MXPA06011018A - Transdermal iontophoretic delivery of piperazinyl-2(3h)-benzoxazolone compounds - Google Patents

Abstract

The use of at least one compound of the general formula wherein R is defined herein, and pharmaceutically acceptable salts and prodrugs thereof;for the manufacture of an lontophoretic device for the treatment of Parkinson's disease and restless leg syndrome. The invention is further related to iontophoretic systems and to cartridges and kits containing the iontophoretic system combined with one or more cartridges containing a compound of formula I, and to cartridges containing a compound of formula I.

Description

TRANSDERMAL IONTOFORETIC SUPPLY OF COMPOUNDS PlPERAZINIL-2 (3H) -BENZOXAZOLONE FIELD OF THE INVENTION The present invention relates to the transdermal ontophoretic delivery of pharmaceutical compounds of the general formula wherein R is methyl, ethyl, ethyl substituted with one or more fluorine atoms, or cyclo- (C3-7) alkylmethyl optionally substituted with one or more fluorine or benzyl atoms, 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl , optionally substituted with one or more substituents of the group consisting of halogen, hydroxyl, cyano, amino, mono or dialkylamino of C1-3, alkoxy of C1-3, CF3, OCF3, SCF3, alkyl of C? -, alkylsulfonylamino of C ? 3, phenyl, furanyl, and thienyl and wherein said phenyl, furanyl and thienyl substituents are further optionally substituted with 1-3 substituents of the hydroxy group, halogen, C? -4 alkoxy, C? - alkyl, cyano, aminocarbonyl, mono or dialkylaminocarbonyl of C -? - 4; and pharmaceutically acceptable salts and prodrugs thereof. More specifically, the invention relates to the transdermal iontophoretic delivery of pharmaceutical compounds of the general formula (I) wherein R is methyl, ethyl, ethyl substituted with one or more fluorine atoms, cyclo- (C3-) - alkylmethoyl optionally substituted with one or more fluorine or benzyl, 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl atoms, groups which may be substituted with one or more substituents of the group consisting of halogen, hydroxyl, cyano, amino , mono- or dialkylamino of C -? - 3, C? -3 alkoxy, CF3, OCF3, SCF3, C-? -4 alkyl, C? -3 alkylsulfonylamino. More specifically, the invention relates to the transdermal iontophoretic delivery of pharmaceutical compounds of the general formula (I) wherein R is methyl or benzyl optionally substituted with 1-3 substituents of the hydroxyl group and halogen. The most preferred compounds in the present invention are compounds wherein R is methyl or benzyl. Even more specifically, the invention relates 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 syndrome of the restless leg and CNS disorders, especially Parkinson's disease.

The present invention also relates to the use of compounds of general formula (I) for the preparation of (a) a solution for use in a device for transdermal administration by iontophoresis or equipment containing cartridges which contain the ready-to-use compound 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 method 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.

BACKGROUND OF THE INVENTION The compounds of the general formula I as defined above are known from WO00 / 29397 and WO01 / 85725. These compounds show variable activities either as partial agonists or agonists at the dopamine D2 receptor and are also agonists of the 5HT1A receptor. These combinations of activities make the compounds valuable for the treatment of afflictions and diseases of the central nervous system caused by alterations in any of the dopaminergic or serotonergic systems, for example, in Parkinson's disease and restless leg syndrome. In certain cases, for example, when the oral delivery or injection of a particular pharmaceutically active compound (also referred to as a drug) may be ineffective or unacceptable due to poor gastrointestinal absorption, an extensive first-pass effect, pain and discomfort of the patient, or other side effects or disadvantages, the transdermal delivery can provide an advantageous method for 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 asleep, in a coma or anesthetized. In addition, there is growing evidence that continuous stimulation with dopamine avoids the development of problems related to intermittent dosing and where it has been shown that the continuous drug supply decreases the incidence of "off" periods (P. Niall and WH Oertel, Congress Report of the 7th 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 obtain drugs to pass through the skin. The iontophoretic transdermal supply refers to introducing ions or soluble salts of pharmaceutically active compounds into body tissues under the influence of an applied electric field.

