HK1098048B - Transdermal iontophoretic delivery of piperazinyl-2(3h)-benzoxazolone compounds - Google Patents

Description

Transdermal iontophoretic delivery of piperazinyl-2 (3H) -benzoxazolone compounds

Technical Field

The present invention relates to transdermal iontophoretic delivery of pharmaceutical compounds of the general formula:

(I)

wherein R is methyl, ethyl substituted by one or more fluorine atoms or a ring- (C) optionally substituted by one or more fluorine atoms or benzyl_3-7) -alkylmethyl, optionally substituted by one or more groups chosen from halogen, hydroxy, cyano, amino, mono-or di-C_1-3Alkylamino radical, C_1-3-alkoxy, CF₃、OCF₃、SCF₃、C_1-4Alkyl radical, C_1-3-2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl substituted with substituents selected from the group consisting of alkylsulfonylamino, phenyl, furyl and thienyl, and wherein said substituents phenyl, furyl and thienyl are optionally further substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, C_1-4Alkoxy radical, C_1-4Alkyl, cyano, aminocarbonyl, mono-or di-C_1-4-substituent substitution of alkylaminocarbonyl.

More particularly, the invention relates to the transdermal iontophoretic delivery of pharmaceutical compounds of general formula (I) wherein R is methyl, ethyl substituted by one or more fluorine atoms or cyclo- (C) optionally substituted by one or more fluorine atoms or benzyl_3-7) -alkylmethyl, optionally substituted by one or more groups chosen from halogen, hydroxy, cyano, amino, mono-or di-C_1-3Alkylamino radical, C_1-3-alkoxy, CF₃、OCF₃、SCF₃、C_1-4Alkyl radical, C_1-3-2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl substituted with a substituent of the group consisting of alkylsulfonamido.

More particularly, the present invention relates to transdermal iontophoretic delivery of pharmaceutical compounds of general formula (I), wherein R is methyl or benzyl optionally substituted with 1-3 substituents selected from the group consisting of hydroxy and halogen. The most preferred compounds of the invention are those wherein R is methyl or benzyl.

More particularly, the invention relates to the use of at least one compound of general formula (I) or mixtures thereof for the preparation of an iontophoretic device for the treatment of pain conditions, especially restless legs syndrome and CNS diseases, especially parkinson's disease.

The invention also relates to compounds of general formula (I): (a) use in the preparation of a solution for a device for transdermal administration by iontophoresis or a kit comprising a cartridge containing a compound to be used in said device, (b) use in the preparation of a device suitable for transdermal administration by iontophoresis, wherein said transdermal device is provided with a reservoir containing a 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 transport profile (delivery profile) of a pharmaceutical compound of formula (I) or a composition thereof; and the invention relates to the use of said controlled transport profile in the treatment of pain conditions, especially restless legs syndrome and CNS diseases, especially Parkinson's disease.

Background

WO00/29397 and WO01/85725 disclose compounds of the general formula I as defined above. These compounds exhibit altered activity at the dopamine D2 receptor as partial agonists or agonists, and are also 5HT1_AAgonists of the receptor. The combination of these activities makes the compounds valuable for the treatment of central nervous system pathologies and diseases caused by disturbances of the dopaminergic or serotonergic systems, such as for the treatment of parkinson's disease and restless legs syndrome.

In some cases, for example, when a particular pharmaceutically active compound (also referred to as a drug) is delivered or injected orally, the patient may experience pain and discomfort or other side effects due to poor gastrointestinal absorption, extended first pass effects, orOr defective and ineffective or unacceptable, transdermal delivery may provide a more advantageous method of delivering the compound. For example, in the case of treatment of parkinson's disease, it is desirable to administer drugs to patients who are sleeping, unconscious or anesthetized. Furthermore, there is increasing evidence that sustained dopamine stimulation avoids the problems associated with intermittent dosing and where continuous drug transport has been demonstrated to reduce the incidence of "refractory" periods (p.niall and w.h.oertel, concentration Report of 7)^thInternational consistency of Parkinson's Disaseand motion Disorders, Miami, Florida, 11 months, 10-14, 2002). Transdermal delivery is also problematic in general, as drugs do not always readily penetrate the skin.

Iontophoretic transdermal transport involves the introduction of ions or soluble salts of pharmaceutically active compounds into body tissues under the influence of an applied electric field.

The features and benefits of iontophoretic transdermal Drug delivery systems, as compared to passive transdermal systems and other means of delivering Drug compounds into the bloodstream, are reviewed in, for example, 0.Wong, "iontophoresis basis" ("lontophoresis: Fundamentals") -Drugs pharm. Sci. (1994), 62(Drug competition Enhancement), 219-46 (1994); singh et al, "iontophoresis in drug transport: basic Principles and applications "(" amount photoresis in Drug Delivery: Basic Principles and applications ") -Critical Reviews in Therapeutic Drug Delivery systems, 11(2& 3): 161-213 (1994); banga, electric Assisted Transdermal and Topical Drug Delivery, Taylor and Francis Group Ltd, London UK, 1998, ISBN 0-7484-.

