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WO2008115586A1 - Appareil et procédé d'administration transdermique d'un agoniste de triptane - Google Patents

Appareil et procédé d'administration transdermique d'un agoniste de triptane Download PDF

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Publication number
WO2008115586A1
WO2008115586A1 PCT/US2008/003772 US2008003772W WO2008115586A1 WO 2008115586 A1 WO2008115586 A1 WO 2008115586A1 US 2008003772 W US2008003772 W US 2008003772W WO 2008115586 A1 WO2008115586 A1 WO 2008115586A1
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WO
WIPO (PCT)
Prior art keywords
triptan
agonist
microprojections
acid
microprojection member
Prior art date
Application number
PCT/US2008/003772
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English (en)
Inventor
Frank Stonebanks
Original Assignee
Alza Corporation
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 Alza Corporation filed Critical Alza Corporation
Publication of WO2008115586A1 publication Critical patent/WO2008115586A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors

Definitions

  • the subject matter described herein related generally to transdermal agent delivery systems and methods. More particularly, the subject matter related to an apparatus and method for transdermal delivery of triptan agonists.
  • a migraine headache is a very common disorder that afflicts numerous people on a regular basis.
  • a migraine headache has been defined in the art, generally, as an episodic headache lasting a finite time, in the range of a small amount of time to days. The small amount of time could be minutes to a few hours.
  • These episodic headaches are often, but not always, associated with an aura followed by gastrointestinal discomfort, nausea, dizziness, pulsatile pain, increased pain through normal physical activity, photophobia, phonophobia and/or visual disturbances. It is common that the discomfort and disturbance is of such a nature and frequencies so as to adversely affect the afflicted individual's lifestyle.
  • vasoconstriction the closing or tightening of arteries, which reduces blood flow
  • vasodilation the opening of the vessels to increase blood flow. It appears that a variety of stimuli, such as intense light, noise, anxiety, exertion, cold, heat, hormones, food additives and certain foods, result rn constriction of extracranial vessels.
  • the vasoconstriction is followed by a sequential or reflex powerful vasodilation, which subsequently spreads to intracranial vessels. It is during this phase that a patient feels an intense, throbbing headache.
  • the phases of a migraine headache have been separated into the prodrome, aura and acute painful headache stages.
  • the prodrome is the primary stage of a migraine attack characterized by an alteration of mood, energy or passive functions. This stage can occur for hours before the onset of the headache.
  • the mood alterations include euphoria, loquaciousness, unprovoked apathy, depression, inertia, drowsiness, irritability, repetitive yawning, aggression and heightened sensitivity to various levels of sound (sonophobia). Nausea and vomiting, as well as paresthesias in the extremities, may also accompany these symptoms.
  • the aura or second stage has been defined by the onset of fear of light (photophobia) and visual disturbances brought on by a reduction of cerebral blood flow due to vasospasm.
  • the headache phase is vascular with distension and increased pulsation of cranial arteries.
  • Increased vascular permeability is associated with the release of peptides, especially bradykrnin and substance P, as well as molecules such as histamine and serotonin, which cause local pain when they reach perivascular nerve endings.
  • Migraine headaches develop suddenly, and reach maximal intensity very quickly, in contrast to ordinary muscular headaches, which develop gradually and rarely, if ever, reach a severity comparable to that of migraine headaches.
  • Patients suffering from migraine headaches are often so well aware of the pain that will ensue from an impending migraine that they become apprehensive and frightened.
  • the patients hyperventilate and/or tense their neck muscles. Both of these effects usually lead to a muscle tension headache.
  • the mere anticipation and fear of an impending migraine headache brings about an ordinary muscular headache in virtually all migraine patients. The patients can thus suffer from two different types of affliction simultaneously.
  • a migraine is a complex process involving many different neuroreceptors and the biochemical pathways that regulate migraines are varied and complex.
  • Migraine-associated neuroreceptors include neurochemical receptors such as serotonin receptors, 5-hydroxytrytamine (5-HT) receptors.
  • 5-HT receptors There are two 5-HT receptors associated with migraines including 5-HTlb, and 5-HTld.
  • agonism of the 5-HTlb and/or HTId receptors can treat or prevent migraines.
  • Antimigraine drugs are well-known. See, e.g., U.S. Pat. Nos. 4,650,810, 4,914,125, 4,916,125, 4,994,483, 5,021,428, 5,200,413, 5,242,949, 5,248,684, 5,273,759, 5,317,103, 5,364,863, 5,399,574, 5,434,154, 5,441,969, 5,464,864, 5,466,699, 5,468,768, 5,491,148 and 5,494,910.
