WO2017135948A1 - Composition topique et système d'administration et son utilisation - Google Patents

Composition topique et système d'administration et son utilisation Download PDF

Info

Publication number
WO2017135948A1
WO2017135948A1 PCT/US2016/016517 US2016016517W WO2017135948A1 WO 2017135948 A1 WO2017135948 A1 WO 2017135948A1 US 2016016517 W US2016016517 W US 2016016517W WO 2017135948 A1 WO2017135948 A1 WO 2017135948A1
Authority
WO
WIPO (PCT)
Prior art keywords
skin
agent
hours
delivery system
therapeutic agent
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2016/016517
Other languages
English (en)
Inventor
Michael H. GREENSPAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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
Priority claimed from US15/014,988 external-priority patent/US10265283B2/en
Application filed by Individual filed Critical Individual
Priority to GB1814047.5A priority Critical patent/GB2564026B/en
Priority to CA3013567A priority patent/CA3013567C/fr
Publication of WO2017135948A1 publication Critical patent/WO2017135948A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/08—Ethers or acetals acyclic, e.g. paraformaldehyde
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances

Definitions

  • the described invention relates to topical formulations of a
  • compositions containing an active therapeutic agent or metabolite, and a delivery system for administering the same topically characterized in that the active(s) remain in the skin and penetration of the active(s) into the bloodstream is limited so as to reduce systemic side effects.
  • the skin is the largest organ in the body consisting of several layers and plays an important role in biologic homeostasis, and is comprised of the epidermis and the dermis.
  • the epidermis which is composed of several layers beginning with the stratum corneum, is the outermost layer of the skin, and the innermost skin layer is the deep dermis.
  • the skin has multiple functions, including thermal regulation, metabolic function (vitamin D metabolism), and immune functions.
  • FIG. 1 presents a diagram of skin anatomy.
  • the usual thickness of the skin is from 1 -2 mm, although there is considerable variation in different parts of the body.
  • the relative proportions of the epidermis and dermis also vary, and a thick skin is found in regions where there is a thickening of either or both layers.
  • the skin may be more than 5 mm thick, whereas on the eyelids it may be less than 0.5 mm.
  • the skin is thicker on the dorsal or extensor surfaces of the body than on the ventral or flexor surfaces; however, this is not the case for the hands and feet.
  • the skin of the palms and soles is thicker than on any dorsal surface except the intrascapular region.
  • the palms and soles have a
  • the epidermis provides the body's buffer zone against the environment. It provides protection from trauma, excludes toxins and microbial organisms, and provides a semi-permeable membrane, keeping vital body fluids within the protective envelope.
  • the epidermis has been divided into several layers, of which two represent the most significant ones physiologically.
  • the basal-cell layer, or germinative layer is of importance because it is the primary source of regenerative cells. In the process of wound healing, this is the area that undergoes mitosis in most instances.
  • the upper epidermis, including stratum and granular layer, is the other area of formation of the normal epidermal-barrier function.
  • Stratum corneum is an avascular, multilayer structure that functions as a barrier to the environment and prevents transepidermal water loss. Recent studies have shown that enzymatic activity is involved in the formation of an acid mantle in the stratum corneum. Together, the acid mantle and stratum corneum make the skin less permeable to water and other polar compounds, and indirectly protect the skin from invasion by microorganisms.
  • Normal surface skin pH is between 4 and 6.5 in healthy people; it varies according to area of skin on the body. This low pH forms an acid mantle that enhances the skin barrier function.
  • stratum corneum Other layers of the epidermis below the stratum corneum include the stratum lucidum, stratum granulosum, stratum germinativum, and stratum basale. Each contains living cells with specialized functions (FIG. 2). For example melanin, which is produced by melanocytes in the epidermis, is responsible for the color of the skin. Langerhans cells are involved in immune processing.
  • Dermal appendages which include hair follicles, sebaceous and sweat glands, fingernails, and toenails, originate in the epidermis and protrude into the dermis hair follicles and sebaceous and sweat glands contribute epithelial cells for rapid reepithelialization of wounds that do not penetrate through the dermis (termed partial-thickness wounds).
  • the sebaceous glands are responsible for secretions that lubricate the skin, keeping it soft and flexible. They are most numerous in the face and sparse in the palm of the hands and soles of the feet. Sweat gland secretions control skin pH to prevent dermal infections.
  • the sweat glands, dermal blood vessels, and small muscles in the skin control temperature on the surface of the body.
  • Nerve endings in the skin include receptors for pain, touch, heat, and cold. Loss of these nerve endings increases the risk for skin breakdown by decreasing the tolerance of the tissue to external forces.
  • the basement membrane both separates and connects the epidermis and dermis.
  • epidermal cells in the basement membrane divide, one cell remains, and the other migrates through the granular layer to the surface stratum corneum.
  • the cell dies and forms keratin. Dry keratin on the surface is called scale.
  • Hyperkeratosis thinened layers of keratin is found often on the heels and indicates loss of sebaceous gland and sweat gland functions if the patient is diabetic.
  • the basement membrane atrophies with aging; separation between the basement membrane and dermis is one cause for skin tears in the elderly.
  • the dermis or the true skin, is a vascular structure that supports and nourishes the epidermis. In addition, there are sensory nerve endings in the dermis that transmit signals regarding pain, pressure, heat, and cold.
  • the dermis is divided into two layers: the superficial dermis and the deep dermis.
  • the superficial dermis consists of extracellular matrix (collagen, elastin, and ground substances) and contains blood vessels, lymphatics, epithelial cells, connective tissue, muscle, fat, and nerve tissue.
  • the vascular supply of the dermis is responsible for nourishing the epidermis and regulating body temperature.
  • Fibroblasts are responsible for producing the collagen and elastin components of the skin that give it turgor. Fibronectin and hyaluronic acid are secreted by the fibroblasts. The structural integrity of the dermis plays a role in the normal function and youthful appearance of the skin.
  • the deep dermis is located over the subcutaneous fat; it contains larger networks of blood vessels and collagen fibers to provide tensile strength. It also consists of fibroelastic connective tissue, which is yellow and composed mainly of collagen. Fibroblasts are also present in this tissue layer. The well-vascularized dermis withstands pressure for longer periods of time than subcutaneous tissue or muscle. The collagen in the skin gives the skin its toughness. Dermal wounds, e.g., cracks or pustules, involve the epidermis, basal membrane, and dermis. Typically, dermal injuries heal rapidly.
  • Substances are applied to the skin to elicit one or more of four general effects: an effect on the skin surface, an effect within the stratum corneum; an effect requiring penetration into the epidermis and dermis; or a systemic effect resulting from delivery of sufficient amounts of a given substance through the epidermis and the dermis to the vasculature to produce therapeutic systemic concentrations.
  • an effect on the skin surface is formation of a film. Film formation may be protective (e.g., sunscreen) and/or occlusive (e.g., to provide a moisturizing effect by diminishing loss of moisture from the skin surface).
  • an effect within the stratum corneum is skin moisturization; which may involve the hydration of dry outer cells by surface films or the intercalation of water in the lipid-rich
  • stratum corneum also may serve as a reservoir phase or depot wherein topically applied substances accumulate due to partitioning into, or binding with, skin components.
  • Percutaneous absorption is the absorption of substances from outside the skin to positions beneath the skin, including into the blood stream.
  • the epidermis of human skin is highly relevant to absorption rates. Passage through the stratum corneum marks the rate-limiting step for percutaneous absorption.
  • the major steps involved in percutaneous absorption of, for example, a drug include the establishment of a concentration gradient, which provides a driving force for drug movement across the skin, the release of drug from the vehicle into the skin-partition coefficient and drug diffusion across the layers of the skin-diffusion coefficient.
  • the many factors that affect the rate of percutaneous absorption of a substance include, without limitation, the following: (i) Concentration. The more concentrated the substance, the greater the absorption rate, (ii) Size of skin surface area. The wider the contact area of the skin to which the substance is applied, the greater the absorption rate, (iii) Anatomical site of application. Skin varies in thickness in different areas of the body. A thicker and more intact stratum corneum decreases the rate of absorbency of a substance. The stratum corneum of the facial area is much thinner than, for example, the skin of the palms of the hands.
  • the facial skin's construction and the thinness of the stratum corneum provide an area of the body that is optimized for percutaneous absorption to allow delivery of active agents both locally and systemically through the body, (iv) Hydration. Hydration (meaning increasing the water content of the skin) causes the stratum corneum to swell which increases permeability, (v) Skin temperature. Increased skin
  • composition (vi) Composition.
  • the composition of the compound and of the vehicle also determines the absorbency of a substance.
  • the protein portion of the stratum corneum is most permeable to water soluble substances and the lipid portion of the stratum corneum is most permeable to lipid soluble
  • wound healing refers to the process by which the body repairs trauma to any of its tissues, especially those caused by physical means and with interruption of continuity.
  • wound healing agent refers to any substance that facilitates the wound healing process.
  • a wound-healing response often is described as having three distinct phases-injury, inflammation and repair.
  • the body responds to injury with an inflammatory response, which is crucial to maintaining the health and integrity of an organism. If however it goes awry, it can result in tissue destruction.
  • MMPs matrix metalloproteinases
  • MMP-2 gelatinase A, Type N collagenase
  • MMP-9 gelatinase B, Type IV collagenase
  • cleave type N collagens and gelatin two important constituents of the basement membrane.
  • MMP-2 and MMP-9 are upregulated, highlighting that tissue-destructive and regenerative processes are common in fibrotic conditions.
  • the activities of MMPs are controlled by several mechanisms including transcriptional regulation, proenzyme regulation, and specific tissue inhibitors of MMPs. The balance between MMPs and the various inhibitory mechanisms can regulate inflammation and determine the net amount of collagen deposited during the healing response.
  • chemokine gradients recruit inflammatory cells. Neutrophils, eosinophils, lymphocytes, and macrophages are observed at sites of acute injury with cell debris and areas of necrosis cleared by phagocytes.
  • Late-stage inflammation may serve an anti-fibrotic role and may be required for successful resolution of wound-healing responses.
  • a late-phase inflammatory profile rich in phagocytic macrophages assisting in fibroblast clearance, in addition to IL-10-secreting regulatory T cells, suppressing local chemokine production and TGF- ⁇ , may prevent excessive fibroblast activation.
  • PAMPs pathogen-associated molecular patterns
  • cytoplasmic proteins that have a variety of functions in regulation of inflammatory and apoptotic responses
  • Endogenous danger signals also can influence local innate cells and orchestrate the inflammatory cascade.
  • the closing phase of wound healing consists of an orchestrated cellular re-organization guided by a fibrin (a fibrous protein that is polymerized to form a "mesh” that forms a clot over a wound site)-rich scaffold formation, wound
  • Myofibroblast-derived collagens and smooth muscle actin form a provisional extracellular matrix, with macrophage, platelet, and fibroblast-derived fibronectin forming a fibrin scaffold. Collectively, these structures are commonly referred to as granulation tissues.
  • the provisional extracellular matrix consists of glycoproteins (such as PDGF), glycosaminoglycans (such as hyaluronic acid), proteoglycans and elastin.
  • glycoproteins such as PDGF
  • glycosaminoglycans such as hyaluronic acid
  • proteoglycans and elastin.
  • Growth factor and TGF-p-activated fibroblasts migrate along the extracellular matrix network and repair the wound. Within skin wounds, TGF- ⁇ also induces a contractile response, regulating the orientation of collagen fibers.
  • Fibroblast to myofibroblast differentiation as discussed above, also creates stress fibers and the neo-expression of a-SMA, both of which confer the high contractile activity within myofibroblasts.
  • MMPs matrix metalloproteinases
  • TIMPs metalloproteinases
  • collagens to collagenases vary throughout the response, shifting from pro-synthesis and increased collagen deposition towards a controlled balance, with no net increase in collagen. For successful wound healing, this balance often occurs when fibroblasts undergo apoptosis, inflammation begins to subside, and granulation tissue recedes, leaving a collagen-rich lesion. From skin studies, re-epithelialization of the wound site re-establishes the barrier function and allows encapsulated cellular re-organization.
  • TGF-a serum-derived transforming growth factor alpha
  • MMP-7 matrix metalloproteinase-7
  • Enteral routes of administration involve administration to any part of the gastrointestinal tract, typically via oral forms, e.g., pills, tablets, emulsions, and syrups, or via rectal forms, e.g., enemas, Murphy drips, and suppositories.
