EP3856140A1 - Système d'administration transdermique de médicament - Google Patents

Système d'administration transdermique de médicament

Info

Publication number
EP3856140A1
EP3856140A1 EP19794747.6A EP19794747A EP3856140A1 EP 3856140 A1 EP3856140 A1 EP 3856140A1 EP 19794747 A EP19794747 A EP 19794747A EP 3856140 A1 EP3856140 A1 EP 3856140A1
Authority
EP
European Patent Office
Prior art keywords
formulation
basement membrane
active ingredient
agent
penetration
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.)
Pending
Application number
EP19794747.6A
Other languages
German (de)
English (en)
Inventor
Zhen Zhu
John J. Masiz
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.)
Biophysics Pharma Inc
Original Assignee
Biophysics Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biophysics Pharma Inc filed Critical Biophysics Pharma Inc
Priority claimed from PCT/US2019/053000 external-priority patent/WO2020069013A1/fr
Publication of EP3856140A1 publication Critical patent/EP3856140A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame

Definitions

  • the present invention relates to a formulation for transdermal delivery of an active
  • the formulation includes at least one penetration agent (e.g., a solvent, a lipophilic agent, a hydrophilic agent, or a combination thereof), at least one basement membrane disruptor that reversibly denatures the basement membrane; at least one vaso-modulator; and at least one active ingredient.
  • penetration agent e.g., a solvent, a lipophilic agent, a hydrophilic agent, or a combination thereof
  • basement membrane disruptor that reversibly denatures the basement membrane
  • vaso-modulator e.g., a vaso-modulator
  • the body surface includes skin, mucosal membranes (e.g., vaginal mucosa, anal mucosa, throat mucosa, nasal mucosa, or ocular tissue), nail surfaces (e.g., fingernail surface or toe nail surface) or any combination thereof.
  • mucosal membranes e.g., vaginal mucosa, anal mucosa, throat mucosa, nasal mucosa, or ocular tissue
  • nail surfaces e.g., fingernail surface or toe nail surface
  • the penetration agent of the present invention allows the basement membrane disruptor, the vaso-modulator, and the active ingredient to pass through the stratum comeum layer and the epidermis.
  • the penetration agent includes solvents such as one or more nonpolar solvents (e.g., carbon tetrachloride, benzene, diethyl ether, hexane, methylene chloride, toluene and a combination thereof), one or more polar aprotic solvents (e.g., propylene carbonate, acetone, ethyl acetate, acetonitrile, dimethylformamide, and a combination thereof), one or more polar protic solvents (e.g., water, methanol, isopropanol, acetic acid, methanol, ethanol, n- propanol, n-butanol and a combination thereof), one or more limonenes (e.g., D-limonene, L- Limonenes and
  • the formulation of the present invention includes basement membrane disruptor that allows the vaso-modulator and the active ingredient pass through the basement membrane.
  • Basement membrane disruptors used in the present invention include, for example, one or more chaotropic agents, or one or more other agents that allow for reversibly denaturing and permeability of the basement membrane proteins.
  • Examples of a basement membrane disruptor include guanidine hydrochloride, a guanidine salt, guanidine analogs, guanidine conjugates, or any combination thereof.
  • the formulation of the present invention includes a vaso-modulator that encompasses a vasodilator or vasoconstrictor.
  • the vasodilator allows for the active ingredient to be delivered systemically or to local tissue.
  • vasodilators examples include amrinone, arginine, bamethan sulphate, bencyclane fumarate, benfurodil hemi succinate, benzyl nicotinate, buflomedil hydrochloride, buphenine hydrochloride, butalamine hydrochloride, cetiedil citrate, ciclonicate, cinepazide maleate, cyclandelate, di isopropylammonium dichloroacetate, ethyl nicotinate, hepronicate, hexyl nicotinate, ifenprodil tartrate, inositol nicotinate, isoxsuprine hydrochloride, kallidinogenase, methyl nicotinate, naftidrofuryl oxalate, nicametate citrate, niceritrol, nicoboxil, nicofuranose, nicotinyl alcohol, nicotiny
  • thymoxamine hydrochloride tocopherol nicotinate, tolazoline, papaverine, xanthinol nicotinate, diazoxide, hydralazine, minoxidil, and sodium nitroprusside, clonidine, quanaberz, methyl dopa, alpha adrenoceptor, indoramin, phenoxybenzamine, phentolamine, prazosin, PDE-5 inhibitors, sildenafil, tadalafil, adrenergic neuron blocking agents, bedmidine, debrisoquine, guanethidine, ACE inhibitors, benazepril, captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, ganglion blocking agents, pentolinium, trimetaphan, calcium channel blockers, amlodip
  • vaso-modulator used in the present invention is a vasoconstrictor
  • the active ingredient is delivered to the dermis.