  • Anti-migraine drugs commonly used in treatment of migraine are the selective 5-HT agonists mentioned above that have direct, or indirect effects on the 5-HT receptor system. The receptor mediates vasoconstriction in the carotid vascular bed and thereby modifies blood flow therein.
  • Intravenous and subcutaneous injections are problematic from the point of view of self-administration; sub-lingual tablets work fast, but present significant after taste concerns, as well as the fact that oral tablets are often difficult to ingest for a migraine sufferer, as he/she is often nauseous and unable to tolerate / swallow a pill. (80-90% of migraine patients also suffer from emesis). Thus, there remains a need to identify new approaches to prevent or treat migraine and related disorders.
  • a device for transdermally delivering at least one compound from the triptan family (“triptan”) of triptan agonists is provided.
  • the device is comprised of a microprojection member having a plurality of microprojections adapted to pierce the stratum corneum of a patient, and at least one triptan agonist disposed on said microprojection member for communication with the plurality of microprojections.
  • the triptan agonist is contained in a biocompatible coating disposed on all or a portion of the external surfaces of the microprojections.
  • the triptan agonist is contained in a reservoir in contact with said microprojection member.
  • the plurality of microprojections comprised a plurality of hollow microprojections having an external surface enclosing an interior surface, and the triptan agonist is contained in a biocompatible coating disposed on all or a portion of interior surfaces of the microprojections.
  • the triptan agonist is selected from the group consisting of sumatriptan, eletriptan, frovatriptan, naratriptan, almotriptan, zolmitriptan, and rizatriptan.
  • a method for transdermally delivering at least one triptan agonist is described.
  • a microprojection member having a plurality of microprojections adapted to pierce the stratum corneum of a patient is provided, and applying the member to a skin site on a patient, whereby the plurality of microprojections pierce the stratum-corneum for delivery of the triptan agonist.
  • the member is applied to a patient prior to, during, or after a migraine.
  • the member is applied to a patient before, during, or after the prodrome phase.
  • the member is applied to a patient before, during, or after the aura phase.
  • the member is applied to a patient before, during, or after the acute painful headache phase.
  • the devices and methods of the present invention will have improved tolerability over known treatments of migraines.
  • the present invention does not have the noxious taste or elicit the nausea experienced with intranasal treatments, does not require needles like subcutaneous or intravenous injections and has a faster onset than oral medications. Further, the present invention does not elicit the nausea experienced with oral treatments. During a migraine attack, 80-90% of patients experience nausea and vomiting, making it difficult to take oral medications.
  • the devices and methods of the present invention further provide for the rapid and sustained relief of migraines over alternative methods of delivery.
  • the present invention enables rapid uptake and distribution of a drug, and therefore, is fast acting and delivers a higher does in the first minutes of treatment, on the order of less than 15 minutes.
  • This profile is comparable to injections and intranasal formulations that act in 10 and 5 minutes, respectively, but without the negative side effect profile of injections and intranasal formulations, and it is superior to oral medications that can take 30-60 minutes.
  • FIG. 1 is a perspective view of a portion of one example of a microprojection member
  • FIG. 2 is a perspective view of a microprojection member where a coating is deposited on the outer surface of each microprojection in the array;
  • FIG. 3 is a side sectional view of a microprojection member having a drug reservoir and an adhesive backing;
  • FIG. 4 is a perspective view of a microprojection having a standard hollow needle-like configuration, where the interior and/or exterior of the microprojections include an agent for delivery;
  • Fig. 5A is an exploded perspective view of a microprojection member enclosed in a retainer and an applicator;
  • Fig. 5B is a side sectional view of a retainer having a microprojection member disposed therein.
  • transdermal means the delivery of an agent into and/or through the skin for local or systemic therapy.
  • transdermal flux means the rate of transdermal delivery.
  • triptan family agonist intends an agent that acts by agonizing 5-HT receptors, and in one embodiment 5-HTi receptors, and preventing or reducing the initiation of the migraine response.
  • triptan agonists include, without limitation, sumatriptan, eletriptan, frovatriptan, naratriptan, almotriptan, zolmitriptan, and rizatriptan. It will be appreciated that the term is intended to encompass the agent in any form, including, but not limited to, a free base, a free acid, a salt, or as a component of a complex.
  • triptan agonist agent can be incorporated into the agent source, reservoirs, and/or coatings described herein below, and that the use of the term "triptan agonist" in no way excludes the use of two or more such agents.
