JP2020109115A - Emulsion comprising nk-1 receptor antagonist - Google Patents

Abstract

To provide an emulsion comprising an NK-1 receptor antagonist.SOLUTION: Disclosed herein are novel pharmaceutical formulations of a neurokinin-1 (NK-1) receptor antagonist suitable for parenteral administration including intravenous administration. Also included are formulations including both the NK-1 receptor antagonist and dexamethasone sodium phosphate. The pharmaceutical formulations are stable oil-in-water emulsions for non-oral treatment of emesis and are particularly useful for treatment of subjects undergoing highly emetogenic cancer chemotherapy.SELECTED DRAWING: None

Description

(Technical field)
The present disclosure generally relates to emulsion formulations and systems for intravenous or parenteral administration of NK-1 receptor antagonists for the treatment of emesis. Emulsion formulations are stable for long periods. Also described are methods of preparing stable NK-1 receptor antagonist emulsions and pharmaceutical formulations.

Emesis is a serious problem experienced as a result of anti-cancer cytotoxic therapy. Up to 80% of patients experience chemo-induced nausea and vomiting (CINV) without prophylactic treatment (Vieira dos Santos et al., 2012, J Natl Cancer Inst, 104: 1280-1292). page). Navari et al. (1999, N Engl J Med, 340: 190-195) have reported that when neurokinin-1 (NK-1) receptor antagonists are used in combination with cisplatin-based chemotherapy, It was shown to improve CINV. NK-1 receptor antagonists block the binding of substance P to the receptor, thereby preventing or limiting the induction of the vomiting pathway mediated by the NK-1 receptor (Aziz, 2012, Ann Palliat). Med, Vol. 1: 130-136).

Currently approved and commercially available NK-1 receptor antagonists include aprepitant and lorapitant HCl, both of which are available in oral form. Not surprisingly, oral dosage forms can cause problems, especially for patients suffering from emesis, for example, on days 2 and 3 of chemotherapy. Therefore, it is desirable to have an injectable formulation that simplifies treatment for these patients. Described herein are emulsions that are formulated for administration to a patient by injection. These emulsions are formulated to contain a neurokinin-1 receptor antagonist that may be poorly soluble in aqueous solvents or unstable in liquid water-based formulations.

Vieira dos Santos et al., 2012, J Natl Cancer Inst, 104:1280-1292. Navari et al. (1999, N Engl J Med, 340:190-195). Aziz, 2012, Ann Pallit Med, 1:130-136.

Liquid formulations containing NK-1 receptor antagonists with poor solubility and/or poor gastrointestinal permeability characteristics can be very challenging to formulate for long term storage and administration .. One means of addressing this challenge is to prepare emulsions that can both allow the preparation of injectable formulations and, once administered, can enhance the bioavailability of the active agent.

Intravenous emulsions should have a very small droplet size to circulate in the bloodstream without causing capillary blockage and embolization. These size limits are typified by the USP 33-NF28 General Rule <729> (hereinafter referred to as USP <729>) for droplet size distribution in injectable lipid emulsions, USP <729> being (1) Mean droplet size not exceeding 500 nm or 0.5 μm, and (2) large diameter fat expressed as volume weighted percentage of fat (PFAT5) greater than 5 μm not exceeding 0.05% regardless of final lipid concentration. Define a universal limit for the population of droplets.

Emulsion formulations must be physically stable. Droplet size limits defined in USP <729> apply over a specified shelf life. All true emulsions are thermodynamically unstable and can undergo a series of processes that tend to increase droplet size over time. These include direct droplet coalescence as two droplets collide to form a single new droplet, and agglomeration, where the droplets adhere together and form a larger mass. Form. Aggregates can optionally be precursors of further adhesions to larger droplets. These processes result in large agglomerates reaching the surface of the container, a phenomenon known as "creaming", and eventually known as "cracking", which results in free oil being visible on the emulsion surface. obtain.

Emulsion formulations must also be chemically stable. The drug substance can decompose. For example, lipophilic drugs partition into the oil phase, which provides some protection, but degradation by hydrolysis can still occur at the oil-water interface. Possible chemical degradation in parenteral fat emulsions involves the oxidation of unsaturated fatty acid residues present in triglycerides and lecithin, and hydrolysis of phospholipids, leading to the formation of free fatty acids (FFA) and lysophospholipids. Be done. Such degradants lower the pH, which in turn can promote further degradation. Thus, the pH should be controlled during manufacture and parenteral emulsion formulations may contain buffers to provide additional control. Any drop in pH over the specified shelf life can be indicative of chemical degradation.

In the present application, emulsion formulations were prepared and characterized so that the NK-1 receptor antagonist compound was incorporated into the emulsion for intravenous injection and remained stable during the shelf life of the formulation. The possible formulations and processes were identified.

(Simple summary)
The following aspects and embodiments thereof described and illustrated below are meant to be illustrative and exemplary rather than limiting in scope.

In one aspect, an oil phase (the oil phase comprises a neurokinin 1 (NK-1) receptor antagonist, a surfactant and a cosurfactant); and an aqueous phase (the aqueous phase is water, an isotonicity agent, and a pH). A pharmaceutical composition suitable for intravenous administration is provided, which comprises a stable emulsion containing a modulator).

In some embodiments, the NK-1 receptor antagonist is aprepitant, lorapitant, netupitant, ranepitant, vestipitant, orbepitant maleate, casopitant, ezlopitant, serlopitant, befetupitant and malopitant, or a pharmaceutically acceptable. Selected from the group consisting of the salts. In another embodiment, the NK-1 receptor antagonist is sparingly soluble in water.

In some embodiments, the NK-1 receptor antagonist is selected from the group consisting of lorapitant, netupitant, casopitant, ezropitant, vestipitant, serlopitant, malopitant, and orbepitant.

In some embodiments, the NK-1 receptor antagonist is not aprepitant.

In some embodiments, the composition is an oil-in-water emulsion comprising an oil, wherein the oil is coconut oil, olive oil, soybean oil, safflower oil, triglyceride, octyl glycerate and decyl glycerate, ethyl oleate, linole. It is selected from the group consisting of glyceryl acidate, ethyl linoleate, glyceryl oleate, cholesteryl oleate/cholate linoleate or mixtures thereof. In other embodiments, the oil is hydrolyzed. In yet other embodiments, the oil is structurally modified.

In some embodiments, the emulsifier comprises phospholipids. In another embodiment, the emulsifier is an egg phospholipid, soybean phospholipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidic acid, mixed chain phospholipid, lysophospholipid, hardened phospholipid, semi-hardened phospholipid. , And mixtures thereof.

In some embodiments, the cosurfactant comprises alcohol. In other embodiments, the cosurfactant is ethanol.

In some embodiments, the pH modifier comprises oleate or a pharmaceutically acceptable salt thereof. In other embodiments, the oleate is sodium oleate, potassium oleate or ammonium oleate. In yet another embodiment, the pH modifier is sodium oleate or a pharmaceutically acceptable salt thereof.

In some embodiments, the pH adjusting substance comprises a buffer. In other embodiments, the buffer is selected from the group consisting of phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer and borate buffer. In yet another embodiment, the buffer is selected from the group of phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer.

In some embodiments, the pH modifier comprises oleate and a buffer. In other embodiments, the oleate is sodium oleate and the buffer is Tris buffer.

In some embodiments, the pH modifier is sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, Tris, sodium linoleate, sodium oleate, potassium oleate, ammonium oleate, potassium carbonate, linoleic acid. It is selected from the group consisting of potassium, and mixtures thereof.

In some embodiments, the composition comprises about 5 wt/wt% (wt/wt%) to 15 wt/wt%, 5 wt/wt% to 10 wt/wt%, 7 wt/wt% to 10 wt%. /Wt%, 8 wt/wt% to 9 wt/wt%, or 9 wt/wt% to 10 wt/wt% oil. In another embodiment, the composition comprises about 8% w/w, 8.5% w/w, 9% w/w, 9.5% w/w, 10% w/w, or 10.5% w/w. /Wt% oil. In yet another embodiment, the oil is soybean oil.

In some embodiments, the composition comprises about 10 wt/wt% to 20 wt/wt%, 12 wt/wt% to 17 wt/wt%, 13 wt/wt% to 16 wt/wt%, 13 wt. /Wt% to 15 wt/wt%, 14 wt/wt% to 15 wt/wt%, or 13 wt/wt% to 14 wt/wt% emulsifier. In other embodiments, the composition comprises about 13% w/w, 13.5% w/w, 14% w/w, 14.5% w/w, 15% w/w, 16% w/w. , 17% w/w, 18% w/w, 19% w/w or 20% w/w of emulsifier. In yet another embodiment, the emulsifier is lecithin. In other embodiments, the lecithin is egg yolk lecithin.

In some embodiments, the composition comprises about 0.05 wt/wt% to 1.5 wt/wt%, 0.1 wt/wt% to 1.0 wt/wt%, 0.2 wt/wt. %-0.8 wt/wt%, 0.3 wt/wt%-0.7 wt/wt%, 0.4 wt/wt%-0.6 wt/wt%, 0.4 wt/wt%- It contains 0.5 wt/wt% oleate or a salt thereof. In other embodiments, the composition comprises about 0.05% w/w, 0.1% w/w, 0.2% w/w, 0.3% w/w, 0.4% w/w. , 0.45% w/w, 0.5% w/w, 0.6% w/w, 0.7% w/w, 0.8% w/w, 0.9% w/w, 1% It contains 0.0 wt/wt% or 1.5 wt/wt% oleate or a salt thereof. In still other embodiments, the oleate is sodium oleate. In yet another embodiment, oleate or sodium oleate is the pH modifier.

In some embodiments, the composition comprises about 20 wt/wt% to 50 wt/wt%, expressed as a percentage of the weight of oil per sum of the weight of oil, emulsifier and oleate in one unit of the composition, 30 wt/wt% to 50 wt/wt%, 35 wt/wt% to 45 wt/wt%, 30 wt/wt% to 45 wt/wt%, 37 wt/wt% to 42 wt/wt%, 38 wt /Wt% to 40 wt/wt%, 30 wt/wt%, 31 wt/wt%, 32 wt/wt%, 33 wt/wt%, 34 wt/wt%, 35 wt/wt%, 36 wt/wt %, 37% w/w, 38% w/w, 39% w/w, 40% w/w, 41% w/w, 42% w/w, 43% w/w, 44% w/w, It contains 45% w/w, 46% w/w, 47% w/w, 48% w/w, 49% w/w, 50% w/w of oil. In another embodiment, the oil is soybean oil.

In some embodiments, the composition comprises about 20 wt/wt% to 50 wt/wt%, 30 wt%, expressed as a percentage of the weight of oil per sum of the weight of oil and emulsifier in one unit of the composition. /Wt% to 50 wt/wt%, 35 wt/wt% to 45 wt/wt%, 30 wt/wt% to 45 wt/wt%, 37 wt/wt% to 42 wt/wt%, 38 wt/wt % To 40% w/w, 30% w/w, 31% w/w, 32% w/w, 33% w/w, 34% w/w, 35% w/w, 36% w/w, 37 wt/wt %, 38 wt/wt %, 39 wt/wt %, 40 wt/wt %, 41 wt/wt %, 42 wt/wt %, 43 wt/wt %, 44 wt/wt %, 45 wt /Wt%, 46 wt/wt%, 47 wt/wt%, 48 wt/wt%, 49 wt/wt%, 50 wt/wt% oil. In another embodiment, the oil is soybean oil.

