EP1742632A2 - Administration iontophoretique transdermique de composes de piperazinyl-2(3h)-benzoxazolone - Google Patents

Administration iontophoretique transdermique de composes de piperazinyl-2(3h)-benzoxazolone

Info

Publication number
EP1742632A2
EP1742632A2 EP05768713A EP05768713A EP1742632A2 EP 1742632 A2 EP1742632 A2 EP 1742632A2 EP 05768713 A EP05768713 A EP 05768713A EP 05768713 A EP05768713 A EP 05768713A EP 1742632 A2 EP1742632 A2 EP 1742632A2
Authority
EP
European Patent Office
Prior art keywords
compound
iontophoretic
use according
pharmaceutically acceptable
piperazinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05768713A
Other languages
German (de)
English (en)
Inventor
Johanna A. SOLVAY PHARMACEUTICALS IPSI BOUWSTRA
Dirk-J. SOLVAY PHARMACEUTICALS IPSI VAN DEN BERG
Frederik J. SOLVAY PHARMACEUTICALS IPSI VERBAAN
R.V. Solvay Pharmaceuticals Inc. CONJEEVARAM
Ajay K. Banga
Viswatej Vemulapalli
J. M. Solvay Pharmaceuticals VAN SCHARRENBURG
Hendrik Solvay Pharmaceuticals TEUNISSEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Healthcare Products BV
Original Assignee
Solvay Pharmaceuticals BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Solvay Pharmaceuticals BV filed Critical Solvay Pharmaceuticals BV
Priority to EP05768713A priority Critical patent/EP1742632A2/fr
Publication of EP1742632A2 publication Critical patent/EP1742632A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0432—Anode and cathode
    • A61N1/044—Shape of the electrode
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0432—Anode and cathode
    • A61N1/0436—Material of the electrode

Definitions

  • the present invention relates to transdermal iontophoretic delivery of pharmaceutical compounds of the general formula
  • R is methyl, ethyl, ethyl substituted with one or more fluorine atoms, or cyclo- ⁇ Cs-rJ-alkylmethyl optionally substituted with one or more fluorine atoms or benzyl, 2-pyr ⁇ dylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, optionally substituted with one or more substituents from the group consisting of halogen, hydroxyl, cya ⁇ o, amino, mono- or di-C ⁇ .
  • the invention is related to transdermal iontophoretic delivery of pharmaceutical compounds of the general formula (l) wherein R is methyl, ethyl, ethyl substituted with one or more fluorine atoms, or cyclo-(C 3 .7)-alkylmethyl optionally substituted with one or more fluorine atoms or benzyl, 2-pyridylmethyl, 3- pyridylmethyl or 4-pyridylmethyl, which groups may be substituted with one or more substituents from the group consisting of halogen, hydroxyl, cyano, amino, mono - or di-C ⁇ -3-alkyIamino, CF 3 , OCF 3 , SCF 3> C ⁇ - 4 -alkyl, C ⁇ - 3 -alkylsulfonyl amino.
  • R is methyl, ethyl, ethyl substituted with one or more fluorine atoms, or cyclo-(C 3 .7)-alkyl
  • the invention is related to transdermal iontophoretic delivery of pharmaceutical compounds of the general formula (I) wherein R is methyl or benzyl optionally substituted with 1-3 substituents from the group hydroxyl and halogen.
  • R is methyl or benzyl optionally substituted with 1-3 substituents from the group hydroxyl and halogen.
  • Most preferred compounds in the present invention are compounds wherein R is methyl or benzyl.
  • the invention is related to the use of at least one compound of the general formula I as defined above, or mixtures thereof, for the manufacture of an iontophoretic device for the treatment of pain disorders, especially restless leg syndrome and CNS disorders, especially Parkinson's disease.
  • the present invention also relates to the use of compounds of the general formula (1) for the preparation of (a) a solution for use in a device for transdermal administration by iontophoresis or kits containing cartridges which contain the compound ready for use in said device, (b) a device suitable for transdermal administration by iontophoresis, wherein said transdermal device has a reservoir containing the compound of formula I or a composition thereof and optionally a pharmaceutically acceptable electrolyte, which device can be used in a meth od for controlling the delivery profile of pharmaceutical compounds of the general formula (I) and compositions thereof, and the use of said controlled delivery profiles in the treatment of pain disorders, especially restless leg syndrome and CNS disorders , especially Parkinson's disease.