  • microprojections refers to piercing elements which are adapted to pierce or cut through the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers, of the skin of a living animal, particularly a mammal and more particularly a human.
  • patient refers to an individual afflicted with a migraine headache.
  • migraine headache refers to an episodic headaches are often, but not always, associated with gastrointestinal discomfort, dizziness, pulsatile pain, increased pain through normal physical activity, photophobia, phonophobia and/or visual disturbances.
  • migraine refers to a severe recurring headache resulting from cerebral vasoconstriction and is classified as either a classical migraine or a common migraine. See, e.g., "Remington's Pharmaceutical Sciences", 17th ed., Mack Publishing Company (1985), p. 946 and Goodman and Gilman's "The Pharmaceutical Basis Of Therapeutics", 8th ed., McGraw-Hill, Inc. (1990), pp. 944-947. A common migraine is much more likely to occur than a classical migraine.
  • the classical migraine is associated with objective prodromal neurological signs and symptoms involving a headache that is preceded by a slowly expanding area of blindness surrounded by a sparkling edge that increases to involve up to one half of the field of vision of each eye.
  • the blindness clears up after approximately 20 minutes, it is often followed by a severe one-sided headache with nausea, vomiting and sensitivity to light.
  • the common migraine is an attack without prodromal symptoms and begins as a slowly developing pain in the form of a headache that transforms into a mounting throbbing pain made worse by the slightest movement or noise. The pain is often on one side of the head only and usually occurs with nausea and sometimes vomiting.
  • the length of migraine is from about two hours to two days.
  • Non-exhaustive examples of causes of migraine are: stress related, e.g., anxiety, anger, worry, excitement, shock, depression, overexertion, changes of routine and changes of climate, food-related, e.g., chocolate, cheese and other dairy products, red wine, fried food and citrus fruits, sensory-related, e.g., bright lights or glare, loud noises and intense or penetrating smells, menstruation and contraceptive drugs.
  • a device for delivery of a triptan agonist includes a plurality of microprojections (or array thereof) that are adapted to pierce through the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers.
  • a portion of such an array from an exemplary device is shown in Fig. 1.
  • a microprojection member 10 is comprised of an array of microprojections, such as microprojections 12, 14.
  • the microprojections extend at a substantially 90° angle from a substrate 16 having openings, such as openings 18, 20.
  • the microprojections typically have a length of less than about 1000 microns, and preferably a length of less than about 500 microns, more preferably, less than about 250 microns.
  • each microprojection is typically in the range of approximately 25 - 500 microns and the thickness of each microprojection is generally in the range of approximately 10-100 microns.
  • the microprojections may be formed in different shapes, such as needles, blades, pins, punches, and combinations thereof.
  • the microprojection member can be formed by etching or punching a plurality of microprojections from a sheet or substrate, such as substrate 16, and folding or bending the microprojections out of the plane of the sheet.
  • the microprojection member can also be formed in other known manners, such as by forming one or more strips having microprojections along an edge of each of the strip(s) as disclosed in U.S. Patent No. 6,050,988, which is hereby incorporated by reference in its entirety.
  • the microprojection member is constructed out of stainless steel, titanium, nickel titanium alloys, or similar biocompatible materials.
  • the microprojection member is constructed out of a non- conductive material, such as a polymeric material.
  • the microprojection member when formed from a conductive material can be coated with a non-conductive material, such as Parylene®, or a hydrophobic material, such as Teflon®, silicon, or the like.
  • the microprojection member in one embodiment, has a microprojection density of at least approximately 10 microprojecuOns/cm 2 , more preferably, in the range of at least approximately 200 - 2000 microprojections/cm 2 .
  • the device is designed for transdermal delivery of a triptan agonist, which is administered to a subject desirous of migraine control.
  • the agonist is administered into the underlying epidermis layer, or epidermis and dermis layers, of a subject via slits or cuts made by the microprojections through the stratum comeum.
  • the triptan agonist is disposed on the device in a way that permits delivery of the agent from the device into the slits made in the stratum corneum.
  • each microprojection such as microprojections 24, 26, in an array 28 can be coated with a biocompatible coating 30.
  • the biocompatible coating may partially or completely cover the microprojections and may be applied to the microprojections before or after the microprojections are formed.
  • the coating 30 on the microprojections can be formed by a variety of known methods.
  • One such method is dip- coating, where the microprojections are partially or totally immersed into a formulation containing a triptan agonist.
  • a coating solution containing a suitable solvent (aqueous or non-aqueous), a triptan agonist, and any additional solution components is prepared and applied to the microprojections.
