WO2000002601A2 - Solution analgesique efficace - Google Patents

Solution analgesique efficace Download PDF

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Publication number
WO2000002601A2
WO2000002601A2 PCT/US1999/015409 US9915409W WO0002601A2 WO 2000002601 A2 WO2000002601 A2 WO 2000002601A2 US 9915409 W US9915409 W US 9915409W WO 0002601 A2 WO0002601 A2 WO 0002601A2
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WO
WIPO (PCT)
Prior art keywords
delivery system
transdermal delivery
penetration enhancer
collagen
molecular weight
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PCT/US1999/015409
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English (en)
Other versions
WO2000002601A3 (fr
Inventor
Frederick L. Jordan
Original Assignee
Oryxe
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oryxe filed Critical Oryxe
Priority to AU50931/99A priority Critical patent/AU5093199A/en
Publication of WO2000002601A2 publication Critical patent/WO2000002601A2/fr
Publication of WO2000002601A3 publication Critical patent/WO2000002601A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • 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).
  • CE cornified envelope
  • 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 "penetration enhancers" or “skin enhancers”.
  • transdermal delivery systems are provided that can be used to administer pharmaceuticals and cosmetic agents of various molecular weights.
  • 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
  • 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.
  • NSAID non-steroidal anti-inflammatory drug
  • 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.
  • a transdermal delivery system 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.
  • 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.
  • inventions 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.
  • the transdermal delivery systems described above have delivery agents that are molecules having a molecular weight of less than 6,000 daltons.
  • 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.
  • 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.
  • 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.
  • the therapeutically effective amount of capsaicin is by weight or volume 0.01 % to 5.0% capsaicin or 1.0% to 13% oleoresin capsicum.
  • the transdermal delivery system further includes by weight or volume 0.1 % to 10% Boswellin.
  • 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.
  • 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.
  • 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.
  • compositions that have high molecular weight delivery agents (e.g., collagens) and methods of use of such compositions are embodiments of the invention.
  • 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.
  • the collagen has a molecular weight less than 6,000 daltons or greater than 6,000 daltons.
  • 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
  • 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%.
  • an apparatus having a vessel joined to an applicator that houses the transdermal delivery system is also an embodiment and preferred applicators includea roll-on or a sprayer.
  • 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.
  • a method of making a transdermal delivery system can involve providing an ethoxylated oil, mixing the ethoxylated oil with an alcohol, nonionic solubilizer, or e uisifier 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 Liliaeacae family; and mixing the penetration enhancer and aqueous adjuvant with a delivery agent and thereby making the transdermal delivery system.
  • the delivery agent is selected from the group consisting of capsaicin, Boswellin, non steroidal anti-inflammatory drug, and collagen.
  • the delivery agent has a molecular weight greater than 6,000 daltons.
  • 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.
  • transdermal delivery systems that can administer an effective amount of a pharmaceutical or cosmetic agent to the human body.
  • 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).
  • NSAID non-steroidal anti-inflammatory drug
  • Another embodiment concerns a transdermal delivery system having a novel pain-relief solution (e.g., a formulation comprising capsaicin or
  • a transdermal delivery system that can administer a collagen preparation (e.g., soluble collagens, h ⁇ drolyzed collagens, and plant collagens).
  • a collagen preparation e.g., soluble collagens, h ⁇ drolyzed collagens, and plant collagens.
  • 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 "delivery agent".
  • 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 "delivery agents".
  • 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.
  • 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 "hydrophobic component” 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 "hydrophilic component” can be, for example, an alcohol, a nonio ⁇ ic 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 pharamceutical grade or absolute alcohols with the exception of methanol.
  • DMSO dimethyl sulfoxide
  • DMPX dimethyl polysiloxane
  • oleic acid caprylic acid
  • isopropyl alcohol 1-octanol
  • ethanol denatured or anhydrous
  • other pharamceutical grade or absolute alcohols with the exception of methanol.
