WO2008097664A1 - Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile - Google Patents
Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile Download PDFInfo
- Publication number
- WO2008097664A1 WO2008097664A1 PCT/US2008/001829 US2008001829W WO2008097664A1 WO 2008097664 A1 WO2008097664 A1 WO 2008097664A1 US 2008001829 W US2008001829 W US 2008001829W WO 2008097664 A1 WO2008097664 A1 WO 2008097664A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dhe
- administered
- max
- administration
- less
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- 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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
-
- 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
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to methods for treatment of migraine.
- the present invention relates to methods for treatment of migraine and related symptoms while minimizing side-effects, or adverse effects, associated with administration of medications that alleviate migraine symptoms.
- the invention relates to pharmaceutical 'compositions containing dihydroergotamine (DHE) and methods in which these pharmaceutical compositions are administered to patients for the treatment of migraine headaches without side effects.
- DHE dihydroergotamine
- Migraine is the most common headache causing patients to consult a physician.
- approximately 28 million people in the United States aged 12 and older (approximately 13 percent of the population) suffer from headaches that fit the medical definition of migraine established by the International Headache Society. This corresponds to one migraine sufferer in every four U.S. households.
- the percentage of patients whose headaches fit the medical definition of migraine who are being diagnosed has increased compared to a decade ago.
- a majority of all migraine sufferers (53 percent) characterize their pain as causing either severe impairment or forcing them to retreat to their beds sometimes for days at a time.
- physicians approach the treatment of migraine in the past 10 years There have been no dramatic changes in the way physicians approach the treatment of migraine in the past 10 years. (Lipton RB et al., Headache. (2001) 41 :638-645, 646- 657)
- a three-item Identification of Migraine (ID Migraine) clinical decision rule for the diagnosis of migraine has been developed.
- ID Migraine A three-item Identification of Migraine (ID Migraine) clinical decision rule for the diagnosis of migraine has been developed.
- a migraine is a type of primary headache that some people get repeatedly over time. Migraines are different from other headaches because they occur with symptoms such as nausea, vomiting, or sensitivity to light. In most people, a throbbing pain is felt only on one side of the head. Migraines are classified as either "with aura” or "without aura.”
- An aura is a group of neurological symptoms, usually vision disturbances that serve as warning sign. Patients who get auras typically see a flash of brightly colored or blinking lights shortly before the headache pain begins. However, most people with migraines do not have such warning signs.
- migraine Multiple humoral agents have been postulated as being the major factor in migraine. These include serotonin, histamine, prostaglandins, platelet factors, endorphins, and vasoactive neuropeptides.
- serotonin histamine
- prostaglandins prostaglandins
- platelet factors platelet factors
- endorphins vasoactive neuropeptides.
- vasoactive neuropeptides The etiology of migraine has been studied by many investigators. Present research no longer fully supports the vasodilator/vasoconstrictor mechanism of vascular headache, i.e., arterial dilation causes pain and constriction equals relief.
- a sterile inflammation possibly occurring in the dura mater, as the causative factor for vascular head pain.
- vasoactive neuropeptides (substance P, calcitonin gene-related peptide, etc.). These agents produce the local inflammation i.e., vasodilation, plasma extravasation, mast cell degranulation which cause transmission of impulses to the brain stem and higher centers which in turn register as head pain (Moskowitz, M. A. (1992) Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol. ScL 13, 307-311).
- Migraine therapy is either prophylactic or symptomatic.
- Prophylactic medication may be selected for a patient having two to four or more headaches per month, if they are severe enough to interfere with daily activities.
- Beta blockers such as propranolol (INDERAL ® ) are the most commonly used.
- Other medications frequently used include serotonin antagonists such as methysergide maleate (SANSERT ® ), calcium channel blockers (VERAPAMIL ® ), amytryptyline (ELAVIL ® ), and ergotamine preparations with belladona alkaloids and phenobarbital.
- ergotamine with caffeine (CAFERGOT ® ) is commonly used.
- Other medications employed for treating migraine include isometheptene mucate (MIDRIN ® ), non-steroidal antiinflammatory drugs (NSAID's such as MOTRIN ® , NAPROXEN ® , etc.), dihydroergotamine and the newer triptans, such as sumatriptan (IMITREX ® ), etc.
- NSAID non-steroidal antiinflammatory drugs
- IMITREX ® sumatriptan
- FIORTNAL WITH CODEINE ® butalbital with codeine
- serotonin agonists are well established for the treatment of migraine headache.
- the serotonin agonists most widely used are the triptans, including sumatriptan, zolmitriptan, naratriptan, rizatriptan, eletriptan, frovatriptan and almotriptan. These compounds bind specifically to serotonin 5-HT I D/I B receptors.
- ergot alkaloids such as ergotamine tartrate (referred to herein as ergotamine) and dihydroergotamine mesylate (also referred to as dihydroergotamine or DHE) are also used to a variety of disease states, including, but not limited to the treatment of acute migraine.
- Ergotamine and DHE have very low rectal, oral, sublingual and intranasal bioavailability (only 2% to 10% of the administered dose reaches the systemic circulation). These administration routes also result in relatively slow onset of therapeutic efficacy, ranging from 45 minutes for intranasal to 2 hours for oral or sublingual delivery. IV administration has high bioavailability and onset of therapeutic efficacy, usually much less than 30 minutes. However, injections are painful, cause local inflammation, reduce compliance, and because administration by IV requires costly clinical supervision, it would be very desirable to administer the ergot alkaloids by pulmonary inhalation.
- Pulmonary inhalation of the ergot alkaloids would minimize metabolism before the drugs can reach the circulation because there is rapid transport from the alveolar epithelium into the capillary circulation and because of the relative absence of mechanisms for metabolism in the lungs. Pulmonary delivery has been demonstrated to result in up to 92% bioavailability in the case of ergotamine tartrate. Pulmonary inhalation administration would also avoid gastrointestinal intolerance typical of migraine medications and minimize the undesirable taste experienced with nasal and sublingual administration due to the bitterness of the ergot alkaloids. Pulmonary inhalation would minimize the reluctance to administer treatment associated with the invasiveness of injection and the cost of clinical supervision. Pulmonary inhalation also would allow for rapid relief from the migraine symptoms, as it would deliver the drug to the systemic circulation as fast as an IV bolus, less than 30 minutes, without the invasive nature of injection.
- DHE Dihydroergotamine
- H. E. 45 ® -Novartis has been administered by intramuscular or intravenous (IV) injection for over 50 years (Belgrade, et al., Neurology 39:590 592 (1989); Winner, Headache 33:471 475 (1993)).
- DHE MIGRANAL ® - Novartis
- DHE is also effective when given subcutaneously (Klapper, et al., Headache 32:21 23 (1992); Winner, et al., Arch. Neurol. 53: 180 184 (1996); and Becker, et al., Headache 36:144 148 (1996)).
- its administration has been associated with an undesirable side effect profile: nausea, emesis, chest tightness and related cardiovascular effects such as blood pressure instability and arterial constriction, have been reported with its use.
- DHE administration is often accompanied by side effects such as nausea, vomiting and chest pain (Winner, et al., Arch. Neurol. 53:180 184 (1996)).
- side effects observed from postmarketing experience in patients receiving D. H. E. 45 ® (dihydroergotamine mesylate) injection, USP include vasospasm, paraesthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, cardiac valvulopathy, and pleural and retroperitoneal fibrosis seen after long-term use of dihydroergotamine.
- At least one side effect nausea, occurs more frequently after intravenous administration than after intramuscular or intranasal administration.
- DHE has been reported to cause nausea in nearly 16% of treated patients (Winner, et al., Arch. Neurol. 53: 80 184 (1996)).
- the currently accepted treatment algorithms for injection or IV use of DHE call for the administration of an antiemetic prior to or concurrent with administration of DHE to prevent nausea.
- Patients with known cardiovascular disease are not qualified to receive DHE treatment.
- DHE is still considered the "gold standard" for treatment of severe migraine, cluster headache, chronic daily headache.
- DHE has a longer duration of action than sumatriptan, so headache recurrence rates are lower with its use.
- Winner P, et al. A double blind study of subcutaneous dihydroergotamine versus subcutaneous sumatriptan in the treatment of acute migraine. Arch Neurol (1996) 53:180-184.)
- the invention relates to a method for rapid treatment of a disease or condition in an individual with a compound that (a) binds to one or more first receptors, wherein binding of the compound to the first receptors alleviates the disease or condition, and (b) binds to one or more second receptors, wherein binding of the compound to the second receptors causes a side effect, the method comprising: administering to the individual an amount of the compound at a rate sufficient to develop a circulating plasma concentration level of the compound such that compound acts as an agonist against the first receptor and provides relief from the disease or condition, wherein the circulating plasma concentration level of the compound remains below a level necessary for binding to the second receptor to cause a side effect.
- the invention relates to a method for rapid treatment of migraine with DHE, while minimizing side effects, the method comprising: dampening the peak plasma concentration (C max ) and slightly delaying the peak such as to avoid saturating the dopaminergic and adrenergic receptors, while achieving sufficient binding to the serotonin receptors to alleviate migraine symptoms within a timeframe that permits rapid resolution of migraine symptoms.
- C max peak plasma concentration
- the invention relates to a method for administering DHE or salts, hydrates, polymorphs, prodrugs, ion pairs and metabolites thereof, to a patient in need thereof, an amount of DHE sufficient to reduce a migraine symptom within a 2 hour period, without inducing side-effects.
- the invention relates to methods for providing an amount of DHE to an individual sufficient to develop a circulating plasma concentration level of DHE effective for DHE to act as an agonist against a serotonin receptor related to alleviating a migraine symptoms, while insufficient for active binding to an adrenergic or dopaminergic receptor related to nausea and other side effects.
- DHE displays reduced ( ⁇ 50%) or absence of ( ⁇ 20%) active binding at dopaminergic receptors such as D 2 . In some embodiments, DHE displays absence of ( ⁇ 20%) active binding at 5-HT 3 receptors. In some embodiments, DHE displays reduced ( ⁇ 60%) or absence of ( ⁇ 20%) active binding at adrenergic receptors.
- the DHE is administered by any method at a rate such that the C max is less than 40,000 pg/ml concentration in the circulating plasma in humans, and the time following administration when the peak plasma concentration is attained (T max ) occurs within 30 minutes after administration.
- C max of DHE is less than 20,000 pg/mL, or less than 15,000 pg/mL, or less than 10,000 pg/mL, or less than 7,500 pg/mL in the circulating plasma.
- T max of DHE is preferably less than 20 minutes, and most preferably 15 minutes in the circulating plasma.
- the C max of DHE administered by a method of the invention is at least 5-fold, 10-fold or 15-fold reduced from the C max of DHE administered by direct or slow bolus intravenous delivery.
- the T max of DHE administered by a method of the invention is at least 1 minute delayed from the T max of DHE administered by direct intravenous delivery, and the AUC (or area of the curve of the concentration of the drug in the systemic circulation versus time) of the drug delivered by the method of the invention is within 75% of the comparable IV delivered dose.
- the DHE formulation is administered to an individual by a breath activated metered dose inhaler, wherein the DHE is administered at a rate such that the peak plasma concentration (C max ) is less than 10,000 pg/ml concentration in the circulating plasma in humans, and the time (T max ) following administration when the peak plasma concentration is attained, is less than 20 minutes after administration, and further wherein the DHE formulation is administered without administering an anti-emetic to the individual.
- C max peak plasma concentration
- T max time following administration when the peak plasma concentration is attained
- administering results in at least partial relief from a migraine syndrome including but not limited to pain, nausea, phonophobia and photophobia, within 30 minutes and sustained relief for 24 hours, but does not result in drug induced nausea, cardiovascular side effects or other adverse effects.
- the at least partial relief from a migraine syndrome is measured by a drop from a IHS score of greater than "0" for a migraine symptom at the time of administration of DHE, to a score of ⁇ 1 at 30, 60, 90 or 120 minutes following administration.
- administration results in peak plasma concentrations of the primary active metabolites, including but not limited to 8-hydroxy dihydroergotamine, at less than 40,000 pg/ml at Cmax.
- C max of the primary metabolites is preferably less than 1,000 pg/mL, more preferably less than 500 pg/mL, and most preferably less than 200 pg/mL in the circulating plasma.
- the Tmax of the primary metabolites is preferably less than 90 minutes, and most preferably 60 minutes in the circulating plasma..
- the method involves administration to the systemic circulation of an unit dose of less than 3.0 mg DHE or salts, hydrates, polymorphs prodrugs, ion pairs and metabolites thereof.
- an unit dose of 1.0 mg is administered.
- the invention also relates to suitable DHE formulations that achieve the desired delivery profile when administered to an individual.
- a DHE formulation may be administered by any mode, including but not limited to, intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, sublingual, buccal, intranasal, oral inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, iontophoresis, transdermal, intraocular, intrathecal, transmucosal, and transdermal delivery.
- the method of administration is by pulmonary inhalation using aerosols, dry powder inhalers, nebulizers, vaporizers, pressurized metered dose inhalers (pMDIs) and the like.
- pMDIs pressurized metered dose inhalers
- a pMDI such as a breath activated metered dose inhaler (for example, TEMPOTM Inhaler from Map Pharmaceuticals, Mountain View, California) is used to administer DHE.