In some embodiments, the composition comprises about 40 wt/wt% to 80 wt/wt%, expressed as a percentage of the weight of emulsifier per total weight of oil, emulsifier and oleate in one unit of the composition, 50% by weight to 70% by weight, 55% by weight to 65% by weight, 57% by weight to 63% by weight, 58 to 60% by weight, 35% by weight to 35% by weight 40 wt/wt%, 30 wt/wt% to 40 wt/wt%, 50 wt/wt%, 51 wt/wt%, 52 wt/wt%, 53 wt/wt%, 54 wt/wt%, 55 wt /Wt%, 56 wt/wt%, 57 wt/wt%, 58 wt/wt%, 59 wt/wt%, 60 wt/wt%, 61 wt/wt%, 62 wt/wt%, 63 wt/wt %, 64% w/w, 65% w/w, 66% w/w, 67% w/w, 68% w/w, 69% w/w, 70% w/w of emulsifier. In another embodiment, the emulsifier is lecithin. In still other embodiments, the lecithin is egg yolk lecithin.

In some embodiments, the composition is about 40 wt/wt% to 80 wt/wt%, 50 wt%, expressed as a percentage of the weight of emulsifier per sum of the weight of oil and emulsifier in one unit of the composition. /Wt% to 70 wt/wt%, 55 wt/wt% to 65 wt/wt%, 57 wt/wt% to 63 wt/wt%, 58 to 60 wt/wt%, 35 wt/wt% to 40 wt /Wt%, 30 wt/wt% to 40 wt/wt%, 50 wt/wt%, 51 wt/wt%, 52 wt/wt%, 53 wt/wt%, 54 wt/wt%, 55 wt/wt %, 56% w/w, 57% w/w, 58% w/w, 59% w/w, 60% w/w, 61% w/w, 62% w/w, 63% w/w, It contains 64 wt/wt%, 65 wt/wt%, 66 wt/wt%, 67 wt/wt%, 68 wt/wt%, 69 wt/wt%, 70 wt/wt% emulsifier. In another embodiment, the emulsifier is lecithin. In still other embodiments, the lecithin is egg yolk lecithin.

In some embodiments, the ratio of oil to NK-1 receptor antagonist (wt%:wt%) in the composition is about 5:1 to 20:1, 5:1 to 15:1, 5:1. -10:1, 11:1-20:1, 11:1-15:1, 12:1-16:1, 12:1-14:1, 11:1-15:1, 12:1-14 1, 12.5:1 to 13.5:1, 13:1 to 14:1, or 12:1 to 15:1. In other embodiments, the ratio of oil to NK-1 receptor antagonist (wt%:wt%) in the composition is about 11:1 to 20:1, 11:1 to 15:1, 12:1 to. 16:1, 12:1 to 14:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 11.5:1, 12:1, 12.5:1, 13:1, 13.5:1, 14:1, 14.5:1 or 15:1, 15.5:1, 16:1.

In some embodiments, the ratio of emulsifier to NK-1 receptor antagonist (wt%:wt%) in the composition is about 10:1 to 30:1, 10:1 to 20:1, 15:1. It is in the range of ˜30:1, 20:1 to 25:1, 18:1 to 22:1, 19:1 to 20:1, or 10:1 to 30:1. In other embodiments, the ratio of emulsifier:NK-1 receptor antagonist (wt%:wt%) in the composition is about 10:1, 11:1, 13:1, 14:1, 15:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, or 30:1.

In some embodiments, the ratio of emulsifier plus oil to NK-1 receptor antagonist (wt%:wt%) in the composition is about 20:1 to 40:1, 25:1 to 35:1. , 30:1 to 35:1, or 32:1 to 34:1. In another embodiment, the ratio of (emulsifier plus oil) to NK-1 receptor antagonist is about 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1. , 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1 or 40:1.

In some embodiments, the ratio of emulsifier to oil in the composition (wt%:wt%) is about 0.5:1 to 4:1, 1:1 to 2:1, 1.25:1. It is in the range of 1.75:1, or 1.4:1 to 1.6:1. In another embodiment, the emulsifier to oil ratio (wt%:wt%) in the composition is about 0.5:1, 0.5:1, 0.6:1, 0.7:1, 0. .8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1 1.7:1, 1.8:1, 1.9:1, 2:1, 1.05:1, 1.15:1, 1.25:1, 1.35:1, 1.45 : 1, 1.55:1, 1.65:1, 1.75:1, 1.85:1, or 1.95:1.

In some embodiments, the therapeutic dose of the pharmaceutical composition is about 1-4 g, 1.5-3 g, 1.8-2.8 g, 2.3-2.8 g, 1.8-2.3 g, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g, 1.9 g, 2 g, 2.1 g, 2.2 g, 2. 3g, 2.4g, 2.5g, 2.6g, 2.7g, 2.8g, 2.9g, 3g, 3.1g, 3.2g, 3.3g, 3.4g, 3.5g, 3. It contains 6 g, 3.7 g, 3.8 g, 3.9 g, 4 g of emulsifier. In another embodiment, the emulsifier is lecithin. In still other embodiments, the emulsifier is egg yolk lecithin.

In some embodiments, the therapeutic dose of the pharmaceutical composition is about 0.5-3 g, 1-2.5 g, 1-2 g, 1-1.5 g, 1.5 g-2 g, 0.5 g, 0. 6g, 0.7g, 0.8g, 0.9g, 1g, 1.1g, 1.2g, 1.3g, 1.4g, 1.5g, 1.6g, 1.7g, 1.8g, 1. Contains 9g, 2g, 2.1g, 2.2g, 2.3g, 2.4g, 2.5g oil. In another embodiment, the oil is soybean oil.

In some embodiments, the therapeutic dose of the pharmaceutical composition is about 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-400 mg, 50-250 mg, 75-. 200 mg, 100-150 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg or 600 mg NK-1 receptor antagonist Including.

In some embodiments, the composition comprises about 0 wt/wt% to 10 wt/wt%, 1 wt/wt% to 9 wt/wt%, 2 wt/wt% to 6 wt/wt%, 2 wt. /Wt% to 4 wt/wt% or 2 wt/wt% to 3 wt/wt% cosurfactant. In other embodiments, the composition is less than 10% w/w, less than 9% w/w, less than 8% w/w, less than 7, less than 6% w/w, less than 5% w/w, less than 4% w/w. </wt%, <3 wt/wt%, <2 wt/wt% or <1 wt/wt% cosurfactant.

In some embodiments, the composition comprises about 0 wt/wt% to 10 wt/wt%, 1 wt/wt% to 9 wt/wt%, or 2 wt/wt% to 6 wt/wt% ethanol. including. In other embodiments, the composition is less than 10% w/w, less than 9% w/w, less than 8% w/w, less than 7, less than 6% w/w, less than 5% w/w, less than 4% w/w. %/Wt%, less than 3 wt/wt%, less than 2 wt/wt% or less than 1 wt/wt% ethanol.

In some embodiments, the aqueous phase of the emulsion comprises a tonicity agent, a pH adjusting substance, and water.

In some embodiments, the aqueous phase of the emulsion comprises an osmotic agent, a pH adjusting substance, and water.

In some embodiments, the aqueous phase of the emulsion comprises a tonicity agent, an osmotic agent, a pH adjusting substance, and water.

In some embodiments, the aqueous phase further comprises a buffer.

In some embodiments, the aqueous phase comprises a buffer but no pH adjusting substance different from the buffer. In other embodiments, the buffer functions as both a pH modifier agent and a buffer.

In some embodiments, when the aqueous phase comprises a buffer, the composition does not contain a tonicity agent.

In some embodiments, the buffer is selected from the group consisting of phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer and borate buffer. .. In another embodiment, the buffer is selected from the group of phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer.

In some embodiments, the aqueous phase comprises a buffer that, when mixed with the oil phase, provides a substantially isotonic oil-in-water emulsion.

In some embodiments, the osmotic agent is selected from the group consisting of glycerol, sorbitol, xylitol, mannitol, glucose, trehalose, maltose, sucrose, raffinose, lactose, dextran, polyethylene glycol, or propylene glycol. In other embodiments, the osmotic agent is an inorganic salt, such as sodium chloride and mixtures thereof.

In some embodiments, the composition is about 6-9, 7-9, 7.5-9, 7.5-8.5, 8-9, 6-8, 7-8, or 6,7. , PH 8 or 9.

In some embodiments, the composition comprises about 0 wt/wt% to 25 wt/wt%, 2 wt/wt% to 20 wt/wt%, 3 wt/wt% to 15 wt/wt%, or 3 wt/wt%. Wt/wt% to 8 wt/wt% tonicity agent. In other embodiments, the composition comprises about 1% w/w, 2% w/w, 3% w/w, 4% w/w, 5% w/w, 6% w/w, 7% w/w. Wt%, 8 wt/wt%, 9 wt/wt%, or 10 wt/wt%, 11 wt/wt%, 12 wt/wt%, 13 wt/wt%, 14 wt/wt%, 15 wt/wt %, 16% w/w, 17% w/w, 18% w/w, 19% w/w, or 20% w/w 21%/w, 22% w/w, 23% w/w , 24 wt/wt%, 25 wt/wt% tonicity agent. In yet other embodiments, the composition does not include a tonicity agent.

In some embodiments, the composition comprises about 0 wt/wt% to 25 wt/wt%, 2 wt/wt% to 20 wt/wt%, 3 wt/wt% to 15 wt/wt%, or 3 wt/wt%. Wt/wt% to 8 wt/wt% osmotic agent. In other embodiments, the composition comprises about 1% w/w, 2% w/w, 3% w/w, 4% w/w, 5% w/w, 6% w/w, 7% w/w. Wt%, 8 wt/wt%, 9 wt/wt%, or 10 wt/wt%, 11 wt/wt%, 12 wt/wt%, 13 wt/wt%, 14 wt/wt%, 15 wt/wt %, 16% w/w, 17% w/w, 18% w/w, 19% w/w, or 20% w/w 21%/w, 22% w/w, 23% w/w , 24 wt/wt%, 25 wt/wt% osmotic agent. In yet other embodiments, the composition does not include an osmotic agent.

In some embodiments, the aqueous phase comprises a dose of dexamethasone sodium phosphate in a therapeutic dose of the pharmaceutical composition. In other embodiments, the dose of dexamethasone sodium phosphate ranges from about 0.5 mg to 30 mg, 0.5 mg to 25 mg, 1 mg to 20 mg, 10 mg to 20 mg, or 3 mg to 16 mg. In still other embodiments, the dose of dexamethasone sodium phosphate is about 9 mg or 16 mg in a therapeutic dose of the pharmaceutical composition. In those embodiments that include a dose of dexamethasone, the therapeutic dose of the pharmaceutical composition is about 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-400 mg, 50-. 250 mg, 75-200 mg, 100-150 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 600 mg NK-1. Includes receptor antagonists.

In some embodiments, the oil phase comprises a dose of dexamethasone in a therapeutic dose of the pharmaceutical composition. In other embodiments, the dose of dexamethasone ranges from about 0.5 mg to 30 mg, 0.5 mg to 20 mg, 1 mg to 18 mg, 10 mg to 20 mg, or 3 mg to 16 mg. In other embodiments, the dose of dexamethasone is about 8 mg or 12 mg in a therapeutic dose of the pharmaceutical composition. In those embodiments that include doses of dexamethasone, the therapeutic dose of the pharmaceutical composition is about 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-400 mg, 50-. 250 mg, 75-200 mg, 100-150 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 600 mg of NK-1. Includes receptor antagonists.

In some embodiments, the emulsion is about 0.002% w/w to 0.2% w/w, 0.003% w/w to 0.16% w/w, 0.02% w/w. ~0.1 wt/wt% dexamethasone sodium phosphate.

