WO1997049382A1 - Dispositifs d'administration iontophoretique d'antagonistes de glycoproteine iib/iiia - Google Patents

Dispositifs d'administration iontophoretique d'antagonistes de glycoproteine iib/iiia Download PDF

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Publication number
WO1997049382A1
WO1997049382A1 PCT/GB1997/001670 GB9701670W WO9749382A1 WO 1997049382 A1 WO1997049382 A1 WO 1997049382A1 GB 9701670 W GB9701670 W GB 9701670W WO 9749382 A1 WO9749382 A1 WO 9749382A1
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WO
WIPO (PCT)
Prior art keywords
llla
iontophoretic
delivery device
antagonist
drug delivery
Prior art date
Application number
PCT/GB1997/001670
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English (en)
Inventor
Allan Baxter
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU31833/97A priority Critical patent/AU3183397A/en
Publication of WO1997049382A1 publication Critical patent/WO1997049382A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine

Definitions

  • the present invention relates the iontophoretic delivery to a patient, in particular, to a patient having a thrombotic disorder, of a compound which blocks the binding of fibrinogen to the glycoprotein complex Gp llb/llla.
  • the invention also relates to an iontophoretic delivery device suitable for such use.
  • iontophoresis is that ionised (or polar) drug molecules can be driven across the skin and into the systemic system if an appropriate electrical potential is applied across the skin.
  • This mode of delivery allows such drugs to be administered at a constant and predictable rate so as to keep drug levels within the narrow therapeutic window.
  • Use of iontophoretic delivery is particularly convenient for conditions where the drug is to be administered chronically over a period of several months as it allows for simple self-administration and encourages patient compliance.
  • an iontophoretic delivery system may be removed quickly and easily by the patient or clinician should the need to suddenly stop drug administration arise and normal platelet aggregation would quickly return.
  • an iontophoretic drug delivery device characterised in that it comprises, as an active ingredient, an antagonist of Gp llb/llla.
  • said Gpllb/llla antagonist is ionised at pH 4 to 7. More suitably, the Gpllb/llla antagonist is highly potent, for example requiring a daily dose of less than 50mg/day, and is of low molecular weight.
  • Gpllb/llla antagonists which may be suitable in the invention include those described in: EP478363B; EP505868B; EP483667A; EP614360B; WO94/22820; Ohman, E.M. et al Eur. Heart J. (1195), 16 (Suppl. L), 50-55; Lincoff, A. et al, Am. J. Cardiol. (1997), 79(3), 286-291 ; and Timm, U. et al, J. Chromatogr., B: Biomed. Sci. Appl. (1997), 691(2), 397-407, all of which are incorporated herein by reference.
  • the Gpllb/llla antagonist is of formula (I)
  • the iontophoretic delivery device comprises, as active ingredient, a compound selected from: ⁇ 4-[6-(2-piperidin-4-yl-(E)-vinyl)-1 H-indazol-3-ylJ-piperidin-1 -yl ⁇ -acetic acid;
  • the iontophoretic delivery device comprises, as active ingredient, a compound selected from: ⁇ 4-[3-methanesulfonyl-5-(2-p ⁇ peridin-4-yl-ethyl)-indazol-1-yl]-piperidin-1-yl ⁇ - acetic acid;
  • pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester, of the compounds of formula (I), or any other compound which upon adminstration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
  • the Gpllb/llla antagonist is in the form of a hydrochloride salt.
  • the iontophoretic drug delivery devices of the present invention are of interest for use in human and veterinary medicine, particularly in the treatment of thrombotic disorders.
  • thrombotic disorders include occlusive vascular diseases such as myocardial infarction, cardiac fatalities, angina, transient ischaemic attacks and thrombotic stroke, arteriosclerosis, vessel wall disease, peripheral vascular disease, nephropathy, retinopathy, postoperative thrombosis, pulmonary embolism, deep vein thrombosis and retinal vein thrombosis.
  • the iontophoretic drug delivery devices of the invention are also of interest for use in the prophylactic treatment of pen- and postoperative complications following organ transplantation (particularly cardiac and renal), coronary artery bypass, peripheral artery bypass, angioplasty, thrombolysis and endarterectomy
  • the iontophoretic drug delivery devices of the invention may also be useful for the treatment of other conditions in which the glycoprotein complex Gp llb/llla or other integrin receptors are implicated.
  • the iontophoretic drug delivery devices of the invention may potentiate wound healing and be useful in the treatment of bone conditions caused or mediated by increased bone resorption.
  • bone diseases are known in the art and include osteoporosis, hypercalcaemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilisation-induced osteopenia and glucocorticoid treatment.
  • the iontophoretic drug delivery devices of the invention may also be useful for the treatment of certain cancerous diseases, for example to prevent or delay metastasis in cancer.