The characteristics and benefits of iontophoretic transdermal delivery systems compared to passive transdermal systems, as well as other means of delivering pharmaceutical compounds into the bloodstream, have been reviewed, for example, in O. Wong, "lontophoresis: Fundamentals," in Drugs Pharm. Sci. (1994), 62 (Drug Permeation Enhancement), 219-46 (1994); P. Singh et al., "Lontophoresis in Drug Delivery: Basic Principles and Applications", Critical Reviews in Therapeutic Drug Carrier Systems, 11 (2 &3): 161-213 (1994); and Ajay K. Banga, Electrically Assisted Transdermal and Topical Drug Delivery, Taylor and Francis Group Ltd., London UK, 1998, ISBN 0-7484-0687-5. In certain cases, for example, when transdermal delivery by means of patches appears to be ineffective or unacceptable due to a low passage through the skin, which leads to very large patches, the transdermal iontophoretic delivery may provide an advantageous method to supply that compound. In addition, the iontophoretic transdermal delivery has the main advantage that the amount administered can be regulated in a precise manner and can be used to easily assess patients up to a certain level of administration for a period of up to several weeks. Despite these advantages, iontophoretic methods appear limited because the drug delivery profile of a particular method depends to a large extent on the particular drug administered. Although a large number of experiments have been conducted with the iontophoretic delivery of various active substances, specific information is not always available that allows a person skilled in the art to adjust the delivery profile of a specific drug. Inasmuch as it has been 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 a variable speed supply of said compounds adjusted to a specific treatment.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to iontophoretic transdermal technology that provides the delivery of the compounds of the general formula (I) and compositions thereof through the human skin. More specifically, it is an object of the present invention to provide the use of a compound of the general formula (I) and pharmaceutically acceptable salts and prodrugs thereof for the preparation of a composition 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 prepared is suitable for use in a device for transdermal administration by iontophoresis for the treatment of Parkinson's disease and restless leg syndrome.

Even more specifically, an object of the present 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. When 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 that can be fixed to the skin, the device includes 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 a source of electrical energy 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.

It is further an object of the invention to provide an equipment 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) that will be used to fill the deposit of the ontophoretic system. The amount of cartridges in the equipment of preference is between 2 and 91, preferably between 7 and 28 and particularly between 14 and 28. The skin through which the supply has to occur, is animal skin, for example, human skin.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 graphically depicts the flow of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone through the human stratum corneum as a function of the concentration of the active compound with respect to time; Figure 2 graphically depicts the flow of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone through the human stratum corneum as a function of the electrolyte concentration with respect to time; Figure 3 graphically depicts the flow of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone through the human stratum corneum as a function of concentration of the active compound with respect to time in the presence of 4 g / l of NaCI; Figure 4 graphically depicts the mesylate flow of 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone through hairless rat skin as a function of concentration of the active compound with respect to time in the presence of 30 millimoles (mM) of NaCl; Figure 5 graphically depicts the mesylate flow of 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone through hairless rat skin as a function of the current density in the presence of 30 mM NaCl; and Figure 6 illustrates a schematic presentation of the iontophoretic installation used for the tests with 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone.