Iontophoretic transdermal delivery may provide an advantageous method of delivering compounds in certain situations, for example, when transdermal delivery through a patch appears to be ineffective or unacceptable due to low amounts through the skin, resulting in the need for very large patches. In addition, the major advantage of iontophoretic transdermal delivery is that the dosage can be precisely adjusted and it is easy to titrate the patient to a determined level of administration over a period of time ranging from one to several weeks.

Despite these advantages, iontophoresis appears to have its limitations due to the drug delivery characteristics (deliveryprofile) of a particular method being heavily dependent on the particular drug administered. Despite numerous experiments with iontophoretic transport of various active substances, the person skilled in the art is not always able to obtain specific information suitable for the transport properties of a specific drug.

Since it is clearly difficult to develop a transdermal patch of acceptable size for a compound having the general formula (I), there remains a need for an iontophoretic delivery method that allows for variable rate delivery of the compound for a particular therapy.

Summary of The Invention

The present invention relates to the iontophoretic transdermal technology which provides for the delivery of compounds of formula (I) and compositions thereof through human skin.

More specifically, it is an object of the present invention to provide the use of a compound of formula (I) and pharmaceutically acceptable salts and prodrugs thereof, in the manufacture of a composition suitable for transdermal administration by iontophoresis in a device, wherein the composition comprises a compound of formula I and optionally a pharmaceutically acceptable electrolyte. The prepared composition is suitable for a device for treating Parkinson's disease and restless legs syndrome by iontophoretic transdermal delivery.

More specifically, the subject of the present invention is the use of a compound of formula (I) and the pharmaceutically acceptable salts and prodrugs thereof for the preparation of a device suitable for the transdermal administration by iontophoresis for the treatment of parkinson's disease and restless legs syndrome, wherein said transdermal device is provided with a reservoir containing a compound of formula I or a composition thereof and optionally a pharmaceutically acceptable electrolyte. When the device is applied to the skin of a living subject and an electric current is passed through the skin, the compound of formula (I) and pharmaceutically acceptable salts and prodrugs thereof are iontophoretically transported across the skin.

It is another object of the present invention to provide an iontophoretic system for the transdermal delivery of a compound of formula (I) and compositions thereof, wherein the system comprises: a transdermal transport device for attachment to the skin, the device comprising a first electrode and a second electrode and a reservoir containing a pharmaceutically acceptable electrolyte and a compound of formula (I) and combinations thereof electrically connected between the first and second electrodes; and a power source connected to the first and second electrodes, wherein the reservoir contains a compound of formula (I) and compositions thereof and optionally a pharmaceutically acceptable electrolyte.

It is yet another object of the present invention to provide: a kit comprising an iontophoretic system in combination with one or more cartridges, wherein said cartridges contain a compound of formula (I); or a kit containing one or more cartridges containing a compound of formula (I) for refilling the reservoir of the iontophoretic system. The number of cartridges in the kit is preferably 2-91, more preferably 7-28, most preferably 14-28.

It is the skin of an animal, such as a human, that is to be administered through the skin.

Brief Description of Drawings

FIG. 1 is a graph showing the flux of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone through the human stratum corneum as a function of the concentration of active compound over time.

Figure 2 plots electrolyte concentration as a function of time, indicating the flux of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone through the human stratum corneum.

FIG. 3 is a graph plotting the concentration of active compound as a function of time in the presence of 4g/l NaCl, representing the flux of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone through the human stratum corneum.

FIG. 4 is a plot of active compound concentration as a function of time in the presence of 30 millimolar (mM) NaCl, showing the flux of 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone mesylate across the skin of dehaired rats.

FIG. 5 is a plot of current density as a function of 30mM NaCl showing the flux of 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone mesylate across the skin of depilated rats.

Figure 6 depicts a schematic of an iontophoretic device for the assay of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone.

Detailed Description

An iontophoretic transdermal transport system may include a first (donor) electrode containing an electrolytically-active compound and optionally a permeation enhancer in a soluble vehicle or carrier, a counter electrode, and a power source, each of the first and second electrodes being conductively connected to the power source. The first and second electrodes may be adapted to be in spaced physical contact with the skin, whereby a therapeutic amount of the active compound is administered to the patient through the skin in response to the current provided by the power source through the electrodes.

Surprisingly, it has been found that the iontophoretic transport (dose and administration profile) of a particular active compound of formula (I) to a patient can be well controlled by appropriate combination of initial concentrations of drug and electrolyte and applied current (constant/variable) in an iontophoretic system. More specifically, it has been found that the combination of current density (constant/variable) and initial amount of electrolyte allows to obtain an iontophoretic device with very reasonable dimensions, which allows to adjust the drug transport profile. The ability to adjust the drug transport profile in iontophoresis may increase control over the drug action of the user. Furthermore, the ability to tailor the drug transport profile in iontophoresis makes iontophoretic transport of the compound of formula (I) a more practical and effective mode of administration.

The term "permeation profile" as used herein refers to a plot of active compound flux versus a given transport time.

The term "cartridge" as used herein refers to a container containing an active compound for storing the active compound prior to delivery of a drug through the device. In at least one embodiment of the present invention, a user-friendly cartridge may be selected. Any means for packaging the active compound separately from the iontophoretic device may be considered a "cartridge". For example, a detachable or replaceable reservoir may be used to transport the active compound to the device.

