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WO1999040900A1 - Compositions a base de droperidol et leurs modes d'administration - Google Patents

Compositions a base de droperidol et leurs modes d'administration Download PDF

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Publication number
WO1999040900A1
WO1999040900A1 PCT/US1999/003059 US9903059W WO9940900A1 WO 1999040900 A1 WO1999040900 A1 WO 1999040900A1 US 9903059 W US9903059 W US 9903059W WO 9940900 A1 WO9940900 A1 WO 9940900A1
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WO
WIPO (PCT)
Prior art keywords
droperidol
present
solution
dosage form
tablet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1999/003059
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English (en)
Inventor
Abu Alam
Pablo J. Cruz
Keith Glad
Dennis Roberts
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Akorn Operating Co LLC
Original Assignee
Taylor Pharmaceuticals Inc
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Filing date
Publication date
Priority claimed from US09/022,436 external-priority patent/US5997884A/en
Priority claimed from US09/133,106 external-priority patent/US5990134A/en
Priority claimed from US09/177,996 external-priority patent/US5981552A/en
Application filed by Taylor Pharmaceuticals Inc filed Critical Taylor Pharmaceuticals Inc
Priority to AU25996/99A priority Critical patent/AU2599699A/en
Publication of WO1999040900A1 publication Critical patent/WO1999040900A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/0043—Nose
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • This invention relates to the field of migraine treatment .
  • migraine migraine is said to be approximately 6% of the male population and 18% of the female population.
  • Treatment for many patients having the occasional migraine usually involves simple analgesics, non-steroidal anti-inflammatory agents, or specific agents such as ergotamines or triptans. Approximately 10% of migraine sufferers have three or more attacks per month and warrant prophylactic treatment.
  • Preventative agents such as beta-blockers, tricyclic antidepressants and divalproex sodium can reduce but not eliminate migraine attacks in some patients.
  • migraine specific medications such as sumatriptan.
  • the remaining population of migraine sufferers, and in those with intolerable side-effects from available drugs there is a lack of conventional pharmaceutical preparations that exhibit therapeutic effect, without severe side-effects.
  • the concentration of droperidol in the Inapsine is 2.5 mg/ml. That is the only concentration of droperidol that has been approved for human injection.
  • droperidol is present as the lactate salt in Inapsine. No droperidol salt, other than the lactate, has been used for human injection. 2
  • droperidol is supplied in a dosage form that provides better patient tolerance and improved ease of administration.
  • the present injectable dosage forms provide a higher concentration of droperidol than has been available previously.
  • the dosage forms contain from 2.75 to 10.0 mg/ml of droperidol.
  • the injectable dosage forms of the present invention may be used to treat migraine episodes, by administration intravenously ("I.V.”), intramuscularly ("I.M.”), or subcutaneously to a patient during a migraine attack, in an amount that is effective to treat symptoms of migraine .
  • the present invention relates to the use of oral dosage forms of droperidol.
  • the oral dosage forms of the present invention comprise tablets, capsules, powders, syrups and effervescent compositions.
  • the present invention relates to the use of sublingual and buccal dosage forms of droperidol.
  • dosage forms comprise sublingual tablets and solution compositions that are administered 4 under the tongue and buccal tablets that are placed between the cheek and gum.
  • the present invention relates to the use of nasal dosage forms of droperidol.
  • dosage forms of the present invention comprise solution, suspension, and gel compositions for nasal delivery.
  • the dosage forms of the present invention may be used to treat migraine episodes, by administration to a patient during a migraine attack, in an amount that is effective to treat symptoms of migraine.
  • the dosage forms of droperidol may be used without pretreatment or in conjunction with other migraine therapies.
  • the present invention also provides an injectable dosage form of droperidol that is more suitable for injection, as by having a tonicity adjusting agent present to render the formulation isotonic.
  • a dosage form may have from 0.1 to 10 mg/ml of droperidol.
  • Such a dosage form may also be pH adjusted to be of a physiologic pH.
