WO2016036588A1

WO2016036588A1 - Pharmaceutical suspensions containing etoricoxib

Info

Publication number: WO2016036588A1
Application number: PCT/US2015/047352
Authority: WO
Inventors: Michael HESLINGA; Amitava Mitra; Sachin Mittal; James D. ORMES; Sanjaykumar Patel
Original assignee: Merck Sharp and Dohme Ltd; Merck Sharp and Dohme LLC
Current assignee: Organon Pharma UK Ltd; Merck Sharp and Dohme LLC
Priority date: 2014-09-03
Filing date: 2015-08-28
Publication date: 2016-03-10
Anticipated expiration: 2017-03-03

Abstract

The present invention provides pharmaceutical suspensions containing etoricoxib particles having a median particle diameter of 0.2 to 14 μm, and an aqueous injection vehicle. The present invention also provides methods for administering and preparing such compositions.

Description

PHARMACEUTICAL SUSPENSIONS CONTAINING ETORICOXIB

FIELD OF THE INVENTION

[0001] The present invention provides pharmaceutical suspensions containing etoricoxib particles having a median particle diameter of 0.2 to 14 μιη, and an aqueous injection vehicle. The present invention also provides methods for administering and preparing such compositions.

BACKGROUND OF THE INVENTION

[0002] Arcoxia® (etoricoxib, see figure below for structure) is a small molecule nonsteroidal anti- inflammatory drug ( SAID) that selectively inhibits isoform 2 of the cyclooxygenase enzyme (COX-2). 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).

[0003] 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

intramuscular (IM) or intravenous (IV) injection/infusion is desirable. In particular, providing injectable formulations suitable for QD dosing are especially desirable.

[0004] The properties of etoricoxib present challenges to the development of injectable formulations of the drug. 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, is utilized in the marketed oral product. However, this form quickly converts to the hemihydrate form when stirred in water. 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. [0005] 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). Use of typical solubilizers, such as buffers, counter ions, co-solvents, and/or surfactants in aqueous solutions fail to overcome the low solubility of etoricoxib so as to yield a suitable solution-based injectable formulation. On the other hand, 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.

SUMMARY OF THE INVENTION

[0006] The present invention provides a pharmaceutical suspension comprising etoricoxib particles having a median particle diameter of 0.2 to 14 μιη; and an aqueous injection vehicle.

[0007] 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.

[0008] Also provided is a method of preparing a pharmaceutical suspension having etoricoxib particles having a median particle diameter of 0.2 to 14 μιη, an aqueous injection vehicle, and at least one pharmaceutically acceptable excipient, the method comprising:

(a) dissolving the at least one pharmaceutically acceptable excipient in the aqueous injection vehicle to form an aqueous solution; and

(b) combining the etoricoxib particles with the aqueous solution to form the pharmaceutical suspension.

BRIEF DESCRIPTION OF THE FIGURES

[0009] 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.

[0010] 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.

[0011] Figure 3 is a flow diagram showing one embodiment of a manufacturing process for an aqueous pharmaceutical suspension of the invention. [0012] Figure 4 is a flow diagram showing one embodiment of a manufacturing process for a powder for suspension embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0013] The applicants have discovered that a 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. 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.

[0014] As noted above, 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

formulations.

Definitions

[0015] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated.

[0016] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0017] The term "buffering agent, as used herein, 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.

[0018] As used herein, the term "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.

[0019] The term "isotonicity agent," as used herein, refers to a chemical component added to a solution or suspension to modify the osmotic pressure of the solution or suspension.

[0020] The term "microsuspension," as used herein, 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.

[0021] The term "nanosuspension," as used herein, refers to a suspension containing particles having a median particle diameter smaller than 1 micron.

[0022] 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.

[0023] The term "surfactant," as used herein, refers to a chemical component added to an aqueous solution or suspension to increase its wetting properties by reducing its surface tension.

[0024] The term "therapeutically effective amount" as used herein, 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.

[0025] The term "treating," as used herein with respect to an inflammatory disorder, 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.

[0026] The term "viscosity modifying agent," as used herein, refers to a chemical component added to a solution or suspension to modify the viscosity of the solution or suspension.

[0027] The term "water for injection," as used herein, refers to water that is purified such that is suitable for parenteral administration.

Pharmaceutical Suspensions of the Invention

[0028] Described below are embodiments of the pharmaceutical suspensions of the invention.

[0029] In embodiment no. 1, the invention provides a pharmaceutical suspension comprising etoricoxib particles having a median particle diameter of 0.2 to 14 μιη; and an aqueous injection vehicle. In embodiment no. 2, 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 μιη. In embodiment no. 3, 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 μιη. Suspensions with median particle size in range of 1 to 14 μιη or 1 to 5 μιη 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.

[0030] In embodiment no. 4, 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.