- kits comprising DHE formulations and instructions for use thereof.
- an inhaler device is included.
- the inhaler device is loaded with a DHE formulation.
- the kit comprises one or more unit doses of the DHE formulation.
- the inhaler device is a pMDI such as a breath activated metered dose inhaler (TEMPOTM Inhaler).
- the invention further relates to an inhaler device comprising one or more unit doses of a DHE formulation wherein each unit dose is administered at a rate such that the peak plasma concentration (C max ) is less than 10,000 pg/ml concentration in the circulating plasma in humans, and the time (T max ) following administration when the peak plasma concentration is attained, is less than 30 minutes after administration.
- C max peak plasma concentration
- T max time following administration when the peak plasma concentration is attained
- FIG. 1 shows percentage of subjects obtaining relief from pain with DHE versus placebo.
- FIG. 2 shows pharmacokinetic profiles for achieving pain relief with minimal side effects.
- FIG. 3 shows radioligand receptor binding profile for serotonergic receptor subtypes based on dose and administration route. Less than 20% was classed as inactive binding, "(h)" represents cloned human receptor subtypes.
- FIG. 4 shows radioligand receptor binding profile for adrenergic and dopaminergic receptor subtypes based on dose and administration route. Less than 20% was classed as inactive binding, "(h)” represents cloned human receptor subtypes and "NS" indicates non-specific binding.
- FIG. 5 shows selective agonism at 5-HTi B and 5-HT 2B receptors at various concentrations of DHE.
- FIG. 6 shows currently accepted treatment algorithms for injection or IV administration of DHE.
- FIG. 7 shows geometric mean 8'OH-DHE concentrations over time following administration of DHE by inhalation and intravenous (IV) routes.
- DHE Dihydroergotamine
- the invention relates to a method for administering DHE or salts, hydrates, polymorphs prodrugs, ion pairs and metabolites thereof, to a patient in need thereof, an amount of DHE sufficient to reduce a migraine symptom within a specified period hour period, without inducing side-effects.
- To reduce a migraine symptom within a specified period hour period may involve providing partial relief from at least one migraine syndrome which includes but is not limited to pain, nausea, phonophobia and photophobia, within a period 30, 60, 90, 120 or 180 minutes. Reduction of a migraine symptom further may comprise providing sustained relief for 6, 12, 18, 24 or 36 hours.
- Relief from any of the migraine symptoms is measured by a drop from a IHS score of greater than "0" (score of >1 for pain) at the time of administration of DHE, to a score of ⁇ 1 at 30, 60, 90, 120 or 180 minutes following administration.
- 0 IHS score of greater than "0"
- ⁇ 1 at 30, 60, 90, 120 or 180 minutes following administration.
- freedom from pain (or other severe symptoms) require a reduction in grading of that symptom from an initial >0 result (score of >1 for pain) to 0 at the time point in question.
- To reduce a migraine symptom without inducing side-effects may involve administration of therapeutically effective amounts of DHE not resulting in drug induced nausea, emesis, chest tightness and related cardiovascular effects such as blood pressure instability and arterial constriction, or any other adverse effects known to be associated with treatment of migraine with DHE.
- the invention relates to methods for providing an amount of DHE to an individual sufficient to develop a circulating plasma concentration level of DHE effective for DHE to act as an agonist against a serotonin receptor related to alleviating a migraine symptoms, wherein the C max is attained within a time period (T max ) sufficient for providing partial relief from at least one migraine syndrome including but not limited to pain, nausea, phonophobia and photophobia, within a period 30, 60, 90, 120 or 180 minutes, or providing sustained relief for 6, 12, 18, 24 or 36 hours.
- T max time period
- the C max attained within a time period (T m ax) according to administration methods of this invention are insufficient for active binding of DHE to an adrenergic or dopaminergic receptor and causing nausea and other side effects.
- DHE When binding of DHE to an adrenergic or dopaminergic receptor is insufficient for causing nausea and other side effects, DHE displays reduced (less than 50%) or absence of (20% or less) binding at dopaminergic receptors such as D 2 ; and DHE displays reduced (less than 60%) or absence of (20% or less) binding at adrenergic receptors.
- DHE is administered by any method at a rate such that the C max is less than 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 pg/ml concentration in the circulating plasma in humans, and the time following administration when the peak plasma concentration is attained (T max ) occurs within 10, 15, 20, 30, 45 or 60 minutes after administration.
- administration results in peak plasma concentrations of the primary active metabolites, including but not limited to 8-hydroxy dihydroergotamine, at less than 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 100,000 or 200,000 pg/ml at C max -
- the T max of the primary metabolites is less than 30, 45, 60, 90, or 120 minutes after administration.
- the C max of DHE administered by a method of the invention is at least 5-fold, 10-fold, or 15-fold reduced from the C max of DHE administered by direct intravenous delivery.
- the T max of DHE administered by a method of the invention is at least 1, 2, 5, 10 or 15 minutes delayed from the T max of DHE administered by direct intravenous delivery, and the AUC (or area the curve of the concentration of the drug in the systemic circulation versus time) of the drug delivered by the method of the invention is within 75% of the comparable IV delivered dose.
- the method involves administration of an unit dose comprising about 0.5, 1.0, 2.0, 3.0 or 5.0 mg DHE or salts, hydrates, polymorphs prodrugs, ion pairs and metabolites thereof.
- the invention relates to packaged vials, canisters, ampoules, packs, or patches comprising one or more unit doses of DHE.
- Unit doses may be formulated and packaged in a manner suitable for administration by intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, sublingual, buccal, intranasal, oral inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, iontophoretic, transdermal delivery.
- the doses of DHE are packaged in a manner suitable for intravenous delivery or pulmonary inhalation.
- the invention also relates to suitable solid, liquid or aerosol formulations of DHE that, when administered to a mammal under appropriate conditions, achieve the desired delivery profile defined by AUC, C max and T max values listed above.
- a DHE formulation may be administered by any mode necessary to achieve the desired delivery profile defined by C max and T max values listed above, including but not limited to, by intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, sublingual, buccal, intranasal, oral inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, iontophoretic, transdermal administration.
- kits comprise one or more of an administration device (e.g., syringes and needles, inhalators, etc) and a plurality of unit dosages or a reservoir or cache configured to deliver multiple unit doses of the composition as described above.
- the administration device is loaded with a DHE formulation
- the kit can additionally comprise a carrier or diluent, a case, and instructions for employing the appropriate administration device.
- an inhaler device is included.
- the inhaler device is loaded with a reservoir containing the DHE formulation.
- the kit comprises one or more unit doses of the DHE formulation.
- the inhaler device is a pMDI such as a breath activated metered dose inhaler (TEMPOTM Inhaler).
- DHE Dihydroergotamine
- Dihydroergotamine is a semi-synthetic ergot alkaloid, which has been used in the treatment of migraine since 1946. Due to structural similarities with physiological molecules, DHE has wide ranging pharmacology (Table 1), mediated by effects on biogenic amine receptors — specifically serotonin (5-HT) subtypes, adrenergic ( ⁇ and ⁇ ) subtypes and dopaminergic (D) subtypes).
- Dihydroergotamine is used extensively to treat cluster migraine, pediatric migraine, status migranosis and chronic daily headache, formerly referred to as "transformed" migraine.
- DHE is currently administered orally and intranasally (MIGRANAL ® - Novartis, US5942251, EP0865789A3, and BE1006872A). However, DHE is most often administered by intramuscular/subcutaneous injection or by intravenous injection (D.H.E. 45 -Novartis) in a clinical setting. (Raskin NH, Neurol Clin. 1990 Nov; 8(4):857-65.)
- Dihydroergotamine binds with high affinity to 5-HTi Da and 5-HTi op receptors. It also binds with high affinity to serotonin 5-HT] A , 5-HT 2A , and 5-HT 2 c receptors, noradrenaline ⁇ 2 A, Ot 2 B and (Xi receptors, and dopamine D 2L and D 3 receptors.
- the therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HTi D receptors.
- Two current theories have been proposed to explain the efficacy of 5-HT I D receptor agonists in migraine.
- One theory suggests that activation of 5-HTI D receptors located on intracranial blood vessels, including those on arteriovenous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache.
- the alternative hypothesis suggests that activation of 5-HTi D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.
- dihydroergotamine possesses oxytocic properties.
- the ergot alkaloids are less selective than the triptans when binding to 5-HT I D , 5-HT IA , 5-HT 2A , 5-HT 2C , noradrenaline ⁇ 2A , ⁇ 2 ⁇ , and ⁇ , dopamine D 2 L and D 3 receptors.
- DHE is thought to mediate its effects through 5-HT J B receptors (constriction of intracranial extra-cerebral blood vessels) and 5-HT ]D receptors (inhibition of trigeminal neurotransmission).
- DHE is known to bind specifically to receptors as shown in Table 1.
- Table 1 shows affinities of DHE (measured as IC 50 ) for specific biogenic amine receptors. Potent activity at 5- HTi B and 5-HTi D receptors and wide ranging receptor-binding activity is observed for DHE. (Silberstein, S. D., McCrory, D. C. Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache (2003) 43: 144-166.)
- DHE intramuscular autoinjectors
- DHE in combination with potent analgesics had also been formulated for treatment by intranasal administration (US5756483, EP0689438A1, AU6428894A1, and WO9422445A3).
- Spray or aerosol formulations have also been developed for the sublingual administration of DHE (US20030017994).
- Ergotamine tartrate has been administered by injection, rectally with suppositories and via inhalation with metered dose inhaler (MEDIHALER-ERGOT AMINE ; 3 M Health Care, Northridge, California), but is most commonly administered orally or sublingually.
- metered dose inhaler MEDIHALER-ERGOT AMINE ; 3 M Health Care, Northridge, California
- Powders for inhalation in dry powder inhalation devices using ergotamine tartrate have also been described (US6200293, US6120613, US6183782, US6129905, US6309623, US5619984, US4524769, US5740793, US5875766, US6098619, US6012454, US5972388, US5922306).
- An aqueous aerosol ergotamine tartrate formulation for pulmonary administration has also been described (US5813597).
- the invention is directed to a pharmaceutical composition in unit dose form containing DHE in an amount such that one or more unit doses are effective in the symptomatic treatment of migraine headache when administered to a patient.
- the composition may contain excipients.
- one or more antioxidants may be added. Any salt of DHE may be used but the mesylate salt is preferred.
- formulations may be prepared using methods that are standard in the art (see, e.g., Remington: The Science and Practice of Pharmacy , 21st ed., Lippincott Williams & Wilkins (2005)).
- patients receive a total dosage of between 0.1 and 10.0 mg, preferably 0.5 to 5.0 mg, or more preferably 1.0 - 2.0 mg per migraine attack.
- the dose of the DHE formulation administered to an individual will vary with the particular composition and the method of administration, such as to achieve the necessary biogenic amine receptor binding profile required for treating migraine without triggering side effects or adverse effects.
- unit dosage form refers to a physically discrete unit suitable as unitary dosages for an individual, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
- suitable pharmaceutical carrier diluent, or excipient.
- unit dosage forms can be stored in a suitable packaging in single or multiple unit dosages and may also be further sterilized and sealed.
- Suitable packaging for compositions described herein are known in the art, and include, for example, vials (such as sealed vials), canisters with metering valves, vessels, ampoules, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. These articles of manufacture may further be sterilized and/or sealed.
- compositions may further comprise additional ingredients, for example preservatives, buffers, tonicity agents, antioxidants and stabilizers, nonionic wetting or clarifying agents, viscosity-increasing agents, absorption enhancing agents, and the like.
- additional ingredients for example preservatives, buffers, tonicity agents, antioxidants and stabilizers, nonionic wetting or clarifying agents, viscosity-increasing agents, absorption enhancing agents, and the like.
- Suitable absorption enhancement agents include N-acetylcysteine, polyethylene glycols, caffeine, cyclodextrin, glycerol, alkyl saccharides, lipids, lecithin, dimethylsulfoxide, and the like.
- Suitable preservatives for use in a solution include polyquaternium-1 , benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, disodium edetate, sorbic acid, benzethonium chloride, and the like.
- such preservatives are employed at a level of from 0.001% to 1.0% by weight.
- Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like, in amounts sufficient to maintain the pH at between about pH 6 and pH 8, and preferably, between about pH 7 and pH 7.5.
- Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, and the like, such that the sodium chloride equivalent of the ophthalmic solution is in the range 0.9 plus or minus 0.2%.
- Suitable antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea, caffeine, chromoglycate salts, cyclodextrins and the like.
- Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol.
- Suitable viscosity-increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxmethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose and the like.
- compositions described herein can be administered to an individual (such as human) via various routes, including, for example, intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, intraocular, intrathecal, transmucosal, and transdermal.
- nanoparticles (including protein or carbohydrate nanoparticles, co-formulated with drug) of the inventive compounds can be administered by any acceptable route including, but not limited to, orally, intramuscularly, transdermally, intravenously, through an inhaler or other air borne delivery systems and the like.
- the continuous phase preferably comprises an aqueous solution of tonicity modifiers, buffered to a pH range of about 4 to about 8.5.
- the pH may also be below 7 or below 6.
- the pH of the composition is no less than about 6, including for example no less than about any of 6.5, 7, or 8 (such as about 7.5 or 8).
