WO2000000120A1 - Compositions antalgiques transdermiques et leurs methodes d'administration - Google Patents

Compositions antalgiques transdermiques et leurs methodes d'administration Download PDF

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Publication number
WO2000000120A1
WO2000000120A1 PCT/US1999/014653 US9914653W WO0000120A1 WO 2000000120 A1 WO2000000120 A1 WO 2000000120A1 US 9914653 W US9914653 W US 9914653W WO 0000120 A1 WO0000120 A1 WO 0000120A1
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WO
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Prior art keywords
compound
transdermal composition
amine containing
transdermal
subject
Prior art date
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PCT/US1999/014653
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English (en)
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WO2000000120A9 (fr
Inventor
Robert W. Murdock
C. Donald Williams
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Pharmaceuticals Applications Asociates, Llc
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.)
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Publication date
Priority claimed from US09/106,684 external-priority patent/US6290986B1/en
Priority to KR1020007014985A priority Critical patent/KR20010078754A/ko
Priority to SK2001-2000A priority patent/SK20012000A3/sk
Priority to HU0102728A priority patent/HUP0102728A3/hu
Priority to BR9912508-0A priority patent/BR9912508A/pt
Priority to IL14042099A priority patent/IL140420A0/xx
Priority to JP2000556706A priority patent/JP2002519310A/ja
Priority to AU48415/99A priority patent/AU4841599A/en
Application filed by Pharmaceuticals Applications Asociates, Llc filed Critical Pharmaceuticals Applications Asociates, Llc
Priority to EP99932017A priority patent/EP1093348A4/fr
Priority to CA002335837A priority patent/CA2335837A1/fr
Priority to MXPA00012767A priority patent/MXPA00012767A/es
Publication of WO2000000120A1 publication Critical patent/WO2000000120A1/fr
Publication of WO2000000120A9 publication Critical patent/WO2000000120A9/fr
Priority to NO20006604A priority patent/NO20006604L/no
Priority to HR20000905A priority patent/HRP20000905A2/hr
Priority to US09/754,500 priority patent/US6572880B2/en
Priority to BG105175A priority patent/BG105175A/bg
Priority to US09/825,524 priority patent/US20020015713A1/en

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    • 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
    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is directed to methods and compositions for transdermal administration.
  • the present invention is directed to methods and compositions for the transdermal administration of an amine containing compound having biphasic solubility and/or an agent which enhances the activity ofthe amine containing compound having biphasic solubility, e.g., a muscle relaxant, to relieve pain.
  • somatic sensory nerves causes a somatic sensory loss.
  • damage can be caused by a variety of means including trauma, diseases such as diabetes, herpes zoster and late-stage cancer, chemotherapy, or by a chemical injury.
  • neural pain circuits rewire themselves, both anatomically and biochemically, after nerve injury.
  • negative symptoms such as numbness are joined by positive sensations, involving a sort of false sensation of pain.
  • the experience can range from mild dysesthesia to excruciating pain, rendering some patients unable to work, walk or do other daily activities.
  • patients were generally treated by administration of analgesics to relieve pain. A vast majority of such patients receive doses of these agents orally.
  • oral administration of such agents has been associated with a variety of side effects, such as liver damage, kidney damage, gastrointestinal side effects, addiction, sedation, and/or weight gain which cannot be tolerated well by the patient.
  • side effects such as liver damage, kidney damage, gastrointestinal side effects, addiction, sedation, and/or weight gain which cannot be tolerated well by the patient.
  • malabsorption of oral preparations have resulted in subtherapeutic plasma levels.
  • the agents have relatively short plasma half-lives, necessitating inconveniently frequent dosing.
  • oral delivery involves a time delay as the analgesic is absorbed via the digestive system before entering the bloodstream.
  • a number of agents which have traditionally been administered orally or by injection have been inappropriate or suboptimal for some patients when so-administered.
  • Oral or injection administration may result in too slow or too rapid increase in blood plasma levels, e.g., may involve an undesirably long time delay as the analgesic is absorbed by the digestive system before entering the bloodstream, or may result in a "spike" in blood plasma levels followed by an undesirably low level, where a more constant level would be preferable.
  • Some analgesics are particularly prone to cause or contribute to kidney or liver damage when administered orally.
  • parenteral (i.e., intravenously or intramuscularly injected) administration is inconvenient and expensive, and is rarely used outside the hospital. Inhalation is believed to be not feasible with many analgesic agents currently in use. Therefore, there is a need for an analgesic delivery system which provides effective and acceptable levels, while preferably avoiding or reducing undesired effects such as liver damage or gastrointestinal side effects.
  • the present invention provides a transdermal composition for the treatment of pain in a subject, particularly a human subject.
  • the transdermal composition for the treatment of pain in a subject includes an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject and a pharmaceutically acceptable carrier suitable for transdermal delivery ofthe amine containing compound, e.g., a lecithin organogel carrier.
  • the transdermal composition further includes an agent which enhances the activity ofthe amine containing compound having biphasic solubility, e.g., a muscle relaxant, such as guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof.
  • a muscle relaxant such as guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof.
  • the agent which enhances the activity ofthe amine containing compound having biphasic solubility e.g., the muscle relaxant, also has a biphasic solubility.
  • the amine containing compound having biphasic solubility is an antidepressant compound, such as a tricyclic antidepressant compound, e.g., doxepin or trimipramine.
  • an antidepressant compound such as a tricyclic antidepressant compound, e.g., doxepin or trimipramine.
  • the amine containing compound having biphasic solubility is a sodium channel blocker, an anti-epileptic compound, or an anti-convulsant compound.
  • transdermal composition which includes an amine-containing compound as described herein and an anti-inflammatory compound, such as a nonsteroidal anti-inflammatory compound, e.g., celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, vioxx ® , and combinations thereof.
  • an anti-inflammatory compound such as a nonsteroidal anti-inflammatory compound, e.g., celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, vioxx ® , and combinations thereof.
  • an agent which enhances the activity of the amine containing compound e.g., a muscle relaxant such as guaifenesin.
  • the invention features a transdermal composition for the treatment of pain in a subject including an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject; a muscle relaxant in an amount effective to enhance the activity ofthe amine containing compound having biphasic solubility; and a pharmaceutically acceptable carrier suitable for transdermal delivery ofthe amine containing compound having biphasic solubility and the muscle relaxant.
  • the invention features a transdermal composition for the treatment of pain in a subject including doxepin in an amount effective to treat pain in a subject; guaifenesin in an amount effective to enhance the activity of doxepin; and a pharmaceutically acceptable carrier suitable for transdermal delivery ofthe doxepin and the guaifenesin.
  • transdermal composition including an amine containing compound having biphasic solubility in an amount effective to treat pain in the subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery ofthe amine containing compound to thereby treat pain in the subject.
  • the transdermal composition is applied to the skin ofthe subject.
  • Another aspect ofthe invention features a method for selecting a compound suitable for treating pain in a subject.
  • the method includes transdermally administering an amine containing compound having biphasic solubility to a subject; and determining whether pain is treated in the subject to thereby select a compound suitable for treating pain in a subject.
  • the method can further include modeling the compound using a computer equipped with a three-dimensional chemical structure modeling program; and determining whether the three-dimensional chemical structure of the compound possesses sufficient characteristics to be useful as a sodium channel blocker, thereby selecting a compound suitable for treating pain in a subject.
  • the invention features a transdermal composition suitable for transdermal delivery, which includes a therapeutically effective amount of a pharmaceutical compound (e.g., a serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for treating attention deficit hyperactivity disorder, a compound suitable for treating hypertension and akathisia, an analgesic compound, or a compound used in the treatment of impotence) and a pharmaceutically acceptable carrier suitable for transdermal delivery ofthe pharmaceutical compound, e.g., a lecithin organogel carrier.
  • a pharmaceutical compound e.g., a serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for treating attention deficit hyperactivity disorder, a compound suitable for treating hypertension and akathisia, an analgesic compound, or a compound used in the treatment of impotence
  • a pharmaceutically acceptable carrier suitable for transdermal delivery ofthe pharmaceutical compound, e.g.,
  • the invention features a transdermal composition for treatment of pain in a subject which includes a compound capable of blocking afferent neuron transmission in an amount effective to block afferent neuron transmission in a subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the compound.
  • Figure 1 is an evaluation form used in evaluating an embodiment ofthe present invention.
  • Figure 2 is a table depicting the results from clinical experiments using compositions ofthe invention.
  • the present invention provides a transdermal composition suitable for treatment of pain in a subject.
  • the transdermal composition includes an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery ofthe amine containing compound having biphasic solubility.
  • the term "subject" includes a mammal, such as a human, a horse, a pig, a cow, a mouse, a rat, a rabbit, or a goat. In preferred embodiment, the subject is a human.
