WO2008030524A2 - Formulations pharmaceutiques liquides pour l'administration orale d'un antagoniste du cgrp - Google Patents

Formulations pharmaceutiques liquides pour l'administration orale d'un antagoniste du cgrp Download PDF

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Publication number
WO2008030524A2
WO2008030524A2 PCT/US2007/019461 US2007019461W WO2008030524A2 WO 2008030524 A2 WO2008030524 A2 WO 2008030524A2 US 2007019461 W US2007019461 W US 2007019461W WO 2008030524 A2 WO2008030524 A2 WO 2008030524A2
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WIPO (PCT)
Prior art keywords
oxo
liquid formulation
cremophor
azepan
ide
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Application number
PCT/US2007/019461
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English (en)
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WO2008030524A3 (fr
Inventor
David Breslin
Joyce Stellabott
Hossain Jahansouz
Laman L. Alani
Karen Thompson
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Merck & Co., Inc.
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Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU2007293032A priority Critical patent/AU2007293032A1/en
Priority to JP2009527409A priority patent/JP2010502710A/ja
Priority to CA002662748A priority patent/CA2662748A1/fr
Priority to EP07837821A priority patent/EP2063708A2/fr
Publication of WO2008030524A2 publication Critical patent/WO2008030524A2/fr
Publication of WO2008030524A3 publication Critical patent/WO2008030524A3/fr