The electrolyte used in the method of the invention may for example comprise monovalent or divalent ions. Examples of the electrolyte used in our process include all those capable of giving Cl^-Water-soluble compounds of (2), e.g. NaCl, KCl, CaCl₂、MgCl₂Triethylammonium chloride and tributylammonium chloride. In a preferred embodiment, the electrolyte comprises NaCl. The amount of electrolyte required may depend on a number of factors, such as the area of transport of the device, the volume of vehicle or carrier, the concentration of active compound, current density, the duration of iontophoresis, and the efficiency of transport. The electrolyte may be present in an amount of, for example, at least about 0.005mmole, at least about 0.01mmole, or at least about 0.05 mmole. The electrolyte may be present in an amount of, for example, no more than about 2mmole, no more than about 1.0mmole, or no more than about 0.3 mmole. The initial amount of electrolyte can be expressed in concentration, for example, at least about 0.005M, at least about 0.01M, or at least about 0.03M. The initial amount of electrolyte can be expressed in concentration, for example, as no more than about 2M, no more than about 0.2M, or no more than about 0.2M.

The compounds that can be administered are as defined above. Prodrugs of the above compounds are also within the scope of the invention. Prodrugs are therapeutic agents that are not active themselves, but which can be converted to one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules that are used to overcome obstacles when using the parent drug molecule. These include, but are not limited to, solubility, permeability, stability, pre-systemic 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 therapeutic agents" ("Prodrugsastherapeutics") -Expert Opin. Ther. Patents, 14(3), 277. 280, 2004; P.Etcayer et al, "teachings from commercial and research prodrugs" ("Lessons spared from labeled and endogenous genes" -J.Med.chem., 47, 2393. 2404, 2004). Prodrugs, i.e. compounds which are metabolized to compounds of the general formula (I) when administered to humans by any known route, belong to the present invention. In particular, it relates to compounds containing primary or secondary amino groups or hydroxyl groups. Such compounds may be reacted with organic acids to produce compounds having the general formula (I) wherein there is a group that is readily removed after administration, such as, but not limited to, amidines, enamines, mannich bases, hydroxy-methylene derivatives, 0- (carbamoyloxymethylene) derivatives, carbamates, esters, amides or enaminones.

As mentioned above, the compounds of formula I may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. Salts of the prodrugs also fall within the scope of the invention. The term "pharmaceutically acceptable salts" means those salts which are, within the scope of sound pharmaceutical practice, 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, j.pharmaceutical Sciences, 1977, 66: pharmaceutically acceptable salts are described in detail in 1 etseq. These salts may be prepared in situ during the final isolation and purification of the compounds of the invention or may be prepared separately by reacting the free basic functional group 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 (camphorate), camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate (palmitate), pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Examples of acids which may be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids and organic acids such as oxalic, maleic, succinic and citric acids.

Active agents that can be administered by the methods described herein include, but are not limited to, compounds such as 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or its hydrochloride salt (SLV308, see Drugs of the Future 2001, 26,128-32) and 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone or its mesylate salt (SLV 318).

7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or its hydrochloride salt and 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone or its mesylate salt are particularly suitable for the treatment of restless legs syndrome or Parkinson's disease.

The compounds of formula (I), prodrugs thereof, pharmaceutically acceptable salts of the foregoing and mixtures of two or more of the foregoing may be administered according to the present invention.

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 may be maintained at a constant level with a buffer, such as a citrate buffer or a phosphate buffer. For 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or its hydrochloride salt, a useful pH range is from about 5.0 to about 6.0. Another possible pH of the compound is about 5.5. For 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone or its mesylate salt, the pH can range, for example, from about 3.5 to about 6.0. Another possible pH for the compound is about 4.0.

During transport, the current may be passed by applying a constant, pulsed or alternating voltage/current. Alternatively, the current may be increased during transport to titrate the increase in the concentration of the compound of formula (I).

The voltage applied during the step of applying the current is selected from a range of voltages that are not harmful to living skin and do not impair the transdermal absorption rate of the active compound. The voltage may be, for example, at least about 0.1V, or at least about 0.5V, or at least about 1V. The voltage may also be, for example, no more than about 40V, or no more than about 20V, or no more than about 10V.

The frequency of the pulsed or interactive voltage may be, for example, at least about 0.01Hz, or at least about 100Hz, or at least about 5 kHz. The frequency of the pulsed or alternating voltage may be, for example, no more than about 200kHz, or no more than about 100kHz, or no more than about 80 kHz. The pulsed or interactive voltages may use substantially any type of waveform including, for example, sinusoidal, square, triangular, saw tooth, rectangular, and the like. Further, the pulsed or alternating voltage may be applied based on a duty cycle of less than 100%.