DETAILED DESCRIPTION OF THE INVENTION An iontophoretic transdermal delivery system may comprise a first electrode (donor) containing an electrolytically available active compound within a suitable carrier or carrier and optionally a penetration enhancer, a counter electrode and a power source, the first and second electrodes are each one in electrically conductive communication with the power source. The first and second electrodes may be adapted for separate physical contact with the skin whereby, in response to a current provided by the energy source through the electrodes, a therapeutic amount of the active compound is delivered through the skin to the a patient. Surprisingly, it has been found that the iontophoretic delivery (dose and profile) through which a particular active compound of the general formula (I) is administered to a patient, can be controlled through the appropriate combination of the initial concentration of the drug and electrolyte and the applied current (constant / variable) in the iontophoretic system. For example, it has been found that the combination of current density (constant / variable) and the initial amount of electrolyte can lead to an iontophoretic device with a very reasonable size that allows to adjust the drug delivery profile. The ability to adapt the drug delivery profile in ontophoresis can provide improved control of the effects of the drug on the user. Additionally, the ability to adapt the drug delivery profile in iontophoresis can make the iontophoretic delivery of the compounds of formula (I) a more effective mode of administration on a practical level. As used herein, the term "penetration profile" means a graph of the flow of the active compound with respect to time for a given delivery period. As used herein, the term "cartridge" means a container that contains the active compound that is used for storage of the active compound before it is delivered through the device. In at least one embodiment of the present invention, a cartridge can be selected by its user friendly nature. Any means for packaging the active compound separately from the iontophoretic device can be considered a "cartridge". For example, removable and replaceable deposits can be used to supply active compound to the device. The electrolytes used in the methods of the present invention can include, for example, univalent or bivalent ions. Examples of electrolytes used in the present method include all CI-donor compounds which are soluble in water, such as HCl, NaCl, KCl, CaCl 2, MgCl 2, triethylammonium chloride and tributylammonium chloride, In a preferred embodiment, the electrolyte comprises NaCl. The required amount of electrolyte may depend on factors such as the transportation area of the device, the volume of the vehicle or carrier, the concentration of the active compound, the current density, the duration of the iontophoresis and the efficiency of the transport. it may be present in amounts, for example, of 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, for example, of not more than about 2 mmole , no more than about 1.0 mmol, or no more than about 0.3 mmol.The initial amount of electrolyte can be expressed as a concentration, for example, of at least about 0.005 M, at least about 0.01 M, or at least about 0.03 M. The initial amount of electrolyte can be expressed as a concentration, for example, no more than about 2 M, no more than about 0.2 M, or no more than about 0.2 M. Compounds that can be administered according to the present invention have already been defined above. Prodrugs of the aforementioned compounds are within the scope of the present invention. Prodrugs are therapeutic agents which in themselves are inactive but are transformed into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the usefulness of the original drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism, and signaling limitations (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed .: F. D. King, p.; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14 (3), 277-280, 2004; P. Ettmayer et al., "Lessons learned from marketed and research prodrugs", J. Med. Chem., 47, 2393-2404, 2004). Prodrugs belong to the invention, that is, compounds which, when administered to humans through any known route, are metabolized into compounds having the formula (I). In particular, this refers to compounds with primary or secondary amino or hydroxy groups. Such compounds can be reacted with organic acids to produce compounds having the formula (I) wherein an additional group is present which is easily removed after administration, for example, but not limited to amidine, enamine, a Mannich base , a hydroxylmethylene derivative, a 0- (acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone. As stated above, the compounds of formula I can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. Prodrug salts are also within the scope of this invention. The phrase "pharmaceutically acceptable salt" means those salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human and lower animals without undue toxicity, irritation, allergic response and the like and are proportional to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are 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 function of free base 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-hydroxyethanesulfonate (isothionate), lactate, maleate, mesylate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Active drugs that can 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 Future 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-piperazinyl) -2 (3H) -benzoxazolone or its monomesylate salt are suitable for the treatment of restless leg syndrome or Parkinson's disease. The compounds of formula (I), prodrugs, pharmaceutically acceptable salts of any of the foregoing, and mixtures of two or more of the foregoing may be administered according to the invention. The pH of the solution in the drug reservoir can be at least about 3.0 in some embodiments. In other embodiments, the pH may be less than or equal to about 7.5. Even in other embodiments, the pH may vary from about 4.0 to about 6.5. The pH can be maintained at a constant level by means of a pH regulator such as a citrate pH regulator or a phosphate pH regulator. For 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone or its monohydrochloride salt, a useful pH ranges from about 5.0 to about 6.0. Another possible pH for said compound is about 5.5. For 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone or its monomesylate salt, the pH may vary, for example, from about 3.5 to about 6.0. Another useful pH for said compound is about 4.0. During the delivery period, the current may be caused to flow by applying a constant or variable voltage / current, such as pulsating, or alternating. Alternatively, the current may be caused to increase during the delivery period in order to assess an increasing concentration of the compound of formula (I). The voltage charged in the current application step is selected on the voltage scale which does not injure the skin of a living body and which does not waste the speed of the transdermal absorption of the active compound. The voltage may be, for example, at least about 0.1 V, or at least about 0.5 V, or at least about 1 V. The voltage may also be, for example, less than about 40 V, or less than about 20 V, or less than about 10 V. The pulsating or alternating voltage may have, for example, a frequency of at least about 0.01 Hz, or at least about 100 Hz, or at least about 5 kHz. The pulsating or alternating voltage may have, for example, a frequency of no more than about 200 kHz, or no more than about 100 kHz, or no more than about 80 kHz. The pulsating or alternating voltage can use substantially any type of waveform configuration, including, for example, sinusoidal, square, triangular, toothed, rectangular, etc. In addition, pulsating or alternating voltage can be applied in a duty cycle less than 100%. The current density, for example, can be at least about 0.001 mA / cm2, or at least about 0.005 mA / cm2, or at least about 0.025 mA / cm2. The current density can also be, for example, no greater than about 1.0 mA / cm2, no greater than about 0.8 mA cm2 or no greater than about 0.5 mA / cm2. The drug reservoir contains the drug and an optional electrolyte with, as the vehicle or carrier, either an aqueous solution or a (hydro) gel. The reservoir gel can be made up of water-soluble polymers or hydrogels. In principle, any gel can be used. The gels can be selected so that they do not adversely affect the skin (corrosion and irritation). The gels may have suitable properties, such as good skin contact (adhesion capacity) and electroconductive properties. Non-limiting examples include agar, agarose, polyvinyl alcohol or entangled hydrogels, such as hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), and polyvinylpyrrolidone (PVP) and polyvinyl acetate phthalate (PVAP) . Suitable skin penetration enhancers include those known in the art, and for example, include C2-C alcohols such as ethanol and isopropanol; surfactants, for example, anionic surfactants such as fatty acid salts of 5 to 30 carbon atoms, for example, sodium lauryl sulfate and other salts of fatty acid sulfate, cationic surfactants such as alkylamines of 8 to 22 carbon atoms carbon, for example, 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; salicylic acid and its derivatives; alkylmethyl sulfoxide such as decylmethyl sulfoxide and dimethyl sulfoxide; 1-substituted azacycloalkan-2-ones such as 1-dodecylazacycloheptan-2-one (AZONE®); amides such as octylamide, oleicamide, hexamethylene lauramide, lauric diethanolamide, polyethylene glycol 3-lauramide, N, N-diethyl-m-toluamide and crotamiton; and any other compound compatible with the compounds of the general formula (I) and with the devices and having an enhancing activity of transdermal penetration. In an alternative embodiment, the carrier or vehicle is separated from the skin through a membrane. This membrane can be selected, for example, by having a low resistance against electric current, and / or substantially avoiding raising the barrier against transport of the active compound, and / or containing the carrier within the device during storage and transportation. A low resistance against electronic current can be defined in a modality like 20% of the resistance of the skin. The barrier against transport of the active compound is not substantially raised by the membrane when the flow of active compound in the device containing the membrane is, for example, more than 75% compared to the device that does not contain a membrane. Examples of membranes that may be used are, for example, membranes having low electrical resistance, as described in DF Stamiatialis et al., J. Controlled Relay 2002, 81, 335-345, such as the CT-10 kDA membranes. , CT-20 kDA, PES-30 kDa and PSf-100 kDa from Sartorius, Dialysis-5 kDA from Diachema, CA-10 kDa, CA-25 kDa, CA-50 kD and CA-100 kDa from Amika and NF-PES -10 and NF-CA-30 of Nadir Filtration.