  • an iontophoretic drug delivery device characterised in that it comprises, as an active ingredient, an antagonist of Gpllb/llla, for use in human or veterinary medicine, particularly for use in the treatment of a condition which is mediated through the Glycoprotein Gpllb/llla, for example a thrombotic disorder.
  • a method of treating a human or animal subject suffering from a condition which is mediated through the Glycoprotein complex Gpllb/llla, for example a thrombotic disorder which comprises administering an effective amount of Gpllb/llla antagonist by iontophoretic action.
  • the method comprises administering the Gpllb/llla antagonist by an iontophoretic drug delivery device according to the invention.
  • the process of iontophoretic drug delivery is performed in general by putting the drug, or preferably an iontophoretic delivery device comprising the drug onto intact skin, for example on the arm, chest or the like.
  • the iontophoretic delivery device may contain the drug in isolated form, but more preferably, the drug is in the form of a composition adapted for use in iontophoretic delivery.
  • This composition may for instance be a solution (absorbed onto some porous material, such as a piece of filter paper or a piece of hydrophilic polyurethane) or a gel.
  • the device is then covered by an electrode.
  • a second electrode covering an inert reservoir composed of mainly ionic species is placed elsewhere on the skin, and a direct current source is connected between the electrodes in such a way that the electrode in contact with the drug assumes the same charge as the ionised drug. Under influence of the electric field present, drug molecules migrate through the skin.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an antagonist of Gp llb/llla, for example, a compound of formula (I) or a pharmaceutically acceptable derivative thereof, adapted for use in an iontophoretic delivery device.
  • a useful dose for a human patient, achievable by a device according to the present invention is up to 50 mg/day, preferably up to 25mg/day.
  • an iontophoretic device substantially as hereinbefore described may be in the form of a matrix of a solid, semi-solid or mucilaginous material having an active ingredient dispersed therein, and optionally having an active ingredient permeable membrane associated therewith.
  • the matrix material is suitably a hydrogel, polyurethane, silicone or other material known in the art for holding a drug in a stable condition prior to release to the skin.
  • the matrix is in the form of a transdermal patch or pad, or the like, for transdermal administration of the active ingredient.
  • a device according to the present invention may be in the form of a reservoir having therein a liquid medium containing therein an active ingredient, the reservoir having a membrane which is permeable for the active ingredient. The former option is preferred.
  • an iontophoretic drug delivery system which comprises:
  • the electrode means conveniently comprise an electrode system of an anode and a cathode which may be metal foils, polymer matrix loaded with metal powder, powdered graphite, carbon fibres or other suitable electrically conductive material.
  • Suitable metals for use in electrodes are for instance platinum, silver, aluminium, copper, lead, iron, tin, chromium or zinc.
  • metal/insoluble salt electrodes may be used, such as silver/silver halide electrodes, particularly silver/silver chloride electrodes. Platinum electrodes are used in some instances, however, silver/silver chloride electrodes are preferred.
  • the combined skin contacting areas of electrode assemblies can vary from less than 1 cm 2 to greater than 200cm 2 .
  • the average device will have a contacting area from about 5cm 2 to about 50cm 2 .
  • a device according to the present invention can be suitably covered by a first electrode.
  • a second electrode can be placed elsewhere on the skin, and a direct current source can be connected between the electrodes in such a way that the first electrode in contact with the device containing the active ingredient assumes the same charge as the ionized active ingredient.
  • active ingredient molecules migrate through the skin. A current flows between the electrodes, part of which is carried by the active ingredient.
  • a delivery system according to the present invention may also preferably further comprise a power source, e.g. batteries and suitable control circuitry.
  • a power source e.g. batteries and suitable control circuitry.
  • Iontophoretic devices and systems as such are known in the art, for instance from, WO-A 9116946, WO-A 9116944, WO-A 9116943, WO-A 9115261 ,W0-A 9115260, WO-A 9115259, WO-A 9115258, WO-A 9115257, WO-A 9115250, WO-A 9109645, WO-A 9108795, WO-A 9004433, WO-A 9004432, WO-A 9003825, EP-A 254965, US 4717378, EP-A 252732 and GB-A 2239803.
  • Test Compound 4-f6-(2-piperidin-4-yl-(E)-vinyl)-1 H-indazol-3-yll- piperidin-1-yl>-acetic acid ( hereinafter referred to as Test Compound)