  • Embodiments of the invention can also comprise a third component termed an "aqueous adjuvant".
  • Aqueous adjuvants include, but are not limited to, water (distilled, deionized, filtered, or otherwise prepared), Aloe Vera juice, and other plant extracts.
  • 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.
  • ethoxylated oil e.g., castor oil, glycerol, corn oil, jojoba oil, or emu oil
  • 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
  • compositions using extracts of plants of the Liliaciae family provide superior benefits in transdermal delivery of high molecular weight delivery agents, including collagen having an average molecular weight greater than 6,000 daltons.
  • an embodiment of the invention is prepared by mixing a hydrophilic component with a hydrophobic component and an aqueous adjuvant.
  • the delivery agent can be solubilized in either the hydrophobic, hydrophilic, or aqueous adjuvant components prior to mixing.
  • heat can be applied to help coalesce the mixture. Desirably, the temperature is not raised above 40°C.
  • transdermal delivery system Several formulations of transdermal delivery system are within the scope of aspects of the invention.
  • One formulation comprises a ratio of hydrophilic component:h ⁇ drophobic 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.
  • 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.
  • 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.
  • a method of reducing wrinkles and increasing skin tightness and flexibility is provided.
  • 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.
  • 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.
  • 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.
  • 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,
  • a low molecular weight compound e.g., a pain relieving substance or mixture of pain relieving substances
  • 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.
  • NSAIDs non- steroidal anti-inflammatory drugs
  • ibuprofen (2- (isobutylphenyl)-propionic acid); methotrexate (N-[4-(2, 4 diamino 6 - pteridinyl - methyl] methylamino] benzoyU-L- glutamic acid); aspirin (acetylsalicylic acid); salicylic acid; diphenhydramine (2-(diphenylmethoxy)-NN- dimethylethylamine hydrochloride); naproxen (2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (-)); phenylbutazone (4-butyl-1 ,2-diphenyl-3,5-pyrazolidinedione); sulindac-(2)-5-f uoro-2-methyI- 1 -[[p-
  • 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.
  • NSAIDs Several studies have determined an appropriate dose of an NSAID for a given treatment or condition. (See e.g., Woodin, /?/!, 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.
  • 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.
  • 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.
  • desirable embodiments include a delivery system that can administer a pain relieving mixture comprising capsaicin (e.g., oleoresin capsicum) or Boswellin or both.
  • capsaicin e.g., oleoresin capsicum
  • Boswellin a pain relieving mixture
  • Capsaicin (8-methyl-N-vanillyl-6-nonenamide), the pungent component of paprika and peppers, is a potent analgesic.
  • Capsaicin produces a level of analgesia comparable to morphine, yet it is not antagonized by classical narcotic antagonists such as naloxone.
  • capsaicin effectively prevents the development of cutaneous hyperalgesia, but appears to have minimal effects on normal pain responses at moderate 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.
  • capsaicin used in several desirable embodiments is oleoresin capsicum.
  • Oleoresin capsicum contains primarily capsaicin, dih ⁇ drocapsaicin, nordihydrocapsaicin, homocapsaicin, and homodihydrocapsaicin.
  • capsaicin collectivelly 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. TABLE 2
  • the delivery systems of the invention having capsaicin desirably comprise by weight or volume 0.01 % to
  • the delivery systems of the invention having capsaicin can comprise by weight or volume less than or equal to 0.01 %, 0.01 %, 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%,
  • 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%.
  • 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%,
  • Boswellin also known as Frankincense
  • Boswellin is an herbal extract of a tree of the Boswellia family.
  • Boswellin can be obtained, for example, from Boswellia thurifera, Boswellia carter/, ' Boswellia sacra, and Boswellia serrata.
  • Some suppliers also provide creams and pills having Boswellin with and without capsaicin and other ingredients.
  • Embodiments of the invention comprise Boswellin and the term "Boswellin” 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.