- the DHE is delivered using inhalation therapy.
- inhalation therapy Many preclinical and clinical studies with inhaled compounds have demonstrated that efficacy can be achieved both within the lungs and systemically. Moreover, there are many advantages associated with pulmonary delivery including rapid onset, the convenience of patient self- administration, the potential for reduced drug side-effects, ease of delivery by inhalation, the elimination of needles, and the like.
- Inhalation aerosols from dry powder inhalers, nebulizers, vaporizers and pressurized metered dose inhalers typically include excipients or solvents to increase stability or deliverability of these drugs in an aerosol form.
- the particle size of the drug aerosols may be controlled to provide the uptake characteristics consistent with the methods of the invention.
- particle sizes are controlled to desirable sizes known by those skilled in the art.
- the drug particles are generated from the bulk drug by attrition processes such as grinding, micronizing, milling, or by multiphase precipitation processes such as spray drying, solution precipitation, , supercritical extraction/precipitation or lyophilization to yield powders that can be dispersed in the propellant to obtain an acceptable particle size for delivery to the lungs.
- Nebulizers generate an aerosol from a liquid, some by breakup of a liquid jet and some by ultrasonic vibration of the liquid with or without a nozzle.
- Liquid formulations are prepared and stored under aseptic or sterile conditions since they can harbor microorganisms. The use of preservatives and unit dose packaging is contemplated. Additionally solvents, detergents and other agents are used to stabilize the drug formulation.
- Pressurized metered dose inhalers are an additional class of aerosol dispensing devices.
- pMDIs package the compound in a canister under pressure with a solvent and propellant mixture, usually chlorofluorocarbons (CFCs,), or hydroflouroalkanes (HFAs).
- a solvent and propellant mixture usually chlorofluorocarbons (CFCs,), or hydroflouroalkanes (HFAs).
- CFCs chlorofluorocarbons
- HFAs hydroflouroalkanes
- WO2005/025506A2 describes suitable, stable formulations of dihydroergotamine, or pharmaceutically acceptable salts thereof, to administer dry powders and propellant suspensions via pulmonary aerosol inhalation or nasal spray inhalation.
- DHE is used as the mesylate salt.
- the DHE powder is generated using supercritical fluid processes which offer significant advantages in the production of DHE particles for inhalation delivery and produce respirable particles of the desired size in a single step.
- the disclosures of US App. Ser. No. 10/572,012 and WO2005/025506A2 are incorporated herein by reference in their entirety.
- the inhaled dosing is carried out with a breath actuated inhaler such as the TempoTM Inhaler (Map Pharmaceuticals, Inc., Mountain View, California).
- the TempoTM Inhaler is a pressurized metered-dose inhaler (pMDI) which addresses limitations of standard pMDI inhalers: inconsistent dosing and drug delivery inefficiency.
- the Tempo Inhaler provides breath actuation, enhancing patient compliance, and efficient, reliable dose-to- dose consistency that is independent of the inhalation flow rate. It achieves these advantages by combining proprietary features such as the breath synchronized trigger and the flow control chamber and dose counter/lockout in a small, easy to use device. These advanced aerodynamic control elements are driven only by the patient's breath, avoiding expensive, power consuming electronics, resulting in an affordable, reliable and disposable platform.
- the current invention teaches a method of administration of DHE that minimizes or eliminates side effects while at the same time achieving a dosing profile sufficient to provide effective and rapid relief from the four primary symptoms of migraine syndrome: pain, nausea, phonophobia and photophobia.
- a very high "spike” in peak plasma concentration was unexpectedly avoided, the side effects of nausea, chest tightness or pain, blood pressure excursions, emesis could be minimized or completely eliminated while still achieving rapid relief from the migraine symptoms.
- Efficacy of a migraine therapy regimen can be evaluated based on primary and secondary endpoints.
- Primary efficacy endpoint may be a pain- free response rate at about 2 hours post-dose.
- Secondary efficacy endpoints examine 3 areas of interest: pain-free response at time points earlier than 2 hours post-dose; non-progression of headache; and impact on normal activities.
- the likely adverse effect profile of DHE is secondary to agonist activity at 5-HTi A , 5- HT 2A , and dopamine D 2 receptors.
- 5-HTi A 5-HT 2A
- dopamine D 2 receptors 5-HTi A receptor binding for all doses and administration routes rules out this receptor as the cause for the differential adverse effect profile, in particular for dizziness.
- 5-HTiA receptors are believed to play a role in DHE-mediated migraine prophylaxis.
- DHE Dihydroergotamine and its metabolite, 8-hydroxy-dihydroergotamine, as 5-HT1 A receptor agonists in the rat brain.
- British Journal of Pharmacology 2003; 139:424-434. DHE has excitatory actions at vascular ⁇ -adrenergic receptors and have agonist activity at constrictor 5-HT 2A receptors. These actions underlie peripheral vasoconstrictor effects, in particular on coronary artery smooth muscle. As such, DHE and related ergot compounds are contraindicated in coronary and peripheral vascular disease. It is notable however that C max binding activity was lower for the higher inhaled (14%) vs. intravenous dosing (83%) at 5-HT 2 A receptors.
- 5-HT 2 B receptors stimulate the NO production in cell lines (Manivet P., et al., PDZ-dependent activation of nitric-oxide synthases by the serotonin 2B receptor. J. Biol. Chem. 2000;275:9324-9331) and relaxation of the pig cerebral artery (Schmuck et al., Eur. J. Neurosci. 1996;8:959-967).
- 5-HT 2B receptorss located on endothelial cells of meningeal blood vessels have been proposed to trigger migraine headache through the formation of NO.
- DHE long half-life of DHE may account for the low rate of headache recurrence at least partially through permanent inhibition of vascular 5-HT 2B - dependent second messengers (NO) via its major active metabolite 8'-OH-DHE.
- NO vascular 5-HT 2B - dependent second messengers
- D2 receptor antagonists i.e. metoclopramide and domperidone
- DHE at IV dose C max levels exhibits 50% receptor binding in D2 assays ( Figure 5) and therefore may result in the clinically reported nausea and dizziness, mediated through agonist activity. Conversely, no binding affinity was reported after inhaled dosing.
- DHE also has minimal binding activity at muscarinic (M) receptors, and thus rules out chemoreceptor trigger zone M receptor-mediated nausea.
- M muscarinic
- the receptor-binding studies described in Examples 2 and 3 may explain the unexpected results from the novel method of treating migraine rapidly with DHE, while minimizing side effects.
- the method dampens the peak plasma concentration (C max ) and slightly delays the peak so as to avoid saturating the dopaminergic and adrenergic receptors, while achieving sufficient binding to the serotonin receptors to have the desired therapeutic effect of treating migraine.
- Example 1 Pharmacokinetic profile of DHE required to achieve pain relief.
- Figure 1 shows the rapid pain relief (within 10 minutes) achieved by administering DHE by a method that achieves the two lower peak plasma concentration profiles shown in Figure 2.
- FIG. 2 shows DHE plasma profiles for 1 mg IV-administered DHE, compared to 6 inhalations (1.22 mg inhaled/fine particle dose), 4 inhalations (0.88 mg inhaled/fine particle dose) and 2 inhalations (0.44 mg inhaled/fine particle dose) of DHE respectively.
- a large plasma spike was observed following IV DHE administration, but not with inhaled delivery of DHE.
- This plasma spike difference (of at least "10" fold) was hypothesized to be associated with the reduced side effect profile, despite smaller differences in AUC between 1 mg IV and 0.88 mg inhaled DHE.
- FIG. 7 shows the plasma profile of the primary metabolite of DHE, 8'-OH Dihydroergotamine, following intravenous and inhalation delivery of DHE.
- a larger plasma spike in 8'-OH Dihydroergotamine was observed following IV DHE administration, but not with inhaled delivery of DHE.
- This plasma spike difference also is hypothesized to be associated with the reduced side effect profile.
- the inhalable administration results in a peak plasma concentration of 8-hydroxy-dihydroergotamine of less than 1,000 pg/ml, preferably less than 500 pg/mL, more preferably less than 200 pg/mL at C max in the circulating plasma.
- the inhalable administration also results in the T max of the primary metabolites (e.g., 8'-OH Dihydroergotamine) to be less than 90 minutes in the circulating plasma.
- Peak Plasma DHE concentrations were determined from plasma samples (LC- MS/MS) following intravenous administration (1 mg) by infusion over 3 minutes, and from plasma samples (LC-MS/MS) following inhaled dosing (0.88 mg and 0.44 mg doses), where doses were given by multiple actuations from an inhaler over a period of 2-4 minutes.
- the inhaled doses represent the expected systemic delivered dose and were estimated from the fine particle dose delivered ex-actuator.
- the observed C max data is presented in Figure 2 for DHE.
- a similar approach was also taken with the primary metabolite, 8'-OH-DHE.
- Table 3 presents in vitro concentrations equivalent to C max . These concentrations were selected for receptor-binding investigations for both DHE and 8'-0H-DHE.
- Radioligand receptor binding assays clearly show that DHE exhibits wide ranging pharmacology at multiple receptor sites. ( Figures 3-5.) For the majority of receptors, DHE achieves significant binding at concentrations equivalent to the IV C max whereas inhaled binding at each dose yields a different profile. In most instances, binding is reduced when non-IV methods are used to administer.
- the dopaminergic receptors Dl and D2 are primarily responsible for nausea and emesis. Concentrations equivalent to the peak plasma spikes (C ma ⁇ ) resulting from the novel administration method that dampened and delayed the peak, as shown in Figure 2, significantly lowered dopaminergic receptor binding, specifically at D2 and Dl, as shown in Figure 4, with the ultimate result of reducing nausea and emesis in the patients.
- Agonists of 5-HT I B subtype receptors are known to be useful in the treatment of migraine and associated symptoms.
- 5-HT 2 B receptors are known to play a triggering role in the onset of migraine.
- Figure 5 shows selective agonism at 5-HTi B and 5-HT 2B receptors following high concentration control (5 ⁇ m), IV at C max (77.6 nM), 4 inhalations at C max (6.25 nM) and at a markedly reduced concentration (0.25 nM).
- 5-HT I B agonism is maintained across all concentrations, indicating high potency, agonism is absent for orally-inhaled DHE at the 5-HT 2B receptors.
- Example 4 Pulmonary Administration of DHE formulations using a TEMPO 1 M Inhaler
- DHE powder is generated using supercritical fluid processes which offer significant advantages in the production of DHE particles for inhalation delivery and produce respirable particles of the desired size in a single step, ⁇ see WO2005/025506A2.
- a property of processed DHE drug substance is that the supercritical fluid processed crystals have remarkably smooth surfaces with low surface energies and therefore tend to disperse effectively in propellant based systems.
- a controlled particle size for the microcrystals was chosen to ensure that a significant fraction of DHE would be deposited in the lung.
- HFA 134a (1,1,1,2-tetrafluoroethane) and HFA 227ea (1,1, 1,2,3, 3,3-heptafluoropropane).
- the finished product contained a propellant blend of 70:30 HFA 227ea:HFA 134a, which was matched to the density of DHE crystals in order to promote pMDI suspension physical stability.
- the resultant suspension did not sediment or cream (which can precipitate irreversible agglomeration) and instead existed as a suspended loosely flocculated system, which is easily dispersed when shaken. Loosely fluctuated systems are well regarded to provide optimal stability for pMDI canisters.
- the formulation contained no ethanol and no surfactants/stabilizing agents.
- TEMPOTM a novel breath activated metered dose inhaler.
- pMDI pressurized metered dose inhalers
- TEMPOTM incorporates four novel features: 1) breath synchronous trigger - can be adjusted for different drugs and target populations to deliver the drug at a specific part of the inspiratory cycle, 2) plume control - an impinging jet to slow down the aerosol plume within the actuator, 3) vortexing chamber - consisting of porous wall, which provides an air cushion to keep the slowed aerosol plume suspended and air inlets on the back wall which drive the slowed aerosol plume into a vortex pattern, maintaining the aerosol in suspension and allowing the particle size to reduce as the HFA propellant evaporates, and 4) dose counter - will determine the doses remaining and prevent more than the intended maximum dose to be administered from any one canister.
- Features 2 and 3 have been shown to dramatically slow the deposition and improve lung deposition of the Emitted Dose (ED), by boosting the Fine Particle Fraction (FPF).