The iontophoretic systems used to practice the present invention may include devices and / or components selected from a wide variety of commercially available devices or components and / or from a wide variety of methods and materials such as those presented, for example, patents and publications. referred to said iontophoretic systems. In particular, the iontophoretic transdermal system may comprise an iontophoretic device such as that available from The Alza corporation of Mountain View, California, E.U.A. (E-trans® Transdermal Technology), Birch Point Medical Inc. of St. Paul, Minnesota E.U.A. (for example, lontoPatch ™ that works according to Wearable Electronic Disposable Delivery (WEDD ™) technology), lomed from Salt Lake City, Utah, E.U.A. (for example, IOMED ™ Phoresor devices using IOGEL®, TransQ @ Flex, TransQ®E, TransQ®1 &2 or Numby Stufl® and GeISponge® containing media), or a device such as that manufactured by Vyteris Fair Lawn, New Jersey, E.UiA. (Active Transdermal System) or a device such as that manufactured by Empi of St. Paul, Minnesota (for example, Empi DUPEL ™), or a device known as the LECTRO ™ Patch, manufactured by General Medical Device Corp. of Los Angeles, California. The electrodes may comprise reactive or non-reactive electrodes. Examples of reactive electrodes are those made of 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 one skilled in the art or are available in the industry. Alternative reactive electrodes can be made from a combination of ion exchange resins, exemplified with available Empi electrodes. Examples of non-reactive electrodes are those made of metals such as gold or platinum, or of carbon particles dispersed in polymer matrices such as that used in the LECTRO ™ patch. The adhesives used to fix the iontophoretic device to the skin may comprise pressure sensitive adhesives used in passive transdermal delivery systems, such as those derived from acrylic or silicone polymers, or those derived from gums such as polyisobutylene. A combination of conductive and pressure sensitive adhesives, such as that described in EPA 0542294, can also be used. In the drug reservoir, the concentration of the drug can be, for example, at least about 0.1 mg / ml. The concentration of the drug in the drug reservoir can be, for example, no more than about 90 mg / ml. In some embodiments, the concentration for 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone or its monohydrochloride salt is, for example, from about 10 to about 75 mg / ml. In other embodiments, that concentration ranges from about 20 to about 55 mg / ml. Even in other embodiments, the concentration for 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone or its monomesylate, for example, is from about 1 to about 30 mg / ml. In other embodiments, that concentration may vary from about 5 to about 10 mg / ml. In addition, the drug reservoir of the iontophoretic system may include other additives. Said additives can be selected from those which are known and which are conventional in the iontophoresis technique. Such additives include, for example, antimicrobial agents, preservatives, antioxidants, penetration enhancers and pH regulators. An example of a unit dosage that can be supplied during a single supply period can vary in quantity. For example, a unit dosage in one embodiment can be at least about 0.05 mg. In another embodiment, the unit dosage may be, for example, not greater than about 100 mg. A unit dosage for 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone or its monohydrochloride in some embodiments may vary from about 0.05 to about 60 mg. In other modalities, that concentration can vary from about 0.05 to about 30 mg. The unit dosage that is delivered may be determined on the basis of one or more of a wide range of factors, including, for example, the compound, condition, age, body weight, clearance, etc. The supply flow rate through the skin of at least one compound of formula I can be, for example, at least about 50 μg per hour. In other embodiments, the flow rate of delivery through the skin may be, for example, no greater than about 4000 μg per hour. In some embodiments of the present invention, the method of iontophoretic delivery of pharmaceutical compounds comprises a drug delivery treatment protocol that includes periodically applying a transdermal iontophoretic device at intervals that can be as frequent as twice a day or not as frequent as once a week or once a month. As regards the present one-step treatment, the device is applied, the drug is iontophoretically delivered and the device is subsequently removed. Although the absolute amount of the drug delivered can vary substantially, herein, a unit dosage is defined as that amount of drug, either large or small, that is delivered during a single treatment step through a single application of the device in an individual site. During a single treatment step, the drug can be delivered in a constant manner or during defined intervals. The intervals may vary, for example, from about 10 minutes to 24 or 48 hours. In some cases, it may be advisable to omit the supply during a part of the day and night cycle, for example, during the night for 6, 7 or 8 hours. After initiating the administration of a drug, it may be advisable to have a linear or gradual increase in the drug for a certain time starting with a low amount of drug up to the normal maintenance dose, which time is also referred to as the time of titration. The period for valuation can be, for example, at least 3 days or no more than 42 days. The period for assessment can vary between 7 and 21 days in some modalities, and even in other modalities around 14 days. The iontophoretic delivery method according to the present invention can be useful for said linear or gradual increase in drug administration, since the administered amount of drug can be regulated through linear or gradual increase in current density. In some embodiments, the iontophoretic system comprises: (a) a transdermal delivery device that can be attached to the skin, the device comprises a first electrode and a second electrode, and a reservoir capable of comprising a compound of formula I as discussed above, and optionally a pharmaceutically acceptable electrolyte, in electrical communication with the first and second electrodes, and (b) means for connecting a source of electrical energy to the first and second electrodes. The source of electrical power may be any suitable source, such as, for example, a battery, a rechargeable battery, or electrical power supplied through an electrical outlet. The means for connecting the electric power source can comprise any suitable conductor, conduit, or electric power carrier. The means may comprise, for example, wiring, a power adapter, an energy controller, an energy monitor, or a combination of two or more of the foregoing. The iontophoretic system may comprise even other methods and materials, such as those described in WO 92/17239, EPA 0547482 and US 4,764,164, the entire contents of which are incorporated herein by reference. In some modalities, the transportation area of the device can be at least about 1.0 cm2. In other embodiments, the transportation area may be no greater than about 30 cm2. Even in other embodiments, the transportation area may vary from about 2 to about 15 cm2, and in other embodiments from about 5 to about 10 cm2. In another embodiment of the invention, the drug reservoir of the ontophoretic system is supplied empty to the user and the reservoir is filled just before or after application of the system to the skin. When this embodiment is used, 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 can be defined as a beginner team. The number of cartridges in an equipment can vary, for example, from 7 to 91, and in other modalities from 14 to 28. The compound and the optional electrolyte can be in the form of a crystalline, amorphous or lyophilized solid material which has to be be dissolved in water before filling the deposit of the iontophoretic device, or in the form of a ready-to-use solution. The iontophoretic system can be filled with a fresh solution for example, every 3-48 hours, or for example once every 24 hours. In another embodiment, for example, a device which is intended for more than one processing step, provided that the ontophoretic system functions properly, contains only one or more of the 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. As used herein, the term "approximately" when modifying a value, indicates the variability inherent in that value understood by one skilled in the art. For example, "approximately" indicates that important digits, rounding errors, and the like provide a scale of values around the mentioned number that is within the scope of the description of that number. The following examples are only intended to further illustrate the invention, in more detail, and therefore, these examples are not considered in any way to limit the scope of the invention.