  • transdermal delivery may provide an advantageous method of delivering that compound. This is the case, for example, for Parkinson's disease, where there is a need to administer medication to patients who are sleeping, comatose or anaesthetized. Further, there is growing evidence that continuous dopamine stimulation avoids the development of problems associated with intermittent dosing and where continuous drug delivery has been shown to decrease the incidence of "off' periods (P. Niall and W.H. Oertel, Congress Report of 7 th International Congress of Parkinson's Disease and Movement Disorders, Miami, Florida, November 10-14, 2002). In general, transdermal administration also has its problems, since it is not always easy to get drugs to cross the skin.
  • Iontophoretic transdermal delivery relates to introducing ions or soluble salts of pharmaceutically active compounds into tissues of the body under the influence of an applied electric field.
  • iontophoretic transdermal delivery may provide an advantageous method of delivering that compound.
  • Further iontophoretic transdermal delivery has the major advantage that the administered amount can be regulated precisely and can be used to easily titrate patients up to a certain level of administration over a period of up to several weeks.
  • iontophoretic methods appear limited as the drug delivery profile of a particular method depends heavily on the particular drug administered. Although a lot of experiments have been done with the iontophoretic delivery of various active substances, specific information allowing a person skilled in the art to tailor the delivery profile of a specific drug is not always available. As it has appeared that it is very difficult to develop transdermal patches with an acceptable size for compounds with the general formula (I), there is a need for an iontophoretic delivery method for said compounds that allows variable rate delivery of said compounds tailored to a specific treatment.
  • the present invention relates to iontophoretic transdermal technology that provides for the delivery of the compounds of the general formula (1) and compositions thereof through human skin.
  • compositions suitable for use in a device for transdermal administration by iontophoresis wherein said composition comprises the compound of formula I and optionally a pharmaceutically acceptable electrolyte.
  • the composition manufactured is suitable for use in a device for transdermal administration by iontophoresis for the treatment of Parkinson's disease and restless leg syndrome.
  • an object of the subject invention is to provide the use of the compounds of the general formula (I) and pharmaceutically acceptable salts and prodrugs thereof for the manufacture of a device suitable for transdermal administration by iontophoresis for the treatment of Parkinson's disease and restless leg syndrome, wherein said transdermal device has a reservoir containing the compound of formula I or a composition thereof and optionally a pharmaceutically acceptable electrolyte.
  • this device is applied to the skin of a living body and electrical current is caused to flow through the skin, the compounds of the general formula (I) and pharmaceutically acceptable salts and prodrugs thereof are iontophoretically delivered through the skin.
  • Another object of the invention is to provide an iontophoretic system for the delivery of the compounds of the general formula (I) and compositions thereof through the skin, wherein the system includes a transdermal delivery device attachable to the skin, the device including a first electrode and a second electrode, and a reservoir for containing a pharmaceutically acceptable electrolyte and the compounds of the general formula (I) and compositions thereof in electrical communication with the first and second electrodes; and an electrical power source connected to the first and second electrodes; wherein the reservoir contains the compounds of the general formula (I) and compositions thereof and optionally a pharmaceutically acceptable electrolyte.
  • kits comprising the iontophoretic system combined with one or more cartridges comprising the compound of the general formula (I) or a kit containing one or more cartridges comprising the compound of the general formula (I) to be used for refilling the reservoir of the iontophoretic system.
  • the amount of cartridges in the kits is preferably between 2 and 91, more preferably between 7 and 28 and most preferably between 14 and 28.
  • the skin through which the delivery has to take place is animal skin, for example human skin.
  • Figure 1 plots the flux of 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazoIone across human stratum corneum as a function of the active compound concentration versus time.
  • Figure 2 plots the flux of 7-(4-methyl-1-piperazinyl) ⁇ 2(3H)-benzoxazolone across human stratum corneum as a function of the electrolyte concentration versus time.
  • Figure 3 plots the flux of 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolone across human stratum corneum as a function of active compound concentration versus time in the presence of 4 g/l NaCI.
  • Figure 4 plots the flux of 7-(4-benzyl-1-piperazinyl)-2(3H)- benzoxazolone mesylate across hairless rat skin as a function of active compound concentration versus time in the presence of 30 millimolar ( M) NaCI.
  • Figure 5 plots the flux of 7-(4-benzyl-1-piperazinyl)-2(3H)- benzoxazolone mesylate across hairless rat skin as a function of the current density in the presence of 30 mM NaCI.
  • Figure 6 depicts a schematic presen tation of the iontophoretic set-up used for the tests with 7-(4-methyl-1-piperazi ⁇ yl)-2(3H)-be ⁇ zoxazolone.
  • An iontophoretic transdermal delivery system may comprise a first (donor) electrode containing an electrolytically available active compound within a suitable vehicle or carrier and optionally a penetration enhancer, a counter electrode and a power source, the first and second electrodes each being in electrically conductive communication with the power source.