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • compositions that are liquid solutions of Compound I 5 said solutions being orally administrable.
  • the active solutions may be administered, for example, as fill in encapsulated dosage forms such as liquid filled and sealed hard gelatin capsules or soft gelatin capsules.
  • Other technologies commonly used for delivering poorly water soluble compounds as oral agents, such as particle size reduction, amorphous formulations (hot melt extrusion or spray drying) are typically explored, as was the case with Compound I.
  • particle size reduction, amorphous formulations hot melt extrusion or spray drying
  • This invention relates to liquid formulations of Compound I (and salts thereof, and solvate forms and free base forms of Compound I) for use in mammals, especially humans, especially in connection with encapsulated formulations including hard and soft gelatin capsules.
  • One salt form of compound I is the potassium ethanolate salt.
  • compositions of the present invention comprising Formulations of compound I, and salts thereof, are useful in the treatment of diseases mediated by the antagonism of the CGRP receptor, including migraine headache and cluster headache.
  • FIGURE 1 is a graph of the mean plasma concentration of Compound I over time generated in the experiment described in Example 6, wherein healthy men ages 18 to 45 were orally administered a 400 mg dosage of Compound I in a liquid filled gelatin capsule and in several different carrier formulations.
  • the present invention relates to pharmaceutical compositions for the oral administration of l-[l-( ⁇ [(3i?,65)-6-(2,3-difluorophenyl)-2-oxo-l-(2,2,2-trifluoroethyl)azepan-3- yl]amino ⁇ carbonyl)piperidin-4-yl]-2-oxo-l ,2-dihydroimidazo[4,5-&]pyridin-3-ide (Compound I) 5 or salts thereof, a compound with low aqueous solubility ( ⁇ 0.05 mg/mL).
  • the invention is a formulation which increases the oral bioavailability, as determined by elevated drug plasma levels, while maintaining chemical integrity of Compound I in the formulation upon long term storage.
  • the formulations of the present invention possess the advantages of increased bioavailability, excellent stability, increased potency per unit dose, good safety and tolerability, and ease of processing.
  • a liquid formulation comprising Compound I or any pharmaceutically acceptable salt or solvate thereof, a surfactant component, a solvent component and other optionally present components such as the solvent water.
  • the surfactant component may comprise one or more surfactants.
  • the solvent component may comprise one or more solvents.
  • Suitable surfactants for use in the present invention include polyethoxylated castor oil (such as Cremophor® EL (polyoxyl 35 castor oil), Cremophor® RH60, Cremophor® RH40); polysorbates (such as Tween-80, Tween-20); Polyethylene glycol ester glycerides (such as Labrasol®, Labrifil® 1944); sorbitan monooleate (such as Span ®-80, Span®-20); Vitamin E- TPGS (vitamin E d-alpha-tocopherol polyethylene glycol succinate); saturated polyglycolized glycerides (such as Gelucire® 44/14 and and Gelucire® 50/13); polypropoxylated stearyl alcohols (such as Acconon® MC-8, Acconon® CC-6).
  • polyethoxylated castor oil such as Cremophor® EL (polyoxyl 35 castor oil), Cremophor® RH60, Cremo
  • Preferred surfactants for use in the present invention include Cremophor® EL, Tween-80, Tween-20, and Labrasol®. Most preferred surfactants for use in the present invention include Tween 80 (polysorbate 80) and Cremophor® EL (polyoxyl 35 castor oil). The surfactants may be used alone or in combination. Most preferably, Tween 80 and Cremophor® EL are used in combination with one another.
  • Suitable solvents for use in the present invention include ethanol, propylene glycol, glycerin, polyethylene glycols (such as PEG 200, PEG 400, PEG 600, PEG 900 and PEG 1000), DMSO, ethoxydiglycol (Transcutol®), diethyleneglycol, polyoxypropylene block copolymers (such as Polaxamer), and water.
  • Preferred solvents for use in the present invention include ethanol and propylene glycols (PEG 400 and PEG 600).
  • Most preferred solvents for use in the present invention include polyethylene glycol 400 (PEG-400) and propylene glycol (PG). The solvents may be used alone or in combination. Most preferably, PEG-400 and PG are used in combination with one another.
  • the liquid formulation comprises Compound I, PEG-400, polysorbate 80, Cremophor® EL, PG and optionally water, in the following amounts:
  • liquid formulation comprises Compound I, PEG-400, polysorbate 80, Cremophor® EL, PG and optionally water, in the following amounts:
  • liquid formulation comprises Compound I 5 PEG-400, polysorbate 80, Cremophor® EL , PG and water, in the following amounts:
  • the invention further relates to an oral pharmaceutical composition comprising the liquid formulations described above.
  • a capsule comprising the liquid formulation of the first embodiment, wherein the capsule is filled with 50 to 1200 mg, and preferably 333 to 1050 mg of the liquid formulation of the first inventive embodiment.