  • the present invention also provides oral dosage forms of droperidol that comprise from 0.5 to 20 mg of droperidol per unit dosage.
  • the present invention further provides sublingual and buccal dosage forms of droperidol that comprise from 0.1 to 10 mg of droperidol per unit dosage.
  • the present invention additionally provides nasal dosage forms of droperidol that comprise from 0.1 to 1.5 mg of droperidol per unit dosage, in solution and gel forms and from 0.1 to 10 mg of droperidol in suspension form.
  • the dosage forms of the present invention also may be used to treat patients that are suffering from tension headache, vertigo, hyperagitation, or hyperemesis gravidarum.
  • the dosage forms also may be used as 5 antiemetics, to treat nausea and the like, such as that caused by chemotherapy. In each instance the dosage is administered in an amount sufficient to treat the patient's symptoms.
  • the present invention provides injectable dosage forms of droperidol at concentrations from 0.1, 2.75, 5.5, 8.25 and 10.0 mg/ml droperidol that are particularly useful.
  • the present invention also provides oral dosage forms of droperidol containing various amounts of droperidol, such as between about 0.5 and 20 mg droperidol per unit dosage, such as tablets and capsules, that are particularly useful.
  • the present invention provides liquid solutions of droperidol, such as syrups, having a concentration of droperidol from about 0.5 mg to about 20 mg.
  • Powders, in dry form will contain from about 0.5 mg to about 20 mg droperidol and effervescent compositions which contain from about 0.5 mg to about 20 mg, by weight.
  • the present invention further provides sublingual and buccal dosage forms of droperidol containing various amounts of droperidol, such as between about 0.1 and 10 mg droperidol per unit dosage, such as tablets and solutions, that are particularly useful. Typically the dosage will be 2 to 4 mg.
  • the present invention still further provides nasal dosage forms of droperidol containing various amounts of droperidol, such as between about 0.5 and 1.5 mg droperidol per ml in the form of solutions and gels, that are particularly useful.
  • the droperidol may be present as a suspension in an amount from about 0.1 to 10 mg per ml. 6
  • the droperidol may be present as the lactate, or other suitable organic salts of droperidol may be used, such as tartrate or acetate.
  • the salt is usually formed in situ by the addition of a suitable organic acid, such as lactic acid, tartaric acid, acetic acid, or the like.
  • the amount of acid that is added is usually sufficient to adjust the solution to a pH from about 3 to about 5.
  • the injectable dosage forms of the present invention may be rendered isotonic, to increase patient tolerance. Accordingly, the solutions may be rendered isotonic by use of a suitable tonicity adjusting agent, such as glycerin. Accordingly, a sufficient amount of a tonicity adjusting agent may be present to render the solution isotonic, or nearly so. After the solution is formed, it should be sterilized, as by filtration, or any other suitable means. Alternatively, the solution may be terminally sterilized by autoclaving after filling into containers.
  • the injectable dosage forms of the present invention include solutions contained in ampules, vials, prefilled syringes, and the like. Also, multi-dose vials may be used. In such an instance it is desirable to have a preservative present in the solution, such as a paraben, usually methyl and/or propyl paraben. Preservatives, of course, may be present in any of the dosage forms of the present invention.
  • patients that are suffering from a migraine episode, tension headache, vertigo, hyperemesis gravidarum, hyperagitation, or nausea may be treated.
  • the patients are administered the droperidol, via I.V., I.M., or subcutaneously.
  • the droperidol is typically administered in dosages of 2.75 to 10.0 mg until the symptoms subside.
  • the maximum dosage of droperidol administered to a patient at a single session usually 7 will be 7.5 mg, although it may on occasion be as high as 10 mg.
  • patients that are suffering from a migraine episode, tension headache, vertigo, hyperemesis gravidarum, hyperactivity, or nausea may be treated.
  • the patients may be orally administered the droperidol, typically in dosages of 2 mg to 20 mg, until the symptoms subside.
  • the maximum dosage of droperidol orally administered to a patient at a single session usually will be 10 mg, although it may on occasion be as high as 20 mg.
  • the patients may be administered the droperidol via the sublingual or buccal route, typically in dosages of 1 mg to 10 mg, until the symptoms subside.