In some embodiments, the composition has an intensity of about 50 nm to 1000 nm, 50 to 500 nm, 50 nm to 400 nm, 50 nm to 300 nm, 50 nm to 200 nm or 50 nm to 100 nm as determined by dynamic light scattering (DLS). It is a stable system that maintains a weighted average particle size. In another embodiment, the average droplet size is maintained below 500 nm for a period of at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years or 3 years at room temperature. In other embodiments, the average droplet size is maintained below 500 nm at 5° C. for at least 1 month, 3 months, 6 months, 9 months, 12 months, 2 years or 3 years.

In another aspect, there is provided a method of preparing an emulsion comprising a NK-1 receptor antagonist compound and suitable for parenteral administration.

In some embodiments, the administration is intravenous administration.

In some embodiments, the method comprises: a) preparing an oil phase by dissolving the antagonist compound and the emulsifier in ethanol and then adding into the oil to produce an oil-based mixture; b). Preparing an aqueous phase by mixing water, optionally an isotonicity agent, optionally an osmotic agent, and optionally a pH adjusting substance, and optionally a buffer, to form an aqueous mixture. C) combining the oil-based mixture and the aqueous mixture and subjecting it to rapid homogenization to produce a crude emulsion; and d) subjecting the crude emulsion to high pressure homogenization to produce a fine emulsion. Including and.

In some embodiments, preparing the oil phase further comprises dissolving dexamethasone in ethanol with the antagonist compound and the emulsifier.

In some embodiments, the method comprises: a) combining an NK-1 receptor antagonist, an emulsifier, and an alcohol with an oil to produce an oil phase; (b) water, a tonicity agent, a pH modifier, And optionally combining buffers to produce an aqueous phase; (c) homogenizing the oil phase with the aqueous phase to produce a pharmaceutical emulsion; (d) sterilizing the pharmaceutical emulsion. In other embodiments, homogenizing comprises rapid homogenization.

In some embodiments, the method comprises: a) preparing an oil phase by dissolving the antagonist compound and the emulsifier in ethanol and an oil, resulting in an oil-based mixture; and b) optionally water. Preparing an aqueous phase by mixing with a tonicity agent, optionally an osmotic agent, and optionally a pH adjusting substance, and optionally a buffer to form an aqueous mixture; c A) combining the oil-based mixture and the aqueous mixture and subjecting it to homogenization to give a crude emulsion; and d) subjecting the crude emulsion to homogenization to give a fine emulsion. In another embodiment, subjecting to homogenization to produce a crude emulsion is rapid homogenization. In yet another embodiment, the homogenization that results in a fine emulsion is high pressure homogenization.

In some embodiments, preparing the oil phase further comprises dissolving dexamethasone in ethanol and oil with the antagonist compound and the emulsifier.

In some embodiments, preparing the aqueous phase further comprises mixing dexamethasone with water, an isotonicity agent, a pH adjusting substance, and a buffer. In other embodiments, the dexamethasone is a salt of dexamethasone. In yet another embodiment, the dexamethasone is dexamethasone sodium phosphate.

In some embodiments, the method further comprises sterilizing the fine emulsion to produce a final emulsion, the final emulsion being suitable for injection into a subject.

In some embodiments, dissolution in ethanol is about 25°C-80°C, 40°C-75°C, 60°C-70°C, or about 25°C, 35°C, 45°C, 60°C, 65°C, 70. Perform at a temperature of ℃ or 75 ℃.

In some embodiments, high speed homogenization is performed at a speed of about 2,000 rpm (revolutions per minute) to 25,000 rpm. In another embodiment, high speed homogenization is performed at a speed of about 20,000 rpm. In yet another embodiment, the high speed homogenization is performed at a speed of about 3600 rpm.

In some embodiments, rapid homogenization occurs for a period of about 0.5 minutes to 1 hour, 1 minute to 45 minutes, or 1 minute to 30 minutes. In other embodiments, rapid homogenization is for a period of about 20-40 minutes or about 30 minutes.

In some embodiments, rapid homogenization is performed at about 10°C to about 60°C, 20°C to about 60°C, about 30°C to about 50°C, or about 35°C to about 45°C. In another embodiment, rapid homogenization is performed at about 25°C, 30°C, 35°C, 40°C, 45°C or 50°C.

In some embodiments, high pressure homogenization is performed at a pressure of about 10,000 psi (pounds per square inch) to 30,000 psi. In another embodiment, the high pressure homogenization is performed at a pressure of about 20,000 psi.

In some embodiments, high pressure homogenization is performed with cooling. In another embodiment, high pressure homogenization brings the temperature of the emulsion at the exit of the process to about 0°C to about 60°C, about 10°C to about 40°C, about 20°C to about 30°C, or about. Perform with sufficient cooling to reach 20°C, 25°C or 30°C.

In some embodiments, sterilizing the microemulsion comprises filtering the microemulsion through a nylon filter. In another embodiment, the nylon filter is a Posidyne® filter. In yet another embodiment, the filter has a pore size of about 0.2 μm (micrometer).

In another aspect, the compositions described herein are for the treatment of a subject and the composition is administered by injection into the subject in need.

In some embodiments, the composition is a chemotherapeutic agent-induced emesis, radiation-induced nausea and vomiting, and/or post-operatively induced nausea and vomiting in a subject. ) For use in a method for the treatment of). In other embodiments, treatment comprises administering to the subject a composition comprising an NK-1 receptor antagonist as described herein. In yet another embodiment, the composition is for use in preventing or treating acute and delayed nausea and vomiting.

Further embodiments, such as the compositions and methods, will be apparent from the description, drawings, examples, and claims that follow. As can be appreciated from the description above and below, each and every feature described herein, as well as each and every combination of two or more such features, is disclosed. However, the features included in such combinations are not mutually exclusive. Moreover, any feature, or combination of features, may be specifically excluded from any embodiment of the invention. Additional aspects and advantages of the invention are set forth in the following description and claims, especially when considered in conjunction with the accompanying examples and drawings.

1A-1D provide microscopic images of samples from Examples 1, 2, 3 and 6 after freeze-thaw cycles. 1A: Example 1, FIG. 1B: Example 2, FIG. 1C: Example 3, FIG. 1D: Example 6

FIG. 2 shows plasma levels of aprepitant after injection of fosaprepitant solution (filled circles) or aprepitant emulsion prepared as described herein (filled triangles).

FIG. 3 shows plasma levels of aprepitant after injection of a solution of fosaprepitant (filled triangles) or after injection of an emulsion containing aprepitant and dexamethasone (filled circles) prepared as described herein. Indicates.

FIG. 4 shows dexamethasone of dexamethasone after injection with a solution of sodium dexamethasone phosphate (filled circles) or after injection of an emulsion containing aprepitant and dexamethasone prepared as described herein (filled triangles). Plasma levels are shown.

(Detailed explanation)
Various aspects are now described more fully below in this specification. However, such aspects may be embodied in many different forms and should not be construed as limiting the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope to those skilled in the art.

I. Definitions As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "polymer" includes a single polymer and two or more of the same or different polymers, and reference to "excipient" refers to a single excipient. , And two or more of the same or different excipients and the like.

Where a range of values is provided, each intervening value between the upper and lower limits of the range, as well as any other stated or intervening value in the stated range, is encompassed within the disclosure. Is intended to For example, if a range of 1 μm to 8 μm is stated, then 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm, and a range of values equal to or greater than 1 μm and values equal to or less than 8 μm. Ranges are also intended to be explicitly disclosed. As used herein, the term “about” means ±5%, ±10%, or ±20% of the modified value.

The term "emulsion" or "emulsion formulation" means a colloidal dispersion of two immiscible liquids in the form of droplets, the diameter of which is generally between 10 nanometers and 100 microns. An emulsion is designated by the symbol O/W (oil in water) when the continuous phase is an aqueous solution and by W/O (water in oil) when the continuous phase is an oil. Other examples of emulsions, such as O/W/O (oil-in-oil-in-oil), include oil droplets contained within aqueous droplets dispersed in a continuous oil phase.

A “physically stable” emulsion does not exceed (1) an average droplet size of 500 nm or 0.5 μm, and (2) 5° C. or room temperature for a specified storage period of 0.05%. Meet the criteria under USP <729>, which defines the universal limit for the population of large diameter fat droplets expressed as a volume weighted percentage of fat greater than 5 μm (PFAT5). Furthermore, physically stable emulsions have no visible NK-1 receptor antagonist crystals upon storage for a specified period of time at 5° C. or room temperature. Crystals are considered visible when viewed at magnifications of 4x-10x. The emulsion is physically stable if it meets the criteria under USP <729> and the NK-1 receptor antagonist crystals are at 5° C. or room temperature for at least 1 week, 2 weeks, 4 weeks, 1 month, Not visible during storage for 2 months, 6 months, 1 year or 2 years or equal period.

"Chemically stable" emulsions of the present disclosure are those in which the concentration of active ingredient (ie, drug to be delivered) does not change by more than about 20% for at least one month under suitable storage conditions. In certain embodiments, the NK-1 receptor antagonist concentration in an emulsion of the present disclosure is at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months under suitable storage conditions. No change by more than about 5%, more than 10%, more than 15% or more than 20% for 12 months, 15 months, 18 months, or 24 months.

In one example, stable emulsion compositions of the present disclosure are stable over a wide range of temperatures, eg, -20°C to 40°C. The compositions of the present disclosure may be stored at about 5°C to about 25°C.

"Oil phase" in a water-in-oil emulsion refers to all components in the formulation that individually exceed their solubility limits in the water phase. Although these are materials that generally have solubilities of less than 1% in distilled water, aqueous phase components, such as salts, can reduce the solubility of certain oils and result in their partitioning into the oil phase. Oil phase refers to the non-aqueous portion of a water-in-oil emulsion.

The “water phase” (“Aqueous phase” or “water phase”) in a water-in-oil emulsion is the water present and any components that are water-soluble, ie, do not exceed their solubility limit in water. Refers to. "Aqueous phase" as used herein refers to pharmaceutically acceptable additives such as acidifying agents, alkalizing agents, buffering agents, chelating agents, complexing agents and solubilizing agents, antioxidants. And water-containing liquids which may contain antimicrobial preservatives, humectants, suspending agents and/or viscosity modifiers, isotonic and wetting agents or other biocompatible materials. Aqueous phase refers to the non-oil portion of a water-in-oil emulsion.

"Emulsifier" refers to a compound that prevents the separation of injectable emulsions into individual oil and water phases. Emulsifiers useful in the present disclosure are generally (1) compatible with the other components of the stable emulsions of the present disclosure, (2) do not interfere with the stability or effectiveness of the drug contained in the emulsion, (3 ) It is stable in the preparation, does not deteriorate, and (4) is nontoxic.

Suitable emulsifiers include, but are not limited to, propylene glycol mono- and di-fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypropylene copolymers and block copolymers, fatty alcohol sulfones. Includes salts of fates, sorbitan fatty acid esters, esters of polyethylene-glycol glycerol ethers, emulsifiers based on oils and waxes, glycerol monostearate, glycerin, sorbitan fatty acid esters and phospholipids. ..