  • the entire device can be immersed into the coating solution.
  • An apparatus for coating a microprojection array is described in U.S. Publication No. 2002/0132054; coatings are also described in US2004/0062813, both of which are incorporated by reference herein in its entirety.
  • the coating device applies the coating solution only to the microprojections and not upon the substrate/sheet from which the microprojections project.
  • Other coating techniques such as microfluidic spray or printing techniques can be used to precisely deposit a coating on the tips of the microprojections.
  • the microprojections may further include means adapted to receive and/or increase the volume of the coating such as apertures, grooves, surface irregularities, or similar modifications, wherein the means provides increased surface area upon which a greater amount of coating may be deposited.
  • a coating solution can also be applied to the microprojections by spraying. Spraying can encompass formation of an aerosol suspension of the coating composition, where droplets having a size of about 10 to about 200 picoliters is sprayed onto the microprojections and then dried.
  • the coating formulation includes a triptan agonist in any desired amount.
  • the coating formulation is applied to the microprojections to obtain a dry solid, biocompatible coating that contains in the range of between about l ⁇ g - 1000 ⁇ g, even more preferably, in the range of 10 ⁇ g - 1000 ⁇ g. of the triptan agonist.
  • the coating thickness is dependent upon the density of the microprojections per unit area, the viscosity and concentration of the coating formulation, as well as the coating method. In general, coating thickness less than 50 micrometers are desired, and a preferred average coating thickness is less than about 30 micrometers, as measured perpendicularly from the microprojection surface.
  • Another embodiment of a microprojection device is shown in cross-sectional view in Fig.
  • device 40 includes a microprojection member 42 comprised of a plurality of microprojections, such as microprojections 44, 46.
  • the microprojections extend from a substrate 48, which is in contact with a reservoir 50 containing a triptan agonist.
  • Reservoir 50 is in fluid communication with openings between and adjacent the microprojections, such as openings 52, 54.
  • the number of openings per unit area through which the agent passes is at least approximately 10 openings/cm2 and less than about 2000 openings/cm2.
  • Agent in reservoir 50 is delivered through the openings and into the slits in the stratum corneum of a subject formed upon piercing with the array of microprojections.
  • a backing layer 56 is disposed on the skin proximal side of the agent reservoir, and can additionally include an adhesive (not shown) for adhering the device to the skin.
  • a device for use in a device for delivery of a triptan agonist to a subject is shown in Fig. 4.
  • a device as described above, includes an array of microprojections, where each microprojection is in the shape of a hollow needle, like needle 60 shown in Fig. 4.
  • Needle 60 has an exterior surface 62, an interior surface 64, and a skin-piercing distal tip 66.
  • the interior surface 64 of the microprojection is coated with a coating formulation to form a solid, dry coating 68.
  • the needle includes slits, perforations, or other openings, and/or is formed of a porous material to facilitate entry of interstitial fluid and dissolution of the triptan agonist.
  • Figs. 5A-5B show an embodiment of a microprojection member 70 suspended in a retainer ring 72 by adhesive tab
  • the retainer ring is placed against the skin and the microprojection member 70 is downwardly displaced for contact with patient's skin.
  • the microprojection member is applied to the patient's skin using an impact applicator 78, such as shown in Fig. 5A, and described in U.S. Publication No. 2002/0123675 Al, which is incorporated by reference herein in its entirety.
  • microprojection members that can be employed for delivery of the triptan agonist can also include, but are not limited to, the members disclosed in U.S. Patent Nos. 6,083, 196, 6,050,988, and 6,091,975, which are incorporated by reference herein in their entirety.
  • microprojection members that can be employed include members formed by etching silicon using silicon chip etching techniques or by molding plastic using etched micro-molds, such as the members disclosed U.S. Patent No.
  • the apparatus includes an applicator device for repeatable impact application of a microprotrusion array, to achieve predefined and consistent penetration of the microprotrusions into the skin.
  • a biocompatible, solid dry coating containing the triptan agonist is formed on the microprojections.
  • the solid coating is deposited from a coating formulation that can contain various additional components, now to be described.
  • the coating formulation includes at least one buffer.
  • buffers include, without limitation, ascorbic acid, citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, fumaric acid, maleic acid, phosphoric acid, tricarballylic acid, malonic acid, adipic acid, citraconic acid, glutaratic acid, itaconic acid, mesaconic acid, eitramalic acid, dimethylolpropionic acid, tiglic acid, glyceric acid, methacrylic acid, isocrotonic acid, p-hydroxybutyric acid, crotonic acid, angelic acid, hydracrylic acid, aspartic acid, glutamic acid, glycine and mixtures thereof.