  • Test Compound and other compounds of formula (I) as defined above may be prepared by methods described in copending applications PCT/EP95/05043 which has the publication number WO96/2012 and GB 9511989.7 which corresponds to PCT application number PCT/EP96/02536.
  • the syntheses of further suitable compounds according to the invention have been described in GB 9613017.4, GB 9613095.0, and GB 9613018.2.
  • the syntheses of all the compounds described above is obvious to a person skilled in the art of chemistry.
  • HPLC High performance liquid chromatography
  • the mobile phase consisted of 70:30 0.05% trifluoroacetic acid (TFA) in purified water: 0.05% TFA in acetonitrile. All solvents were HPLC grade.
  • the ⁇ max was determined to be 237nm by scanning techniques and was used for the wavelength of detection in this assay. Flow rate was maintained at 1. ⁇ mUmin. A 15 x 0.46 cm Spherisorb phenyl column, 3 ⁇ m packing was used.
  • Electrodes were fabricated in the lab from silver wire (99.9985% pure, 0.5mm in diameter, Alfa Aesar Puratronic, Johnson Matthey). Preparation involved placing two equal lengths of silver wire in 0.5M KCI and applying a current of 1mA for 12 hours. This process is taken from the procedure demonstrated by Burnette and Ongpipattanakul, (1988), Journal of Pharmaceutical Sciences, 77(2), 132-7.
  • the Ag:AgCI electrodes produced were coiled around a 22G 1.5inch syringe needle to produce a coil approximately 1.125inches in length and a lead of approximately 1.25inches. The total area of the electrode was 3.39cm 2 .
  • the anode (+) electrode (Ag) was placed in the donor solution in order to repel the positively charged drug substance across the membrane.
  • the cathode (-) electrode (AgCI) was placed in the receptor side of the diffusion cell. The electrodes were located approximately 3cm apart.
  • the donor solution consisted of an 8 5mg Test Compound/ml aqueous solution, pH 5, unadjusted
  • the receptor solution consisted of 0 1M NaCI aqueous solution adjusted to pH 5 with NaOH/HCI.
  • the volume of the donor and receptor compartments were 3.5mL and the receptor compartment was emptied at each sample interval and filled with 3.5mL of fresh, pre-heated receptor solution. A mass balance was performed at the completion of each run.
  • Standard area counts were entered into a spreadsheet and a linear regression analysis was performed on the average area counts versus concentration ( ⁇ g Test Compound/mL). Content data for the samples were generated from area counts using the standard regression curve. The amount of Test Compound transported for each sample was calculated based on 3.5mL receptor solution volume. Cumulative amounts, instantaneous fluxes, and cumulative amounts per cm 2 of skin or culture were subsequently determined from these values.
  • Steady state flux values were determined from cumulative ⁇ g Test Compound/cm 2 versus time (hr) plots of the data. Regression analysis conducted on the steady state portion of these profiles provided flux data from the slope and lag time data from the x-intercept.
  • the predicted anode area was determined by dividing the desired delivery rate (750 ⁇ g Test Compound/hr) by the flux ( ⁇ g Test Compound/cm 2 hr).
  • the predicted patch size was calculated by multiplying the anode area by 2.5 (anode + cathode + additional housing area) as recommended Sage Jr. & Riviere, (1992). "Model systems in iontophoresis-transport efficacy" Advanced Drug Delivery Reviews, 9, 265-287. Flux data was scaled linearly in order to predict the flux, anode area, and system size at other current densities.
  • Plasma levels were predicted based on the relationship:
  • C p is the predicted plasma level (ng/mL)
  • J is the steady-state flux ( ⁇ g/cm 2 hr)
  • a an o d e is the area of the anode (cm 2 )
  • Cl is the clearance (mL/min).
  • Test Compound/cm 2 of culture available for transport Active cells were run at a current density of 0.1mA/cm 2 . System suitability standard checks were run five times throughout the analysis and results were found to be between 97.7 and 98.7% of the actual concentration based on regression analysis. A mass balance conducted at the conclusion of this experiment demonstrated at least 100% recovery from each diffusion cell set-up. All results are corrected for purity and reported in terms of the free base of the Test Compound.
  • Test Compound/cm 2 of skin available for transport The results obtained from this set of experiments are listed in Tables 3 and 4 as ⁇ g Test Compound/cm 2 of skin available for transport. Active cells were run at a current density of 0.1mA/cm 2 . System suitability standard checks were run seven times throughout the analysis and results were found to be between 93.5 and 94.6% of the actual concentration based on regression analysis. A mass balance conducted at the conclusion of this experiment demonstrated at least 100% recovery from each diffusion cell set-up. All results are corrected for purity and reported in terms of the free base of the Test Compound.
  • Test Compound can be obtained by iontophoretic delivery of its hydrochlo ⁇ de salt