  • the term "pain” is art recognized and includes a bodily sensation elicited by noxious chemical, mechanical, or thermal stimuli, in a subject, e.g., a mammal such as a human.
  • the term “pain” includes chronic pain, such as lower back pain; pain due to arthritis, e.g., osteoarthritis; joint pain, e.g., knee pain or carpal tunnel syndrome; myofascial pain, and neuropathic pain.
  • the term “pain” further includes acute pain, such as pain associated with muscle strains and sprains; tooth pain; headaches; pain associated with surgery; or pain associated with various forms of tissue injury, e.g., inflammation, infection, and ischemia.
  • amine containing compound having biphasic solubility includes compounds having at least one amine moiety and having sufficient lipid solubility (e.g., solubility in polar solvents such as ethanol, ethoxydiglycerol, ethoxydiglycol, chloroform, benzene, and the like) such that the compound passes through the stratum corneum, and has sufficient aqueous solubility to be active in the aqueous environment ofthe dermis and the underlying tissue.
  • lipid solubility e.g., solubility in polar solvents such as ethanol, ethoxydiglycerol, ethoxydiglycol, chloroform, benzene, and the like
  • Transdermal compositions ofthe present invention include an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject.
  • amount effective to treat pain in a subject and “effective amount” are used interchangeably herein and include an amount effective, at dosages and for periods of time necessary, to achieve the desired result, e.g., sufficient to treat pain in a subject.
  • An effective amount of an amine containing compound or a pharmaceutical compound as defined herein may vary according to factors such as the disease state, age, and weight ofthe subject, and the ability ofthe amine containing compound or pharmaceutical compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • An effective amount is also one in which any toxic or detrimental effects ofthe amine containing compound having biphasic solubility or pharmaceutical compound are outweighed by the therapeutically beneficial effects.
  • the transdermal compositions ofthe invention can further include an agent which enhances the activity ofthe amine containing compound having biphasic solubility.
  • an "agent which enhances the activity ofthe amine containing compound having biphasic solubility" includes an agent which enhances the pharmacological activity ofthe amine containing compound having biphasic solubility (e.g., the ability ofthe amine containing compound to treat pain), or enhances the transdermal delivery ofthe amine containing compound having biphasic solubility (e.g., the ability ofthe amine containing compound to cross the stratum corneum), or enhances both the pharmacological activity and the transdermal delivery ofthe amine containing compound.
  • agents which enhance the activity ofthe amine containing compound having biphasic solubility include muscle relaxants, described in further detail below.
  • transdermal composition includes compositions capable of passing through the stratum corneum of a subject.
  • transdermal further includes compositions capable of passing through the epidermis of a subject, compositions capable of passing through the dermis of a subject, and compositions capable of passing through the hypodermis of a subject.
  • transdermal includes compositions capable of passing through the skin of a subject and reaching the underlying tissues and organs.
  • transdermal delivery includes delivery of, for example, a compound through the stratum corneum of a subject.
  • the term transdermal delivery further includes delivery of, for example, a compound through the epidermis of a subject, delivery of, for example, a compound through the dermis of a subject, and delivery of, for example, a compound through the hypodermis of a subject.
  • the term transdermal delivery includes delivery of, for example, a compound through the skin of a subject to the underlying tissues and organs.
  • the present invention further features a transdermal composition for treatment of pain in a subject which includes a compound capable of blocking afferent neuron transmission in an amount effective to block afferent neuron transmission in a subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery ofthe compound.
  • the term "compound capable of blocking afferent neuron transmission” includes a compound which is capable of blocking the ability of an afferent neuron, i.e., a sensory neuron, to carry an impulse toward the central nervous system.
  • Amine Containing Compounds Having Biphasic Solubility include antidepressant compounds, antiepileptic compounds, anticonvulsant compounds, and sodium channel blockers.
  • antidepressant compounds includes compounds capable of alleviating the symptoms of depression.
  • antidepressant compounds include all tricyclic antidepressants (e.g., amitriptyline, dothiepin, or lofepramine), bupropion (sold under the trade name Wellbutrin), reboxetine (sold under the trade name Edronax), nefazodone (sold under the trade name Serzone) and trazodone (sold under the trade name Desyrel).
  • antidepressant compounds are described in, for example, the 1998 SIGMA catalogue and the "The Merck Index", 12t:h Ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J., 1996, the contents of which are incorporated herein by reference.
  • a transdermal composition ofthe present invention includes a tricyclic antidepressant compounds.
  • exemplary tricyclic antidepressants include adinazolam, amitriptylinoxide, amoxapine, clomipramine, demexiptiline, dimetacrine, dothiepin, doxepin, imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine, noxiptilin, pizotyline, propizepine, quinupramine, tianeptine, and trimipramine.
  • a particularly preferred tricyclic antidepressant for use in the compositions ofthe invention is doxepin.
  • Tricyclic antidepressant compounds are described in, for example, "Guide to
  • the tricyclic antidepressant compound is selected from the group consisting of doxepin, trimipramine, other tricyclics having biphasic solubility, and combinations thereof.
  • the tricyclic antidepressant When combined with other compounds, such as an agent which enhances the activity ofthe amine containing compound, e.g., a muscle relaxant, and/or an anti-inflammatory compound, e.g., a nonsteroidal anti-inflammatory compound, as discussed below, the tricyclic antidepressant preferably constitutes from about 1 % by weight (% by wt.) to about 30 % by wt.
  • the amine containing compounds having biphasic solubility used in the transdermal compositions ofthe invention further include antiepileptic compounds.
  • antiepileptic compound includes compounds capable of alleviating the symptoms of epilepsy.
  • Exemplary antiepileptic compounds for use in the compounds ofthe invention include lamotrigine, felbamate, and carbamazepine.
  • the antiepileptic compound is selected from the group consisting of lamotrigine, felbamate, carbamazepine, and combinations thereof.
  • the antiepileptic compound constitutes from about 1 % by wt. to about 30 % by wt. ofthe total amount of the pharmaceutical, more preferably from about 3 % by wt. to about 20 % by wt., and most preferably from about 5 % by wt. to about 15 % by wt.
  • Antiepileptic compounds are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J., 1996, and the "Guide to Clinical Neurology” by J.P. Mohr et al. (Churchill Livingstone, 1995) the contents of which are incorporated herein by reference.
  • the amine containing compounds having biphasic solubility ofthe present invention include anticonvulsant compounds.
  • anticonvulsant compound includes compounds capable of alleviating the symptoms of convulsion, i.e., the violent involuntary tetanic contractions of an entire group of muscles.
  • exemplary anticonvulsant compounds which for use in the compositions ofthe invention include felbamate, lamotrigine and carbamazepine.
  • the anticonvulsant compound is selected from the group consisting of felbamate, lamotrigine, and combinations thereof.
  • the anticonvulsant compound When combined with other compounds, such as an agent which enhances the activity ofthe amine containing compound, e.g., a muscle relaxant, and/or an anti-inflammatory compound, e.g., a nonsteroidal anti-inflammatory compound as discussed below, the anticonvulsant compound constitutes from about 1 % by wt. to about 30 % by wt. ofthe total amount of the pharmaceutical, more preferably from about 3 % by wt. to about 20 % by wt., and most preferably from about 5 % by wt. to about 15 % by wt.
  • Anticonvulsant compounds are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed., Budavari et al., eds., Merck & Co.. Inc., Rahway, N.J., 1996, and the "Guide to Clinical Neurology” by J.P. Mohr et al. (Churchill Livingstone, 1995) the contents of which are incorporated herein by reference.
  • the amine containing compounds having biphasic solubility ofthe present invention include adrenergic agonist compounds.
  • the adrenergic agonist compound is tizanidine.
  • the adrenergic agonist compound constitutes from about 1 % by wt. to about 30 % by wt. ofthe total amount ofthe pharmaceutical, more preferably from about 3 % by wt. to about 20 % by wt., and most preferably from about 5 % by wt. to about 15 % by wt.
  • Adrenergic agonist compounds are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J., 1996, and the "Guide to Clinical Neurology” by J.P. Mohr et al. (Churchill Livingstone, 1995) the contents of which are incorporated herein by reference.
  • the amine containing compounds having biphasic solubility used in the transdermal compositions ofthe invention further include sodium channel blockers.
  • sodium channel blockers includes compounds which are capable of blocking the activity of a sodium channel. Examples of sodium channel blockers include tetrodoxin, flecainide, disopyramide, and terfenadine.
  • Sodium channel blockers are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed.. Budavari et al, eds., Merck & Co., Inc., Rahway, N.J., 1996, and the "Guide to Clinical Neurology" by J.P. Mohr et al. (Churchill Livingstone, 1995) the contents of which are incorporated herein by reference.