The current density can be, for example, at least about 0.001mA/cm²Or at least about 0.005mA/cm²Or at least about 0.025mA/cm². The current density can also be, for example, up to about 1.0mA/cm²Or up to about 0.8mA/cm²Or up to about 0.5mA/cm²。

The drug reservoir contains the drug and optionally an electrolyte and a vehicle or carrier that is an aqueous solution or (hydro) gel. The reservoir gel may be composed of a water-soluble polymer or hydrogel. Generally any gel may be used. The gel may be selected so that it does not adversely affect the skin (corrosion and irritation). The gel may exhibit suitable properties, such as good skin contact (adhesiveness) and electrical conductivity. Non-limiting examples include agar, agarose, polyvinyl alcohol or cross-linked hydrogels, such as hydroxypropyl methylcellulose (HPMC), Methylcellulose (MC), hydroxyethyl cellulose (HEC), carboxymethyl cellulose (CMC) and polyvinyl pyrrolidone (PVP) and polyvinyl acetate phthalate (PVAP).

Suitable skin penetration agents include those skin penetration enhancers well known in the art, including, for example, C₂-C₄Alcohols such as ethanol and isopropanol; surfactants, for example anionic surfactants, such as salts of fatty acids of 5 to 30 carbon atoms, for example sodium lauryl sulfate and the sulfuric acid ester salts of other fatty acids, cationic surfactants, such as alkylamines of 8 to 22 carbon atoms, for example oleylamine; and nonionic surfactants, such as polysorbates and poloxamers, aliphatic monohydric alcohols of 8 to 22 carbon atoms, such as decanol, lauryl alcohol, myristyl alcohol, palmityl alcohol, linseed 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 esters thereof, such as ethyl octanoate, isopropyl myristate, methyl laurate, hexamethylene palmitate, glycerol monolaurate, polypropylene glycol monolaurate and polyethylene glycol monolaurate; salicylic acid and its derivatives; alkyl methyl sulfoxides such as decyl methyl sulfoxide and dimethyl sulfoxide; 1-substituted azacycloalkane-2-ones, e.g. 1-dodecylazacyclo-hept-2-oneAmides, such as caprylamide, oleamide, cyclohexyllauramide, lauric diethanolamide, polyethylene glycol 3-lauramide, N-dimethyl-m-toluamide and crotamiton, and any other compound compatible with the compound of formula (I) and with the device and having an activity of enhancing transdermal penetration.

In an alternative embodiment, the carrier or vehicle is separated from the skin by a membrane. Such a membrane may for example be selected such that it has a lower resistance to electrical current, and/or substantially avoids increased barriers to transport of the active compound, and/or comprises the carrier in the device during storage and transport. In one embodiment, the low resistance to current may be defined as 20% of the skin resistance. When the active compound flow in a device containing a membrane is higher than a device without a membrane, e.g., 75%, the barrier to transport compounds is not primarily increased by the membrane. Examples of useful films are, for example, films having low resistance, as disclosed in D.F. Stamialis et al, J.controlled Release2002, 81, 335-; such as membranes from Sartorius CT-10 kDA, CT-20 kDA, PES-30 kDA and PSf-100 kDA; dialysis-5 kDA from Diachema; amika CA-10 kDa, CA-25 kDa, CA-50 kD and CA-100 kDa; and NF-PES-10 and NF-CA-30 of NadirFilation A.

Iontophoretic systems for practicing the present invention may include devices and/or elements broadly selected from various commercially available devices or elements and/or various methods and materials, such as those taught in patents and publications relating to such iontophoretic systems. In particular, the transdermal ionic transfer system may include an iontophoretic device, such as those sold by the following companies: alza corporation of Mountain View, California, U.S. A. (Transderma lTechnology); birch Point medical Inc. of St.Paul, Minnesota U.S.A. (e.g., according to Werable Electronic Di spasable Delivery (WEDD))^TM) IontoPatch (TM) for technical operation), Salt Lake City, Utah, Iomed of U.S. A. (e.g. usingFlex、1&2 or NumbyAn electrode andiomed comprising media^TMPhoresor device); or devices such as those produced by Vyteris of Fair law, New Jersey, u.s.a. (active transdermal systems); or a device such as Empi production of St.Paul, Minnesotad (e.g. Empi DUPEL)^TM) (ii) a Or LECTRO, produced by general medical Device Corp. of Los Angeles, California^TMThe device of Patch.

The electrodes may include reactive or non-reactive electrodes. Examples of reactive electrodes are those made from metal salts, such as silver chloride or the materials described in US4,752,285. Silver chloride electrodes can be prepared based on the knowledge of one of ordinary skill in the art or purchased from lomed. Alternative reactive electrodes may be made from composite ion exchange resins, such as the electrode sold by Empi. Examples of non-reactive electrodes are made of metals, such as gold or platinum, or as for LECTRO^TMPatch, an electrode made of carbon particles dispersed in a polymeric matrix. Adhesives for affixing iontophoretic devices to skin may include pressure sensitive adhesives for passive transdermal transport systems, such as those derived from silicone or acrylic polymers; or those derived from rubber, such as polyisobutylene. Combinations of pressure sensitive and conductive adhesives, such as those disclosed in EPA0542294, may also be used.

In the drug reservoir, the drug concentration may be, for example, at least about 0.1 mg/ml. In the drug reservoir, the drug concentration may be, for example, up to about 90 mg/ml. In some embodiments, the concentration of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or its hydrochloride salt is, for example, from about 10 to about 75 mg/ml. In other embodiments, the concentration ranges from about 20 to about 55 mg/ml. In still other embodiments, the concentration of 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone or its mesylate salt is, for example, from about 1 to about 30mg/ml, and in other embodiments, the concentration ranges from about 5 to about 10 mg/ml.

