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WO2001035883A1 - Systeme d'administration transdermique d'alcaloides de l'espece aconitum - Google Patents

Systeme d'administration transdermique d'alcaloides de l'espece aconitum Download PDF

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Publication number
WO2001035883A1
WO2001035883A1 PCT/US2000/031821 US0031821W WO0135883A1 WO 2001035883 A1 WO2001035883 A1 WO 2001035883A1 US 0031821 W US0031821 W US 0031821W WO 0135883 A1 WO0135883 A1 WO 0135883A1
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Prior art keywords
set forth
formulation
aconitine
transdermal formulation
mixtures
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PCT/US2000/031821
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English (en)
Inventor
Weihong Xiong
Dinesh C. Patel
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Xel Pharmaceuticals Inc
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Xel Herbaceuticals Inc
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Priority to AU17801/01A priority Critical patent/AU1780101A/en
Publication of WO2001035883A1 publication Critical patent/WO2001035883A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention relates generally to a composition and method for ameliorating pa and inflammation More particularly, the present invention relates to a pain and inflammation ameliorating composition, which contains an alkaloid compound extracted from an A conitum plant species BACKGROUND OF THE INVENTION
  • a pain and inflammation ameliorating composition which contains an alkaloid compound extracted from an A conitum plant species BACKGROUND OF THE INVENTION
  • Man> analgesics such as codeine, tramadol. and dextropropoxyphene ha ⁇ e been used to manage mild to moderate pam Additionally . for more severe pain.
  • opioids such as morphine, methadone. oxycodone. buprenorphme, hydromorphone. fentanyl. and heroin have been used Unfortunateh . hea ⁇ use of opioids. or other narcotics often leads to chemical dependence, or addiction Chemical dependence is often extremely difficult and painful to overcome.
  • One common treatment involves administering opioids and opioid analgesics in decreasing doses over an extended duration.
  • methadone is known for treating heroin addiction by being administered in gradually decreasing amounts. While such regimens do tend to alleviate many of the withdrawal symptoms associated with detoxification, they take months to complete and are therefore only marginally successful in helping the addict take a permanent step away from chemical dependence.
  • an analgesic agent formulation which can be delivered with long lasting potency and at infrequent intervals would be advantageous. Additionally, it has been recognized that an analgesic agent which also imparts an anti-inflammatory effect, and which imparts minimal side effects, such as drug dependency would be advantageous.
  • Plant extracts from different species of Aconitum plant have been employed in many holistic medicine cultures for their various medicinal and positive health properties.
  • traditional Chinese medicine has long used Aconitum extracts for their various analgesic, anti-rheumatic, anti-narcotic, and antipyretic properties. These properties have now been largely attributed to the diterpenoid alkaloids found within the various Aconitum plant species.
  • aconitine Among the Aconitum plant derived alkaloids, aconitine, 3-acetylaconitine, lappaconitine, N-deacetyl-lappaconitine, songtiening, and bulleyaconitine A, have become particularly known for their powerful analgesic properties. Further, 3- acetylaconitine and lappaconitine have been shown to be centrally acting analgesics without affinity for opioid receptors.
  • extracts of Aconite roots have no affinity for opioid receptors, they may be used to expediently relieve drug addiction.
  • lappaconitine and bulleyaconitine A dosage regimens have been shown to relieve drug dependence and remove withdrawal syndrome within 3-4 days. Significant results in such a shortened duration provide a great improvement over known treatment using successively less potent opioids. Accordingly, in the present invention provides a transdermal formulation for ameliorating pain and inflammation.
  • the transdermal formulation includes an amount of an aconitine alkaloid, which is sufficient to achieve an aconitine alkaloid blood plasma level of from about 0.5 to about 400 ng/ml, an inert carrier and, a permeation enhancer selected from the group consisting of: fatty acids, fatty acid esters, fatty alcohols, fatty acid esters of lactic acid, fatty acid esters of glycolic acid, amides, amines, pyrrolidones, glycerol triesters, terpenes, surfactants, complexing agents, biologies, their salts, and mixtures thereof.
  • an inert carrier and, a permeation enhancer selected from the group consisting of: fatty acids, fatty acid esters, fatty alcohols, fatty acid esters of lactic acid, fatty acid esters of glycolic acid, amides, amines, pyrrolidones, glycerol triesters, terpenes, surfactants,
  • the blood plasma concentration of an aconitine alkaloid achieved is from about 5 to about 200 ng/ml.
  • the transdermal formulation achieves the blood plasma level of from about 0.5 to about 400 ng/ml within about 0.25 to about 18 hours after administration of the formulation.
  • the blood plasma level may be achieved within about 0.5 to about 12 hours after administration.
  • the transdermal formulation may be configured to provide an extended or sustained aconitine alkaloid release.
  • a single dosage of the transdermal formulation may be sufficient to achieve and sustain the aconitine alkaloid blood plasma level of from about 0.5 to 400 ng/ml for a duration of at least about 24-96 hours.
  • the aconitine alkaloid may be a member selected from the group consisting of lappaconitine, N-deacetyl-lappaconitine, songtiening, bulleyaconitine A, 3-acetylaconitin, isolappaconitine, deoxylappaconitine, neofinaconitine, ranaconitine, N-deacetylranaconitine, finaconitine, N-deacetylfinaconitine, mesaconitine, jesaconitine, and salts, analogs, derivatives, prodrugs, and mixtures thereof.
  • the aconitine alkaloid may be lappaconitine. In a further aspect, the aconitine alkaloid may be songtiening. In yet another aspect, the aconitine alkaloid may be bulleyaconitine A. In another aspect, the aconitine alkaloid may be ranaconitine. In a further aspect, the aconitine alkaloid may be finaconitine. In another aspect, the aconitine alkaloid may be mesaconitine. In yet another aspect, the aconitine alkaloid may be jesaconitine.
  • the transdermal delivery system of the present invention may include additional analgesics for ameliorating pain and inflammation.
  • the analgesic may be a narcotic agent.
  • the analgesic may be a non-narcotic agent.
  • the narcotic agent may be selected from the group consisting of: alfentanil, benzylmorphine, codeine, desomorphine, endorphins, ethylmorphine, fentanyl, hydromorphone, lavorphanol, levomethadyl acetate, meperidine, Methadone, morphine, normorphine, normethadone, opium, oxycodone, oxymorphone, remifentanil, sufentanil, tilidine, and salts, analogs, derivatives, and mixtures thereof.
  • the narcotic agent may be a member selected from the group consisting of: buprenorphine, butorphanol, dezocine, eptazocine, nalbuphine, pentazocine, and salts, analogs, derivatives, and mixtures thereof.
  • the additional analgesic may be a non- narcotic agent.
  • the non-narcotic agent may be a member selected from the group consisting of: acetaminophen, aspirin, clonidine, diflunisal, methotrimeprazine, salicylates, salicylic acid, tramadol, and salts, analogs, derivatives, and mixtures thereof.
  • the non-narcotic agent may be a non- steroidal anti-inflammatory drug (NSAID).
  • the NSAID may be a member selected from the group consisting of: butibufen, carprofen, celecoxib, diclofenac, diflunisal, etodolac, flurbiprofen, fennoprofen calcium, flunixin meglumine, ibuprofen, idomethacetin, ketoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, naproxen, nabumetone, oxaprozin, phenylbutazone.
  • the non-narcotic agent may be melatonin. In a further aspect, the non-narcotic agent may be tetrahydropalmatin. In yet another aspect of the invention, the non-narcotic may be ferulic acid. In an additional aspect of the invention, the non-narcotic may be sinomenine. In yet another aspect of the invention, the non-narcotic agent may be anisodin. In a further aspect of the invention, the non-narcotic agent may be dicentrin. In another aspect of the invention, the non-narcotic agent may be anisodamin. In an additional aspect of the invention, the non-narcotic agent may be capsaicin. In a further aspect of the invention, the non-narcotic may be glucosamine. In yet another aspect of the invention, the non-narcotic may be a rhynochophylla- derived alkaloid.