Abstract
Description
Claims
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020157007681A KR20150041804A (en) | 2007-02-11 | 2008-02-11 | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
DK08725456.1T DK2120875T3 (en) | 2007-02-11 | 2008-02-11 | METHOD OF THERAPEUTIC ADMINISTRATION OF DHE TO POSSIBLE QUICK PREVENTION OF MIGRANE AT THE MINIMUM OF THE SIDE EFFECT PROFILE |
KR1020167023885A KR20160106200A (en) | 2007-02-11 | 2008-02-11 | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
AU2008214205A AU2008214205B2 (en) | 2007-02-11 | 2008-02-11 | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
EP08725456.1A EP2120875B1 (en) | 2007-02-11 | 2008-02-11 | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
JP2009549138A JP5825757B2 (en) | 2007-02-11 | 2008-02-11 | Method of therapeutic administration of DHE that allows rapid relief of migraine while minimizing side effect profile |
CA2677838A CA2677838C (en) | 2007-02-11 | 2008-02-11 | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
CN200880011629A CN101677954A (en) | 2007-02-11 | 2008-02-11 | Therapeutic administration DHE is used for alleviating migraine fast and makes the side effect minimized method that distributes |
MX2009008582A MX2009008582A (en) | 2007-02-11 | 2008-02-11 | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile. |
ES08725456.1T ES2691033T3 (en) | 2007-02-11 | 2008-02-11 | Therapeutic administration method of DHE to activate rapid migraine relief while minimizing the profile of side effects |
IL200333A IL200333A (en) | 2007-02-11 | 2009-08-11 | Compound which is dihydroergotamine or a salt, hydrate, polymorph or ion pair thereof for use in a method of treatment of migraine and pharmaceutical composition comprising it |
ZA2009/05628A ZA200905628B (en) | 2007-02-11 | 2009-08-13 | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US90085007P | 2007-02-11 | 2007-02-11 | |
US60/900,850 | 2007-02-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008097664A1 true WO2008097664A1 (en) | 2008-08-14 |
Family
ID=39400937
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2008/001829 WO2008097664A1 (en) | 2007-02-11 | 2008-02-11 | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
Country Status (19)
Country | Link |
---|---|
US (10) | US8148377B2 (en) |
EP (3) | EP2120875B1 (en) |
JP (4) | JP5825757B2 (en) |
KR (3) | KR20090129998A (en) |
CN (2) | CN101677954A (en) |
AU (3) | AU2008214205B2 (en) |
CA (1) | CA2677838C (en) |
CY (1) | CY1116546T1 (en) |
DK (2) | DK2425820T3 (en) |
ES (2) | ES2538082T3 (en) |
HK (1) | HK1204918A1 (en) |
HU (1) | HUE026884T2 (en) |
IL (1) | IL200333A (en) |
MX (1) | MX2009008582A (en) |
PL (1) | PL2425820T3 (en) |
PT (1) | PT2425820E (en) |
SI (1) | SI2425820T1 (en) |
WO (1) | WO2008097664A1 (en) |
ZA (1) | ZA200905628B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3893877A4 (en) * | 2018-12-11 | 2022-09-14 | Satsuma Pharmaceuticals, Inc. | Compositions, devices, and methods for treating or preventing headaches |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8022095B2 (en) * | 1996-08-16 | 2011-09-20 | Pozen, Inc. | Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs |
EP1663159A4 (en) * | 2003-09-10 | 2010-06-09 | Map Pharmaceuticals Inc | Aerosol formulations for delivery of dihydroergotamine to the systemic circulation via pulmonary inhalation |
KR20090129998A (en) | 2007-02-11 | 2009-12-17 | 맵 파마슈티컬스, 인코포레이티드 | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
ES2648196T3 (en) | 2008-02-07 | 2017-12-29 | The University Of Washington | Circumferential spray device |
US20110082150A1 (en) * | 2008-02-11 | 2011-04-07 | Robert Owen Cook | Headache pre-emption by dihydroergotamine treatment during headache Precursor events |
WO2010151804A1 (en) * | 2009-06-26 | 2010-12-29 | Map Pharmaceuticals, Inc. | Administration of dihydroergotamine mesylate particles using a metered dose inhaler |
WO2011079313A1 (en) * | 2009-12-23 | 2011-06-30 | Map Pharmaceuticals, Inc. | Novel ergoline analogs |
AU2012223160B2 (en) | 2011-03-03 | 2016-08-18 | Impel Pharmaceuticals Inc. | Nasal drug delivery device |
CA2835208C (en) | 2011-05-09 | 2019-08-20 | Impel Neuropharma, Inc. | Nozzles for nasal drug delivery |
CN103827113A (en) | 2011-06-23 | 2014-05-28 | Map药物公司 | Novel fluoroergoline analogs |
CA2859173A1 (en) | 2011-12-19 | 2013-06-27 | Map Pharmaceuticals, Inc. | Novel iso-ergoline derivatives |
WO2013095708A1 (en) | 2011-12-21 | 2013-06-27 | Map Pharmaceuticals, Inc. | Novel neuromodulatory compounds |
US9012640B2 (en) | 2012-06-22 | 2015-04-21 | Map Pharmaceuticals, Inc. | Cabergoline derivatives |
CA2895834A1 (en) * | 2012-12-21 | 2014-06-26 | Map Pharmaceuticals, Inc. | Novel ergoline derivatives and uses thereof |
WO2014100353A1 (en) * | 2012-12-21 | 2014-06-26 | Map Pharmaceuticals, Inc. | 8'-hydroxy-dihydroergotamine compounds and compositions |
CA2895816C (en) * | 2012-12-21 | 2021-02-23 | Map Pharmaceuticals, Inc. | 8'-hydroxy-dihydroergotamine compounds and compositions |
CA2909954C (en) | 2013-04-28 | 2021-03-23 | Impel Neuropharma, Inc. | Medical unit dose container |
IL257845B (en) | 2015-09-10 | 2022-07-01 | Impel Neuropharma Inc | In-line nasal delivery device |
WO2019104192A1 (en) | 2017-11-21 | 2019-05-31 | Impel Neuropharma, Inc. | Intranasal device with inlet interface |
EP3713628A4 (en) | 2017-11-21 | 2021-08-18 | Impel Neuropharma Inc. | Intranasal device with dip tube |
BR112020013744A8 (en) * | 2018-01-05 | 2022-10-18 | Impel Neuropharma Inc | DIHYDROERGOTAMINE INTRANASAL DISPENSATION BY PRECISION OLFATIVE DEVICE |
CN111836615A (en) | 2018-01-05 | 2020-10-27 | 英倍尔药业股份有限公司 | Intranasal delivery of olanzapine by precision nasal device |
US11083712B1 (en) | 2018-03-20 | 2021-08-10 | Relevale, Inc. | Low concentration delivery of an ergoline derivative for treatment of a headache |
CN112955134A (en) | 2018-07-19 | 2021-06-11 | 英倍尔药业股份有限公司 | Respiratory delivery of levodopa and dopa decarboxylase inhibitors for the treatment of parkinson's disease |
AU2019418744B2 (en) | 2019-01-03 | 2023-08-03 | Impel Pharmaceuticals Inc. | Nasal drug delivery device |
KR20220010011A (en) | 2019-05-17 | 2022-01-25 | 임펠 뉴로파마 인코포레이티드 | Disposable nasal delivery device |
US11786512B2 (en) | 2019-09-23 | 2023-10-17 | Slayback Pharma Llc | Stable pharmaceutical compositions of dihydroergotamine mesylate |
JP2023507890A (en) * | 2019-12-23 | 2023-02-28 | サイエンチュア, インコーポレイテッド | Dihydroergotamine mesylate formulations and prefilled syringes for their therapeutic delivery |
AU2021207626A1 (en) * | 2020-01-14 | 2022-09-01 | Impel Pharmaceuticals Inc. | Repeated administration of dihydroergotamine for treatment of frequent migraine headaches |
KR20230152083A (en) * | 2021-03-03 | 2023-11-02 | 풀매트릭스 오퍼레이팅 컴퍼니, 인크 | Dihydroergotamine dry powder formulation and method of use |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030091513A1 (en) * | 2001-10-03 | 2003-05-15 | Mohsen Nahed M. | Method to generate water soluble or nonwater soluble in nanoparticulates directly in suspension or dispersion media |
WO2005025506A2 (en) * | 2003-09-10 | 2005-03-24 | Map Pharmaceuticals, Inc. | Aerosol formulations for delivery of dihydroergotamine to the systemic circulation via pulmonary inhalation |
Family Cites Families (358)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US147389A (en) * | 1874-02-10 | Improvement in sawing-machines | ||
US605674A (en) | 1898-06-14 | Combined pencil-case and comb-case | ||
BE555319A (en) | 1956-03-21 | 1900-01-01 | ||
US2885427A (en) | 1956-11-15 | 1959-05-05 | Dow Chemical Co | Fluorination of trichloroethylene |
BE556587A (en) | 1957-01-31 | 1957-04-11 | ||
US2865427A (en) | 1957-05-10 | 1958-12-23 | Robert E Garfield | Sliding automobile seat attachment |
BE629985A (en) | 1962-11-29 | |||
US3320125A (en) | 1964-04-28 | 1967-05-16 | Merck & Co Inc | Inhalation aerosol composition |
US3261748A (en) | 1964-07-17 | 1966-07-19 | Dow Chemical Co | 1,1,1,2-tetrafluoroethane anesthetic |
GB1200886A (en) | 1966-09-23 | 1970-08-05 | Allen & Hanburys Ltd | Phenylaminoethanol derivatives |
GB1429184A (en) | 1972-04-20 | 1976-03-24 | Allen & Hanburys Ltd | Physically anti-inflammatory steroids for use in aerosols |
US4044126A (en) | 1972-04-20 | 1977-08-23 | Allen & Hanburys Limited | Steroidal aerosol compositions and process for the preparation thereof |
US3809294A (en) | 1973-06-27 | 1974-05-07 | American Cyanamid Co | Dispensing lung contacting powdered medicaments |
US3897779A (en) | 1973-06-27 | 1975-08-05 | American Cyanamid Co | Triamcinolone acetonide inhalation therapy |
US3994421A (en) | 1975-09-29 | 1976-11-30 | American Cyanamid Company | Unitary therapeutic aerosol dispenser |
US4405598A (en) | 1976-01-30 | 1983-09-20 | Fisons, Limited | Composition for treating asthma |
FI770215A (en) | 1976-01-30 | 1977-07-31 | Fisons Ltd | |
NL7708731A (en) | 1976-08-13 | 1978-02-15 | Montedison Spa | PROCESS FOR THE PREPARATION OF NEW DRIVER COMPOSITIONS FOR AEROSOLS. |
JPS5325284A (en) | 1976-08-19 | 1978-03-08 | Daikin Ind Ltd | Aerosol composition |
DE2750090A1 (en) | 1976-11-19 | 1978-06-01 | Sandoz Ag | NEW FORMS OF ADMINISTRATION FOR ORGANIC COMPOUNDS |
GB2001334B (en) | 1977-07-19 | 1982-03-03 | Fisons Ltd | Pressurised aerosol formulation |
US4129603A (en) | 1978-02-07 | 1978-12-12 | Imperial Chemical Industries Limited | Manufacture of halogenated compounds |
US4241048A (en) | 1979-05-01 | 1980-12-23 | Bristol-Myers Company | Suspension composition of benzocaine |
IT1121513B (en) | 1979-05-28 | 1986-04-02 | Chiesi Farma Spa | PROCESS FOR THE CONVERSION OF ANTI-INFLAMMATORY STEROID UMO IN A SUSCEPTIBLE FORM OF BEING ADMINISTERED AS AN AEROSOL |
JPS6034925B2 (en) | 1979-07-31 | 1985-08-12 | 帝人株式会社 | Long-acting nasal preparation and its manufacturing method |
US4335121A (en) | 1980-02-15 | 1982-06-15 | Glaxo Group Limited | Androstane carbothioates |
US4352789A (en) | 1980-03-17 | 1982-10-05 | Minnesota Mining And Manufacturing Company | Aerosol compositions containing finely divided solid materials |
WO1981002975A1 (en) | 1980-04-21 | 1981-10-29 | Univ California | Prolonged action drug formulation |
EP0039369B1 (en) | 1980-05-02 | 1983-06-15 | Schering Corporation | Beclomethasone ester solvates, process for their preparation, and preparation of a formulation |
DE3017101C2 (en) | 1980-05-03 | 1983-07-21 | PS Pharma Maschinen und Geräte GmbH, 6800 Mannheim | Coating wall |
FI63672C (en) | 1980-05-19 | 1983-08-10 | Orion Yhtymae Oy | FOERFARANDE FOER FRAMSTAELLNING AV EN BLANDNING AV BEKLOMETASONDIPROPIONAT OCH TRIKLORFLUORMETAN ELLER DIKLORDIFLUORMETAN |
US4311863A (en) | 1980-06-11 | 1982-01-19 | E. I. Du Pont De Nemours & Company | Process for the manufacture of 1,1,1,2-tetrafluoroethane |
GB2078422B (en) | 1980-06-19 | 1983-12-21 | Standard Telephones Cables Ltd | Matrix addressing of display devices |
US4710495A (en) | 1980-07-10 | 1987-12-01 | Otsuka Pharmaceutical Co., Ltd. | Soft steroids having anti-inflammatory activity |
US4423099A (en) | 1980-07-28 | 1983-12-27 | Ciba-Geigy Corporation | Membrane modified hydrogels |