[0031] In embodiment no. 6, 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. 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). In embodiment no. 7, the aqueous injection vehicle comprises a surfactant is selected from the group consisting of a polysorbate, a poloxamer and sodium deoxycholate. In embodiment no. 8, the surfactant is selected from the group consisting of polysorbate 80, poloxyamer 188 and sodium deoxycholate. In embodiment no. 9, the surfactant is polysorbate 80.

[0032] In embodiment no. 10, 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.

[0033] In embodiment no. 12, 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.

[0034] In embodiment no. 13, 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. In embodiment 14, the viscosity modifying agent is polyethylene glycol 3350. In embodiment no. 15, 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%.

[0035] In embodiment no. 16, 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.

[0036] In embodiment no. 17, 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.

[0037] In embodiment no. 19, 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%.

[0038] In embodiment no. 21, the isotonicity agent is selected from the group consisting of a parenterally acceptable sugar and sodium chloride.

[0039] In embodiment no. 22, the isotonicity agent is sodium chloride. In embodiment no. 23, the sodium chloride is present in the injection vehicle at a concentration of from 0.5 to 1.2 w/v%.

[0040] In embodiment no. 24, the isotonicity agent is a parenterally acceptable sugar. In embodiment no. 25, the parenterally acceptable sugar is selected from the group consisting of mannitol, sucrose, dextrose, sorbitol, and lactose. In embodiment no. 26, the parenterally acceptable sugar is mannitol. In embodiment no 27, mannitol is present in the injection vehicle at a concentration of from 2.0 to 8.0 w/v%.

[0041] Based on the compound's solubility profile, an appropriate pH for a suspension product is greater than pH 4.5. As can be seen in Table 2 below, the solubility of etoricoxib in aqueous vehicles having a higher pH. Table 2: Etoricoxib solubility vs. vehicle pH in 0.1M buffer at 25°C

[0042] 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.

[0043] In embodiment no. 28, 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. In embodiment no. 29, the buffering agent is a phosphate buffer, a citrate buffer, an acetate buffer, a carbonate buffer or TRIS.

[0044] In embodiment no. 30, 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.

[0045] In embodiment no. 31, 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. In embodiment no. 32, the suspension comprises 30 mg of etoricoxib. In embodiment no. 32, the suspension comprises 60 mg of etoricoxib. In embodiment no. 33, the suspension comprises 90 mg of etoricoxib. In embodiment no. 34, the suspension comprises 120 mg of etoricoxib.

[0046] In embodiment no. 35, the invention provides a pharmaceutical suspension comprising etoricoxib particles having a median particle diameter of 0.2 to 14 μηι; an aqueous injection vehicle, and a surfactant.

[0047] In embodiment no. 36, the invention provides a pharmaceutical suspension as set forth in embodiment no. 35, further comprising a viscosity modifying agent. [0048] In embodiment no. 37, the invention provides a pharmaceutical suspension as set forth in embodiment no. 36, further comprising an isotonicity agent.

[0049] In 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; and

the isotonicity agent is as set forth in embodiment no. 21.

[0050] In embodiment no. 39, 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.

Forms and Uses of the Pharmaceutical Suspensions

[0051] Pharmaceutical suspension of the present invention 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.

[0052] Typically, 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. Thus, in one embodiment, the present invention provides a syringe comprising pharmaceutical suspension as described in any one of embodiment nos. 1-39 and a syringe needle.

[0053] 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. Advantageously, 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.

[0054] 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. Thus, in one embodiment the present invention provides a vial for injection comprising a pharmaceutical suspension as set forth in any one of embodiment nos. 1-39. [0055] Alternatively, 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.

[0056] In still other embodiments, 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.

[0057] The pharmaceutical suspensions can be used for the treatment of inflammatory disorder and for the treatment of pain from other disorders.

[0058] In particular, 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.

[0059] In particular embodiments, the pharmaceutical suspensions of the invention are administed to a patient for the treatment of osteoarthritis. In specific embodiments 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.

[0060] In certain embodiments, the pharmaceutical suspensions of the invention are administed to a patient for the treatment of rheumatoid arthritis. In specific embodiments 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.

[0061] In particular embodiments, the pharmaceutical suspensions of the invention are administed to a patient for the treatment of ankylosing spondylitis. In specific embodiments 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.

[0062] In certain embodiments, 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. In specific embodiments 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. [0063] In particular embodiments, the pharmaceutical suspensions of the invention are administed to a patient for the treatment of postoperative dental surgery pain. In specific embodiments 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.

Methods of Preparing the Pharmaceutical Suspensions

[0064] 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.

