Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

• the field of the invention is liquid pharmaceutical compositions comprising aprepitant, especially as oral suspension dosage forms for the prevention and control of acute and delayed chemotherapy induced nausea and vomiting, and/or for prevention of postoperative nausea and vomiting.
• Aprepitant (5-([(2R,3S)-2-((R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluoro-phenyl)morpholino]methyl)-1H-1,2,4-triazol-3(2H)-one) is an antiemetic compound that belongs to the class of substance P antagonists that mediate their effect by blocking the neurokinin (NK1) receptor.
• NK1 receptor neurokinin receptor
• Aprepitant is a selective, high-affinity antagonist at human substance P NK-1 receptors and is manufactured by Merck & Co. (available under the brand name, Emend®).
• Solid capsules 40, 80 and 125 mg or powder (115 and 150 mg) for injection for the prevention and control of acute and delayed chemotherapy induced nausea and vomiting, and for prevention of postoperative nausea and vomiting.
• the recommended dose of EMEND capsules is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg orally once daily in the morning on Days 2 and 3 and also indicated for the postoperative nausea and vomiting (PONV) 40 mg within 3 hours prior to induction of anesthesia.
• PONV postoperative nausea and vomiting
• mean area under the plasma concentration-time curve (AUCo- ⁇ ) was 7.8 mcg/hr/mL and mean peak plasma concentration (Cmax) was 0.7 mcg mL, occurring at approximately 3 hours post-dose (tmax). The absolute bioavailability at the 40-mg dose has not been determined.
• the AUCo-24 hr was approximately 19.6 mcg*hr/mL and 21.2 mcg*hr/mL on Day 1 and Day 3, respectively.
• the Cmax of 1.6 mcg mL and 1.4 mcg/mL were reached in approximately 4 hours (Tmax) on Day 1 and Day 3, respectively.
• the mean absolute oral bioavailability of aprepitant is approximately 60 to 65%.
• an aprepitant oral suspension can be prepared at the point of use by grinding a 125 mg capsule and combining the ground powder with Ora-BlendTM (gum-based fluid, commercially available from Paddock laboratories). Here, contents of an aprepitant capsule were emptied into a mortar and ground to a fine powder.
• Ora-Blend® A small amount of Ora-Blend® was added to the fine powder and triturated to a smooth paste. More Ora-Blend was added and the mixture transferred to a graduate. The mortar was rinsed with Ora-Blend and the mixture added to the graduate. Finally, sufficient Ora-Blend was added to final volume and mixed well. Unfortunately, such preparations are not stable and will generally not achieve a uniform suspension, which may affect bioavailability.
• nanoparticulate compositions of aprepitant are disclosed with stabilizers adsorbed on its surface to maintain an effective average particle size of less than about 1000 nm.
• US 2014/0272100 teaches coatings of carrier particles with aprepitant microparticles, and WO 2008/104512 describes different polymorphs in an attempt to increase solubility.
• all or almost all of compositions fail to provide a premade liquid formulation that is stable over a prolonged time, particularly where suspensions are prepared.
• the particles in the suspensions tend to agglomerate over time and precipitate out of solution and/or become less bioavailable due to increase in size.
• the inventive subject matter is directed to compositions and methods for stabilized aqueous suspension of aprepitant particles for oral administration in which aprepitant is provided in a suspension having a cellulosic stabilizer and an anionic surfactant in amounts sufficient to limit growth of the aprepitant particles.
• the inventors contemplate a method of producing a stabilized aqueous suspension of aprepitant for oral administration.
• a pharmaceutically effective amount of aprepitant particles, a cellulosic stabilizer, and an anionic surfactant are combined with an acidic aqueous buffer to form a stabilized aqueous suspension.
• the aprepitant particles have an average particle size of less than 0.5 micron, and the cellulosic stabilizer and the anionic surfactant are present in an amount that limits growth of the aprepitant particles in the stabilized aqueous suspension to equal or less than 20% within a month at ambient conditions.
• the so prepared stabilized aqueous suspension is then packaged in a form that is suitable for oral administration.
• the aprepitant particles have an average particle size of less than 0.4 micron, and/or aprepitant is present in the stabilized aqueous suspension in an amount of between 10.0 mg/g and 20.0 mg/g.
• the acidic aqueous buffer has a pH of between 3.0 and 5.0.
• the cellulosic stabilizer comprises a substituted cellulose (e.g., hydroxypropyl methylcellulose) and is present in the stabilized aqueous suspension in an amount of between 2.0 mg/g and 10.0 mg/g.
• the anionic surfactant is an alkylsulfate (e.g., sodium docecylsulfate) and is present in the stabilized aqueous suspension in an amount of between 0.5 mg/g and 5.0 mg/g.