  • Parenteral routes of administration involve administration by some means other than oral or rectal, typically via injection. While such administration routes allow for accurate and consistent dosing, such routes necessarily yield systemic effects, e.g., vestibular symptoms, headache and general malaise, and gastrointestinal symptoms, which in certain circumstances are not desirable.
  • Topical routes of administration involve administration to a body surface, such as the skin, or mucous membranes. Many forms of topical
  • Topical administration involve applying a therapeutic agent directly to the skin; inhalable mediations, eye drops, and ear-drops also are considered topical administration forms.
  • topical administration generally provides a local effect
  • many topically administered drugs likewise can exhibit systemic effects, such as vestibular symptoms (e.g., vertigo, dizziness or blurred vision), headache and general malaise, gastro-intestinal symptoms, such as diarrhea, nausea, gas, cramps, dry nose and dry mouth.
  • Formulations for topical application can take the compositional form of a liquid, a semisolid dosage form (e.g., a paste, a cream, a lotion, a powder, an ointment or a gel) or a patch.
  • Topical patches which are available in multiple forms including single and multi-layer drug-in-adhesive forms, matrix forms, and reservoir forms, address several of the shortcomings of semisolid formulations, for example, reducing the need for repeated application, providing accurate, and controlled release of active agent, and reducing the likelihood of unintentional removal or transfer of drug or active agent via contact with objects or other persons, but have a finite size and shape. Because topical patches have a finite size and shape, the application area is determined by the dimensions of the patch rather than the dimensions of the affected site. Accordingly, it may be necessary to use a number of patches in order to cover a large affected site. Furthermore, topical patches typically lack sufficient flexibility to be effectively administered to joints or other areas of skin subject to significant stretching movements. Topical patches can also lead to user discomfort, particular in warmer climates, and can be aesthetically unpleasing, which can also lead to poor user compliance.
  • the described invention addresses and overcomes these shortcomings.
  • the described composition and method provides a safe and effective topical therapeutic drug delivery platform that can deliver drugs locally into the skin.
  • the described invention is effective to deliver the components of the pharmaceutical formulation into the skin, to keep them in the skin, and to reduce the potential of the active therapeutic agent or its metabolites to enter the bloodstream. Consequently, the active therapeutic agent executes its effective biological function locally at the tissue of interest once being released from the skin.
  • the described invention provides a topical delivery system comprising a pharmaceutical composition for application directly to a skin of a subject in need thereof comprising (a) a therapeutic amount of an active therapeutic agent to treat symptoms of a disease, disorder or condition; (b) chemical drivers comprising an amino benzoate local anesthetic, ethoxydiglycol and
  • methylsulfonylmethane wherein the chemical drivers are effective at acting synergistically to deliver the therapeutic agent and (c) a depot component that is effective to keep the active agent locally in the skin;to reduce distribution of the active agent to the blood stream; to encapsulate the pharmaceutical composition and to facilitate controlled or delayed type release of the active therapeutic agent.
  • the active therapeutic agent has a molecular weight below 500 Da.
  • the active therapeutic agent is selected from the group consisting of a steroidal or non-steroidal analgesic agent, a wound healing agent, an antihistamine and an anti-neoplastic agent.
  • the amino benzoate local anesthetic is selected from the group consisting of benzocaine, lidocaine, tetracaine or a combination thereof.
  • the pharmaceutical composition is in an administration form selected from the group consisting of a cream, gel, or a spray.
  • the topical delivery system further comprises a vasoconstrictor.
  • the vasoconstrictor is nonirritating when applied to skin.
  • the depot component is a liposome.
  • the liposome comprises a phosphatidyl choline, cholesterol, and a pharmaceutically acceptable salt of an active therapeutic agent and at least one anionic or cationic phospholipid.
  • the depot component comprises a polymer.
  • the depot component comprises a liposome and a polymer.
  • the depot component comprises a polymersome.
  • the described invention provides a method of delivering a pharmaceutical composition topically that is effective to reduce systemic side effects of the active agent comprising (a) applying a
  • the pharmaceutical composition comprises: (i) a chemical driver effective to penetrate the stratum corneum of skin containing an active therapeutic agent, wherein the active therapeutic agent is an amino benzoate local anesthetic; ethoxydiglycol and methylsulfonylmethane (MSM); and (ii) a depot component that is effective to keep the pharmaceutical composition in the skin and to minimize distribution systemically.
  • the active therapeutic agent has a molecular weight below 500 Da.
  • the active therapeutic agent does not get into the bloodstream.
  • the depot component of the composition is effective to facilitate controlled or delayed type release of the active therapeutic agent.
  • the depot component is a polymer.
  • the depot component is a liposome.
  • the liposome comprises a
  • the depot component comprises a liposome and a polymer. According to other embodiments, the depot component is a polymersome.
  • FIG. 1 presents a diagram of skin anatomy. Taken from Stedman's Medical Dictionary, 27th Ed., Lippincott, Williams & Wilkins, Baltimore, MD (2000), at 1647.
  • FIG. 2 depicts layers of the epidermis.
  • FIG. 3 shows the study schema for the Phase I Clinical Study for determining the uptake kinetics of NeuroMed 7TMpain relief cream composed of lidocaine HCI 4% w/w in base formula with dosing at 0 and 4 hours, and self- reported visual analog scale (VAS); and venous blood draws at 0 (baseline), 1 , 3, 5, 7, 9 and 1 1 hours.
  • VAS visual analog scale
  • FIG. 4 shows the percentage of pain reduction for the study subjects.
  • FIG. 5 shows the average pain reduction for the study subjects.
  • FIG. 6 shows the maximal pain reduction for the study subjects.
  • FIG. 7 shows the time of maximum pain relief for the study subjects. DETAILED DESCRIPTION OF THE INVENTION Glossary
  • active therapeutic agent refers to a drug, molecule, nucleic acid, protein, composition or other substance that provides a therapeutic effect.
  • active refers to the ingredient, component or constituent of the compositions of the described invention responsible for the intended therapeutic effect.
  • therapeutic agent and “active agent” are used interchangeably.
  • administer means to give or to apply.
  • administering includes in vivo administration, as well as administration directly to tissue ex vivo.
  • alginate as used herein is an anionic biopolymers produced by a variety of microorganisms and marine algae.
  • Alginate is a polysaccharide that comprises ⁇ -D-mannuronic acid units and a-L-guluronic acid units.
  • Some alginate polymers are block copolymers with blocks of the guluronic acid (or salt) units alternating with blocks of the mannuronic acid (or salt) units.
  • Some alginate molecules have single units of guluronic acid (or salt) alternating with single units of mannuronic acid (or salt). The ratio and distribution of the mannuronic and guluronic unit, along with the average molecular weight, affect the physical and chemical properties of the copolymer.
  • Alginate polymers have viscoelastic rheological properties and other properties that make it suitable for some medical applications. See Klock, G. et al., "Biocompatibility of mannuronic acid-rich alginates,” Biomaterials, Vol. 18, No. 10, 707-13 (1997).
  • analgesic refers to any member of a group of drugs used to provide relief from pain.
  • Analgesic agents act in various ways on the peripheral and central nervous systems, and are distinct from “anesthetic agents..
  • analog refers to a compound having a structure similar to another, but differing from it, for example, in one or more atoms, functional groups, or substructure.
  • anesthesia agent refers to an agent that reversibly produces a reduction or loss of sensation.
  • anionic lipid refers to a lipid which has a negative charge.
  • exemplary anionic lipids include, without limitation,
  • diacylglycerolhemisuccinates e.g. DOGS, DMGS, POGS, DPGS, DSGS;
  • diacylglycerolhemimalonates e.g. DOGM or DMGM
  • diacylglycerolhemiglutarates e.g. DOGG, DMGG
  • diacylglycerolhemiadipates e.g. DOGA, DMGA;
  • diacylglycerolhemicyclohexane-1 4-dicarboxylic acids, e.g. DO-cHA, DM-cHA; (2, 3- Diacyl-propyl) amino ⁇ -oxoalkanoic acids e.g. DOAS, DOAM, DOAG, DOAA, DMAS, DMAM, DMAG, DMAA; Diacyl-alkanoic acids, e.g. DOP, DOB, DOS, DOM, DOG, DOA, DMP, DOB, DMS, DMM, DMG, DMA; Chemicals and derivatives thereof, e.g.
  • fatty acids e.g. Oleic acid, Myristic Acid, Palmitic acid, Stearic acid, Nervonic Acid, Behenic Acid
  • the aforementioned lipids may be formed with or without cholesterol, or with a derivative of cholesterol (e.g., cholesterol sulfate).
  • a derivative of cholesterol e.g., cholesterol sulfate.
  • chemotherapeutic agent are used interchangeably to refer to an agent that inhibits growth, proliferation, and spread of a neoplasm.
  • antineoplastic agents include 5-fluorouracil, adriamycin, daunorubicin, cytarabine, vincristine, actinomycin D, mitomycin, bleomycin, acrarubicin, and combinations thereof.
  • the anti-neoplastic agent can be entrapped in a lysosome.
  • any such agent can be selected, provided the agent does not inhibit liposome formation.
  • antihistamine agent refers to any of various compounds that counteract histamine in the body and that are used for treating allergic reactions (such as hay fever) and cold symptoms.
  • antihistamines usable in context of the described invention include chlorpheniramine, brompheniramine, dexchlorpheniramine, tripolidine, clemastine, diphenhydramine, promethazine, piperazines, piperidines, astemizole, loratadine and terfenadine.
  • anti-inflammatory agent refers to a compound having a reactive oxygen species.
  • non-steroidal anti-inflammatory agent refers to a large group of agents that are aspirin-like in their action, including, but not limited to, ibuprofen (Advil®), naproxen sodium (Aleve®), and acetaminophen (Tylenol®).
  • non-steroidal anti-inflammatory agents include, without limitation, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic acid
  • anti-oxidant agent refers to a substance that inhibits oxidation or reactions promoted by oxygen or peroxides.
  • anti-oxidants include ascorbic acid (vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g., magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl sorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherol acetate, other esters of tocopherol, butylated hydroxy benzoic acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commercially available under the tradename TroloxR), gallic acid and its alkyl esters, especially propyl gallate, uric acid and its salts and alkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g., ⁇ ,
  • anti-static refers to a compound used to treat materials or their surfaces in order to reduce or eliminate buildup of static electricity.
  • arabinose refers to a wood sugar extracted from the Western Larch tree (also known as larch gum).
  • Arabinogalactans are complex, highly branched polymers of arabinose and galactose in the ratio of from about 1 :3 to about 1 :10, i.e., 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9 or 1 :10.
  • Laracare®200 from Lonza, Inc.
  • Bactericide refers to a substance that kills bacteria. Bactericides may be disinfectants, antiseptics, antibiotics, etc.
  • bio-distribution refers to a method of tracking where drugs, active therapeutic agents, compounds of interest etc. travel in the subject in need thereof.
  • buffer refers to an aqueous solution consisting of a mixture of a weak acid and its conjugate base, or vice versa. The pH changes very little when a small or moderate amount of strong acid or base is added to it, and thus it is used to prevent changes in the pH of a solution.
  • carrier as used herein describes a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the compound of the composition of the described invention. Carriers must be of sufficiently high purity and of sufficiently low toxicity to render them suitable for administration to the mammal being treated.
  • the carrier can be inert, or it can possess pharmaceutical benefits.
  • excipient “carrier”, or “vehicle” are used interchangeably to refer to carrier materials suitable for formulation and administration of pharmaceutically acceptable compositions described herein.
  • cationic lipid refers to a lipid which has a positive charge.
  • exemplary cationic lipids include, without limitation, DOTAP, DMTAP, DPTAP, DSTAP, POTAP, DODAP, PODAP, DMDAP, DPDAP, DSDAP, DODMHEAP or DORI, PODMHEAP or PORI, DMDMHEAP or DMRI, DPDMHEAP or DPRI,
  • DSDMHEAP or DSRI DOMDHEAP, POMDHEAP, DMMDHEAP, DPMDHEAP, DSMDHEAP, DOMHEAP, POMHEAP, DMMHEAP, DPMHEAP, DSMHEAP, DODHEAP, PODHEAP, DMDHEAP, DPDHEAP, DSDHEAP, DDAB, DODAC, DOEPC, DMEPC, DPEPC, DSEPC, POEPC, DORIE, DMRIE, DOMCAP,
  • the term "chemical driver” as used herein refers to a component or components of the formulation of the described invention that provides the driving force for a drug to diffuse from the vehicle, into and through the stratum corneum of the skin. According to some embodiments, the chemical drivers of the described invention synergistically cooperate to deliver the therapeutic agent.
  • the term "cholesterol” as used herein refers to a monohydric secondary alcohol of the cyclopentenophenantrene (4-ring fused) system containing one double bond. According to some embodiments, cholesterol is a liposome component.
  • colorant refers to a substance used to impart a color on a composition to improve the attractiveness of the composition and/or to enable easy product identification.
  • Non-limiting examples of colorants include oil- soluble dyes, oil dispersible dyes, water-soluble dyes, e.g. acid blue 3, acid blue 104, acid green 1 , acid green 25, acid yellow 3, acid yellow 73 sodium salt, D&C green No. 5, 6, & 8, D&C yellow No. 7, 8, 10, & 1 1 , D&C violet No. 2, FD&C blue No. 1 & 2, FD&C green No. 3, FD&C yellow No. 5 & 6, and mixtures thereof.
  • components of a composition whereby the components are capable of being combined with each other in a manner such that there is no interaction that would substantially reduce the efficacy of the composition under ordinary use conditions.