  • the maximum dosage of droperidol administered to a patient at a single session usually will be 10 mg.
  • the patients also may be nasally administered the droperidol, typically in dosages of 1 mg to 3 mg, until the symptoms subside. Fifty (50) percent of the dose is administered into each nostril.
  • the maximum dosage of droperidol administered to a patient at a single session usually will be 10 mg.
  • the patients receiving droperidol to treat migraine may be treated with droperidol as a single therapy.
  • droperidol By this it is meant that other agents used to treat an active episode of migraine need not be used prior to or in conjunction with the droperidol treatment.
  • Many patients receive various medications for prophylaxis against active migraine episodes, but such prophylactic therapy is not considered to be pretreatment of an active migraine episode, prior to droperidol treatment.
  • Such therapy is nonspecific in that the goal is to prevent or reduce the number of occurrences of active migraine headache, but not the treatment of a specific migraine episode.
  • the present dosage forms will be useful as a 8 first-line treatment of active migraine headache without the prior use of traditional migraine therapy, or as a rescue medication when other treatment has failed.
  • an active migraine episode may be treated with any of a number of therapies, including the following: Simple analgesics, such as aspirin or acetaminophen, combination analgesics as with caffeine, vasoconstrictors, narcotics, and the like.
  • Simple analgesics such as aspirin or acetaminophen
  • combination analgesics as with caffeine, vasoconstrictors, narcotics, and the like.
  • droperidol in accordance with the present invention does not require the prior administration of such other agents for treating migraine .
  • migraine patients to whom droperidol should be administered are those that are experiencing a migraine episode or are at risk of such an episode.
  • Such patients may be generally described as those meeting the diagnostic criteria for "migraine with aura” or “migraine without aura” as detailed in: "Classification Committee of the International Headache Society. Classification and Diagnostic Criteria For Headache Disorders, Cranial Neuroalgia and Facial Pain", Cephalgia , 1988, Vol. 8, Supp. 77 at pp. 19-21; or meeting the diagnostic criteria for "status migrainosus” , as detailed therein at pp. 26- 27.
  • an additional dose of droperidol may be used to avoid the use of a sedative or other analgesics within the next few hours after the headache symptoms have subsided.
  • an additional dose of droperidol may be used to avoid the use of a sedative or other analgesics within the next few hours after the headache symptoms have subsided.
  • present invention may avoid the need for such remedies.
  • the droperidol of use in accordance with the present invention may be administered by I.V., I.M. or subcutaneously. If administered intravenously, the rate of infusion is not critical and will usually be administered by I.V. push in a pre-established line. Usually the droperidol will be administered intramuscularly or subcutaneously as a bolus. Sublingual and buccal delivery allows droperidol to dissolve in the immediate vicinity where the product is placed and then the drug enters directly into the blood stream to exert its pharmacological effect rapidly, thereby, by-passing the gastric juices, acid environment and enzymes present in the gastrointestinal tract and at the same time by-passing the liver which is the target organ for metabolism of the drug when administered orally.
  • Nasal delivery allows droperidol to be absorbed directly into the systemic circulation from the nasal mucosa thus, enabling the drug to exert its pharmacological effect immediately.
  • Nasal delivery unlike the oral route, escapes degradation which can be caused by gastrointestinal environment and liver first- past metabolism. The bioavailability by nasal delivery would, therefore, closely approximate the intramuscular route . 10 TABLETS
  • carriers such as vehicles (e.g. lactose, white sugar, sodium chloride, glucose, urea, starches, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.), binders (e.g. water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrators (e.g.
  • dry starch sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, etc.), disintegration inhibitors (e.g. white sugar, stearin, cacao butter, hydrogenated oils, etc.), absorption promoters (e.g. quaternary ammonium base, sodium laurylsulfate, etc.), wetting agents (e.g. glycerin, starches, etc.), adsorbents (e.g. starches, lactose, kaolin, bentonite, colloidal silicates, etc.), lubricants (e.g.