In addition, the drug reservoir of the iontophoretic system may also include other additives. Such additives may be selected from those well known and commonly used in the art of iontophoresis. Such additives include, for example, antimicrobials, preservatives, antioxidants, penetration enhancers, and buffers.

Typically, representative unit doses that may be delivered during a delivery period may vary from about 0.05mg to about 100 mg. A preferred unit dosage of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or its hydrochloride salt is from about 0.05 to about 60mg, more preferably from about 0.05 to about 30 mg.

The unit dose delivered is determined based on a wide variety of factors, including, for example, the compound, condition, age, weight, clearance, and the like.

The transdermal transport flow rate of the compounds of formula I may be, for example, at least 50. mu.g per hour. In other embodiments, the transdermal transport flow rate may be, for example, up to 4000 μ g per hour.

In some embodiments of the invention, the method of iontophoretic delivery of a drug compound includes a drug delivery treatment regimen that includes periodic administration of a transdermal iontophoresis device at intervals, which may be generally twice daily, or infrequently, such as once a week or once a month. During what is referred to herein as one treatment step, i.e., administering the device, the drug is transported by iontophoresis and then the device is removed. Although the absolute amount of drug delivered may vary significantly, regardless of size, a unit dose is defined herein as the amount of drug delivered in one treatment step administered at a single site by a single device.

In one treatment step, the drug may be delivered constantly or at defined intervals. Typical time intervals range from about 10 minutes to 24 hours. In some cases it may be advantageous not to carry out the transfer during part of the day and night periods, for example 6, 7 or 8 hours at night.

At the beginning of drug delivery, it is often desirable that the drug be linearly or stepwise increased over a period of time, from a low dose of drug to a normal maintenance dose, which is also referred to as the titration time. The titration period may be, for example, at least 3 days or at most 42 days. In some embodiments, the titration period may be from 7 to 21 days, and in other embodiments about 14 days. The iontophoretic transport method of the present invention can be used for such administration in a linear or stepwise increase, because the amount of administration can be precisely adjusted by a linear or stepwise increase in current density.

In some embodiments, the iontophoretic system includes

(a) A transdermal transport device connectable to the skin comprising a first electrode and a second electrode and a reservoir in electrical connection between said first and second electrodes capable of containing a compound of formula I as hereinbefore described and optionally a pharmaceutically acceptable electrolyte, and

(b) means for connecting a power source to said first and second electrodes.

The power source may be any suitable power source, such as a battery, rechargeable battery, or a power source powered through an outlet. The means for connecting to the power source may comprise any suitable conductor, conduit, or electrical energy carrier. The device may include, for example, a wire, a power adapter, a power regulator, a power monitor, or a combination of two or more of the foregoing.

The iontophoretic system may also include other methods and material compositions, such as those disclosed in WO92/17239, EPA 0547482, and US4,764,164, which are incorporated herein by reference in their entirety.

In some embodiments, the transport area of the device may be at least about 1.0cm². In other embodiments, the transport area may be up to about 30cm². In still other embodiments, the transport area may be from about 2 to about 15cm²And in still other embodiments from about 5 to about 10cm²。

In another embodiment of the invention, the iontophoretic drug reservoir is transported to the user empty and the reservoir is filled before or after the system is applied to the skin. When this embodiment is used, the iontophoretic system is used in combination with one or more cartridges containing a compound of formula I as defined above, including salts or prodrugs thereof or a combination of two or more thereof and optionally a pharmaceutically acceptable electrolyte. Such an iontophoretic system in combination with one or more cartridges may also be defined as a priming kit. The number of cartridges in a kit may for example be 7 to 91, in other embodiments 14 to 28. The compound and optional electrolyte may be in the form of a solid crystalline, amorphous or lyophilized substance that must be dissolved in water prior to filling the reservoir of the iontophoretic device, or ready for use as a solution. The iontophoretic system may be refilled with fresh solution, for example, every 3-48 hours, or for example every 24 hours. In another embodiment, the kit is intended for more than one treatment step, as long as the iontophoretic system works properly, there may be only one or more cartridges comprising a compound of formula I as defined above, including salts or prodrugs thereof or a combination thereof and optionally a pharmaceutically acceptable electrolyte.

In the present application, the term "about" when modifying a numerical value denotes the inherent variability of the numerical value as such variability is understood by those skilled in the art. For example, "about" means a significant number, an error in rounding, etc., and provides a numerical range for the number in question, and values within the range that fall within the numerical range disclosed.

The following examples are merely intended to explain the invention in further detail and are therefore not to be considered as limiting the scope of the invention.