"Phospholipid" is a triester of glycerol in which one of a secondary alcohol and a primary alcohol is esterified with a fatty acid, and the other primary alcohol is esterified with a phosphate group. Refers to. Exemplary phospholipids useful in the present invention include, but are not limited to, phosphatidyl choline, lecithin (a mixture of choline esters of phosphorylated diacyl glycerides), phosphatidyl ethanolamine, phosphatidyl glycerol, about 4 to about 22. Included are phosphatidic acids having 4 carbon atoms, and more generally from about 10 to about 18 carbon atoms and varying degrees of saturation. The phospholipids can have any combination of fatty acids as their fatty acid acyl side chains, for example, the phospholipids can be saturated fatty acids such as decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, icosanoic acid ( C20 saturated fatty acid); sodium behenic acid, or unsaturated fatty acids such as myristoleic acid, palmitoleic acid, oleic acid, sodium linoleic acid, alpha linolenic acid, sodium arachidonic acid. acid), eicosapentaenoic acid, and the like. The two fatty acid acyl residues on the phospholipid can be the same or they can be different fatty acids. The phospholipid component of the drug delivery composition can be a single phospholipid or a mixture of several phospholipids. Phospholipids should be tolerated for the route of administration chosen.

In one aspect, the phospholipids used as emulsifiers in the present invention are naturally occurring phospholipids from natural sources. For example, naturally occurring lecithin is a mixture of diglycerides of stearic acid, palmitic acid, and oleic acid linked to a choline ester of phosphoric acid, commonly referred to as phosphatidylcholine, obtained from a variety of sources, such as eggs and soybeans. You can Soybean lecithin and egg lecithin, including hardened versions of these compounds, have been characterized in a variety of compositions and are generally recognized as safe, have combined emulsifying and solubilizing properties, and are largely Synthetic surfactants tend to disintegrate into harmless substances more rapidly.

The term "lecithin" comprises complex mixtures of acetone-insoluble phosphatides, of which phosphatidylcholine is a crucial constituent. The term lecithin is also used as a synonym for phosphatidylcholine. Useful lecithins include, but are not limited to, lecithin derived from egg yolk, egg, soybean, and corn. In one embodiment, the emulsifier is lecithin, eg, lecithin derived from egg yolk. The terms egg lecithin and lecithin derived from egg yolk are used interchangeably throughout. The compositions described herein preferably include lecithin as an emulsifier.

The amount by weight of phospholipids in the emulsions of the present disclosure is from about 10 wt/wt% to about 20 wt/wt%, 11 wt/wt% to 19 wt/wt%, 11 wt/wt% to 15 wt/wt. %, 12 wt/wt% to 13 wt/wt%, 13 wt/wt% to 14 wt/wt%, 13 wt/wt% to 20 wt/wt%, or 12 wt/wt% to 18 wt/wt% Can be within the range. In certain embodiments, the phospholipids in the emulsion are about 11% w/w, 12% w/w, 12.5% w/w, 13% w/w, 13.5% w/w, by weight. /Wt%, 14 wt/wt%, 14.5 wt/wt%, or 15 wt/wt%.

"Oil" means, for example, organic liquids of mineral, vegetable, animal, extract or synthetic origin, containing, for example, wax-based hydrocarbons, aromatic hydrocarbons or mixed aliphatic and aromatic hydrocarbons. Refers to.

The term "buffer" or "buffered" as used herein means a solution containing both a weak acid and its conjugate base whose pH changes only slightly upon addition of an acid or base. To do. As used herein, the phrase "buffering agent" refers to a species, the inclusion of which in solution results in a buffered solution. Buffers are well known in the art and are readily available. Buffers for use with the methods and compositions described herein include, but are not limited to, phosphoric acid, citric acid, tris, carbonic acid, succinic acid, maleic acid, boric acid, MES, bis. -Tris, ADA, aces, PIPES, MOPSO, bis-Trispropane, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, Trizma, HEPPSO, POPSO, TEA, EPPS, Tricine, Gly-Gly, Bicine, GEPBS, Includes TAPS, AMPD, TABS, AMPSO, CHES, CAPSO, AMP, CAPS, and CABS.

The term "therapeutic agent" describes any natural or synthetic compound that has biological activity. A "therapeutically effective amount" is an amount that, when administered to an animal or subject for treating or preventing a disorder, condition, or disease, is sufficient to effect treatment for that disorder, condition, or disease. means.

As used herein, the term "emesis" includes nausea and vomiting.

The term “substantially” in connection with a particular feature or entity means to a considerable extent or almost completely (ie, to 85% or more) with respect to the feature or entity.
II. NK-1 Receptor Antagonist Emulsion and Method of Making

The present disclosure is directed to stable pharmaceutical compositions comprising an NK-1 receptor antagonist, a surfactant or a mixture of surfactants, cosurfactants, oils, together with an aqueous phase. The composition may be an injectable emulsion, which is in the form of an oil-in-water emulsion, which remains stable over time and is suitable for dilution and intravenous administration.

The NK-1 receptor antagonist compound is present in the oil phase along with the emulsifier, cosurfactant and oil. The oil phase is then combined with water and an aqueous phase containing a tonicity agent as described below to form a stable emulsion. Prior to combining the oil phase with the aqueous phase, the oil phase has an oil:antagonist compound ratio of about 11:1 to 30:1, 11:1 to 15:1, or about 13:11. For example, in formulating an oil phase comprising aprepitant, the use of an oil:aprepitant ratio of about 13:1 surprisingly results in an oil phase of less than about 12:1 or less than 11:1, and/or about 15:1. It was found to produce emulsions that were more stable when mixed with the aqueous phase when compared to emulsions containing oil:aprepitant ratios of greater than 20:1 or greater than 30:1. Thus, in some embodiments, stable emulsions that include an NK-1 receptor antagonist and are administered to a subject are about 11:1 to 30:, 11:1 to 15:1, or about 13:11. Oil:antagonist compound ratio. However, also contemplated are emulsions in which the ratio of oil:antagonist compound is about 5:1 to 20:1, 5:1 to 15:1 or 5:1 to 10:1.

Moreover, the composition also has favorable stability properties when the amount of emulsifier in the oil phase is higher than the amount of oil. For example, the oil phase contains an emulsifier:oil ratio of about 5:1 to 1:1, 3:1 to 1:1 or a ratio of about 1.5:1. Such an emulsifier:oil ratio was surprisingly found to give greater stability to the final emulsion, which is suitable for injection into a patient. For example, an aprepitant emulsion having a phospholipid:oil ratio in the oil phase of about 1.5:1 was found to be more stable than a similar aprepitant emulsion, but the oil phase was about 0. A phospholipid:oil ratio of 01:1, 0.1:1, 0.5:1 or 0.9:1 is included.

Suitable NK-1 receptor antagonists for use in the presently described pharmaceutical emulsions include RP67580 ((3aR,7aR)-octahydro-2-[, including all pharmaceutically acceptable salts thereof. 1-imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4H-isoindole)), WIN 51078 (17-β-hydroxy-17-α-ethynyl-5-α-androstano[3 ,2-b]Pyrimido[1,2-a]benzimidazole), 1-733,060((2S,3S)-3-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-2- Phenylpiperidine hydrochloride), 1-703,606 (cis-2-(Diphenylmethyl(Diphenylmethyl))-N-([2-iodophenyl]methyl)-1-azabicyclo(2.2.2)octane-3- Amine), MDL105,212((R)-1-[2-[3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl]-ethyl]. -4-phenylpiperidine-4-carboxamide hydrochloride), serlopitant, malopitant, antagonist D, aprepitant, fosprepitant, R116301, CGP49823, CP-96345, CP-99994, GR-203040, MDL-103392, 1-760735, SDZ. -NKT-343, norpititanium (SR-140333), AV608, lorapitant, SCH900978, AV608, GSK4244887 (GlaxoSmithKline), GSK206136 (GlaxoSmithKline), GR-994, GR-9947, GR-205171, GR-205171, GR-205171. 3,5-Bis-trifluoromethyl-benzyl)-9-methyl-5-p-tolyl-8,9,10,11-tetrahydro-7H-1,7,11a-triaza-cycloocta[b]naphthalene-6 , 12-dione), LY303870([(R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4 -(Piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane]), LY686017 ((2-chloro-phenyl)-{2-[5-pyridin-4-yl-1-(3,5 -Bistrifluoromethyl- )-1H-[1,2,3]Triazol-4-yl]-pyridin-3-yl}-methanone), E-6006, Casopitant/GW679769((2R,4S)-4-(4-acetylpiperazine) -1-yl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl)ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1 -Carboxamide), vestipitant, orbepitant and orbepitant maleate, befetupitant, netupitant, ezropitant, CP-122721, MPC-4505 (Myriad Genetics, Inc. ), CP-122721 (Pfizer, Inc.), CJ-12,255 (Pfizer, Inc.), SRR240600 (Sanofi-Aventis), or TA-5538 (Tanabe Seiyaku Co.).
1. Oil phase

The oil (hydrophobic) phase comprises oil. Triglyceride is an exemplary oil for use in the compositions described herein. In certain embodiments, the oil is or comprises a vegetable oil. "Vegetable oil" refers to oils derived from plant seeds or tree nuts. Vegetable oils typically have 3 fatty acids (usually 14-22 carbons in length, with varying numbers and positions of unsaturated bonds depending on the source of the oil) of 3 on glycerol. Is a "long chain triglyceride" (LCT) formed when an ester bond is formed with the hydroxyl group of. In certain embodiments, highly refined grade (also referred to as "super refined") vegetable oils are used to ensure the safety and stability of oil-in-water emulsions. In certain embodiments, hydrogenated vegetable oils produced by the controlled hydrogenation of vegetable oils may be used. Exemplary vegetable oils include, but are not limited to, tonsil oil, babassu oil, black currant seed oil, borage oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, olive oil, peanut oil, palm oil, palm oil, Includes palm kernel oil, rapeseed oil, safflower oil, soybean oil, sunflower oil and sesame oil. Hardened and/or semi-hardened forms of these oils may also be used. In certain embodiments, the oil is or comprises safflower oil, sesame oil, corn oil, olive oil and/or soybean oil. In a more particular embodiment, the oil is or comprises safflower oil and/or soybean oil. The oil is present in the emulsion at about 9 wt/wt%, which varies between about 5 wt/wt% and 12 wt/wt% or between 9 wt/wt% and 10 wt/wt%. obtain.

The NK-1 receptor antagonist is first mixed with an emulsifier, eg, a phospholipid emulsifier, to produce an oily phase. Examples 1-6 and 11-19 are examples of NK-1 receptor antagonist emulsions made using egg lecithin. 15% w/w of a phospholipid emulsifier, more than 10% w/w of the emulsion, more than 11% w/w, more than 12% w/w or more than 13% w/w, but more than 13% w/w of the emulsion. %, less than 17% w/w or less than 20% w/w.

The mixture of antagonist and emulsifier is dissolved in a cosurfactant, eg a short chain alcohol (1-6 carbons). Examples 1-6 and 11-19 below are some examples where the cosurfactant is ethanol. The mixture is mixed at an elevated temperature, eg, about 60° C. or 70° C., or an elevated temperature within the range of about 50° C. or 70° C., until the NK-1 receptor antagonist and emulsifier are dissolved. This mixture is then remixed at elevated temperature, eg, about 60° C., to combine with an oil, eg, soybean oil, to produce an oily phase containing the NK-1 receptor antagonist. Excess cosurfactant can be removed by standard evaporation methods including heating, such as those used in rotary evaporators, or reduced pressure, or a combination thereof. In this process, about 10% to 100%, 20% to 95%, 80% to 100%, 90% to 100%, or 95% to 100% of ethanol, depending on the preparation scale, optional vacuum, and heating time. % Evaporates.

In one embodiment, the NK-1 receptor antagonist and emulsifier are dissolved in cosurfactant and oil. Although Examples 1-6 and 11-19 below are some examples where the cosurfactant is ethanol and the oil is soybean oil, the method is for the cosurfactant and oil described herein. It can be used with any one or more. The mixture is heated at an elevated temperature, eg, about 60° C. or 70° C., or about 50° C., until at least the NK-1 receptor antagonist and the emulsifier are dissolved to produce an oily phase containing the NK-1 receptor antagonist. Alternatively, they are mixed at a high temperature within the range of 70°C. The mixture of the NK-1 receptor antagonist, the emulsifier, the cosurfactant and the oil is heated to about 15 minutes to 120 minutes, about 15 minutes to 45 minutes, about 30 minutes to 90 minutes, or about 15 minutes, 30 minutes or 50 minutes at elevated temperature. Mix with.