  • component refers to a constituent part, element or ingredient.
  • composition and “formulation” are used interchangeably herein to refer to a product of the described invention that comprises all active and inert ingredients.
  • condition refers to a variety of health states and is meant to include disorders or diseases caused by any underlying mechanism or disorder, injury, and the promotion of healthy tissues and organs.
  • sequence refers to an effect, result or outcome of something that occurred earlier.
  • controlled release refers to a drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This includes immediate as well as non-immediate release formulations, with non-immediate release formulations including, but not limited to, sustained release and delayed release formulations.
  • sustained release also referred to as "extended release” is used herein in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may result in substantially constant levels of a drug over an extended time period.
  • delayed release is used herein in its conventional sense to refer to a drug formulation in which there is a time delay between
  • “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”
  • the term "long-term” release means that the drug formulation is constructed and arranged to deliver therapeutic levels of the active ingredient for at least: 2 hours, 3 hours, 4 hours, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 1 1 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58
  • copolymer refers to a polymer derived from more than one species of monomer.
  • polymer refers to a large molecule, or macromolecule, composed of many repeated subunits.
  • monomer refers to a molecule that may bind chemically to other molecules to form a polymer.
  • derivative means a compound that may be produced from another compound of similar structure in one or more steps. A derivative of a compound retains at least a degree of the desired function of the compound. Accordingly, an alternate term for “derivative” may be "functional derivative.” Derivatives can include chemical modifications, such as alkylation, acylation, carbamylation, iodination or any modification that derivatizes the
  • Such derivatized molecules include, for example, those molecules in which free amino groups have been derivatized to form amine hydrochlorides, p- toluene sulfonyl groups, carbobenzoxy groups, t-butyloxycarbonyl groups,
  • Free carboxyl groups can be derivatized to form salts, esters, amides, or hydrazides.
  • Free hydroxyl groups can be derivatized to form O-acyl or O-alkyl derivatives. See, e.g., Methods and Analytical Procedures, Elsevier Biomedical Press, New York (1975).
  • disease or “disorder” as used herein refers to an impairment of health or a condition of abnormal functioning.
  • drug refers to a substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or disorder, or to affect the structure or function of the body.
  • an effective therapeutic amount an “amount effective”, or “pharmaceutically effective amount” of one or more of the active agents is used interchangeably to refer to an amount that is sufficient to provide the intended benefit of treatment.
  • An effective amount of an active agent that can be employed according to the described invention generally ranges from about 0.01 mg/kg body weight to about 100 g/kg body weight.
  • dosage levels are based on a variety of factors, including the type of injury, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular active agent employed. Thus the dosage regimen may vary widely, but can be determined routinely by a physician using standard methods.
  • emollient or “moisturizer” as used herein are used interchangeably to refer to complex mixtures of chemical agents specially designed to make the external layers of the skin (epidermis) softer and more pliable.
  • An emollient increases the skin's hydration (water content) by reducing evaporation.
  • emulsifier refers to an additive that help two liquids mix. For example, water and oil separate in a glass, but adding an emulsifier will help the water and oil to mix together.
  • excipient refers to any inactive ingredient that is added to the composition of the described invention and that is not intended to exert therapeutic effects at the intended dosage, although it may act to improve product delivery. Additional characteristics of excipients can be found in the
  • locculant refers to a substance that promotes the clumping of particles.
  • fragrance refers to an aroma compound, also known as odorant, or flavorant, which is a chemical compound that has a smell or odor r when it is sufficiently volatile to be transported to the olfactory system in the upper part of the nose.
  • odorant also known as odorant, or flavorant
  • molecules meeting this specification will have molecular weights of ⁇ 300 g/mole.
  • Flavors affect both the sense of taste and smell, whereas fragrances affect only smell. Generally, flavors tend to be naturally occurring, while fragrances tend to be synthetic.
  • Aroma compounds can be found in food, wine, spices, perfumes, fragrance oils, and essential oils.
  • hydrogel refers to a network of polymer chains that are hydrophilic, sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are highly absorbent (they can contain over 90% water) natural or synthetic polymeric networks. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content.
  • hydrophilic refers to a material or substance having an affinity for polar substances, such as water.
  • impregnate as used herein in its various grammatical forms refers to causing to be infused or permeated throughout, or to fill interstices with a substance.
  • inflammation refers to a physiologic response to infection and injury in which cells involved in detoxification and repair are mobilized to the compromised site by inflammatory mediators.
  • acute inflammation refers to inflammation, usually of sudden onset, characterized by the classical signs, with predominance of the vascular and exudative processes.
  • chronic inflammation refers to inflammation of slow progress and marked chiefly by the formation of new
  • connective tissue it may be a continuation of an acute form or a prolonged low- grade form, and usually causes permanent tissue damage.
  • lipid refers to a group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins (e.g. vitamins A, D, E, and K), mono-di or triglycerides phospholipids, and others.
  • fat-soluble vitamins e.g. vitamins A, D, E, and K
  • mono-di or triglycerides phospholipids and others.
  • the main biological functions of lipids include storing energy, signaling, and acting as structural components of cell membranes.
  • Exemplary lipids include natural phospholipids (e.g., egg yolk lecithin (phosphatidyl choline), soybean lecithin, lysolecithin, sphingomyelin, phosphatidic acid, phosphatidyl serine, phosphatidyl glycerol, phosphatidyl inositol, phosphatidyl ethanol amine, diphosphatidyl glycerol, cardiolipin and plasmalogen); synthetic lipids (e.g., dicetyl phosphate, distearoyl phosphatidyl choline,
  • natural phospholipids e.g., egg yolk lecithin (phosphatidyl choline), soybean lecithin, lysolecithin, sphingomyelin, phosphatidic acid, phosphatidyl serine, phosphatidyl glycerol, phosphatidyl inositol, phosphatid
  • dioleoylphosphatidyl ethanol amine dipalmitoyl phosphatidyl choline, diphalmitoyl phosphatidyl ethanol amine, diphalmitoyl phosphatidyl serine, eleostearoyl phosphatidyl choline, eleostearoyl phosphatidyl ethanol amine and eleostearoyl phosphatidyl serine); hydrogenated products that may be obtained from the natural phospholipids or synthetic lipids; derivatives of the natural phospholipids or synthetic lipids; and fatty acid mixtures that may be obtained by hydrolysis of the natural phospholipids or synthetic lipids.
  • lipophilic refers to preferring or possessing an affinity for a non-polar environment compared to a polar or aqueous environment.
  • liposome refers to a man-made spherical vesicle containing at least one lipid bilayer.
  • the liposome can be used as a vehicle for administration of components, such as, but not limited to, pharmaceutical compositions and pharmaceutical formulations, active therapeutic agents, drugs, enzymes, other proteins and peptides, and DNA and RNA fragments, etc.
  • “Local anesthetic” as used herein also encompasses drugs not
  • non-narcotic analgesics such as, acetylsalicylic acid, ketoprofen, piroxicam, diclofenac, indomethacin, ketorolac, rofecoxib, and celecoxib, and pharmaceutically acceptable salts thereof, or mixtures thereof.
  • localized administration refers to administration of a therapeutic agent in a particular location in the body.
  • localized pharmacologic effect refers to a consequence of treatment or a therapeutic effect limited to a certain location, i.e. in proximity to a certain location, place, area or site.
  • predominantly localized pharmacologic effect refers to a therapeutic effect of a drug that is limited to a certain location by at least 1 to 3 orders of magnitude, which is achieved by a localized administration as compared to a systemic administration.
  • lubricant refers to a substance introduced to reduce friction between surfaces in mutual contact, which ultimately reduces the heat generated when the surfaces move. It may also have the function of transmitting forces, transporting foreign particles, or heating or cooling the surfaces.
  • matrix refers to a three dimensional network of fibers that contains voids (or "pores") where the fibers intersect.
  • the structural parameters of the pores including the pore size, porosity, pore
  • interconnectivity/tortuosity and surface area affect how substances (e.g., fluid, solutes) move in and out of the matrix.
  • maximum tolerated dose refers to the highest dose of a drug that does not produce unacceptable toxicity.
  • minimum effective concentration “minimum effective dose,” or “MEC” are used interchangeably to refer to the lowest concentration of a drug required to produce a desired pharmacological effect in most patients.
  • Neoplasms may be benign (not cancer) or malignant (cancer).
  • a benign neoplasm or benign tumor is a tumor that stops growing by itself, does not invade other tissues and does not form metastases
  • neutral lipid refers to a lipid which has neither a positive or negative charge.
  • exemplary neutral lipids include, without limitation, cholesterol, cholesterol esters, triglycerides and fatty acids.
  • non-cellulosic copolymer refers to a copolymer not containing or derived from cellulose.
  • cellulose refers to a natural carbohydrate high polymer (polysaccharide) consisting of anhydroglucose untis joined by an oxygen linkage to form long molecular chains that are essentially linear that can be hydrolyzed to glucose.
  • pain refers to a distressing feeling often caused by intense or damaging stimuli. As such, the term “pain” is characterized by an unpleasant sensory detected and signaled by the nerves and emotional experience associated with actual or potential tissue damage.
  • penetration enhancer and “permeation enhancer” are used interchangeably to refer to natural or synthetic molecules that facilitate the transport of co-administered active agents across biological membranes.
  • pharmaceutical composition is used herein to refer to a composition that is employed to prevent, reduce in intensity, cure or otherwise treat a target condition or disease.
  • salts refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof.
  • Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic.
  • such salts may be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
  • salts are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. For example, P. H. Stahl, et al. describe pharmaceutically acceptable salts in detail in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley VCH, Zurich, Switzerland: 2002).
  • the salts may be prepared in situ during the final isolation and purification of the compounds described within the described invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate,
  • benzenesulfonate bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • Basic addition salts may be prepared in situ during the final isolation and purification of compounds described within the invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • salts also may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal for example, sodium, potassium or lithium
  • alkaline earth metal for example calcium or magnesium
  • the phrase "pharmaceutically acceptable carrier” refers to any substantially non-toxic carrier useable for formulation and administration of the composition of the described invention in which the product of the described invention will remain stable and bioavailable.
  • the pharmaceutically acceptable carrier must be of sufficiently high purity and of sufficiently low toxicity to render it suitable for administration to the mammal being treated. It further should maintain the stability and bioavailability of an active agent.
  • the pharmaceutically acceptable carrier can be liquid or solid and is selected, with the planned manner of administration in mind, to provide for the desired bulk, consistency, etc., when combined with an active agent and other components of a given composition.
  • [001 1 1 ] The term "pharmacokinetics" as used herein describes how the body affects a specific drug after administration through the mechanisms of absorption and distribution, as well as the chemical changes of the substance in the body (e.g. by metabolic enzymes such as cytochrome P450 or glucuronosyltransferase enzymes), and the effects and routes of excretion of the metabolites of the drug.
  • metabolic enzymes such as cytochrome P450 or glucuronosyltransferase enzymes
  • plasticizer refers to an additive that increases the plasticity or fluidity of a material.
  • polyethylene glycol as used herein is used to refer to a condensation polymer of ethylene glycol with the general formula
  • Polyethylene glycols can be used as medicaments for topical application in the treatment of wounds, for the treatment of inflammatory skin disease, for the prevention of scar formation and/or for enhancing the repair of damaged skin or mucosa.
  • polymer refers to a molecule formed by the chemical union of two or more monomer or oligomer units.
  • the chemical units are normally linked together by covalent linkages.
  • the two or more combining units in a polymer can be all the same, in which case the polymer is referred to as a
  • the polymer can also be different and, thus, the polymer will be a
  • polymers are referred to as copolymers.
  • the relationship between the polymer subunits may be oriented head-to-head or head-to- tail relative to each subunit.
  • Polymers can be divided into two broad groups:
