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WO2016036588A1 - Suspensions pharmaceutiques contenant de l'étoricoxib - Google Patents

Suspensions pharmaceutiques contenant de l'étoricoxib Download PDF

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Publication number
WO2016036588A1
WO2016036588A1 PCT/US2015/047352 US2015047352W WO2016036588A1 WO 2016036588 A1 WO2016036588 A1 WO 2016036588A1 US 2015047352 W US2015047352 W US 2015047352W WO 2016036588 A1 WO2016036588 A1 WO 2016036588A1
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WO
WIPO (PCT)
Prior art keywords
suspension
etoricoxib
pharmaceutical
pharmaceutical suspension
particles
Prior art date
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Ceased
Application number
PCT/US2015/047352
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English (en)
Inventor
Michael HESLINGA
Amitava Mitra
Sachin Mittal
James D. ORMES
Sanjaykumar Patel
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.)
Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Sharp and Dohme Ltd, Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme Ltd
Publication of WO2016036588A1 publication Critical patent/WO2016036588A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals

Definitions

  • the present invention provides pharmaceutical suspensions containing etoricoxib particles having a median particle diameter of 0.2 to 14 ⁇ , and an aqueous injection vehicle.
  • the present invention also provides methods for administering and preparing such compositions.
  • Arcoxia® etoricoxib, see figure below for structure
  • SAID small molecule nonsteroidal anti- inflammatory drug
  • COX-2 cyclooxygenase enzyme
  • Etoricoxib is approved and marketed as an oral tablet in more than 70 countries outside of the United States for, inter alia, the symptomatic relief of pain associated with osteoarthritis (OA) and rheumatoid arthritis (RA).
  • the currently available oral strengths are 30, 60, 90 and 120 mg once-daily (QD).
  • Oral dosing of etoricoxib is less practical in certain settings, for instance, for the relief of acute pain and the short-term treatment of perioperative pain in hospital patients. For that reason, providing an injectable image for etoricoxib for administration by either
  • IM intramuscular
  • IV intravenous
  • injectable formulations suitable for QD dosing are especially desirable.
  • Etoricoxib is an anhydrous free base with five identified polymorphs (Forms I - V) of the free base and two hydrates (sesquihydrate and hemihydrate).
  • Form V the thermodynamically stable polymorph
  • Etoricoxib has limited solubility in water; the relative equilibrium solubility of the hemihydrate being 0.07 mg/mL.
  • Etoricoxib has a pKa of 4.6 due to its pyridine functionality and, accordingly, the aqueous solubility is strongly pH dependent with extremely limited solubility with pH above its pKa.
  • the limited aqueous solubility of the compound combined with the requirements of a high daily dose (up to 120 mg) are major challenges for the development of an IV or IM product for once-daily administration. These challenges suggest an inadequate dose loading in a solution formulation and sub-therapeutic release from an insoluble matrix (e.g., suspension).
  • solubilizers such as buffers, counter ions, co-solvents, and/or surfactants
  • etoricoxib's limited aqueous solubility suggests that injection of a suspension-based formulation would result in prolonged elimination of the drug from the intramuscular space, and consequently, would fail to result in a successful once daily administration therapeutic regimen.
  • the present invention provides a pharmaceutical suspension comprising etoricoxib particles having a median particle diameter of 0.2 to 14 ⁇ ; and an aqueous injection vehicle.
  • the present invention also provides a method of treating a disorder selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and signs of inflammation associated with acute gouty arthritis, and pain associated with dental surgery, comprising administering such a pharmaceutical suspension 1 to a patient in need of such treatment.
  • Figure 1 is a graph showing the effect of the etoricoxib drug load on suspension viscosity for one embodiment of a pharmaceutical suspension of the invention.
  • Figure 2 is a graph showing the etoricoxib particle size (D50) of one embodiment of a pharmaceutical suspension of the invention over time while being milled on an acoustic mixer.