  • the fill amount corresponds to the presence of 100 to 300 mg of the active agent Compound I or a pharmaceutically acceptable salt or solvate thereof, 81.6 to 245 mg PEG-400, 47.5 to 190 mg polysorbate 80, 47.5 to 190 mg Cremophor® EL, 25 to 75 mg propylene glycol and up to 50 mg water; and preferably 300 mg the active agent Compound I, 245 mg PEG-400, 190 mg polysorbate 80, 190 mg Cremophor® EL, 75 mg propylene glycol and 50 mg water; or 150 mg the active agent Compound I, 122.5 mg PEG-400, 95 mg polysorbate 80, 95 mg Cremophor® EL, 37.5 mg propylene glycol and 25 mg water.
  • the capsule is selected from a soft gelatin capsule and a hard gelatin capsule.
  • a method of making the liquid formulation of the first embodiment and a method of making the liquid filled capsule of the second embodiment of the invention, wherein the method of making the liquid formulation comprises the steps of combining a pharmaceutically effective amount of Compound I with one or more solvents and one or more surfactants, and the method of making the liquid filled capsule further comprises filling a capsule with the liquid formulation and sealing the capsule.
  • Compound I is combined with one or more solvents selected from ethanol, propylene glycol, glycerin, PEG 200, PEG 400, PEG 600, PEG 900, PEG 1000, DMSO, Transcutol®, diethyleneglycol, Polaxamer, water, and one or more surfactants selected from Cremophor® EL, Tween-80, Tween-20, Labrasol®, Labrifil® 1944, Cremophor® RH60.
  • solvents selected from ethanol, propylene glycol, glycerin, PEG 200, PEG 400, PEG 600, PEG 900, PEG 1000, DMSO, Transcutol®, diethyleneglycol, Polaxamer, water, and one or more surfactants selected from Cremophor® EL, Tween-80, Tween-20, Labrasol®, Labrifil® 1944, Cremophor® RH60.
  • Compound I is combined with the surfactants Cremophor® EL and polysorbate 80 and the solvents PEG 400 and propylene glycol, and optionally water, and the resulting liquid formulation is filled into a softgel and sealed.
  • a method of treating one or more conditions selected from: migraine headache and cluster headache with the capsule of the second embodiment of the invention with the filled capsules of the present invention (containing Compound I).
  • the method includes administering one or more capsules to a patient in need thereof, either to treat or prevent migraine headache or cluster headache, or both.
  • a soft gelatin capsule "softgel” being an abbreviation for soft gelatin capsules. It is understood that when reference is made to the term “softgel” alone, it shall be understood that the invention applies equally to all types of gelatin and non-gelatin capsules, regardless of hardness, softness, and so forth, hi one embodiment of the present invention, the soft gelatin capsule contains plasticizers, such as glycerin and sorbitol. Colorant may be added to the gel mixture prior to encapsulation to produce soft gelatin capsules of a desired hue.
  • Cremophor® EL and polyoxyl 35 castor oil are used interchangeably.
  • Tween-80 and polysorbate 80 are interchangeable as used in this document.
  • polyethylene glycol polyethylene glycol 400 and PEG 400 are used interchangeably.
  • propylene glycol is sometimes referred to as PG.
  • references to a specific weight or percentage of "active ingredient", or Compound I is on the basis of the free base weight, absent the weight of any counterion or solvate present, unless otherwise indicated.
  • the phrase "1 mg l-[l-( ⁇ [(3/?,65)-6-(2,3- difluorophenyl)-2-oxo-l-(2,2,2-trifluoroethyl)azepan-3-yl]amino ⁇ carbonyl)piperidin-4-yl]-2- oxo-l,2 ⁇ lihydroimidazo[4,5- ⁇ ]pyridin-3-ide, M or "1 mg Compound I" means that the amount of the compound selected is based on 1 mg of the free base form of Compound I absent the weight of the solvent present in the solvate.
  • treatment means any administration of a compound of the invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
  • controlling includes preventing treating, eradicating, ameliorating or otherwise reducing the severity of the condition being controlled.
  • the liquid formulations of the invention are solutions of Compound I 5 one or more solvents, and optionally one or more surfactants.
  • a “solution” refers to a clear liquid state where the drug is dispersed at the molecular level, dissolved with no apparent solid particles, in a liquid environment provided by the solvent.
  • the invention is not limited to a particular mechanism of action. However, it is believed that upon release into the gastrointestinal fluids that the surfactants of the formulation will form micelle assemblies and micro-emulsions which are able to solubilize Compound 1 above the solubility limit without surfacants present.
  • the solubilized drug is available for absorption through the intestinal membrane, and hence systemic exposure in vivo. In the absence of surfactants the drug precipitates from the gastric juices, and the poorly soluble drug is not bioavailable.
