicle cruise control, and where said maximum vehicle over speed is at least equal to or higher than said vehicle set target speed, and where said desired vehicle speed equals said maximum vehicle over speed.
According to another embodiment of the invention a minimum vehicle under speed is set, having a predetermined relation to said vehicle set target speed. According to a further embodiment said predetermined relation is one of:                said minimum vehicle under speed is a predetermined percentage of said vehicle set target speed;        said minimum vehicle under speed is a predetermined amount below said vehicle set target speed.
In a further embodiment of the invention said crest, said second position and said minimum vehicle speed are predicted with information about present vehicle position and coming road topography of said hill.
According to a further embodiment of the invention if said second distance is shorter than a predetermined value, then said minimum vehicle speed is set to be equal to said first vehicle speed.
The invention also relates to a vehicle cruise control system that comprises (includes, but is not necessarily limited to) a control unit, driver input interface, vehicle position identifying device, road topography identifying device. Said system is characterized in that said control unit is arranged to perform the above mentioned method steps and use information from said vehicle position identifying device and said road topography identifying device in order to calculate said minimum vehicle speed.
Further advantageous embodiments of the invention emerge from the dependent patent claims following patent claim 1.

Method and system for controlling a vehicle cruise control


A control circuit for a wearable device includes: a power supply circuit, a DC blocking circuit, and a voltage comparison circuit. The power supply circuit is connected to a high voltage end, a low voltage end, a first signal input end, a second signal input end; the DC blocking circuit is connected to the first node, the second node, and a sensor in the wearable device; the voltage comparison circuit is connected to the first node, a reference voltage end and an output end, and configured to compare voltages of the first node and the reference voltage end; and output a first control signal through the output end when the voltage of the first node is smaller than the voltage of the reference voltage end, and output a second control signal through the output end when the voltage of the first node is larger than the voltage of the reference voltage end.

With continuous acceleration of life rhythm, people's pressure is increasing constantly. Most people have different levels of heart problems, sleep problems, etc., thus generating wearable devices for monitoring physical health.
However, wearable devices in the related art are provided with a power switch. Users need to manually operate the power switch to switch on and off, which is very inconvenient to use.

Control circuit for wearable device, wearable device

BEIJING BOE TECHNOLOGY DEVELOPMENT CO., LTD.


In accordance with one aspect of the disclosure, an apparatus is provided that includes a database configured to store one or more vehicle status parameters of a vehicle and one or more secured space status parameters of a secured space. The apparatus further includes a server-based processor operatively coupled or connected to the database and configured to receive one or more of the one or more vehicle status parameters and one or more of the one or more secured space status parameters. The server-based processor is further configured to determine, based on at least one of the one or more vehicle status parameters and at least one of the one or more secured space status parameters whether to change a state of the vehicle.

A garage is a confined space and as automotive technology advances more and more vehicles are coming equipped with auto-start functionality. Auto-start functionality allows for remote starting of a vehicle, and many vehicles that have auto-start functionality have keyless ignitions. Because the user of a vehicle with auto-start functionality does not need to be in the vehicle to start the vehicle, or take the keys out of the ignition, the likelihood that noxious and potentially harmfully gases will fill the garage increases. For example, the user may forget the vehicle is running.
Electric vehicles are quiet, and users of electric vehicles often forget that they are running. Leaving electric vehicle running drains the vehicle's batteries and creates the potential for unwanted use of the vehicle. For example, a parent may accidently leave an electric vehicle running, increasing the risk that a child may operate the vehicle.
Improved control systems for auto-start and auto-shutoff of vehicles parked in or proximate to a secured space such as a garage are needed. A central problem in developing such a system is the development of appropriate data to enable modern control systems to decide when to start a vehicle, when to shut off a vehicle, and when to let a user make that choice. Moreover, modern controls systems must be designed in a way that is intuitive and easy to use for the user while minimizing the potential harm to users or their property.
The business model of a modern automotive manufacturer is becoming more service oriented. For example, Ford®, in addition to selling the consumer a vehicle, sells the consumer the service that comes along with the vehicle. The quality of that service is telling indicia of the quality of the auto manufacturer's brand, just like the quality of vehicle itself. As such, auto manufactures need reliable sources of data and reliable algorithms to implement decision based on that data that are intuitive and easy to use for the customer while minimizing the potential harm to customers or their property.
A system that addresses these concerns is described in detail below.

Cloud-enabled vehicle autostart monitoring


The present disclosure relates to a method for M2M devices in an idle mode to perform a network reentry procedure in a wireless access network supporting machine-to-machine communication (M2M), and the method may include receiving information related to selection of a group delegate (GD) from a base station; receiving a response to a ranging request from the base station, wherein the ranging request is transmitted by an M2M device which is selected as the GD among a plurality of M2M devices in an M2M device group based on the information related to selection of the GD; and performing a network reentry procedure on the basis of the received response.