EXAMPLES EXAMPLE 1 General methods Isolation of human stratum corneum. Human stratum corneum (HSC) was prepared from dermatomized healthy human skin. 24 hours after surgical removal of human skin (abdominal or breast), residual subcutaneous fat was removed. To avoid interference with contaminating subcutaneous fat, the surface of the skin was carefully cleaned with a tissue paper soaked in 70% ethanol. The skin was dermatomized to a thickness of approximately 300 μm using an Electro Dermatoma Padgett Model B (Kansas City, USA). Subsequently it was incubated with the dermal site in Whatman paper soaked in a 0.1% trypsin solution in PBS overnight at 4 ° C and then for 1 hour at 37 ° C. The HSC was then detached from the underlying epidermis and dermis. The 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 desiccator containing silica gel in an N2 environment to inhibit lipid oxidation.

Hairless Rats Skin Isolation Hairless rats were euthanized by inhaling carbon dioxide using an exposure chamber designed for such use half an hour before starting the experiment. The skin of the abdomen was carefully removed, ensuring that no muscle or fat was attached to the skin. Then the skin was cut into small squares to fit the Franz diffusion kit (Membrane Transport System, PermeGear, E.U.A) and placed in 0.1 M potassium phosphate pH buffer until assembly.

Synthesis of the active compound The hydrochloric acid salt of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone was synthesized as described in WO00 / 29397 and Drugs of the Future 2001, 26, 128-32. The 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone mesylate was prepared as described in WO01 / 85725 and WO02 / 066449.

Solutions in iontophoresis experiments 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone as an HCl salt was dissolved in a solution of 10 mM sodium citrate. The pH was adjusted to pH 5.5 with 10mM citric acid. 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone as a mesylate salt was dissolved in a pH regulator of 0.1 M potassium phosphate. The pH was adjusted to pH 4.0 using o-phosphoric acid.