  • nerves are damaged, for example, by trauma, by diseases such as diabetes, herpes zoster, or late-stage cancer, or by chemical injury (e.g., as an untoward consequence of agents including the false-nucleoside anti-HIV pharmaceuticals), neural pain circuits rewire themselves, anatomically and/or biochemically.
  • new sodium channels are formed which is believed to constitute the basis for chronic pain development.
  • chronic regional pain syndromes may develop. Each time one of these sodium channels depolarizes, a nerve impulse originates.
  • the amine moiety ofthe amine containing compounds having biphasic solubility ofthe present invention may function similar to a sodium ion upon entry into the sodium channel of a nerve cell membrane.
  • a non-polar moiety which is preferably present in the amine containing compound having biphasic solubility ofthe present invention may interact with the nerve cell membrane, perhaps through Van der Waals forces. In such cases, it is believed that the presence ofthe non-polar moiety prevents or inhibits a complete uptake ofthe amine containing compound having biphasic solubility through the nerve cell membrane. It is believed that one or more these interactions prevent or reduce the amount and/or the rate of depolarization and ion exchange involved in stimulus conduction, thereby decreasing pain sensation.
  • the amount of an amine containing compound having biphasic solubility useful in relieving pain transdermally may be determined by methods known in the art, and typically ranges from about 1 mg to about 300 mg per subject per dose, preferably from about 5 mg to about 100 mg per subject per dose, and more preferably from about 10 mg to about 50 mg per subject per dose, depending on a variety of factors including the particular amine containing compound having biphasic solubility used, whether the area of transdermal application is the site of action, and the intended size ofthe site of action.
  • the amount of an amine containing compound having biphasic solubility useful in relieving pain transdermally is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg per subject per dose.
  • Transdermal compositions ofthe present invention may also include a muscle relaxant.
  • muscle relaxant includes compounds which facilitate or enhance the relaxation of muscles (e.g., provide relief from muscle spasm) and, thus, facilitate or enhance the transdermal delivery ofthe transdermal compositions ofthe invention.
  • exemplary muscle relaxants include both skeletal muscle relaxants and smooth muscle relaxants such as anticholinergics, antispasmodics, bronchodilators, and vasodilators.
  • Muscle relaxants are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J., 1996, pp. THER-1 to THER-28, and the "Guide to Clinical Neurology” by J.P. Mohr et al. (Churchill Livingstone, 1995) the contents of which are incorporated herein by reference.
  • the muscle relaxant is selected from the group consisting of guaifenesin, benzodiazepines (e.g., clozapine or diazopam), chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, other muscle relaxants having biphasic solubility, and combinations thereof. More preferably, the muscle relaxant is selected from the group consisting of guaifenesin, chlorzoxazone, and combinations thereof.
  • a preferred muscle relaxant for use in the compositions ofthe invention is guaifenesin.
  • the muscle relaxant has biphasic solubility.
  • the muscle relaxant when present in the pharmaceutical composition, constitutes from about 1 % by wt. to about 30 % by wt. ofthe total amount ofthe pharmaceutical, more preferably from about 3 % by wt. to about 20% by wt., and most preferably from about 5 % by wt. to about 15 % by wt.
  • the transdermal compositions ofthe present invention may also include an anti-inflammatory compound.
  • an anti-inflammatory compound includes a compound which is capable of reducing cell migration, caused by ischemic and trauma associated events, and therefore reduces edema formation to thereby provide pain relief.
  • the anti-inflammatory compound is a nonsteroidal anti-inflammatory compound (i. e., NTHE) including ketoprofen.
  • NTHE nonsteroidal anti-inflammatory compound
  • Anti-inflammatory compounds, e.g., NTHEs are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed., Budavari et al, eds., Merck & Co., Inc., Rahway, N.J., 1996, pp.
  • the NTHE is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, Vioxx ® , COX-2 NTHEs having biphasic solubility, and combinations thereof.
  • the NTHE is selected from the group consisting of celecoxib, etodolac, naproxen, COX-2 NTHEs having biphasic solubility, and combinations thereof.
  • the NTHE has biphasic solubility.
  • the NTHE, when present in the transdermal composition preferably, constitutes from about 1 % by wt. to about 30 % by wt. ofthe total amount ofthe pharmaceutical, more preferably from about 3 % by wt. to about 30 % by wt., and most preferably from about 5 % by wt. to about 30 % by wt.
  • the concentration as well as the quantity ofthe amine containing compounds having biphasic solubility, the agents which enhance the activity ofthe amine containing compounds, e.g., the muscle relaxants, and the anti-inflammatory compounds can be varied independently in order to achieve the desired effect.
  • concentrations ofthe amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds contained in a dosage form of decreased viscosity may result in an analgesic with fast onset and short duration.
  • High concentrations ofthe amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds contained in a dosage form of increased viscosity may result in potent analgesic with fast onset and long duration.
  • Low concentrations ofthe amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds in a dosage form of decreased viscosity may result in mild analgesic with longer onset and short duration.
  • Low concentrations ofthe amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds contained in a dosage form of increased viscosity may have mild analgesic properties with longer onset and longer duration.
  • the ability to vary the concentration ofthe amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds from very low to high ofthe total composition, combined with the ability to coat thin (about 0.1 mm) or thick (about 0.5 mm) enables the practitioner of the invention to vary the dosage ofthe system as needed for particular level of pain and anatomical sites of interest. It should be appreciated, however, that onset time as well as duration of analgesic effect ofthe transdermal composition ofthe present invention will vary from subject to subject as well as on the basis ofthe site of application, and properties ofthe amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds.
  • the concentration ofthe amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds can range, on a weight basis, from about 1 % to about 30 % ofthe total composition, preferably from about 3 % to about 20 %, and more preferably from about 5 % to about 15 %.
  • transdermal compositions ofthe present invention also includes a pharmaceutically acceptable carrier which is capable of transdermal delivery ofthe amine containing compound having biphasic solubility.
  • a pharmaceutically acceptable carrier which is capable of transdermal delivery ofthe amine containing compound having biphasic solubility.
  • pharmaceutically acceptable carrier suitable for transdermal delivery includes a carrier capable of delivering the amine containing compound transdermally as defined above. Suitable carriers for transdermal delivery of pharmaceuticals are described in U.S. Patent No. 5,446,070, the contents of which are incorporated herein by reference. Briefly, pharmaceutically acceptable carriers ofthe present invention include any suitable finite (i. e, solid) or non-finite (i. e., non-solid, such as liquid or semi-liquid) carrier including liquids, semi-liquids or solid carriers, such as a bioadhesive.
  • the amine containing compounds having biphasic solubility may be admixed with a pharmaceutically acceptable carrier such as a cream, gel, emulsion, lotion, salve, paste, plaster, ointment, spray solution, or any other "non-finite" carrier known in the art of pharmaceutical delivery.
  • a pharmaceutically acceptable carrier such as a cream, gel, emulsion, lotion, salve, paste, plaster, ointment, spray solution, or any other "non-finite" carrier known in the art of pharmaceutical delivery.
  • the base of a non-finite carrier may be lipid including phospholipids such as lecithins; fatty oils; lanolin; vasoline; paraffins; glycols; higher fatty acids; and higher alcohols.
  • bioadhesive as used herein includes an adhesive which attaches to a biological surface such as skin or mucosal tissue.
  • the bioadhesive ofthe present invention is self-adhesive in that it attaches to the site of interest without the need to reinforce its attachment by way of another adhesive.
  • Suitable bioadhesive include natural or synthetic polysaccharides such as cellulose derivatives including methylcellulose, cellulose acetate, carboxymefhylcellulose, hydroxyethylcellulose and the like; pectin; a mixture of sulfated sucrose and aluminum hydroxide; hydrophilic polysaccharide gums including natural plant exudates, such as karaya gum, ghatti gum, tragacanth gum, xanthan gum, jaraya gum and the like; seed gums including guar gum, locust bean gum, psillium seed gum and the like; and lecithins such as soya lecithin.
  • natural or synthetic polysaccharides such as cellulose derivatives including methylcellulose, cellulose acetate, carboxymefhylcellulose, hydroxyethylcellulose and the like
  • pectin a mixture of sulfated sucrose and aluminum hydroxide
  • hydrophilic polysaccharide gums including natural
  • compositions ofthe present invention may also include other ingredients such as various pharmaceutically acceptable additives available to those skilled in the art. These additives include binders, stabilizers, preservatives, flavorings, fragrances, and pigments.
  • the pharmaceutically acceptable carrier ofthe present invention includes van pen cream (cetyl alcohol, stearyl alcohol, steric acid, gllycerol monosterate, isopropyl myristate, soya lecithin, BHT alcohol 95%, simethicone, sodium hydroxide 30% solution, polyoxyl stearate, edetate disodium 5%, purified water, urea).