  • non-natural polymers include, but are not limited to polyalcohols such as ethylene vinyl alcohol (EVAL), hydroxyethyl acrylate, poly(ethylene glycol), polyvinyl alcohol), poly(hydroxypropyl methacrylamide), poly(propylene glycol); polyamines (such as polyvinylamine, polyallylamine, tetramethyleneamine, pentamethyleneamine, hexamethyleneamine, bis(2- hydroxyethyl)amine, bis(2-aminoethyl)amine, tris(2-aminoethyl)amine, branched or linear polyethyleneimine e.g., LubrasolsTM - and salts thereof, and derivatives of polyethyleneimine such as acylated polyethyleneimine); dendrimers (such as polyamidoamine (PAMAM) Starburst dendrimers); polyalkylene glycol derivatives (such as amine-substituted polyethylene and polypropylene glycols); polyacryl
  • EVAL
  • anionic biopolymers include carboxymethylcellulose and salts thereof, salts of carboxymethyl and carboxymethylhydroxyethyl starches, and other glucoaminoglycans such as chondroitin sulfate, dermatan sulfate, heparin and heparin sulfate and keratin sulfates.
  • Examples of natural polymers include, without limitation, hyaluronic acid, chondroitin sulfate, alginate, guar gum, fructan, arabinogalactan and any corresponding salt or derivative of thereof.
  • Hyaluronic acid is a linear polysaccharide (long-chain biological polymer) formed by repeating disaccharide units consisting of D-glucuronic acid and N-acetyl-D- glucosamine linked by ⁇ (1 -3) and ⁇ (1 -4) glycosidic linkages.
  • Hyaluronic acid is distinguished from other glycosaminoglycans in that is free from covalent links to protein and sulphonic groups.
  • Hyaluronic acid is ubiquitous in animals, with the highest concentration found in soft connective tissue.
  • hyaluronic acid that is, hard elastic under static conditions though less viscous under small shear forces, enables hyaluronic acid to basically function as a shock absorber for cells and tissues.
  • Hyaluronic acid also has a relatively large capacity to absorb and hold water. These properties of hyaluronic acid are dependent on the molecular weight, the solution concentration, and physiological pH. At low concentrations, the individual chains entangle and form a continuous network in solution, which gives the system pronounced viscoelasticity and pseudoplasticity that is unique for a water-soluble polymer at low concentration.
  • fructan refers to all oligosaccharides and polysaccharides that have a majority of anhydro fructose units and derivatives thereof.
  • the fructan can have a polydisperse chain length distribution and can be straight-chain or branched.
  • the fructans include primarily ⁇ -2,6 bonds as in levan, or ⁇ -2,1 bonds as in a carboxyl modified fructant, e.g., inulin.
  • Examples of synthetic polymers include, without limitation, polyethylene, polystyrene, polyester, polyvinyl chloride, polyamide, polypropylene, and nylon.
  • polymersome refers to a class of artificial vesicles, tiny hollow spheres that enclose a solution. Polymersomes are made using amphiphilic synthetic block copolymers to form the vesicle membrane, and have radii ranging from 50 nm to 5 ⁇ or more. Most reported polymersomes contain an aqueous solution in their core and are useful for encapsulating and protecting sensitive molecules, such as but not limited to pharmaceutical compositions and pharmaceutical formulations, active therapeutic agents, drugs, enzymes, other proteins and peptides, and DNA and RNA fragments, etc. The polymersome membrane provides a physical barrier that isolates the encapsulated material from external materials, such as those found in biological systems.
  • potency refers to efficacy, effectiveness, or strength of a drug.
  • the potency of a drug is the reciprocal of dose, and has the units of persons/unit weight of drug or body weight/unit weight of drug.
  • Relative potency compares the relative activity of drugs in a series relative to some prototypic member of the series.
  • Efficacy connotes the property of a drug to achieve the desired response, and maximum efficacy denotes the maximum achievable effect.
  • PVP polyvinylpyrrolidone
  • PVP polyvinylpyrrolidone
  • the viscosity of solutions containing 10% or less PVP is essentially the same as that of water; solutions more concentrated than 10% become more viscous, depending on the concentration and molecular weight of the polymer used.
  • preservative refers to a substance that is added to a product to prevent decomposition by microbial growth or by undesirable chemical changes.
  • the term “reduced” or “to reduce” as used herein refers to a diminution, a decrease, an attenuation or abatement of the degree, intensity, extent, size, amount, density or number.
  • release refers to dissolution of an active drug component and diffusion of the dissolved or solubilized species. According to some embodiments, this occurs by a combination of the following processes: (1 ) hydration of a matrix, (2) diffusion of a solution into the matrix; (3) dissolution of the drug; and (4) diffusion of the dissolved drug out of the matrix.
  • soluble and solubility refer to the property of being susceptible to being dissolved in a specified fluid (solvent).
  • insoluble refers to the property of a material that has minimal or limited solubility in a specified solvent.
  • a “suspension” is a dispersion (mixture) in which a finely-divided species is combined with another species, with the former being so finely divided and mixed that it doesn't rapidly settle out. In everyday life, the most common suspensions are those of solids in liquid.
  • solubility enhancer or “solubilizing agent” are used interchangeably to refer to any chemical and/or biological agent able to improve the solubility of an agent in a solvent.
  • exemplary solubility enhancers include povidone, cholesterol, cyclodextrins, and polyethylene glycols.
  • exemplary solubility enhancers also include surfactants, which act as solubilizing agents by forming micelles.
  • the HLB system is used to describe the characteristics of a surfactant. It is an arbitrary scale to which HLB values are experimentally determined and assigned. If the HLB value is low, the number of hydrophilic groups on the surfactant is small, which means it is more lipophilic (oil soluble) than hydrophilic (water soluble).
  • HLB value if the HLB value is high, there are a large number of hydrophilic groups on the surfactant, which makes it more hydrophilic (water soluble) than oil soluble.
  • An HLB value of 10 or higher means that the agent is primarily hydrophilic.
  • solvent refers to a substance capable of dissolving another substance (termed a "solute”) to form a uniformly dispersed mixture (solution).
  • stabilizer refers to a chemical which tends to inhibit the reaction between two or more other chemicals.
  • steroidal anti-inflammatory agent refers to any one of numerous compounds containing a 17-carbon 4-ring system and includes the sterols, various hormones (as anabolic steroids), and glycosides.
  • steroidal anti-inflammatory drugs include, without limitation, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha- methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide
  • prednisolone prednisone
  • beclomethasone dipropionate triamcinolone, and mixtures thereof.
  • subject or “individual” or “patient” are used interchangeably to refer to a member of an animal species of mammalian origin an animal species of mammalian origin, including but not limited to, mouse, rat, cat, goat, sheep, horse, hamster, ferret, pig, dog, platypus, guinea pig, rabbit and a primate, such as, for example, a monkey, ape, or human.
  • subject in need thereof refers to a subject that (i) will be administered a topical composition of the described invention; (ii) is applying the topical composition of the described invention; or (iii) has applied the topical composition of the described invention, unless the context and usage of the phrase indicates otherwise.
  • substantially amount of a substance in a composition is an amount which provides for a technical effect exhibited by the substance to a degree which provides for a technical effect in terms of the described invention.
  • a composition is indicated as comprising “substantially no” with respect to a substance, this means that the composition is allowed to include insignificant amounts of the substance, as long as these amounts do not have any technical impact on the other ingredients in the composition and does not in itself "make a difference” or put in other words, "substantially no” and “essentially no” means that e.g. trace amounts or effects may be present as long as they do not have an overall technical influence.
  • surfactant refers to a compound that lowers the surface tension (or interfacial tension) between two liquids or between a liquid and a solid.
  • systemic administration refers to administration of a therapeutic agent with a pharmacologic effect on the entire body.
  • Systemic administration includes enteral administration (e.g. oral) through the gastrointestinal tract and parenteral administration (e.g. intravenous, intramuscular, etc.) outside the gastrointestinal tract.
  • therapeutic amount is an amount that is sufficient to provide the intended benefit of treatment.
  • an effective prophylactic or therapeutic treatment regimen may be planned which does not cause substantial toxicity and yet is effective to treat the particular subject.
  • a maximum dose should be used, that is, the highest safe dose according to some medical judgment.
  • dosage levels are based on a variety of factors, including the type of injury, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular therapeutic agent employed. Thus the dosage regimen may vary widely, but can be determined routinely by a surgeon using standard methods. "Dose” and “dosage” are used interchangeably herein. Additionally, the terms “therapeutically effective amounts” and “pharmaceutically effective amounts” include prophylactic or preventative amounts of the compositions of the described invention.
  • compositions or medicaments are administered to a patient susceptible to, or otherwise at risk of, a disease, disorder or condition in an amount sufficient to eliminate or reduce the risk, lessen the severity, or delay the onset of the disease, disorder or condition, including biochemical, histologic and/or behavioral symptoms of the disease, disorder or condition, its complications, and intermediate pathological phenotypes presenting during development of the disease, disorder or condition.
  • Topical administration in contrast to transdermal administration, generally provides a local rather than a systemic effect.
  • therapeutic component refers to a therapeutically effective dosage (i.e., dose and frequency of administration) that eliminates, reduces, or prevents the progression of a particular disease
  • ED50 describes the dose in a particular dosage that is therapeutically effective for a particular disease manifestation in 50% of a population.
  • terapéutica effect refers to a consequence of treatment, the results of which are judged to be desirable and beneficial.
  • therapeutic effect may include, directly or indirectly, the arrest, reduction, or elimination of a disease manifestation.
  • a therapeutic effect may also include, directly or indirectly, the arrest reduction or elimination of the progression of a disease manifestation.
  • thickening agent refers to a substance that can increase the viscosity of a liquid without substantially changing its other properties.
  • the term "thinning agent” as used herein refers to a substance that reduces the viscosity of a liquid making it easier to apply.
  • topical refers to administration of a pharmaceutical composition at, or immediately beneath, the point of application.
  • topically “topically”, “topical administration” and “topically applying” are used interchangeably to refer to delivering a pharmaceutical composition of the described invention onto one or more surfaces of a tissue or cell, including epithelial surfaces.
  • composition may be applied by pouring, dropping, or spraying, if a liquid; rubbing on, if an ointment, lotion, cream, gel, or the like; dusting, if a powder; spraying, if a liquid or aerosol composition; or by any other appropriate means.
  • Topical administration generally provides a local rather than a systemic effect.
  • the term “treat” or “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a disease, condition or disorder, substantially ameliorating clinical or esthetical symptoms of a condition, substantially preventing the appearance of clinical or esthetical symptoms of a disease, condition, or disorder, and protecting from harmful or annoying symptoms.
  • the term “treat” or “treating” as used herein further refers to accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting development of symptoms characteristic of the disorder(s) being treated; (c) limiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting recurrence of the
  • vasoconstrictor is used to describe an active therapeutic agent that causes a narrowing of blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vessels.
  • vitamin refers to any of various organic substances essential in minute quantities to the nutrition of most animals act especially as coenzymes and precursors of coenzymes in the regulation of metabolic processes.
  • wetting agent refers to a substance that reduces the surface tension of water in order to allow it to spread drops onto a surface, thereby increasing the spreading abilities of a liquid.
  • wound healing agent refers to an agent that promotes an intricate process where the skin or other body tissue repairs itself after injury. In normal skin, the epidermis (surface layer) and dermis (deeper layer) form a protective barrier against the external environment. As such, the term “wound healing agent” refers to any substance that facilitates the wound healing process.
  • zwitterion is a neutral molecule with a positive and a negative electrical charge.
  • the described invention provides a topical delivery system comprising a pharmaceutical composition formulated for application directly to a skin of a subject in need thereof comprising (a) a therapeutic amount of an active therapeutic agent that is effective to treat symptoms of a disease, disorder or condition; (b) a chemical driver comprising an amino benzoate local anesthetic, ethoxydiglycol and methylsulfonylmethane (MSM), wherein the chemical drivers are effective to deliver the therapeutic agent to the skin; and (c) a depot component that is effective to keep the active agent locally in the skin and to reduce distribution of the active to the blood stream.
  • a pharmaceutical composition formulated for application directly to a skin of a subject in need thereof comprising (a) a therapeutic amount of an active therapeutic agent that is effective to treat symptoms of a disease, disorder or condition; (b) a chemical driver comprising an amino benzoate local anesthetic, ethoxydiglycol and methylsulfonylmethane (MSM), wherein the chemical drivers are effective to