  • the transdermal aconitine alkaloid formulation may further include one or more treatment agents, or drugs for treating specific diseases or conditions.
  • the treatment agent may be an anticholinergic agent.
  • the anticholinergic agent may be a member selected from the group consisting of: adiphenine, anisotropine, atropine, benzetimide, clidinium, deptropine. dicyclomine, diponium, glycopyrrolate, hydroxyzine, orphenadrine, oxybutynin, propantheline, scopolamine, as well as salts, derivatives, analogs, and mixtures thereof.
  • the treatment agent may include anti-migraine agents.
  • the migraine agent may be a seratonin 5-HT receptor agonist.
  • the seratonin 5-HT receptor agonist may be a member selected from the group consisting of: naratriptan, rizatriptan, sumatriptin, zolmitriptan, salts, derivatives, analogs, prodrugs, and mixtures thereof.
  • the anti- migraine agent may be methylsergide maleate as well as salts, derivatives, analogs, prodrugs, and mixtures thereof.
  • the anti-migraine agent may include ergotamine derivatives.
  • ergotamine derivatives may be a member selected from the group consisting of: dihydroergotamine mesylate, ergotamine tartrate, as well as salts, derivatives, analogs, prodrugs, and mixtures thereof.
  • the treatment agent may be an antiemetic/antivertigo agent.
  • the antiemetic/antivertigo agent may be a member selected from the group consisting of: chloropromazine, perphenazine, prochlorperazine, promethazine, thiethylperazine, triflupromazine, metoclopramide, benzquinamide, cannabinoids, corticosteroids, hydroxyzine HC1, diphenidol, phosphorated carbohydrates, as well as salts, derivatives, analogs, prodrugs, and mixtures thereof.
  • the transdermal formulation of the present invention may also contain various other positive health-imparting agents.
  • the health imparting agent may be a member selected from the group consisting of: vitamins, minerals, amino acids, herbal and botanical extracts, anti-oxidants, and mixtures thereof.
  • the health-imparting agent may be a vitamin.
  • the health-imparting substance may be a mineral. In yet another aspect, the health-imparting agent may be an amino acid. In yet another aspect, the health-imparting agent may be an herbal extract. In another aspect of the invention, the health-imparting agent may be a botanical extract. In a further aspect of the invention, the health-imparting substance may be an anti-oxidant.
  • transdermal formulations may be used as part of the present invention for transdermally delivering aconitine alkaloids.
  • the transdermal formulation may be a topical formulation.
  • the transdermal formulation may be an adhesive matrix patch.
  • the transdermal formulation may be a liquid reservoir system, or patch.
  • the transdermal formulation of the present invention may include a variety of enhancers, no enhancer is necessary in order to achieve the desired blood plasma levels in many instances. Therefore, in one aspect the transdermal formulation of the present invention may be free of an enhancer.
  • the present invention encompasses a method of ameliorating pain and inflammation. In one aspect, the method includes transdermally administering an amount of an aconitine alkaloid sufficient to achieve an aconitine alkaloid blood plasma level of from about 0.5 to about 400 ng/ml.
  • the transdermal administration of an aconitine alkaloid is sufficient to achieve an aconitine alkaloid blood plasma level of from about 5 to about 200 ng/ml.
  • the aconitine alkaloid blood plasma level is achieved within about 0.25 to about 18 hours after initial aconitine alkaloid administration.
  • the aconitine alkaloid blood plasma level is achieved within about 0.5 to about 12 hours after initiation of the aconitine alkaloid administration.
  • the aconitine alkaloid blood plasma level of about 0.5 to about 400 ng/ml is sustained for a period of at least about 24-96 hours from a single transdermal administration.
  • the method of the present invention further encompasses the co-delivery of an aconitine alkaloid and additional pain and inflammation ameliorating substances, such as the narcotic agents and non-narcotic agents recited herein.
  • good health imparting substances as contained herein may additionally be co-delivered with the aconitine alkaloid of the present invention.
  • an aconitine alkaloid includes reference to one or more of such alkaloids
  • an adhesive includes reference to one or more of such adhesives
  • reference to "a mineral” includes reference to a mixture of two or more of such excipients.
  • alkaloids As used herein, the terms "aconitine alkaloid,” “aconitine-derived alkaloid,” or “aconitine” may be used interchangeably and refer to alkaloids, which are found in or derived from one or more species of Aconitum plant, including the analogues, derivatives, salts, and prodrugs, of such alkaloids, as well as mixtures thereof. Further, such alkaloids may be obtained by synthesis, extraction as a natural product from one or more Aconitum plant species, or by partial extracted and further synthesis.
  • analgesic refers to a compound or agent, which imparts a pain and/or inflammatory ameliorating effect when administered.
  • narcotic As used herein, “narcotic,” “narcotic agent,” “opioid analgesic,” and “opioid analgesic agent” may be used interchangeably, and refer to an analgesic, which ameliorates pain by binding to opioid receptors.
  • non-narcotic refers to an analgesic, which ameliorates pain by a mechanism other than binding to, or otherwise occupying, opioid receptors.
  • treatment agent or “drug” may be used interchangeably, and refer to a physiologically active substance other than huperzine, or other cholinesterase inhibitors, which may be used to treat or improve a physiological condition.
  • treatment agents include, but are not limited to: hormones, anticholinergics, anti-migraines, antiemetics, and mixtures thereof.
  • positive health benefit conveying, or imparting agent refers to any substance either synthesized or extracted from a natural source, which is beneficial to the human body when imparted thereto.
  • Examples of general positive health benefit conveying substances include, but are not limited to vitamins, minerals, anti-oxidants, amino acids, botanical and herbal extracts.
  • aconitine delivery formulation As used herein, "aconitine delivery formulation,” “aconitine alkaloid delivery formulation,” “transdermal delivery formulation,” or “transdermal formulation” refer to any aconitine containing device, system, product, chemical combination, or mechanism capable of being applied to, or against the skin, to effect transdermal delivery, of aconitine alkaloids.
  • the term “skin” refers to any membrane of the human body to which a chemical formulation or composition may be applied including the external skin of the body, the mucosa membranes of the nasal, oral, vaginal, and rectal cavities.
  • transdermal or “percutaneous” delivery means delivery of a substance or agent, by passage into and through the skin.
  • the terms “enhancement”, “penetration enhancement”, or “permeation enhancement” refer to an increase in the permeability of the skin, to a delivery substance or agent, so as to increase the rate at which the delivery substance permeates through the skin.
  • Perfectment refers to an increase in the permeability of the skin, to a delivery substance or agent, so as to increase the rate at which the delivery substance permeates through the skin.
  • Perfectation enhancer refers a material, or materials that achieve or facilitate such permeation enhancement, and an "effective amount" of an enhancer means an amount effective to enhance penetration through the skin, of an aconitine alkaloid, to a selected degree.
  • An index of permeation enhancers is disclosed by David W. Osborne and Jill J. Henke, in their publication entitled Skin Penetration Enhancers Cited in the Technical Literature, published in “Pharmaceutical Technology” (June).
  • pharmtech.com/technical/osborne/osborne.htm which is incorporated by reference herein.
  • Enhanced permeation as affected through the use of such enhancers can be observed, for example, by measuring the rate of diffusion of the delivery substance through animal or human skin using a diffusion cell apparatus.
  • a diffusion cell is described by Merritt et al., Diffusion Apparatus for Skin Penetration, J. of Controlled Released 61 (1984), inco ⁇ orated herein by reference.
  • effective amount refers to the minimal amount of a substance or agent, which is sufficient to achieve a desire therapeutic effect. Therefore, when used in connection with an aconitine alkaloid, effective amount connotates an amount of such agent, which is sufficient to achieve a desired aconitine alkaloid plasma level. Such plasma levels may be achieved within and sustained for various time intervals as determined by the parameters of each particular formulation.
  • the type and amount of aconitine alkaloid, the type and amount of inert carrier, the size of the transdermal formulation, as well as the presence and amount of specific penetration enhancers may all be adjusted to arrive at a formulation which achieves the desired blood levels within a specific time interval.