• alkylsulfate e.g., sodium docecylsulfate
• the cellulosic stabilizer comprises a substituted cellulose that is present in the stabilized aqueous suspension in an amount of between 2.0 mg/g and 10.0 mg/g, and that the anionic surfactant is an alkylsulfate that is present in the stabilized aqueous suspension in an amount of between 0.5 mg/g and 5.0 mg/g.
• contemplated aspects will include stabilized aqueous suspension where the cellulosic stabilizer is hydroxypropyl methylcellulose (especially having a viscosity grade of E3 to E15, translating to a viscosity of 2.4 Cps to 18 Cps of a 2.0% solution of the polymer) and is present in the stabilized aqueous suspension in an amount of between 4.0 mg/g and 8.0 mg/g, while the anionic surfactant is sodium docecylsulfate and is present in the stabilized aqueous suspension in an amount of between 1.0 mg/g and 4.0 mg/g.
• the cellulosic stabilizer is hydroxypropyl methylcellulose (especially having a viscosity grade of E3 to E15, translating to a viscosity of 2.4 Cps to 18 Cps of a 2.0% solution of the polymer) and is present in the stabilized aqueous suspension in an amount of between 4.0 mg/g and 8.0 mg/g
• a stabilized aqueous suspension of aprepitant for oral administration that includes a pharmaceutically effective amount of aprepitant particles (e.g., having an average particle size of less than 0.5 micron), an acidic aqueous buffer, and a cellulosic stabilizer and an anionic surfactant in an amount effective that limits growth of the aprepitant particles to equal or less than 20% within a month at ambient conditions.
• aqueous suspension of aprepitant is formulated for oral administration and packaged into a container for use (e.g., single use container containing between 5 and 15 ml of the stabilized aqueous suspension).
• the aprepitant is present in the stabilized aqueous suspension in an amount of between 10.0 mg/g and 20.0 mg/g, and/or that the acidic aqueous buffer is a citrate buffer.
• the cellulosic stabilizer comprises a substituted cellulose (e.g., hydroxypropyl methylcellulose), and that the cellulosic stabilizer is present in the stabilized aqueous suspension in an amount of between 2.0 mg/g and 10.0 mg/g.
• contemplated that the anionic surfactant is an alkylsulfate (e.g., sodium docecylsulfate), and that the anionic surfactant is present in the stabilized aqueous suspension in an amount of between 0.5 mg/g and 5.0 mg/g.
• contemplated stabilized aqueous suspensions include those in which the cellulosic stabilizer comprises a substituted cellulose that is present in the stabilized aqueous suspension in an amount of between 2.0 mg/g and 10.0 mg/g, and in which the anionic surfactant is an alkylsulfate that is present in the stabilized aqueous suspension in an amount of between 0.5 mg/g and 5.0 mg/g.
• suitable stabilized aqueous suspension will include those in which the cellulosic stabilizer is hydroxypropyl methylcellulose and present in an amount of between 4.0 mg/g and 8.0 mg/g, and in which the anionic surfactant is sodium docecylsulfate and is present in an amount of between 1.0 mg/g and 4.0 mg/g.
• exemplary formulations will include aprepitant particles having an average particle size of less than 0.5 or less than 0.4 micron in combination with one or more cellulosic stabilizer and anionic surfactant (preferably at an acidic pH using a buffer).
• Such formulations are typically stable at ambient conditions (25° C., 60% relative humidity) for at least one month while limiting growth of aprepitant particles to equal or less than 20%.
• Such solutions are typically packaged in single use containers at a volume to provide a desired (e.g., 40 mg, 80 mg, 125 mg, etc.) quantity of aprepitant to a patient in need thereof.
• a desired quantity of aprepitant e.g. 40 mg, 80 mg, 125 mg, etc.
• Most typically, such formulations are administered to the patient to prevent nausea and vomiting upon or after chemotherapy treatment for cancer and/or to prevent postoperative nausea and vomiting.
• compositions and methods of formulating a stable pharmaceutical oral liquid formulation that comprises aprepitant and one or more pharmaceutically acceptable excipients in a single or multiple dosage form.
• compositions and methods for stable pharmaceutical oral liquid formulation comprising of aprepitant are contemplated where aprepitant is present in the formulation at a concentration of 40-125 mg/ml and a fill volume from 5-25 ml per container.
• pharmaceutically acceptable means biologically or pharmacologically compatible for in-vivo use in animals or humans, and can mean approved by a regulatory agency of the Federal or a state government or listed in the U.S.
• compositions and methods provide stable pharmaceutical oral liquid formulations comprising aprepitant and pharmaceutically acceptable excipients in which the formulation is a ready to use suspension of aprepitant nanoparticles.