  • the coating formulation includes at least one antioxidant, which can be a sequestering agent, such sodium citrate, citric acid, EDTA (ethylene-dinitrilo-tetraacetic acid) or free radical scavengers such as ascorbic acid, methionine, sodium ascorbate and the like.
  • Preferred antioxidants comprise EDTA and methionine.
  • the concentration of the antioxidant is in the range of approximately 0.01-20 wt. % of the coating formulation.
  • the antioxidant is in the range of approximately 0.03-10 wt. % of the coating formulation.
  • the coating formulation can additionally include at least one surfactant, which can be zwitterionic, amphoteric, canonic, anionic, or nonionic, including, without limitation, sodium lauroamphoacetate, sodium dodecyl sulfate (SDS), cetylpyridinium chloride (CPC), dodecyltrimethyl ammonium chloride (TMAC), benzalkonium, chloride, poiysorbates, such as Tween 20 and Tween 80, other sorbitan derivatives, such as sorbitan laurate, alkoxylated alcohols, such as laureth-4 and polyoxyethylene castor oil derivatives, such as Cremophor®.
  • the concentration of the surfactant is in the range of approximately 0.01-20 wt. % of the coating formulation.
  • the surfactant is in the range of approximately 0.05-1 wt. % of the coating formulation.
  • the coating formulation can also include at least one polymeric material or polymer that has amphiphilic properties, which can comprise, without limitation, cellulose derivatives, such as hydroxyethylcellulose (HEC), hydroxypropylmethylcell-ulose (HPMC), hydroxypropycellulose (HPC), methylcellulose (MC), hydroxyethylmethylcellulose (HEMC), or ethylhydroxy-ethylcellulose (EHEC), as well as a PluronicTM.
  • the concentration of the polymer presenting amphiphilic properties in the coating formulation is preferably in the range of approximately 0.01- 20 wt. %, more preferably, in the range of approximately 0.03-10 wt. % of the coating formulation.
  • the coating formulation can optionally include a hydrophilic polymer selected from the following group: hydroxyethyl starch, carboxymethyl cellulose and salts of, dexrran, polyvinyl alcohol), poly(ethylene oxide), poly(2- hydroxyethylmethacrylate), poly(n-vinyl pyrrolidone), polyethylene glycol and mixtures thereof, and like polymers.
  • a hydrophilic polymer selected from the following group: hydroxyethyl starch, carboxymethyl cellulose and salts of, dexrran, polyvinyl alcohol), poly(ethylene oxide), poly(2- hydroxyethylmethacrylate), poly(n-vinyl pyrrolidone), polyethylene glycol and mixtures thereof, and like polymers.
  • the concentration of the hydrophilic polymer in the coating formulation is in the range of approximately 1-30 wt. %, more preferably, in the range of approximately 1-20 wt. % of the coating formulation.
  • the coating formulation can optionally include a biocompatible carrier, which can comprise, without limitation, human albumin, bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acids, sucrose, trehalose, melezitose, raffrnose, stachyose, mannitol, and other sugar alcohols.
  • a biocompatible carrier can comprise, without limitation, human albumin, bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acids, sucrose, trehalose, melezitose, raffrnose, stachyose, mannitol, and other sugar alcohols.
  • concentration of the biocompatible carrier in the coating formulation is in the range of approximately 2-70 wt. %, more preferably, in the range of approximately 5-50 wt. % of the coating formulation.
  • the coating formulation can also include a stabilizing agent, which can comprise, without limitation, a non-reducing sugar, a polysaccharide or a reducing sugar.
  • a stabilizing agent can comprise, without limitation, a non-reducing sugar, a polysaccharide or a reducing sugar.
  • Suitable non-reducing sugars for use in the methods and compositions of the invention include, for example, sucrose, trehalose, stachyose, or raffrnose.
  • Suitable polysaccharides for use in the methods and compositions of the invention include, for example, dextxan, soluble starch, dextrin, and insulin.
  • Suitable reducing sugars for use in the methods and compositions of the invention include, for example, monosaccharides such as, for example, apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol, quinovose, rhamnose, allose, altrose, fructose, galactose, glucose, gulose, hamamelose, idose, mannose, tagatose, and the like; and disaccharides such as, for example, primeverose, vicianose, rutinose, scillabiose, cellobiose, gentiobiose, lactose, lactulose, maltose, mehbiose, sophorose, and turanose, and the like.