  • One of ordinary skill in the transdermal arts would be able to readily determine the amount and type of each component in the combination, which are required to achieve the target blood levels within a specified time frame.
  • matrix By the term “matrix”, “matrix system”, or “matrix patch” is meant a pre- determined amount of an aconitine alkaloid dissolved or suspended in a polymeric carrier or phase, in one aspect a pressure-sensitive adhesive, that can also contain other ingredients, or in which a permeation enhancer and other positive health benefit promoting substances may also dissolved or suspended.
  • This definition is meant to include embodiments wherein such polymeric phase is laminated to a pressure sensitive adhesive or used within an overlay adhesive to form an adhesive matrix patch with a reservoir.
  • a matrix system usually and preferably comprises an adhesive layer having an impermeable film backing laminated onto the distal surface thereof and, before transdermal application, a release liner on the proximal surface of the adhesive. The film backing protects the polymeric phase of the matrix patch and prevents release of the delivery substance and/or enhancer to the environment.
  • a matrix system therefore is a unit dosage form, or type of formulation, which includes a predetermined amount of an aconitum alkaloid, as well as other optional ingredients, such as additional analgesics, and good health- imparting ingredients, in a polymeric carrier, which optionally contains an enhancer.
  • adhesive matrix transdermal patches are those described or referred to in U.S. Patent Nos. 5,122,383 and 5,460,820, which are inco ⁇ orated by reference in their entirety.
  • liquid reservoir system As used herein, "liquid reservoir system,” its acronym “LRS,” or “liquid reservoir patch” refers to a transdermal delivery patch or system, in which an aconitine alkaloid and other optional ingredients, such as a permeation enhancer, are admixed with a carrier vehicle.
  • the carrier vehicle comprises a fluid of desired viscosity, such as a gel or ointment, which is formulated for confinement in a reservoir having an impermeable backing and a skin contacting permeable membrane, or membrane adhesive laminate providing diffusional contact between the reservoir contents and the skin.
  • a peelable release liner is removed and the patch is attached to the skin surface.
  • LRS patches are known in the art of transdermal drug delivery. Examples without limitation, of LRS transdermal patches are those described or referred to in U.S. Patent Nos. 4,849,224, 4,983,395, which are inco ⁇ orated by reference in their entirety.
  • inert carrier refers to a polymeric carrier, or other carrier vehicle into which aconitine, or an aconitine-derived alkaloid may be admixed in order to form a transdermal delivery formulation.
  • Inert carriers must generally be pharmaceutically acceptable, in that they are suitable for administration to the skin without causing significant instances of adverse results. Further, inert carriers must not react with the active substance to substantially degrade it, or otherwise form impurities, which may be delivered to the skin.
  • topical formulation refers to a chemical formulation in which an aconitine alkaloid may be inco ⁇ orated, which is capable of being applied directly to the skin, and which does not include supporting structures such as backing films, etc.
  • topical formulations without limitation include, gels, aerosols, creams, lotions, pastes, ointments, etc.
  • areaunderthecurve, areaundertheplasmaconcentration-timecurve, or similar terms are well known in the pharmaceutical arts. These values are calculated by plotting a graph with data from plasma concentration of a given drug or its metabolites as a function of time, with the X-axis generally representing time and the Y-axis generally representing plasma concentration. The area under the line formed by joining the various data points is then integrated into a numerical value. See for •Concentrations, amounts, solubilities, and other numerical data may be presented herein in a range format.
  • a concentration range of 0.5 to 400 ng/ml should be inte ⁇ reted to include not only the explicitly recited concentration limits of 0.5 ng/ml and 400 ng/ml, but also to include individual concentrations within that range, such as 0.5 ng/ml, 0.7 ng/ml, 1.0 ng/ml, 5.2 ng/ml, 8.4 ng/ml, 1 1.6 ng/ml, 14.2 ng/ml, 100 ng/ml, 200 ng/ml, 300, ng/ml, and sub-ranges such as 0.5-2.5 ng/ml, 4.8-7.2 ng/ml,
  • the present invention encompasses a transdermally administered aconitine alkaloid formulation for ameliorating pain and/or inflammation.
  • the aconitine alkaloid is administered in an amount sufficient to affect and maintain an aconitine alkaloid blood plasma level of about 0.5 ng/mL to about 400 ng/mL.
  • the blood plasma level may be about 5 ng/mL to about 200 ng/mL.
  • the time frame for achieving such blood plasma levels may be determined by such parameters as the type and size of the aconitine alkaloid formulation, the amount of alkaloid present in the formulation, and the skin flux rate achieved by the formulation. Further, the flux rate may be determined in part by the presence and amount of various penetration enhancers.
  • Elements such as patch size, aconitine alkaloid content and concentration, enhancer amount, and enhancer type may all be coordinated in order to achieve the desired blood plasma levels within a desired amount of time, as can be readily determined by one skilled in the art.
  • Others physiological factors, such as variations in individual skin type and permeability may effect the ultimate aconitine alkaloid blood plasma level and the time frame in which it is achieved.
  • aconitine blood plasma levels which will result from a particular aconitine alkaloid formulation determined using the following First Order Elimination and Zero-Order Input equations in connection with single compartment skin flux data. 13
  • Cp Plasma concentration (ng/ml or ⁇ g/ml)
  • k 0 Zeor-order input rate ( ⁇ g/h, interval skin flux)
  • Cl: Clearance V K cl (L/hr/kg)
  • Vd Volume of distribution (L or L/kg)
  • Kel First-order elimination rate constant
  • T Duration of zero-order input
  • t t time point of plasma concentration
  • permeation rates of aconitine alkaloids through living human skin may be in the range of about 0.1 ug/cm 2 /hr to about 50 ug/cm 2 /hr.
  • therapeutic blood levels may be achieved in about 0.25-18 hours after initial formulation application.
  • therapeutic blood levels may be achieved in about 0.5 to about 12 hours after initial formulation application.
  • the aconitine alkaloid dosage arriving from a limited area of skin may be from about .1-20 mg over a period of 24 hours.
  • the aconitine alkaloid dosage arriving from a limited area of skin may be from about 1- 10 mg over a 24-hour period.
  • the dosage for lappaconitine may be from about 4-10 mg over a period of about 24 hours.
  • the dosage for 3-acetylaconitine may be from about .2-1 mg over a 24-hour period.
  • the dosage for bulleyaconitine A may be from about .2-2 mg over a 24-hour period.
  • the transdermal formulation may have a size of from about 1-200 cm 2 . In another aspect, the size of the transdermal formulation may be from about 5-100 cm 2 .
  • a single dosage of the transdermal delivery formulation may achieve and sustain the aconitine alkaloid plasma level of from about 0.5 to about 400 ng/ml for a duration of at least about 24-96 hours.
  • Specific aconitine alkaloid delivery formulation types include but are not limited to: 1) topical formulations such as ointments, lotions, gels, pastes, mousses, aerosols, and skin creams; 2) transdermal patches such as adhesive matrix patches and liquid reservoir systems; 3) transmucosal tablets such as buccal or sublingual tablets or lozenges; and 4) suppositories. In short, any transdermal administration form is acceptable.
  • the aconitine alkaloid delivery formulation may also include a permeation enhancer, or mixture of permeation enhancers in order to increase the permeability of the skin to aconitine alkaloids.
  • permeation enhancers include but are not limited to: fatty acids, fatty acid esters, fatty alcohols, fatty acid esters of lactic acid or glycolic acid and their salts, amides, amines, pyrrolidones, glycerol triesters, te ⁇ enes, classical surfactants, organic acids, surfactants, complexing agents, biologies, and mixtures thereof.
  • Azone One enhancer that has been found to be unacceptable is Azone. Although Azone may provide penetration enhancement of various substances, the side effects experienced are considered intolerable. Particularly, Azone has been deemed unusable because of the severe skin irritation that results. Not only does Azone cause irritation to all layers of the epidermis, but also irritates all the dermis layers as well. Further, the skin irritation caused by Azone is irreversible damage, which results in alteration of the tissue and scarring.