  • vasoconstrictors used with the inventive formula of the present invention encompass adenosine triphosphate, amphetamine, antazoline, asymmetric dimethylarginine, cocaine, dopamine, endothelin, ephedrine,
  • epinephrine ergine, hydroxyamphetamine, isoproterenol, levonordefrin, metaraminol, methamphetamine, methoxamine, methylphenidate, neuropeptide Y, naphazoline,
  • norepinephrine norepinephrine, oxymetazoline, phenylephrine, pseudoephedrine, tetrahydozoline, thromboxane, tramazoline, tyramine, and any combination thereof.
  • the transdermal delivery formulation or system of the present invention can deliver a wide variety of active ingredients.
  • Active ingredients can be used to treat a number of diseases, disorders, or conditions including musculoskeletal disease, vascular disease, neurological diseases, viral, bacterial or parasitic disease, blood disease, skin disease, autoimmune diseases, organ disease, pain, and others. Accordingly, active ingredients of pharmaceuticals used to treat these diseases can be used in the transdermal delivery system of the present invention.
  • active ingredients include acetaminophen, acetohydoxamic acid, acetophenazine, acyclovir, albuterol, allopurinol, amiloride, amoxicillin, amphetamine, ampicillin, antisense polymers, atenolol, baclofen, beclomethasone, benfotiamine, betamethasone, budesonide, bumetanide, butorphanol, carbamazepine, carphenazine, celacoxhib, cefuroxime, cephradine, chloramphenicol, chlorothiazide, chlorzoxazone, cinoxacin, clorazepate, cloxacillin, cyclacillin, dapsone, dicloxacillin, diethylstilbestrol, dopamine, doxorubicin, erythropoietin, estradiol, fenoprofen, gabapentin,
  • HC Toxin ITSA1, nullscript, phenylbutyrate, sodium, scriptaid, splitomicin, suberoyl bis- hydroxamic acid, a sirtuin activators, resveratrol, isonicotinamide, butein, luteolin, plant extract, and any combination thereof.
  • the transdermal delivery system also includes
  • transpiration barrier wherein the transpiration barrier can be a chemical barrier or a physical barrier.
  • the present invention relates to methods for transdermal delivery of a formulation having an active ingredient to a mammal, wherein the mammal has a body surface that includes a stratum corneum, an epidermis, a basement membrane, and a dermis.
  • the steps of the method include applying the formulation, described herein, to the body surface.
  • the agents of the formulation can be in a single step, in separate steps or the agents can be applied in any combination thereof to allow for delivery of the active ingredient.
  • the method of the present invention can include, in one embodiment, the steps of administering at least one penetration agent to the body surface; administering at least one basement membrane disruptor to the body surface, wherein the basement membrane disruptor reversibly denatures the basement membrane;
  • the penetration agent, basement membrane, vaso-modulator, and active ingredient are applied sequentially, and in another method, they are applied in combination.
  • the method can optionally further include applying an occlusive barrier to the body surface.
  • the present invention further includes systems or kit for transdermal delivery of an active ingredient to a mammal.
  • the kit or system encompasses the agents described herein and include at least one penetration agent, at least one basement membrane disruptor that reversibly denatures the basement membrane; at least one vaso-modulator; and at least one active ingredient.
  • the kit or system creates a formulation that allows for penetration of the active ingredient to the dermis.
  • the present invention also includes a set of written instructions for use, by or on said mammal.
  • the transdermal delivery formulation of the present invention results in an expanded range of active ingredients that can be delivered through the skin.
  • active ingredients that can be delivered through the skin.
  • the inventive formulation addresses a difficult-to-penetrate skin layer, the basement membrane, and allows for the passage of the active pharmaceutical agents into the dermis and subsequent delivery into localized tissue or the blood stream. This delivery avoids side effects of orally delivered medications.
  • FIG. 1 is a flow diagram showing the steps of method 100 of the transdermal delivery system of the present invention.
  • the skin being the barrier organ of the body, consists of various structural layers.
  • the basement membrane is a very dense protein layer that separates the living tissue of the skin (dermis) from the non- living skin layers (epidermis, stratum corneum).
  • the basement membrane is one of the densest tissues in the human body. In the skin, it functions to not only prevent foreign particles from penetrating into living tissue (the dermis), but it also functions to prevent fluids and living tissue constituents from moving out of the dermis and into the epidermis. In fact, in addition to providing a barrier and separation function, the basement membrane structurally anchors the epidermis to the dermis.
  • G00201 Each layer is unique and designed to either limit the rate of penetration of a foreign matter or completely block its penetration.
  • the present invention utilizes the concept that layers of the skin, including the difficult-to-penetrate basement membrane, can be penetrated with certain chemical components.
  • the present invention provides a novel transdermal delivery system that has a (e.g., one or more) basement membrane disruptor that allows for passage of the active ingredient through the basement membrane.
  • the transdermal delivery system of the present invention further includes a (e.g., one or more) penetration agent that allows for penetration of the stratum corneum, epidermis and a delivery package that encompasses a (e.g., one or more) vaso-modulator and an (e.g., one or more) active ingredient.