  • the concentration of the stabilizing agent in the coating formulation is at ratio of approximately 0.1 -2.0:1 with respect to the triptan agonist
  • the coating formulation includes a vasoconstrictor, which can comprise, without limitation, amidephrine, cafaminol, cyclopentamine, deoxyepinephrine, epinephrine, felypressin, indanazoline, metizoline, midodrine, naphazoline, nordefrin, octodrine, omipressin, oxymethazoline, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline, tramazoline, tuaminoheptane, tyrnazoline, vasopressin, xylometazoline and the mixtures thereof.
  • a vasoconstrictor which can comprise, without limitation, amidephrine, cafaminol, cyclopentamine, deoxyepinephrine, epinephrine, felypress
  • vasoconstrictors include epinephrine, naphazoline, tetrahydrozoline indanazoline, metizoline, tramazoline, tyrnazoline, oxymetazoline and xylometazoline.
  • a vasoconstrictor to the coating formulations and, hence, solid biocompatible coatings is particularly useful to prevent bleeding that can occur following application of the microprojection member or array and to prolong the pharmacokinetics of the triptan agonist through reduction of the blood flow at the application site and reduction of the absorption rate from the skin site into the system circulation.
  • concentration of the vasoconstrictor if employed, is preferably in the range of approximately 0.1 wt. % to 10 wt. % of the coating formulation.
  • the coating formulation includes at least one "pathway patency modulator", which can comprise, without limitation, osmotic agents (e.g., sodium chloride), zwitterionic compounds (e.g., amino acids), and antiinflammatory agents, such as betamethasone 21 -phosphate disodium salt, triamcinolone acetonide 21-disodium phosphate, hydrocortamate hydrochloride, hydrocortisone 21 -phosphate disodium salt, methylprednisolone 21 -phosphate disodium salt, methylprednisolone 21-succinaate sodium salt, paramethasone disodium phosphate and prednisolone 21 -succinate sodium salt, and anticoagulants, such as citric acid, citrate salts (e.g., sodium citrate), dextrin sulfate sodium, aspirin and EDTA.
  • pathway patency modulator can comprise, without limitation, osmotic agents (e.g., sodium chloride
  • the coating formulation includes a solubilising/complexing agent, which can comprise alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, glucosyl-alpha-cyclodextrin, maltosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, 2-hydroxypropyI-beta- cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-beta-cyclodextrin, methyl-beta-cyclodextrin, sulfobutylether-alpha-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfobutylether
  • solubilising/complexing agents are beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, 2-hydroxypropyl-beta- cyclodextrin, and sulfobutylether7 beta-cyclodextrin.
  • concentration of the solubilising/complexing agent, if employed, is preferably in the range of approximately 1 wt. %.to 20 wt. % of the coating formulation.
  • the coating formulation includes at least one non-aqueous solvent, such as ethanol, isopropanol, methanol, propanol, butanol, propylene glycol, dimethysulfoxide, glycerin; N,N-dimethylformamide and polyethylene glycol 400.
  • the non-aqueous solvent is present in the coating formulation in the range of approximately 1 wt. % to 50 wt. % of the coating formulation.
  • the coating formulations have a room temperature (about 20-25 0 C) viscosity less than approximately 500 centipoise and greater than 3 centipoise.
  • the coating formulation includes a non-volatile counterion, wherein the non-volatile counterion causes the formation of a first species of the triptan agonist that has improved solubility when the formulation is dried.
  • the first species of the triptan agonist dissolves quickly to provide rapid attainment of a therapeutically relevant blood level of the triptan agonist.
  • the formulation further includes a counte ⁇ on comprising a volatile counterion, wherein the volatile counterion causes the formation of a second species of the triptan agonist that has reduced solubility when the formulation is dried.
  • the second species of the triptan agonist dissolves at a slower rate to provide sustained blood levels of the triptan agonist.
  • the non- volatile counterions of the invention include weak acids and weak bases, acidic zwitterions and basic zwitterions, and strong acids and strong bases.
  • volatile counterions of the invention include weak acids or weak bases.
  • the addition of a non- volatile counterion results in the formation of a species of the triptan agonist that has improved solubility.
  • the addition of a volatile counterion results in the formation of a species of the triptan agonist that has reduced solubility.
  • the non- volatile counterion and the volatile counterion are added in approximately equimolar amounts.
  • the non- volatile counterion comprises a non- volatile weak acid that presents at least one acidic pKa and a melting point higher than about 50 0 C or a boiling point higher than about 170 o C at Patm.
  • such acids include citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, and fumaric acid.