  • the composition of the described invention contains a depot component that is effective for keeping the active agent concentrated locally in the skin.
  • the depot component is effective to facilitate controlled or delayed type release of the active therapeutic agent.
  • the depot component reduces the potential of the active agent, active metabolite, the chemical drivers, or a combination thereof to enter the bloodstream.
  • the chemical driver component that remains in the skin is effective to allow the active agent and/or the active metabolite to further diffuse away from the skin, such that the active agent can execute its biological function at the specific tissue of interest.
  • the depot component comprises a liposome.
  • the depot component comprises a polymer.
  • the depot component comprises a complex of a liposome and a polymer or a polymersome.
  • depot components include, without limitation, micelles, reverse micelles, emulsions, microemulsions, etc.
  • Liposomes are generally known as sub-micron spherical vesicles comprised of phospholipids and cholesterol that form a hydrophobic bilayer surrounding an aqueous core. These structures have been used with a wide variety of therapeutic agents and allow for a drug to be entrapped within the liposome based in part upon its own hydrophobic (e.g. bilayer entrapment) or hydrophilic properties (e.g. entrapment in the aqueous compartment). Liposomes are generally used for controlled release and for drug targeting of lipid-capsulated compounds (Betageri et al, Liposome Drug Delivery Systems, Technomic Publishing Co., Inc., Lancaster, PA, 1993).
  • encapsulating a drug, an active therapeutic agent or a pharmaceutical composition in a liposome can alter the pattern of bio-distribution and the pharmacokinetics for the drugs.
  • liposomal encapsulation has been found to lower drug toxicity. For example, long circulating liposomal
  • such long- circulating liposomes may include a surface coat of flexible water soluble polymer chains that act to prevent interaction between the liposome and plasma components that play a role in liposome uptake.
  • such liposomes can be made of saturated, long-chain phospholipids and cholesterol, without this coating.
  • Exemplary liposomes may comprise a lipid layer comprising liposome forming lipids.
  • the lipid may include at least one phosphatidyl choline which provides the primary packing/entrapment/structural element of the liposome.
  • the phosphatidyl choline comprises mainly Ci6 or longer fatty-acid chains. Chain length provides for both liposomal structure, integrity, and stability.
  • one of the fatty-acid chains may have at least one double bond.
  • phosphatidyl choline includes, without limitation, soy PC, egg PC dielaidoyl phosphatidyl choline (DEPC), lecithin, dioleoyl phosphatidyl choline (DOPC), distearoyl phosphatidyl choline (DSPC), hydrogenated soybean phosphatidyl choline (HSPC), dipalmitoyl phosphatidyl choline (DPPC), 1 -palmitoyl-2-oleo phosphatidyl choline (POPC), dibehenoyl phosphatidyl choline 30 (DBPC), and dimyristoyl phosphatidyl choline (DMPC).
  • soy PC soy PC
  • DEPC egg PC dielaidoyl phosphatidyl choline
  • DOPC dioleoyl phosphatidyl choline
  • DSPC distearoyl phosphatidyl choline
  • HSPC hydrogen
  • Soy-PC refers to phosphatidyl choline compositions including a variety of mono-, di-, tri-unsaturated, and saturated fatty acids.
  • Soy-PC may include palmitic acid present in an amount of about 12% to about 33% (i.e., about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31 %, about 32%, or about 33%) by weight; stearic acid present in an amount of about 3% to about 8% (i.e., about 3%, about 4%, about 5%, about 6%, about 7%, or about 8%) by weight; oleic acid present in an amount of about 4% to about 22% (i.e., about 4%, about 5%, about 4%, about 5%, about 4%
  • Egg-PC refers to a phosphatidyl choline composition including, but not limited to, a variety of saturated and unsaturated fatty acids.
  • Egg-PC may comprise palmitic acid present in an amount of 10 about 34% (i.e., about 10%, about 1 1 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31 %, about 32%, about 33% or 3 about 4%) by weight;
  • stearic acid present in an amount of about 10% by weight; oleic acid present in an amount of about 31 % by weight; and linoleic acid present in an amount of about 18% by weight.
  • the liposome comprises cholesterol.
  • the ratio of phosphatidyl choline to cholesterol may be, for example, from about 0.5:1 to about 4:1 by mole ratio.
  • the ratio of phosphatidyl choline to cholesterol may be from about 1 :1 to about 2:1 by mole ratio, e.g., about 1 .1 ; about 1 .1 :1 ; about 1 .2:1 : about 1 .3:1 ; about 1 .4:1 ; about 1 .5:1 ; about 1 .6:1 ; about 1 .7:1 ; about 1 .8:1 ; about 1 .9:1 , or about 2:1 .
  • the ratio of phosphatidyl choline to cholesterol may be about 2:1 by mole ratio.
  • total lipid includes phosphatidyl cholines and any anionic phospholipid present in the liposome membrane.
  • the liposome may also comprise physiologically acceptable salts to maintain proper isotonicity. Any pharmaceutically acceptable salt that achieves isotonicity is acceptable, including, without limitation, for example, e.g. NaCI.
  • the liposomes of the described invention may comprise a lipid layer of phospholipids and cholesterol. According to some embodiments, the ratio of phospholipid to cholesterol is sufficient to form a liposome that will not dissolve or disintegrate once administered to the animal.
  • the phospholipids and cholesterol may be dissolved in suitable solvent or solvent mixtures. After a suitable amount of time, the solvent is removed via vacuum drying and/or spray drying. The resulting solid material can be stored or used immediately.
  • the resulting solid material is hydrated in an aqueous solution containing an appropriate concentration of the therapeutic agent at an appropriate temperature, resulting in multilamellar vesicles (MLV).
  • MLV multilamellar vesicles
  • SUVs Small Unilameller Vesicles
  • the resulting liposome solution can be separated from unencapsulated therapeutic agent, for example by chromatography or filtration, and then filtered for use.
  • an anionic liposome may also be used.
  • an anionic liposome provides a Coulombic character to the liposomes.
  • anionic lipids can help stabilize the system upon storage, can prevent fusion or aggregation or flocculation, and can facilitate or enable freeze drying.
  • Exemplary anionic lipids include, without limitation, phospholipids in the phosphatidic acid, phosphatidylglycerol, and phosphatidylserine classes (PA, PG, and PS). Further examples include Ci 6 or larger fatty-acid chains.
  • anionic phospholipid include, without limitation, Egg-PG (Egg Phosphatidyglycerol), Soy-PG (Soy-Phosphatidylglycerol), DSPG 20 (DistearoyI Phosphatidyglycerol), DPPG (DipalmitoyI Phosphatidyglycerol), DEPG (Dielaidoyl Phosphatidyglycerol), DOPG (DioleoyI Phosphatidyglycerol), DSPA (DistearoyI Phosphatidic Acid), DPPA (DipalmitoyI Phosphatidic Acid), DEPA (Dielaidoy Phosphatidic Acid), DOPA (DioleoyI Phosphatidic Acid), DSPS (DistearoyI Phosphatidylserine), DPPS (DipalmitoyI Phosphatidylserine),
  • a cationic liposome may be used.
  • exemplary cationic lipids include, without limitation, stearylamine (SA), lauryltrimethylammonium bromide; cetyltrimethylammonium bromide, myristyl trimethylammonium bromide, dimethyldioctadecylammonium bromide (DDAB), 3 ⁇ - [N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Cholesterol), 1 ,2- ditetradecanoyl-3-trimethylammonium-propane (DMTAP), 1 ,2-dioctadecanoyl-3- trimethylammonium-propane (DOTAP) and DOTAP derivatives such as 1 ,2-di-(9Z- octadecenoyl)-3-trimethylammonium-propane and 1 ,2-dihexade
  • SA stearyl
  • DOSPA polycationic lipid 2,3-dioleyloxy-N-[2(spermine-carboxamido)ethyl]-N,N-dimethyl-1 - propanaminiumtrifluoroacetate
  • DOSPA polycationic lipid 2,3-dioleyloxy-N-[2(spermine-carboxamido)ethyl]-N,N-dimethyl-1 - propanaminiumtrifluoroacetate
  • GL67TM polycationic lipid 2,3-dioleyloxy-N-[2(spermine-carboxamido)ethyl]-N,N-dimethyl-1 - propanaminiumtrifluoroacetate
  • the liposomes may contain about 10-40 (i.e., about 10, about 1 1 , about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21 , about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31 , about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40) mole percent of an amine-derivatized lipid component in which a charged amine group is spaced from a lipid polar head region by a carbon-containing spacer arm at least 3 atoms in length.
  • about 10-40 i.e., about 10, about 1 1 , about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21 , about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31 , about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40
  • the liposomes have a close packed lipid structure produced by inclusion of between 20-50 (i.e., about 20, about 21 , about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31 , about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41 , about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, or about 50) mole percent of cholesterol or an amine-derivatized
  • the liposomes may be suspended in an aqueous medium containing a high-viscosity polymer, formulated in paste form, or embedded in a polymer matrix, to further enhance liposome retention.
  • Polymers can also be used for controlled or delayed type release procedures (Langer, Accounts Chem. Res. 26:537, 1993).
  • the block copolymer, polaxamer 407 exists as a viscous yet mobile liquid at low temperatures but forms a semisolid gel at body temperature. It has been shown to be an effective vehicle for formulation and sustained delivery of recombinant interleukin-2 and urease (Johnston et al, Pharm. Res. 9:425, 1992; Pec, J. Parent. Set Tech. 44(2):58, 1990).
  • hydroxyapatite has been used as a microcarrier for controlled release of proteins (Ijntema et al, Int. J. Pharm. 1 12:215, 1994).
  • polymers utilized either alone, in combination, in association with a liposome, or as a polymersome may include for example, Poly(ethylene glycol) (PEG/PEO), Poly(2-methyloxazoline), Polydimethylsiloxane (PDMS),
  • PEG/PEO Poly(ethylene glycol)
  • PDMS Polydimethylsiloxane
  • PCL Poly(caprolactone
  • PLA Poly(lactide)
  • PMMA Poly(methyl methacrylate)
  • povidone povidone
  • CAP cellulose acetate phthalate
  • HPPMCP hydroxypropyl methylcellulose phthalate
  • PVAP polyvinyl acetate phthalate
  • methylcellulose acetate succinate HPMCAS
  • cellulose acetate trimellitate hydroxypropyl methylcellulose succinate
  • cellulose acetate succinate cellulose acetate hexahydrophthalate
  • cellulose propionate phthalate copolymer of
  • methylmethacrylic acid and methyl methacrylate copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g., EUDRAGIT® L30D55, EUDRAGIT® FS30D, EUDRAGIT® L100, KOLLICOAT® EMM30D, ESTACRYL® 30D, COATERIC®, and
  • the therapeutic agent and/or active metabolite remains in the skin and does not enter the bloodstream.
  • the chemical drivers are configured to generate the chemical drivers.
  • MSM methylsulfonylmethane
  • ethoxydiglycol work together cooperatively and synergistically to deliver the active therapeutic agent.
  • MSM formula (CH 3 )2SO 2
  • DMSO2 methyl sulfone
  • dimethyl sulfone methyl sulfone
  • CAS Registry Number 67-71 -0 is an organosulfur compound, and as shown in Formula (I), is a polar molecule having two oxygen atoms that can readily interact with positively charged atoms or molecules.
  • MSM can be administered in a maximum daily dose of up to 6 g/day; aaccording to some embodiments MSM is present as from 1 -10 % w/w of the pharmaceutical composition, i.e., 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w of the pharmaceutical composition.
  • MSM has a very low toxicity when administered topically (see Liu, P. et al., "Metal Chelator combined with permeability enhancer ameliorates oxidative stress-associated neurodegeneration in rat eyes with elevated intraocular pressure,” Free Radic. Biol. Med. 69: 289-99 (2014)).
  • MSM could also be an adjuvant for delivering ciprofloxacin and other chemical compounds to specific, local tissue sites (See “Assessment of methylsulfonylmethane as a permeability enhancer for regional EDTA chelation therapy"; Drug Delivery; Vol. 16; Pages 243-248, 2009), the disclosure of which is incorporated by reference.
  • Ethoxydiglycol also known as diethylene glycol monoethyl ether having formula CH 3 CH 2 OCH 2 CH 2 OCH 2 CH 2 OH) 2-(2-ethoxyethyoxy)ethanol, CAS Registry Number 1 1 1 -90-0
  • Ethoxydiglycol is a low molecular weight cosmetic grade synthetic solvent and viscosity decreasing agent used in cosmetics and personal care products to ensure even distribution of the ingredients throughout a product.
  • Glycols are a class of alcohols that contain two hydroxyl groups, and are also called a diols.
  • ethoxydiglycol is present in a range of 0.10-5% w/w of the pharmaceutical composition, i.e., 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1 .0%, 1 .1 %, 1 .2%, 1 .3%, 1 .4%, 1 .5%, 1 .6%, 1 .7%, 1 .8%, 1 .9%, 2.0%, 2.1 %, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1 %, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1 %, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9% or 5% w/w of the pharmaceutical composition.
  • the molecular weight of the first organic compound [00175] According to some embodiments, the molecular weight of the second organic compound
  • therapeutic agent of the described invention is less than 500 Da.
  • the chemical drivers enhance delivery of active therapeutic agents having a molecular weight of less than 500 Da.
  • the chemical drivers may also be able to enhance delivery of active therapeutic agents having a molecular weight higher than 500 Da.
  • the synergistic effect of the MSM, amino benzoate local anesthetic, and ethoxydiglycol is effective to provide
  • the amino benzoate local anesthetic blocks nerve signals where applied.
  • the chemical drivers are effective to increase percutaneous perfusion wherein heat, pH and the polarity of the chemical drivers are factors that affect percutaneous perfusion.
  • Exemplary amino benzoate local anesthetics include, without limitation, lidocaine (1 -10%, i.e., 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%) w/w of the composition), benzocaine (5-20% (i.e., 5%, 6%, 7%, 8%, 9%, 10%, 1 1 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%) w/w of the composition), and tetracaine (2% w/w of the composition).
  • any other suitable local anesthetic can be used including, without limitation, ambucaine, amolanone, amylcaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperodon, dyclonine, ecogonidine, ecogonine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxyteteracaine, isobutyl p-aminobenzoate, leucinocaine, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, octacaine, ortho
  • Amide type local anesthetics are characterized by an amide functionality, while ester type local anesthetics contain an ester functionality.