  • a penetration agent that allows for penetration of the stratum corneum, epidermis
  • a delivery package that encompasses a (e.g., one or more) vaso-modulator and an (e.g., one or more) active ingredient.
  • the basement membrane consists of two major protein layers.
  • the first protein layer is
  • the basil lamina is a dense structural protein layer with a thickness of approximately 20nm-l00nm consisting of Type IV collagen. This layer has two component layers: lumina lucida and lumina densa.
  • the second layer in the basement membrane consists of reticular connective tissue which is made up of collagen and connects to the basil lamina. Left unaltered, the basement membrane layers synergistically work to either prevent active pharmaceutical movement into the dermis or reduce the rate of flux to a level of sub-therapeutic drug flow. If the active pharmaceutical agent is not able to move into the dermis, it cannot move into deep local tissue or the blood stream for therapeutic benefit.
  • using a basement membrane disruptor in the inventive delivery system allows for efficient permeation by the active drug compound through the basement membrane into the dermis and from there into local tissue or the blood stream for therapeutic purposes.
  • the present invention relates to a transdermal drug delivery formulation that has at least three components. These component parts consist of: penetration agents, basement membrane disruptors and a delivery package. Each component can work by itself, or in combination with other agents/chemicals.
  • the penetration agents function by allowing the delivery package and basement membrane disruptors to pass through the stratum corneum and epidermal skin layers and reach the basement membrane.
  • the basement membrane disruptors function by temporarily or reversibly denaturing the basement membrane. In other words, the disrupter allows for basement membrane to denature and renature. During this action the basement membrane becomes permeable. This permeability then allows the delivery package to move into the dermis.
  • the delivery package which encompasses the active pharmaceutical agents and optionally other agents, is now, if desired, positioned to move out of the dermis and into either the blood stream or their intended therapeutic tissue.
  • Fig. 1 is a flow diagram, which outlines steps of method 100 for allowing an active agent to penetrate the skin, thereby entering the dermis, to deliver the active agent to localized tissue or the systemic circulation.
  • the transdermal delivery formulation includes one or more penetration agents, one or more basement membrane disruptors and a delivery package which encompasses one or more active ingredients in combination with one or more vaso-modulator (e.g., a vasodilator or vasoconstrictor) (step 102).
  • the formulation is applied to or within the skin in step 104, and once applied, steps 106, 108 and 110 occur.
  • the penetration agent allows for passage of the basement membrane disruptor and the delivery package through the stratum corneum and the epidermis to the basement membrane in step 106.
  • the basement membrane disruptors induce reversible denaturing of the proteins which makes the basement membrane permeable and allows for passage of the delivery package through the basement membrane to the dermis.
  • the vaso-modulator causes a fluid dynamic event to deliver the active ingredient to the local tissue or systemically.
  • the formulation can include excipients, penetration enhancers, lipids, or other substances.
  • the formulation can also be a patch or a component of a patch or similar drug delivery device.
  • Penetration agents refers to one or more agents that function to penetrate through both the stratum corneum layer and the epidermal layer of the skin to the basement membrane.
  • Penetration agents include one or more of the following: a solvent, a lipophilic agent, a hydrophilic agent, or a combination thereof.
  • the solvent used in the inventive transdermal delivery system can be one or more nonpolar solvents, one or more polar aprotic solvents (including dipolar aprotic solvents), one or more polar protic solvents, one or more limonenes, or combination thereof.
  • the penetration agent used in the present invention can be any combination of a solvent, a lipophilic agent, and/or a hydrophilic agent.
  • a solvent can be used as the penetration agent alone or in combination with a lipophilic agent and/or a hydrophilic agent.
  • a combination of a lipophilic agent and/or a hydrophilic agent can be used to penetrate the stratum corneum layer and the epidermal layer of the skin.
  • the penetration agents allow the basement membrane disruptor and delivery package to pass through the stratum corneum and epidermal layers and arrive at the basement membrane.
  • Polar solvents are those that have large dipole moments (aka“partial charges”) and generally contain bonds between atoms with very different electronegativities, such as oxygen and hydrogen. Polarity can be measured using the dielectric constant or from directly measuring the dipole moment.
  • Non-polar solvents generally have bonds between atoms with similar electronegativities, such as carbon and hydrogen.
  • Examples of non-polar solvents encompass carbon tetrachloride (CC14), benzene (C6H6), diethyl ether (CH3CH20CH2CH3), hexane (CH3(CH2)4CH3), and methylene chloride (CH2C12).
  • An example of a non-polar, protic solvent further includes toluene.
  • protic solvents are those that contain a hydrogen atom linked to an oxygen
  • polar protic agents have high dielectric constants and high polarity. Examples of polar protic solvents: water (H-OH), methanol, isopropanol, acetic acid (CH3CO-OH) methanol (CH3-OH), ethanol (CH3CH2-OH), n- propanol (CH3CH2CH2-OH), n-butanol (CH3CH2CH2CH2-OH). Polar aprotic solvents exhibit intermediate dielectric constants, they are polar and are highly miscible in water.