  • the tablets may be in the form of a conventional non-coated tablet, or a sugar-coated tablet, gelatin-coated tablet, enteric coated tablet, film coated tablet, or double or multiple layer tablet.
  • the capsules may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, PrimogelTM, cornstarch and the like; a lubricant such as magnesium stearate or SterotexTM; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent 11 such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, PrimogelTM, cornstarch and the like
  • a lubricant such as magnesium stearate or SterotexTM
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or sac
  • the droperidol may be admixed with at least one inert customary excipient (or carrier) such as sodium citrate of dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acadia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (a) fillers or extenders
  • Effervescent powder may be formulated by the aid of agents such as sodium bicarbonate, citric acid anhydrous, calcium phosphate monobasic, calcium phosphate dibasic, polyvinylpyrrolidone, polyethylene glycol powder, silica gel, L-Leucine, sodium benzoate, simethicone, mineral oil, isopropyl alcohol, water, flavoring agents, sugar, sorbitol, aspartame, saccharin and coloring agents. 12 SYRUPS AND SOLUTIONS
  • Droperidol syrups and solutions may be made by adding ingredients such as water, sugar, fructose, sorbitol, aspartame, saccharin, polyethylene glycol, propylene glycol, alcohol, bentonite, tragacanth, alginates, gelatin, carboxymethylcellulose, methylparaben, propylparaben, sodium benzoate, flavoring agents and coloring agents.
  • ingredients such as water, sugar, fructose, sorbitol, aspartame, saccharin, polyethylene glycol, propylene glycol, alcohol, bentonite, tragacanth, alginates, gelatin, carboxymethylcellulose, methylparaben, propylparaben, sodium benzoate, flavoring agents and coloring agents.
  • carriers such as vehicles (e.g. lactose, white sugar, mannitol, glucose, starches, calcium carbonate, crystalline cellulose, silicic acid, etc.), binders (e.g. water, ethanol, myranol, glucose solution, starch solution, gelatin solution, polyvinylpyrrolidone, etc.), disintegrators (e.g. dry starch, sodium, alginate, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, etc.), absorption promoters (e.g.
  • the tablets may be in the form of a conventional tablet, or a molded tablet .
  • various carriers and excipients are used to offer the acceptable characterists such as: lactose, sugar, mannitol, acacia, providone, cyclodextrins, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, Carbapol 934, stearic acid, magnesium stearate, locust 13 bean gum, xanthan gum, water, alcohol, isopropanol and artificial flavoring and sweetening agents.
  • SOLUTIONS In order to formulate into solutions, various carriers, excipients, pH adjusters are employed such as: water, sugar, lactic acid, acetic acid, fructose, glucose, saccharin, polyethylene glycol, propylene glycol, alcohol, bentonite, tragacanth, gelatin, alginates, aspartame, sorbitol, methylparaben, propylparaben, sodium benzoate, artifical flavoring and coloring agents.
  • water sugar, lactic acid, acetic acid, fructose, glucose, saccharin, polyethylene glycol, propylene glycol, alcohol, bentonite, tragacanth, gelatin, alginates, aspartame, sorbitol, methylparaben, propylparaben, sodium benzoate, artifical flavoring and coloring agents.
  • Tablet Process The ingredients of 1,000 tablets (61 g for 0.5 mg formulation and 81 g for 20 mg formulation) are blended in a suitable mixer and then are compressed into tablets using standard concave punches. Tablets are packaged into bottles or individual blister strips. The tablets can be further coated using either aqueous film coating in a suitable coating pan and dried. The coated tablets are packaged into bottles or individual blister strips.
  • the tablets can be further coated using conventional sugar coating procedure in a suitable coating pan and dried.
  • the tablets are packaged into bottles or individual blister strips.
  • Capsule Process The ingredients are blended for 1,000 capsules (81.5 g for 0.5 mg formulation and 102 g for 20 mg formulation) in a suitable mixer, then filled 15 into hard shell capsules using conventional procedure. The capsules are cleaned and packaged into bottles or individual blister strips.
  • Carboxymethylcellulose 10 10 10 Peppermint Spray Dried Flavor 2 3 (mg)
  • Powder Process The ingredients of 1,000 powder units (62.5 g for 0.5 mg formulation and 83 g for 20 mg formulation) are blended in a suitable mixer and filled into individual blister packs.