  • the first and second electrodes can be adapted for spaced apart physical contact with the skin whereby, in response to a current provided by the power source through the electrodes, a therapeutic amount of tine active compound is administered through the skin to a patient.
  • the iontophoretic delivery (dose and profile) by which a particular active compound of the general formula (I) is administered to a patient may be controlled by suitable combination of the initial concen tration of the drug and electrolyte and the applied current (constant variable) in the iontophoretic system.
  • the combination of current density (constant/variable) and the initial amount of electrolyte may lead to an iontophoretic device with a very reasonable size that allows the drug delivery profile to be adjusted.
  • the ability to tailor the drug delivery profile in iontophoresis may provide increased control of the drug's effects on the user. Additionally, the ability to tailor drug delivery profile in iontophoresis may make the iontophoretic delivery of the compounds of formula (I) a more practically effective mode of administration.
  • permeation profile means a plot of the flux of the active compound versus time for a given delivery period.
  • the term "cartridge” means a container containing the active compound that is used for storage of the active compound before it is delivered by the device.
  • a cartridge can be selected for its user-friendliness. Any means for packaging the active compound separately from the iontophoretic device may be considered a "cartridge.”
  • detachable and replaceable reservoirs may be used to deliver active compound to the device.
  • the electrolytes used in the methods of the present invention may include u ⁇ ivalent or divalent ions, for example.
  • electrolytes used in our method include all Ci" donating compounds that are water soluble, such as HCI, NaCI, KCI, CaCI 2 , MgCI 2 , triethylammonium chloride and tributylammonium chloride.
  • the electrolyte comprises NaCI.
  • the required amount of electrolyte may depend on factors such as the transport area of the devi ce, the volume of the vehicle or earner, the concentration of the active compound, the current density, the duration of the iontophoresis and the efficiency of the transport.
  • the electrolyte may be present in amounts of, for example, at least about 0.005 mmole, at least about 0.01 mmole, or at least about 0.05 mmole.
  • the electrolyte may be present in amounts of, for example, not more than about 2 mmole, not more than about 1.0 mmole, or not more than about 0.3 mmole.
  • the initial amount of electrolyte may be expressed as a concentration of, for example, at least about 0.005 M, at least about 0.01 M, or at least about 0.03 M.
  • the initial amount of electrolyte may be expressed as a concentration of, for example, not more than about 2 M, not more than about 0.2 M, or not more than about 0.2 M.
  • Prodrugs of the compounds mentioned above are within the scope of the present invention.
  • Prodrugs are therapeutic agents which are inactive per se but are transformed into one or more active metabolites.
  • Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are n ot limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F. D. King, p. 215; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14(3), 277-280, 2004; P.
  • Pro-drugs i.e., compounds which when administered to humans by any known route, are metabolized to compounds having formula (I), belong to the invention. In particular this relates to compounds with primary or secondary amino or hydroxy groups.
  • Such compounds can be reacted with organic acids to yield compounds having formula (I) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl - methylene derivative, an 0-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
  • an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl - methylene derivative, an 0-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
  • the compounds of formula I can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. Salts of prodrugs also fall within the scope of this invention.
  • pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well -known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isothionate), lactate, maleate, mesylate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluene
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succ inic acid and citric acid.
  • Active drugs that may be administered by the method described herein include, but are not limited to, compounds such as 7-(4-methyl-1-piperazinyl)-2(3H)- benzoxazolone or its monohydrochloride salt (SLV308, see Drugs of the Futu re 2001, 26, 128-32) and 7-(4-benzyl-1-piperazinyl)-2(3H)-benzoxazolone or its monomesylate salt (SLV318).
  • compounds such as 7-(4-methyl-1-piperazinyl)-2(3H)- benzoxazolone or its monohydrochloride salt (SLV308, see Drugs of the Futu re 2001, 26, 128-32) and 7-(4-benzyl-1-piperazinyl)-2(3H)-benzoxazolone or its monomesylate salt (SLV318).
  • 7-(4-methyl-1-piperazinyl)-2(3H)- benzoxazolone or its monohydrochloride salt and 7- (4-benzyl-1-piperazinyI)-2(3H benzoxazolone or its monomesylate salt are suitable for the treatment of restless leg syndrome or Parkinson's disease.
  • the pH of the solution in the drug reservoir may be at least about 3.0 in some embodiments. In other embodiments, the pH may be less than or equal to about 7.5. In still other embodiments, the pH may range from about 4.0 to about 6.5.
  • the pH can be maintained on a constant level by means of a buffer such as a citrate buffer or a phosphate buffer.
  • a useful pH ranges from about 5.0 to about 6.0. Another possible pH for said compound is about 5.5.