  • polar aprotic solvents are propylene carbonate.
  • polar protic and/or polar aprotic solvents are preferred.
  • Limonenes used as a solvent in the present invention to penetrate the stratum corneum layer and the epidermis include D-limonene (citrus oils) or L-Limonenes (mint oils), and optionally together with a liquid hydrocarbon.
  • Additional examples of some penetration agents include individual fatty acids, fatty acid esters, polyols, amides, various anionic, cationic and nonionic surfactants such as but not limited to sodium laurate and sodium lauryl sulfate, phospholipids, cholesterol and cholesterol derivatives, m-pyrrole, dimethyl acetamide, limonene, sphingo lipids, ceramides, terpenes, alkanones, menthol, various organic acids, such as but not limited to salicylic acid, citric and succininc acid, prostaglandins, decyl-methyl sulfoxide, sulfoxide alcohols, plant extract oils.
  • various anionic, cationic and nonionic surfactants such as but not limited to sodium laurate and sodium lauryl sulfate, phospholipids, cholesterol and cholesterol derivatives, m-pyrrole, dimethyl acetamide, limonene, sphingo lipids, ceramide
  • Suitable fatty acids include without limitation: linoleic acids, linolenic acids, oleic acids, stearic acids, and myristic acids.
  • Phospholipids include without limitation: phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine.
  • Plant extract oils include, but are not limited to, oils of peanut, grape seed, hemp, borage, tea tree, winter green, lemon, olive, sunflower, soy- bean, eucalyptus, monoi and macadamia.
  • the plant extract oil can be mixed with an alcohol such as ethyl alcohol, isopropyl alcohol, and methyl alcohol.
  • Penetration agents can also include vitamins for example like vitamin E, C or D.
  • G00321 Some penetration agents are commercially available from Fisher Scientific (Pittsburgh).
  • Penetration agents now known, or developed in the future, can be used in the compositions and methods of the inventive transdermal delivery system so long as the penetration agents allow for penetration of the basement membrane disruptor and delivery package through the stratum comeum layer and/or epidermal layer.
  • the penetration agent can be included in the formulation in sufficient concentration and in effective amounts to allow for penetration through both the stratum corneum layer and/or the epidermal layer of the skin to the basement membrane.
  • a pharmaceutical transdermal formulation includes a concentration of penetration agents from about 1% w/w to about 60% w/w (e.g., 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60% w/w).
  • the transdermal delivery system and methods of the present invention utilize one or more basement membrane disruptors. They are agents that cause the basement membrane to become permeable.
  • a basement membrane disruptor can be used by itself or in combination with others.
  • the proteins in the basement membrane will be reversibly denatured. This denaturing process disrupts the quaternary, tertiary and/or secondary structures of the protein. Disrupting these structures will reversibly and temporarily alter the shape and confinnation of the protein allowing for permeability through the basement membrane and therefore allow for penetration of the delivery package of the transdermal delivery system.
  • basement membrane disruptor agents include one or more chaotropic agents or one or more other agents that allow for denaturing or permeability of the basement membrane proteins, or a combination thereof.
  • Chaotropic agents are agents that disrupt the hydrogen bonding network between water molecules.
  • Examples of a basement membrane disruptors include guanidine hydrochloride, a guanidine salt, guanidine analogs, guanidine conjugates or any combination thereof.
  • An analog, as used herein, is a compound that has similar structural, physical, chemical, biochemical, functional, or pharmacological properties to that of guanidine, and is able to reversibly denature the basement membrane.
  • the basement membrane disruptor can be included in the formulation in sufficient concentration (and therefore at sufficient activity) to create a condition of reversible denaturing of the proteins in the basement membrane.
  • a pharmaceutical transdermal formulation includes a concentration of basement permeation disruptors from about 0.2% w/w to about 10% w/w (e.g., 0.2, 0.3, .0.4, 0.5, .0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.4, 1.6, 1.8, 2.0,
  • Basement membrane disruptors now known, or developed in the future, can be used in the formulations of the inventive transdermal delivery system so long as the disruptor causes permeability of the basement membrane or reversibly denatures the proteins of the basement membrane.
  • the delivery package includes of the active pharmaceutical agents that are targeted to reach the living skin layer (dermis).
  • the delivery package includes at least two types of compounds: the therapeutic drug or drugs having an“active agent” or“active ingredient” and a vaso- modulating agent.
  • Therapeutic drugs having an“active agent” or“active ingredient” and a vaso- modulating agent.
  • G00401 A“therapeutic drug,”“active agent” or an“active ingredient” are interchangeable and refers to any component of a formulation that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, amelioration, or prevention of disease, condition or disorder.