Excess cosurfactant can be removed by standard evaporation methods including heating in a rotary evaporator, or reduced pressure, or a combination thereof. During this process, depending on the preparation scale, optional vacuum, and heating time, about 10%-100%, 20%-95%, 80%-100%, 90%-100%, or 95%-100%. % Ethanol evaporates.

In one embodiment, dexamethasone is added to an oil phase containing the NK-1 receptor antagonist, emulsifier and oil to form an oil phase containing both the NK-1 receptor antagonist and dexamethasone prior to mixing with the aqueous phase. , To produce a pharmaceutical emulsion for injection. Dexamethasone is added to the oil phase to provide a dose of about 12 mg of dexamethasone.
2. Water phase

The aqueous phase of the NK-1 receptor antagonist emulsion may be a mixture of water and a tonicity agent including, but not limited to, sucrose, mannitol, glycerine or dextrose or mixtures thereof. Also included in the aqueous phase are pH regulators (pH regulators). Sodium oleate is used in Examples 1-3, 5, 6, and 11-15, and 17-19 below to adjust the pH of the emulsion to about 6-9 depending on the desired emulsion formulation. It However, it is understood that the pH adjustor can be other oleic acids or salts thereof including, but not limited to, sodium oleate, potassium oleate and ammonium oleate. Oleic acid may comprise about 0.1% w/w to 1.0% w/w or about 0.4% w/w or 0.5% w/w of a stable injectable emulsion as provided herein. It can account for weight percent. The aqueous phase is purified by mixing water with a tonicity agent and a pH adjusting substance (eg sodium oleate). Further pH modifiers that may be used include, but are not limited to, sodium hydroxide, potassium hydroxide, magnesium hydroxide, Tris, sodium carbonate and sodium linoleate. In some embodiments, the pH modifier comprises more than one pH modifier. For example, the aqueous phase can include both oleate and a buffer such as Tris buffer. The pH modifier used is effective to adjust the pH of the emulsion to a preferred pH of about 6-9, 7-8, or about 6, 7, 8 or 9. The aqueous phase can be easily formed by mixing at room temperature.

The aqueous phase of the emulsion may further contain buffers which promote the stability of the emulsion formulation. The drug substance can decompose. For example, lipophilic drugs partition into the oil phase, which provides some protection, but degradation by hydrolysis can still occur at the oil-water interface. Possible chemical degradation in parenteral fat emulsions involves the oxidation of unsaturated fatty acid residues present in triglycerides and lecithin, and hydrolysis of phospholipids, leading to the formation of free fatty acids (FFA) and lysophospholipids. Be done. Such degradants lower the pH, which in turn can promote further degradation. As such, the pH should be controlled during manufacture and the emulsion formulation may include buffers to provide additional control. Any drop in pH over the specified shelf life can be indicative of chemical degradation. Suitable buffers are well known to those skilled in the art and include, but are not limited to, phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer or borate buffer. Liquid is included. Tris buffer is used in Examples 11 and 19 below to adjust the pH of the emulsion to about 8-9. As shown in Examples 11 and 19, in some embodiments, a buffer, eg, Tris buffer, is used in addition to another pH adjusting agent (eg, oleate or sodium oleate) to form an emulsion. The pH can be adjusted or modified. In some embodiments, the buffer is selected from the group of phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer. In certain embodiments, the aqueous phase comprises a buffer that, when mixed with the oil phase, provides a substantially isotonic oil-in-water emulsion.

Buffering agents useful for the presently described compositions include, but are not limited to, phosphate buffer, citrate buffer, Tris buffer, carbonate buffer, succinate buffer, maleate buffer. Alternatively, borate buffer is included. In a particular embodiment, the buffer is selected from the group of phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer. In certain embodiments, the aqueous phase comprises a buffer that, when mixed with the oil phase, provides a substantially isotonic oil-in-water emulsion. In some embodiments, when the aqueous phase contains a buffer, the aqueous phase is free of tonicity agents. Also, when the buffer solution is added to the aqueous phase, the pH adjustor need not be added to the aqueous phase. It is understood that the buffer can be added to the aqueous phase or the buffer can be added to the emulsion.

In some embodiments, the aqueous phase of the emulsion contains a tonicity agent, such as sucrose. The isotonicity agent is added to the aqueous phase with about 0% to 30%, 0% to 25% or about 20% isotonicity agent (weight/weight). It was surprisingly found that a composition containing about 20% w/w sucrose in the aqueous phase produced an emulsion that was particularly stable as determined by freeze-thaw tests. Accordingly, preferred embodiments include less than about 10 wt/wt%, less than about 15 wt/wt% or less than about 20 wt/wt% isotonic agents, or greater than about 30 wt/wt% aqueous phase. An isotonicity agent that provides greater chemical and/or physical stability to the aqueous phase as compared to an emulsion containing greater than 40% w/w or greater than about 50% w/w isotonicity agent. Including emulsions.

In one embodiment, the aqueous phase further comprises dexamethasone sodium phosphate (also referred to as "dexamethasone phosphate"). Dexamethasone sodium phosphate is a water-soluble corticosteroid. The daily dosage for dexamethasone sodium phosphate will vary from about 0.5 mg to 20 mg, more preferably about 14 mg to 18 mg or 16 mg, depending on the severity of the disease or disorder. Thus, an NK-1 receptor antagonist emulsion further containing dexamethasone may contain dexamethasone sodium phosphate in the aqueous phase. Thus, the aqueous phase of the emulsion suitable for intravenous administration may contain about 0.5 mg to 20 mg, 14 mg to 18 mg or about 16 mg of dexamethasone sodium phosphate.

In another embodiment, a solution of dexamethasone sodium phosphate can be mixed into a fine emulsion prior to sterile filtration to prepare an emulsion containing dexamethasone sodium phosphate in the aqueous phase.
3. Pharmaceutical emulsion formulation

The pharmaceutical composition comprising the NK-1 receptor antagonist as disclosed herein is a sterile oil-in-water emulsion containing the aqueous and oil phases described above. Also encompassed by this disclosure are methods for preparing stable emulsions containing receptor antagonists that are suitable for intravenous administration and can be prepared by conventional manufacturing procedures using preservative techniques. is there.

The aqueous phase is combined with the oil phase under rapid homogenization to produce a coarse emulsion. Examples 1-6 and 12-19 provide examples of NK-1 receptor antagonist emulsions produced using the compositions and methods disclosed herein. The combined aqueous and oil phases are homogenized for 1 minute at a speed of 20,000 rpm using an IKA Ultra-Turrax T25 disperser as described in these examples. The speed used in this first homogenization step can vary, for example, from 2000 rpm to 25,000 rpm, or from 15,000 rpm to 22,000 rpm. The time of the homogenization step can also vary, for example 0.5 minutes to 1 hour, or 1 minute to 45 minutes. This crude emulsion is then homogenized into a fine emulsion by a high pressure homogenizer, which can be a microfluidizer. The interaction chamber and cooling coil portion of the microfluidizer is cooled with water, for example an ice bath. The temperature of the ice bath may be between 0-10°C, or 2-6°C. The temperature of the emulsion emerging from high pressure homogenization can be between 0 and 60°C, 15°C to 60°C, 20°C to 40°C, or about 25°C. Prime the microfluidizer first and then introduce the crude emulsion. The effluent from the homogenizer is first discarded, the priming water, and the mixture of priming water and emulsion are removed and then collected in a clean vessel when the stream is uniform in appearance. The high pressure homogenizer cycle can be repeated to sufficiently reduce the oil drop size. The pressure used for homogenization can vary. The pressure may be between 5000 and 30,000 psi. The number of passes through the microfluidizer can be varied to achieve the desired droplet size. The number of passes can be about 2-20, 2-15, 4-15, 4-12 or 7-8.

The pharmaceutical formulation may then be passed through the filter system at room temperature and/or autoclaved to achieve sterilization. The filter used to achieve sterilization may be selected by one of ordinary skill in the art and may have a nominal pore size of 0.2 μm. The filter material used can vary. In one embodiment, the filter is nylon. In another embodiment, the filter is a Posidyne® filter (covalently charged charge modified nylon 6,6 membrane that exhibits a net positively charged zeta potential in aqueous solution). For large scale production, the above method may need to be modified. Those skilled in the art can combine these materials in different orders and using different processing equipment to achieve the desired end result.

In one embodiment of the present disclosure, homogenization achieves an emulsion with oil particle/droplet size of less than 2 microns (μm) with intermediate cooling of the homogenized product to a temperature of less than about 25°C. Can be done in repeated cycles for.

The final emulsion comprises an oil part (oil phase) dispersed in an aqueous part (aqueous phase). The ratio of components to NK-1 receptor antagonist in the oil phase is an important feature of emulsions that can affect the stability of formulations prepared for injection, and each of these ratios in the final pharmaceutical emulsion. Will be presented in more detail below. As mentioned above, the oil phase comprises NK-1 receptor antagonists, oils and emulsifiers, examples of which are provided herein.

The final emulsion contains about 0.7 wt/wt% NK-1 receptor antagonist, but from about 0.2 wt/wt% to 1.5 wt/wt%, 0.4 wt/wt% to 1 It can range from 0.0 wt/wt%, 0.6 wt/wt% to 0.7 wt/wt%, or 0.7 wt/wt% to 0.8 wt/wt%. An emulsion is prepared that can contain about 130 mg of the NK-1 receptor antagonist, but a preparation containing about 100 mg to 1000 mg, 100 mg to 500 mg, 250 mg to 750 mg or 100 mg to 200 mg of the NK-1 receptor antagonist. It may also be prepared according to the present disclosure.

In one embodiment, the ratio of oil:NK-1 receptor antagonist (wt%:wt%) in the oil phase of the final emulsion is about 13:1 to 14:1, but about 11:1 to 15:1. , 12:1 to 14:1, 13:1 to 13.5:1, or 12:1 to 15:1. In another embodiment, the ratio of oil:NK-1 receptor antagonist is about 11:1, 11.5:1, 12:1, 12.5:1, 13:1, 13.5:1, 14. : 1:14.5:1 or 15:1.

The ratio of emulsifier to NK-1 receptor antagonist in the final emulsion can be about 20:1, but can also vary. For example, the ratio of emulsifier:NK-1 receptor antagonist in the oil portion (wt%:wt%) is about 15:1 to 30:1, 20:1 to 25:1, 18:1 to 22:1, It is in the range of 19:1 to 20:1, or 10:1 to 30:1. In one embodiment, the emulsifier:NK-1 receptor antagonist (wt%:wt%) is about 15:1, 18:1, 19:1, 20:1, 21:1, 22:1 or 23:1. Is.

The ratio of components in the oil phase of the final emulsion may alternatively be expressed as the ratio of (emulsifier plus oil):NK-1 receptor antagonist (wt%:wt%). The ratio of (emulsifier plus oil):NK-1 receptor antagonist may be about 33:1, while for this emulsion the ratio is about 20:1 to 40:1, 25:1 to 35:1, 30:. It may range from 1 to 35:1 or 33:1 to 37:1, or for example about 30:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1. , 38:1 or 40:1.