Examples

Example 1 general procedure

Separation of human stratum corneum

Human Stratum Corneum (HSC) was prepared from healthy human skin removed with a dermatome. Residual subcutaneous fat was removed within 24 hours after surgical removal of human skin (abdomen or breast). To prevent interference from contaminated subcutaneous fat, the skin surface was carefully wiped with a tissue soaked with 70% ethanol. The skin was cut to a thickness of about 300 μm using a dermatome Padgett Electro derm Model B (Kansas City, USA). It was then incubated overnight with the skin side on Whatman paper soaked in 0.1% trypsin PBS solution at 4 ℃ and subsequently incubated for 1 hour at 37 ℃. HSCs are then peeled away from beneath the epidermis and dermis. Residual trypsin activity was blocked by soaking HSCs in a 0.1% trypsin inhibitor in PBS at pH 7.4. HSC were washed several times in water and stored in N₂Silica gel containing a desiccant in a gaseous environment to inhibit lipid oxidation.

Isolation of depilated rat skin

Depilated rats were euthanized half an hour prior to the start of the experiment by inhalation of carbon dioxide using a contact chamber designed for this type of application. The skin of the abdomen was carefully removed to ensure that no muscle or fat was adhered to the skin. The skin was cut into small squares to fit into a Franz diffusion device (membrane transport System, PermeGear, u.s.a) and placed in 0.1M potassium phosphate buffer until fixation.

Synthesis of active Compounds

7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone hydrochloride 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 WO 02/066449.

Solutions in iontophoresis tests

7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone hydrochloride was dissolved in a 10mM sodium citrate solution. The pH was adjusted to 5.5 with 10mM citric acid.

7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone mesylate was dissolved in 0.1M potassium phosphate buffer. The pH was adjusted to 4.0 with o-phosphoric acid.

Iontophoretic assays Using 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone

Iontophoretic testing of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone was performed with a constant current supplied by a 9-channel computer-controlled Power supply (Electronics Department, Gorraeus Laboratories, Leiden University, The Netherlands. alternatively, a commercially available Power supply PCT-MK1. silver plate electrode from UK, Moor Instruments was used as The anode (e.g., silver foil purity)>99.99%, thickness 1.0mm (Aldrich aromatic nr.36, 943-8), length 5cm, width 3mm) and silver/silver chloride electrode as cathode (by repeatedly (2 or 3 times) impregnating silver wire: (>The purity of the product is 99.99 percent,1.0mm (Aldrich art. Nr.26,559-4) preparation, bent at its tip to fit into the molten silver chloride powder: (>99-99% pure, Aldrich art. nr.20, 438-2) produced small protrusions (approximately 3mm) at right angles to the perpendicular electrode axis. (alternatively, silver plates and silver/silver chloride electrodes can be prepared as described in: electrocalluryassisted transfer and Topical Drug delivery, Chapter 3.4.3, of AjayK. Banga, Taylor and Francis Group Ltd., London UK, 1998, ISBN0-7484-

All diffusion tests were performed at O.5mA/cm²And at room temperature using three chambers to continuously flow through the diffusion cell. The diffusion setup consisted of a peristaltic pump, a fraction collector and 8 diffusion cells (see fig. 4). The stratum corneum was used for all diffusion studies. The human stratum corneum was hydrated in PBS at pH7.4 for two hours and thereafter fixed in the cell. Two sheets of stratum corneum were placed between the anode and receptor sides and between the receptor and cathode sides, with the end side facing the cathode and anode compartments. The dialysis membrane (cut-off 5,000D) serves as a supporting membrane for the stratum corneum.The addition of a secondary membrane ring (Parafilm rings) makes the compartment connection tighter. The temperature of the receiver chamber was 37 ℃. The flow of PBS through the receptor chamber during the experiment remained almost constant for each cell: 6-8ml per hour. And electrifying after the passive diffusion for six hours. The current is turned off at t =15 h. During another 5 hours period (the post iontophoresis period), passive diffusion following iontophoresis was performed. During iontophoresis, the current density was 0.5mA/cm². The total electrical resistance of the stratum corneum sheet was monitored in the test with two additional silver electrodes. A very low resistance indicates a leak of stratum corneum cells in the cell. When this phenomenon is observed, the diffusion data obtained should be discarded. Each condition was repeated at least three times. The number of skin donors per condition is at least 3.

Iontophoretic assays Using 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone

Iontophoresis experiments (Membrane transport systems tem, PermeGear, u.s.a.) of 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone were performed using a vertical Franz dispersion cell attached to a Keithley 2400 source meter and the current was monitored using a multimeter. The donor half of the cell was exposed to room temperature (25 deg.C) while the acceptor half was maintained at 37 deg.C. The receptor compartment was continuously stirred. Freshly excised depilated rat skin was mounted on a vertical diffusion cell after the receptor compartment was filled with an appropriate receptor medium that maintained sedimentation conditions. The acceptor medium has the same composition as the donor solution without the drug, so that settling conditions can be maintained. The article is placed in the donor compartment. A silver wire was used as the anode in the donor and silver/silver chloride as the cathode in the acceptor. The current was maintained for 3 hours with a constant power supply. However, sampling was continued until 24 hours to see if enhanced transport would cease at the termination of the current. Samples were taken from the recipients at predetermined time intervals and analyzed by HPLC as described below. The samples were replaced with fresh receptor medium and taken into account in the calculation.