  • the pH may range, for example, from about 3.5 to about 6.0. Another useful pH for said compound is about 4.0.
  • the current may be caused to flow by applying a constant or variable, such as pulsed, or alternating voltage/current.
  • the current may be caused to increase during the delivery period in order to titrate an increasing concentration of the compound of formula (I).
  • the voltage charged in the current application step is selected in the range of voltage that does not injure the skin of a living body and that does not disadvantage the rate of the transdermal absorption of the active compound.
  • the voltage can be, for example, at least about 0.1 V, or at least about 0.5 V, or at least about 1 V.
  • the voltage also can be, for example, less than about 40 V, or less than about 20 V, or less than about 10 V.
  • the pulsed or alternating voltage may have a frequency of, for example, at least about 0.01 Hz, or at least about 100 Hz, or at least about 5 kHz.
  • the pulsed or alternating voltage may have a frequency of, for example, no more than about 200 kHz, or no more than about 100 kHz, or no more than about 80 kHz.
  • the pulsed or alternating voltage may use substantially any type of waveform shape, including for example, sine, square, triangular, sawtooth, rectangular, etc.
  • the pulsed or alternating voltage may be applied on a duty cycle less than 100%.
  • the current density can be, for example, at least about 0.001 mA cm 2 , or at least about 0.005 mA cm 2 , or at least about 0.025 mA/cm 2 .
  • the current density also can be, for example, not more than about 1.0 mA cm 2 , not more than about 0.8 mA/cm 2 or not more than about 0.5 mA cm 2 .
  • the drug reservoir contains the drug and optional electrolyte with, as the vehicle or carrier, either an aqueous solution or a (hydro)gel.
  • the reservoir gel may be comprised of water soluble polymers or hyd rogels. In principle any gel can be used. Gels can be selected so that they do not adversely affect the skin (corrosion and irritation).
  • Gels may exhibit suitable properties, such as good skin contact (adhesiveness) and electroconductive property.
  • suitable properties such as good skin contact (adhesiveness) and electroconductive property.
  • No ⁇ -limiting examples include agar, agarose, polyvinyl alcohol, or crosslinked hydrogels, such as Hydroxypropylmethylcellulose (HPMC), Methylcellulose (MC), Hydoxyethylcellulose (HEC), Carboxymethylcellulose (CMC) and Polyvinylpyrrolidone (PVP) and Polyvinyl Acetate Phthalate (PVAP).
  • HPMC Hydroxypropylmethylcellulose
  • MC Methylcellulose
  • HEC Hydoxyethylcellulose
  • CMC Carboxymethylcellulose
  • PVAP Polyvinylpyrrolidone
  • PVAP Polyvinyl Acetate Phthalate
  • Suitable skin penetration enhancers include those well known in the art, and for example, include C 2 -C 4 alcohols such as ethanol and isopropanol; surfactants, e.g., anionic surfactants such as salts of fatty acids of 5 to 30 carbon a oms, e.g. sodium lauryl sulphate and other sulphate salts of fatty acids, cationic surfactants such as alkylamines of 8 to 22 carbon atoms, e.g.
  • oleylamine, and nonionic surfactants such as polysorbates and polyoxamers
  • aliphatic monohydric alcohols of 8 to 22 carbon atoms such as decanol, lauryl alcohol, myristyl alcohol, palmityl alcohol, linolenyl alcohol and oleyl alcohol
  • fatty acids of 5 to 30 carbon atoms such as oleic acid, stearic acid, linoleic acid, palmitic acid, myristic acid, lauric acid and capric acid and their esters such as ethyl caprylate, isopropyl myristate, methyl laurate, hexamethylene palmitate, glyceryl monolaurate, polypropylene glycol monolaurate and polyethylene glycol monolaurate
  • alkyl methyl sulfoxides such as decyl methyl sulfoxide and dimethyl sulfoxide
  • the carrier or vehicle i s separated from the skin by a membrane.
  • This membrane may be chosen, for example, to have a low resistance against the electric current, and/or to avoid substantially raising the barrier against the transport of the active compound, and/or to contain the carrier within the device during storage and transport.
  • a low resistance against the electronic cu ent may be defined in one embodiment as 20% of the resistance of the skin.
  • the barrier against transport of the active compound is not substantially raised by the membrane when the flux of active compound in the membrane containing device is, for example, more than 75% compared with the device not containing a membrane.
  • membranes that can be used are e.g., the membranes having low electrical resistance as disclosed in D.F. Stamiatialis et al., J.
  • Controlled Release 2002, 81, 335-345 such a the membranes CT-10 kDA, CT-20 kDA, PES-30 kDA and PSf-100 kDA of Sartorius, Dialysis -5 kDA of Diachema, CA-10 kDa, CA-25 kDa, CA-50 kD and CA-100 kDa of Amika and NF-PES-10 and NF-CA-30 of Nadir Filtration.