  • the invention features a transdermal composition suitable for transdermal delivery, which includes a therapeutically effective amount of a pharmaceutical compound (e.g., a serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for treating attention deficit hyperactivity disorder, a compound suitable for treating hypertension and akathisia, an analgesic compound, or a compound used in the treatment of impotence) and a pharmaceutically acceptable carrier suitable for transdermal delivery ofthe pharmaceutical compound.
  • a pharmaceutical compound e.g., a serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for treating attention deficit hyperactivity disorder, a compound suitable for treating hypertension and akathisia, an analgesic compound, or a compound used in the treatment of impotence
  • a pharmaceutical compound e.g., a serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound
  • the term "pharmaceutical compound” includes compounds suitable for treating a targeted condition and capable of being delivered in active form, in vivo.
  • examples of pharmaceuticals include drugs, enzymes, chemical compounds, combinations of chemical compounds, biological macromolecules and analogs thereof. Examples of pharmaceutical compounds are described in detail below.
  • the pharmaceutical compound is a serotonin specific reuptake inhibitor (SSRI).
  • SSRIs are commonly prescribed for patients with diagnoses of mood disorders, some forms of anxiety disorder (particularly panic disorder), obsessive compulsive disorders, some forms of menopausal disorders, and eating disorders (especially bulimia nervosa).
  • SSRIs examples include sertraline (sold under the trade name Zoloft), paroxetine (sold under the trade name Paxil), fluoxetine (sold under the trade name Prozac), venlafaxine (sold under the trade name Effexor), and fluvoxamine (sold under the trade name Luvox).
  • the pharmaceutical compound is a mood stabilizing medication, such as carbamazepine (sold under the trade name
  • Tegretol Tegretol
  • valproic acid sold under the trade name Depakote.
  • augmentation medications to render antidepressants more effective
  • anti-manic medications in the treatment of bipolar mood disorder.
  • Mood stabilizing medications are also used in neurologic practice for the treatment of seizure disorders and for the treatment of certain pain disorders.
  • the pharmaceutical compound is a compound used for treating Attention Deficit Hyperactivity Disorder (ADHD), one example of which is permoline, sold under the trade name Cylert.
  • Permoline is a medication that is used in the treatment of Attention Deficit Hyperactivity Disorder in children and adults. It is practically insoluble in water, but soluble in ethylene glycol and lipids, making it a good candidate for transdermal administration.
  • the pharmaceutical compound is a dopamine compound, used for treating Parkinson's disease, examples of which are pergolide, sold under the trade name Permax and bromocriptine mesylate, sold under the trade name Parlodel.
  • the pharmaceutical compound is a compound used for treating hypertension and akathisia, one example of which is propranalol, sold under the trade name Inderal.
  • the pharmaceutical compound is a compound used in the treatment of impotence such as sildenafil, sold under the tradename Viagra. It is believed that transdermal administration of sildenafil may be useful, for at least some subjects, as compared to oral administration which has been found, in at least some situations, to be associated with gastrointestinal side effects.
  • Another embodiment ofthe present invention provides a method for preparing the above described transdermal compositions, by admixing a therapeutically effective amount ofthe amine containing compound having biphasic solubility, optimally an agent which enhances the activity ofthe amine containing compound, e.g., a muscle relaxant, optimally an anti-inflammatory compound with the carrier suitable for transdermal delivery ofthe amine containing compound.
  • a transdermal composition is prepared by dispersing or dissolving crushed tablets, capsules or other preparation(s) of the amine containing compound having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds, which were intended for oral delivery, in a gel formed of soya lecithin and isopropyl palmitate or isopropyl myristate, alcohol, or ethoxy diglycol.
  • Pluronic gel formed of Pluronic such as Pluronic F127, potassium sorbate and water is used.
  • a transdermal composition including a combination of doxepin with guaifenesin is useful for treating pain. It is believed that transdermal administration of such combination can be advantageous, for at least some patients, as compared to oral administration, because higher local pharmaceutical concentrations at the site(s), e.g., of injury, can be achieved yielding an improved therapeutic response without systemic side effects such as weight gain, drowsiness, gastrointestinal upset and/or other known side effects of these pharmaceuticals.
  • the invention feature methods for treating pain in a subject in which the subject is contacted with a transdermal composition including an amine containing compound having biphasic solubility in an amount effective to treat pain in the subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery ofthe amine containing compound to thereby treat pain in the subject.
  • the transdermal composition is applied to the skin ofthe subject as often as needed for the alleviation of pain.
  • the transdermal composition may be applied daily, weekly, monthly, yearly, for a length of time sufficient to alleviate pain.
  • Detailed examples ofthe preparation are provided below, along with examples of results obtained from transdermal administration to human patients.
  • a gel preparation is applied to the skin at the site or sites of pain.
  • Patients can be evaluated by means of a structured evaluation form, e.g., completed at a frequency of at least one time per week. Evaluation of patients are for the present symptoms as well as any side effects from currently administered medications. This makes it possible to note changes on an ongoing basis.
  • compositions ofthe invention can be self-administered doses in the form of a gel applied to the skin by the patient, or be implemented by providing a transdermal preparation in premeasured doses preferably in connection with an adhesive or other covering or patch so that the dosage may be administered e.g., by placing the adhesive patch on the skin ofthe patient.
  • a transdermal preparation in premeasured doses preferably in connection with an adhesive or other covering or patch so that the dosage may be administered e.g., by placing the adhesive patch on the skin ofthe patient.
  • the location ofthe skin to which the pharmaceutical is applied is selected so as to relatively increase or decrease the delay, speed, duration, or rate of delivery ofthe pharmaceutical, either with respect to a particular tissue or systemically.
  • a placement which enhances delivery rate such as behind the ear, can be used.
  • the transdermal formulation may be positioned adjacent the desired treatment area.
  • Membranes or matrices, such as a polymer matrix, may be used to limit or control delivery rates.
  • delivery ofthe transdermal or aerosol formulation can be achieved, e.g. by administration as nose drops, eardrops, eyedrops and/or suppositories.
  • medications dispensed in transdermal gel form will be dispensed in unit doses, such as blister packs.
  • the gel will be extruded from the blister pack, and rubbed on the administration site.
  • the dosage will be adjusted by varying the number of unit dose applied. This will ensure accurate dosimetry and will avoid contamination ofthe gel.
  • the invention features a method for selecting a compound suitable for treating pain in a subject.
  • the method includes transdermally administering an amine containing compound having biphasic solubility to a subject; and determining whether pain is treated in the subject to thereby select a compound suitable for treating pain in a subject.
  • the method can further include modeling the compound using a computer equipped with a three-dimensional chemical structure modeling program (e.g., Molecules-3D Professional Edition, version 2.60, copyright 1991-1998, Molecular Arts Corp., ⁇ 1994-1998 WCB/McGraw Hill); and determining whether the three-dimensional chemical structure ofthe compound possesses sufficient characteristics to be useful as a sodium channel blocker, thereby selecting a compound suitable for treating pain in a subject.
  • the effectiveness ofthe amine containing compound having biphasic solubility to treat pain can be tested in vitro or in vivo.
  • An animal model for pain e.g., such as the one described in Krai M.G. et al.
  • Example 1 One hundred grams of lecithin soya (granular) and 0.66 grams sorbic acid (NF-1)
  • FCC powder were dispersed in 100 grams (117 milliliters (mL)) of isopropyl palmitate NF and allowed to stand overnight. Approximately 220 milliliters of lecithin-isopropyl palmitate in a form of a liquid of a syrup consistency was formed.
  • lecithin soya granular
  • 0.66 grams sorbic acid NF- FCC powder
  • isopropyl myristate NF isopropyl myristate NF and allowed to stand overnight.
  • a beaker was prepared by measuring to a volume of 100 milliliters. It was considered important to measure the volume accurately rather than using beaker markings.
  • An amount of Pluronic F127 NF (20 grams for a 20 percent gel, 30 grams for a 30 percent gel, 40 grams for a 40 percent gel) was mixed with 0.3 grams potassium sorbate NF. Refrigerated purified water was added in an amount sufficient to bring the volume to 100 milliliters. When all ofthe granules had been wet the gel was refrigerated. Solution took place upon cooling, taking 12 to 24 hours. The resulting 100 milliliters of Pluronic gel was kept refrigerated, since the gel will solidify at room temperature.
  • Example 6 600 milligrams of fluoxetine HC1 (in the form of thirty 20 milligram capsules) was placed in a beaker and dissolved in approximately 18 cc of 95 percent ethyl alcohol. The solution was filtered through a filter funnel using fine filter paper. The residue was washed with 95 percent alcohol. The filtrate was heated, maintaining a temperature less than 85° C, to evaporate the alcohol to concentrate to 1 to 2 milliliters. 600 milligrams of isopropyl palmitate was combined with 600 milligrams of soya lecithin (granular), set aside and allowed to liquefy. Upon liquefaction, a thick syrupy consistency was obtained.