The compositions of the present disclosure have significant advantages in terms of reduced toxicity as compared to injectable formulations that may contain less desirable excipients, such as detergents, such as Tween-20 or Tween-80. The formulation takes advantage of the ability to solubilize a therapeutically effective amount of the NK-1 receptor antagonist in the oil phase, which can then be used to produce an emulsion suitable for injection. Accordingly, described herein is a pharmaceutical emulsion composition containing an NK-1 receptor antagonist and optionally dexamethasone or dexamethasone sodium phosphate, the emulsion being detergent-free.

The compositions of the present disclosure yield products suitable for parenteral use due to their small particle size. The product can be diluted with a drug such as an aqueous solution of sucrose, an aqueous solution of maltose, or dextrose 5% injection or saline to achieve the required concentration for parenteral administration. The disclosed compositions are easy to use. The compositions of the present disclosure also have an extended shelf life and are therefore suitable for readily marketable products.

The compositions of the present disclosure are both chemically and physically stable. The physically stable emulsions of the present invention can be used for at least 1 month, 2 months, 3 months, without an increase in average droplet size beyond what is acceptable as described in USP <729>. It can be stored under suitable conditions for 4, 5, 6, 9, 9, 12, 15, 18, 24 or 36 months. Moreover, the population of large diameter fat droplets should be within the limits described in USP <729>.

Droplet size limits as defined in USP <729> apply over a specified shelf life which may extend up to 2-3 years or longer for commercial pharmaceutical formulations. All true emulsions are thermodynamically unstable and can undergo a series of processes that tend to increase droplet size over time. These include direct droplet coalescence as two droplets collide to form a single new droplet, and agglomeration, where the droplets adhere together and form a larger mass. Form. Aggregates can optionally be precursors of further adhesions to larger droplets. These processes result in large agglomerates reaching the surface of the container, a phenomenon known as "creaming", and eventually known as "cracking", which results in free oil being visible on the emulsion surface. obtain.

Droplet size limits are typified by the USP 33-NF28 general rule <729> (hereinafter referred to as USP <729>) for droplet size distribution in injectable lipid emulsions, where USP <729> is (1 ) Average droplet size not exceeding 500 nm or 0.5 μm and (2) of large diameter expressed as volume weighted percentage of fat (PFAT5) greater than 5 μm not exceeding 0.05% regardless of final lipid concentration. Define a universal limit for the population of fat droplets.

Droplet size measurements, such as those defined in USP <729>, are able to measure an initial increase in size, and thus the physics of the emulsion early before the formulation shows a macroscopic visible change. Predictive stability. Thus, an emulsion as described herein is a stable composition having an intensity weighted mean droplet diameter of less than about 500 nm, less than 400 nm, less than 300 nm, less than 200 nm or less than 100 nm.

Oil droplet size or particle droplet size, or diameter, according to the present disclosure is measured using a dynamic light scattering (DLS) instrument, such as a Malvern Zetasizer 4000, Malvern Zetasizer Nano S90 or preferably a Malvern Zetasizer Nano ZS. .. The intensity weighted particle size was recorded. This is because the intensity weighted particle size does not require knowledge of the refractive index of the particles. On the Malvern Zetasizer instrument, there are two fits for determining the intensity weighted diameter of oil droplet size. The first fit is the cumulant fit used to determine the Z-mean diameter. This fit can further provide a polydispersity index (PDI). This cumulant fit is recommended for monodisperse samples with PDI less than 0.2. The second fit is a non-negative least squares (NNLS) fit. This gives rise to peak 1 diameter, peak 2 diameter and peak 3 diameter. This is more suitable for polydisperse samples with PDI greater than 0.2.

Emulsion preparations as described herein may further include preservatives in amounts that preserve the composition. Suitable preservatives used in some of the embodiments of the present disclosure include, but are not limited to, disodium edetate, tocopherol, benzalkonium chloride, methyl, ethyl, propyl or butyl paraben, benzyl alcohol, phenyl. Included are ethyl alcohol, benzethonium, chlorobutanol, potassium sorbate or combinations thereof.
III. Medical use

The pharmaceutical compositions of the present disclosure can be used for the prevention or treatment of emesis, following highly or moderately emetogenic chemotherapy, eg chemotherapy used in cancer patients. Providing parenteral options for existing patients. As such, the present disclosure is directed to subjects receiving highly or moderately emetogenic chemotherapy, whether the chemotherapy is an initial treatment or a repeating course of chemotherapy. A method of treatment comprising intravenously administering an emulsion containing an NK-1 receptor antagonist as described in 1. The pharmaceutical emulsions described herein can be used, for example, in the prevention or treatment of acute and delayed nausea and vomiting associated with chemotherapy or radiation therapy.

Another embodiment relates to the use of the pharmaceutical formulations of the present disclosure in the manufacture of a medicament for use in preventing or treating emesis in a subject in need thereof.

The amount of NK-1 receptor antagonist and optionally dexamethasone required for use in the disclosed methods may vary depending on the mode of administration and the condition of the patient, and the degree of treatment required, Ultimately it is at the discretion of the attending physician or clinician.

IV. Examples The following examples are exemplary in nature and are not intended to be limiting in any way.
(Example 1)
Preparation of aprepitant emulsion for intravenous injection To prepare an aprepitant emulsion, the oil phase was first prepared by combining 750 mg aprepitant and 15.0 g egg lecithin (LIPOID E80) with 12.0 ml ethanol. Prepared. This mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution was added 10.0 g soybean oil. Heating at 60° C. and stirring at 200 rpm were continued for another 15 minutes. The aqueous phase was prepared by dissolving 5.60 g sucrose and 0.500 g sodium oleate in 70.0 ml water for injection. The mixture was stirred at 300 rpm for 30 minutes at room temperature. The aqueous phase was then added to the oil phase followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to produce a crude emulsion. The crude emulsion was then passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi for 8 passes. The resulting fine emulsion was sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 1 below. Intensity-weighted particle size analyzed by dynamic light scattering (Malvern® Zetasizer Nano ZS) using a non-negative least squares (NNLS) fit gave a peak 1 diameter of 99 nm. The intensity weighted average particle size determined using the Cumulant fit provided a Z-average diameter of 87 nm. The zeta potential was measured to be -43 mV by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.74. The aprepitant-containing emulsion can be injected neat or diluted for injection with 5% dextrose or 0.9% saline.
(Example 2)
Preparation of aprepitant emulsion for intravenous injection

To prepare an aprepitant emulsion, the oil phase was first prepared by combining 450 mg aprepitant and 9.00 g egg lecithin (LIPOID E80) with 4.0 ml ethanol. This mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution was added 6.00 g soybean oil. Heating at 60° C. and stirring at 200 rpm were continued for another 15 minutes. The aqueous phase was prepared by dissolving 3.36 g sucrose and 0.300 g sodium oleate in 42.0 ml water for injection. The mixture was stirred at 300 rpm for 30 minutes at room temperature. The aqueous phase was then added to the oil phase followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to produce a crude emulsion. The crude emulsion was then passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi for 8 passes. The resulting fine emulsion was sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 2 below. Dynamic light scattering (Malvern® Zetasizer Nano
Intensity-weighted particle size analyzed by ZS) using the NNLS fit gave a peak 1 diameter of 127 nm. The intensity weighted average particle size determined using the Cumulant fit provided a Z-average diameter of 101 nm. The zeta potential was determined to be -47 mV by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.77. The aprepitant-containing emulsion can be injected neat or diluted for injection with 5% dextrose or 0.9% saline.
(Example 3)
Preparation of aprepitant emulsion for intravenous injection

To prepare the aprepitant emulsion, the oil phase was first prepared by combining 450 mg aprepitant and 9.00 g egg lecithin (LIPOID E80) with 6.0 ml ethanol. This mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution was added 6.00 g soybean oil. Heating at 60° C. and stirring at 200 rpm were continued for another 15 minutes. The aqueous phase was prepared by dissolving 15.62 g sucrose and 0.300 g sodium oleate in 42.0 ml water for injection. The mixture was stirred at 300 rpm for 30 minutes at room temperature. The aqueous phase was then added to the oil phase followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to produce a crude emulsion. The crude emulsion was then passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi for 8 passes. The resulting fine emulsion was sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 3 below. Intensity-weighted particle size analyzed by dynamic light scattering (Malvern® Zetasizer Nano ZS) using the NNLS fit gave a peak 1 diameter of 88 nm. The intensity weighted average particle size determined using the Cumulant fit provided a Z-average diameter of 68 nm. The zeta potential was determined to be -42 mV by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.80. This aprepitant-containing emulsion is diluted 4-fold with water for injection before injection.
(Example 4)
Preparation of alternative aprepitant emulsion formulations for intravenous injection

An aprepitant emulsion was prepared having less than 10% w/w phospholipid emulsifier and adjusted to a pH below 8.0. To prepare the aprepitant emulsion, the oil phase was first prepared by combining 450 mg aprepitant and 6.67 g egg lecithin (LIPOID E80) with 7.2 ml ethanol. This mixture was dissolved by heating and stirring at 60° C. and 200 rpm. Heating and stirring were carried out until the ethanol had evaporated and a thick residue was observed. To the resulting solution, 6.00 g of soybean oil and an appropriate amount of ethanol were added, and heating at 60°C gave a transparent oil phase. An aqueous phase was prepared by dissolving 3.36 g sucrose in 50.5 ml water for injection at 60°C. The aqueous phase was then added to the oil phase followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to produce a crude emulsion. The pH of this crude emulsion was adjusted to 7.0 and then passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) 8 times at a pressure of 18,000 psi. .. The resulting fine emulsion was sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 4 below. Crystals were observed in the product by microscopy within 4 days of preparation at room temperature.
(Example 5)
Preparation of aprepitant emulsion for intravenous injection

An aprepitant emulsion containing oleic acid was prepared. To prepare the aprepitant emulsion, the oil phase was first prepared by combining 250 mg aprepitant, 2.50 g egg lecithin (LIPOID E80) with 15.0 g soybean oil and 125 mg oleic acid. 10 ml of ethanol was added and the mixture was melted at 70°C. The ethanol was removed by vacuum in a 70° C. water bath, yielding a clear oily phase. A preheated aqueous phase containing 82.1 ml of water for injection at 70° C. was added to the oil phase followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute. Produced a crude emulsion. The crude emulsion was passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) eight times at a pressure of 18,000 psi. The resulting fine emulsion was sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 5 below. Crystals were observed in the product by microscopy within 4 days of preparation at room temperature.
(Example 6)
Preparation of emulsion containing aprepitant and dexamethasone sodium phosphate for intravenous injection

To prepare an injectable emulsion containing aprepitant and dexamethasone sodium phosphate, the oily phase was first combined by combining 773 mg aprepitant and 15.5 g egg lecithin (LIPOID E80) with 10.3 ml ethanol. Was prepared. This mixture was dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solutions was added 10.3g soybean oil. Heating at 60° C. and stirring at 200 rpm were continued for another 15 minutes. The aqueous phase was prepared by dissolving 5.77 g sucrose and 0.515 g sodium oleate in 71.1 ml water for injection. The mixture was stirred at 300 rpm for 30 minutes at room temperature. The aqueous phase was then added to the oil phase followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to produce a crude emulsion. The crude emulsion was then passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi for 8 passes. Dexamethasone sodium phosphate (93.5 mg) dissolved in 1 ml water for injection was mixed into the fine emulsion. The resulting fine emulsion, containing both aprepitant and dexamethasone sodium phosphate, was sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 6 below. Intensity-weighted particle size analyzed by dynamic light scattering (Malvern® Zetasizer Nano ZS) using the NNLS fit gave a peak 1 diameter of 95 nm. The intensity weighted average particle size determined using the Cumulant fit provided a Z-average diameter of 70 nm. The zeta potential was determined to be -43 mV by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion was 8.92. This emulsion containing aprepitant and dexamethasone sodium phosphate can be injected neat or diluted for injection with 5% dextrose or 0.9% saline.
(Example 7)
Stability of aprepitant emulsion at room temperature and 5°C