HPLC analysis

7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone (Water S chromatography, Etten Leur, The Ne therlands) was analyzed by HPLC with a UV monitor. A Chromsep SS column (250 x 3mm L i.d.) was used, thermostatted at 30 ℃. The mobile phase consisted of acetonitrile/methanol/0.7 g/l ammonium acetate buffer pH 5.6 (12/6/82v/v) at a flow rate of 0.5 ml/min. The detection wavelength is 215nm.

No oxidation or degradation products of the compounds were found in the chromatographic analysis of the sample solutions.

7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone (Waters Alliance system) was analyzed by HPLC with a UV monitor. A Chromsep SS column (150. about.3 mmL. i.d.) was used, with a particle size of 5 μm, thermostatted at 40 ℃. The mobile phase used 1.54g of ammonium acetate (pH adjusted to 4.6 with acetic acid) in 460ml of water and 540ml of methanol and degassed. The flow rate was 0.5 ml/min. The detection wavelength is 243 nm. The injection volume was 10. mu.l.

EXAMPLE 2 iontophoresis of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone monohydrochloride at different active substance concentrations

A solution of 75mg/ml of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone monohydrochloride in citrate buffer was prepared (this is 85% of the maximum solubility of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone monohydrochloride in citrate buffer at ph 5.5). From this solution, further dilutions in citrate buffer at ph5.5 were prepared. The test concentration is: 20mg/ml, 35mg/ml, 55mg/ml and 75 mg/ml.

As can be seen from FIG. 1, the flux of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone increases sharply after the application of electricity. During iontophoresis, a very high flux of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone was observed. For donor concentrations of 20, 35, 55, 75mg/ml, the mean values of transport during iontophoresis were 394 + -26, 383 + -42, 459 + -59, 418 + -31 μ g/hr/cm, respectively². There were no significant differences between these values (p-values between groups) by one-way ANOVA test>0.05)。

The donor solution pH did not change by more than 0.2 pH units during the experiment.

Example 3 iontophoresis of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone monohydrochloride at variable active electrolyte concentrations

(7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone monohydrochloride is dissolved in 10mM sodium citrate solution, the pH is adjusted to 5.5 with 10mM citric acid, sodium chloride is added, giving a solution of 0, 2 or 4mg/ml NaCl, keeping the concentration of (7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone monohydrochloride constant, i.e., 35mg/ml, at 4mg/ml NaCl, the selected (7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone monohydrochloride concentration is 80% of its maximum solubility, with decreasing NaCl concentration, the solubility of (7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone monohydrochloride increases.

FIG. 2 illustrates a dramatic increase in (7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone flux upon energization, during iontophoresis very high (7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone fluxes were observed, and the mean values of transport during iontophoresis were 471 + -65, 377 + -37, and 424 + -50 μ g/hr/cm for NaCl concentrations of 0, 2, 4mg/ml, respectively²(mean ± s.e.m.). There were no significant differences between these values (p-values between groups) by one-way ANOVA test>0.05). The donor solution pH did not change more than 0.2 pH units during the experiment.

The strong increase and decrease during current switching indicates that a large transport change can be obtained by iontophoresis.

Example 4 iontophoresis of (7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone monohydrochloride with variable active substance concentration at 4g/l NaCl

A55 mg/ml solution of (7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone monohydrochloride in citrate buffer (this is 85% of the maximum solubility of 7- (4-methyl-1-piperazinyl) -2(3H) -1 benzoxazolone monohydrochloride in citrate buffer pH5.5 in the presence of 4g/l NaCl.) other dilutions in citrate buffer pH5.5 were prepared from this solution.

FIG. 3 shows that the iontophoretic flux of 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone monohydrochloride in the presence of NaCl is slightly dependent on its concentration flux. The flow rates were 409 + -47, 467 + -74 and 580 + -87 mug/hr/cm²(mean ± s.e.m.) corresponding to donor concentrations of 20, 35 and 55mg/ml, respectively. However, this trend was shown to be non-statistically significant (p-value between groups) as measured by one-way ANOVA>0.05)。

The pH of the donor solution did not change by more than 0.2 pH units during the experiment.

Example 5 iontophoresis of 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone with variable active substance concentration at 30mM/l NaCl

A10 g/ml solution of (7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone mesylate in phosphate buffer was prepared (this is approximately the maximum solubility of (7- (4-methyl-1-piperazinyl) -2(3H) -1 benzoxazolone monohydrochloride in phosphate buffer at pH 4.0) in the presence of 30mM/l NaCl. other dilutions in phosphate buffer at pH4.0 were prepared from this solution. the test concentrations were 1mg/ml, 5mg/ml, and 10mg/ml and NaCl was added to give a concentration of 30 mM.

FIG. 4 shows that there is an increase in iontophoretic flux when the active substance concentration is increased from 1mg/ml to 5mg/ml, and there is no increase in iontophoretic flux when the active substance concentration is further increased to 10 mg/ml.

Example 6 iontophoresis of 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone at a concentration of 5mg/ml was performed using a variable current density in the presence of 30mM/l NaCl.

A solution of 5g/ml of (7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone mesylate, prepared as described in example 5, in phosphate buffer was used to study the effect of current density.the flux was measured at current densities of 0, 0.1, 0.3 and 0.5 mA.FIG. 5 shows that iontophoresis significantly enhanced the penetration of 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone compared to passive transport.