  • Exemplary amide type local anesthetics include bupivacaine, prilocaine, mepivacaine, etidocaine, ropivacaine, dibucaine, and mixtures thereof.
  • Exemplary ester type local anesthetics include procaine, chloroprocaine, their pharmaceutically acceptable salt, or a mixture thereof.
  • the amino benzoate local anesthetic is lidocaine (or lidocaine HCI), also known as 2-(diethylamino)-/V-(2,6- dimethylphenyl)acetamide shown in Formula (II).
  • Lidocaine can be administered in amounts of 0.5 to 4.5 mg/kg/dose (i.e., 0.5, 1 .0, 1 .5, 2.0, 2.5, 3.0, 3.5, 4.0, or 4.5 mg/kg/dose).
  • the lidocaine can be in the form of viscous lidocaine 2% w/w generally used to treat sore throat, teething, mouth or esophageal sores, or swelling inside the mouth. Viscous lidocaine can also be used to prevent gagging during dental procedures.
  • Lidocaine spray 4% w/w can be used under "crash" circumstances, where speed is of the essence.
  • Lidocaine spray is generally used when a breathing tube is inserted down the larynx during intubation to numb the gag reflex. Combined with the other components of the topical composition for fast anesthesia, time to perform intubation can be decreased where even a few seconds reduced can save a life. Lidocaine spray can also be used during childbirth. Lidocaine spray is commercially available as a 10% w/w solution, and the maximum dose per day is 30 mg within 30 minutes.
  • lidocaine Other amino benzoate local anesthetics with similar dosing to lidocaine include tetracaine (2-(dimethylamino)ethyl 4-(butylamino)benzoate), shown in
  • Exemplary active therapeutic agents may include without limitation, analgesic agents, wound healing agents, anti-inflammatory agents (steroidal and non-steroidal); anti-oxidant agents; antihistamines or anti-neoplastics either singly or as a combination thereof.
  • the active agent of the topical composition of the described invention can be an analgesic agent.
  • analgesics may include the following molecules but not limited to non-steroidal antiinflammatory drugs (NSAIDS), e.g., paracetamol (acetaminophen), ibuprofen, naproxen, and, COX-2 inhibitors, opioids, flupirtine, and specific agents including, but not limited to tricyclic antidepressants, such as amitriptyline, nefopam, and anticonvulsants, including carbamazepine, gabapentin, and pregabalin.
  • NSAIDS non-steroidal antiinflammatory drugs
  • acetaminophen e.g., paracetamol (acetaminophen), ibuprofen, naproxen, and, COX-2 inhibitors, opioids, flupirtine
  • specific agents including, but not limited to tricyclic antidepressants, such as amitriptyline, nefopam, and anti
  • the active agent of the topical composition of the described invention is an antineoplastic agent.
  • exemplary antineoplastics may include, without limitation 5-fluorouracil, temozolomide, busulfan, ifosamide, melphalan, carmustine, lomustine, mesna, capecitabine, gemcitabine, floxuridine, decitabine, mercaptopurine, pemetrexed disodium, methotrexate, vincristine, vinblastine, vinorelbine tartrate, paclitaxel, docetaxel, ixabepilone, daunorubicin, epirubicin, doxorubicin, idarubicin, amrubicin, pirarubicin, mitoxantrone, etoposide, etoposide phosphate, teniposide, mitomycin C, actinomycin D, colchicine, topotecan, irinotecan, gemcitabine
  • the active agent of the topical composition of the described invention comprises an anti-inflammatory agent.
  • non-steroidal anti-inflammatory agents include, ibuprofen (Advil®), naproxen sodium (Aleve®), and acetaminophen (Tylenol®), oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, fel
  • Non-limiting examples of steroidal anti-inflammatory agents include corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone aceton
  • prednisolone prednisone
  • beclomethasone dipropionate triamcinolone, and mixtures thereof.
  • the active agent of the topical composition of the described invention comprises an anti-oxidant agent.
  • anti-oxidants may include ascorbic acid (vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g., magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl sorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherol acetate, other esters of tocopherol, butylated hydroxy benzoic acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commercially available under the tradename TroloxR), gallic acid and its alkyl esters, especially propyl gallate, uric acid and its salts and alkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g., ⁇ , ⁇ -diethylhydroxylamine, amino
  • the antioxidant may be alpha tocopherol (Vitamin-E), ascorbic acid, ascorbic acid esters, glutathione, lipoic acid, uric acid, carotenes, propyl gallate, sodium bisulfite, sodium sulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or cysteine.
  • Vitamin-E alpha tocopherol
  • ascorbic acid ascorbic acid esters
  • glutathione lipoic acid
  • uric acid carotenes
  • propyl gallate sodium bisulfite
  • sodium sulfite sodium sulfite
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • the active agent of the topical composition of the described invention comprises an antihistamine.
  • antihistamines include, without limitation, chlorpheniramine,
  • brompheniramine dexchlorpheniramine, tripolidine, clemastine, diphenhydramine, promethazine, piperazines, piperidines, astemizole, loratadine and terfenadine.
  • the topical composition of the described invention further contains a topical vasoconstrictor as an additional active agent.
  • topical vasoconstrictors include, for example, oxymetazoline, isoproterenol, phenylephrine, norepinephrine, ephedrine,
  • the vasoconstrictor is not a substance that causes a dermatitis or other irritation, e.g., epinephrine, synephrine, or ephedrine.
  • the topical composition is
  • MEC minimum effective concentration
  • the intensity of effect of a drug can be plotted as a function of the dose of drug administered (X-axis).
  • X-axis The intensity of effect of a drug
  • concentration-effect relationships can be viewed as having four characteristic variables: potency, slope, maximal efficacy, and individual variation.
  • the location of the dose-effect curve along the concentration axis is an expression of the potency of a drug. Id. If the active therapeutic agent is to be administered by transdermal absorption, a highly potent active therapeutic agent is required, since the capacity of the skin to absorb active therapeutic agents is limited.
  • the slope of the dose-effect curve reflects the mechanism of action of a drug.
  • the steepness of the curve dictates the range of doses useful for achieving a clinical effect.
  • Maximal or clinical efficacy refers to the maximal effect that can be produced by a drug. Maximal efficacy is determined principally by the properties of the drug and its receptor-effector system and is reflected in the plateau of the curve. In clinical use, a drug's dosage may be limited by undesired effects.
  • Biological variability may exist. An effect of varying intensity may occur in different individuals or subjects at a specified concentration or a drug. It follows that a range of concentrations may be required to produce an effect of specified intensity in all subjects. [00201 ] Lastly, different individuals may vary in the magnitude of their response to the same concentration of a drug when the appropriate correction has been made for differences in potency, maximal efficacy and slope.
  • the duration of a drug's action is determined by the time period over which concentrations exceed the MEC. Following administration of a dose of drug, its effects usually show a characteristic temporal pattern. A plot of drug effect vs. time illustrates the temporal characteristics of drug effect and its relationship to the therapeutic window. A lag period is present before the drug concentration exceeds the minimum effective concentration (MEC) for the desired effect. Following onset of the response, the intensity of the effect increases as the drug continues to be absorbed and distributed. This reaches a peak, after which drug elimination results in a decline in the effect's intensity that disappears when the drug concentration falls back below the MEC. The therapeutic window reflects a concentration range that provides efficacy without unacceptable toxicity. Accordingly another dose of drug should be given to maintain concentrations within the therapeutic window.
  • the potency of the active therapeutic agent in the claimed pharmaceutical composition is maintained within a range of from 3 to 5% w/w of the composition i.e., at least 2% w/w of the composition when the local anesthetic is lidocaine; from 10 to 20 % (10%, 1 1 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%) w/w of the composition i.e., at least 5% w/w of the composition when the local anesthetic is benzocaine and from 1 to 2 % (i.e., 1 .0%, 1 .1 %, 1 .2%, 1 .3%, 1 .4%, 1 .5%, 1 .6%, 1 .7%, 1 .8%, 1 .9% or 2.0%) w/w of the composition i.e., at least 1 % w/w of the composition when the local anesthetic is tetracaine.
  • the concentration of the active therapeutic agent is at least 1 % w/w of the composition, at least 2% w/w of the composition, at least 3% w/w of the composition, at least 4% w/w of the composition, at least 5% w/w of the composition, at least 6% w/w of the composition, at least 7% w/w of the composition, at least 8% w/w of the composition, at least 9% w/w of the composition, at least 10% w/w of the composition; at least 1 1 % w/w of the composition, at least 2% w/w of the composition, at least 3% w/w of the composition, at least 4% w/w of the composition, at least 5% w/w of the composition, at least 6% w/w of the composition, at least 7% w/w of the composition, at least 8% w/w of the composition, at least 9% w/w of the composition, at least 10% w/w of the composition; at least 1 1
  • composition at least 12% w/w of the composition; at least 13% w/w of the
  • composition at least 14% w/w of the composition; at least 15% w/w of the composition; at least 16% w/w of the composition; at least 17% w/w of the composition; at least 18% w/w of the composition; at least 19% w/w of the
  • composition at least 20% w/w of the composition, at least 30% w/w of the
  • composition at least 40% w/w of the composition, at least 50% w/w of the
  • composition or at least 60% w/w of the composition.
  • the concentration of the active agent is from about 1 % to about 10% w/w of the composition, i.e., at least 1 %, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or 10% w/w of the composition when the local anesthetic is lidocaine. According to some
  • the concentration of the active agent is from about 5% to about 20% w/w of the composition, i.e., at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 1 1 %, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19% or 20% w/w of the composition when the local anesthetic is benzocaine.
  • the concentration of the active agent is from about 5% to about 20% w/w of the composition, i.e., at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 1 1 %, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19% or 20% w/w of the composition when the local anesthetic is benzocaine.
  • the concentration of the active agent is from about 1 % to about 2% w/w of the composition, i.e. at least 1 %, or 2% w/w of the composition when the local anesthetic is tetracaine.
  • the content of the active agent retained on skin and its permeation/flux into the skin can be measured as a function of time.
  • flux is determined using one of many available artificial membranes attached to a Franz diffusion cell.
  • permeation and retention are determined using human cadaver skin attached to a Franz diffusion cell.
  • the retained concentration is correlated to the minimum effective concentration.
  • the pharmaceutical composition can be applied directly to the skin.
  • the pharmaceutical composition may further include auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavorants and/or fragrances and the like which are compatible with the active compounds, carriers, excipients,
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavorants and/or fragrances and the like which are compatible with the active compounds, carriers, excipients,
  • flocculants penetration enhancers, plasticizers, pH balancers, moisturizers, emollients, surfactants and emulsifiers, bactericides, thickening agents, softening agents, etc.
  • the composition can also include agents that assist in maintaining the molecular structure integrity of the therapeutic or help deliver the therapeutic agent through the skin, such as but not limited to solvents that break down lipophilic therapeutics or adjust ionic charge for easier delivery into skin, detergents such as but not limited to anionic detergents (e.g., alkylbenzenesulfonates), cationic detergents, non-ionic detergents (e.g., ethoxylates, PEGylates), or zwitterionic detergents (3-[(3-cholamidopropyl)dimethylammonio]-1 -propanesulfonate)), cyclodextrins that readily complex with lipophilic therapeutics like steroids, including cc-cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin, other complexing agents (i.e.
  • chelating agents with two or more separate coordinate bonds between a multiple bonded ligand and a central atom (metal), such as, but not limited to, glutamic acid, histidine, malate, phytochelatin, hemoglobin, chlorophyll, ethylenediaminetetraacetic acid (EDTA), amino acid chelates, and dimercaprol), and other amphipathic chemicals.
  • metal such as, but not limited to, glutamic acid, histidine, malate, phytochelatin, hemoglobin, chlorophyll, ethylenediaminetetraacetic acid (EDTA), amino acid chelates, and dimercaprol
  • Exemplary plasticizers include, without limitation, phthalic anhydride esters, esters of adipic acid, epoxidized esters, trimellitic esters, triacetin, N-methyl- 2-pyrrolidone, glycerol formaldehyde, triethyl citrate (TEC), acetyltributylcitrate, ethanol, and polyethylene glycol.
  • Non-limiting examples of penetration enhancers include propylene glycol (PG), dimethylsulfoxide (DMSO), dimethyl formamide (DMF), allantoin, urazole, ⁇ , ⁇ -dimethylacetamide (DMA), decylmethylsulfoxide (C10 MSO), polyethylene glycol monolaurate (PEGML), propylene glycol monolaurate (PGML), glycerol monolaurate (GML), lecithin, the 1 -substituted azacycloheptan-2-ones, e.g., 1 -n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone® from Whitby Research Incorporated, Richmond, Va.), alcohols, and the like.
  • PG propylene glycol
  • DMSO dimethylsulfoxide
  • DMF dimethyl formamide
  • DMA decylmethylsulfoxide
  • C10 MSO decylmethylsulfoxide
  • the penetration enhancer may also be a vegetable oil, for example, safflower oil, cottonseed oil and corn oil. Additional penetration enhancers may generally be found in Remington's Pharmaceutical Sciences, 18th or 19th editions, published by the Mack Publishing Company of Easton, Pennsylvania which is incorporated herein by reference. [0021 1 ] Exemplary anti-oxidants may include the following, but not limited to, ascorbic acid and glutathione (GSH) etc.