The stability of aprepitant emulsions prepared as described in Examples 1, 2, 3 and 6 was measured by incubating each emulsion preparation at room temperature (about 25°C) or at 5°C. The average particle size and percentage of fat droplets larger than 5 μm were measured using DLS and light screening, respectively, to determine if they meet USP<729>. The emulsion was also examined microscopically for aprepitant crystals. Example 1 was stable at room temperature for 2 months. That is, the average particle size and percentage of fat droplets larger than 5 μm met USP<729>. Moreover, aprepitant crystals were not visible by microscopy. After storage for 2 months at room temperature, creaming was observed in Examples 1 and 6. This was consistent with the observation of aprepitant crystals. Examples 2 and 3 were stable at room temperature for 3 months and 2 months, respectively. After these time points, aprepitant crystals were observed in these formulations. Storage at 5°C resulted in longer emulsion stability for Examples 1, 2, 3 and 6. Table 7 shows the characterization of Examples 1, 2, 3 and 6 and their respective stability at room temperature and 5°C.
(Example 8)
Stability of aprepitant emulsion against freeze-thaw cycles

The aprepitant emulsion prepared according to Examples 1, 2, 3 and 6 was tested for stability by exposure to freeze-thaw cycles. The samples from Examples 1, 2, 3 and 6 were stored overnight at -20°C. The next day, they were thawed to room temperature and visualized by microscopy. Prior to freezing, all samples showed no visible particles when examined microscopically. Figure 1 shows microscopic images at 10X of the emulsion after freeze-thaw cycles (Examples 1, 2, 3 and 6 are shown as Figures 1A, B, C and D, respectively). The emulsions prepared as described in Examples 1, 2 and 6 showed visible particles after exposure to freezing. Only Example 3 was stable after freezing. As FIG. 1C shows, no visible particles were observed for the formulation of Example 3. This enhanced stability was conferred by the presence of high concentrations of sucrose (20 w/w% in Example 3, compared to 5 w/wt% in Examples 1, 2 and 6).
(Example 9)
Pharmacokinetics of aprepitant emulsion

The pharmacokinetics of the aprepitant emulsion prepared according to Example 1 was determined. Two groups of 6 male Sprague-Dawley rats each were injected intravenously with fosaprepitant in solution or the aprepitant emulsion prepared according to Example 1, respectively. All drugs were administered at effective concentrations equal to 14 mg/kg aprepitant. Blood from all rats was collected at appropriate time intervals and processed into plasma by centrifugation. Plasma samples were optionally analyzed by LC-MS/MS for aprepitant and fosaprepitant. The plasma concentration versus time curves of aprepitant for the emulsion described in Example 1 and for fosaprepitant are presented in Figure 2 (fosaprepitant in solution, filled circles; aprepitant emulsion, filled triangles). The curve showed that the first aprepitant level reached shortly after injection of the aprepitant emulsion was almost 3 times higher than the first aprepitant level reached shortly after injection of the fosaprepitant solution. However, the plasma levels of aprepitant resulting from each injection were essentially the same up to the 3 hour time point, which was the result of the formulation being bioequivalent except for the delay in conversion of fosaprepitant to aprepitant. It was shown that.
(Example 10)
Pharmacokinetics of aprepitant and dexamethasone emulsions

The pharmacokinetics of the combined emulsion of aprepitant and dexamethasone sodium phosphate prepared according to Example 6 was determined. In each of the male Sprague-Dawley rats, phosaprepitant solution (group 1), dexamethasone sodium phosphate solution (group 2), or an emulsion containing aprepitant prepared according to Example 6 and dexamethasone sodium phosphate (group 3) was administered intravenously. ) Was injected. Groups 1 and 2 consisted of 6 rats each. For group 3, 12 rats were injected with a combined emulsion of aprepitant and dexamethasone sodium phosphate, allowing collection of sufficient samples for measurement of both active ingredients.

In groups 1 and 3 the dose was administered at an effective drug concentration equal to 2 mg/kg aprepitant. In groups 2 and 3, the dose was administered at an effective drug concentration equal to 0.24 mg/kg dexamethasone sodium phosphate. Blood from all rats was collected at appropriate time intervals and processed into plasma by centrifugation. Plasma samples were optionally analyzed by LC-MS/MS for dexamethasone, aprepitant, and fosaprepitant.

Figures 3 and 4 present plasma concentration versus time curves for aprepitant and dexamethasone, respectively. FIG. 3 compares the plasma concentration versus time curves of aprepitant produced by injection of a solution of fossaprepitant (FIG. 3, filled triangles) versus injection of the emulsion described in Example 6 (FIG. 3, filled circles). FIG. 4 compares the plasma concentration versus time curves of dexamethasone resulting from injection of the emulsion described in Example 6 versus injection of dexamethasone sodium phosphate solution (FIG. 4, filled circles). The curve shows that aprepitant in the emulsion is released at about the same time as dexamethasone sodium phosphate. The presence of dexamethasone sodium phosphate in the emulsion does not affect the pharmacokinetics of aprepitant.
(Example 11)
Preparation of aprepitant emulsion for intravenous injection

To prepare an aprepitant emulsion containing a buffer, the oil phase was first mixed by combining 750 mg aprepitant, 15.0 g egg lecithin (LIPOID E80) with 10.0 g soybean oil and 3.75 ml ethanol. To prepare. The mixture is dissolved by heating and stirring at 70° C. and 200 rpm for 30 minutes. The aqueous phase is prepared by dissolving 2.17 g sucrose and 0.500 g sodium oleate in a mixture of 4.1 ml 1 M Tris buffer (pH 8.4) and 65.9 ml water for injection. The mixture is stirred at 300 rpm at room temperature for 30 minutes. The aqueous phase is then added to the oil phase, followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to produce a crude emulsion. The crude emulsion is then passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi for 8 passes. The resulting fine emulsion is sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Dynamic light scattering was used to determine the intensity weighted particle size using the NNLS fit to yield the peak 1 diameter and the cumulant fit to determine the intensity weighted average particle size to determine the Z-average diameter. provide. The zeta potential is measured by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The aprepitant-containing emulsion can be injected neat or diluted for injection with 5% dextrose or 0.9% saline.
(Example 12)
Preparation of lorapitant emulsion for intravenous injection

To prepare the lorapitant emulsion, 1.080 g of lorapitant and 21.6 g of egg lecithin (LIPOID E80) were combined with 14.4 g of soybean oil and 5.40 ml of ethanol in a glass jar. The phases were prepared first. The mixture was incubated at room temperature for 30 minutes, followed by heating and stirring at 70° C. and 200 rpm for an additional 30 minutes. The aqueous phase was prepared by dissolving 8.06 g sucrose and 0.720 g sodium oleate in 100.8 ml water for injection by heating and stirring at 35° C. and 300 rpm for 15 minutes. The aqueous phase was then added to the oil phase followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to produce a crude emulsion. The crude emulsion was passed through a high pressure microfluidizer (Microfluidizer® M-110P, F12Y interaction chamber) 8 times at a pressure of 20,000 psi. Cooling water was used to maintain the exit fine emulsion temperature at approximately 25°C. The resulting fine emulsion was sterilized by passing through a 0.2 μm nylon filter (Nalgene). Details of the emulsion composition are provided in Table 8 below. The intensity-weighted particle size analyzed by dynamic light scattering (Malvern® Zetasizer Nano ZS) using a non-negative least squares (NNLS) fit gave a peak 1 diameter of 127 nm (Table 9). The intensity weighted average particle size determined using the Cumulant fit provided a Z-average diameter of 100 nm. The pH and osmolality of the injectable emulsion were 8.51 and 318 mmol/kg, respectively. The lorapitant-containing emulsion can be injected neat, or diluted for injection with 0.9% saline or 5% dextrose.

(Example 13)
Preparation of Netupitant Emulsion for Intravenous Injection To prepare an emulsion containing a therapeutically effective amount of Netupitant, about 750 mg netupitant and 15.0 g egg lecithin (LIPOID E80) and 12.0 ml ethanol were prepared. The oily phase is first prepared by combining The mixture is dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution is added 10.0 g soybean oil. Heating at 60° C. and stirring at 200 rpm is continued for another 15 minutes. The aqueous phase is prepared by dissolving 5.60 g sucrose and 0.500 g sodium oleate in 70.0 ml water for injection. The mixture is stirred at 300 rpm at room temperature for 30 minutes. The aqueous phase is then added to the oil phase, followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to form a crude emulsion. The crude emulsion is then passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi for 8 passes. The resulting fine emulsion is sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 10 below. Intensity-weighted particle size is analyzed by dynamic light scattering (Malvern® Zetasizer Nano ZS) using a non-negative least squares (NNLS) fit to obtain the peak 1 diameter of the particles. The intensity weighted average particle size was also determined using the cumulant fit to provide the Z-average diameter. The zeta potential is measured to be -43 mV by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion is also measured, preferably about pH 7.8-8.8. The emulsion containing the NK-1 receptor antagonist can be injected neat or diluted for injection with 5% dextrose or 0.9% saline.

(Example 14)
Preparation of Netupitant Emulsion for Intravenous Injection To prepare a Netupitant emulsion, by combining about 450 mg netupitant and 9.00 g egg lecithin (LIPOID E80) with 4.0 ml ethanol. The oil phase is first prepared. The mixture is dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution is added 6.00 g soybean oil. Heating at 60° C. and stirring at 200 rpm is continued for about another 15 minutes. The aqueous phase is prepared by dissolving 3.36 g sucrose and 0.300 g sodium oleate in 42.0 ml water for injection. The mixture is stirred at 300 rpm at room temperature for 30 minutes. The aqueous phase is then added to the oil phase, followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to form a crude emulsion. The crude emulsion is then passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi for 8 passes. The resulting fine emulsion is sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 11 below. Intensity-weighted particle size is analyzed by dynamic light scattering (Malvern® Zetasizer Nano ZS) using the NNLS fit to give the peak 1 diameter. The intensity weighted average particle size is determined using the cumulant fit and provides the Z-average diameter. Zeta potential is measured by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion is also measured, preferably about pH 7.8-8.8. The netupitant-containing emulsion can be injected neat or diluted for injection with 5% dextrose or 0.9% saline.

(Example 15)
Preparation of Netupitant Emulsion for Intravenous Injection To prepare Netupitant emulsion, oil was prepared by combining 450 mg Netupitant and 9.00 g egg lecithin (LIPOID E80) with 6.0 ml ethanol. The phases are prepared first. The mixture is dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution is added 6.00 g soybean oil. Heating at 60° C. and stirring at 200 rpm is continued for another 15 minutes. The aqueous phase is prepared by dissolving in 15.62 g sucrose and 0.300 g sodium oleate in 42.0 ml water for injection. The mixture is stirred at 300 rpm at room temperature for 30 minutes. The aqueous phase is then added to the oil phase, followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to form a crude emulsion. The crude emulsion is then passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi for 8 passes. The resulting fine emulsion is sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 12 below. Intensity-weighted particle size is analyzed by dynamic light scattering (Malvern® Zetasizer Nano ZS) using the NNLS fit to give the peak 1 diameter. The intensity weighted average particle size is determined using the cumulant fit and provides the Z-average diameter. Zeta potential is measured by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The pH of the injectable emulsion is also measured, preferably about pH 7.8-8.8. This netupitant-containing emulsion is diluted 4-fold with water for injection prior to injection.