Iontophoresis experiments with 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone Iontophoresis experiments were performed with 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone using a 9-channel computer-controlled power to provide constant current (Electronics Department, Gorlaeus Laboratories, Leiden University, The Netherlands). Alternatively, the Power Supply PCT-MK1 from Moor Instruments, R.U. commercially available. A silver plate electrode was used as an anode (e.g., silver sheet> 99.99% purity, 1.0 mm thickness (Aldrich article number 36,943-8), 5 cm length, 3 mm width) and a silver / silver chloride electrode (prepared by repeatedly immersing (2 or 3 times) silver wire (> 99.99% purity, 0 1.0 mm (Aldrich article number 26,559-4), flexed at the tip to produce a small projection (approximately 3 mm) at a right angle to the axis of the vertical powder electrode of molten silver chloride (> 99.999% purity, article Aldrich number 20,438-2) as a cathode. (Alternatively, the silver plate and electrodes silver / silver chloride 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). The diffusion rates were carried out at a constant current density of 0.5 mA / cm2, using continuous flow of three chambers through diffusion cells at room temperature. The installation of the diffusion consisted of a peristaltic pump, a fraction collector and 8 diffusion cells (for the diffusion cell, see figure 4). Stratum corneum was used for all dissemination studies. The human stratum corneum was hydrated for two hours in PBS pH 7.4 before assembly in the cells. Two pieces of stratum corneum were placed between the anode side and the acceptor side, and between the acceptor and cathode side, with the apical side facing the anode and cathode compartments. Dialysis membrane (5,000 D cut) was used as support membrane for the stratum corneum. Parafilm rings were added to make an impermeable connection between the compartments. The temperature of the acceptor chamber was 37 ° C. The flow of PBS through the acceptor chamber remained approximately constant for each cell during the experiment: 6-8 ml per hour. After six hours of passive diffusion, the current went on. The current was turned off at t = 15 h. During a period of another 5 hours (post-iontophoretic period) passive diffusion post-iontophoresis was carried out. During iontophoresis, the current density was 0.5 mA / cm2. The total resistance of stratum corneum sheets was monitored during the experiment with two additional silver electrodes. A very low resistance indicates leakage of the stratum corneum in a cell. When this was observed, the dissemination data obtained were discarded. All the conditions were repeated at least three 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 cells from Vertical diffusion of Franz (Membrane Transport System, PermeGear, USA) hooked to a Keithley 2400 source meter and the current was monitored using a multimeter. Half of the cell donor was exposed to room temperature (25 ° C) while half of the receptor was maintained at 37 ° C. The receptor compartment was continuously shaken. The skin of freshly cut hairless rats was mounted in the vertical diffusion cells, after the receptor compartment had been filled with suitable receptor media, which can maintain the condition of the skin. The receptor media had the same composition as the donor solution without the drug, so that the conditions of the skin could be maintained. The formulation was placed in the donor compartment. Silver wire was used as the anode in the donor and a silver / silver chloride wire was used as the cathode in the receiver. Current was applied for three hours using a constant current energy source. However, sampling still continued 24 hours to see if the intensified supply stops at the end of the flow. Samples were taken at predetermined time intervals from the receiver and analyzed by HPLC as described below. The samples were replaced with fresh receptor medium and this was taken into account in the calculations.

HPLC analysis 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone was analyzed using HPLC with ultraviolet detection (Waters Chromatography, Etten Leur, The Netherlands). A Chromsep SS column (250 * 3 mm L * i.d) thermofixed at 30 ° C was used. The mobile phase consisted of acetonitrile / methanol / 0.7 g / l pH buffer of ammonium acetate at pH 5.6 (12/6/82 v / v) and was used at 0.5 ml / min. The detection wavelength was 215 nm. No oxidation or degradation products of the compound were observed in the chromatograms of the sample solutions. 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone was analyzed using HPLC with ultraviolet detection (Waters Alliance system). A Chromsep SS column (150 * 3 mm L * i.d) with a particle size of 5 μm thermofixed at 40 ° C was used. The mobile phase was made using 1.54 g of ammonium acetate in 460 ml of water (the pH was adjusted to 4.6 using acetic acid) and 540 ml of methanol and degassed. The flow rate was 0.5 ml / min. The detection wavelength was 243 nm. The injection volume was 10 μl.

EXAMPLE 2 lontophoresis of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone monohydrochloride with variable active substance concentration A 75 mg / ml solution of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone monohydrochloride was prepared in citrate pH buffer (this is 85% of the maximum solubility of monohydrochloride of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone in citrate pH buffer at pH 5.5) From this solution, further dilutions were made in citrate pH 5.5 pH regulator. The concentrations analyzed were: 20 mg / ml, 35 mg / ml, 55 mg / ml and 75 mg / ml. As can be seen in figure 1, after turning on the current, there is a marked increase in flow of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone. During the iontophoresis period, the flows of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone observed were extremely high. Mean transport during the iontophoretic period was 394 ± 26, 383 ± 42, 459 ± 59, 418 ± 31 μg / hr / cm2 for donor concentrations of 20, 35, 55, 75 mg / ml respectively. There was no significant difference between these values as analyzed 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.