  • the antioxidant agent is present at a concentration from 10%-20% (i.e., 10%, 1 1 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%) w/w of the composition for ascorbic acid and from 2%-5% (i.e., 2%, 2.1 %, 2,2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7% 2.8%, 2.9%, 3%, 3.1 %, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1 %, 4,2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5%) for glutathione.
  • 10%-20% i.e., 10%, 1 1 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%
  • 2%-5% i.e., 2%, 2.1 %, 2,2%, 2.3%, 2.4%, 2.5%,
  • Surfactants are organic compounds that are amphiphatic, containing both hydrophobic groups and hydrophilic groups. Surfactants include, but are not limited to anionic surfactants, cationic surfactants and non-ionic surfactants.
  • Anionic surfactants include fatty acid soaps (including sodium oleate, sodium palmitate, sodium myristate, sodium sterate, potassium oleate and
  • alkyi sulfates including sodium dodecyl sulfate, ammonium lauryl sulfate, triethanolamine lauryl sulfate and sodium alkyi sulfate
  • alkyi lactylates including calcium stearoxyl-2-lactylate
  • alkyi lactates including sodium-O- stearyllactate and sodium stearoyllactylate
  • alkyi benzenesulfonates including calcium dodecyl benzene sulfonate
  • alkyi sulfonates including alkyi aryl sulfonate
  • alkyi phosphates alkyi oleates
  • alkyi stearates including self-emulsifying glycerol monostearate
  • alkyi esters including dioctyl ester of sodium sulphosuccininc acid (AOT, Aerosol OT); acyl sulfates
  • Cationic surfactants include alkyi primary, secondary, tertiary, or quaternary amines; high-molecular-weight amine and fatty amine blends;
  • polyoxyethylene fatty amines including tallow amine
  • alkyi sulfates including N- cetyl-N-ethyl morpholinium ethyl sulfate(35%)
  • alkyi pyridinium and quaternary ammonium salts including N- cetyl-N-ethyl morpholinium ethyl sulfate(35%)
  • Non-ionic surfactants include alcohol ethoxylate, alkylphenol ethoxylate, fatty acids (such as oleic acid), lanolin alcohols (such as polyoxyethylene (5) lanolin alcohol (ether and ester), polyoxyethylene (50) lanolin (ether and ester), acetylated polyoxyethylene (10) lanolin, polyoxyethylene (16) lanolin alcohol, acetylated polyoxyethylene (9) lanolin), alkyi polyglycosides, mono-, di- or glyceride esters (such as diglycerine sesquioleate), acetylated monoglycerides, polyglycerols, polyglycerol esters (such as decaglycerol decaoleate, decaglycerol octaoleate, decaglycerol tetraoleate), phospholipids (such as lecithin), mono- or diglyceride esters of citric acid, tartaric acid, lan
  • nonylphenol polyoxyethylene (10) nonylphenol, poly(ethylene glycol) 200 distearate, poly(ethylene glycol) 300 dilaurate, poly(ethylene glycol) 400 distearate,
  • polyoxyethylene octylphenol poly(ethylene glycol) 400 dilaurate, poly(ethylene glycol) 400 monostearate, poly(ethylene glycol) 400 monolaurate, poly(ethylene glycol) 4000 distearate, polyoxyethylene (10) octylphenol, poly(ethylene glycol) 600 monostearate, Polyoxyethylene (14) nonylphenol, polyoxyethylene (24) cholesterol, polyoxyethylene (25) soyasterol, poly(ethylene glycol) 1000 monooleate,
  • copolymers of polyethylene oxide and polypropylene oxide polyoxyethylene fatty ethers (such as polyoxyethylene fatty ethers derived from lauryl, cetyl, stearyl and oleyl alcohols, polyoxyethylene (4) lauryl ether, polyoxyethylene (23) lauryl ether (Brij 35), polyoxyethylene (2) cetyl ether (Brij 52), polyoxyethylene (10) cetyl ether, polyoxyethylene (20) cetyl ether (Brij 58), polyoxyethylene (2) stearyl ether (Brij 72), polyoxyethylene (10) stearyl ether, polyoxyethylene (20) stearyl ether,
  • polyoxyethylene fatty ethers such as polyoxyethylene fatty ethers derived from lauryl, cetyl, stearyl and oleyl alcohols, polyoxyethylene (4) lauryl ether, polyoxyethylene (23) lauryl ether (Brij 35), polyoxyethylene (2) cetyl ether (Brij 52), polyoxyethylene (10) cetyl
  • Exemplary pharmaceutical carriers also include starch, glucose, lactose, sucrose, gelatin, saline, gum acacia, keratin, urea, malt, rice flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, and ethanol.
  • the carrier can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • Formulations for topical application can take the compositional form of a liquid, a semisolid dosage form (e.g., a paste, a cream, a lotion, a powder, an ointment or a gel), a patch or a spray.
  • the topical composition may be a cream or gel that can be applied to an affected area of the skin of a subject in need thereof.
  • Different release profiles can be achieved with different forms, such as but not limited to controlled release, delayed release, extended release, or sustained release.
  • the topical pharmaceutical composition may be applied multiple times a day, once per day, or as often as needed.
  • an exemplary pharmaceutical cream formulation may include: Lidocaine (local anesthetic agent), MSM (chemical driver), ethoxydiglycol (chemical driver), deionized water, polyacrylamide (a flocculant), Ci 3- 14 isoparaffin (an emollient), laureth-7 (surfactant and emulsifier), propylene glycol (penetration enhancer), triethanol amine (pH balancer), emu oil (antifungal agent), tea tree oil (antifungal agent), arnica Montana extract (anti-inflammatory agent); ethylhexylglycerin (fragrant), phenoxyethanol (bactericide), isopropyl palmitate (emollient, moisturizer, thickening agent, anti-static), stearic acid (surfactant and softening agent), 5-fluorouracil (anti-neoplastic). Any suitable excipients in these categories also can be used in accordance with the embodiments of the described invention.
  • Lidocaine is a widely used local anesthetic that was first synthesized by Lofgren in 1 943 (Lofgren N, Lundqvist B (1 946). Svensk Kemisk Tidskrift 58: 206- 1 7). Its lUPAC name is: 2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide, and its CAS number is: 1 37-58-6 / 73-78-9 (hydrochloride). Lidocaine is used as a topical pain reliever/numbing agent in both prescription and over the counter (OTC) forms (Drug Bank. (201 3, February 08). Lidocaine.
  • Lidocaine also is a first line anti-arrhythmic drug when used at high doses (Sleight PJ (1 990). Cardiovasc Pharmacol 1 6: S1 1 3-1 1 9); (Collinsworth, K. Circulation 50: 1 21 7-30 (1 974).
  • lidocaine is often the local anesthetic of choice during intubation, minimally invasive surgery, and many dental procedures (Mehta P, Caiazzo A, Maloney P (1 998). Anesth Prog 45: 38-41 ).
  • lidocaine as a local anesthetic is distinguished by its accelerated onset of action and intermediate duration. As a result, lidocaine is suitable for infiltration, block and surface anesthesia (Alabdalla J, Hoffart L.
  • lidocaine provides excellent results in providing anesthetic effects for local, acute pain.
  • Advantages include, but are not limited to, avoidance of hepatic first-pass
  • Disadvantages may include skin irritation, and also may include poor or variable permeability through the skin, which can result in insufficient therapeutic effect for the patient (Moody ML (2010). Topical Medications in the Treatment of Pain. New York City: McMahon Publishing).
  • Table 1 Exemplary cream formulation.
  • formulations and doses can be tailored to a subject's fat content, as some therapeutic can be lost to the fat layer (the rate and extent of the diffusion of the therapeutic and amino benzoate local anesthetic can vary).
  • GMP Good Medical Practice's
  • FDA Food and Drug Administration
  • the pharmaceutically "effective amount" for purposes herein is thus determined by such considerations as are known in the art.
  • the amount must be effective to achieve improvement including but not limited to improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those having ordinary skill in the art.
  • the topical delivery system of the described invention can be used in the manufacture of a medicament for treating a plurality of skin conditions, disorders or diseases.
  • diseases or disorders that can be treated with the pharmaceutical composition of the described invention include, without limitation, pruritus, atopic dermatitis, psoriasis, acne, skin infections, skin infestations, skin neoplasms, wounds to the skin, pain causing disorders and skin manifestations of autoimmune disorders or uses for anesthesia prior to procedures including, but not limited to, for example superficial dermal instrumentation.
  • the described invention provides a method for treating a disease, disorder or condition susceptible to treatment topically comprising administering the topical composition described herein to skin.
  • the pharmaceutical composition of the described invention can be administered as the pharmaceutical formulation alone, or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants and other auxiliary vehicles.
  • the subject is for example, a warm-blooded animal, for example a mammal, including man.
  • the pharmaceutically acceptable carriers, diluents, adjuvants and vehicles, as well as implant carriers generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating material not reacting with the active ingredients of the invention.
  • the doses given may be as a single dose, or as multiple doses over a predetermined period stretching a plurality of days, months or years.
  • the term "plurality" refers to an event characterized by more than one.
  • the pharmaceutical composition is administered multiple times at a plurality of treatment dates, or as needed in the judgment of a treating physician.
  • treatment can be continuous or discontinuous.
  • continuous refers to an activity that is unbroken and without interruption.
  • discontinuous refers to an activity that is broken and with interruption for a predetermined amount of time as judged by the treating physician.
  • the treatment may advantageously be conducted continuously over a period of days, months, or years or discontinuously over a period of days, months, or years.
  • VAS self-reported visual analog scale
  • lidocaine • estimating rates of absorption and distribution, and also of metabolism by simultaneous determination of lidocaine and of monoethylglycinexylidide (MEGX), the primary metabolite of lidocaine.
  • lidocaine Tattoo, surgical scar or skin condition at the site of administration that might interfere with penetration of agent into the skin; and • Currently using lidocaine or any related amide-containing agent that might provide a false positive result in the clinical analysis of lidocaine.
  • the lidocaine preparation marketed as NeuroMed7TM was obtained from SambriaTM Pharmaceuticals at 4% (w/w) in a cream that includes
  • MSM methylsulfonylmethane
  • the 4% lidocaine cream was provided by Sambria Pharmaceuticals (Woodstock, GA). Whole blood (10 imL per bleed) was collected using standard venipuncture into serum Vacutainer tubes (Franklin Lakes, IL). Following
  • the selected method also will detect levels of drug that fall within the clinical range, which is necessary to verify the relationship between dosage and physiological response.
  • 10 mL of venous blood was collected throughout the study period, at time intervals likely to capture peak and trough levels (Greenblatt DJ et al. (1985). Arch Otolaryngol 1 1 1 : 2988-3000); (Baumann LS, et al. (2010). J Drugs Dermatol 9: 1500-1504).
  • Each subject provided self-rated pain evaluations at those same time intervals, focusing on pain at the identified site of acute pain and of drug application, using the 1 -10 Visual Analog Scale (VAS) (Meier T, et al. (2003). Pain 106: 151 -158).
  • VAS Visual Analog Scale
  • Venous blood samples were taken prior to the initial dosing at 0 h, and 1 , 3, 5, 7, 9 and 1 1 hours following the initial (1 h) drug application, which for the last 4 samples (indicated on Figure 3. Study Schema) also corresponds to 1 , 3, 5 and 7 hours after the second (4 h) drug application. Lidocaine levels were below the detection limit of 0.1 imcg/mL ⁇ g/mL) in all blood samples.
  • the level of MEGx was at the detection limit, i.e., 0.1 imcg/mL
  • the study was designed to approximate the peak drug levels resulting from each lidocaine dose.
  • Toxic levels of lidocaine typically occur at levels greater than 6.0 imcg/mL, with symptoms including central nervous excitation, lightheadedness, dizziness, tinnitus, confusion, and blurred or double vision (Valdes R et al. (1998). Clin Chem 44(5): 1096-1099).
  • subjects were contacted with questions regarding side effects. There were no such reports of adverse effects related to drug activity.
  • Three subjects did experience slight lightheadedness that appeared to result from venipuncture, as they were felt after each blood draw. It is concluded from the measured blood levels, as well as clinical signs, that the subjects in this study expressed no symptoms of lidocaine toxicity.
  • Pain reduction was 50% or greater among 82% of subjects (28 of 34), with the time elapsed to reach maximal pain reduction being 1 h for 27% of subjects, followed by 21 % (3 h), 18% (5 h), 9% (7 h), 12% (9 h), and 6% (1 1 h).
  • lidocaine formulation presented no measurable safety issues, either in measureable serum levels (since the highest measurable level was 0.10 imcg/mL, whereas toxicity is indicated at >5 imcg/mL), or in physiological response, and was effective among the majority of these subjects.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un système d'administration topique comprenant une composition pharmaceutique à appliquer directement sur la peau d'un sujet en ayant besoin comprenant (a) une quantité thérapeutique efficace d'un agent thérapeutique actif ; (b) des vecteurs chimiques comprenant un anesthésiant local à base d'aminobenzoate, de l'éthoxydiglycol et du méthylsulfonylméthane (MSM) qui sont efficaces combinés pour administrer synergiquement l'agent thérapeutique ; et (c) un composant de dépôt permettant de maintenir la composition pharmaceutique dans la peau. Les modes de réalisation de l'invention décrite concernent aussi des procédés d'administration d'un agent thérapeutique actif dans la peau, de son maintien dans la peau, de réduction des effets secondaires systémiques attribuables à l'entrée de l'agent actif dans le flux sanguin, et un procédé pour traiter un état, une maladie ou un trouble cutané topique.
PCT/US2016/016517 2016-02-03 2016-02-04 Composition topique et système d'administration et son utilisation Ceased WO2017135948A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB1814047.5A GB2564026B (en) 2016-02-03 2016-02-04 Topical composition and delivery system and its use
CA3013567A CA3013567C (fr) 2016-02-03 2016-02-04 Composition topique et systeme d'administration et son utilisation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15/014,988 2016-02-03
US15/014,988 US10265283B2 (en) 2012-12-07 2016-02-03 Topical composition and delivery system and its use