  • acceptable fatty acids include but are not limited to, oleic acid, alkanoic acids, capric acid, hexanoic acid, lactic acid, lauric acid, linoleic acid and mixtures thereof.
  • acceptable fatty acid esters include but are not limited to methyl laurate, glycerol monooleate (GMO), sorbitanmonooleate (SMO), glycerol monolaurate (GML), glycerol monolinoleate (GMLO), isopropyl myristate, isopropyl palmitate, methyl propionate, monoglycerides, propylene glycol monolaurate, sorbitan monolaurate, and mixtures thereof.
  • GMO glycerol monooleate
  • SMO sorbitanmonooleate
  • GML glycerol monolaurate
  • GMLO glycerol monolinoleate
  • isopropyl myristate isopropyl palmitate
  • methyl propionate monoglycerides
  • propylene glycol monolaurate propylene glycol monolaurate
  • sorbitan monolaurate and mixtures thereof.
  • acceptable fatty alcohols include but are not limited to lauryl alcohol, caprylic alcohol, myristyl alcohol, cetyl alcohol, aliphatic alcohols, linolenyl alcohol, nerolidol, oleyl alcohol, and mixtures thereof.
  • acceptable fatty acid esters of lactic acid or glycolic acid or their salts include but are not limited to lauroyl glycolate, sodium lauryol glycolate, caproyl glycolate, sodium caproyl glycolate, cocyl glycolate, sodium cocyl glycolate, isostearoyl glycolate, tromethamine lauroyl glycolate, lauroyl lactylate, sodium lauroyl lactylate, caproyl lactylate, sodium caproyl lactylate, cocoyl lactylate, sodium cocyl lactylate, isostearoyl lactylate, tromethamine lauryol lactylate, and mixtures thereof.
  • acceptable amides include but are not limited to lauramide diethanolamide, alkanolamides, ethoxylated alkanolamides, ethylene bisamides, urea, and mixtures thereof.
  • pyrrolidones include but are not limited to N-methyl-pyrrolidone N-alkyl-pyrrolidones, pyrrolidone carboxylic acids, pyrrolidone carboxylic esters, and mixtures thereof.
  • acceptable glycerol triesters include but are not limited to triacetin, diacetin, monoacetin, tributylrin, tricaproin, tricaprylin, trilaurin, trymyristin, tripalmitin, tristearin, triethyl citrate, tributyl citrate, and mixtures thereof.
  • acceptable te ⁇ enes include but are not limited to lemonene, methone, pipertone, 1-8 cineole, te ⁇ ineol, te ⁇ inen-4-ol pulegone, carvone, carveol, and mixtures thereof.
  • Specific examples of acceptable amines include but are not limited to lauryl- amine (dodecylamine), unsaturated cyclic ureas, urea, and mixtures thereof.
  • acceptable classical surfactants include, but are not limited to Brij surfactants, (such as Brij 30, Brij 36T, Brij, 35, Brij 52), Pluronic surfactants, (such as Pluronic F68, and Pluronic L62), Span surfactants, (such as Span 20 and Span 85), Tween surfactants, (Such as Tween 20, Tween 40, and Tween
  • Poloxomer surfactants Myrj surfactants, bile salts, sodium laurate, sodium lauryl sulfate, and mixtures thereof.
  • acceptable complexing agents include but are not limited to cyclodextrine complexes and derivatives thereof, liposomes, microcapsules, microspheres, and mixtures thereof.
  • organic acids include, but are not limited to salicylic acid, citric acid, salicylates, and mixtures thereof.
  • acceptable biologies include but are not limited to L- - amino acids, lecithin, phospholipids, and mixtures thereof.
  • enhancer substances many natural substances are capable of acting as permeation enhancers. These natural substances include, but are not limited to: arecoline, berbamine, berberine, camphol, capsaicin, capsaicine, capsic acid, eucalyptus (oil), eucalyptols, ferulic acid, menthol, oleummenthae, paeonol, peppermint oil, tanshinone, and mixtures thereof.
  • the aconitine alkaloids used in the formulation of the present invention may be those found in many species of Aconitum plant.
  • aconitum species include, but are not limited to: Aconitum sinomontanum Nakai, A. finetianum Hand-Mazz., A. episcopate Le'vl, A. bulleyanum Diels, A. coreanum (Levl.) Raipaics, A. tatsinenense, A. pendulum, A. japonicum Thunberg, A. sinense Siebold, A. zuccarini Nakai, A. Subcuneatum Nakai, A. aizuense Nakai, A. sanyoense
  • aconitine alkaloids may be used in the transdermal formulation of the present invention.
  • General alkaloid types may be aconines, aconitines, aconitanes, and mixtures thereof.
  • aconitine alkaloid species include without limitation, lappaconitine, N-deacetyl-lappaconitine, songtiening, bulleyaconitine A, 3-acetylaconitin, isolappaconitine, deoxylappaconitine, neofinaconitine, ranaconine, ranaconitine, N- deacetylranaconitine, finaconitine, N-deacetylfinaconitine, mesaconitine, jesaconitine, and salts, analogs, derivatives, prodrugs, and mixtures thereof.
  • Other aconitine alkaloids considered to be within the scope of the present invention are disclosed in U.S. patent nos. 5,290,784, 5,547,956, 5,514,684, and 5,770,604, which are inco ⁇ orated herein by reference in their entirety.
  • the transdermal delivery system of the present invention may include additional analgesics for ameliorating pain and inflammation.
  • analgesics may be either narcotic or non-narcotic.
  • acceptable narcotic agents include, but are not limited to, alfentanil, benzylmo ⁇ hine, codeine, desomo ⁇ hine, endorphins, ethylmo ⁇ hine, fentanyl, hydromo ⁇ hone, lavo ⁇ hanol, levomethadyl acetate, meperidine, Methadone, morphine, normo ⁇ hine, normethadone, opium, oxycodone, oxymo ⁇ hone, remifentanil, sufentanil, tilidine, bupreno ⁇ hine, buto ⁇ hanol, dexocine, eptazocine, nalbuphine, pentazocine, and salts, analogs, derivatives, and
  • analgesics for inclusion with the transdermal formulation of the present invention may be non-narcotic agents.
  • suitable non-narcotic agents include without limitation, acetaminophen, aspirin, clonidine, diflunisal, methotrimeprazine, salicylates, salicylic acid, tramadol, and salts, analogs, derivatives, and mixtures thereof.
  • non-narcotic agents include without limitation, NSAID 's, such as butibufen, ca ⁇ rofen, celecoxib, diclofenac, diflunisal, etodolac, flurbiprofen, fennoprofen calcium, flunixin meglumine, ibuprofen, idomethacetin, ketoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, naproxen, nabumetone, oxaprozin, phenylbutazone, piroxicam, rofecoxib, sulindac, tolmetin, tiaprofenic, and salts, analogs, derivatives, and mixtures thereof.
  • NSAID 's such as butibufen, ca ⁇ rofen, celecoxib, diclofenac, diflunisal, etodolac, flurb
  • the aconitine alkaloid formulation of the present invention may further include other treatment agents for treating a condition or disorder with which pain is associated.
  • treatment agents include without limitation, anticholinergic agents, such as, adiphenine, anisotropine, atropine, benzetimide, clidinium, deptropine, dicyclomine, diponium, glycopyrrolate, hydroxyzine, O ⁇ henadrine, oxybutynin, propantheline, scopolamine, as well as salts, derivatives, analogs, prodrugs, and mixtures thereof.
  • anticholinergic agents such as, adiphenine, anisotropine, atropine, benzetimide, clidinium, deptropine, dicyclomine, diponium, glycopyrrolate, hydroxyzine, O ⁇ henadrine, oxybutynin, propantheline, scopolamine, as well as salts, derivatives, analogs, prodrugs, and mixtures thereof.
  • Other treatment agents may include anti-migraine agents such as seratonin 5-HT receptor agonists, including, but not limited to members selected from the group consisting of: naratriptan, rizatriptan, sumatriptin, zolmitriptan, salts, derivatives, analogs, prodrugs, and mixtures thereof.