  • Tablet Process The ingredients are blended for 1,000 tablets (86.5 g for 0.5 mg formulation and 158 g for 20 mg formulation) in a suitable mixer and compressed into tablets under controlled environmental condition with relative humidity ⁇ 30%.
  • the tablets are packaged in 16 glass bottles or individually in an aluminum foil pouch to protect from moisture during storage.
  • Powder Process The ingredients are blended for 1,000 powder units (86.5 g for 0.5 mg formulation and 15£ g for 20 mg formulation) in a suitable mixer in an environmental condition of relative humidity ⁇ 30%.
  • the individual powder units are packaged in an aluminum foil pouch to protect form moisture during storage.
  • Lactic Acid qs to pH (mg) 3.5 3.5
  • Sucrose mg) 50 mg 250 Citrus Flavor (mg) 0.1 0.5 Methylparaben (mg) 1 5 Propylparaben (mg) 0.2 1 Water, qs . ad (ml) 1 5
  • Syrup and Solution Process In a suitable vessel, droperidol is dissolved with lactic acid with pH adjusted to about 3.5 in sufficient quantity of water. The remaining ingredients are then added and dissolved.
  • Microcrystalline cellose (mg) 20 20
  • Magnesium stearate (mg) 0.1 0.1
  • Tablet Process The ingredients of 1,000 tablets (25.6 g for 0.1 mg formulation and 40.1 g for 10 mg formulation) are blended in a suitable mixer and then compressed into tablets. Tablets are packaged into bottles or individual blister strips.
  • Tablet Process The ingredients of 1,000 tablets (30.23 g for 0.1 mg formulation and 42.6 g for 10 mg formulation) are blended in a suitable mixer and then compressed into tablets. Tablets are packaged into bottles or individual blister strips.
  • Tablet Process The ingredients of 1,000 tablets (45.4 g of the 0.1 mg formulation and 80.5 g of the 10 mg formulation) are blended in a suitable mixer and compressed into tablet by using flat faced punches and die. The tablets are filled into bottles or individual blister strips.
  • Solution process In a suitable vessel, droperidol is dissolved with lactic acid with pH adjusted to about 3.5 in sufficient quantity of water. The remaining ingredients are then added and dissolved. Sufficient water is then added for 1,000 units (100 ml for 0.5 mg formulation and 500 ml for 10 mg formulation) . The solution is filtered and put into bottles equipped with a dropper to allow the solution to be placed accurately under the tongue. The filtered solution can also be 19 packaged into bottles with a metered spray to allow accurate dosing under the tongue.
  • Lactic acid qs to pH 3.5 3.5
  • Solution Process In a suitable vessel, droperidol is dissolved in lactic acid with pH adjusted to about 3.5 in a sufficient quantity of water. Glycerin is then dissolved. Sufficient water is then added for 1,000 units (100 ml for each 0.1 mg and 1.5 mg formulation).
  • the solution is filtered through a 0.22 micron filter and placed in a suitable container equipped with a metered spray cap to deliver accurately the required volume.
  • Lactic acid qs to pH 3.5 3.5
  • Glycerin (mg) 0.16 0.16 Water qs.ad. (mg) 0.1 ml (0.1 g ) 0.1 ml (0.
  • SUBSTniiTHSHEET(RULE e) 20 an autoclave. Or the mixture is first sterilized in bulk and then filled into tubes. The syringe or the tube is affixed with a nasal applicator for administration.
  • Suspension Process In a suitable vessel droperidol (micronized powder) is suspended in water. Guar gum is then suspended with agitation. Glycerin is then added and mixed. Sufficient water is then added and mixed for 1,000 units (100 g each for 0.1 mg formulation and 10 mg formulation) . The mixture is then filled into a syringe and sterilized in an autoclave, or the mixture is first sterilized in bulk and then filled into tubes. The syringe or the tube is affixed with a nasal applicator for administration.
  • droperidol lactate solutions were prepared having concentrations of 0.1, 2.75, 5.5, 8.25 and 10.0 mg droperidol per ml (Examples 13-17). Lactic acid was added to water-for- injection, which was then heated to 65° C. The droperidol was then added and mixed until dissolved. The droperidol was filled into syringes (1 cc/1.5 cc syringe) . These dosage forms were terminally sterilized and placed on stability. The results of the stability study at 25° and 40° C are shown in Table I. 2 1
  • a solution of droperidol lactate was prepared (10 mg/ml) using glycerin to render the solutions isotonic, filled into syringes (1 cc/1.5cc syringe) , terminally sterilized, and placed on stability (Example 18).
  • the results of the stability study at 25° C and 40° C are shown in Table II.
  • a solution of droperidol tartrate was prepared (using tartaric acid in place of lactic acid) and similarly filled, sterilized and placed on stability (Example 19) .
  • the results of the stability study at 25° C and 40° C are shown in Table III.
  • Osmolality 150 162 159 154 153