  • Figure 3 is a flow diagram showing one embodiment of a manufacturing process for an aqueous pharmaceutical suspension of the invention.
  • Figure 4 is a flow diagram showing one embodiment of a manufacturing process for a powder for suspension embodiment of the invention.
  • suspension-based composition containing etoricoxib with median particle diameter of approximately 0.2 to 14 microns when administered intramuscularly, surprisingly provide a 24 hour area under the curve (AUC) value greater than or similar to a reference oral formulation of etoricoxib containing the same amount of etoricoxib.
  • AUC area under the curve
  • Suspensions containing larger-sized etoricoxib particles, e.g., with a median diameter greater than 14 microns show limited 24 hour exposure, and consequently, are not expected to be useful for once-daily administration due to the requirement of higher doses for daily administration.
  • the applicants have found that the pharmacokinetic exposure after intramuscular injections of etoricoxib suspensions strongly depends on the drug's particle size. Selecting a suitable particle size allow achievement of therapeutic blood levels (24 hour AUC) for once-daily dosing for treating inflammatory disorders. Indeed, in certain embodiments of the invention, matching the pharmacokinetic properties (e.g., the 24 h AUC) of the injectable suspension with approved oral formulations leverages use of the oral safety package in filing with various regulatory filings. In other words, regulatory approval for the suspension-based formulation could be based on bioequivalence with the already-approved, oral tablet
  • buffering agent refers to a chemical component added to an aqueous solution or suspension so that the aqueous solution or suspension resists change in pH when acid or base is added or when the aqueous solution or suspension is diluted.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • isotonicity agent refers to a chemical component added to a solution or suspension to modify the osmotic pressure of the solution or suspension.
  • microsuspension refers to a suspension containing particles having a median particle diameter of larger than 1 micron and less than 10,000 microns, typically on the order of 1 to about 100 microns.
  • nanosuspension refers to a suspension containing particles having a median particle diameter smaller than 1 micron.
  • a "patient” is a human or non-human mammal. In one embodiment, a patient is a human. In another embodiment, a patient is a non-human mammal.
  • surfactant refers to a chemical component added to an aqueous solution or suspension to increase its wetting properties by reducing its surface tension.
  • terapéuticaally effective amount refers to an amount of etoricoxib, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from an inflammatory disorder.
  • treating refers to reversing the effects of the disorder, reducing the progression of the disorder, or providing relief from the discomfort or pain associated with the disorder.
  • viscosity modifying agent refers to a chemical component added to a solution or suspension to modify the viscosity of the solution or suspension.
  • water for injection refers to water that is purified such that is suitable for parenteral administration.
  • the invention provides a pharmaceutical suspension comprising etoricoxib particles having a median particle diameter of 0.2 to 14 ⁇ ; and an aqueous injection vehicle.
  • the invention provides a pharmaceutical suspension as set forth in embodiment no. 1, wherein the suspension comprises etoricoxib particles having a median particle diameter of 1 to 14 ⁇ .
  • the invention provides a pharmaceutical suspension as set forth in embodiment no. 1, wherein the suspension comprises etoricoxib particles having a median particle diameter of 1 to 5 ⁇ .
  • Suspensions with median particle size in range of 1 to 14 ⁇ or 1 to 5 ⁇ may be easier to manufacture and stabilize than suspensions containing smaller-sized particles of etoricoxib, e.g., with a median diameter below 1 micron, which suspensions are more complex to manufacture and prone to aggregation and physical instability.
  • Particle size may be measured by techniques such as laser diffraction, dynamic light scattering and image analysis.
  • the invention provides a pharmaceutical suspension as set forth in any one of embodiment nos. 1 to 3, wherein etoricoxib is present in the suspension at a concentration of from 50 to 300 mg/mL. In embodiment no. 5, the concentration of the etoricoxib in the suspension is 75 to 150 mg/mL.