  • anti-migraine agents include, methylsergide maleate and ergotamine derivatives, such as dihydroergotamine mesylate, ergotamine tartrate, as well as salts, derivatives, analogs, prodrugs, and mixtures thereof.
  • Additional treatment agents which may be included in the aconitine alkaloid composition of the present invention, are antiemetic/antivertigo agents.
  • specifically acceptable antiemetics/antivertigo agents include without limitation, chloropromazine, pe ⁇ henazine, prochlorperazine, promethazine, thiethylperazine, triflupromazine, metoclopramide, benzquinamide, cannabinoids, corticosteroids, hydroxyzine HC1, diphenidol, phosphorated carbohydrates, as well as salts, derivatives, analogs, prodrugs, and mixtures thereof.
  • the transdermal formulation of the present invention may also contain various other positive health-imparting agents, and salts, derivatives, analogs, and mixtures thereof.
  • analgesics include both narcotic and non-narcotic agents.
  • Such analgesic substances, as well as other drugs and treatment agents that may be included in the aconitine alkaloid formulation of the present invention may be found in U.S. patent nos. 5,446,070, and 5,719,197, which are inco ⁇ orated herein by reference in their entirety.
  • Additional analgesic substances, as other drugs and treatment agents that may be included in the aconitine alkaloid formulation of the present invention may be found in the publication "Drug Facts and Comparisons" (Jan. 2000), which is inco ⁇ orated herein by reference.
  • aconitine alkaloids may be combined with other positive health benefit conferring substances, or treatment agents, either before, during, or after its inclusion in the transdermal delivery formulation.
  • positive health benefit conferring substances include but are not limited to vitamins, amino acids, minerals, herbal and botanical extracts, anti-oxidants, other materials which are essential to the body, and mixtures thereof.
  • acceptable vitamins include both water-soluble and oil soluble vitamins.
  • Water-soluble vitamins include but are not limited to the B 1 , B2, B3, B4, B5, B6, B12, B13, B15, B17, biotin, choline, folic acid, inositol, para-amino benzoic acid (PABA), Vitamin C, Vitamin P, and mixtures thereof.
  • oil soluble vitamins include Vitamin A, Vitamin D, Vitamin E, Vitamin K and mixtures thereof.
  • acceptable amino acids include but are not limited to alanine arginine, carnitine, gamma-aminobutyric acid (GABA), glutamine, glycine, histidine, lysine, methionine, N-acetyl systeine, ornithine, phenylalanine, taurine, tyrosine, valine, and mixtures thereof.
  • GABA gamma-aminobutyric acid
  • acceptable minerals include but are not limited to calcium, potassium, iron, chromium, phosphorous, magnesium, zinc, copper and mixtures thereof, as well as any other minerals essential to the human body.
  • herb and botanical extracts include but are not limited to Green tea plant, Causena Lansium, Crocus Sativus, danshen (saliva miltiorrhize), Dongui (Radix angelicae sinesis), Eucommia, Evening primrose,
  • Gastrodia elata German chamomile, Ginseng, Gingko Baloba, Hopes, Horn goat weed (epimedium sagittatum), Kava, Lemon balm, Mishmi bitter (coptis sinesis), Morning star (Uncaria rhychophylla), Passion flower, Physostigmine, Securinega Suffructicosa, Scutellaria baicalensis, Siberian cork tree (phellodendron amurense), Skullcap, St. John's Wort, Valerian, and mixtures thereof.
  • antioxidants include but are not limited to polyphenols such as catechin, beta-carotene, coenzyme Q10, grapnel, and mixtures thereof.
  • the aconitine alkaloids, analgesics, and other positive health benefit conveying substances may be either produced synthetically, or harvested from plants and other natural sources by methods such as extraction and concentration.
  • the source of the delivery substance may be either artificial, natural, or a combination thereof.
  • the transdermal delivery formulation of the present invention may be a topical formulation.
  • topical formulations may take a variety of specific forms, such as gels, ointments, pastes, aerosols, creams, lotions, and other hydrophobic or water-mi scible vehicles.
  • suitable hydrophobic and water-mi scible agents include but are not limited, hydrocarbons (e.g. liquid paraffin, mineral oil, paraffin oil, white petrolatum, squalane), silicones (e.g. liquid polymethylsilaxanes, dimethicone), alcohols (e.g.
  • ethanol isopropyl alcohol, lauryl alcohol
  • polyols and polyglycols e.g. propyl glycol, glycerin, triacetin, polyethylene glycols
  • Sterols e.g. lanolin, cholesterol
  • carboxylic acids e.g. lauric acid, oleic acid
  • esters and polyesters e.g. ethylene glycol monostearate, sorbitan monoesters, glyceryl tristearate, olive oil, soybean oil, isopropyl myristate, isopropyl palmitate.
  • suitable emulsifiers include, but are not limited to sterols and sterol eaters (e.g.
  • esters and polyesters e.g. ethylene glycol monoesters, propylene glycol monoesters, glycerol monoesters, sorbitan monoesters, sorbitol monoesters, polyoxyethylene esters, sorbitan diesters, polyoxy ethylene sorbitan polyesters - tweens
  • ethers and polyethers e.g. polyethylene glycol monocetyl ethers, polyethylene-polypropylene glycols - pluronics
  • others e.g. sodium lauryl sulfate, borax, ethanolamine.
  • suitable thickeners include, but are not limited to acrylate copolymers, algin, behenyl alcohol, 18-36 acid triglycerides, calcium carboxymethyl celluse, PVP/MA copolymers, carbomer (910, 934, 934p, 940, 941, 1342), carboxymefhylcelluse sodium, cellulose, cetyl alcohol, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, methyl hydroxyethylcellulose, PEGs, poloxamine (304, 504, 701, 904, 1 102, 1304, 1502, etc.), polycarbophil, polyethylene, propylene glycol alginate,
  • PVP PVP, PVP/VA copolymer, silica, silicones, beeswax.
  • the transdermal delivery formulation of the present invention may take the form of an occlusive device, such as a transdermal patch, in order to provide an aconitine alkaloid formulation.
  • a transdermal patch may either be an adhesive matrix patch, a liquid reservoir system type patch, a buccal or sublingual tablet, lozenge, or the like.
  • an amount of an aconitine alkaloid sufficient to produce the desired therapeutic blood plasma level is dissolved or suspended in a polymeric phase or carrier.
  • a selected permeation enhancer, or mixture of enhancers may be included in the polymeric phase, as well as additional positive health benefit imparting substances as mentioned above.
  • the size of an adhesive matrix patch may be adjusted to provide varying dosage amounts, and may vary from about 1 to 200 cm 2 . In another aspect, the size of an adhesive matrix patch may be from about 5 to about 100 cm 2 .
  • a wide range of adhesives useful in connection with transdermal patches will be known to those skilled in the art of transdermal drug delivery.
  • acceptable adhesives may include polyacrylate polymers, rubber-based adhesives, and polysiloxanes adhesives.
  • polyacrylate polymers can be any of the homopolymers, copolymers, te ⁇ olymers, and the like of various acrylic acids.
  • the acrylate polymers may be a combination of one or more monomers of acrylic acids and other copolymerizable monomers.
  • Acrylate polymers may also include copolymers of alkyl acrylates and/or methacrylates, and/or copolymerizable secondary monomers or monomers with functional groups.
  • Specific examples of acrylate monomers which are suitable for use with the present invention include, but are not limited to methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecylmethacrylate, tridecyl acrylate, tridecyl methacrylate, and mixtures thereof.
  • functional monomers which are copolymerizable with the above-recited alkyl acrylates or methacrylates, which can also be used include, but are not limited to acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert- butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxethyl acrylate, methoxyethyl methacrylate, and mixtures thereof.
  • acrylic adhesives examples include polyacrylate adhesives sold under the trademarks DUROTAK ® by National
  • utilizing a mixture of two or more acrylic polymers may facilitate sustained release of aconitine alkaloids.