Claims (23)

1. Use of at least one compound of formula (I), and pharmaceutically acceptable salts thereof, or mixtures of any of the foregoing, and optionally a pharmaceutically acceptable electrolyte, in the preparation of an iontophoretic device,

wherein R is a methyl group or a benzyl group,

the iontophoretic device may be used for iontophoretic transport of the compound or mixture of compounds for the treatment of parkinson's disease and restless legs syndrome.

2. The use of claim 1, wherein the iontophoretic device is provided with a reservoir containing a compound of formula I or a composition thereof and optionally a pharmaceutically acceptable electrolyte.

3. Use according to any one of claims 1-2, wherein the compound of general formula I and optionally an electrolyte are dissolved in a vehicle or carrier consisting of an aqueous solution or gel.

4. The use of claim 3, wherein the iontophoretic device further comprises a membrane separating the vehicle or carrier from the skin when used for transdermal administration by iontophoresis.

5. The use according to claims 1-4, wherein in transdermal administration by iontophoresis,

a) the compound of formula I is 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or a pharmaceutically acceptable salt thereof;

b) the concentration of the compound is 0.1-90 mg/ml;

c) giving Cl^-The initial amount of electrolyte of (a) is 0.005-2 mmole;

d) the voltage of the load in the step of applying current is 0.1-40V;

e) the current density in the step of applying current is 0.001-1mA/cm²；

f) The pH is 3.0-7.5.

6. The use as claimed in claim 5, wherein

a) The compound of formula I is 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone) or monohydrochloride thereof

b) The concentration of the compound is 1-75mg/ml

c) The pH is 5.0-6.0.

7. The use according to claims 1-4, wherein in transdermal administration by iontophoresis,

a) the compound of formula I is 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone or a pharmaceutically acceptable salt thereof;

b) the concentration of the compound is 0.1-90 mg/ml;

c) giving Cl^-The initial amount of electrolyte of (a) is 0.005-2 mmole;

d) the voltage of the load in the step of applying current is 0.1-40V;

e) the current density in the step of applying current is 0.001-1mA/cm²；

f) The pH is 3.0-7.5.

8. The use as claimed in claim 7, wherein

a) The compound of formula I is 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone or a mesylate thereof

b) The concentration of the compound is 1-30mg/ml

c) The pH is 3.5-6.0.

9. An iontophoretic system for the delivery of a compound through the skin comprising (a) a transdermal delivery device connectable to the skin comprising a first electrode and a second electrode and a reservoir containing a compound of formula I as claimed in claim 1 or a composition thereof and optionally a pharmaceutically acceptable electrolyte electrically connected between said first and second electrodes and (b) means for connecting a power source to said first and second electrodes and (c) optionally a membrane enclosing the reservoir.

10. The iontophoretic system of claim 9, wherein the compound is 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or a pharmaceutically acceptable salt thereof.

11. The iontophoretic system of claim 9, wherein the compound is 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone or a pharmaceutically acceptable salt thereof.

12. The iontophoretic system of claim 9, wherein the reservoir contains a pharmaceutically acceptable dielectric and 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or its hydrochloride salt or a combination thereof in a solution having a pH in the range of 5.0-6.0.

13. The iontophoretic system of claim 12, wherein the solution has a pH of about 5.5.

14. The iontophoretic system of claim 9, wherein the reservoir contains a pharmaceutically acceptable dielectric and 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone or its mesylate salt or a combination thereof in a solution having a pH in the range of 3.5-6.0.

15. The iontophoretic system of claim 14, wherein the solution has a pH of about 4.0.

16. A cartridge capable of being filled or refilled with an iontophoretic system comprising 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or a pharmaceutically acceptable salt thereof or a combination thereof and optionally a pharmaceutically acceptable electrolyte.

17. The cartridge of claim 16 comprising 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or its hydrochloride salt and the optional pharmaceutically acceptable electrolyte in a solution having a pH in the range of 5.0-6.0.

18. A cartridge according to claims 16-17 comprising 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or its hydrochloride salt in a solution having a concentration of 10-75 mg/ml.

19. A cartridge capable of being filled or refilled with an iontophoretic system comprising 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone or a pharmaceutically acceptable salt thereof or a composition thereof and optionally a pharmaceutically acceptable electrolyte.

20. The cartridge of claim 19, comprising 7- (4-methyl-1-piperazinyl) -2(3H) -benzoxazolone or its mesylate salt and the optional pharmaceutically acceptable electrolyte in a solution having a pH in the range of 3.5-6.0.

21. A cartridge according to claims 19-20 comprising 7- (4-benzyl-1-piperazinyl) -2(3H) -benzoxazolone or its mesylate salt in a solution having a concentration of 1-30 mg/ml.

22. A kit, comprising:

(1) an iontophoretic system for the transdermal delivery of a compound through the skin, the system comprising (a) a transdermal delivery device connectable to the skin, the device comprising a first electrode and a second electrode, and a reservoir capable of containing a composition of the active compound and (b) means for connecting a power source to said first and second electrodes and (c) a membrane optionally enclosing the reservoir during transport, storage and/or application

(2) One or more cartridges according to claims 16-21.

23. A kit comprising one or more cartridges according to claims 16-21.