  • the iontophoretic systems used to practice the subject invention may include devices and/or components selected from a wide variety of commercially available devices or components and/or from a wide range of methods and materials such as taught, for example, by patents and publications relating to such iontophoretic systems.
  • the iontophoretic transdermal system may comprise an iontophoretic device such as is available from The Alza corporation of Mountain View, California, U.S.A. (E-trans® Transdermal Technology), Birch Point Medical Inc. of St. Paul, Minnesota U.S.A. (e.g., lontoPatchTM working according to the Wearable Electronic Disposable Delivery (WEDDTM) technology), lomed of Salt Lake City, Utah, U.S.A.
  • WEDDTM Wearable Electronic Disposable Delivery
  • IOMEDTM Phoresor devices using IOGEL®, TransQ®Flex, TransQ®E, TransQ®1&2 or Numby Stuff® electrodes and the GelSponge® containment medium e.g. IOMEDTM Phoresor devices using IOGEL®, TransQ®Flex, TransQ®E, TransQ®1&2 or Numby Stuff® electrodes and the GelSponge® containment medium
  • a device such as manufactured by Vyteris of Fair Lawn, New Jersey, U.S.A. (Active Transdermal system) or a device such as manufactured by Empi of St. Paul, Minnesota (e.g. Empi DUPELTM), or a device known as the LECTROTM Patch, manufactured by General Medical Device Corp. of Los Angeles, California.
  • the electrodes may comprise reactive or non -reactive electrodes.
  • reactive electrodes are those made from metal salts, such as silver chloride or materials described in US 4,752,285.
  • the silver chloride electrodes can be prepared based on the knowledge of a person skilled in the art or are available from lomed.
  • Alternative reactive electrodes can be made from a combination of ion -exchange resins, exemplified by electrodes available from Empi.
  • non -reactive electrodes are those made from metals such as gold or platinum, or from carbon particles dispersed in polymeric matrices such as one used in the LECTROTM Patch.
  • Adhesives used to fix the iontophoretic device to the skin may comprise pressure sensitive adhesives used in passive transdermal delivery systems, such those derived from silicone or acrylic polymers, or those derived from rubbers such as polyisobutylene.
  • pressure sensitive adhesives used in passive transdermal delivery systems, such those derived from silicone or acrylic polymers, or those derived from rubbers such as polyisobutylene.
  • a combination of pressure sensitive and conductive adhesives can also be used, such as those described EPA 0542294.
  • the concentration of the drug may be, for example, at least about 0.1 mg/ml.
  • the concentration of the drug in the drug reservoir may be, for example, not more than about 90 mg/ml.
  • the concentration for 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolone or its monohydrochloride salt is, for example, about 10 to about 75 mg/ml. In other embodiments, that concentration ranges from about 20 to about 55 mg/ml.
  • the concentration for 7-(4-benzyl-1-piperazinyl)-2(3H)-benzoxazolone or its monomesylate is, for example, about 1 to about 30 mg/ml. In other embodiments, that concentration can range from about 5 to about 10 mg/ml.
  • the drug reservoir of the iontophoretic system may include further additives.
  • additives can be chosen from those that are well known and conventional in the iontophoresis art.
  • additives include, for example, antimicrobial agents, preservatives, antioxidants, penetration enhancers and buffers.
  • a unit dosage that may be delivered during a s ingle delivery period may vary in amount.
  • a unit dosage in one embodiment may be at least about 0.05 mg.
  • the unit dosage in another embodiment may be, for example, no more than about 100 mg.
  • a unit dosage for 7-(4-methyl-1-piperazinyI)-2(3H)- benzoxazolone or its monohydrochloride in some embodiments can range from about 0.05 to about 60 mg. In other embodiments, that concentration can range from about 0.05 to about 30 mg.
  • the unit dosage that is delivered may be determined on the basis of on e or more of a wide range of factors, including, for example, the compound, condition, age, body weight, clearance, etc.
  • the flux rate of delivery through the skin of at least one compound of formula I can be, for example, at least about 50 ⁇ g per hour. In other embodiments, the flux rate of delivery through the skin can be, for example, no more than about 4000 ⁇ g per hour.
  • the iontophoretic delivery method of pharmaceutical compounds comprises a drug delivery treatment protocol that includes periodically applying an iontophoretic transdermal device at intervals that may be as frequent as twice daily or as infrequent as once a week or once a month.
  • a single treatment step the d evice is applied, the drug is iontophoretically delivered and the device is then removed.