[0065] In one embodiment, the present invention provides a method of preparing a pharmaceutical suspension having etoricoxib particles having a median particle diameter of 0.2 to 14 μιη, an aqueous injection vehicle, and at least one pharmaceutically acceptable excipient, the method comprising:

(a) dissolving the at least one pharmaceutically acceptable excipient (e.g. , a surfactant, viscosity modifying agent, an isotonicity agent, a buffering agent) in the aqueous injection vehicle to form an aqueous solution; and

[0066] In one embodiment, 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 μιη. Materials suitable for the milling media include media comprised of ceramic-, polystyrene- or yttria-coated zirconia-based materials.

[0067] In another embodiment, 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

reconstitituting the lyophilate with the water for injection.

[0068] The following examples are provided so that the invention may be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

[0069] The following reagents and other designations may be referred to by their abbreviations: [0070] cP: centipoise

[0071] G: needle gauge

[0072] h: hours

[0073] kg: kilogram

[0074] w/v: weight/volume

[0075] μηι: micrometer

[0076] mg: milligram

[0077] mL: milliliter

[0078] mM: millimolar

[0079] PEG: polyethylene glycol

[0080] QS: quantity sufficient

[0081] D50: median particle diameter by volume

[0082] AMB: ambient relative humidity

[0083] RH: relative humidity

[0084] TRIS : tris(hydroxymethyl)aminomethane)

EXAMPLES

Example 1 - Pharmacokinetic Study in Rodents

[0085] Pharmacokinetic studies in Sprague Dawley rats were performed comparing injectable suspensions with an oral suspension. The rats (n=3-4) were given a 2 mg/kg dose either orally or intramuscularly. The oral suspension was prepared as a 0.57 mg/mL etoricoxib suspension in 0.5% methocel and dosed at 3.5 mL/kg. The injectable nanosuspension (with a particle diameter of 0.4 μπι) with was prepared as 1.1 mg/mL etoricoxib in 0.5% polysorbate 80, 0.5%) PEG3350 and 5% mannitol and was dosed at 1.8 mL/kg. 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)

[0086] As can seen in Table 1 , 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 μιη. The injectable suspension containing etoricoxib with a median particle diameter larger than ~14 μιη resulted in a lower exposure than did the oral suspension.

Example 2 - Preparation of Microsuspensions and Assessment of Associated Properties

[0087] 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) were added in the desired amounts to water-for-injection and stirred until dissolved. 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.

[0088] A representative suspension was prepared with the composition given below in

Table 2:

[0089] Approximately 7 mL of water-for- injection was added to a vessel. 500 mg polyethylene glycol with molecular weight -3350 was added to the vessel. The vessel was heated to ~40°C, and stirred until the polyethylene glycol dissolved. The solution was allowed to cool to room temperature. 20 mg polysorbate 80 was added to the vessel and the mixture was stirred until the polysorbate 80 dissolved. 50 mM of sodium phosphate was added to the vessel, and the mixture stirred until the sodium phosphate dissolved. 90 mg sodium chloride was added to the vessel, and the mixture was stirred until the sodium chloride dissolved. The solution was filtered through a 0.22 μιη filter. 1000 mg pin-milled etoricoxib (D₅₀ = 13.9 μιη) was added to the vessel, and the mixture was stirred until a uniform suspension was achieved. The pH was adjusted to 7.0 ± 0.1 with hydrochloric acid or sodium hydroxide as needed. Water- for- injection was added to the suspension as needed to bring the final volume to 10 mL.

[0090] 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. 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.

Table 4: zeta potential, osmolarity and viscosity of the suspension medium for suspension prototypes. Not measured = nm.

[0091] 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.

Example 3 - Additional Stability Assays for Suspensions 9 and 15

Stability:

[0092] Additional stability studies were conducted for etoricoxib powder (particles having a median diameter of 4.6 microns), and for Suspension Nos. 9 and 15 from Example 2. The percentage of etoricoxib remaining and accumulation of degradation products under the aging conditions was determined using HPLC methods.

[0093] Gamma irradiation of etoricoxib powder was performed at 15, 25 or 40 kGy. No degradation was observed at any radiation dose and gamma-irradiated powder (40 kGy) was stable for at least one month at 40°C/75%RH and 60°C/AMB (Table 5). Additionally, gamma- irradiated powders suspended in Suspension Nos. 9 and 15 were stable, and no degradation was observed for at least one month at 40°C/75%RH, similar to suspensions not subjected to radiation (Tables 6 and 7).

Table 5 : Stability of gamma-irradiated (40 kGy) etoricoxib powder

Table 6: Stability at 25°C/60%RH of etoricoxib suspended in buffered formulations

Table 7: Stability at 40°C/75%RH of etoricoxib suspended in buffered formulations

API stuck to vial in mannitol formulation at 40°/75%RH, nm = not measured

Example 4 - Evaluation of the Suspension Formulations for Syringe Configurations fitted with Needles of Various Gauges

[0094] 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.