EXAMPLE 3 lontophoresis of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone monohydrochloride with variable active electrolyte concentration 7- (4-Methyl-1-piperazinyl) -2 (3H) -benzoxazolone monohydrochloride was dissolved in 10 mM sodium citrate solution. The pH was adjusted to pH 5.5 with 10mM citric acid. Sodium chloride was added resulting in solutions of 0, 2 or 4 mg / ml of NaCl. The monohydrochloride concentration of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone was kept constant, especially at 35 mg / ml. At 4 mg / ml of NaCl, the concentration of selected 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone monohydrochloride is 80% of its maximum solubility. The monohydrochloride solubility of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone increases with a reduced concentration of NaCl. Figure 2 illustrates, that after turning on the current, there is a marked increase in the flow of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone. During the iontophoresis period, the flows of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone observed were extremely high. The mean transport during the iontophoretic period was 471 ± 65, 377 ± 37 and 424 ± 50 μg / hr / cm2 (averages ± standard error of the mean) for the concentrations of sodium chloride 0, 2, 4mg / ml, respectively. There was no significant difference between these values as analyzed by one-way ANOVA (p-value among 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 the turning on and off of the current indicates that a great variation in transportation can be obtained through iontophoresis.

EXAMPLE 4 lontophoresis of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone monohydrochloride with variable active substance concentration in the presence of 4g / l of NaCl A 55 mg / ml solution of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone monohydrochloride was prepared in citrate pH buffer (this is 85% of the maximum solubility of monohydrochloride of - (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone in citrate pH buffer at pH 5.5 in the presence of 4 g / l of NaCl). From this solution, additional dilutions were made in citrate pH 5.5 pH regulator. The concentrations analyzed were: 20 mg / ml, 35 mg / ml, 55 mg / ml and NaCl was added in an amount to produce a concentration of 4 g / l. Figure 3 shows that in the presence of NaCl, the iontophoretic flow of 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone monohydrochloride was slightly dependent on its concentration flux. The flows were: 409 ± 47, 467 ± 74 and 580 ± 87 μg / hr / cm2 for the donor concentrations of 20, 35 and 55 mg / ml respectively (averages ± standard error of the mean). However, the trend did not seem to be statistically significant as analyzed by one-way ANOVA (p-value among all groups> 0.05). The pH of the donor solution did not change more than 0.2 pH units during the experiment.

EXAMPLE 5 lontophoresis of 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone with concentration of active substance in the presence of 30 mM NaCl A solution of 10 g / ml of 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone mesylate was prepared in phosphate buffer (this is approximately the maximum solubility of monohydrochloride of 7- (4 -methyl-1-piperazinyl) -2 (3H) -benzoxazolone in phosphate pH regulator at pH 4.0 in the presence of 30mM NaCl). From this solution, additional dilutions were made in pH 4.0 phosphate buffer. The concentrations analyzed were: 1 mg / ml, 5 mg / ml, and 10 mg / ml and NaCl was added in quantity to produce a concentration of 30mM. Figure 4 shows that there is an increase in iontophoretic flow with an increase from 1 mg / ml to 5 mg / ml in concentration of active substance and that there is no increase in iontophoretic flow with a further increase in the concentration of active substance to 10 mg / ml.

EXAMPLE 6 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone lontophoresis at a concentration of 5mg / ml, variable current density in the presence of 30mM NaCl The 5 g / ml solution of 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone mesylate in phosphate buffer as prepared in example 5 was used to study the effect of density of current. The flows were measured at current densities of 0, 0.1, 0.3 and 0.5 mA. Figure 5 shows that iontophoresis significantly enhances the penetration of 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone compared to passive delivery. In addition, it was shown that there is a linear relationship between the flow and the current density.

Claims (30)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of at least one compound of the general formula wherein R is methyl, ethyl, ethyl substituted with one or more fluorine atoms, or cyclo- (C3-7) alkylmethyl optionally substituted with one or more fluorine atoms or a benzyl, 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl radical; -pyridylmethyl, optionally substituted with one or more substituents which are the same or different and are independently selected from halogen, hydroxyl, cyano, amino, C? -3 monoalkylamino, C? -3 dialkylamino, C-alkoxy ? -3, CF3, OCF3, SCF3, C1-4 alkyl, C1-3 alkylsulfonylamino, phenyl, furanyl and thienyl and wherein said phenyl, furanyl and thienyl substituents are optionally substituted with 1-3 portions which are the same or different and selected from hydroxy, halogen, C? -4 alco alkoxy, C? -4 alquilo alquiloalkyl, cyano, aminocarbonyl, C mono-4 mono monoalkylaminocarbonyl or C dial --- dialkylaminocarbonyl; and pharmaceutically acceptable salts thereof, or a mixture of any of the foregoing, and optionally a pharmaceutically acceptable electrolyte for the manufacture of an iontophoretic device for the treatment of Parkinson's disease and restless leg syndrome.

2. The use as claimed in claim 1, wherein R is methyl, ethyl, ethyl substituted with one or more fluorine atoms, or cyclo- (C3-7) alkylmethyl optionally substituted with one or more carbon atoms. fluorine or a benzyl radical, 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, radicals which are optionally substituted with one or more substituents which are the same or different and are independently selected from halogen, hydroxyl, cyano, amino , C1-3 monoalkylamino? dialkylamino of C? -3, C1-3 alkoxy, CF3, OCF3, SCF3, C? _4 alkyl, and C? -3 alkylsulfonylamino.