  • active ingredients that are useful in the topically applied pharmaceutical formulations and methods of the instant invention include antifungal agents; anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDS) and steroidal anti
  • inflammatory drugs antibiotics; antiviral agents; anti -neoplastic agents; astringents; anesthetics; systemic drugs; steroid hormones, such as estradiol and testosterone; cosmetic agents, such as skin moisturizers, protectants, and emollients; nutrients, such as vitamins; and ceramides, and other known to those skilled in the art (e.g., those ingredients listed by the U.S. Food and Drug Agency in“Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)”, available at: http://www.fda.gov/Drugs/InformationOnDrugs/ucml29662.htm that are judged suitable by those skilled in the art), the entire teaches are hereby incorporated by reference.
  • active ingredients include acetaminophen, acetohydoxamic acid,
  • acetophenazine acyclovir, albuterol, allopurinol, amiloride, amoxicillin, amphetamine, ampicillin, antisense polymers, atenolol, baclofen, beclomethasone, benfotiamine,
  • the active ingredient can also be a sirtuin inhibitors such as nicotinamide, AIII, coumarin, sirtinol, alpha- NAD, carbamido-NAD, trichostatin A, suramin sodium, apicidin, BML-210, BML-266, depudecin, HC Toxin, ITSA1, nullscript, phenylbutyrate, sodium, scriptaid, splitomicin, or suberoyl bis-hydroxamic acid.
  • the active ingredient can be sirtuin activators such as resveratrol, isonicotinamide, butein, or luteolin.
  • active ingredients can also be compounds extracted from plants including hemp and cannabis including compounds like CBD, THC, terpenes etc. Therapeutic drug or active ingredients now known, or developed in the future, can be used in the compositions and methods of the inventive transdermal delivery system.
  • the active ingredient comprises a biological agent.
  • biological agents include peptides, small proteins and protein fragments; antibody fragments; small nucleic acids and nucleic acid fragments such as aptamers and siRNA; or combinations of these.
  • the active ingredient can be included in the formulation in sufficient concentration and in effective amounts to confer the desired effect of the active ingredient.
  • the actual effective amounts of the active agent/ingredient or drug can vary according to the specific composition being utilized, the age, weight and condition of the patient. Dosages for a particular individual patient can be determined by one of ordinary skill in the art using conventional considerations, (e.g. by means of an appropriate, conventional pharmacological protocol). In an aspect, dosing will also depend on the therapeutic effect to be achieved for the disease state.
  • the amount of active ingredient present in the inventive formulation ranges from about .00l%w/w to about 30%w/w (e.g., .001, .005, .01, .05, .1, .5, 1.0, 1.5, 2.0,
  • a vaso-modulating agent A vaso-modulating agent
  • A“vaso-modulating agent” or“vasoactive agent” refer to either a vasodilator or a
  • vasoconstrictor component of a formulation includes pro-drugs of such components.
  • “vaso-modulating agent” or“vasoactive agent” are agents that create intra-dermis fluid dynamic events.
  • the vaso-modulating agent is the active chemical agent designed to create a fluid dynamic event in the dermis in order to move the therapeutic drug from the skin into either the blood stream, lymphatic system or deep into local tissue so that the drug can impart therapeutic benefit.
  • a vaso-modulating agent may not be needed and is optional, or a vasoconstrictor can be used to keep the active agent local.
  • the vaso-modulating agent acts also as the therapeutic drug.
  • a vasodilating agent can be included in the formulation in sufficient concentration and in effective amounts to create a fluid dynamic event in the dermis in order to move the therapeutic drug from the skin into either the blood stream, lymphatic system or deep into local tissue.
  • a pharmaceutical transdermal formulation includes a concentration of vaso- modulating agent from about .005% w/w to about 15% w/w (e.g., .005, .01, .05, .1, .5, 1.0, 1.5,
  • the vascular modifying agent can be a vasodilator.
  • the vasodilator can be in an amount that is effective to cause dilation of capillaries in the dermis, increased blood and fluid flow through the capillaries in the dermis, and/or increased permeation of fluid through the walls of blood vessels in the skin of the patient.
  • the species of vasodilator can be chosen depending on the speed with which the active drug should move from the dermis and therefore affect the tissue being targeted. Aggressive vasodilators like tolazoline, sodium nitroprusside and papaverine can be used to quickly move the active drug from the dermis into the bloodstream.
  • Vasodilators can be used to slowly release the drug from the dermis into the blood stream so that it can be predominately taken up by the localized tissue or provide release over an extended period of time.
  • Vasodilators include, for example, amrinone, arginine, bamethan sulphate, bencyclane fumarate, benfurodil hemi succinate, benzyl nicotinate, buflomedil hydrochloride, buphenine hydrochloride, butalamine hydrochloride, cetiedil citrate, ciclonicate, cinepazide maleate, cyclandelate, di isopropylammonium dichloroacetate, ethyl nicotinate, hepronicate, hexyl nicotinate, ifenprodil tartrate, inositol nicotinate, isoxsuprine hydrochloride, kallidinogenase, methyl nicotinate
  • oxpentifylline papaverine, papaveroline, pentifylline, peroxynitrite, pinacidil, pipratecol, propentofyltine, raubasine, suloctidil, teasuprine, thymoxamine hydrochloride, tocopherol nicotinate, tolazoline, papaverine, xanthinol nicotinate, diazoxide, hydralazine, minoxidil, and sodium nitroprusside.