  • the invention provides a pharmaceutical suspension as set forth in any one of embodiment nos. 1 to 5, wherein the aqueous injection vehicle comprises a surfactant, for example a surfactant approved for intramuscular administration.
  • a surfactant for example a surfactant approved for intramuscular administration.
  • Surfactants aid in wetting the etoricoxib particles with the aqueous injection vehicle.
  • the vehicle may include a single surfactant or a combination of surfactants (e.g., two surfactants).
  • the aqueous injection vehicle comprises a surfactant is selected from the group consisting of a polysorbate, a poloxamer and sodium deoxycholate.
  • the surfactant is selected from the group consisting of polysorbate 80, poloxyamer 188 and sodium deoxycholate.
  • the surfactant is polysorbate 80.
  • the invention provides a pharmaceutical suspension as set forth in any one of embodiment nos. 1 to 9, wherein the suspension has a ratio of
  • etoricoxib surfactant of from 2000: 1 to 10: 1. In embodiment no. 1 1, the etoricoxib: surfactant ratio is from 200: 1 to 25: 1.
  • the invention provides a pharmaceutical suspension as set forth in any one of embodiment nos. 1 to 1 1, wherein the injection vehicle comprises a viscosity modifying agent.
  • Viscosity modifiers can enhance the suspension's stability, and permit the suspension to have an acceptable shelf life. Such modifiers can be added to retard settling of the etoricoxib particles in a vial or syringe.
  • the aqueous injection vehicle comprises a viscosity modifying agent selected from the group consisting of a polyethylene glycol (e.g., polyethylene glycol 3350) and sodium carboxymethylcellulose, although other viscosity modifying agents could be used.
  • the viscosity modifying agent is polyethylene glycol 3350.
  • the pharmaceutical suspension is as set forth in any one of embodiment nos. 12 to 14, wherein the concentration of the viscosity modifying agent is from 0.1 to 6 w/v%.
  • the pharmaceutical suspension is as set forth in any one of embodiment nos. 1 to 15, wherein the aqueous injection vehicle has a viscosity of from 0.84 to 1.79 cP.
  • the invention provides a pharmaceutical suspension as set forth in any one of embodiment nos. 1 to 16, wherein the pharmaceutical suspension has a viscosity of 1.98 to 5.31 cP. In embodiment no. 18, the pharmaceutical suspension has a viscosity of from 2.2 to 3.2 cP.
  • the invention provides a pharmaceutical suspension as set forth in any one of embodiment nos. 1 to 18, wherein the injection vehicle comprises an isotonicity agent. Isotonicity agents are added to adjust the tonicity of the vehicle to improve the biocompatibility of the suspension. In embodiment no. 20, the isotonicity agent is present at from 0.5 to 8.0 w/v%.
  • the isotonicity agent is selected from the group consisting of a parenterally acceptable sugar and sodium chloride.
  • the isotonicity agent is sodium chloride.
  • the sodium chloride is present in the injection vehicle at a concentration of from 0.5 to 1.2 w/v%.
  • the isotonicity agent is a parenterally acceptable sugar.
  • the parenterally acceptable sugar is selected from the group consisting of mannitol, sucrose, dextrose, sorbitol, and lactose.
  • the parenterally acceptable sugar is mannitol.
  • mannitol is present in the injection vehicle at a concentration of from 2.0 to 8.0 w/v%.
  • an appropriate pH for a suspension product is greater than pH 4.5.
  • Table 2 Etoricoxib solubility vs. vehicle pH in 0.1M buffer at 25°C
  • Buffering agents can be included to provide pharmaceutical suspensions having pHs compatible for injection into the intramuscular space.
  • Suitable buffering agents are those which are parenterally acceptable and that can provide a buffering range somewhere in the range of pH 5 to 9.
  • the invention provides a pharmaceutical suspension as set forth in any one of embodiment nos. 1 to 27, wherein the injection vehicle comprises a buffering agent.
  • the buffering agent is a phosphate buffer, a citrate buffer, an acetate buffer, a carbonate buffer or TRIS.