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Abstract

La présente invention concerne diverses formes posologiques du droperidol - à administrer par voie perorale, sublinguale, buccale, nasale et par injection - ainsi qu'une méthode de traitement de la migraine à l'aide de ces formes posologiques. Ce médicament peut se présenter sous les formes posologiques suivantes: comprimés, capsules, poudres, formulations effervescentes et sirop administrés par voie orale; comprimés et solutions sublinguaux; comprimés buccaux; solutions, suspensions et gels administrés par voie nasale; et solutions injectables.
PCT/US1999/003059 1998-02-12 1999-02-11 Compositions a base de droperidol et leurs modes d'administration Ceased WO1999040900A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU25996/99A AU2599699A (en) 1998-02-12 1999-02-11 Droperidol compositions and method for using same

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US09/022,436 US5997884A (en) 1998-02-12 1998-02-12 Compositions and method for treating migraine
US09/022,436 1998-02-12
US09/133,106 US5990134A (en) 1998-08-12 1998-08-12 Oral droperidol compositions and method for treating migraine
US09/133,106 1998-08-12
US17799798A 1998-10-23 1998-10-23
US09/177,996 US5981552A (en) 1998-10-23 1998-10-23 Sublingual and buccal compositions of droperidol and method for treating migraine
US09/177,996 1998-10-23
US09/177,997 1998-10-23

Publications (1)

Publication Number Publication Date
WO1999040900A1 true WO1999040900A1 (fr) 1999-08-19

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PCT/US1999/003059 Ceased WO1999040900A1 (fr) 1998-02-12 1999-02-11 Compositions a base de droperidol et leurs modes d'administration

Country Status (2)

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AU (1) AU2599699A (fr)
WO (1) WO1999040900A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001030337A3 (fr) * 1999-10-22 2002-01-24 Orbon Corp Traitement topique de l'hypertension oculaire, du glaucome, de la retinopathie ischemique et de la degenerescence maculaire liee a l'age par une formulation ophtalmique d'antagonistes de la dopamine
US20140066498A1 (en) * 2010-05-18 2014-03-06 National Cheng Kung University Triterpenoid derivatives, benzenoid derivatives, and pharmaceutical compositions containing the same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5118508A (en) * 1990-02-07 1992-06-02 Showa Yakuhin Kako Co., Ltd. Pharmaceutical composition
US5310561A (en) * 1990-09-10 1994-05-10 Alza Corporation Antiemetic therapy

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5118508A (en) * 1990-02-07 1992-06-02 Showa Yakuhin Kako Co., Ltd. Pharmaceutical composition
US5310561A (en) * 1990-09-10 1994-05-10 Alza Corporation Antiemetic therapy

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KYMER P.J. et al., "The Effects of Oral Droperidol Versus Oral Metoclopramide Versus Both Oral Droperidol & Metoclopramide on Postoperative Vomiting when Used as a Premedicant for Strabismus Surgery", JOURNAL OF CLINICAL ANESTHESIA, February 1995, Vol. 7, pages 35-39. *
WANG S.J., "Droperidol Treatment of Status Migrainosus and Refractory Migraine", HEADACHE, June 1997, Vol. 37, pages 377-382. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001030337A3 (fr) * 1999-10-22 2002-01-24 Orbon Corp Traitement topique de l'hypertension oculaire, du glaucome, de la retinopathie ischemique et de la degenerescence maculaire liee a l'age par une formulation ophtalmique d'antagonistes de la dopamine
US20140066498A1 (en) * 2010-05-18 2014-03-06 National Cheng Kung University Triterpenoid derivatives, benzenoid derivatives, and pharmaceutical compositions containing the same

Also Published As

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