  • Centrally acting agents include clonidine, quanaberz, and methyl dopa.
  • Alpha adrenoceptor blocking agents include indoramin, phenoxybenzamine, phentolamine, and prazosin.
  • PDE-5 inhibitors including sildenafil, tadalafil.
  • Adrenergic neuron blocking agents include bedmidine, debrisoquine, and guanethidine.
  • ACE inhibitors include benazepril, captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, and ramipril.
  • Ganglion blocking agents include pentolinium and trimetaphan.
  • Calcium channel blockers include amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil.
  • Prostaglandins including: prostacyclin, thrombuxane A2, leukotrienes, PGA, PGA1, PGA2, PGE1, PGE2, PGD, PGG, and PGH.
  • Angiotensin II analogs include saralasin.
  • Other suitable vasodilators include nitroglycerin, labetalol, thrazide, isosorbide dinitrate,
  • Natural vasodilators include cinnamaldehyde, tea tree oil, eucalyptus, lemon, coriander, peppermint, helichrysum, cistus, cypress, lentisque, juniper berry, niaouli, ginger, rosemary, basil, sage, geranium and cumin.
  • Vasodilators for use with the present invention are commercially available, for example, from Sigma Aldrich (St.
  • Vasodilators now known, or developed in the future, can be used in the compositions and methods of the inventive transdermal delivery system so long as the vasodilators creates a fluid dynamic event in the dermis to move the therapeutic drug from the skin into either the blood stream, lymphatic system or deep into local tissue.
  • the vascular modifying agents can be vasoconstrictors in order to keep the active ingredient/active drug in the skin (e.g., at the dermis) to treat skin disorders or the like.
  • a vasoconstrictor that can be used in the present invention includes an agent that narrows blood vessels in the dermis.
  • a vasoconstrictor can be used in the instance when local dermal tissue is targeted. The vasoconstrictor allows the active ingredient to remain localized and reduces or eliminates release into systemic circulation.
  • vasoconstrictors examples include adenosine triphosphate, amphetamine, antazoline, asymmetric dimethylarginine, cocaine, dopamine, endothelin, ephedrine, epinephrine, ergine, hydroxyamphetamine, isoproterenol, levonordefrin, metaraminol, methamphetamine, methoxamine, methylphenidate, neuropeptide Y, naphazoline, norepinephrine, oxymetazoline, phenylephrine, pseudoephedrine,
  • vasoconstrictors are commercially available, for example, from Spectrum Chemical MFG Corp (New Brunswick, New Jersey, EISA), BASF (Florham Park New Jersey, EISA), or Thermo Fischer Scientific (Waltham Massachusetts EISA).
  • Vasoconstrictors now known, or developed in the future, can be used in the compositions and methods of the inventive transdermal delivery system so long as the vasoconstrictors creates a fluid dynamic event in the dermis involving a narrowing of the blood vessels to keep the active ingredient in the dermis and prevent or reduce release of the active ingredient from the skin
  • the vasoactive agent can be chosen to exert effects rapidly (e.g., within 10 minutes or less), over a longer period of time (e.g., over the course of an hour or more).
  • the vasoactive agent can also be chosen to give a delayed release (e.g., release begins after 10 minutes). Multiple vasoactive agents can be combined to result in both rapid and longer-term effects on the skin.
  • the transdermal delivery system of the present invention can be a formulation having the agents described herein.
  • A“formulation” is a preparation in which various chemical substances are combined with an active ingredient.
  • a formulation includes a composition of the invention in the form of an emulsion, ointment, cream, lotion, gel, salve or the like, for topical application or delivery of the drug to a patient.
  • a formulation is used in conjunction with a delivery system (such as a patch) impregnated with or containing a composition suitable for topical application.
  • the term“patient” or“individual” refers to any animal, including mammals such as a human, non-human primate, mouse, rat, guinea pig, rabbit, pig, horse or dog.
  • Topical application shall mean application of a formulation to body surfaces such as the skin or mucous membranes, for example the vagina, anus, throat, nose, eyes and ears.
  • topical application shall include application to the stratum corneum, microinjection to the epidermis (such as can be achieved with microneedles), or use of sonophoresis, iontophoresis or other permeation-enhancing methods, without piercing of the basement membrane and subsequent injection to the dermis or subcutaneous structures.
  • the application of the topical/transdermal formulation of the components can occur simultaneously or sequentially in time.
  • the term "co-administration" is used herein to mean that the components of the transdermal delivery system will be administered at times to achieve delivery of the active ingredient.
  • the formulation is applied in order to penetrate layers of the skin, starting from the outside layers and going inward.