  • 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%,
  • 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.
  • 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.
  • the amount of NSAID that can be used can be an amount recommended in the literature (See e.g., Woodin, RN, August: 26-33 (1993) and Amadio, et al., Postgrduate Medicine, 93(4):73-97 (1993)), or an amount listed in Table 1.
  • 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%,
  • 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%, 3.5%, 3.0%, 3.1 %, 3.15%, 3.2%
  • Hepsyls 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 9BU629 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.
  • a transdermal. delivery system that can administer a medium molecular weight compound (e.g., a form of Hepsyl) to cells of the body.
  • a medium molecular weight compound e.g., a form of Hepsyl
  • 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.
  • 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.
  • glycoproteins are found in the body.
  • glycoproteins are glycoproteins
  • the substances that fill the intercellular spaces e.g., extracellular matrix proteins
  • glycoproteins the substances that fill the intercellular spaces
  • 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).
  • a transdermal delivery system that can administer a high molecular weight compound (e.g., a form of collagen) to cells of the body.
  • a high molecular weight compound e.g., a form of collagen
  • 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.
  • 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,
  • the commercially available collagen "Hydrocoll EN-55" 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.
  • the commercially available collagen "Solu-Coll” 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 "Plantsol”, 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%,
  • delivery systems of the invention having Plantsol can comprise by weight or volume less than or equal to 0.1 %,
  • 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.
  • 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%,.
  • 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.
  • 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%
  • a penetration enhancer included in many embodiments of the invention is comprised of two components -- a hydrophobic component and a hydrophilic component.
  • 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.
  • ethoxylated oils can be obtained or created from, for example, castor oil, jojoba oil, corn oil, and emu oil.
  • the ethoxylated compound comprises at least 20-25 ethoxylations per molecule and preferably the ethoxylated compound comprises at least 30-35 ethoxylations per molecule.
  • 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.
  • 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.
  • another hydrophobic compound e.g., Y-Ling-Y-Lang oil; Young Living Essential Oils, Lehl, Utah
  • 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%,.
  • the hydrophilic component of the penetration enhancers of the invention desirably comprise an alcohol, a non-ionic solubilizer, or an emulsifier.
  • an alcohol e.g., absolute isopropyl alcohol
  • DMSO dimethyl sulfoxide
  • DMPX dimethyl polysiloxane
  • 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%,
  • desirable transdermal delivery devices comprise a third component -- an aqueous adjuvant.
  • an aqueous adjuvant 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.
  • Aloe 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. WB Saunders, Philadelphia (1992)). Over 300 species of Aloe are known, most of which are indigenous to Africa.
  • 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, ⁇ -estradiol, and testosterone propionate. (Davis, et al, JAPMA 81:1 (1991) and U.S. Pat. No. 5,708,038 to Davis)).
  • 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,
  • 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.
  • 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.
  • 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%,.
  • 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.
  • an embodiment of the invention is prepared by combining a penetration enhancer with an aqueous adjuvant and a delivery agent.
  • the delivery agent can be solubilized in either the hydrophobic or hydrophilic components of the penetration enhancer.
  • some delivery agents can be solubilized in the aqueous adjuvant prior to mixing with the penetration enhancer.
  • the pH of the mixture is maintained between 3 and 11 and preferably between 5 and 9.
  • 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 1 1.0.
  • 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.
  • 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 40°C so that labile aqueous adjuvants or labile delivery agents are not degraded.
  • 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.
  • 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.
  • 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.
  • 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 trasndermal delivery system.
  • 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 1.5mls of a
  • 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.
  • Hepsyl CGA 1501 K., 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, nomonic solubilizers.or emulsifiers (e.g., isopropyl. alcohol, DMSO, etc.), and 0-50 mL of aqueous adjuvant (e.g., water, Aloe Vera extract, etc.).