  • the invention provides a pharmaceutical suspension as set forth in any one of embodiment nos. 1 to 29, wherein the suspension has a pH of between 5 and 9.
  • the invention provides a pharmaceutical suspension as set forth in any one of embodiment nos. 1 to 30, wherein the suspension comprises 30, 60, 90, or 120 mg of etoricoxib.
  • the suspension comprises 30 mg of etoricoxib.
  • the suspension comprises 60 mg of etoricoxib.
  • the suspension comprises 90 mg of etoricoxib.
  • the suspension comprises 120 mg of etoricoxib.
  • the invention provides a pharmaceutical suspension comprising etoricoxib particles having a median particle diameter of 0.2 to 14 ⁇ ; an aqueous injection vehicle, and a surfactant.
  • the invention provides a pharmaceutical suspension as set forth in embodiment no. 35, further comprising a viscosity modifying agent.
  • embodiment no. 38 the invention provides a pharmaceutical suspension as set forth in embodiment no. 36, wherein:
  • the suspension comprises etoricoxib particles as set forth in embodiment no. 2, the surfactant is as set forth in embodiment no. 7,
  • the viscosity modifying agent is as set forth in embodiment no. 13;
  • the isotonicity agent is as set forth in embodiment no. 21.
  • the invention provides a pharmaceutical suspension as set forth in embodiment no. 38, further comprising a buffering agent as set forth in embodiment no. 29.
  • compositions may be presented in unit dose forms containing a predetermined amount of etoricoxib per unit dose. Such unit doses may be administered once a day, or more frequently.
  • Preferred unit dosage compositions are those containing a daily dose of etoricoxib.
  • the pharmaceutical suspensions of the invention are administered to a patient by injecting the pharmaceutical suspension into the patient's intramuscular space.
  • the administration typically comprises injection from a needle fixed to the syringe.
  • the present invention provides a syringe comprising pharmaceutical suspension as described in any one of embodiment nos. 1-39 and a syringe needle.
  • Needles useful for administering the pharmaceutical suspensions of the invention include needles having a needle gauge of 19 to 25. As will be apparent to those skilled in the art, injecting parenteral suspensions using as small a needle as possible is desirable to minimize the patient's discomfort.
  • the pharmaceutical suspensions of the invention can be administered using needles with a needle gauge of 21 to 23, and in certain embodiments the suspensions may be administered through a 25G needle.
  • the pharmaceutical suspensions may be provided in vials as preformed suspensions with etoricoxib particles and an aqueous injection vehicle ready for injection in a single container, e.g., a vial for injection.
  • a vial for injection comprising a pharmaceutical suspension as set forth in any one of embodiment nos. 1-39.
  • etoricoxib particles prepared as a powder for injection are provided in a first container and the aqueous injection vehicle is provided in a second container.
  • the medical practitioner could constitute the pharmaceutical suspension by adding the aqueous injection vehicle from the second container to the first container, mix the suspension to prepare a uniform suspension, and then transfer the uniform suspension to a needle and syringe for injection administration.
  • a lyophilate containing etrocoxib and one or more pharmaceutically acceptable excipients is provided in a first container and water for injection is provided in a second container.
  • a medical practitioner could reconstitute and administer the pharmaceutical suspension as described above.
  • the pharmaceutical suspensions can be used for the treatment of inflammatory disorder and for the treatment of pain from other disorders.
  • the pharmaceutical suspensions can be administered to a patient in need thereof for the symptomatic relief of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, the pain and signs of inflammation associated with acute gouty arthritis, and postoperative dental surgery pain.
  • the pharmaceutical suspensions of the invention are administed to a patient for the treatment of osteoarthritis.
  • the pharmaceutical suspensions administered to a patient in need of treatment for osteoarthritis are in unit dosage forms which contain 30 or 60 mg of etoricoxib.
  • the pharmaceutical suspensions of the invention are administed to a patient for the treatment of rheumatoid arthritis.