(Example 16)
Alternative Netupitant Emulsion Formulation for Intravenous Injection Prepare a netupitant emulsion with less than 10% w/w phospholipid emulsifier and adjusted to a pH below 8.0. To prepare the Netupitant emulsion, the oil phase is first prepared by combining 450 mg of Netupitant and 6.67 g of egg lecithin (LIPOID E80) with 7.2 ml of ethanol. The mixture is dissolved by heating and stirring at 60°C and 200 rpm. Heat and stir until the ethanol has evaporated and a thick residue is observed. To the resulting solution, 6.00 g soybean oil and the appropriate amount of ethanol are added and heating at 60° C. gives a clear oil phase. The aqueous phase is prepared by dissolving 3.36 g sucrose in 50.5 ml water for injection at 60°C. The aqueous phase is then added to the oil phase, followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to form a crude emulsion. The pH of this crude emulsion is adjusted to 7.0 and then passed 8 times through a high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) cooled with ice at a pressure of 18,000 psi. The resulting fine emulsion is sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 13 below. Within 4 days of preparation at room temperature, the emulsion product is analyzed by microscope for the presence of crystals.

(Example 17)
Alternative Netupitant Emulsion Formulation for Intravenous Injection A neupitant emulsion containing oleic acid is prepared. To prepare a netupitant emulsion, an oil phase is first prepared by combining 250 mg netupitant, 2.50 g egg lecithin (LIPOID E80), 15.0 g soybean oil and 125 mg oleic acid. 10 ml of ethanol are added and the mixture is melted at 70°C. The ethanol is removed by vacuum in a 70° C. water bath to give a clear oil phase. A preheated aqueous phase containing 82.1 ml of water for injection at 70° C. was added to the oil phase followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute. , To produce a crude emulsion. The crude emulsion is passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) eight times at a pressure of 18,000 psi. The resulting fine emulsion is sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 14 below. Within 4 days of preparation at room temperature, the emulsion product is analyzed by microscope for the presence of crystals.

(Example 18)
Preparation of an emulsion containing netupitant and dexamethasone sodium phosphate for intravenous injection To prepare an injectable emulsion containing netupitant and dexamethasone sodium phosphate, 773 mg netupitant and 15.5 g egg lecithin (LIPOID E80 ) And 10.3 ml ethanol are combined to first prepare an oil phase. The mixture is dissolved by heating and stirring at 60° C. and 200 rpm for 15 minutes. To the resulting solution is added 10.3 g soybean oil. Heating at 60° C. and stirring at 200 rpm is continued for another 15 minutes. The aqueous phase is prepared by dissolving 5.77 g sucrose and 0.515 g sodium oleate in 71.1 ml water for injection. The mixture is stirred at 300 rpm at room temperature for 30 minutes. The aqueous phase is then added to the oil phase, followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to form a crude emulsion. The crude emulsion is then passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi for 8 passes. Dexamethasone sodium phosphate (93.5 mg) dissolved in 1 ml water for injection is mixed into the fine emulsion. The resulting fine emulsion containing both netupitant and dexamethasone sodium phosphate is sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Details of the emulsion composition are provided in Table 6 below. Intensity-weighted particle size is analyzed by dynamic light scattering (Malvern® Zetasizer Nano ZS) using the NNLS fit to determine the peak 1 diameter. The intensity weighted average particle size is determined using the cumulant fit and the Z-average diameter is determined. The zeta potential is measured to be -43 mV by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The preferred pH of the injectable emulsion is about 8.5-9.5. This netupitant and dexamethasone sodium phosphate-containing emulsion can be injected neat or diluted for injection with 5% dextrose or 0.9% saline.

(Example 19)
Preparation of NK-1 Receptor Antagonist Emulsion for Intravenous Injection To prepare NK-1 receptor antagonist emulsion containing buffer, 750 mg aprepitant, 15.0 g egg lecithin (LIPOID E80), 10.0 g The oily phase is first prepared by combining the soybean oil of 3. and 3.75 ml of ethanol. The mixture is dissolved by heating and stirring at 70° C. and 200 rpm for 30 minutes. The aqueous phase is prepared by dissolving 2.17 g sucrose and 0.500 g sodium oleate in a mixture of 4.1 ml Tris buffer (1M) (pH 8.4) and 65.9 ml water for injection. The mixture is stirred at 300 rpm at room temperature for 30 minutes. The aqueous phase is then added to the oil phase, followed by rapid homogenization (Ultra-Turrax® IKA T25) at a speed of 20,000 rpm for 1 minute to form a crude emulsion. The crude emulsion is then passed through an ice-cooled high pressure microfluidizer (Microfluidizer® M-110L, F12Y interaction chamber) at a pressure of 18,000 psi for 8 passes. The resulting fine emulsion is sterilized by passing through a 0.2 μm nylon syringe filter (Corning). Dynamic light scattering was used to determine the intensity weighted particle size using the NNLS fit to give the peak 1 diameter and the intensity weighted average particle size was determined using the cumulant fit to provide the Z-mean diameter. To do. The zeta potential is measured by laser Doppler microelectrophoresis (Malvern® Zetasizer Nano ZS). The aprepitant-containing emulsion can be injected neat or diluted for injection with 5% dextrose or 0.9% saline.

(Example 20)
Stability of lorapitant emulsion at room temperature and 5°C Stability of lorapitant emulsion prepared as described in Example 12 was tested by incubating the emulsion preparation at room temperature (about 25°C) or at 5°C. It was measured by The average particle size and percentage of fat droplets larger than 5 μm were measured using DLS and light screening, respectively, and shown to meet USP<729> after 2 months storage. The emulsion was also examined microscopically for lorapitant crystals and visually for the presence of emulsion creaming. The absence of crystalline or emulsion creaming further indicated product stability.

(Example 21)
Stability of Netupitant Emulsions at Room Temperature and 5° C. The stability of Netupitant emulsions prepared as described in Examples 13-17 was determined at room temperature (about 25° C.) or at 5° C. for each emulsion preparation It can be measured by incubating the object. The average particle size and percentage of fat droplets larger than 5 μm are measured using DLS and light screening, respectively, to determine if they meet USP<729>. The emulsions are also examined microscopically for netupitant crystals and/or visually for the presence of emulsion creaming. The absence of crystals or emulsion creaming indicates product stability.

(Example 22)
Stability of Netupitant Emulsions to Freeze-Thaw Cycles Netupitant emulsions prepared according to Examples 13-17 can be tested for stability upon exposure to freeze-thaw cycles. Samples from Examples 13-17 are stored overnight at -20°C. The absence of visible particles when the sample is viewed under a microscope indicates product stability.

While some exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. Accordingly, the following appended claims, which are to be introduced below, are to be construed to include all such modifications, permutations, additions and subcombinations, as are within their true spirit and scope. Is intended.
The present invention provides the following items, for example.
(Item 1)
A neurokinase-1 (NK-1) receptor antagonist;
11 wt/wt% to 15 wt/wt% emulsifier;
oil;
Cosurfactants containing alcohol;
Tonicity agents;
An injectable emulsion comprising a pH adjusting substance; and water,
An emulsion in which the pH of the emulsion is in the range of about 7.5 to 9.0.
(Item 2)
An emulsion according to item 1, wherein the ratio of the oil to the NK-1 receptor antagonist is in the range of about 5:1 to 15:1 (weight/weight %).
(Item 3)
An emulsion according to item 1 or 2, wherein the ratio of the oil to the NK-1 receptor antagonist is in the range of about 10:1 to 15:1 (weight/weight %).
(Item 4)
The emulsion according to any one of items 1 to 3, wherein the ratio of the emulsifier to the NK-1 receptor antagonist is in the range of about 10:1 to 30:1 (weight/weight %).
(Item 5)
The emulsion according to any one of items 1 to 4, wherein the ratio of the emulsifier to the NK-1 receptor antagonist is in the range of about 15:1 to 30:1 (weight/weight %).
(Item 6)
An emulsion according to any one of items 1 to 5, wherein the ratio of emulsifier to oil is in the range of about 1:1 to 3:1 (weight/weight %).
(Item 7)
The emulsion according to any one of items 1 to 6, wherein the emulsifier is a phospholipid. (Item 8)
Item 8. The emulsion according to any one of Items 1 to 7, wherein the emulsifier is egg lecithin.
(Item 9)
The emulsion according to any one of items 1 to 8, further comprising sodium dexamethasone phosphate, wherein the sodium dexamethasone phosphate is present in the aqueous phase.
(Item 10)
Item 10. The emulsion according to any one of items 1 to 9, wherein the NK-1 receptor antagonist is selected from the group consisting of lorapitant, netupitant, ezropitant, vestipitant, serlopitant, malopitant, casopitant, befetupitant, and orbepitant.
(Item 11)
The emulsion according to any one of Items 1 to 10, wherein the pH adjusting substance is sodium oleate or a salt thereof.
(Item 12)
The emulsion according to any one of Items 1 to 10, wherein the pH adjusting substance is a buffer solution.
(Item 13)
Item 13. The emulsion according to Item 12, wherein the buffer solution is Tris buffer solution.
(Item 14)
The emulsion according to any one of items 1 to 13, wherein the oil is soybean oil.
(Item 15)
The emulsion according to any one of items 1 to 14, wherein the alcohol is ethanol.
(Item 16)
16. The emulsion of item 15, wherein the ethanol is present in the emulsion at less than 10% w/w.
(Item 17)
The emulsion according to any one of items 1 to 16, wherein the NK-1 receptor antagonist is not aprepitant.
(Item 18)
A method of preparing a pharmaceutical emulsion comprising:
(A) combining an NK-1 receptor antagonist, an emulsifier, and an alcohol with an oil to form an oil phase;
(B) combining water, a tonicity agent, a pH adjusting substance, and optionally a buffer to form an aqueous phase;
(C) homogenizing the oil phase with the aqueous phase to produce the pharmaceutical emulsion;
(D) sterilizing the pharmaceutical emulsion.
(Item 19)
Step (c) comprises homogenizing the oil phase with the aqueous phase to produce a crude emulsion, and step (c) further comprising homogenizing the crude emulsion to produce a fine emulsion; 19. The method according to item 18, wherein the fine emulsion is the pharmaceutical emulsion.
(Item 20)
20. The method of item 19, wherein homogenizing the crude emulsion comprises using a microfluidizer at a pressure of 10,000 to 30,000 psi.
(Item 21)
21. The method of item 20, wherein homogenizing the crude emulsion comprises 4-15 passes through the microfluidizer.
(Item 22)
22. The method of any of items 18-21, wherein the sterilizing comprises passing the pharmaceutical emulsion through a filter having a pore size of about 0.2 microns.
(Item 23)
23. The method according to any one of items 18 to 22, further comprising adding a solution of dexamethasone sodium phosphate sodium to the pharmaceutical emulsion prior to sterile filtration.
(Item 24)
24. The method of any one of items 18-23, wherein the receptor antagonist is selected from the group consisting of lorapitant, netupitant, ezropitant, casopitant, befetupitant, vestipitant, serlopitant, malopitant, and orbepitant.
(Item 25)
25. The method according to any one of items 18 to 24, wherein the NK-1 receptor antagonist is not aprepitant.
(Item 26)
A method of preventing or treating a subject in need of prophylaxis or treatment, said method comprising administering to said subject a composition comprising an emulsion according to any one of items 1 to 17.
(Item 27)
27. The method of item 26, wherein the subject is at risk of or suffering from nausea and/or vomiting.
(Item 28)
28. The method according to item 26 or 27, wherein the nausea and/or vomiting is induced by surgery, radiation therapy or chemotherapy.

Claims (1)

The invention described in the specification.