[0095] 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.

Table 8: The impact of needle gauge on the syringeability of microsuspension formulation

Example 5 - Preparation of Nanosuspensions

[0096] Etoricoxib nanosuspension formulations were prepared in the following manner.

Suspension media components (surfactants, viscosity modifiers, buffers, isotonicity agents) were added in the desired amounts to water-for-injection and stirred until dissolved. 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.

[0097] For example, a nanosuspension was prepared with the composition given below:

[0098] Approximately 7 mL of water-for-injection was added to a vessel. 50 mg polyethylene glycol with molecular weight -3350 was added to the vessel and stirred until dissolved. 50 mg polysorbate 80 was added to the vessel and stirred until dissolved. The solution was filtered through a 0.22 μιη filter. 500 mg un-milled etoricoxib was added to the vessel and stirred until a uniform suspension was achieved. Water-for-injection was added to the suspension as needed to bring the final volume to 10 mL. Approximately 7 mL of suspension was added to a custom ceramic tube filled with zirconium beads and the tube was placed on a Resodyn™ acoustic mixer (LabRAM) and milled for 120 minutes at 70% intensity. The particle size D50 was monitored over time and is shown in Figure 2.

Example 6 - Manufacturing Preparation of an Aqueous Suspension for Injection Product Image

[0099] The description provided for this process is prophetic.

[00100] A suspension for administration is made by combining sterile etoricoxib as the active pharmaceutical ingredient (API) (sterilized via gamma irradiation or sterile

recrystallization) and sterile filtered excipents in a class 100 area (Figure 3). The vehicle and API is mixed aseptically into a homogenous suspension and filled into vials under bulk mixing. Lyophilization of the filled suspension is performed after this step. Example 7 - Manufacturing Preparation of a Powder for Suspension Product Image

[00101] The description provided for this process is prophetic.

[00102] 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.

[00103] While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical suspension comprising etoricoxib particles having a median particle diameter of 0.2 to 14 μηι; and an aqueous injection vehicle.

2. The pharmaceutical suspension of claim I, wherein etoricoxib is present in the suspension at a concentration of from 50 to 300 mg/mL.

3. The pharmaceutical suspension of claim I, wherein the aqueous injection vehicle comprises a surfactant.

4. The pharmaceutical suspension of claim 3, wherein the surfactant is selected from the group consisting of a polysorbate, a poloxamer and sodium deoxycholate.

5. The pharmaceutical suspension of claim 3, wherein the suspension has a ratio of etoricoxib: surfactant of from 2000: 1 to 10: 1.

6. The pharmaceutical suspension of claim 1, wherein the aqueous injection vehicle comprises a viscosity modifying agent.

7. The pharmaceutical suspension of claim 6, wherein the viscosity modifying agent is selected from the group consisting of a polyethylene glycol and sodium carboxymethylcellulose.

8. The pharmaceutical suspension of claim 1, wherein the aqueous injection suspension has a viscosity of 1.98 to 5.31 cP.

9. The pharmaceutical suspension of claim 1, wherein the injection vehicle comprises an isotonicity agent.

10. The pharmaceutical suspension of claim 9, wherein the isotonicity agent is selected from the group consisting of a parenterally acceptable sugar and sodium chloride.

11. The pharmaceutical suspension of claim 1, wherein the injection vehicle comprises a buffering agent.

12. The pharmaceutical suspension of claim 1, wherein the buffering agent is a phosphate buffer, a citrate buffer, an acetate buffer, a carbonate buffer and TRIS.

13. The pharmaceutical suspension of claim 1, wherein the suspension has a pH of between 5 and 9.

14. The pharmaceutical suspension of claim 1, wherein the suspension comprises 30, 60, 90, or 120 mg of etoricoxib.

15. 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 the pharmaceutical suspension of claim 1 to patient in need of such treatment.

16. The method of claim 15, wherein the patient has an intramuscular space and the administration comprises injecting the pharmaceutical suspension into the patient's intramuscular space.

17. The pharmaceutical suspension of claim 1 for use in 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.

18. A method of preparing a pharmaceutical suspension having etoricoxib particles having a median particle diameter of 0.2 to 14 μτη, an aqueous injection vehicle, and at least one pharmaceutically acceptable excipient, the method comprising:

19. The method of claim 18, further comprising the step of: milling the pharmaceutical suspension of (b) with a milling media to provide a suspension comprising particles having a median diameter of from 0.2 to 1 μιη.

20. The method of claim 18 further comprising the steps of: lyophilizing the suspension of (b) to form a lyophilate; and

combining the lyophilate with water for injection to form the pharmaceutical composition.

21. A syringe comprising the pharmaceutical suspension of claim 1 and a syringe needle.

22. A vial for injection comprising the pharmaceutical suspension of claim 1.