  • the non-volatile counterion comprises a non- volatile weak base that presents at least one basic pKa and a melting point higher than about 50oC or a boiling point higher than about 170 o C at
  • such bases include monoethanolomine, diethanolamine, triethanolamine, tromethamine, methylglucarnine, glucosamine
  • the non- volatile counterion comprises a non-volatile acidic zwitterion that presents at least two acidic pKa, and at least one basic pKa, so that there is at least one extra acidic group as compared to the number of basic groups.
  • such compounds include glutamic acid and aspartic acid.
  • the non-volatile counterion comprises a non- volatile basic zwitterion that presents at least one acidic pKa, and at least two basic pKa's, so that there is at least one extra basic group as compared to the number of acidic groups.
  • such compounds include lysine, arginine, and histidine.
  • the non-volatile counterion comprises a nonvolatile strong acid that presents at least one pKa lower than about 2.
  • such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzene sulfonic acid and methane sulfonic acid.
  • the non-volatile counterion comprises a non-volatile strong base that presents at least one pKa higher than about 12.
  • bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide.
  • the volatile counterion comprises a weak acid that presents at least one pKa higher than about 2 and a melting point lower than about 50oC or a boiling point lower than about 170oC at Patm.
  • such acids include acetic acid, propionic acid, pentanoic acid and the like.
  • the volatile counterion comprises a weak base that presents at least one pKa lower than about 12 and a melting point lower than about 50oC or a boiling point lower than about 170oC at Patm.
  • such bases include ammonia and morpholine.
  • the volatile and non-volatile counterfoils are preferably present in amounts necessary to neutralize the charge present on the triptan agonist at the pH of the formulation. Excess of counterion (as the free acid or base or as a salt) can be added to the triptan agonist in order to control pH and to provide adequate buffering capacity.
  • a method for administering a triptan agonist to a subject is provided.
  • a device as described above in provided.
  • the microprojection member is initially applied to the patient's skin to cause the microprojections to pierce the stratum corneum.
  • the microprojection member is preferably left on the skin for a period lasting from 5 seconds to 24 hours. Following the desired wearing time, the microprojection member is removed.
  • the amount of triptan agonist contained in the biocompatible coating (i.e., dose) or in a reservoir in communication with the microprojections is in the range of approximately 1 micrograms -1000 micrograms, more preferably, in the range of approximately 10-200 micrograms. Even more preferably, the amount of triptan agonist contained in the biocompatible coating is in the range of approximately 10-100 micrograms per device.
  • the triptan agonist is delivered to the patient on a daily basis, or as needed to control migraine.
  • the agonist is delivered prior to, during, and/or after the migraine episode , again as needed to control migraines.
  • delivery of the triptan agonist transdermally using the apparatus described herein provides beneficial pharmacokinetics, as evidenced by a larger area under the curve and longer blood circulation lifetime, when compared to the same dose administered subcutaneously.
  • the present device in order to facilitate drug transport across the skin barrier, can also be employed in conjunction with a wide variety of iontophoresis or electrorransport systems.
  • Illustrative electrorransport drug delivery systems are disclosed in U.S. Pat. Nos. 5,147,296, 5,080,646, 5,169,382 and 5,169383, the disclosures of which are incorporated by reference herein in their entirety.
  • a microprojection device is formed via photo/chemical etching to have an area of 2 cm 2 , a microprojection density with 320 microprojections/cm 2 , and a projection length of 200 ⁇ m.
  • microprojections are coated with a 25% aqueous solution of sumatriptan at 40 ⁇ 10 ⁇ g per 2 cm 2 array, with a solid coaling limited to the first 100 ⁇ m of the microprojections.
  • the coated microprojection array is attached to a flexible polymeric adhesive backing and then assembled onto a retainer ring. The assembly is then loaded on a reusable impact applicator at the time of application to the HGP.
  • a group of HGP serve as a control and receive a subcutaneous injection of sumatriptan. Blood samples are taken for determination of plasma sumatriptan levels.
  • Another group of HGP receive an intravenous (IV) injection of sumatriptan and blood samples are taken at various times to ascertain the area under the curve (AUC), and to serve as reference to calculate the total amounts absorbed/delivered following subcutaneous or microneedle array administration.
  • IV intravenous
  • AUC area under the curve

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  • Health & Medical Sciences (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un appareil et un procédé d'administration transdermique d'au moins un composé agoniste de la famille du triptane (triptane). L'appareil comprend un élément de microprojection comprenant plusieurs microprojections de perçage du derme, conçu pour percer la couche cornée d'un patient.