  • the composition can be formulated as a fill encapsulated in a gelatin capsule of appropriate gelatin composition, a hard gelatin capsule with an appropriate seal, a non-gelatin capsule such as a hydroxypropyl methylcellulose capsule, or an oral liquid or emulsion by methods commonly employed in the art.
  • the fill is encapsulated in a sealed hard gelatin capsule or a soft gelatin capsule containing plasticizers, such as glycerin and sorbitol.
  • the hard gelatin capsule is sealed by band sealing using a gelatin ribbon, or LEMS (i.e., spraying with a hydroalcoholic solution to locally melt and seal the gelatin capsule pieces).
  • the fill is prepared by mixing the excipients and Compound I with heating if required.
  • antioxidants butylated hydroxyanisole
  • BHT butylhydroxytoluene
  • tocopherol propyl gallate
  • preservatives such as benzyl alcohol or parabens.
  • the antioxidant or preservative is present in a weight percent range of 0.01 % to 0.1 %.
  • composition can be formulated as a fill encapsulated in a soft gelatin capsule, a hard gelatin capsule with an appropriate seal, a non- gelatin capsule such as a hydroxypropyl methylcellulose capsule or an oral liquid or emulsion by methods commonly employed in the art.
  • compositions of this invention will be administered in such an amount that an effective dose of Compound I is administered to the patient.
  • the amount of Compound I will generally be known or determined by the attending physician.
  • the amount or volume of administered dose will be determined by the amount of Compound I prescribed and/or otherwise desired as a dose and the solubility of the Compound I in the formulation.
  • an effective dose for Compound I is from 100 mg to about 1000 mg per day, in single or divided doses; preferably from about 200 mg to about 800 mg per day, more preferably from about 100 mg to about 600 mg per day, even more preferably about 150 or 300 mg per day, in single or divided doses.
  • the compositions are preferably provided in the form of one or more liquid-filled capsules containing (in total, if more than one liquid-filled capsule is administered) from 100 to 1000 mg, preferably 100, 200, 300, 400, 500, 600, 700, 800, 900 and 1000, most preferably 200, 300, 400, 500 and 600 milligrams of the active ingredient, for the symptomatic adjustment of the dosage to the patient to be treated.
  • the liquid formulations of the present invention are pre-concentrates which are generally administered orally, in soft or hard gelatin capsules, gelatin encapsulation technology being well known to the pharmaceutical arts.
  • the liquid formulations of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases: headache; migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus; inflammatory bowel disease, irritable bowel syndrome, cystitis; and other conditions that may be treated or prevented by antagonism of CGRP receptors.
  • the subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
  • the subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.
  • administering a should be understood to mean providing the composition of the invention to the individual in need of treatment.
  • composition of the present invention to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the patient in need of such treatment or prophylaxis.
  • the need for a prophylactic administration according to the methods of the present invention is determined via the use of well known risk factors.
  • the effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration, other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.
  • a water bath was preheated 35 0 C (5 0 C variance).
  • Liquids PEG 400, propylene glycol, Cremophor® EL, and polysorbate 80 were dispensed directly into a stainless steel vessel (diameter is 5 VA inches) and stirred at 600 RPM stirring using a 2 inch mixer blade.
  • Compound 1 (powder) was added into the vortex.
  • the contents were mixed for approximately 2 hours at 600 rpm while maintaining the temperature at 35°C (5°C variance).
  • As the formulation was mixed it was periodically tested by visual inspection for undissolved particles. After 2 hours of mixing only air bubbles were present (which was attributed to the high level of surfactant), and Compound I was completely dissolved.
  • the solution was deaerated for about 2.5 hours under vacuum, placed at 40 0 C (5 0 C variance) overnight, and then again placed under vacuum for an additional 1 hour under to complete deaeration.
  • the formulation was ready for encapsulation.
  • Liquids PEG 400, Propylene Glycol, Cremophor EL, Polysorbate 80 and water were placed into a 5 % inch diameter container equipped and mixed with a 2 inch blade at 600 RPM.
  • Compound I was added to the mixture and mixing continued for an additional 2.5 hours at 25 0 C ⁇ 5 0 C.
  • the mixture was sampled once per hour and examined under microscope to determine visual end point (the lack of solid particles).
  • the solution was mixed for an additional 1 hr.