  • the absolute quantity of the drug delivered may vary substantially, a unit dosage is herein defined to be that quantity of drug, however large or small, that is delivered during a single treatment step by a single device application at an individual site.
  • the drug may be delivered constantly or during defined intervals.
  • the intervals may range, for example, from about 10 minutes to 24 or 48 hours. In some cases it may be advantageous to omit delivery during a part of the day and night cycle, e.g., during the night for 6, 7 or 8 hours.
  • a linear or stepwise increase of the drug over a certain time starting with a low amount of drug up to the normal maintenance dose, which time is also referred to as titration time.
  • the period for titration can be, for example, at least 3 days or not more than 42 days.
  • the period for titration can range between 7 and 21 days in some embodiments, and in still other embodiments around 14 days.
  • the iontophoretic delivery method according to the present invention may be useful for such a linear or stepwise increase of the drug administration as the administered amount of drug can be regulated by linear or stepwise increase of the current density.
  • the iontophoretic system comprises
  • a transdermal delivery device attachable to the skin, the device comprising a first electrode and a second electrode, and a reservoir capable of comprising a compound of the formula I as set forth above, and optionally a pharmaceutically acceptable electrolyte, in electrical communication with the first and second electrodes, and
  • the electrical power source may be any appropriate source, such as for example, a battery, a rechargeable battery, or electrical power delivered by an electrical ou tlet.
  • the means for connecting the electrical power source may comprise any suitable conductor, conduit, or carrier of electrical energy.
  • the means may comprise, for example, wiring, a power adaptor, a power controller, a power monitor, or a combination of two or more of the foregoing.
  • the iontophoretic system may comprise still other methods and materials, such as described in WO 92/17239, EPA 0547482 and US 4,764,164, the entire contents of which are incorporated herein by reference.
  • the transport area of the device can be at least about 1.0 cm 2 . In other embodiments, the transport area might be no more than about 30 cm 2 . In still other embodiments, the transport area can range from about 2 to about 15 cm 2 , and in still other embodiments from about 5 to about 10 cm 2 .
  • the drug reservoir of the iontophoretic system is delivered empty to the user and the reservoir is filled just before or after application of the system to the skin.
  • the iontophoretic system is combined with one or more cartridges containing the compound of general formula I as defined above, including a salt or prodrug thereof, or a composition of two or more thereof and optionally a pharmaceutically acceptable electrolyte.
  • This combination of an iontophoretic system and one or more cartridges may be defined as a starter kit .
  • the number of cartridges in one kit can range, for example, from 7 to 91, and in other embodiments from 14 to 28.
  • the compound and the optional electrolyte may be in the form of a solid crystalline, amorphous or lyophilized material which material has to be dissolved in water before filling of the reservoir of the iontophoretic device, or in the form of a solution ready for use.
  • the iontophoretic system may be refilled with a fresh solution for example every 3-48 hours, or for example once every 24 hours.
  • a kit which is intended for more than one treatment step, as long as the iontophoretic syste m is working properly contains only one or more of cartridges comprising the compound of general formula I as defined above, including a salt or prodrug thereof, or a composition thereof and optionally a pharmaceutically acceptable electrolyte may be present.
  • the term "about” when modifying a value indicates the variability inherent in that value that would be understood by one of ordinary skill in the art. For example, “about” indicates that significant digits, rounding errors, and the like provide a range of values about the recited number that falls within the scope of the disclosure of that number.
  • HSC Human Stratum Corneum
  • HSC Remaining trypsin activity was blocked by bathing HSC in a 0.1% trypsin inhibitor solution in PBS, pH 7.4. HSC was washed several times in water and stored in a silica gel containing desiccator in a N z environment to inhibit oxidation of lipids.
  • Hairless rats were euthanized by inhalation of carbon dioxide using an exposure chamber designed for such use half hour before start of experiment.
  • the skin from the abdomen was carefully removed, making sure no muscle or fat was attached to the skin.
  • the skin was then cut into small squares to fit the Franz diffusion set (Membrane Transport System, PermeGear, U.S.A) and placed in 0.1 M potassium phosphate buffer until mounted.
  • Franz diffusion set Membrane Transport System, PermeGear, U.S.A
  • 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolo ⁇ e hydrochloric acid salt was synthesized as described in WO00/29397 and Drugs of the Future 2001 , 26, 128-32.
  • 7-(4-benzyl-1-piperazinyl)-2(3H)- benzoxazolone mesylate was prepared as described in WO01/85725 and WO02/066449.
  • the silver plate and silver/silver chloride electrodes can be prepared according to chapter 3.4.3. of Ajay K. Banga, Electrically Assisted Transdermal and Topical Drug Delivery, Taylor and Francis Group Ltd., London UK, 1998, ISBN 0-7484-0687-5. or can be purchased from a commercial supplier such as lomed.)