NL8103769A (en) | 1980-08-12 | 1982-03-01 | Glaxo Group Ltd | HETEROCYCLIC COMPOUNDS, PROCESS FOR THE PREPARATION THEREOF, AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS AS AN ACTIVE COMPONENT. |
CY1492A (en) | 1981-07-08 | 1990-02-16 | Draco Ab | Powder inhalator |
EP0072046B1 (en) | 1981-07-24 | 1986-01-15 | FISONS plc | Inhalation drugs, methods for their production and pharmaceutical formulations containing them |
GB2105189B (en) | 1981-07-24 | 1985-03-20 | Fisons Plc | Inhalation drugs |
KR890000664B1 (en) | 1981-10-19 | 1989-03-22 | 바리 안소니 뉴우샘 | Preparation method for micronised be clomethasone dispropionate mono-hydrate |
US4659696A (en) | 1982-04-30 | 1987-04-21 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its nasal or vaginal use |
JPS5921613A (en) | 1982-07-28 | 1984-02-03 | Takeda Chem Ind Ltd | Pharmaceutical preparation for rectum administration |
US4582731A (en) | 1983-09-01 | 1986-04-15 | Battelle Memorial Institute | Supercritical fluid molecular spray film deposition and powder formation |
HU196752B (en) | 1983-12-06 | 1989-01-30 | Glaxo Group Ltd | Process for production of medical compositions containing indole-derivatives and these compounds |
US4514574A (en) | 1984-01-09 | 1985-04-30 | The Dow Chemical Company | Process for separating isomeric mixtures |
JPS60224638A (en) | 1984-04-23 | 1985-11-09 | Kao Corp | Percutaneous absorption promoter and external drug containing same |
JPS60227805A (en) | 1984-04-26 | 1985-11-13 | Mitsubishi Plastics Ind Ltd | Composite diaphragm |
US4629478A (en) | 1984-06-22 | 1986-12-16 | Georgia Tech Research Corporation | Monodisperse aerosol generator |
NO163899C (en) | 1984-07-25 | 1990-08-08 | Hovione Int Ltd | PROCEDURE FOR THE PREPARATION OF DIISOPROPYLETERS SOLVATES OF BECLOMETASON-17,21-DIPROPIONATE. |
GB8432063D0 (en) | 1984-12-19 | 1985-01-30 | Riker Laboratories Inc | Physically modified steroids |
GB8501015D0 (en) | 1985-01-16 | 1985-02-20 | Riker Laboratories Inc | Drug |
US5069911A (en) | 1985-02-05 | 1991-12-03 | Sandoz Ltd. | Pharmaceutical 9,10-dihydrogenated ergot alkaloid containing compositions |
US5192528A (en) * | 1985-05-22 | 1993-03-09 | Liposome Technology, Inc. | Corticosteroid inhalation treatment method |
US5021428A (en) | 1985-07-02 | 1991-06-04 | Merrell Dow Pharmaceuticals Inc. | Novel chemical compounds for the prophylactic treatment of migraine |
US4737384A (en) | 1985-11-01 | 1988-04-12 | Allied Corporation | Deposition of thin films using supercritical fluids |
ES2053549T3 (en) | 1986-08-11 | 1994-08-01 | Innovata Biomed Ltd | A PROCESS FOR THE PREPARATION OF AN APPROPRIATE PHARMACEUTICAL FORMULATION FOR INHALATION. |
US5200413A (en) | 1987-01-05 | 1993-04-06 | Beecham Group P.L.C. | Indolyl carboxamides useful treating migraine, cluster headache, trigeminal neuralgia or emesis |
US4767612A (en) | 1987-01-23 | 1988-08-30 | Rorer Pharmaceutical Corporation | Triamcinolone acetonide for the treatment of allergic rhinitis |
US4851595A (en) | 1987-07-07 | 1989-07-25 | E. I. Du Pont De Nemours And Company | Liquid phase halogen exchange process for the manufacture of 1,1,1,2-tetrafluoroethane |
IT1222509B (en) | 1987-08-17 | 1990-09-05 | Miat Spa | INSUFFLATOR FOR THE ADMINISTRATION OF DRUGS IN THE FORM OF PRE-DOSED POWDER IN OPERATIONS |
US5364863A (en) | 1987-09-08 | 1994-11-15 | Eli Lilly And Company | Specific 5-HT3 antagonists |
US4963557A (en) | 1987-09-28 | 1990-10-16 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
DE3787533T2 (en) | 1987-12-21 | 1994-01-20 | Union Carbide Corp | Use of supercritical liquids as a thinner when spraying coatings. |
DE3744329A1 (en) | 1987-12-28 | 1989-07-06 | Schwarz Pharma Gmbh | METHOD FOR THE PRODUCTION OF AT LEAST ONE ACTIVE AGENT AND A TRAITER COMPRISING PREPARATION |
JPH01176437A (en) | 1987-12-29 | 1989-07-12 | Ono Pharmaceut Co Ltd | Method for rendering organic substance into fine particles |
DE3823378A1 (en) | 1988-07-09 | 1990-01-11 | Knoll Ag | (S) -EMOPAMIL FOR USE IN TREATING MIGRAENE |
US5066522A (en) | 1988-07-14 | 1991-11-19 | Union Carbide Chemicals And Plastics Technology Corporation | Supercritical fluids as diluents in liquid spray applications of adhesives |
US5206268A (en) | 1988-08-16 | 1993-04-27 | Burroughs Wellcome Co. | Medicaments |
GB8820398D0 (en) | 1988-08-27 | 1988-09-28 | Fisons Plc | Pharmaceutical formulation |
AU624421B2 (en) | 1988-10-05 | 1992-06-11 | Pharmacia & Upjohn Company | Finely divided solid crystalline powders via precipitation into an anti-solvent |
US5707634A (en) | 1988-10-05 | 1998-01-13 | Pharmacia & Upjohn Company | Finely divided solid crystalline powders via precipitation into an anti-solvent |
US5225183A (en) | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
GB8828477D0 (en) | 1988-12-06 | 1989-01-05 | Riker Laboratories Inc | Medical aerosol formulations |
US5766573A (en) | 1988-12-06 | 1998-06-16 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
GB8828544D0 (en) | 1988-12-07 | 1989-01-11 | Ici Plc | Chemical process |
GB8900267D0 (en) | 1989-01-06 | 1989-03-08 | Riker Laboratories Inc | Narcotic analgesic formulations and apparatus containing same |
US5011678A (en) | 1989-02-01 | 1991-04-30 | California Biotechnology Inc. | Composition and method for administration of pharmaceutically active substances |
DE3905726A1 (en) | 1989-02-24 | 1990-08-30 | Hoechst Ag | COMPRESSED GAS PACKING AND DRIVING AGENT FOR AEROSOLS |
GB8904370D0 (en) | 1989-02-25 | 1989-04-12 | Cosmas Damian Ltd | Liquid delivery compositions |
SE466684B (en) | 1989-03-07 | 1992-03-23 | Draco Ab | DEVICE INHALATOR AND PROCEDURE TO REGISTER WITH THE DEVICE INHALATOR MEDICATION |
GB8908250D0 (en) | 1989-04-12 | 1989-05-24 | Fisons Plc | Formulations |
GB8909891D0 (en) | 1989-04-28 | 1989-06-14 | Riker Laboratories Inc | Device |
ES2087911T3 (en) | 1989-04-28 | 1996-08-01 | Riker Laboratories Inc | DRY DUST INHALATION DEVICE. |
US4945119A (en) | 1989-05-10 | 1990-07-31 | The Dow Chemical Company | Foaming system for rigid urethane and isocyanurate foams |
US4940171A (en) | 1989-05-18 | 1990-07-10 | Gilroy Gordon C | Aerosol package having compressed gas propellant and vapor tap of minute size |
US5176878A (en) | 1989-05-23 | 1993-01-05 | Teledyne Industries, Inc. | Zirconium-hafnium separation process |
AU633584B2 (en) | 1989-06-15 | 1993-02-04 | Tokyo Tanabe Company Limited | Aerosols of pyrido(1,2-a)pyrimidine compounds |
US5232707A (en) | 1989-07-10 | 1993-08-03 | Syntex (U.S.A.) Inc. | Solvent extraction process |
US4916125A (en) | 1989-07-11 | 1990-04-10 | Sandoz Ltd. | Method of treating migraine |
US5130137A (en) | 1989-08-09 | 1992-07-14 | The General Hospital Corporation | Continuous delivery of luteinizing hormone releasing hormone compositions in combination with sex steroid delivery for use in treating benign ovarian secretory disorders |
WO1991002645A1 (en) | 1989-08-18 | 1991-03-07 | Foster-Miller, Inc. | Vessel construction |
GB8918879D0 (en) | 1989-08-18 | 1989-09-27 | Danbiosyst Uk | Pharmaceutical compositions |
US5225163A (en) | 1989-08-18 | 1993-07-06 | Angenics, Inc. | Reaction apparatus employing gravitational flow |
US5238920A (en) | 1989-08-22 | 1993-08-24 | Abbott Laboratories | Pulmonary surfactant protein fragments |
US5270305A (en) | 1989-09-08 | 1993-12-14 | Glaxo Group Limited | Medicaments |
GB2235627B (en) | 1989-09-08 | 1993-09-01 | Glaxo Group Ltd | Inhalation medicaments for treating respiratory disorders |
GB8921222D0 (en) | 1989-09-20 | 1989-11-08 | Riker Laboratories Inc | Medicinal aerosol formulations |
US5178878A (en) | 1989-10-02 | 1993-01-12 | Cima Labs, Inc. | Effervescent dosage form with microparticles |
US5223264A (en) | 1989-10-02 | 1993-06-29 | Cima Labs, Inc. | Pediatric effervescent dosage form |
US5106659A (en) | 1989-10-04 | 1992-04-21 | Nordson Corporation | Method and apparatus for spraying a liquid coating containing supercritical fluid or liquified gas |
US5439670A (en) | 1989-11-28 | 1995-08-08 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
GB9001635D0 (en) | 1990-01-24 | 1990-03-21 | Ganderton David | Aerosol carriers |
US5376386A (en) | 1990-01-24 | 1994-12-27 | British Technology Group Limited | Aerosol carriers |
DE4003270A1 (en) | 1990-02-03 | 1991-08-08 | Boehringer Ingelheim Kg | NEW SPEED GASES AND THEIR USE IN MEDICINE PREPARATIONS |
IL97065A (en) | 1990-02-02 | 1994-01-25 | Fisons Plc | Aerosol propellant compositions |
DE4003272A1 (en) | 1990-02-03 | 1991-08-08 | Boehringer Ingelheim Kg | NEW GAS MIXTURES AND THEIR USE IN MEDICINE PREPARATIONS |
DE4004904A1 (en) | 1990-02-16 | 1990-09-13 | Gerhard Brendel | DRUM APPLICATOR |
US5118494A (en) | 1990-03-23 | 1992-06-02 | Minnesota Mining And Manufacturing Company | Use of soluble fluorosurfactants for the preparation of metered-dose aerosol formulations |
CA2077354A1 (en) | 1990-03-23 | 1991-09-24 | Minnesota Mining And Manufacturing Company | Use of soluble fluorosurfactants for the preparation of metered-dose aerosol formulations |
US4970093A (en) | 1990-04-12 | 1990-11-13 | University Of Colorado Foundation | Chemical deposition methods using supercritical fluid solutions |
US5123924A (en) * | 1990-04-25 | 1992-06-23 | Spire Corporation | Surgical implants and method |
JP3122671B2 (en) | 1990-05-23 | 2001-01-09 | 協和醗酵工業株式会社 | Heterocyclic compounds |
SK281621B6 (en) | 1990-06-07 | 2001-05-10 | Astrazeneca Ab | Therapeutic heterocyclic compounds |
EP0461930B1 (en) | 1990-06-15 | 1995-09-13 | Merck & Co. Inc. | A crystallization method to improve crystal structure and size |
US5273579A (en) | 1990-06-19 | 1993-12-28 | Mitsubishi Mining And Cement Co., Ltd. | Quick setting compositions |
CA2020018A1 (en) | 1990-06-27 | 1991-12-28 | Don L. Simmons | Method and composition for treating the migraine complex |
CA2086096A1 (en) | 1990-06-27 | 1991-12-28 | Robert A. Moris | Use of soluble fluorosurfactants for the preparation of metered-dose aerosol formulations |
US5126123A (en) | 1990-06-28 | 1992-06-30 | Glaxo, Inc. | Aerosol drug formulations |
AU649702B2 (en) | 1990-06-28 | 1994-06-02 | Glaxo Inc. | Aerosol drug formulations |
EP0536235B1 (en) | 1990-06-29 | 1997-01-22 | FISONS plc | Pressurised aerosol compositions |
ATE187839T1 (en) | 1990-06-29 | 2000-01-15 | Sony Corp | RECORDING/REPRODUCTION SYSTEM FOR A MAGNETO-OPTICAL DISC |
GB9017155D0 (en) | 1990-08-03 | 1990-09-19 | Ici Plc | Spray drying |
US5230884A (en) | 1990-09-11 | 1993-07-27 | University Of Wales College Of Cardiff | Aerosol formulations including proteins and peptides solubilized in reverse micelles and process for making the aerosol formulations |
US5292499A (en) | 1990-09-11 | 1994-03-08 | University Of Wales College Of Cardiff | Method of preparing medical aerosol formulations including drug dissolved in reverse micelles |
MX9203481A (en) | 1990-10-18 | 1992-07-01 | Minnesota Mining & Mfg | FORMULATIONS. |
DE69105212T2 (en) | 1990-10-18 | 1995-03-23 | Minnesota Mining & Mfg | AEROSOL PREPARATION CONTAINING BECLOMETASON 17.21 DIPROPIONATE. |
GB9024366D0 (en) | 1990-11-09 | 1991-01-02 | Glaxo Group Ltd | Medicaments |
US5919435A (en) | 1990-11-09 | 1999-07-06 | Glaxo Group Limited | Aerosol formulation containing a particulate medicament |
GB9024365D0 (en) | 1990-11-09 | 1991-01-02 | Glaxo Group Ltd | Medicaments |