Publications (1)

Publication Number Publication Date
WO2017135948A1 true WO2017135948A1 (fr) 2017-08-10

Family

ID=59499809

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/016517 Ceased WO2017135948A1 (fr) 2016-02-03 2016-02-04 Composition topique et système d'administration et son utilisation

Country Status (3)

Country Link
CA (1) CA3013567C (fr)
GB (2) GB2564026B (fr)
WO (1) WO2017135948A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200085741A1 (en) * 2018-09-14 2020-03-19 Pharmosa Biopharm Inc. Pharmaceutical composition for controlled release of weak acid drugs and uses thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070243132A1 (en) * 2005-12-22 2007-10-18 Apollo Life Sciences Limited Transdermal delivery of pharmaceutical agents
US20070269379A1 (en) * 2003-07-23 2007-11-22 Samir Mitragotri Penetration Enhancer Combinations for Transdermal Delivery
US20080154210A1 (en) * 2004-05-28 2008-06-26 Oryxe Mixture for Transdermal Delivery of Low and High Molecular Weight Compounds
US20130337031A1 (en) * 2006-03-06 2013-12-19 Nuvo Research Inc. Topical formulations, systems and methods
US20140163105A1 (en) * 2012-12-07 2014-06-12 Michael Harvey Greenspan Topical preparation for pain relief
WO2014130761A2 (fr) * 2013-02-22 2014-08-28 President And Fellows Of Harvard College Véhicules thérapeutiques actifs nanostructurés et leurs utilisations
WO2014176417A1 (fr) * 2013-04-24 2014-10-30 Sambria Pharmaceuticals, Llc Préparation topique pour contourner un tractus gastro-intestinal, administration d'agents thérapeutiques et système d'administration de médicament trans-épithéliale
US20150290151A1 (en) * 2014-04-15 2015-10-15 Vizuri Health Sciences Llc Topical compositions for pain relief, manufacture and use

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070269379A1 (en) * 2003-07-23 2007-11-22 Samir Mitragotri Penetration Enhancer Combinations for Transdermal Delivery
US20080154210A1 (en) * 2004-05-28 2008-06-26 Oryxe Mixture for Transdermal Delivery of Low and High Molecular Weight Compounds
US20070243132A1 (en) * 2005-12-22 2007-10-18 Apollo Life Sciences Limited Transdermal delivery of pharmaceutical agents
US20130337031A1 (en) * 2006-03-06 2013-12-19 Nuvo Research Inc. Topical formulations, systems and methods
US20140163105A1 (en) * 2012-12-07 2014-06-12 Michael Harvey Greenspan Topical preparation for pain relief
WO2014130761A2 (fr) * 2013-02-22 2014-08-28 President And Fellows Of Harvard College Véhicules thérapeutiques actifs nanostructurés et leurs utilisations
WO2014176417A1 (fr) * 2013-04-24 2014-10-30 Sambria Pharmaceuticals, Llc Préparation topique pour contourner un tractus gastro-intestinal, administration d'agents thérapeutiques et système d'administration de médicament trans-épithéliale
US20150290151A1 (en) * 2014-04-15 2015-10-15 Vizuri Health Sciences Llc Topical compositions for pain relief, manufacture and use

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200085741A1 (en) * 2018-09-14 2020-03-19 Pharmosa Biopharm Inc. Pharmaceutical composition for controlled release of weak acid drugs and uses thereof

Also Published As

Publication number Publication date
CA3013567C (fr) 2023-09-05
GB2564026A (en) 2019-01-02
CA3013567A1 (fr) 2017-08-10
GB202201845D0 (en) 2022-03-30
GB2564026B (en) 2022-07-13
GB2600651A (en) 2022-05-04
GB201814047D0 (en) 2018-10-10

Similar Documents

Publication Publication Date Title
US11771669B2 (en) Topical composition and delivery system and its use
US20210015740A1 (en) Topical cannabinoid compositions, delivery systems, and uses for pain relief
US10080763B2 (en) Topical film delivery system
Ali et al. The structure of skin and transdermal drug delivery system-a review
PT95729B (pt) Metodo para humidificacao dos tecidos, nomeadamente de celulas epiteliais de mamiferos
CA2446060A1 (fr) Compositions et systemes d'administration d'un anesthesique local
EP1824488B1 (fr) Les phycotoxines et leur utilisation
EP1796676B1 (fr) Administration transdermique de phycotoxines
US20230210787A1 (en) Topical cannabinoid compositions, delivery systems, and uses for pain relief
Varshosaz et al. Development of bioadhesive chitosan gels for topical delivery of lidocaine
KR20090130217A (ko) 수분 투과에 대하여 방향성을 지닌 시트를 이용한 마스크팩
More et al. Nasal in-situ gel: a novel approach for nasal drug delivery system
CA3013567C (fr) Composition topique et systeme d'administration et son utilisation
RU2289417C1 (ru) Способ биологического омоложения кожи
US20250134811A1 (en) Ultraflexible liposomes in gel formulation
WO2015181746A1 (fr) Sel de sodium d'heparine sous forme de gel pour administration dermique, et procede de preparation associe
CN107595766B (zh) 一种利多卡因微乳凝胶及其制备方法
KR102221499B1 (ko) 위축성 피부 흉터를 치료하기 위한 프로스타글라딘 F2α 및 그 유사체
PL246515B1 (pl) Kompozycja kosmetyczna, zastosowanie kompozycji, preparat kosmetyczny bio-maska hydrożelowa w formie okładu, sposób wytwarzania preparatu
Nounou et al. Topical Liposomal Dibucaine Delivery System: Development And Characterization
HK1257645B (en) Topical film delivery system
Nazmi In-vitro release and antifungal activity of ketoconazole from different dermatological vehicles with reduced level of drug
Sharma Investigation of the role of calcium channels in penetration enhancing effect of L-menthol ex-vivo studies
US20190021995A1 (en) Formulation for treatment of peripheral joints, spinal joints and/or extracellular matrix elements of connective tissue, method of manufacture and uses
PL203478B1 (pl) Zastosowanie pochodnych biguanidu i ich soli do wytwarzania leku do bliznowacenia

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16889597

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 3013567

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 201814047

Country of ref document: GB

Kind code of ref document: A

Free format text: PCT FILING DATE = 20160204

122 Ep: pct application non-entry in european phase

Ref document number: 16889597

Country of ref document: EP

Kind code of ref document: A1