  • a Luer-oral adapter was attached to the mixture and transferred to six 1 milliliter oral syringes, was filled with 1 milliliter ofthe gel. In this way, each syringe contained five 20 milligram doses, or ten 10 milligram doses to yield a total of 60 doses of fluoxetine in lecithin organogel having a strength of 10 milligrams per 0.1 milliliters.
  • Example 7 Twelve 250 milligram tablets of nefazadone were crushed in a mortar and pestle and put through a strainer. 4.8 milliliters of ethoxy diglycol (8 percent) was added and mixed. In cases in which all particles were not dissolved, 2 milliliters of Pluronic were added and mixed. 13.6 milliliters of soya lecithin were added and mixed. The resulting mixture was put into syringes with a Luer adapter and mixed well. Sufficient Pluronic F127 gel, prepared according to Example 3, was added to achieve a volume of 60 cc and mixed well to yield 60 cc of nefazadone organogel having a strength of 50 milligrams per milliliter.
  • Example 8 Thirty 40 milligram tablets of paroxetine were crushed and run through a strainer, discarding green coating material. 4.8 milliliters of ethoxy diglycol was added to the powder and mixed in a mortar and pestle. Forty milliliters of Pluronic F127 gel 20 percent, formed according to Example 3, was added in graduated amounts to the powder and mixed until smooth using a spatula. 13.2 milliliters of soya lecithin was added and mixed well and the resulting material placed into syringes and sufficient quantity of Pluronic gel was added to bring the volume to 60 milliliters. In those such cases where particle size ofthe resulting material was too large, the cream was run through an ointment mill to yield 60 milliliters of paroxetine organogel having a strength of 20 milligrams per milliliter.
  • Example 9 Thirty 100 milligram tablets of sertraline were crushed into a fine powder and strained, discarding the yellow coating. Sufficient amount of Pluronic F127 gel 20 percent (formed according to Example 3) was added to achieve a volume of 38 milliliters and mixed well in a mortar and pestle until a smooth cream was achieved. This material was placed into syringes and mixed between the syringes to obtain a compact cream. 13.2 milliliters of soya lecithin was added and mixed well between the syringes using about 20 pumps. Sufficient quantity of Pluronic F127 gel 20 percent was added to yield 60 milliliters of sertraline gel having a strength of 15 milligrams per milliliter.
  • Venlafaxine hydrochloride has a solubility in water of 572 mg/mL (adjusted to ionic strength of 0.2 M with sodium chloride). Forty-five 100 milligram tablets of venlafaxine were crushed and put through a strainer. The powder was dissolved in 15 cc purified water, the solution placed into a filter and washed with 10 cc purified water. The filtrate was used to make a 20 percent Pluronic gel using the procedures of Example 3 (substituting the filtrate for an equivalent amount of water) and placed into a refrigerator overnight. 13.2 milliliters of soya lecithin were drawn into a syringe with a Luer loc.
  • the venlafaxine Pluronic gel was drawn into another syringe coupled to the first syringe and mixed well. Sufficient Pluronic F127 gel was added to achieve a volume of 60 cc with a strength of 75 mg. per cc.
  • Paroxetine hydrochloride has a solubility in water of 5.4 mg/mL.
  • Paroxetine (Paxil) gel was prepared, according to the procedures of example 8. A dosage of 40 mg per day was self-administered by a 59 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 210 days, blood was drawn and blood serum level of Paxil was determined to be 0 nanograms (ng) per mL, while typical reference levels are 49 ⁇ 26 ng/mL, indicating possible poor absorption or lab error. Clinical evaluation ofthe patient over a 210 day period of such transdermal administration indicated benefit to patient without GI side effects similar to that noted with oral preparation.
  • Sertraline hydrochloride is slightly soluble in water and isopropyl alcohol and sparingly soluble in ethanol.
  • Sertraline (Zoloft) gel was prepared, according to the procedures of example 9. A dosage of 100 mg per day was self-administered by a 54 year old female patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 19 days, blood was drawn and blood serum level of Zoloft was determined to be 5 ng/mL, while typical reference levels are 30-200 mg/mL indicating possible limited abso ⁇ tion or lab error.
  • Fluoxetine hydrochloride has a solubility in water of 14 mg/mL.
  • Fluoxetine (Prozac) gel was prepared, according to the procedures of example 6. A dosage of 20 mg per day was self-administered by a 54 year old female patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 7 days, blood was drawn and blood serum level of fluoxetine was determined to be 45 ng/ml, while the plasma level ofthe primary active metabolite norfluoxetin was also 45 ng/ml. There was evidence of patient benefit from the clinical evaluation.
  • Carbamazepine is practically insoluble in water and soluble in alcohol and in acetone.
  • Carbamazepine (Tegretol) gel was prepared, according to the procedures of example 4. A dosage of 400 mg per day was self-administered by a 55 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 120 days, blood was drawn and blood serum level of Tegretol was determined to be 4.6 micrograms ( ⁇ g) per mL, while typical therapeutic levels are 4-10 ll ⁇ g/mL indicating good absorption. There were no GI side effects and the patient demonstrated clinical improvement.
  • Carbamazepine (Tegretol) gel was prepared, according to the procedures of example 4. A dosage of 200 mg per day was self-administered by a 53 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 60 days, blood was drawn and blood serum level of Tegretol was determined to be 10.8 ⁇ g/mL, while typical therapeutic levels are 4-10 ll ⁇ g/mL indicating excellent absorption. There were no GI side effects and the patient demonstrated clinical improvement.
  • Sertraline (Zoloft) gel was prepared, according to the procedures of example 9. A dosage of 50 mg per day was self-administered by a 53 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 63 days, blood was drawn and blood serum level of Zoloft was determined to be 23 ng/mL, while typical reference levels are 30-200 mg/mL. The patient demonstrated a good clinical response without GI side effects.
  • Carbamazepine (Tegretol) gel was prepared, according to the procedures of example 4. A dosage of 200 mg per day was self-administered by a 47 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 91 days, blood was drawn and blood serum level of Tegretol was determined to be less than 0.5 ⁇ g/mL, while typical therapeutic levels are 4-10 ⁇ g/mL, indicating poor abso ⁇ tion, lab error, or patient non-compliance.
  • Tegretol Carbamazepine
  • Buproprion is highly soluble in water.
  • Buproprion (Wellbutrin) gel was prepared, according to the procedures of example 5. A dosage of 100 mg per day was selfadministered by a 47 year old male patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 44 days, blood was drawn and blood serum level of Wellbutrin was determined to be less than 0.5 ng/mL, while typical therapeutic levels are 10-30 indicating poor abso ⁇ tion, lab error, or patient non- compliance.
  • Fluoxetine gel was prepared, according to the procedures of example 6..
  • a total daily adult dosage of fluoxetine as applied to the skin according to the present invention is between about 20mg and 200 mg, more preferably between about 120 mg and about 200 mg.
  • Dosages for non-adults and/or non-human mammals may need to be adjusted, e.g. proportionally to body weight.
  • a dosage of 20-60 mg per day was self-administered by 5 patients, including that of example 13 and also including a 44 year old male patient, a 53 year old female patient, a 47 year old male patient and a 36 year old female patient by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation ofthe patients over a 30-180 day period of such transdermal administration indicated a clinical response ranging from complete remission of symptoms to moderate improvement.
  • Example 21 Fluoxetine gel was prepared, according to the procedures of example 6. A dosage of 80-160 mg per day was selfadministered by a 50 year old female by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 7 days at the 80 mg dosage level blood was drawn and the blood serum of fluoxetine was determined to be 34 ng/mL fluoxetine and 25 ng/mL norfluoxetine, while typical reference levels are 50-480 ng/mL, indicating good abso ⁇ tion. There was evidence of patient benefit from the clinical evaluation. The dosage was then increased to 160 mg per day and administered by the same method.
  • Fluoxetine gel was prepared, according to the procedures of example 6. A dosage of 80-160 mg/day was self administered by a 38 year old female by application to the skin, for a period of at least 1 hour. No skin irritation was reported. After 7 days at the 80 mg dosage level, blood was drawn and the blood serum level of fluoxetine was determined to be 25 ng/mL of fluoxetine and 25 ng/mL norfiuoxetine. There was evidence of patient benefit from the clinical evaluation. The dosage was then increased to 160 mg per day and administered by the same method.
  • Sertraline (Zoloft) gel was prepared, according to the procedures of example 9.
  • a dosage of 50-200 mg per day was self-administered by 6 patients, including those of examples 12 and 16 and also including a 60 year old male patient, a 53 year old male patient, a 48 year old male patient, a 38 year old male patient and a 47 year old male patient, by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation ofthe patients over a 7-90 day period of such transdermal administration indicated responses ranging from complete resolution of depression to no noticeable response.