  • the pharmaceutical suspensions administered to a patient in need of treatment for rheumatoid arthritis are in unit dosage forms which contain 90 mg of etoricoxib.
  • the pharmaceutical suspensions of the invention are administed to a patient for the treatment of ankylosing spondylitis.
  • the pharmaceutical suspensions administered to a patient in need of treatment for ankylosing spondylitis are in unit dosage forms which contain 90 mg of etoricoxib.
  • the pharmaceutical suspensions of the invention are administed to a patient for the treatment of the pain and signs of inflammation associated with acute gouty arthritis.
  • the pharmaceutical suspensions administered to a patient in need of treatment for the pain and signs of inflammation associated with acute gouty arthritis are in unit dosage forms which contain 120 mg of etoricoxib.
  • the pharmaceutical suspensions of the invention are administed to a patient for the treatment of postoperative dental surgery pain.
  • the pharmaceutical suspensions administered to a patient in need of treatment for postoperative dental surgery pain are in unit dosage forms which contain 90 mg of etoricoxib.
  • the pharmaceutical suspensions of this invention may be made by a number of methods described below and in the examples.
  • Etoricoxib can be prepared by the methods described in U.S. Patent Nos. 5,861,419 and 6,040,319, as well as other methods.
  • the present invention provides a method of preparing a pharmaceutical suspension having etoricoxib particles having a median particle diameter of 0.2 to 14 ⁇ , an aqueous injection vehicle, and at least one pharmaceutically acceptable excipient, the method comprising:
  • the method is as set forth above, wherein the method further comprises milling the pharmaceutical suspension of (b) with a milling media to provide a suspension comprising particles having a median diameter of rom 0.2 to 1 ⁇ .
  • Materials suitable for the milling media include media comprised of ceramic-, polystyrene- or yttria-coated zirconia-based materials.
  • the suspension of (b) is lyophilized to form a lyophilate, and the lyophilate is combined with water for injection to form the pharmaceutical suspension.
  • This embodiment is useful for providing a product wherein the lyophilate is provided in a first container and the water for injection is provided in a second container. The medical practitioner can prepare the pharmaceutical suspension immediately prior to administration by
  • G needle gauge
  • PEG polyethylene glycol
  • D50 median particle diameter by volume
  • AMB ambient relative humidity
  • RH relative humidity
  • TRIS tris(hydroxymethyl)aminomethane
  • the injectable microsuspensions were prepared as 2 mg/mL etoricoxib in 0.2% polysorbate 80, 0.5%> PEG3350 and 5%> mannitol and were dosed at 1.0 mL/kg.
  • Table 1 Pharmacokinetic parameters (mean) in rats following administration of etoricoxib formulations at a dose of 2 mg/kg (n>3)
  • a pharmaceutical suspension achieved better or similar 24 hour exposure to an equivalent oral dose containing etoricoxib wherein the median particle size is smaller than ⁇ 5 ⁇ .
  • the injectable suspension containing etoricoxib with a median particle diameter larger than ⁇ 14 ⁇ resulted in a lower exposure than did the oral suspension.
  • Etoricoxib microsuspension formulations were prepared in the following manner.
  • Etoricoxib was jet-milled or pin-milled to the desired particle size.
  • Suspension media components surfactants, viscosity modifiers, buffers, isotonicity agent
  • Milled etoricoxib was added to the suspension medium and stirred until a uniform suspension was made. Water-for-injection was added to bring the suspension to the desired volume.
  • Suspension prototypes were prepared and evaluated for physical stability. Several of these prototype compositions are given below in Table 3. Particle size was measured on a Malvern Mastersizer 2000 with a Hydro S accessory using a Frauhofer method with 30 seconds of sonication. Suspensions 1 - 24 contain jet-milled etoricoxib API with mean particle diameter approximately 4.6 microns. Suspension 25 contained pin-milled etoricoxib API with mean particle diameter of approximately 13.9 microns.