  • Many variations and combinations of acrylics may be employed to achieve the desired increase in release duration. Examples of such combinations may be found in U.S. patent no. 6,024,976, which is incorporated herein by reference in its entirety. Other examples of such acrylic combinations will be readily recognized by those skilled in the art.
  • suitable rubber-based pressure sensitive adhesives include, but are not limited to hydrocarbon polymers, such as natural and synthetic polyisoprenes, polybutylenes and polyisobutylene (PIB), styrene/butadiene polymers, styrene-isoprene-styrene block copolymers, hydrocarbon polymers such as butyl rubber, halogen-containing polymers such as polyacrylic nitrile, polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride, and polychlorodiene, and polysiloxanes, and other copolymers thereof.
  • hydrocarbon polymers such as natural and synthetic polyisoprenes, polybutylenes and polyisobutylene (PIB), styrene/butadiene polymers, styrene-isoprene-styrene block copolymers, hydrocarbon polymers such as butyl rubber, halogen-containing polymers such as poly
  • suitable polysiloxanes include but are not limited to silicone pressure sensitive adhesives, which are a based on two major components: a polymer, or gum, and a tackifying resin.
  • the polysiloxane adhesive may be prepared by cross-linking the gum, typically a high molecular weight polydiorganosiloxane with the resin to produce a three-dimensional silicate structure via a condensation reaction in an appropriate organic solvent.
  • Various aspects of formulating polysiloxane adhesives are disclosed by Sobieski et al, in "Silicone Pressure sensitive Adhesives," I.d. at Pp. 508-517, which is inco ⁇ orated herein by reference.
  • Suitable silicone pressure-sensitive adhesives are commercially available and include the silicone adhesives sold under the trademarks BIO-PSA ® Dow Corning Co ⁇ oration, Medical Products, Midland. MI.
  • the matrix patch contains a distal backing and a proximal release liner laminated on the polymer layer.
  • the distal backing defines the side of the matrix patch that faces the environment, (i.e., distal to the skin or mucosa). and the release liner is adhered to the proximal side and must be removed before patch application.
  • the backing layer functions to protect the matrix polymer layer with the delivery substances and optional enhancer, and to provide an impenetrable layer that prevents loss of delivery substance to the environment.
  • the material chosen for the backing should be compatible with the polymer layer, delivery substances, and enhancer, and should be minimally permeable to any components of the matrix patch.
  • the backing can be opaque to protect components of the matrix patch from degradation caused by exposure to ultraviolet light. Further, the backing should be capable of binding to and supporting the polymer layer, yet should be pliable to accommodate the movements of a person using the matrix patch.
  • Suitable materials for the backing include, but are not limited to: metal foils, metalized polyfoils, composite foils or films containing polyester such as polyester terephthalate, polyester or aluminized polyester, polytetrafluoroethylene, polyether block amide copolymers, polyethylene methyl methacrylate block copolymers. polyurethanes, polyvinylidene chloride, nylon, silicone elastomers, rubber-based polyisobutylene, styrene, styrene-butadiene, and styrene-isoprene copolymers, polyethylene, and polypropylene. A thickness of about 0.0005 to about 0.01 inch may be preferred.
  • the release liner can be made of the same materials as the backing, or other suitable films coated with an appropriate release surface.
  • the matrix patch can further comprise various additives in addition to the polymer layer, delivery substances, and permeation enhancer that are the fundamental components of the adhesive matrix patch formulation.
  • additives are generally those pharmaceutically acceptable ingredients that are known in the art of transdermal substance delivery and, more particularly, in the art of transdermal substance delivery.
  • suitable diluents can include mineral oil, low molecular weight polymers, plasticizers, and the like.
  • Many transdermal delivery substance formulations have a tendency to irritate the skin after prolonged exposure thereto, thus addition of a skin irritation reducing agent aids may be desirable.
  • the LRS patch generally contains a backing layer having a reservoir portion configured to contain the carrier vehicle in which the aconitine alkaloid is admixed or dissolved.
  • carrier vehicles may be the same as those used for topical applications described above.
  • a micro porous membrane may be heat sealed across the opening of the reservoir in order to control the rate at which the aconitine alkaloid is transmitted to the skin.
  • an adhesive layer will generally be applied to a portion of the backing layer surrounding the reservoir for adhering the
  • LRS patch to the skin. Further, a release liner that is removed prior to application is placed upon the adhesive to prevent adhesion of the patch prior to application.
  • the release liner is removed, and the patch is adhered to the skin at a selected application situs.
  • the patch may be removed.
  • transdermal formulations having a variety of aconitine alkaloid containing formulations are provided to promote a more clear understanding of the possible combinations of the present invention, and are in no way meant as a limitation thereon.
  • the temperature of the skin surface was maintained at 32°C by placing the cells in a circulating water bath positioned over a stirring module.
  • the epidermal membrane was separated from the human cadaver whole skin by the heat-separation method of Kligman and Christopher (Arch.
  • the heat separated human epidermal membrane was cut into rectangular strips.
  • the matrix was cut into 0.71 cm ⁇ circular discs.
  • the release liner was peeled and discarded and the matrix disc was laminated onto the stratum corneum surface of the epidermal membrane.
  • the skin-matrix sandwich was then loaded onto the diffusion cells.
  • Each piece of the skin matrix sandwich was loaded between the donor and receiver compartments of a diffusion cell, with the epidermal side facing the receiver compartment, and clamped in place.
  • the receiver compartment was then filled with 0.02% sodium azide aqueous solution. The solubility of the drug in this medium is adequate to ensure sink conditions throughout the experiment.
  • the diffusion cell was then placed in a circulating water bath calibrated to maintain the skin surface temperature at 32 ⁇ 1°C. At predetermined sampling intervals, the entire contents of the receiver compartment were collected for drug quantitation and the receiver compartment was filled with fresh receiver solution, taking care to eliminate any air bubbles at the skin/solution interface.
  • the epidermal membrane was cut and placed between two halves of the permeation cell with the stratum corneum facing the donor compartment.
  • the skin was allowed to hydrate at 32°C overnight with 0.02% (w/v) sodium azide solution in the receiver compartment.
  • 75 ⁇ l of a gelled formulation was placed into a cavity created by placing a Teflon washer over the stratum corneum surface. The cavity was then occluded by clamping an occlusive backing over the Teflon washer and gel.
  • a 0.02% sodium azide aqueous solution was placed in the receiver compartment in contact with the dermal side of the epidermis, to ensure sink conditions for the drug.
  • the entire contents of the receiver compartment were collected for drug quantitation and the receiver compartment was filled with fresh receiver solution, taking care to eliminate any air bubbles at the skin/solution interface.
  • C n is the concentration ( ⁇ g/ml) of the drug in the receiver sample for the corresponding sample time
  • V is the volume of fluid in the receiver chamber (-6.3 cm3)
  • A is the diffusion area of the cell (0.64 c ⁇ _2).
  • the slope of the best fit line to the Q vs. t plot gives the steady state flux (J ss , ⁇ g/cm7hr); the intercept of this line on the time axis give the lag time 0L,h).
  • Examples I - III include skin flux results from various embodiments of a transdermal matrix system according to the present invention containing aconitine - derived alkaloids.
  • Adhesive pressure sensitive acrylic copolymers
  • LAP Lappaconitine
  • SMO Sorbitan Monooleate
  • L-DEA Lauramide DEA
  • transdermal matrix systems containing aconitine, or aconitine-derived alkaloids examples of other formulations of transdermal matrix systems containing aconitine, or aconitine-derived alkaloids and their derivatives or analogs may be as follows. 28
  • Formulation II-l Composition (%, w/w)
  • Formulation II-2 Composition (%, w/w)
  • Formulation II-3 Composition (%, w/w)
  • Formulation II-4 Composition (%, w/w)
  • Formulation II-5 Composition (%, w/w)
  • Formulation II-6 Composition (%, w/w)
  • Formulation II-7 Composition (%, w/w)
  • Formulation II-8 Composition (%, w/w)
  • a single Eudragit or mixture of different grades of Eudragits e.g. NE 30 D. LlOO. L12/5.S100,S12/5,L30D-55.L100-55,E100,E12/5.RL100.RL12/5.R100,RL PO, RL PM, RL 30 D. RS 100. RS 12/5, RS PM, RS PO.. RS 30 D.