3. The use as claimed in claim 1 or 2, wherein said iontophoretic device has a reservoir containing the compound of formula I or a composition thereof and optionally a pharmaceutically acceptable electrolyte.

4. The use as claimed in any of claims 1-3, wherein the compound of formula I and the optional electrolyte are dissolved in a vehicle or carrier consisting of an aqueous solution or a gel.

5. The use as relayed in claim 3 or 4, wherein the iontophoretic device additionally contains a membrane which separates the vehicle or carrier from the skin when applied for transdermal administration by iontophoresis.

6. The use as claimed in claims 1-5, wherein said iontophoretic device is capable of supplying a constant current during the current application step in the transdermal administration by iontophoresis.

7. The use as claimed in claims 1-5, wherein said iontophoretic device is capable of supplying a variable current during the step of application of current in the transdermal administration by iontophoresis.

8. The use as claimed in claim 6 or 7, wherein said iontophoretic device is capable of supplying an increasing current during the step of application of current in the transdermal administration by iontophoresis.

9. The use as claimed in claims 1-7, wherein said iontophoretic device is capable of supplying a current density at a level of about 0.001 to about 1.0 mA / cm2.

10. The use as claimed in claims 1-7, wherein said iontophoretic device is capable of delivering a flow velocity through the skin of the compound of formula I of between 50 μg and 4000 μg per hour.

11. - The use as claimed in claims 1-10, wherein the concentration of compound in the solution is 0.1 to 90 mg / ml.

12. The use as claimed in claims 1-11, where the pH of the solution is between 3.0 and 7.5.

13. The use as claimed in claims 1-12, wherein said iontophoretic device is capable of delivering a unit dosage of about 0.05 mg to about 100 mg of the compound of formula I through the skin during the step of supply.

14. The use as claimed in claims 1-13, wherein said iontophoretic device is capable of delivering the unit dosage for a period of about 10 minutes to about 48 hours.

15. The use as claimed in claims 1-14, wherein the compound of formula I is 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone or a pharmaceutically acceptable salt thereof .

16. The use as claimed in claim 15, wherein the compound of formula I is 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone monohydrochloride.

17. The use as claimed in claims 1-14, wherein the compound of formula I is 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone or a pharmaceutically acceptable salt thereof .

18. - The use as claimed in claim 17, wherein the compound of formula I is 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone monomesylate.

19. An iontophoretic system for the delivery of a compound through the skin, comprising (a) a transdermal delivery device that can be fixed to the skin, the device includes a first electrode and a second electrode, and a reservoir containing a compound of general formula I or a composition thereof and optionally a pharmaceutically acceptable electrolyte in electrical communication with the first and second electrodes and (b) means for connecting a source of electrical energy to the first and second electrodes and (c) optionally a membrane that closes the deposit.

20.- The iontophoretic system in accordance with the claim 19, further characterized in that the compound is 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone or a pharmaceutically acceptable salt thereof.

21.- The iontophoretic system in accordance with the claim 20, further characterized in that the compound is 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone or a pharmaceutically acceptable salt thereof.

22. The iontophoretic system according to claims 19-21, further characterized in that the reservoir contains the pharmaceutically acceptable electrolyte and compound of the general formula I or a composition thereof in a solution having a pH ranging from about 3.5 to approximately 7.5.

23. The iontophoretic system according to claims 19-22, further characterized in that the compound of general formula I or a composition thereof is present in the reservoir in a solution at a concentration of about 0.1 to about 90 mg / ml.

24. A cartridge capable of filling or filling an iontophoretic system, comprising a compound of general formula I or a composition thereof of claim 1 or 2 and optionally a pharmaceutically acceptable electrolyte.

25. The cartridge according to claim 24, further characterized in that it comprises the pharmaceutically acceptable electrolyte in a solution having a pH ranging from about 3.5 to about 7.5.

26. The cartridge according to claims 24-25, further characterized in that it comprises the compound of general formula I or a composition thereof in a solution at a concentration of about 0.1 to about 90 mg / ml.

27. The cartridge according to claims 24-26, further characterized in that the compound is 7- (4-methyl-1-piperazinyl) -2 (3H) -benzoxazolone or a pharmaceutically acceptable salt thereof.

28. The cartridge according to claims 24-26, further characterized in that the compound is 7- (4-benzyl-1-piperazinyl) -2 (3H) -benzoxazolone or a pharmaceutically acceptable salt thereof.

29. - A kit comprising: (1) an iontophoretic system for the delivery of a compound through the skin, comprising (a) a transdermal delivery device that can be fixed to the skin, the device includes a first electrode and a second electrode, and a reservoir capable of containing a composition of an active compound and (b) means for connecting a source of electrical energy to the first and second electrodes and (c) optionally a membrane that closes the reservoir during transportation, storage and / or application; (2) one or more cartridges of claims 24-28.

30. A device comprising one or more cartridges of claims 24-28.