  • Carbamazepine (Tegretol) gel was prepared, according to the procedures of example 4.
  • a dosage of 200-400 mg per day was self-administered by 6 patients, including those of examples 14, 15 and 17, and also including a 48 year old female patient, a 48 year old male patient and a 54 year old female patient, by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported.
  • Example 25
  • Paroxetine (Paxil) gel was prepared, according to the procedures of example 8. A dosage of 20 mg per day was self-administered by the patient of example 12 as well as by a 15 year old female patient by application to the skin, for a period of at least 1 hour. No skin irritation was reported. Clinical evaluation ofthe patients over a 30-210 day period of such transdermal administration indicated equivocal clinical improvement of the depression which may (or may not) have been related to the transdermally administered Paxil.
  • Example 27 Amitriptyline (Elavil) gel was prepared, according to the procedure of example
  • Trazodone (Desyrel) gel was prepared, according to a procedure similar to that of example 7. A dosage of 50-150 mg per day was self-administered by 2 patients, including a 36 year old female patient and a 47 year old male patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation ofthe patients over a 42-90 day period of such transdermal administration indicated a good to excellent clinical response.
  • Example 29 Venlafaxine (Effexor) gel was prepared, according to a procedure similar to that of example 9. A dosage of 150-225 mg per day was self-administered by 2 patients, including a 54 year old female patient and a 55 year old male patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation ofthe patients over a 15— 165 day period of such transdermal administration indicated a response ranging from no clinical improvement to mild clinical improvement.
  • Propranolol (Inderal) gel was prepared, according to a procedure similar to that of example 8 to produce a gel having a strength of 40 mg of propranalol per mL of gel.
  • a dosage of 80 mg per day was self-administered by 2 patients, including a 36 year old female patient and a 47 year old male patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation ofthe patients over a 100 day period of such transdermal administration indicated results comparable to those achieved with oral medication.
  • Buproprion (Wellbutrin) gel was prepared, according to a procedure described in example 5.
  • a dosage of 150-200 mg per day was self-administered by 3 patients, including that of example 18, and also including a 38 year old male patient and a 53 year old female patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation ofthe patients over a 5-45 day period of such transdermal administration indicated equivocal results.
  • Example 32
  • Valproic acid (Depakote) gel was prepared, according to a procedure similar to that of example 4. A dosage of 1000 mg per day was self-administered by a 38 year old male patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation ofthe patients over a 30 day period of such transdermal administration indicated results comparable to those achieved with oral medication.
  • Example 33 Valproic acid (Depakote) gel was prepared according to the procedure of example 1 1.
  • a dosage of 500-1000 mg was self administered by two male patients, ages 41 and 49. Administration was by application to the skin, for a period of at least one hour. Significant skin irritation occurred with one patient, but no gastrointestinal side effects were reported. Clinical evaluation ofthe patients over a period of two months revealed improvement, but upon longer term follow-up it appeared that other factors may have been responsible.
  • blood was drawn and a serum valproic acid level of 26 ⁇ g/mL was obtained for the 49 year old patient (while taking 250 mg twice daily), with a therapeutic reference range of 50-150 ⁇ g/mL.
  • a gel containing reboxetine (sold under the trade name Edronax) is prepared according to a procedure similar to that described in example 5 but using reboxetine in place of boproprion.
  • the resulting mixture will be selfadministered by patients by application to the skin for a period of at least I hour. No skin irritation or gastrointestinal side effects are expected. Clinical evaluation of patients over a 5-45 day period of such transdermal administration is expected to indicate a good response to treatment.
  • Nefazodone (Serzone) gel was prepared, according to a procedure described in example 7. A dosage of 100 mg per day was self-administered by a 61 year old (male, female) patient. Administration was by application to the skin, for a period of at least 1 hour. No skin irritation or gastrointestinal side effects were reported. Clinical evaluation ofthe patients over a 21 day period of such transdermal administration indicated a good response to treatment.
  • Example 37 A 1 6-year-old female with an established diagnosis of Attention Deficit Disorder had been treated successfully with oral pemoline (Cylert) for about 6 months.
  • permoline prepared according to the procedure of example 36 will be administered transdermally, by application to the skin in the post auricular region for a period of at least one hour, at two sites, twice daily. No skin irritation is expected.
  • the clinical results are expected to be comparable to those obtained with the oral medication, although the dosage may have to be adjusted upwards to achieve adequate plasma levels, and more time may be required to achieve satisfactory plasma levels.
  • Valproic acid appears to cause skin irritation in some patients necessitating discontinuation. Both the laboratory measure of Buproprion and the patient clinical responses indicated poor or equivocal abso ⁇ tions and results. Patient tolerance of transdermal administration has been good to excellent. Patients in the example above who suffered very severe GI side effects using oral preparations were more tolerant of the inconvenience of rubbing on the gel than were patients who had experienced only mild to moderate side effects. In general, more highly motivated and treatment-compliant patients also had a higher rate of sustained compliance.
  • Fig. 1 Patients in the examples above were evaluated by means of a structured evaluation form depicted in Fig. 1, which was completed at a frequency of at least one time per week for each patient receiving transdermal medication according to the present invention.
  • the patients were evaluated both for all present psychiatric symptoms as well as any side effects from currently-administered medications.
  • Fig. 1 a structured evaluation form depicted in Fig. 1, which was completed at a frequency of at least one time per week for each patient receiving transdermal medication according to the present invention.
  • the patients were evaluated both for all present psychiatric symptoms as well as any side effects from currently-administered medications.
  • patients with the most clear cut and uncomplicated diagnosis of major depression experienced the best results.
  • patients with severe personality disorders or with concealed substance abuse disorders did less well.
  • Gabapentin mixtures of 2% and 4% will be prepared by substituting 1200 mg gabapentin or 600 mg gabapentin in place of 1800 mg gabapentin, in example 38.
  • Example 40
  • Gabapentin prepared according to Example 38 or 39, will be combined with either 3% or 5% Lidocaine in varying ratios.
  • 2% gabapentin, prepared according to Example 38 or 39, will be combined with 2% carbamazepine and 1 % Piroxicam, which is expected to yield better penetration into muscle tissue.
  • Gabapentin prepared according to Example 38 or 39, in concentrations ranging from 2%-6% will be combined with clonidine in concentrations between .2% and .3%.
  • Example 44 A 56-year-old woman had painful upper and lower extremity spasms as a result of spastic quadriparesis resulting from an injury. Oral gabapentin, an anticonvulsant, had been administered previously, but had caused a "drugged" feeling, one ofthe commonly reported side effects with this agent. It was believed that use of transdermal gabapentin might provide local relief by achieving high local tissue concentrations near the site of administration without correspondingly elevated blood plasma levels. It is known that other anticonvulsants, such as carbamazepine, are useful in reducing neurogenic pain. Gabapentin's solubility in water exceeds 10%, making systemic abso ⁇ tion less likely.
  • Gabapentin prepared according to the procedure of example 38 was self-administered by application to the skin in the area of pain.
  • the patient reported moderate relief of spasms over a period of one week, with no systemic side effects and no report of skin irritation.
  • Example 45
  • doxepin 6 grams was added to 20 milliliters Pluronic 33% F127 and put into a refrigerator to dissolve. 24 grams of ketoprofen and 12 grams of guaifenesin was added to 10 milliliters of 95% alcohol and mixed well. 26.4 milliliters of soya lecithin was added and mixed well and the doxepin composition was mixed with the ketoprofen/ guaifenesin composition. The resulting mixture was added to sufficient Pluronic 33% to yield 120 milliliters. The resulting composition was mixed well to yield a composition having about 20% ketoprofen, 5% doxepin and 10% guaifenesin.
  • Example 47 6 grams of doxepin was added to 26 milliliters Pluronic 33%> and refrigerated to dissolve. 2 milliliters ethoxy diglycol was added 4.8 grams carbamazepine and mixed.
  • the resultant mixture was added to 24 grams ketoprofen and six milliliters alcohol and the result was mixed well. 26.4 milliliters soya lecithin was added to the ketoprofen composition and mixed well.
  • the doxepin composition was mixed with the carbamazepine/ ketoprofen composition and sufficient Pluronic 33% was added to yield
  • the resultant composition was mixed well to yield a composition having about 20% ketoprofen, 4% carbamazepine and 5% doxepin.
  • Example 48 15 grams sildenafil was crushed and strained and dissolved in 5 milliliters
  • Example 49 A mixture of Sildenafil 15 mg/ml was applied to the penis and scrotum of a 51 year old male. An immediate and strong erection resulted with sexual stimulation, without any irritation or burning. It is believed the composition will possess the therapeutic results claimed for orally administered Sildenafil, without any time delay, without any systemic GI side effects, and possibly without the degree of drug interaction with nitrates used in cardiac disease. It is believed that this will contribute both to the convenience of use ofthe pharmaceutical and to its safety.