  • EtOH Ethanol.
  • a hybrid transdermal system may be employed for delivering aconitine and aconitine-derived alkaloids.
  • a hybrid system generally contains a polymeric, or other type of reservoir with an adhesive overlay.
  • Bioactive agents may be contained in both the reservoir and the adhesive layer.
  • a wide variety of substances may be used for the reservoir, and include, but are not limited to polymers (including adhesives), solutions, gels, emulsified gels. lotions and creams.
  • Other variations of such a hybrid patch, as well as other particular substances for both the adhesive layer and reservoir will be readily recognized by those skilled in the art. Examples of such hybrid transdermal systems in accordance with the present invention may be as follows. 31
  • Formulation IV-1 Composition (%, w/w)
  • Formulation IV-2 Composition (%, w/w)
  • Formulation IV-3 Composition (%, w/w)
  • Aconitine alkaloids can be formulated with other active agents such as analgesics, anti-inflammatories, pain regulators, drugs or agents which impart a sense of well-being, and good health imparting substances, such as herb extracts or other related substances to provide enhanced benefits.
  • active agents such as analgesics, anti-inflammatories, pain regulators, drugs or agents which impart a sense of well-being, and good health imparting substances, such as herb extracts or other related substances to provide enhanced benefits.
  • active agents such as analgesics, anti-inflammatories, pain regulators, drugs or agents which impart a sense of well-being, and good health imparting substances, such as herb extracts or other related substances to provide enhanced benefits.
  • Formulation V-l Composition (%, w/w)
  • Formulation V-2 Composition (%, w/w)
  • Tetrahydropalmatin (Corydalis B) 0.01 - 20
  • Formulation V-3 Composition (%, w/w)
  • Formulation V-4 Composition (%, w/w)
  • Formulation V-5 Composition (%, w/w)
  • Formulation V-7 Composition (%, W/ ⁇ V)
  • Formulation V-8 Composition (%, w/w)
  • Formulation V-9 Composition (%, w/w)
  • Formulation V-10 Composition (%, w/w)
  • Formulation V-ll Composition (%, w/w)
  • Formulation V-12 Composition (%, w/w)
  • One or more vitamins can be selected from either water-soluble (e.g. Vitamin B 1. B2, B3. B5, B6. B12. B13, B15. B17, Biotin. Choline. Folic acid. Inositol. PABA.
  • water-soluble e.g. Vitamin B 1. B2, B3. B5, B6. B12. B13, B15. B17, Biotin. Choline. Folic acid. Inositol. PABA.
  • Vitamin C and Vitamin P
  • oil soluble vitamins e.g. Vitamins A. D. E and K.
  • Formulation V-13 Composition (%, w/w)
  • Amino acids are selected from but not limited to Alanine. Arginine. Carnitine.
  • Formulation V-14 Composition (%, w/w)
  • One or more minerals necessary to human body can be selected, but not limited to copper, manganese, iron. zinc, calcium, magnesium, chromium, galenium. cobalt, etc.
  • Formulation V-15 Composition (%, w/w)
  • Herb/botanical extracts which are good for pain relief and drug addiction relief, can be selected from but not limited to. Asarum L. sieboldi Mig.. Camphol. Clove (Flos syzygii Aromatici). Corydalis ambigua, Danshen (salvia miltiorrhize). Dongui (Radix angelicae sinensis). Forsythia suspensa (thunb.) Vahl.. Ginseng. Ginkgo Biloba. Impatients balsamina L. lb.. Ligusticum wallichii Franch, Myrrha. Olibanum. Pearl. Polygalaceae L..speranskia tuberculata Bail. St.. St. John's Wort. Valerian, etc.
  • Formulation V-16 Composition (%, w/w)
  • Anti-oxidant agents can be selected from but not limited to Polvphenols. such as Catechins. Beta-carotene. Co-enzyme Q-10. Grapnol. Vitamin C. Vitamin E. etc.
  • Formulation V-17 Composition (%, w/w)
  • NSAIDs Nonsteroidal Antiinflammatory Drugs
  • NSAIDs are selected from, but not limited to. Butibufen. Carprofen. Celecoxib. Diclofenac. Difluisal. Etodolac. Flurbiprofen.
  • Fennoprofen calcium Flunixin Meglumine. Ibuprofen. Indomethacin. Ketoprofen, Ketorolac tromethamine, Magnesium Salicylate. Meclofenamate sodium. Mefenamic acid. Naproxen, Nabumetone. Oxaprozin. Phenylbutazone. Piroxicam. Rofecoxib. Sulindac. Tolmetin, and Tiaprofenic acid. etc.
  • Formulation V-18 Composition (%, w/w)
  • Narcotic agonist analgesics can be selected from, but not limited to. Alfentanil. Benzylmorphine. Codeine, Desomo ⁇ hine. Endo ⁇ hins, Ethylmo ⁇ hine. Fentanyl. Hydromorphone. Lavo ⁇ hanol, Levomethadyl Acetate. Meperidine. Methadone.
  • Narcotic agonist-antagonist analgesics can be selected from, but not limited to. Buprenorphine. Butorphanol. Dezocine. Eptazocine. Methotrimeprazine. Nalbuphine. and Pentazocine. etc.
  • Formulation V-20 Composition (%, w/w)
  • Anti-migraine agents can be selected from, but not limited to. seratonin 5-HT receptor agonists, including, but not limited to naratriptan. rizatriptan. sumatriptin. zolmitriptan. salts, derivatives, analogs, prodrugs. and mixtures thereof.
  • Other anti- migraines include, methylsergide maleate and ergotamine derivatives, such as dihydroergotamine mesylate. ergotamine tartrate. etc.
  • Formulation V-21 Composition (%, w/w)
  • Antiemetic/antivertigo agents include but are not limited to. chloropromazine. pe ⁇ henazine, prochlo ⁇ erazine, promethazine, thiethylperazine. triflupromazine. metoclopramide. benzquinamide. cannabinoids. corticosteroids. hydroxyzine HC1. diphenidol. phosphorated carbohydrates, etc.
  • Formulation V-22 Composition (%, w/w)
  • Anticholinergics can be selected from, but not limited to. Adiphenine. Anisotropine, Atropine, Benzetimide, Clidinium.. Deptropine. Dicyclomine.
  • Topical formulations such as, gels, creams, lotions, ointments, paste, mousses, aerosols, etc. may be used to so long as when applied to the desired area of the skin the formulation will stay in place. Further, such formulations may be utilized in connection with an LRS patch.
  • Formulation VI-1 Composition (%, w/w)
  • Formulation VI-2 Composition (%, w/w)
  • Sorbitan Monooleate 0.1-10% Polysorbate 80 0.1-10% Methyl Paraben 0.01-2% Propyl Paraben 0.01-2% Water 40-95%
  • Formulation VI-3 Composition (%, w/w)
  • Formulation VI-4 Composition (%, w/w)
  • Aconitine 0.01-40% Stearic Acid 0.1-30% Stearyl Alcohol 0.1-10% Cetyl Alcohol 0.1-10% Glycerin 1 - 30% Methyl Paraben 0.01-2% Propyl Paraben 0.01 -2% Potassium Hydroxide 0.01-3% Water 40 - 95%
  • Formulation VI-5 Composition (%, w/w)
  • Formulation VI-6 Composition (%, w/w)
  • Formulation VI-7 Composition (%, w/w)

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition d'alcaloïdes aconitine administrée par voie transdermique destinée à soulager la douleur et à améliorer les inflammations. Dans un aspect, un alcaloïde aconitine est administré en une dose suffisante pour obtenir et maintenir un niveau d'alcaloïde aconitine dans le plasma sanguin d'environ 0,5 ng/ML à environ 400 ng/mL. Les alcaloïdes aconitine peuvent être administrés par eux-mêmes, ou en combinaison avec d'autres éléments, tels que des analgésiques additionnels, d'autres médicaments, ou des substances bénéfiques améliorant la santé. Diverses formulations pour l'administration transdermique d'alcaloïdes aconitine sont décrites, et peuvent contenir des améliorants de pénétration sélectionnés.