US5254755A (en) | 1990-12-04 | 1993-10-19 | Allied-Signal Inc. | Partially fluorinated alkanols having a tertiary structure |
DE4118230A1 (en) | 1990-12-20 | 1992-06-25 | Bayer Ag | METHOD OF ISOLATING POLYMERS FROM THEIR SOLVENTS WITH CARBON DIOXIDE-CONTAINING LIQUIDS |
US6006745A (en) | 1990-12-21 | 1999-12-28 | Minnesota Mining And Manufacturing Company | Device for delivering an aerosol |
US5290539A (en) | 1990-12-21 | 1994-03-01 | Minnesota Mining And Manufacturing Company | Device for delivering an aerosol |
DE4041563A1 (en) | 1990-12-22 | 1992-06-25 | Sanol Arznei Schwarz Gmbh | METHOD FOR PRODUCING ACTIVE MICROPARTICLES FROM HYDROLYTICALLY DEGRADABLE POLYMERS |
US5317103A (en) | 1991-01-15 | 1994-05-31 | Merck Sharp & Dohme Limited | Indole-substituted five-membered heteroaromatic compounds as 5-HT1 agonists |
US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
US5190029A (en) | 1991-02-14 | 1993-03-02 | Virginia Commonwealth University | Formulation for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content |
US5182097A (en) | 1991-02-14 | 1993-01-26 | Virginia Commonwealth University | Formulations for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content |
EP0504112A3 (en) | 1991-03-14 | 1993-04-21 | Ciba-Geigy Ag | Pharmaceutical aerosol formulations |
US5186164A (en) | 1991-03-15 | 1993-02-16 | Puthalath Raghuprasad | Mist inhaler |
US5182040A (en) | 1991-03-28 | 1993-01-26 | E. I. Du Pont De Nemours And Company | Azeotropic and azeotrope-like compositions of 1,1,2,2-tetrafluoroethane |
GB9107628D0 (en) | 1991-04-10 | 1991-05-29 | Moonbrook Limited | Preparation of diagnostic agents |
US5491148A (en) | 1991-04-26 | 1996-02-13 | Syntex (U.S.A.) Inc. | Isoquinolinone and dihydroisoquinolinone 5-HT3 receptor antagonists |
DE4117751A1 (en) | 1991-05-30 | 1992-12-03 | Bayer Ag | METHOD FOR INSULATING POLYCARBONATES |
ES2158911T5 (en) | 1991-06-10 | 2009-12-09 | Schering Corporation | FORMULATIONS IN AEROSOL WITHOUT CHLOROFLUOROCARBONOS. |
DE69231991T2 (en) | 1991-06-10 | 2002-04-04 | Schering Corp | Chlorofluorocarbon free aerosol formulations |
AU2178392A (en) | 1991-06-12 | 1993-01-12 | Minnesota Mining And Manufacturing Company | Albuterol sulfate suspension aerosol formulations |
GB9113802D0 (en) | 1991-06-26 | 1991-08-14 | Smithkline Beecham Plc | Medicaments |
ATE359842T1 (en) | 1991-07-02 | 2007-05-15 | Nektar Therapeutics | DISPENSING DEVICE FOR MIST-FORMED MEDICATIONS |
US5464632C1 (en) | 1991-07-22 | 2001-02-20 | Prographarm Lab | Rapidly disintegratable multiparticular tablet |
US6123924A (en) | 1991-09-25 | 2000-09-26 | Fisons Plc | Pressurized aerosol inhalation compositions |
NZ244439A (en) | 1991-09-25 | 1994-01-26 | Fisons Plc | Pressurised aerosol compositions comprising hydrofluoroalkane, dispersed |
US6063910A (en) | 1991-11-14 | 2000-05-16 | The Trustees Of Princeton University | Preparation of protein microparticles by supercritical fluid precipitation |
US5916540A (en) | 1994-10-24 | 1999-06-29 | Glaxo Group Limited | Aerosol formulations containing P134A and/or P227 and particulate medicament |
JP3280974B2 (en) | 1991-12-12 | 2002-05-13 | グラクソ、グループ、リミテッド | Medicine |
CA2125666C (en) | 1991-12-12 | 2002-07-16 | Rachel Ann Akehurst | Medicaments |
IL104068A (en) | 1991-12-12 | 1998-10-30 | Glaxo Group Ltd | Surfactant-free pharmaceutical aerosol formulation comprising 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n- propane as propellant |
US5683676A (en) | 1991-12-12 | 1997-11-04 | Glaxo Group Limited | Canister containing aerosol formulations containing P134a and particulate medicaments |
US5736124A (en) | 1991-12-12 | 1998-04-07 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicament |
US5658549A (en) | 1991-12-12 | 1997-08-19 | Glaxo Group Limited | Aerosol formulations containing propellant 134a and fluticasone propionate |
US5674471A (en) | 1991-12-12 | 1997-10-07 | Glaxo Group Limited | Aerosol formulations containing P134a and salbutamol |
US5744123A (en) | 1991-12-12 | 1998-04-28 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicaments |
NZ246421A (en) | 1991-12-18 | 1996-05-28 | Minnesota Mining & Mfg | Aerosol formulation containing a drug and a propellant and which is substantially free of surfactant |
CA2084531A1 (en) | 1991-12-19 | 1993-06-20 | David W. Smith | Antimigraine 4-pyrimidinyl and pyridinyl derivatives of indol-3yl-alkyl piperazines |
GB9200148D0 (en) | 1992-01-06 | 1992-02-26 | Minnesota Mining & Mfg | Aerosol valves |
US5320094A (en) | 1992-01-10 | 1994-06-14 | The Johns Hopkins University | Method of administering insulin |
US5202110A (en) | 1992-01-22 | 1993-04-13 | Virginia Commonwealth University | Formulations for delivery of beclomethasone diproprionate by metered dose inhalers containing no chlorofluorocarbon propellants |
GB9202519D0 (en) | 1992-02-06 | 1992-03-25 | Glaxo Group Ltd | Medicaments |
US5196575A (en) | 1992-02-19 | 1993-03-23 | Hoechst Celanese Corp. | Supercritical separation of isomers of functional organic compounds at moderate conditions |
US5639441A (en) | 1992-03-06 | 1997-06-17 | Board Of Regents Of University Of Colorado | Methods for fine particle formation |
US5242949A (en) | 1992-03-13 | 1993-09-07 | Rugby-Darby Group Companies, Inc. | Treating classic migraine |
JPH05280282A (en) | 1992-03-31 | 1993-10-26 | Kubota Corp | Device for drawing buried pipe underground |
EP0611567B1 (en) | 1992-06-12 | 2002-08-28 | Teijin Limited | Ultrafine powder for inhalation and production thereof |
US5376359A (en) | 1992-07-07 | 1994-12-27 | Glaxo, Inc. | Method of stabilizing aerosol formulations |
MX9304585A (en) | 1992-07-31 | 1994-03-31 | Glaxo Group Ltd | PHARMACEUTICAL FORMULATION IN AEROSOL, CAN SUITABLE TO RELEASE THE FORMULATION AND INHALER OF DOSE DOSE THAT COMPRISES THE CAN. |
US5833950A (en) | 1992-07-31 | 1998-11-10 | Glaxo Group Limited | Aerosol formulations containing beclomethasone dipropionate-1, 1, 1, 2-tetrafluoroethane solvate |
US5314682A (en) | 1992-09-21 | 1994-05-24 | Great Lakes Chemical Corp. | Ozone friendly sterilant mixture |
DE69332105T2 (en) | 1992-09-29 | 2003-03-06 | Inhale Therapeutic Systems San | PULMONAL DELIVERY OF ACTIVE FRAGMENT OF PARATHORMON |
WO1994008599A1 (en) | 1992-10-14 | 1994-04-28 | The Regents Of The University Of Colorado | Ion-pairing of drugs for improved efficacy and delivery |
AU678788B2 (en) | 1992-11-02 | 1997-06-12 | Ferro Corporation | Method of preparing coating materials |
GB9226474D0 (en) | 1992-12-18 | 1993-02-10 | Ici Plc | Production of particulate materials |
DK154092D0 (en) | 1992-12-23 | 1992-12-23 | Neurosearch As | IMIDAZOLE COMPOUNDS, THEIR PREPARATION AND USE |
US5364838A (en) | 1993-01-29 | 1994-11-15 | Miris Medical Corporation | Method of administration of insulin |
US5354934A (en) | 1993-02-04 | 1994-10-11 | Amgen Inc. | Pulmonary administration of erythropoietin |
DE59308043D1 (en) | 1993-02-24 | 1998-02-26 | Sulzer Chemtech Ag | Purification of salt-laden wastewater by wet oxidation under supercritical conditions |
US6162234A (en) | 1993-03-23 | 2000-12-19 | Freedland; Yosef | Adjustable button cinch anchor orthopedic fastener |
PT689438E (en) | 1993-03-26 | 2003-10-31 | Franciscus Wilhelmus He Merkus | PHARMACEUTICAL COMPOSITIONS FOR INTROMASSAL ADMINISTRATION OF APOMORPHINE |
BE1006872A6 (en) | 1993-03-26 | 1995-01-10 | Merkus Franciscus W H M | Nasal pharmaceutical preparations with di-hydro-ergotamine (DHE) |
US5492688A (en) | 1993-04-28 | 1996-02-20 | The Center For Innovative Technology | Metered dose inhaler fomulations which include the ozone-friendly propellant HFC 134a and a pharmaceutically acceptable suspending, solubilizing, wetting, emulsifying or lubricating agent |
IL105658A (en) | 1993-05-11 | 1995-10-31 | Ultrasonic Dryer Ltd | Spray drying system |
TW402506B (en) | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
DE4322181A1 (en) | 1993-06-29 | 1995-01-12 | Hottinger Adolf Masch | Device and method for gripping a foundry core, in particular a sole core |
GB9313642D0 (en) | 1993-07-01 | 1993-08-18 | Glaxo Group Ltd | Method and apparatus for the formation of particles |
GB9313650D0 (en) | 1993-07-01 | 1993-08-18 | Glaxo Group Ltd | Method and apparatus for the formation of particles |
JP3750872B2 (en) | 1993-07-14 | 2006-03-01 | 株式会社小松製作所 | Supercharger for vehicle engine and control method thereof |
EP0728037B1 (en) | 1993-11-08 | 1999-01-13 | The Gillette Company | Method of forming particles using a supercritical fluid, aerogel particles formed thereby, and antiperspirants containing aerogel particles |
EP0655237A1 (en) | 1993-11-27 | 1995-05-31 | Hoechst Aktiengesellschaft | Medicinal aerosol formulation |
IT1265473B1 (en) | 1993-12-30 | 1996-11-22 | Otefal Srl | PROCEDURE FOR THE PRODUCTION OF POWDERS WITH CONTROLLED GRANULOMETRY AND PRODUCT IN POWDER SO OBTAINED |
US5468768A (en) | 1994-01-06 | 1995-11-21 | Bristol-Myers Squibb Company | Antimigraine derivatives of indolylcycloalkanylamines |
US5595761A (en) | 1994-01-27 | 1997-01-21 | The Board Of Regents Of The University Of Oklahoma | Particulate support matrix for making a rapidly dissolving tablet |
US5635210A (en) | 1994-02-03 | 1997-06-03 | The Board Of Regents Of The University Of Oklahoma | Method of making a rapidly dissolving tablet |
SI9400079B (en) | 1994-02-15 | 2003-02-28 | Dr. Weidner Eckhard, Dipl. Ing. | Method and device for extraction and fractionation of small particles from solutions saturated with gas |
MX9603936A (en) | 1994-03-07 | 1997-05-31 | Inhale Therapeutic Syst | Methods and compositions for pulmonary delivery of insulin. |
GB9404945D0 (en) | 1994-03-15 | 1994-04-27 | Glaxo Group Ltd | Pharmaceutical composition |
US5508023A (en) | 1994-04-11 | 1996-04-16 | The Center For Innovative Technology | Pharmaceutically acceptable agents for solubilizing, wetting, emulsifying, or lubricating in metered dose inhaler formulations which use HFC-227 propellant |
AU696387B2 (en) | 1994-05-18 | 1998-09-10 | Inhale Therapeutic Systems, Inc. | Methods and compositions for the dry powder formulation of interferons |
JPH0817132A (en) | 1994-06-30 | 1996-01-19 | Rohm Co Ltd | Reproducing apparatus of disc-type information recording medium |
GB9413202D0 (en) | 1994-06-30 | 1994-08-24 | Univ Bradford | Method and apparatus for the formation of particles |
DE4425255A1 (en) | 1994-07-16 | 1996-01-18 | Asta Medica Ag | Formulation for inhalation application |
US6290991B1 (en) | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
US5560543A (en) | 1994-09-19 | 1996-10-01 | Board Of Regents, The University Of Texas System | Heat-resistant broad-bandwidth liquid droplet generators |
GB9419536D0 (en) | 1994-09-28 | 1994-11-16 | Glaxo Inc | Medicaments |
US6117455A (en) | 1994-09-30 | 2000-09-12 | Takeda Chemical Industries, Ltd. | Sustained-release microcapsule of amorphous water-soluble pharmaceutical active agent |
DE4438978A1 (en) | 1994-10-31 | 1996-05-02 | Helmut Wurzer | Electrosurgical unit and method for its operation |
DE59509057D1 (en) | 1994-11-07 | 2001-04-05 | Eupec Gmbh & Co Kg | Bridge module |
US5693609A (en) | 1994-11-17 | 1997-12-02 | Eli Lilly And Company | Acylated insulin analogs |