Abstract

Dispositif de d'administration iontophorétique d'un médicament caractérisé par la présence en tant qu'ingrédient actif d'un antagoniste de Gp IIb/IIa et son utilisation dans le traitement de troubles dont le médiateur est le complexe glycoprotéine GpIIb/IIa ou un autre récepteur d'intégrine.
PCT/GB1997/001670 1996-06-21 1997-06-20 Dispositifs d'administration iontophoretique d'antagonistes de glycoproteine iib/iiia WO1997049382A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31833/97A AU3183397A (en) 1996-06-21 1997-06-20 Iontophoretic delivery devices for antagonists of glycoprotein iib/iiia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9613096.8 1996-06-21
GBGB9613096.8A GB9613096D0 (en) 1996-06-21 1996-06-21 Medicaments

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Publication Number Publication Date
WO1997049382A1 true WO1997049382A1 (fr) 1997-12-31

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AU (1) AU3183397A (fr)
GB (1) GB9613096D0 (fr)
WO (1) WO1997049382A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0950407A1 (fr) * 1998-04-14 1999-10-20 Takeda Chemical Industries, Ltd. Méthode pour l'administration transdermique de l'antagoniste de GP IIb/IIIa
WO2004009548A1 (fr) * 2002-07-18 2004-01-29 Wyeth Ligands de la 5-hydroxytryptamine-6 a base de derives de 1-heterocyclylalkyl-3-sulfonyl-indole ou -indazole

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5458568A (en) * 1991-05-24 1995-10-17 Cortrak Medical, Inc. Porous balloon for selective dilatation and drug delivery
US5510328A (en) * 1994-04-28 1996-04-23 La Jolla Cancer Research Foundation Compositions that inhibit wound contraction and methods of using same
WO1996020192A1 (fr) * 1994-12-23 1996-07-04 Glaxo Group Limited Derives d'acide piperidinacetiques agissant comme antagonistes de fibrinogene
WO1996041803A1 (fr) * 1995-06-13 1996-12-27 Glaxo Group Limited Derives d'acide piperidineacetique comme inhibiteurs d'agregat de plaquettes sanguines dependant du fibrinogene

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5458568A (en) * 1991-05-24 1995-10-17 Cortrak Medical, Inc. Porous balloon for selective dilatation and drug delivery
US5510328A (en) * 1994-04-28 1996-04-23 La Jolla Cancer Research Foundation Compositions that inhibit wound contraction and methods of using same
WO1996020192A1 (fr) * 1994-12-23 1996-07-04 Glaxo Group Limited Derives d'acide piperidinacetiques agissant comme antagonistes de fibrinogene
WO1996041803A1 (fr) * 1995-06-13 1996-12-27 Glaxo Group Limited Derives d'acide piperidineacetique comme inhibiteurs d'agregat de plaquettes sanguines dependant du fibrinogene

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0950407A1 (fr) * 1998-04-14 1999-10-20 Takeda Chemical Industries, Ltd. Méthode pour l'administration transdermique de l'antagoniste de GP IIb/IIIa
US6322550B2 (en) 1998-04-14 2001-11-27 Hisamitsu Pharmaceutical Co., Inc. Method for transdermal administration of GP IIb/IIIa antagonist
WO2004009548A1 (fr) * 2002-07-18 2004-01-29 Wyeth Ligands de la 5-hydroxytryptamine-6 a base de derives de 1-heterocyclylalkyl-3-sulfonyl-indole ou -indazole
US6995176B2 (en) 2002-07-18 2006-02-07 Wyeth 1-heterocyclylalkyl-3-sulfonyl-indole or -indazole derivatives as 5-hydroxytryptamine-6 ligands
US7589108B2 (en) 2002-07-18 2009-09-15 Wyeth 1-Heterocyclylalkyl-3-sulfonylindole or -indazole derivatives as 5-hydroxytryptamine-6 ligands

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GB9613096D0 (en) 1996-08-28
AU3183397A (en) 1998-01-14

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