  • Parafilm rings were added for making a tight connection between the compartments.
  • the temperature of the acceptor chamber was 37 °C.
  • the flow of PBS through the acceptor chamber was kept approximately constant for each cell during the experiment: 6 - 8 ml per hour.
  • the current was switched on.
  • passive diffusion post iontophoresis was carried out.
  • the current density was 0.5 mA cm 2 .
  • the total resistance of the stratum corneum sheets was monitored during the experiment with two additional silver electrodes. A very low resistance is indicative of leakage of the stratum corneum in a cell. When this was observed, the diffusion data obtained were discarded. All conditions were repeated at least 3 times.
  • the number of skin donors used for each condition was at least 3.
  • Iontophoresis experiments with 7-(4-benzyl-1-piperazinyl)-2(3H)- benzoxazolone Iontophoresis experiments with 7-(4-benzyl-1-piperazinyl)-2(3H) ⁇ benzoxazolone were performed using vertical Franz diffusion cells (Membrane Transport System, PermeGear, U.S.A) hooked up to a Keithley 2400 source meter and the current monitored using a multimeter. The donor half was of the cell was exposed to room temperature (25°C) while the receptor half was maintained at 37° C. Receptor compartment was continuously stirred.
  • vertical Franz diffusion cells Membrane Transport System, PermeGear, U.S.A
  • Freshly excised hairless rat skin was mounted on the vertical diffusion cells, after the receptor compartment had been filled with a suitable receptor media, which can maintain the sink condition.
  • the receptor media had the same composition as the donor solution wi thout the drug, so that the sink conditions could be maintained.
  • the formulation was placed in the donor compartment.
  • a silver wire was used as the anode in the donor and a silver/silver chloride wire was used as the cathode in the receptor.
  • Current was applied for 3 hours using a constant current power source. However, sampling was continued till 24 hrs to see if enhanced delivery will stop on terminating current. Samples were taken at pre -determined time intervals from the receptor and analyzed by the HPLC as described below. Samples were replaced with fresh receptor medium and this was taken into consideration in the calculations.
  • Example 2 Iontophoresis of 7-(4-methyI-1-piperazinyl)-2(3H)-be ⁇ zoxazolone monohydrochloride with varying active substance concentration
  • Example 3 Iontophoresis of 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolone monohydrochloride with varying active electrolyte concentration
  • 7-(4-methyl-1-piperazi ⁇ yl)-2(3H)-benzoxazolone monohydrochloride was dissolved in 10 mM sodium citrate solution. The pH was adjusted to pH 5.5 with 10 mM citric acid. Sodium chloride was added resulting in solutions of either 0, 2 or 4 mg/ml NaCI.
  • the 7-(4-methyl-1 -piperazinyl)-2(3H)-benzoxazolone monohydrochloride concentration was kept constant, namely 35 mg/ml.
  • the selected 7 -(4-methyl-1- piperazi ⁇ yl)-2(3H)-benzoxazolone monohydrochloride concentration is 80% of its maximum solubility. The solubility of 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolone monohydrochloride increases with reducing NaCI concentration.
  • Figure 2 illustrates that, after switching on the current, there is a steep increase in 7- (4-methyl-1-piperazinyl)-2(3H)-benzoxazolone flux.
  • the mean transport during the iontophoretic period was 471 ⁇ 65, 377 ⁇ 37 and 424 ⁇ 50 ⁇ g/hr/cm 2 (averages ⁇ s.e.m.) for the sodium chloride concentrations 0, 2, 4 mg/ml, respectively. There was no significant difference between these values as 5 tested by one way ANOVA (p-value between all groups > 0.05).
  • the pH of the donor solution did not change more than 0.2 pH units during the experiment. The strong increase and decrease during switching on and off the current indicates that a large variation in transport can be achieved by iontophoresis.
  • Example 4 Iontophoresis of 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolone monohydrochloride with varying active substance concentration in the presence of 4 g/l NaCI.
  • Figure 3 shows that in the presence of NaCI the iontophoretic flux of 7 -(4-methyl-1- piperazinyl)-2(3H)-benzoxazolone monohydrochloride was slightly dependent on its concentration flux.
  • the fluxes were 409 ⁇ 47, 467 ⁇ 74 and 580 ⁇ 87 ⁇ g/hr/cm 2 for the donor concentrations of 20, 35 and 55 mg/ml respectively (averages ⁇ s.e.m.). 25
  • the pH of the donor solution did not change more than 0.2 pH units during the experiment.