  • compositions according the examples 45 through 47, 53, 55 were transdermally applied to numerous patients, for the pu ⁇ ose of treating pain including as described in other examples herein, with the results summarized in Table I below.
  • Table II The meaning of certain entries in Table I is indicated in Table II below. Blank results indicate no treatment at the pertinent site for this patient. Where a given line of Table I shows more than one site, one "best" (greatest pain relief) result if shown in bold.
  • ketoprofen and sufficient guaifenesin to result in a 10% final guaifenesin concentration was mixed well with 10 milliliters 95% alcohol.
  • 1200 mg gabapentin was dissolved in one ml propylene glycol in a syringe with a luer loc.
  • 26.4 ml of soya lecithin was added to the ketoprofen-guaifenesin-alcohol mixture and mixed well.
  • the resulting mixture was added to the gabapentin-propylene glycol mixture and mixed well.
  • 4.8 gm of carbamazepine was combined with the resultant combination and mixed well to form a smooth paste.
  • the resulting paste was combined with the ketoprofen-guaifenesin-alcoholgabapentin mixture and mixed well with sufficient pluronic to yield 120 ml of a composition containing ketoprofen 20%, carbamazepine 4%, gabapentin 4%, guaifenesin 10%.
  • Example 54 A 58 year old female with damage to her cervical spinal cord with a resultant spastic quadreparesis reported moderate relief of both pain and muscle spasms when she applied a mixture prepared generally according to example 53, containing ketoprofen 20%, carbamazepine 4%, gabapentin 4%, guaifenesin 10% for a period of 8 weeks to her back and hip. She had been unable to tolerate both oral carbamazepine and oral gabapentin because of systemic side effects, including skin rash with the carbamazepine and dizziness and sedation with the gabapentin. She experienced no skin irritation nor other side effects with the transdermal formulation.
  • Example 55 Six grams of doxepin powder combined with 26 milliliters pluronic and placed in the refrigerator until dissolved. 1200 mg gabapentin was mixed with 1 ml propylene glycol and placed in a syringe with luer lock. 6.6 ml of soya lecithin was added and mixed well between syringes. 24 gm of ketoprofen and 8 milliliters alcohol was mixed well between two syringes with luer loc. The doxepin mixture was mixed well with the gabapentin mixture and subsequently the ketoprofen mixture was added and mixed well. Sufficient pluronic 20% (about 54 ml) was added to yield 60 ml of a composition having about 20%) ketoprofen, 4% weight percent gabapentin and 5% weight percent doxepin.
  • Example 56 A 57 year old female applied a mixture, prepared generally according to example
  • ketoprofen 20% containing ketoprofen 20%, gabapentin 4%, and doxepin 5% for a period of 8 weeks to her neck and reported major relief. She applied the same mixture to her shoulder and reported moderate relief. A mixture that substituted piroxicam for the doxepin produced only mild shoulder relief.
  • Example 57 A 41 year old woman with history of back surgery applied a mixture, prepared generally according to example 45, containing 4% carbamazepine and 5% gabapentin to her back for a period of 2 weeks. She reported mild pain relief.
  • Example 58 A 53 year old man with a history of two total bilateral knee replacements applied a mixture, prepared generally according to example 45, containing 4% carbamazepine and 5% amitriptyline to both knees for a period of 4 weeks. He reported no pain relief.
  • Example 58A A 54 year old man with a history of 7 back surgeries applied a mixture, prepared generally according to example 45, containing 4% carbamazepine and 5% amitriptyline to his back for a period of 2 weeks. He reported mild to moderate pain relief, over and above that he was receiving from a transdermal opiate medication (Duragesic). He reported no side effects, and specifically no skin irritation.
  • Example 65 12 g doxepin was mixed with 50 ml Pluronic F 127 33% and placed in a refrigerator to dissolve. 12 g gabapentin was dissolved in 9 ml ethoxy diglycol and mixed to form a smooth paste. 52.8 ml of soya lecithin was added and mixed well. The doxepin/Pluronic mixture was added and mixed well. Sufficient quantity of Pluronic F 127 20% was added to produce 240 ml of a composition having about 5 wt% gabapentin and 5 wt% doxepin.
  • Example 66 12 g doxepin was mixed with 50 ml Pluronic F 127 33% and placed in a refrigerator to dissolve. 12 g gabapentin was dissolved in 9 ml ethoxy diglycol and mixed to form a smooth paste. 52.8 ml of soya lecithin was added and mixed well. The doxepin/Pluronic mixture was added and mixed well. Su
  • a 36 year old man with a knee injury involving joint surface damage and vascular comprise applied a mixture, prepared generally according to Example 65 to his knee several times per day. He reported moderate to major (40%) relief of pain that persisted for 4 to 6 hours. An earlier trial of carbamazepine-amitriptyline gel produced no relief when applied to his knee.
  • 6 gm doxepin was mixed with 18 ml of Pluronic 33% to and placed in a refrigerator to dissolve.
  • 6 gm gabapentin was ground in a mortar and pestle to a fine powder, added to 6 ml ethoxy diglycol and mixed to form a smooth paste.
  • 12 gm guaifenesin was added and mixed well.
  • 26.4 ml soya lecithin was added and mixed well.
  • the doxepin/Pluronic mixture was added and mixed well.
  • Pluronic gel Sufficient quantity of Pluronic gel (25.2 ml of 33% Pluronic, although 30% or 20% Pluronic can be used), was added to produce 120 ml of a composition having about 5 wt% gabapentin, about 5 wt% doxepin and about 10 wt% guaifenesin.
  • a 59 year old woman with cervical and back strain applied a mixture, prepared generally according to example 51 , but without steps involving ketoprofen) containing about 5 wt % doxepin and about 10 wt% guaifenesin, to her neck for a period of two weeks, two to four times per day, and achieved total relief. She applied the same mixture to her back and achieved major to total relief.
  • Example 70
  • doxepin HCI 4.5 gm was dissolved using 2.5 ml 95% alcohol and mixed well between syringes. It is also possible to mix the doxepin with 5 ml Pluronic 20% and place in a refrigerator to dissolve. Sufficient quantity of 20% Pluronic F127 was added to produce 90 ml of a composition having about 5 wt% doxepin. Preferably this and other disclosed compositions are protected from light.
  • Example 72 A formulation of 7% antidepressant and about 10% muscle relaxant was prepared by dissolving 3.15 g of trimipramine and 4.5 g of guaifenesin in a mixer jar using 2.7 mL of ethoxy diglycol. About 9.9 mL of soya lecithin was added and the mixture was mixed well. Sufficient quantity of Pluronic F127 NF (20%) to make total volume of about 45 mL was added and mixed well.
  • a gel formulation of 30% NTHE was prepared from 36 g of celecoxib, 7.2 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (20%) to make total volume of 120 mL.
  • a gel formulation containing about 7% antidepressant and about 13% muscle relaxant was prepared from 14.4 g of doxepin, 31.2 g of guaifenesin, 12 mL of ethoxy diglycol, 52.8 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 240 mL.
  • a gel formulation containing 5% antiepileptic was prepared from 6 g of lamotrigine, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F 127 NF (33%) to make total volume of 120 mL.
  • a gel formulation containing 10% adrenergic agonist was prepared from 12 g of crushed tizanidine, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
  • a gel formulation containing 10% muscle relaxant was prepared from 12 g of crushed metaxalone, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
  • a gel formulation containing 10% muscle relaxant was prepared from 12 g of crushed carisoprodol, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
  • a gel formulation containing 10% methocarbamol was prepared from 12 g of crushed methocarbamol, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
  • a gel formulation containing 10% muscle relaxant was prepared from 12 g of crushed dantrolene sodium, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
  • a gel formulation containing 7% antidepressant, 10% muscle relaxant was prepared from 8.4 g of crushed doxepin, 12 g of chlorzoxazone, 6 mL of ethoxy diglycol, 26.4 mL of soya lecithin and sufficient quantity of Pluronic F127 NF (33%) to make total volume of 120 mL.
  • Doxepin appears to provide about three times the positive response rate compared to at least some other pharmaceutical agents described herein, regardless of whether such other pharmaceutical agents are administered singly or in combination. Doxepin appears to be substantially more effective than amitriptyline as a pain, e.g., neuropathic pain agent when administered transdermally. This appears to be true regardless of whether doxepin is administered as a single agent or is administered in combination with other pharmaceuticals as described herein.
  • Carbamazepine appears to provide positive effects as a pain, e.g., neuropathic pain agent, at least in properly selected patients. Carbamazepine appears to cause a rash in at least some patients, requiring its discontinuation.
  • Gabapentin appears to be free of side effects when administered transdermally. Although some patients appear to derive some benefit from a combination of transdermally administered ketoprofen, gabapentin, and prioxicam, the effect appears to be relatively weak compared to the effect provided by doxepin.