  • hydrophobic penetration enhancers e.g., ethoxylated castor oil, jojoba oil, etc.
  • aqueous adjuvant
  • 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 L of Aloe Vera extract.
  • other delivery agents can incorporated into a transdermal delivery system.
  • Formulations of trannsdermal delivery systems having collagens are described in Example 2.
  • 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.
  • delivery agents such as NSAIDs, capsaicin, and Boswellin interfere and/or inhibit cyclooxygenase enzymes (COX 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.
  • 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).
  • a COX enzyme inhibitor e.g., a subject suffering from cancer or Alzheimer's disease
  • a transdermal delivery system comprising a delivery agent that inhibits a COX enzyme (e.g., NSAIDS, capsaicin, Boswellin, or any combination thereof).
  • 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.
  • restoring skin tone an approach to reduce wrinkles and increase skin tightness and flexibility (collectively referred to as "restoring skin tone”) is provided.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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 foccused application.
  • a device that facilitates a foccused 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.
  • a transdermal delivery system of the invention can administer a therapeutically effective amount of a low molecular weight delivery agent (e.g., 0.225% oleoresin capsicum).
  • a transdermal delivery system of the invention comprising 0.225% capsaicin (“EPRS") as compared to a commercially available cream comprising Boswellin, 10% methyl salicylate, and 0.25% capsaicin. (Nature's Herbs).
  • the two pain relief preparations were tested on six subjects who suffer from degenerative arthritis, debilitating back pain, and/ or bursitis. For the first five days of the study, the subjects applied the commercially available cream three times a day.
  • the cream was reported to irritate the skin, have a noxious smell, and provide little decrease in pain or increase in flexibility or range of motion.
  • the five day use of EPRS was reported to provide significant pain relief, relative to the relief obtained from the oral consumption of NSAIDs.
  • EPRS was reported to increase flexibility and range of motion within five to twenty minutes after application. Additionally, EPRS did not present a significant odor nor did it cause skin irritation.
  • the results of this study demonstrate that a delivery system comprising a low molecular weight compound, capsaicin, can effectively administer the delivery agent to cells of the body where it provides therapeutic benefit.
  • a transdermal delivery system of the invention can administer a therapeutically effective amount of a low and high molecular weight delivery agent (e.g., a low and high molecular weight collagen).
  • a transdermal delivery system of the invention can administer a therapeutically effective amount of a low and high molecular weight delivery agent (e.g., a low and high molecular weight collagen).
  • a clinical study was performed to evaluate the effectiveness of several transdermal delivery systems of the invention comprising various penetration enhancers, aqueous adjuvents, and collagen delivery agents.
  • the various transdermal delivery systems that were evaluated are provided in Table 3.
  • Table 3 Of the formulations that were originally screened, three were extensively evaluated by ten subjects (three men and seven women) in a single blind study. The formulations analyzed in the single blind study are indicated in Table 3 by a dagger. That is, the three different formulations ("P1 ", "P2", and "F4") were evaluated.
  • the P1 formulation comprised approximately 0.73% to 1.46% Solu-Coll, a soluble collagen having a molecular weight of 300,000 daltons.
  • the P2 formulation comprised approximately 1.43% to 2.86% Plantsol, a plant collagen obtained from yeast having a molecular weight of 500,000 daltons.
  • the F4 formulation comprised approximately 11.0% of HydroColl EN-55, a hydrolyzed collagen having a molecular weight of 2,000 daltons.
  • the evaluation of the P1, P2, and F4 formulations was as follows. Left, right, and center mug-shot photographs were taken with a Pentax camera having a zoom 60X lens and Kodak-Gold 100 film before beginning the study. Shortly after, each subject was given a bottle having a formulation of transdermal delivery system and was instructed to apply the solution to the right side of the face and neck, leaving the left side untreated, twice daily for 15 days. The F4 formulation was tested first and the application was carried out after showering or washing and before application of any other product to the treated area of the face.