  • the penetration agents are applied first, then the basement disruptors and subsequently or simultaneously the delivery package.
  • the methods of the present invention are not limited to the sequence in which the compounds are administered, so long as the delivery package penetrates through the outer layers of the skin to the dermis.
  • a transpiration barrier can also be applied sequentially with respect to the other components one or more times.
  • the functions of two or more penetration agents, basement membrane disruptors and/or vaso-modulators can be provided by a single compound.
  • a single compound can have more than one function, and act as a penetration agent, a basement membrane disruptor and/or a vaso-modulator.
  • the transdermal delivery formula may be used with a transpiration barrier or an occlusive barrier.
  • A“transpiration barrier” shall mean a component such as a solid patch, a hydrophobic chemical component, or a self-assembling chemical component (including components that form gels) that is capable of preventing water loss from skin tissue due to transpiration when applied to the skin of a patient.
  • An“occlusive barrier” can be used to apply the formula to the skin or other tissue (e.g., application device), to prevent against cross contamination of clothes or other individuals (e.g., barrier device), to allow for timed release or enhanced delivery (e.g., delivery device).
  • the occlusive barrier is in the form of a physical patch like material, a tegaderm like barrier material, or a transpirational barrier (silicone, vasoline etc).
  • the method includes optionally applying a transpiration barrier.
  • transpiration barrier can be a water impermeable drug administration patch; for example, a sheet of water-resistant plastic with an adhesive layer or other attachment mechanism.
  • the patch can be applied atop a formulation applied to the skin.
  • the patch can be impregnated with the formulation and applied to the skin to contact the vaso-modulator agent, active ingredient, the basement membrane or the penetration agent with the skin while forming the transpiration barrier.
  • a water-impermeable wrap, glove, sock, mitten, or the like can also serve to create a physical barrier.
  • the transpiration barrier can include a molecular
  • the molecular barrier can include silicone, titanium oxide, polyvinyl alcohol and hydrogels. It should be noted that both a chemical barrier and a physical barrier can be used together or sequentially.
  • the formulation can be applied to the skin; i.e., topically (step 104).
  • the skin i.e., topically (step 104).
  • the formulation can be applied to the skin; i.e., topically (step 104).
  • the formulation can be a cream, lotion, ointment, gel, or other substance suitable for topical application to the skin.
  • the skin can be mechanically worked to enhance the penetration of the active ingredient past the epidermis (e.g., into or through the basement membrane).
  • mechanical work can be used in the form of massaging, or sonophoresis.
  • Mechanical working processes also include processes of cutting, ulceration, wound formation or piercing.
  • piercing the skin with microneedles e.g., with a device having projections designed to pierce the stratum comeum without the substantial triggering of deeper pain receptors
  • Microneedles are disclosed, for example, in U.S. Pat. No. 6,611,707, issued on Aug.
  • the formulation can be delivered into the skin.
  • the formulation can be injected into the epidermis with microneedles.
  • the formulation can also include excipients or carriers such as Stearyl Alcohol, Polysorbate
  • Caprylic/Capric Glyceride Petrolatum, Beeswax, Lecithin, Dimethicone, Alkylmethyl Siloxane, Stearic Acid, Palmitic Acid, Lanolin, Linoleic Acid, Isopropyl Myristate, Stearyl Octanoate and Cetyl Octanoate, and Polysorbate 80.
  • Embodiments of the invention can be useful for medical conditions, diseases or disorders such as musculoskeletal diseases, vascular diseases, neurological diseases, viral, bacterial or parasitic diseases, blood disorders, skin diseases, autoimmune diseases, organ diseases, pain, and others.
  • diseases or disorders such as musculoskeletal diseases, vascular diseases, neurological diseases, viral, bacterial or parasitic diseases, blood disorders, skin diseases, autoimmune diseases, organ diseases, pain, and others.
  • the number of diseases is numerous, but some examples include basal cell carcinomas, melanoma, cervical carcinomas, cervical condylomas, genital warts, herpetic lesions, diabetic neuropathy, chemotherapy-derived neuropathy, general neuropathy, benign prostatic hypertrophy, solid tumors, psoriasis, and eczema.
  • the active ingredient is a sirtuin inhibitor or sirtuin activator and the formulation is applied to the skin of a patient to treat one of these medical conditions.
  • the formulation can be applied to a region of the skin or tissue associated with the medical condition.
  • the formulation is cosmetically suitable in that it can be applied to the skin without detrimentally affecting the appearance of the skin.
  • the formulation can be applied to other exterior regions of the body including to the fingernails, toenails, ocular tissue, vagina, rectum (as a suppository), and other tissue surfaces containing an epithelial cell layer.
  • G00601 A formulation can be tested for its ability to increase circulation using laser Doppler
  • the test can be performed on participants after a 20-minute acclimatization period in a warm environment (room temperature 24° C.). For each subject, the blood flow response is measured with the non-invasive test before and after the application of the test formulation and at various intervals of time after the application until the blood flow has returned to a pre-application level.