  • Guaifenesin appears to provide benefit as an adjunctive treatment, of painful spasticity.
  • amitriptyline appeared to offer limited pain relief when administered transdermally. It appears that combining gabapentin with doxepin may offer some additional benefit.
  • the addition of guaifenesin to doxepin may be of particular value when painful spasticity is present.
  • the invention provides treatment to patients for whom oral delivery is suboptimal, such as patients who experience gastrointestinal or other side effects, patients who experience poor absorption for orally delivered pharmaceuticals and/or patients who benefit from delivery over an extended period or a relatively rapid delivery or higher rate of increase of plasma levels.
  • the present invention achieves delivery of therapeutic amounts of pharmaceuticals, for at least some patient populations, substantially without skin irritation, gastrointestinal or other side effects associated with orally-delivered pharmaceuticals, especially psychopharmaceuticals, and yields clinical benefits comparable to or greater than those received by patients to whom corresponding pharmaceuticals were administered orally.
  • particularly effective pain medications are those described in examples 65, 67, 69 and 70.
  • blood plasma levels may be increased by providing for two or more transdermal applications per day and/or applying a transdermal composition to two or more sites.
  • a Prozac gel formulation twice daily appeared to approximately double the plasma level. It is believed that an approach such as applying a Prozac gel formulation twice daily to two sites will yield middle range therapeutic levels of about 140-250 ng/ml. At least partially on the basis ofthe results described herein for fluoxetine, it is believed olanzapine (sold under the trade name Zyprexa) or a fluoxetine/olanzapine mixture in a lecithin organogel will prove useful.
  • a psychostimulant medication is Methylphenidate (sold under the trade name Ritalin) used in the treatment of attention deficit hyperactivity disorder (ADHD). Methylphenidate typically has a 2-4 hour duration of action necessitating frequent dosing of a patient which is particularly difficult to accomplish with children in school. It is believed that by using transdermal administration, it will be possible to achieve an extension of effective dosing throughout the day, eliminating the need for frequent oral medication administration. It is believed that transdermal administration will also eliminate peaks and valleys of blood plasma levels which, it is believed, will be more clinically effective.
  • Dextroamphetamine under the trade name Dexedrine
  • Dexedrine Another group of psychotropic medications which, it is believed, will benefit from transdermal delivery includes antipsychotic medication such as those used in the treatment in schizophrenia.
  • antipsychotic medication such as those used in the treatment in schizophrenia.
  • Embodiments ofthe invention include, but are not necessarily limited to, use by patients with enteric absorption deficits. Equivalents

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Abstract

La présente invention concerne des compositions antalgiques transdermiques et leurs méthodes d'administration. Selon un mode de réalisation, l'invention concerne des compositions à administration transdermique qui renferment un composé avec amine à solubilité biphasique et/ou un agent qui favorise l'activité antalgique dudit composé en tant que décontractant musculaire.
PCT/US1999/014653 1996-10-24 1999-06-29 Compositions antalgiques transdermiques et leurs methodes d'administration WO2000000120A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
EP99932017A EP1093348A4 (fr) 1998-06-29 1999-06-29 Compositions antalgiques transdermiques et leurs methodes d'administration
CA002335837A CA2335837A1 (fr) 1998-06-29 1999-06-29 Compositions antalgiques transdermiques et leurs methodes d'administration
SK2001-2000A SK20012000A3 (sk) 1998-06-29 1999-06-29 Transdermálny prostriedok na zmiernenie bolesti
MXPA00012767A MXPA00012767A (es) 1998-06-29 1999-06-29 Metodos y composiciones transdermicas para el alivio del dolor.
IL14042099A IL140420A0 (en) 1998-06-29 1999-06-29 Methods and transdermal compositions for pain relief
JP2000556706A JP2002519310A (ja) 1998-06-29 1999-06-29 疼痛軽減のための方法および経皮組成物
AU48415/99A AU4841599A (en) 1998-06-29 1999-06-29 Methods and transdermal compositions for pain relief
KR1020007014985A KR20010078754A (ko) 1998-06-29 1999-06-29 통증 경감 방법 및 통증 경감용 경피 조성물
BR9912508-0A BR9912508A (pt) 1998-06-29 1999-06-29 Métodos e composições transdérmicas para alìvio da dor
HU0102728A HUP0102728A3 (en) 1998-06-29 1999-06-29 Methods and transdermal compositions for pain relief
NO20006604A NO20006604L (no) 1998-06-29 2000-12-22 Fremgangsmåter og transdermale sammensetninger for lindring av smerte
HR20000905A HRP20000905A2 (en) 1998-06-29 2000-12-28 Methods and transdermal compositions for pain relief
US09/754,500 US6572880B2 (en) 1996-10-24 2001-01-03 Methods and transdermal compositions for pain relief
BG105175A BG105175A (bg) 1998-06-29 2001-01-24 Методи и трансдермални състави за облекчаване на болка
US09/825,524 US20020015713A1 (en) 1996-10-24 2001-04-02 Methods and transdermal compositions for pain relief

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US09/106,684 US6290986B1 (en) 1996-10-24 1998-06-29 Method and composition for transdermal administration of pharmacologic agents
US12290399P 1999-03-05 1999-03-05
US60/122,903 1999-03-05
US09/106,684 1999-03-05

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US6613803B1 (en) 1997-04-22 2003-09-02 Euro-Celtique S.A. Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof
US6696442B2 (en) 1997-04-22 2004-02-24 Euro-Celtique S.A. Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof
US6638947B2 (en) 1997-04-22 2003-10-28 Euro-Celtique S.A. Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof
US7338953B2 (en) 1999-07-01 2008-03-04 Pharmacia & Upjohn Company Method of treating chronic fatigue syndrome
US7241762B2 (en) 1999-07-01 2007-07-10 Pharmacia & Upjohn Company Method of treating peripheral neuropathy
US7317011B2 (en) 1999-07-01 2008-01-08 Pharmacia & Upjohn Method of treating peripheral neuropathy
US7276503B2 (en) 1999-07-01 2007-10-02 Pharmacia & Upjohn Company Method of treating chronic fatigue syndrome
US6987107B2 (en) 1999-07-01 2006-01-17 Pharmacia & Upjohn Company Method of treating incontinence
EP1500396A1 (fr) * 1999-07-01 2005-01-26 Pharmacia & Upjohn Company Reboxétine pour traiter les migraines
EP1500395A1 (fr) * 1999-07-01 2005-01-26 Pharmacia & Upjohn Company Reboxétine pour traiter les fibromyalgies et d'autres troubles somatoformes
EP1459750A1 (fr) * 1999-07-01 2004-09-22 Pharmacia & Upjohn Company (S,S)-réboxétine pour traiter les fibromyalgies et d'autres troubles somatoformes
EP1459751A1 (fr) * 1999-07-01 2004-09-22 Pharmacia & Upjohn Company (S,S)-réboxétine pour traiter les migraines
EP1493442A1 (fr) * 1999-07-01 2005-01-05 Pharmacia & Upjohn Company Réboxétine pour traiter les neuropathies périphériques
WO2001041732A1 (fr) * 1999-12-06 2001-06-14 Gore Stanley L Compositions et procedes d'administration intranasale d'agents actifs destines au cerveau
WO2001052897A3 (fr) * 2000-01-21 2002-03-14 Panacea Biotec Ltd Composition therapeutique anti-inflammatoire et analgesique contenant des medicaments selectifs inhibiteurs cox-2 a utiliser transdermiquement, et procede de fabrication de la composition
WO2001052897A2 (fr) * 2000-01-21 2001-07-26 Panacea Biotec Limited Composition therapeutique anti-inflammatoire et analgesique contenant des medicaments selectifs inhibiteurs cox-2 a utiliser transdermiquement, et procede de fabrication de la composition
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SK20012000A3 (sk) 2001-08-06
CN1331576A (zh) 2002-01-16
KR20010078754A (ko) 2001-08-21
HUP0102728A2 (hu) 2002-03-28
CA2335837A1 (fr) 2000-01-06
PL345216A1 (en) 2001-12-03
AU4841599A (en) 2000-01-17
EP1093348A1 (fr) 2001-04-25
BR9912508A (pt) 2001-05-02
NO20006604D0 (no) 2000-12-22
HUP0102728A3 (en) 2002-12-28
IL140420A0 (en) 2002-02-10
WO2000000120A9 (fr) 2000-03-30
EP1093348A4 (fr) 2003-07-16
MXPA00012767A (es) 2002-08-09
TR200003801T2 (tr) 2001-06-21
HRP20000905A2 (en) 2001-08-31
NO20006604L (no) 2001-02-28
BG105175A (bg) 2001-11-30
ID28213A (id) 2001-05-10
JP2002519310A (ja) 2002-07-02

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