PCT/US2008/003772 2007-03-21 2008-03-20 Appareil et procédé d'administration transdermique d'un agoniste de triptane WO2008115586A1 (fr)

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US60/896,161 2007-03-21

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012075209A1 (fr) * 2010-12-02 2012-06-07 Lanco Biosciences, Inc. Administration de triptans par des systèmes de micro-injection
JP2013177376A (ja) * 2012-02-09 2013-09-09 Hisamitsu Pharmaceut Co Inc マイクロニードル用ゾルミトリプタン含有コーティング組成物及びマイクロニードルデバイス
WO2017143345A1 (fr) * 2016-02-19 2017-08-24 Zp Opco, Inc. Procédé pour obtenir rapidement des concentrations thérapeutiques de triptans pour le traitement de migraines
WO2019040063A1 (fr) * 2017-08-23 2019-02-28 Zp Opco, Inc. Procédé d'obtention rapide de concentrations thérapeutiques de zolmitriptan pour le traitement de migraines et de céphalées de horton
US20190070103A1 (en) * 2017-08-23 2019-03-07 Zp Opco, Inc. Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches
US11660265B2 (en) 2018-06-28 2023-05-30 Emergex USA Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches

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* Cited by examiner, † Cited by third party
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US20040028707A1 (en) * 2001-06-29 2004-02-12 Pinkerton Thomas C. Enhanced pharmacokinetic profile of intradermally delivered substances
US20040214861A1 (en) * 2003-03-28 2004-10-28 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitors and 5-HT1B1D antagonists for the treatment and prevention of migraine
US20050137536A1 (en) * 2001-09-28 2005-06-23 Gonnelli Robert R. Microneedle with membrane

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040028707A1 (en) * 2001-06-29 2004-02-12 Pinkerton Thomas C. Enhanced pharmacokinetic profile of intradermally delivered substances
US20050137536A1 (en) * 2001-09-28 2005-06-23 Gonnelli Robert R. Microneedle with membrane
US20040214861A1 (en) * 2003-03-28 2004-10-28 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitors and 5-HT1B1D antagonists for the treatment and prevention of migraine

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012075209A1 (fr) * 2010-12-02 2012-06-07 Lanco Biosciences, Inc. Administration de triptans par des systèmes de micro-injection
JP2013177376A (ja) * 2012-02-09 2013-09-09 Hisamitsu Pharmaceut Co Inc マイクロニードル用ゾルミトリプタン含有コーティング組成物及びマイクロニードルデバイス
WO2017143345A1 (fr) * 2016-02-19 2017-08-24 Zp Opco, Inc. Procédé pour obtenir rapidement des concentrations thérapeutiques de triptans pour le traitement de migraines
US9918932B2 (en) 2016-02-19 2018-03-20 Zosano Pharma Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines
US11839683B2 (en) 2016-02-19 2023-12-12 Emergex USA Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines
US11058630B2 (en) 2016-02-19 2021-07-13 Zosano Pharma Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines
JP2021500397A (ja) * 2017-08-23 2021-01-07 ゾサノ・ファーマ・コーポレイションＺｏｓａｎｏ Ｐｈａｒｍａ Ｃｏｒｐｏｒａｔｉｏｎ 片頭痛および群発頭痛の治療に適したゾルミトリプタン治療濃度を迅速に得る方法
US20190070103A1 (en) * 2017-08-23 2019-03-07 Zp Opco, Inc. Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches
AU2017428907B2 (en) * 2017-08-23 2021-12-16 Zosano Pharma Corporation Method of rapidly achieving therapeutic concentrations of zolmitriptan for treatment of migraines and cluster headaches
JP7219384B2 (ja) 2017-08-23 2023-02-08 エマージェクス ユーエスエイ コーポレーション 片頭痛および群発頭痛の治療に適したゾルミトリプタン治療濃度を迅速に得る方法
US11660264B2 (en) 2017-08-23 2023-05-30 Emergex USA Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches
WO2019040063A1 (fr) * 2017-08-23 2019-02-28 Zp Opco, Inc. Procédé d'obtention rapide de concentrations thérapeutiques de zolmitriptan pour le traitement de migraines et de céphalées de horton
JP7602732B2 (ja) 2017-08-23 2024-12-19 ガイルデン ユーエスエイ コーポレーション 片頭痛および群発頭痛の治療に適したゾルミトリプタン治療濃度を迅速に得る方法
US11660265B2 (en) 2018-06-28 2023-05-30 Emergex USA Corporation Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches

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