  • a score (e.g., a numerical value that represents effectiveness) on characteristics of the transdermal delivery system formulation. Characteristics that were evaluated included tackiness, odor, marketability, and overall effectiveness of the formulation, as well as, whether the formulation tightened the skin, decreased lines, conditioned or softened the skin, and had any negative side-effects.
  • the scale for the scoring was 1-10, with 1 being the worst rating and 10 being the best rating. Following the test of F4, the evaluation detailed above was conducted on the P1 formulation.
  • Plantsol - Yeast extract collagen (Brooks Industries Inc., Code No. 06485)
  • Skin barrier function can be analyzed by examining the diffusion of fluorescent and colored proteins and dextra ⁇ s of various molecular weights ("markers") across the skin of nude mice or swine. Swine skin is preferred for many studies because it is inexpensive, can be maintained at -20°C, and responds similarly to human skin. Prior to use, frozen swine skin is thawed, hair is removed, and subcutaneous adipose tissue is dissected away. Preferably, a thickness of skin that resembles the thickness of human skin is obtained (e.g., several millimeters) so as to prepare a membrane that accurately reflects the thickness of the barrier layer. A dermatome can be pushed across the surface of the skin so as to remove any residual dermis and prepare a skin preparation that accurately reflects human skin.
  • markers various molecular weights
  • Elevation of temperature can also be used to loosen the bond between the dermis and the epidermis of hairless skin. Accordingly, the excised skin is placed on a hot plate or in heated water for 2 minutes at a temperature of approximately 50°C - 60°C and the dermis is removed by blunt dissection. Chemical approaches (e.g., 2M salt solutions) have also been used to separate the dermis from the epidermis of young rodents. Many different buffers or receptor fluids can be used to study the transdermal delivery of delivery agents across excised skin prepared as described above.
  • the buffer is isotonic, for example a normal saline solution or an isotonic buffered solution.
  • More physiological buffers which contain reagents that can be metabolized by the skin, can also be used.
  • reagents that can be metabolized by the skin can also be used.
  • Collier et al. Toxicol. Appl. Pharmacol. 99:522-533 (1989)
  • markers with molecular weight from 1,000 daltons to 2,000,000 daltons are commercially available and can be used to analyze the transdermal delivery systems of the invention.
  • FITC conjugated protein markers having a wide range of molecular weights (6,500 to 205,000 daltons) and FITC conjugated protein markers (e.g., FITC conjugated markers from 6,500 to 205,000 daltons) are available from Sigma (C3437, M0163, G7279, A2065, A2190, C1311, T9416, L8151, and A2315). Further, high molecular weight FITC conjugated dextrans (e.g., 250,000, 500,000, and 2,000,000 daltons) are obtainable from Sigma. (FD250S, FD500S, and FD2000S).
  • swine skin preparations obtained as described above, are treated with a delivery system lacking a delivery agent and control swine skin preparations are treated with water. Subsequently, the skin is contacted with a 1mM solution of a marker with a known molecular weight suspended in Ringer's solution
  • the skin is frozen and sliced at a thickness of 5 ⁇ m.
  • the sections are counter stained with 5 ⁇ g/ml propidium iodide and, if the marker is FITC conjugated, the sections are analyzed by fluoresence microscopy. If the marker is a colored marker, diffusion of the marker can be determined by light microscope. The marker will be retained in the upper layers of the stratum corneum in the untreated mice but the delivery system treated mice will be found to have the dye distributed throughout the stratum corneum and any dermal layer that remains.
  • modifications of the experiments described above can be performed by using a delivery system comprising various molecular weight markers. Accordingly, skin preparations are treated with the delivery system comprising one or more markers and control skin preparations are treated with water. After one hour, the skin is frozen and sliced at a thickness of 5 ⁇ m. The sections can be counter stained with 5 ⁇ g/ml propidium iodide and can be analyzed by fluoresence microscopy (e.g., when a fluorescent marker is used) or alternatively, the sections are analyzed under a light microscope. The various markers will be retained in the upper layers of the stratum corneum in the untreated mice but the delivery system treated mice will be found to have the marker distributed throughout the stratum corneum and any dermal layer that remains.