  • the solution was filtered through a -100 micron filter and de-aerated until a yellowish clear solution free of foam and bubbles was obtained.
  • the fill solution obtained in Example 2 (1050 mg) and the gelatin component was supplied by Banner Pharmacaps and were fed into an encapsulation machine.
  • the gelatin formulation was cast into sheets on two cooled rollers. These sheets were passed through a series of rolls where a food grade lubricant was applied. The sheets were then fed through the rotary die rolls where the softgel was formed.
  • a reciprocating pump injected 1050 mg of the fill solution into the center of the softgel, after which the upper edge of the die came together to seal the softgel.
  • the newly formed softgels were dislodged from the sheet and pneumatically conveyed to a tumble dryer where they stayed for 45-60 minutes.
  • the softgels Upon exiting the dryer, the softgels were spread on trays and placed in a drying tunnel (low humidity chamber) and dried. Upon completion of the drying process, the softgels were visually inspected for defects. Subsequently, the capsules were sized to remove oversized and undersized capsules and polished. The resulting filled softgel capsules each contained 300 mg Compound I.
  • Example 1 Using a peristaltic pump the solution of Example 1 was pumped into a hopper for encapsulation.
  • the liquid formulation was dispensed into the size 1, white, opaque hard gelatin capsules (CAPSUGEL, containing gelatin and titanium dioxide) to a target fill weight of 667 mg.
  • the filled capsules were transferred to a LEMS 30 capsule sealer and they were sealed by spraying with a mixture of 1:1 (weight:weight) wate ⁇ ethanol (dehydrated, 190 proof) solution. After spraying the capsules were dried by gentle heating to approximately 45°C.
  • the sealed capsules were placed onto trays lined with tray paper and were placed into a depression chamber (ZANASI 4OE vacuum trap). After the completion of the vacuum, cycle the capsules were visually inspected for leaking.
  • the acceptable capsules were passed through a ZANASI capsule sorter to remove empty capsules.
  • the finished capsules were then packaged into appropriate containers.
  • the resulting filled capsules each contain 200 mg Compound I.
  • the analyte and its internal standard were on-line extracted with a Cohesive C 1R column (0.5x50 mm, 6Ou) using 10:90 acetonitrile:0.1% formic acid, back-eluted with 50:50 acetonitrile:0.1% formic acid, and analyzed on a Thermo-Keystone FluophaseRP column (100x2. lmm, 5u) using ramping gradient from 50:50 to 70:30 acenitonitrile:0.1% formic acid.
  • Detection was accomplished on a Sciex API4000 mass spectrometer in multiple-reaction monitoring (MRM) mode using positive ionization with a turbo ion-spray interface.
  • MRM multiple-reaction monitoring
  • the assay had a lower limit of quantification (LOQ) 5 nM based on 0.05-mL aliquots of human plasma.
  • the standard curve range was from 5 to 5000 nM.
  • the analysis time was 10.0 minutes per sample on the TXl system.
  • phase separation is the common term for the point when the two liquid solvents are immiscible and the mixture becomes cloudy.
  • the surfactant In order to have a completely miscible PEG 400 / polysorbate 80 mixture the surfactant must be above 40% by weight. However, this level of surfactant is above the allowable limit to dose to human patients. Thus, another surfactant was required in the formulation to allow for a proper balance of PEG and surfactant.
  • the preferred ingredients in terms of phase separation include ethanol, polysorbate 20, Labrasol®, Cremophor® EL, and Carpryol® 90.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des formulations liquides qui renferment le composé 1-[1-({[(3R,6S)-6-(2,3-difluorophényl)-2-oxo-1-(2,2,2-trifluoroéthyl)azepan-3-yl]amino}carbonyl)pipéridin-4-yl]-2-oxo-1,2-dihydroimidazo[4,5-b]pyridin-3-ide. Les formulations de l'invention possèdent une biodisponibilité et une stabilité étonnament améliorées, en ce qu'elles comprennent du polyéthylène glycol, du Tween (polysorbate 80), du Cremophor® EL (polyoxyle 35-huile de ricin), du propylène glycol et, facultativement, de l'eau, et peuvent être placées dans des capsules de gélatine souple ou dure afin de traiter des troubles, parmi lesquels les maux de tête et les céphalées vasculaires de Horton.
PCT/US2007/019461 2006-09-08 2007-09-06 Formulations pharmaceutiques liquides pour l'administration orale d'un antagoniste du cgrp WO2008030524A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU2007293032A AU2007293032A1 (en) 2006-09-08 2007-09-06 Liquid pharmaceutical formulations for oral administration of a CGRP antagonist
JP2009527409A JP2010502710A (ja) 2006-09-08 2007-09-06 Ｃｇｒｐ拮抗薬の経口投与のための液体医薬製剤
CA002662748A CA2662748A1 (fr) 2006-09-08 2007-09-06 Formulations pharmaceutiques liquides pour l'administration orale d'un antagoniste du cgrp
EP07837821A EP2063708A2 (fr) 2006-09-08 2007-09-06 Formulations pharmaceutiques liquides pour l'administration orale d'un antagoniste du cgrp