GB9425160D0 (en) | 1994-12-10 | 1995-02-08 | Glaxo Group Ltd | Medicaments |
MX9504934A (en) | 1994-12-12 | 1997-01-31 | Morton Int Inc | Smooth thin film powder coatings. |
GB9426252D0 (en) | 1994-12-24 | 1995-02-22 | Glaxo Group Ltd | Pharmaceutical composition |
US6013245A (en) | 1995-01-26 | 2000-01-11 | Glaxo Group Limited | Aerosol formulation containing beclomethasone dipropionate and 1,1,1,2,3,3,3-heptafluoro-n-propane as propellant |
US5639475A (en) | 1995-02-03 | 1997-06-17 | Eurand America, Incorporated | Effervescent microcapsules |
GEP20002266B (en) | 1995-04-14 | 2000-10-25 | Glaxo Wellcome Inc | Metered Dose Inhaler, the Inhaler System Comprising the Same and Method for Treatment of Respiratory Disturbances |
EP1166811B1 (en) | 1995-04-14 | 2006-12-06 | SmithKline Beecham Corporation | Metered dose inhaler for fluticasone propionate |
WO1996032150A1 (en) | 1995-04-14 | 1996-10-17 | Glaxo Wellcome Inc. | Metered dose inhaler for salmeterol |
DK0820279T3 (en) | 1995-04-14 | 2002-10-07 | Smithkline Beecham Corp | Dosing metered inhaler for Albuterol |
US5607697A (en) | 1995-06-07 | 1997-03-04 | Cima Labs, Incorporated | Taste masking microparticles for oral dosage forms |
CA2234957C (en) | 1995-10-17 | 2006-12-19 | Inge B. Henriksen | Insoluble drug delivery |
US5807578A (en) | 1995-11-22 | 1998-09-15 | Lab Pharmaceutical Research International Inc. | Fast-melt tablet and method of making same |
GB9526392D0 (en) | 1995-12-22 | 1996-02-21 | Glaxo Group Ltd | Medicaments |
AU709384B2 (en) | 1996-03-01 | 1999-08-26 | University Of Kansas, The | Methods and apparatus for particle precipitation and coating using near-critical and supercritical antisolvents |
US5874029A (en) | 1996-10-09 | 1999-02-23 | The University Of Kansas | Methods for particle micronization and nanonization by recrystallization from organic solutions sprayed into a compressed antisolvent |
GB9606677D0 (en) | 1996-03-29 | 1996-06-05 | Glaxo Wellcome Inc | Process and device |
US5875776A (en) | 1996-04-09 | 1999-03-02 | Vivorx Pharmaceuticals, Inc. | Dry powder inhaler |
US5776573A (en) | 1996-04-16 | 1998-07-07 | Cd Magic, Inc. | Compact disc revitalizer formulations and revitalizer |
US5648004A (en) | 1996-04-19 | 1997-07-15 | Simpson; Claudie | Kit and method to retrofit heating elements for curling iron holder |
DE19617487A1 (en) | 1996-05-02 | 1997-11-06 | Merck Patent Gmbh | Taste improvement of active pharmaceutical ingredients |
US6503480B1 (en) | 1997-05-23 | 2003-01-07 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US5874064A (en) | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US6054488A (en) | 1996-06-11 | 2000-04-25 | 3M Innovative Properties Company | Medicinal aerosol formulations of formoterol |
US6284267B1 (en) | 1996-08-14 | 2001-09-04 | Nutrimed Biotech | Amphiphilic materials and liposome formulations thereof |
WO1998007414A1 (en) | 1996-08-22 | 1998-02-26 | Research Triangle Pharmaceuticals Ltd. | Compositions comprising microparticles of water-insoluble substances and method for preparing same |
US6068832A (en) | 1996-08-29 | 2000-05-30 | Schering Corporation | Chlorofluorocarbon-free mometasone furoate aerosol formulations |
FR2753639B1 (en) | 1996-09-25 | 1998-12-11 | PROCESS FOR THE PREPARATION OF MICROCAPSULES OF ACTIVE MATERIALS COATED WITH A POLYMER AND NOVEL MICROCAPSULES OBTAINED IN PARTICULAR BY THE PROCESS | |
EP1007012A4 (en) | 1996-10-01 | 2006-01-18 | Cima Labs Inc | Taste-masked microcapsule compositions and methods of manufacture |
US5891885A (en) | 1996-10-09 | 1999-04-06 | Algos Pharmaceutical Corporation | Method for treating migraine |
US5813597A (en) | 1996-10-15 | 1998-09-29 | Ethicon Endo-Surgery, Inc. | Dual orientation dispenser carton |
GB9622173D0 (en) | 1996-10-24 | 1996-12-18 | Glaxo Group Ltd | Particulate Products |
US6077539A (en) | 1996-11-12 | 2000-06-20 | Pozen, Inc. | Treatment of migraine headache |
GB9702799D0 (en) | 1997-02-12 | 1997-04-02 | Scherer Corp R P | Process for preparing solid pharmaceutical dosage forms |
IT1291779B1 (en) | 1997-02-17 | 1999-01-21 | Magnetek Spa | PROCEDURE FOR THE REALIZATION OF PRINTED CIRCUITS AND PRINTED CIRCUITS THUS OBTAINED |
GB9703673D0 (en) | 1997-02-21 | 1997-04-09 | Bradford Particle Design Ltd | Method and apparatus for the formation of particles |
US6236747B1 (en) | 1997-02-26 | 2001-05-22 | Acuity Imaging, Llc | System and method for image subtraction for ball and bumped grid array inspection |
US6024981A (en) | 1997-04-16 | 2000-02-15 | Cima Labs Inc. | Rapidly dissolving robust dosage form |
US6129905A (en) | 1997-04-21 | 2000-10-10 | Aeropharm Technology, Inc. | Aerosol formulations containing a sugar as a dispersant |
US5916125A (en) | 1997-05-16 | 1999-06-29 | Allison Engine Company, Inc. | Forced purge wave rotor |
US6120752A (en) | 1997-05-21 | 2000-09-19 | 3M Innovative Properties Company | Medicinal aerosol products containing formulations of ciclesonide and related steroids |
SE9701956D0 (en) | 1997-05-23 | 1997-05-23 | Astra Ab | New composition of matter |
US6315122B1 (en) | 1997-05-29 | 2001-11-13 | Mitsubishi Polyester Film, Llc | Palletless packaging system |
US6236647B1 (en) | 1998-02-24 | 2001-05-22 | Tantivy Communications, Inc. | Dynamic frame size adjustment and selective reject on a multi-link channel to improve effective throughput and bit error rate |
US6200293B1 (en) | 1997-08-27 | 2001-03-13 | Science Incorporated | Fluid delivery device with temperature controlled energy source |
US6309623B1 (en) | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
WO1999017742A2 (en) | 1997-10-03 | 1999-04-15 | Elan Corporation, Plc | Taste masked formulations |
US5954047A (en) | 1997-10-17 | 1999-09-21 | Systemic Pulmonary Development, Ltd. | Methods and apparatus for delivering aerosolized medication |
US6089911A (en) | 1997-12-05 | 2000-07-18 | The Whitaker Corporation | Apparatus and method for mounting a plurality of surface mount contacts |
GB9804379D0 (en) | 1998-03-02 | 1998-04-22 | Bradford Particle Design Ltd | Method of particle formation |
US6120613A (en) | 1998-04-30 | 2000-09-19 | Micell Technologies, Inc. | Carbon dioxide cleaning and separation systems |
SE9801287D0 (en) | 1998-04-14 | 1998-04-14 | Astra Ab | Incorporation of active substances into carrier matrixes |
SE9801288D0 (en) | 1998-04-14 | 1998-04-14 | Astra Ab | Vaccine delivery system and method of production |
GB9808802D0 (en) | 1998-04-24 | 1998-06-24 | Glaxo Group Ltd | Pharmaceutical formulations |
GB9810126D0 (en) | 1998-05-13 | 1998-07-08 | Glaxo Group Ltd | |
GB9810559D0 (en) | 1998-05-15 | 1998-07-15 | Bradford Particle Design Ltd | Method and apparatus for particle formation |
SE9802073D0 (en) | 1998-06-11 | 1998-06-11 | Astra Ab | New use |
CA2336139C (en) | 1998-06-24 | 2008-10-14 | Advanced Inhalation Research, Inc. | Large porous particles emitted from an inhaler |
NZ509328A (en) | 1998-07-24 | 2002-11-26 | Jago Res A | Medicinal aerosol formulations |
SE513162C2 (en) | 1998-07-24 | 2000-07-17 | Allgon Ab | Antenna device |
US6387410B1 (en) | 1998-09-10 | 2002-05-14 | Norton Healthcare Ltd | Anti-inflammatory pharmaceutical formulations |
US6190029B1 (en) | 1998-09-25 | 2001-02-20 | Stanley Electric Co., Ltd. | Headlamp with beam distribution switch mechanism |
US5992306A (en) | 1998-10-15 | 1999-11-30 | Century Machinery Corp. | Structure of a hand holding net basket for frying |
SE9804001D0 (en) | 1998-11-23 | 1998-11-23 | Astra Ab | New process |
SE9804003D0 (en) | 1998-11-23 | 1998-11-23 | Astra Ab | A method of producing drug particles |
CA2351720C (en) | 1998-11-25 | 2006-11-21 | Cima Labs Inc. | Taste masking rapid release coating system |
GB9825883D0 (en) | 1998-11-27 | 1999-01-20 | Aea Technology Plc | Formation of monodisperse particles |
US6390291B1 (en) | 1998-12-18 | 2002-05-21 | Smithkline Beecham Corporation | Method and package for storing a pressurized container containing a drug |
US6119853A (en) | 1998-12-18 | 2000-09-19 | Glaxo Wellcome Inc. | Method and package for storing a pressurized container containing a drug |
CA2323739C (en) | 1999-01-14 | 2008-08-05 | Teijin Limited | Device and method for feeding a constant amount of powder body |
JP4812167B2 (en) | 1999-02-12 | 2011-11-09 | モレキュラー インサイト ファーマスーティカルズ インコーポレイテッド | Drug transport matrix and methods for making and using the same |
SI1165044T1 (en) | 1999-03-26 | 2004-10-31 | Pozen, Inc. | High potency dihydroergotamine compositions |
SE9901667D0 (en) | 1999-05-07 | 1999-05-07 | Astra Ab | Method and device for forming particles |
US6395300B1 (en) | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
US6858199B1 (en) | 2000-06-09 | 2005-02-22 | Advanced Inhalation Research, Inc. | High efficient delivery of a large therapeutic mass aerosol |
GB9915975D0 (en) | 1999-07-07 | 1999-09-08 | Bradford Particle Design Ltd | Method for the formation of particles |
US20020081266A1 (en) | 1999-08-20 | 2002-06-27 | Norton Healthcare Ltd. | Spray dried powders for pulmonary or nasal administration |
US7678364B2 (en) | 1999-08-25 | 2010-03-16 | Alkermes, Inc. | Particles for inhalation having sustained release properties |
GB9920558D0 (en) | 1999-08-31 | 1999-11-03 | Bradford Particle Design Ltd | Methods for particle formation and their products |
WO2001038002A1 (en) | 1999-09-13 | 2001-05-31 | Sheffield Pharmaceuticals, Inc. | Aerosol airflow control system and method |
US6346323B1 (en) | 1999-10-07 | 2002-02-12 | Sig Pack Systems Ag | Multi-layer synthetic film |
US6264981B1 (en) | 1999-10-27 | 2001-07-24 | Anesta Corporation | Oral transmucosal drug dosage using solid solution |
US6367471B1 (en) | 1999-11-01 | 2002-04-09 | Sheffield Pharmaceuticals, Inc. | Internal vortex mechanism for inhaler device |
AU4305101A (en) * | 1999-11-22 | 2001-06-04 | Research Foundation Of The State University Of New York, The | Magnetic nanoparticles for selective therapy |
KR100311975B1 (en) * | 1999-12-16 | 2001-10-17 | 윤종용 | semiconductor device and method for manufacturing the same |
KR20010088139A (en) | 2000-03-10 | 2001-09-26 | 백승헌 | Apparatus and method for displaying lips shape according to taxt data |
PE20011227A1 (en) | 2000-04-17 | 2002-01-07 | Chiesi Farma Spa | PHARMACEUTICAL FORMULATIONS FOR DRY POWDER INHALERS IN THE FORM OF HARD AGGLOMERATES |
GB0011807D0 (en) | 2000-05-16 | 2000-07-05 | Quadrant Holdings Cambridge | Formulation for inhalation |
US6316029B1 (en) | 2000-05-18 | 2001-11-13 | Flak Pharma International, Ltd. | Rapidly disintegrating solid oral dosage form |
US6620351B2 (en) | 2000-05-24 | 2003-09-16 | Auburn University | Method of forming nanoparticles and microparticles of controllable size using supercritical fluids with enhanced mass transfer |
US6451287B1 (en) | 2000-05-26 | 2002-09-17 | Smithkline Beecham Corporation | Fluorinated copolymer surfactants and use thereof in aerosol compositions |
US6656492B2 (en) | 2000-06-30 | 2003-12-02 | Yamanouchi Pharmaceutical Co., Ltd. | Quick disintegrating tablet in buccal cavity and manufacturing method thereof |
FR2812040B1 (en) | 2000-07-18 | 2003-02-07 | Cit Alcatel | MONOBLOCK HOUSING FOR VACUUM PUMP |