  • the transdermal water loss (TEWL) of penetration enhancer-treated skin preparations can be compared to that of untreated skin preparations. Accordingly, skin preparations are obtained, as described above, and are treated with a delivery system of the invention lacking a delivery agent (e.g., a penetration enhancer). Control skin preparations are untreated.
  • a delivery system of the invention lacking a delivery agent (e.g., a penetration enhancer).
  • Control skin preparations are untreated.
  • an evaporimeter is used to analyze the skin preparation.
  • the Courage and Khazaka Tewameter TM210 an open chamber system with two humidity and temperature sensors, can be used to measure the water evaporation gradient at the surface of the skin. The parameters for calibrating the instrument and use of the instrument is described in Barel and Clarys Skin Pharmacol. 8: 186-195 (1995) and the manufacturer's instructions.
  • TEWL will be low.
  • TEWL in penetration enhancer-treated skin preparations will be significantly greater.
  • skin barrier function can be analyzed by examining the percutaneous absorption of labeled markers (e.g., radiolabeled, fluorescentl ⁇ labeled, or colored) across skin preparations in a diffusion chamber.
  • labeled markers e.g., radiolabeled, fluorescentl ⁇ labeled, or colored
  • Delivery systems of the invention having various molecular weight markers, for example, the proteins and dextrans described above, are administered to swine skin preparations. Swine skin preparations are mounted in side-by-side diffusion chambers and are allowed to stabilize at 37°C with various formulations of penetration enhancer.
  • Donor and receiver fluid volumes are 1.5ml. After 1 hour of incubation, a labeled marker is added to the epidermal donor fluid to yield a final concentration that reflects an amount that would be applied to the skin in an embodiment of the invention.
  • transdermal delivery systems can be evaluated for their ability to transport low and high molecular weight delivery agents across the skin.

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Abstract

La présente invention se rapporte à la découverte d'un système de diffusion transdermique pouvant véhiculer des produits pharmaceutiques de poids moléculaire élevé et des produits cosmétiques dans les cellules cutanées. On décrit un nouveau système de diffusion transdermique pouvant être utilisé à des fins thérapeutiques ou d'application de produits cosmétiques, et des procédés d'utilisation desdits éléments.
PCT/US1999/015409 1998-07-08 1999-07-08 Solution analgesique efficace WO2000002601A2 (fr)

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US5614212A (en) * 1992-04-08 1997-03-25 International Medical Associates, Inc. Method of transdermally administering high molecular weight drugs with a polymer skin enhancer
US5318960A (en) * 1992-06-03 1994-06-07 Frank Toppo System for transdermal delivery of pain relieving substances

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7220427B2 (en) 1998-07-08 2007-05-22 Oryxe Mixture for transdermal delivery of low and high molecular weight compounds
WO2000067798A2 (fr) * 1999-05-05 2000-11-16 Elan Corporation Plc Apport ameliore de medicaments a base d'acide nucleique
WO2000067798A3 (fr) * 1999-05-05 2001-02-08 Elan Corp Plc Apport ameliore de medicaments a base d'acide nucleique
DE10056009A1 (de) * 2000-11-11 2002-05-16 Beiersdorf Ag Hautfreundliches Wirkstoffpflaster zur transdermalen Verabreichung hyperämisierender Wirkstoffe
WO2005049026A1 (fr) * 2003-11-19 2005-06-02 Acrux Dds Pty Ltd Methode et composition permettant de traiter ou de prevenir l'amylose
US11260018B2 (en) 2015-09-17 2022-03-01 Jrx Biotechnology, Inc. Approaches for improving skin hydration and moisturization

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