  • Table 3 Evaluated suspension formulations of etoricoxib (ETO) for intramuscular injection.
  • ETO etoricoxib
  • NaCl sodium chloride
  • T80 polysorbate 80
  • NaDeoxy sodium deoxycholate
  • P0II88 poloxamer 188
  • PEG3350 polyethylene glycol with 3350 MW
  • NaCMC sodium carboxymethylcellulose
  • buffer phosphate buffer (in mM)
  • % % w/v.
  • Zeta potential was measured using a Malvern Zetasizer NanoSeries. Suspension zeta potentials were slightly negative. Osmolarity was measured using an Osmette III freezing point osmometer. All suspension formulations measured had osmolarity values above 290 mOsm and are acceptable for injection. Viscosity was measured using a VISCOlab 3000. Suspension samples generally had viscosities greater than lcP and may reduce the risk of caking over the shelf life.
  • Suspensions Nos. 10, 9, 1 1 and 24 were evaluated for viscosity of the suspensions and suspension vehicle as a function of etoricoxib concentration. Viscosity of the above samples was measured using a VISCOlab 3000. Figure 1 displays the effect of etoricoxib concentration on the viscosities of the suspensions.
  • Suspension Nos. 10, 9, 11, 24, 25, 21 and 23 from Example 2 were evaluated for syringeability and injectability of the suspensions.
  • 1 mL of the suspension was withdrawn from a vial into a 3 mL syringe and injected over 5 seconds through varying needle gauges.
  • the force required to complete the simulated injection was recorded with a texture analyzer and the needle gauge was determined to be acceptable if the 5 second injection required less than 15 N to empty the syringe and no cake filtration was observed.
  • Etoricoxib nanosuspension formulations were prepared in the following manner.
  • Suspension media components surfactants, viscosity modifiers, buffers, isotonicity agents
  • surfactants surfactants, viscosity modifiers, buffers, isotonicity agents
  • Un-milled etoricoxib was added to the suspension medium, and the mixture was stirred until a uniform suspension was achieved.
  • Water-for-injection was added to bring the suspension to the desired volume.
  • a nanosuspension was prepared with the composition given below:
  • a suspension for administration is made by combining sterile etoricoxib as the active pharmaceutical ingredient (API) (sterilized via gamma irradiation or sterile
  • a powder for suspension prior to administration is made with a two vial product for combination at the time of administration ( Figure 4).
  • the vehicle is compounded, sterile filtered, filled into vials, stopperd and sealed, and may optionally be followed by terminal steam sterilization.
  • the API is sterilized via gamma irradiation or sterile recrystallization and aseptically filled into vials under a class 100 environment, stoppered and capped.

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Abstract

La présente invention concerne des suspensions pharmaceutiques contenant des particules d'étoricoxib ayant un diamètre particulaire moyen de 0,2 µm à 14 µm, et un véhicule d'injection aqueux. L'invention concerne également des méthodes d'administration et de préparation de telles compositions.
PCT/US2015/047352 2014-09-03 2015-08-28 Suspensions pharmaceutiques contenant de l'étoricoxib Ceased WO2016036588A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Publication number Priority date Publication date Assignee Title
WO2019130049A1 (fr) 2017-12-29 2019-07-04 Grünenthal GmbH Combinaison pharmaceutique comprenant du chlorhydrate de tramadol à libération prolongée et de l'étoricoxib à libération immédiate, et son utilisation pour le traitement de la douleur
WO2022084967A1 (fr) * 2020-10-23 2022-04-28 Cadila Healthcare Limited Solutions parentérales d'inhibiteur sélectif de cyclooxygénase-2 (cox-2) et leur utilisation pour le traitement de la douleur/de l'arthrite
CN113332250A (zh) * 2021-07-15 2021-09-03 诺言医药科技(上海)有限公司 一种谷氨酰胺酶抑制剂冻干粉及其制备方法和应用
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