US20040137424A1 (en) | 2000-07-24 | 2004-07-15 | Tan Yin Hwee | Nucleic acids and methods for detecting viral infection, uncovering anti-viral drug candidates and determining drug resistance of viral isolates |
US6941569B2 (en) | 2000-08-18 | 2005-09-06 | Hewlett-Packard Development Company, L.P. | System and method utilizing a conductive brush for providing power signals to a cartridge access device |
US6406681B1 (en) | 2000-08-21 | 2002-06-18 | Aeropharm Technology, Inc. | Method of treating a systemic disease |
CA2419623A1 (en) | 2000-08-30 | 2002-03-07 | Lilly Icos Llc | Method for treatment of migraine using pde5 inhibitors |
US6514482B1 (en) | 2000-09-19 | 2003-02-04 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
US6613308B2 (en) | 2000-09-19 | 2003-09-02 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
FR2815540B1 (en) | 2000-10-19 | 2005-06-10 | Separex Sa | PROCESS FOR MANUFACTURING VERY FINE PARTICLES COMPRISING A PRINCIPLE INSERTED IN A HOST MOLECULE |
GB0027357D0 (en) | 2000-11-09 | 2000-12-27 | Bradford Particle Design Plc | Particle formation methods and their products |
US6932861B2 (en) | 2000-11-28 | 2005-08-23 | Fmc Corporation | Edible PGA coating composition |
GB0102075D0 (en) | 2001-01-26 | 2001-03-14 | Astrazeneca Ab | Process |
JP2005503425A (en) | 2001-05-24 | 2005-02-03 | アレックザ モレキュラー デリヴァリー コーポレイション | Delivery of drug ester by the prescribed inhalation route |
US20030198669A1 (en) * | 2001-07-05 | 2003-10-23 | R.T. Alamo Ventures I, Llc | Compositions and methods for rapid dissolving formulations of dihydroergotamine and caffeine for the treatment of migraine |
US20030017175A1 (en) * | 2001-07-05 | 2003-01-23 | R.T. Alamo Ventures I, Inc. | Sublingual administration of dihydroergotamine for the treatment of migraine |
US6685951B2 (en) | 2001-07-05 | 2004-02-03 | R. T. Alamo Ventures I, Inc. | Administration of dihydroergotamine as a sublingual spray or aerosol for the treatment of migraine |
US20030022910A1 (en) | 2001-07-05 | 2003-01-30 | R.T. Alamo Ventures I, Inc. | Compositions and methods for sublingual formulations of dihydroergotamine for the treatment of migraine |
US20030008005A1 (en) * | 2001-07-05 | 2003-01-09 | R.T. Alamo Ventures, Inc. | Sublingual administration of dihydroergotamine for the treatment of migraine |
GB0208742D0 (en) | 2002-04-17 | 2002-05-29 | Bradford Particle Design Ltd | Particulate materials |
TW586963B (en) | 2001-07-20 | 2004-05-11 | Nektar Therapeutics Uk Ltd | Method and apparatus for preparing target substance in particulate form and fluid inlet assembly for said apparatus |
GB0117696D0 (en) | 2001-07-20 | 2001-09-12 | Bradford Particle Design Plc | Particle information |
US20030181462A1 (en) | 2001-08-17 | 2003-09-25 | Boehringer Ingelheim Pharma Kg | Use of BIBN4096 in combination with other antimigraine drugs for the treatment of migraine |
AU2003208761A1 (en) | 2002-02-21 | 2003-09-09 | Amarin Development Ab | A method for releasing nanosized particles of an active substance from a diffusion-controlled pharmaceutical composition for oral use |
AU2003209475A1 (en) | 2002-03-07 | 2003-09-16 | Vectura Limited | Fast melt multiparticulate formulations for oral delivery |
WO2003075829A2 (en) | 2002-03-08 | 2003-09-18 | M/S. Ind-Swift Limited | Tasteless directly compressible fast-dissolving complexes and pharmaceutical formulations thereof |
DE10212564B4 (en) * | 2002-03-12 | 2007-04-19 | Neurobiotec Gmbh | 1-Allyl ergot alkaloid derivatives and their use for the prophylaxis and treatment of migraine |
US7582284B2 (en) | 2002-04-17 | 2009-09-01 | Nektar Therapeutics | Particulate materials |
JP2004184809A (en) | 2002-12-05 | 2004-07-02 | Nitto Denko Corp | Method for manufacturing polarizing plate, polarizing plate, and image display device using the same |
GB0300338D0 (en) | 2003-01-08 | 2003-02-05 | Bradford Particle Design Ltd | Particle formation |
AU2003900081A0 (en) | 2003-01-08 | 2003-01-23 | George Moore | Drilling jig |
GB0300339D0 (en) | 2003-01-08 | 2003-02-05 | Bradford Particle Design Ltd | Particle formation |
GB0304636D0 (en) | 2003-02-28 | 2003-04-02 | Britannia Pharmaceuticals Ltd | Pharmaceutical composition for nasal delivery |
US20060147389A1 (en) * | 2004-04-14 | 2006-07-06 | Vectura Ltd. | Devices and pharmaceutical compositions for enhancing dosing efficiency |
US7354601B2 (en) | 2003-05-08 | 2008-04-08 | Walker Stephen E | Particulate materials |
JP2007516259A (en) | 2003-12-09 | 2007-06-21 | メッドクリスタルフォームズ、エルエルシー | Method for preparing mixed phase co-crystal with activator |
US20070020299A1 (en) | 2003-12-31 | 2007-01-25 | Pipkin James D | Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid |
US20060246070A1 (en) | 2004-09-30 | 2006-11-02 | Heavner George A | Methods and compositions for treating renal cell carcinoma related pathologies |
US20060240043A1 (en) | 2004-10-08 | 2006-10-26 | Meyerson Laurence R | Methods and compositions for treating migraine pain |
WO2006103407A2 (en) | 2005-03-28 | 2006-10-05 | Orexo Ab | New pharmaceutical compositions useful in the treatment of migraine |
US7219664B2 (en) * | 2005-04-28 | 2007-05-22 | Kos Life Sciences, Inc. | Breath actuated inhaler |
EP1906919A4 (en) | 2005-07-15 | 2012-12-26 | Map Pharmaceuticals Inc | Multiple active pharmaceutical ingredients combined in discrete inhalation particles and formulations thereof |
SE530445C2 (en) | 2006-10-23 | 2008-06-10 | Volvo Lastvagnar Ab | Cab suspension system |
EP2117506A2 (en) | 2006-12-13 | 2009-11-18 | Stephen M. Tuel | Methods of making pharmaceutical components for customized drug products |
KR20090129998A (en) * | 2007-02-11 | 2009-12-17 | 맵 파마슈티컬스, 인코포레이티드 | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
GB2448183A (en) | 2007-04-05 | 2008-10-08 | Optinose As | Nasal powder delivery device |
EP2235627A1 (en) | 2007-12-07 | 2010-10-06 | Krass, Maren | Using function calls as compiler directives |
TW200938236A (en) | 2008-03-13 | 2009-09-16 | Fei-Peng Lin | Deodorization material composition, manufacturing method thereof, and deodorization method |
EP2105189A1 (en) | 2008-03-27 | 2009-09-30 | Siemens Aktiengesellschaft | Method and device for separating carbon dioxide from an exhaust gas of a fossil fuel-powered power plant |
EP2829265B1 (en) | 2008-04-28 | 2016-08-24 | Zogenix, Inc. | Novel formulations for treatment of migraine |
CN102089027A (en) * | 2008-07-11 | 2011-06-08 | Map药物公司 | Containers for aerosol drug delivery |
US20110053913A1 (en) * | 2009-06-25 | 2011-03-03 | Khem Jhamandas | Methods and Therapies for Alleviating Pain |
EP2322326A1 (en) | 2009-11-13 | 2011-05-18 | Frederik Daniël Nossbaum | Multifunctional tool |
-
2008
- 2008-02-11 KR KR1020097019032A patent/KR20090129998A/en not_active Application Discontinuation
- 2008-02-11 AU AU2008214205A patent/AU2008214205B2/en active Active
- 2008-02-11 DK DK11191794.4T patent/DK2425820T3/en active
- 2008-02-11 JP JP2009549138A patent/JP5825757B2/en active Active
- 2008-02-11 HU HUE11191794A patent/HUE026884T2/en unknown
- 2008-02-11 KR KR1020157007681A patent/KR20150041804A/en not_active Application Discontinuation
- 2008-02-11 DK DK08725456.1T patent/DK2120875T3/en active
- 2008-02-11 PT PT111917944T patent/PT2425820E/en unknown
- 2008-02-11 KR KR1020167023885A patent/KR20160106200A/en not_active Application Discontinuation
- 2008-02-11 SI SI200831425T patent/SI2425820T1/en unknown
- 2008-02-11 ES ES11191794.4T patent/ES2538082T3/en active Active
- 2008-02-11 EP EP08725456.1A patent/EP2120875B1/en active Active
- 2008-02-11 CN CN200880011629A patent/CN101677954A/en active Pending
- 2008-02-11 ES ES08725456.1T patent/ES2691033T3/en active Active
- 2008-02-11 CN CN201410379903.5A patent/CN104188907A/en active Pending
- 2008-02-11 CA CA2677838A patent/CA2677838C/en active Active
- 2008-02-11 MX MX2009008582A patent/MX2009008582A/en active IP Right Grant
- 2008-02-11 US US12/069,667 patent/US8148377B2/en active Active
- 2008-02-11 EP EP11191794.4A patent/EP2425820B1/en active Active
- 2008-02-11 WO PCT/US2008/001829 patent/WO2008097664A1/en active Application Filing
- 2008-02-11 PL PL11191794T patent/PL2425820T3/en unknown
- 2008-02-11 EP EP20110191793 patent/EP2425819A1/en not_active Withdrawn
-
2009
- 2009-08-11 IL IL200333A patent/IL200333A/en active IP Right Grant
- 2009-08-13 ZA ZA2009/05628A patent/ZA200905628B/en unknown
- 2009-08-26 US US12/548,304 patent/US20100081664A1/en not_active Abandoned
- 2009-08-26 US US12/548,292 patent/US7994197B2/en active Active
-
2010
- 2010-07-19 US US12/839,190 patent/US8119639B2/en active Active
-
2012
- 2012-02-27 US US13/406,391 patent/US20120245179A1/en not_active Abandoned
-
2013
- 2013-08-05 JP JP2013162032A patent/JP5908439B2/en active Active
-
2014
- 2014-06-23 AU AU2014203389A patent/AU2014203389B2/en active Active
- 2014-10-14 US US14/514,322 patent/US20150057287A1/en not_active Abandoned
-
2015
- 2015-06-08 HK HK15105429.3A patent/HK1204918A1/en unknown
- 2015-06-26 CY CY20151100551T patent/CY1116546T1/en unknown
- 2015-10-23 US US14/921,860 patent/US9833451B2/en active Active
- 2015-12-03 JP JP2015236886A patent/JP2016040317A/en active Pending
- 2015-12-03 JP JP2015236885A patent/JP6209198B2/en active Active
-
2016
- 2016-11-04 AU AU2016253689A patent/AU2016253689B2/en active Active
-
2017
- 2017-03-28 US US15/471,334 patent/US10172853B2/en active Active
-
2018
- 2018-09-11 US US16/127,734 patent/US20190247393A1/en not_active Abandoned
-
2019
- 2019-12-05 US US16/704,867 patent/US20200352939A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030091513A1 (en) * | 2001-10-03 | 2003-05-15 | Mohsen Nahed M. | Method to generate water soluble or nonwater soluble in nanoparticulates directly in suspension or dispersion media |
WO2005025506A2 (en) * | 2003-09-10 | 2005-03-24 | Map Pharmaceuticals, Inc. | Aerosol formulations for delivery of dihydroergotamine to the systemic circulation via pulmonary inhalation |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3893877A4 (en) * | 2018-12-11 | 2022-09-14 | Satsuma Pharmaceuticals, Inc. | Compositions, devices, and methods for treating or preventing headaches |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10172853B2 (en) | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile | |
MXPA02009718A (en) | The treatment of respiratory diseases. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200880011629.9 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 08725456 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2009549138 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2677838 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200333 Country of ref document: IL Ref document number: 578953 Country of ref document: NZ Ref document number: MX/A/2009/008582 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008214205 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008725456 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2008214205 Country of ref document: AU Date of ref document: 20080211 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 5339/CHENP/2009 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020097019032 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020157007681 Country of ref document: KR |