M2M Communication (Machine Type Communication; MTC)
Hereinafter, machine-to-machine (M2M) communication (or machine type communication (MTC)) will be described in brief.
Machine-to-machine (M2M) communication may denote communication between an electronic device and an electronic device as its expression. In other words, M2M communication may denote communication between objects. In general, M2M communication may denote wired or wireless communication between electronic devices or communication between a human-controlled device and a machine, but it may be also used as a meaning of particularly referring to wireless communication between an electronic device and an electronic device, namely, between machines. M2M terminals used in a cellular network may have lower performance or capability than that of typical terminals.
A lot of terminal may exist within a cell, and those terminals may be distinguished from one another based on its type, class, service, and the like.
For example, based on their operation type, terminals may be largely classified into a human type communication (HTC) terminal and a machine type communication (MTC) terminal. The machine type communication (MTC) may include communication between M2M terminals. Here, human type communication (HTC) may denote the transmission and reception of signals for which the transmission of signals is determined by a human, whereas MTC may denote the transmission of signals triggered by itself or event occurrence in each terminal or periodically without the intervention of a human.
Furthermore, if machine-to-machine (M2M) communication (or machine type communication (MTC)) is taken into consideration, then the number of whole terminals may suddenly increase. M2M terminal may have the following features based on support services.
1. A lot of terminal within a cell
2. Low amount of data
3. Transmission of low frequency (may have periodicity)
4. Limited number of data characteristics
5. Insensitive to time delay
6. Having low mobility or fixed
Furthermore, M2M communication may be used in various fields, such as protected access and surveillance, pursuit and discovery, public safety (emergency situation, disaster), payment (vending machine, ticket machine, parking meter), health care, remote control, smart meter, and the like.
Idle Mode
Idle mode is a mechanism capable of periodically receiving a downlink broadcast message without registering with a specific base station even when a terminal wanders in a wireless link environment having a plurality of base stations over a wide region.
Idle mode is a state in which only downlink synchronization is carried out to suspend all normal operations as well as handover (HO), and receive a paging message which is a broadcast message only for a predetermined interval. Paging message is a message for indicating paging action to a terminal. For example, the paging action may include ranging operation, network reentry, and the like.
Idle mode may be initiated by a terminal or initiated by a base station. In other words, the terminal may transmit a deregistration request (DREG-REQ) message to the base station, and receive a deregistration response (DREG-RSP) message in response to the deregistration request (DREG-REQ) message, thereby entering an idle mode. Furthermore, the base station may transmit a deregistration request (DREG-REQ) message or deregistration command (DREG-CMD) to the terminal, thereby entering an idle mode.
When a terminal receives a paging message corresponding to the terminal itself during an available interval (AI) in an idle mode, the terminal is switched to a connected mode through a network entry process with the base station to transmit and receive data.
Ranging
A user terminal performs a ranging process with the base station when accessing a network. The ranging process is a process for controlling a "time offset", a "frequency offset", and the like between the user terminal and base station and exchanging information such as management information. The user terminal may access the relevant network through such a ranging process, and performs a ranging process even when moving into a target base station through a handover procedure.
Furthermore, when the communication system is transited from an idle mode presented as a power reduction scheme of the user terminal to a normal operation mode, a network access should be attempted by selecting the best base station at a transition time point for the operation in the normal operation mode, and even at this time the ranging process is carried out. In this manner, the ranging process is carried out for various purposes.
The procedure of the ranging process may be typically classified into a code ranging and a RNG-REQ message ranging, and only the code ranging may be independently carried out, and the code ranging and RNG-REQ message ranging may be sequentially combined and carried out.
In describing the code ranging, it may be carried out using a process in which the user terminal transmits a specific CDMA code and the base station that has sensed the CDMA code responds using a RNG-RSP message. The base station determines whether or not it is required to control the "time offset", "frequency offset", and power of the relevant user terminal for a CDMA code index sensed by the base station itself, and the result is sent through a RNG-RSP message. The user terminal determines whether or not the code ranging attempted by the user terminal itself through receiving such a RNG-RSP message is successful, and then performs the required offset control.
The CDMA code is distinguished by a CDMA code index, and the user terminal should use a specific range of CDMA codes based on the purpose of the ranging operation. The base station grasps the purpose of the ranging process of the relevant user terminal based on a CDMA code index transmitted by the user terminal, and then performs a support corresponding to each purpose.
An uplink channel descriptor (UCD) message transmitted by the base station may include a parameter indicating a range of CDMA code indices supported by the relevant base station. The IEEE 802.16e standard may include the following information in the UCD message. The UCD message uses an uplink interval usage code (UIUC) used when the base station notifies the uplink region of each user terminal through UP-MAP. Each user terminal may know a modulation scheme/channel encoding scheme that should be applied to an uplink region assigned to the user terminal itself through the UIUC information. The UCD message may include information mapped with the UIUC value and modulation scheme/channel encoding scheme. Furthermore, the UCD information may include a range of CDMA codes that should be used for an operation such as "initial ranging", "periodic ranging", "bandwidth request", "handover", and the like.

Data transmission method in M2M device group


The thermal shrinkage and pyrolysis rate of plastic foam moldings are successfully controlled by coating the expandable plastic beads used in the preparation of the moldings with varying amounts of substantially water-insoluble inorganic siliceous materials. The plastic foam moldings are useful as patterns in an evaporative casting process, wherein the molding is vaporized and replaced by molten metal.

It is well-known that metal castings having complex or intricate shapes may be obtained using plastic foam moldings, embedded in a support material such as sand, which vaporize upon contact with the molten metal. The molten metal replaces the vaporized plastic foam, thus creating a metal replica of the molding in the support medium.
However, the plastic foam moldings are typically prepared using thermoplastic polymers having relatively low melting or softening points. For example, polystyrene has an ignition point of 380.degree. C. but a softening point of only about 100.degree. C. At a temperature of about 100.degree. C., a polystyrene foam molding begins to shrink and crumble. This lack of heat resistance can adversely affect the quality of the metal casting obtained therefrom. The problem is aggravated by the relatively high ambient temperatures present in an industrial foundry setting.
Additionally, the rate of pyrolysis of a plastic foam molding is generally not readily controllable. Due to this lack of control, defects in the metal castings resulting from the escaping gas generated by the vaporized foam cannot be easily eliminated. It is thus apparent there is a great need for a method whereby the heat resistance and pyrolysis rate of a plastic foam molding can be adjusted as desired in response to the particular requirements of an evaporative pattern casting process.

Method of controlling the pyrolysis rate of a plastic foam