PCT/US2000/031821 1999-11-19 2000-11-17 Systeme d'administration transdermique d'alcaloides de l'espece aconitum Ceased WO2001035883A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU17801/01A AU1780101A (en) 1999-11-19 2000-11-17 Transdermal delivery system for alkaloids of aconitum species

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US16649799P 1999-11-19 1999-11-19
US60/166,497 1999-11-19
US24938000P 2000-11-16 2000-11-16
US60/249,380 2000-11-16

Publications (1)

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WO2001035883A1 true WO2001035883A1 (fr) 2001-05-25

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CN (1) CN100409847C (fr)
AU (1) AU1780101A (fr)
WO (1) WO2001035883A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002111A1 (fr) * 2000-07-01 2002-01-10 Lts Lohmann Therapie-System Ag Systeme therapeutique dermique contenant des antiphlogistiques non steroidiens a inhibition selective de la cox-2
WO2003051363A1 (fr) * 2001-12-17 2003-06-26 Aryx Therapeutics Systemes d'administration d'analgesiques et methodes d'utilisation
EP1611882A1 (fr) * 2004-06-01 2006-01-04 Hisamitsu Pharmaceutical Co. Inc. Patch adhésif
EP1539069A4 (fr) * 2002-05-31 2007-11-14 Univ Mississippi Administration par voie transmuqueuse de cannabinoides
WO2009002935A1 (fr) * 2007-06-22 2008-12-31 Sciele Pharma, Inc. Système d'administration transdermique contenant du glycopyrrolate destiné à traiter une sialorrhée
WO2008082507A3 (fr) * 2006-12-20 2009-03-19 Schering Plough Ltd Compositions pharmaceutiques et procédé de traitement d'une inflammation dans le bétail et autres animaux
WO2009139213A1 (fr) 2008-05-15 2009-11-19 日本臓器製薬株式会社 Composition pharmaceutique pour application externe contenant de la prochlorpérazine
US8053626B2 (en) * 2002-06-12 2011-11-08 Sca Hygiene Products Ab Absorbent article containing a skincare composition and method of making and using same
EP2552486A4 (fr) * 2010-03-30 2014-07-09 Phosphagenics Ltd Timbre transdermique
US9006462B2 (en) 2013-02-28 2015-04-14 Dermira, Inc. Glycopyrrolate salts
US9006461B2 (en) 2013-02-28 2015-04-14 Dermira, Inc. Crystalline glycopyrrolate tosylate
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
CN106074453A (zh) * 2016-06-14 2016-11-09 浙江中医药大学 高乌甲素凝胶贴膏及其制备方法
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US9610278B2 (en) 2013-02-28 2017-04-04 Dermira, Inc. Glycopyrrolate salts
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

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CN100417376C (zh) * 2006-11-03 2008-09-10 昆明制药集团股份有限公司 草乌甲素巴布剂
CN102085174B (zh) * 2009-12-03 2014-06-18 大连理工大学 一种具有镇痛抗炎作用的苯甲酰乌头原碱透皮凝胶剂
CN102406640A (zh) * 2010-09-26 2012-04-11 上海泰因生物技术有限公司 镇痛消炎类药物及镇痛消炎类药物微针透皮给药方法
CN103040829B (zh) * 2012-02-17 2015-02-11 北京人福军威医药技术开发有限公司 含有高乌甲素和羟考酮的药物组合物
CN102813924B (zh) * 2012-05-17 2014-06-18 高同强 一种基于青藤碱的用于镇痛的药物组合产品
CN104788374A (zh) * 2015-04-29 2015-07-22 新疆医科大学附属中医医院 白喉乌头生物碱的分离方法
CN110478350A (zh) * 2018-07-27 2019-11-22 上海品姗医药咨询有限公司 草乌甲素及其衍生物在制备抑制药物成瘾性的药物中的应用

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US5719197A (en) * 1988-03-04 1998-02-17 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002111A1 (fr) * 2000-07-01 2002-01-10 Lts Lohmann Therapie-System Ag Systeme therapeutique dermique contenant des antiphlogistiques non steroidiens a inhibition selective de la cox-2
WO2003051363A1 (fr) * 2001-12-17 2003-06-26 Aryx Therapeutics Systemes d'administration d'analgesiques et methodes d'utilisation
EP1539069A4 (fr) * 2002-05-31 2007-11-14 Univ Mississippi Administration par voie transmuqueuse de cannabinoides
US8053626B2 (en) * 2002-06-12 2011-11-08 Sca Hygiene Products Ab Absorbent article containing a skincare composition and method of making and using same
EP1611882A1 (fr) * 2004-06-01 2006-01-04 Hisamitsu Pharmaceutical Co. Inc. Patch adhésif
US8173155B2 (en) 2004-06-01 2012-05-08 Hisamitsu Pharmaceutical Co., Inc. Adhesive patch
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
WO2008082507A3 (fr) * 2006-12-20 2009-03-19 Schering Plough Ltd Compositions pharmaceutiques et procédé de traitement d'une inflammation dans le bétail et autres animaux
RU2466715C2 (ru) * 2006-12-20 2012-11-20 Шеринг-Плоу Лтд. Фармацевтические композиции и способ лечения воспаления у крупного рогатого скота и других животных
CN101588789B (zh) * 2006-12-20 2013-12-11 先灵-普劳有限公司 用于治疗牛和其它动物炎症的药物组合物和方法
US9006272B2 (en) 2006-12-20 2015-04-14 Intervet Inc. Pharmaceutical compositions and method for treating inflammation in cattle and other animals
JP2010530902A (ja) * 2007-06-22 2010-09-16 サイエル ファーマ，インコーポレイティド 流涎症治療のためのグリコピロレートを含む経皮送達システム
WO2009002935A1 (fr) * 2007-06-22 2008-12-31 Sciele Pharma, Inc. Système d'administration transdermique contenant du glycopyrrolate destiné à traiter une sialorrhée
WO2009139213A1 (fr) 2008-05-15 2009-11-19 日本臓器製薬株式会社 Composition pharmaceutique pour application externe contenant de la prochlorpérazine
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
EP2552486A4 (fr) * 2010-03-30 2014-07-09 Phosphagenics Ltd Timbre transdermique
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US10188670B2 (en) 2011-03-15 2019-01-29 Phosphagenics Limited Composition
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US9259414B2 (en) 2013-02-28 2016-02-16 Dermira, Inc. Glycopyrrolate salts
US11291652B2 (en) 2013-02-28 2022-04-05 Journey Medical Corporation Glycopyrrolate salts
US9610278B2 (en) 2013-02-28 2017-04-04 Dermira, Inc. Glycopyrrolate salts
US10004717B2 (en) 2013-02-28 2018-06-26 Dermira, Inc. Glycopyrrolate salts
US9006461B2 (en) 2013-02-28 2015-04-14 Dermira, Inc. Crystalline glycopyrrolate tosylate
US9006462B2 (en) 2013-02-28 2015-04-14 Dermira, Inc. Glycopyrrolate salts
US11291651B2 (en) 2013-02-28 2022-04-05 Journey Medical Corporation Glycopyrrolate salts
US10543192B2 (en) 2013-02-28 2020-01-28 Dermira, Inc. Glycopyrrolate salts
US10548875B2 (en) 2013-02-28 2020-02-04 Dermira, Inc. Glycopyrrolate salts
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
CN106074453A (zh) * 2016-06-14 2016-11-09 浙江中医药大学 高乌甲素凝胶贴膏及其制备方法
CN106074453B (zh) * 2016-06-14 2019-11-15 浙江中医药大学 高乌甲素凝胶贴膏及其制备方法
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

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