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US84305206P 2006-09-08 2006-09-08
US60/843,052 2006-09-08

Publications (2)

Publication Number Publication Date
WO2008030524A2 true WO2008030524A2 (fr) 2008-03-13
WO2008030524A3 WO2008030524A3 (fr) 2008-10-02

Family

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PCT/US2007/019461 WO2008030524A2 (fr) 2006-09-08 2007-09-06 Formulations pharmaceutiques liquides pour l'administration orale d'un antagoniste du cgrp

Country Status (6)

Country Link
EP (1) EP2063708A2 (fr)
JP (1) JP2010502710A (fr)
CN (1) CN101511184A (fr)
AU (1) AU2007293032A1 (fr)
CA (1) CA2662748A1 (fr)
WO (1) WO2008030524A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010002763A1 (fr) * 2008-06-30 2010-01-07 Merck & Co., Inc. Formes pharmaceutiques posologiques solides telcagepant potassique
US20120322892A1 (en) * 2010-02-25 2012-12-20 Tian XIE Oral microemulsion of elemene
WO2015038736A2 (fr) 2013-09-16 2015-03-19 Merck Sharp & Dohme Corp. Formulations pour antagonistes du récepteur cgrp
WO2015164657A1 (fr) * 2014-04-23 2015-10-29 Bcs Business Consulting Services Pte Ltd Incorporation de composant(s) soluble(s) dans l'eau dans des formulations anhydres
WO2023220109A1 (fr) * 2022-05-11 2023-11-16 Eli Lilly And Company Compositions pharmaceutiques à base de glp1

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3134550A1 (fr) * 2019-04-11 2020-10-15 R.P. Scherer Technologies, Llc Formulation pour administration orale de proteines, de peptides et de petites molecules a faible permeabilite

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6191105B1 (en) * 1993-05-10 2001-02-20 Protein Delivery, Inc. Hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin
WO2004092166A2 (fr) * 2003-04-15 2004-10-28 Merck & Co., Inc. Antagonistes des recepteurs cgrp

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6191105B1 (en) * 1993-05-10 2001-02-20 Protein Delivery, Inc. Hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin
WO2004092166A2 (fr) * 2003-04-15 2004-10-28 Merck & Co., Inc. Antagonistes des recepteurs cgrp

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010002763A1 (fr) * 2008-06-30 2010-01-07 Merck & Co., Inc. Formes pharmaceutiques posologiques solides telcagepant potassique
JP2011526909A (ja) * 2008-06-30 2011-10-20 メルク・シャープ・エンド・ドーム・コーポレイション テルカゲパントカリウムの固形投与製剤
US20120322892A1 (en) * 2010-02-25 2012-12-20 Tian XIE Oral microemulsion of elemene
CN105531275A (zh) * 2013-09-16 2016-04-27 默沙东公司 用于cgrp受体拮抗剂的制剂
WO2015038736A3 (fr) * 2013-09-16 2015-11-12 Merck Sharp & Dohme Corp. Formulations pour antagonistes du récepteur cgrp
WO2015038736A2 (fr) 2013-09-16 2015-03-19 Merck Sharp & Dohme Corp. Formulations pour antagonistes du récepteur cgrp
KR20160055149A (ko) * 2013-09-16 2016-05-17 머크 샤프 앤드 돔 코포레이션 Cgrp 수용체 길항제를 위한 제제
AU2014318741B2 (en) * 2013-09-16 2018-12-06 Merck Sharp & Dohme Llc Formulations for CGRP receptor antagonists
RU2690006C2 (ru) * 2013-09-16 2019-05-30 Мерк Шарп И Доум Корп. Композиции антагонистов рецепторов cgrp
CN105531275B (zh) * 2013-09-16 2020-12-18 默沙东公司 用于cgrp受体拮抗剂的制剂
CN112545981A (zh) * 2013-09-16 2021-03-26 默沙东公司 用于cgrp受体拮抗剂的制剂
EP3915561A1 (fr) * 2013-09-16 2021-12-01 Merck Sharp & Dohme Corp. Formulations pour antagonistes du récepteur cgrp
KR102337994B1 (ko) 2013-09-16 2021-12-13 머크 샤프 앤드 돔 코포레이션 Cgrp 수용체 길항제를 위한 제제
WO2015164657A1 (fr) * 2014-04-23 2015-10-29 Bcs Business Consulting Services Pte Ltd Incorporation de composant(s) soluble(s) dans l'eau dans des formulations anhydres
WO2023220109A1 (fr) * 2022-05-11 2023-11-16 Eli Lilly And Company Compositions pharmaceutiques à base de glp1

Also Published As

Publication number Publication date
CA2662748A1 (fr) 2008-03-13
CN101511184A (zh) 2009-08-19
JP2010502710A (ja) 2010-01-28
WO2008030524A3 (fr) 2008-10-02
EP2063708A2 (fr) 2009-06-03
AU2007293032A1 (en) 2008-03-13

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