  • the measurement of skin blood flow can be evaluated using a Laser Doppler Perfusion Imager (LDPI Lisca 2.0, Lisca development AB, Linkoping,
  • This apparatus employs a 1 mW Helium-Neon laser beam of 633 nm wavelength, which sequentially scans the tested area. Typically, maximum number of measured spots is 4096 and the apparatus produces a color-coded image of the tissue perfusion distribution on a computer monitor.
  • the data acquired from the instrument can be statistically analyzed with The Minitab statistical package (Minitab, State College, Pa.) for personal computers.
  • the Minitab statistical package (Minitab, State College, Pa.) for personal computers.
  • the paired t-test can be used to compare changes between baseline and the maximal vasodilation.
  • the test can be used for comparison between the two groups of patients. Changes in the microvascular blood flow can be expressed as the difference between the peak response and the baseline blood flow (e.g., in ml/min, laser-doppler velocimetry voltage readout, or other suitable units).
  • application of the formulation can cause an increase in blood flow at or near the region of application.
  • the increase can range from about 1% to greater than about 500%.
  • Animal models can be used to evaluate the effectiveness of a topically applied formulation in penetrating the skin tissue for either intradermal or transdermal systemic distribution of the active ingredient.
  • Animal models that are preferred include pigs, guinea pigs, rabbit and mini pigs.
  • An example of the procedure used for such a study using guinea pigs is as follows: Male Hartley guinea pigs (250-300 g) are shaved on the back, and an area of 4x4 cm depilated with Nair® depilatory cream. After approximately 24 hours, 0.5 g of test compound in a topical formulation is applied to the 4x4 cm area and covered with an occlusive wrap.
  • the amount of active ingredient in the blood and the amount of active ingredient in the skin tissue may be compared to give information about the pharmacokinetics of the active ingredient.
  • skin tissue e.g., a skin tumor or lesion
  • a higher amount in the skin relative to the blood is more efficacious, whereas when the goal is systemic delivery of the active ingredient, a higher distribution in the blood is more efficacious.
  • the transdermal delivery system of the present invention is effective in delivering the active ingredient.
  • the inventive transdermal delivery system is as effective in delivering the active ingredient, as compared to traditional methods of administration such as oral administration.
  • the inventive transdermal delivery system delivers the active ingredient more effectively, as compared to its oral administration or other transdermal administrations (at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% more effective).
  • kits or systems are used for topical or transdermal delivery of an
  • the kit includes one or more of the following: a penetration agent, a basement membrane disruptor and a delivery package comprising a vaso-modulator and active ingredient.
  • the kit can also include a set of written instructions for use thereof according to one of the methods of topical or transdermal delivery described herein.
  • the kit optionally includes an occlusive barrier.
  • a kit is supplied to a compounder.
  • the kit contains the
  • components/agents described herein e.g., a penetration agent, a basement membrane disruptor and a delivery package
  • a penetration agent e.g., a basement membrane disruptor and a delivery package
  • G00661 in another embodiment, there is a method of manufacturing a medicament for transdermal administration.
  • the method includes combining a penetration agent, a basement membrane disruptor and a delivery package comprising a vaso-modulator and active ingredient in sufficient amounts to cause permeation of the active ingredient to at least one affected region of a patient when applied to one of the skin and other exterior region of the patient.
  • G00801 The terms,“comprise,”“include,”“having” and/or plural forms of each are open ended and include the listed items and can include additional items that are not listed.
  • the phrase“And/or” is open ended and includes one or more of the listed items and combinations of the listed items.

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Abstract

La présente invention concerne des systèmes, des méthodes et des kits d'administration transdermique qui comprennent un agent qui permet de pénétrer dans la membrane basale, une membrane de la peau auparavant décrite comme difficile à pénétrer. En particulier, la formulation comprend un perturbateur de la membrane basale qui dénature de manière réversible la membrane basale de la peau. La formulation de la présente invention comprend en outre au moins un agent de pénétration, au moins un vaso-modulateur et au moins un principe actif. Dans un mode de réalisation, l'agent de pénétration comprend un solvant, un agent lipophile, un agent hydrophile, le perturbateur de la membrane basale, le modulateur vasculaire et le principe actif passant à travers la couche cornée et l'épiderme. Le perturbateur de la membrane basale permet au modulateur vasculaire et au principe actif de passer à travers la membrane basale afin de pénétrer dans le derme. Le principe actif, une fois au niveau du derme, est administré localement au tissu ou de façon systémique au flux sanguin.
EP19794747.6A 2018-09-25 2019-09-25 Système d'administration transdermique de médicament Pending EP3856140A1 (fr)

Applications Claiming Priority (3)

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US201816582922A 2018-09-25 2018-09-25
US201862737479P 2018-09-27 2018-09-27
PCT/US2019/053000 WO2020069013A1 (fr) 2018-09-27 2019-09-25 Système d'administration transdermique de médicament

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