  • Example 5 Iontophoresis of 7 -(4-benzyl-1-piperazinyl)-2(3H)- benzoxazolone varying active substance concentration in the presence of 30 mM NaCI.
  • Example 6 Iontophoresis of 7-(4-benzyl-1-pi ⁇ erazinyl)-2(3H)- benzoxazolone at a concentration of 5 mg/ml, varying current density in the presence of 30 mM NaCI.

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Abstract

L'invention concerne l'utilisation d'au moins un composé de formule générale (I) dans laquelle R est tel que défini dans la description, et des sels pharmaceutiquement acceptables et des promédicaments de ce composé, pour la fabrication d'un dispositif iontophorétique pour le traitement de la maladie de Parkinson et du syndrome des jambes sans repos. L'invention concerne en outre des systèmes iontophorétiques, ainsi que des cartouches et des kits contenant ledit système iontophorétique, combiné avec une ou plusieurs cartouches contenant un composé de formule (I). L'invention concerne également les cartouches contenant un composé de formule (I).
EP05768713A 2004-03-26 2005-03-25 Administration iontophoretique transdermique de composes de piperazinyl-2(3h)-benzoxazolone Withdrawn EP1742632A2 (fr)

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EP04101253A EP1595542A1 (fr) 2004-03-26 2004-03-26 Administration iontophoretique de composés piperazinyl-2(3h)-benzoxazoloniques
EP05768713A EP1742632A2 (fr) 2004-03-26 2005-03-25 Administration iontophoretique transdermique de composes de piperazinyl-2(3h)-benzoxazolone
PCT/EP2005/051401 WO2005107754A2 (fr) 2004-03-26 2005-03-25 Administration iontophoretique transdermique de composes de piperazinyl-2(3h)-benzoxazolone

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WO2009106516A1 (fr) * 2008-02-25 2009-09-03 Solvay Pharmaceuticals B.V. Compositions, kits et procédés pour un schéma de titration de composés du pardoprunox
RU2374245C1 (ru) 2008-08-22 2009-11-27 Андрей Александрович Иващенко Лиганд с широким спектром одновременной рецепторной активности, фармацевтическая композиция, способ ее получения и лекарственное средство
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WO2001085725A1 (fr) * 2000-05-12 2001-11-15 Solvay Pharmaceuticals B.V. Composes de piperazine et piperidine

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US5207752A (en) * 1990-03-30 1993-05-04 Alza Corporation Iontophoretic drug delivery system with two-stage delivery profile
DE4127951C2 (de) * 1991-08-23 1994-06-09 Boehringer Ingelheim Kg Verfahren und Vorrichtung zur gegenfeldkontrollierten Iontophorese
US6929801B2 (en) * 1996-02-19 2005-08-16 Acrux Dds Pty Ltd Transdermal delivery of antiparkinson agents
UA71590C2 (en) * 1998-11-13 2004-12-15 Duphar Int Res Piperazine and piperidine derivatives
AU1280701A (en) * 1999-11-17 2001-05-30 Novartis Ag Iontophoretic transdermal delivery of peptides
WO2001085168A1 (fr) * 2000-05-12 2001-11-15 Solvay Pharmaceuticals B.V. Utilisation de composes presentant une combinaison des activites de l'agoniste du recepteur adrenergique alpha, de la dopamine d2 et du 5-ht1a, pour le traitement de troubles du systeme nerveux central
EP1448263B1 (fr) * 2001-10-24 2009-01-07 Power Paper Ltd. Dispositif de liberation controlee d'une substance active dans la peau
EP1336406A1 (fr) * 2002-02-14 2003-08-20 Solvay Pharmaceuticals B.V. Agonistes partiels du récepteur D2 de la dopamine et inhibiteurs de la sérotonine et/ou de la noradrénaline
US20040147581A1 (en) * 2002-11-18 2004-07-29 Pharmacia Corporation Method of using a Cox-2 inhibitor and a 5-HT1A receptor modulator as a combination therapy

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EP1595542A1 (fr) 2005-11-16
AU2005239833A1 (en) 2005-11-17
JP2007530512A (ja) 2007-11-01
AU2005239833B2 (en) 2010-02-25
SA05260067A (ar) 2005-12-03
RU2371179C2 (ru) 2009-10-27
CN1938030A (zh) 2007-03-28
TW200536839A (en) 2005-11-16
BRPI0508848A (pt) 2007-08-28
CA2558113A1 (fr) 2005-11-17
RU2006137714A (ru) 2008-05-10
CN1938030B (zh) 2010-10-20
WO2005107754A2 (fr) 2005-11-17
WO2005107754A3 (fr) 2005-12-29
HK1098048A1 (en) 2007-07-13
UA87493C2 (ru) 2009-07-27

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