• Such nanoparticles will typically have an average particle size of between 0.050 and 1000 microns.
• suitable sizes include those between 0.050 and 0.100 microns, between 0.100 and 0.500 microns, between 0.500 and 0.700 microns, or between 0.700 and 1.000 microns.
• compositions and methods contemplated herein also include additional agents to enhance one or more desirable properties, including flavor and palatability.
• contemplated formulations may also include preservatives, coloring agents, and/or flavoring agents.
• the stable pharmaceutical oral liquid formulation contemplated herein has pharmacokinetic parameters that are comparable to that of the pharmacokinetic parameters after administration of oral capsules.
• contemplated formulations are palatable, oral ready-to-use formulations of aprepitant (i.e., do not require dilution, mixing with other solvents, or further manipulation that change the composition). It should be particularly appreciated that aprepitant has been used in parenteral and solid oral medicinal products, but has not previously been used in oral liquid preparations that were stable over extended periods and that could be retrieved from the packing in a ready to use form.
• the particle size of the active pharmaceutical ingredient may have important effects on the bioavailability of a formulation. Smaller particle sizes often have increased surface area and will thus dissolve faster than larger particles. However, decreasing the particle size will often increase agglomeration of the particles, and an increased surface area of smaller particles can result in faster degradation of the compound, e.g., due to oxidation and/or hydrolysis.
• a fine particle size and especially an average particle size between 0.250 and 0.400 micron, could achieve a desirable bioavailability (typically identical to that of commercially available solid oral aprepitant, EMEND).
• Such particle size may preferably be achieved using air-jet milling, ball milling, or mortar milling.
• contemplated formulations exhibited remarkable stability against agglomeration (e.g., increase of average particle size) while maintaining desired pharmacokinetic parameters.
• aprepitant was and remained evenly dispersed in the thickened aqueous vehicle and had a homogeneity so that the aprepitant was uniformly present but undissolved in the formulation for extended periods (e.g., at least one month, or two months, or three months at ambient conditions).
• the inventors produced a stabilized aqueous suspension of aprepitant for oral administration by combining a pharmaceutically effective amount of aprepitant particles, a cellulosic stabilizer, and an anionic surfactant with an acidic aqueous buffer to form a stabilized aqueous suspension.
• the average particle size was less than 0.5 micron, and in most cases between 0.200 and 0.400 micron (e.g., 0.300+/ ⁇ 50 micron), and the so prepared stabilized aqueous suspension had a stability (i.e., particle growth less than 20 absolute) of over 1 month at ambient conditions.
• aprepitant was present between 10.0 mg/g and 20.0 mg/g (e.g., 15+/ ⁇ 10%) of the stabilized aqueous suspension, while the acidic aqueous buffer has a pH of between 3.0 and 5.0 (e.g., citrate buffer).
• Preferred cellulosic stabilizers will act as a thickening agent, and especially preferred were hydroxypropyl methylcellulose that was included in a range of between 2.0 mg/g and 10.0 mg/g or between 4.0 mg/g and 8.0 mg/g (e.g., 6+/ ⁇ 1 mg/g).
• preferred anionic surfactants were alkylsulfates, and especially sodium docecylsulfate that was included in a range of between 0.5 mg/g and 5.0 mg/g or between 1.0 mg/g and 4.0 mg/g (e.g., 1.5+/ ⁇ 0.5 mg/g).
• Such formulations provided superior stability and had desirable pharmacokinetic parameters.
• preferred stabilized aqueous suspension of aprepitant for oral administration will include a pharmaceutically effective amount of aprepitant particles, wherein the aprepitant has an average particle size of less than 0.5 micron.
• Contemplated suspensions will further include a cellulosic stabilizer and an anionic surfactant in an amount effective that limits growth of the aprepitant particles to equal or less than 20% within a month at ambient conditions, and also include an acidic aqueous buffer, and wherein the aqueous suspension of aprepitant is formulated for oral administration.
• contemplated suspensions may comprise at least one additional component selected from the group consisting of sweetening agents, flavoring agents, coloring agents, preservatives, oily vehicles, solvents, suspending agents, dispersing agents, antioxidants, permeation enhancing agents, oral bioavailability enhancing agents, and stabilizing agents.
• exemplary surfactants include various anionic surfactants, and to a lesser degree also nonionic and amphoteric surfactants.
• exemplary surfactants include water-soluble salts of C 8-20 alkyl sulfates, sulfonated monoglycerides of C 8-20 fatty acids, sarcosinates, taurates, and mixtures thereof.
• Illustrative examples of these and other surfactants are sodium lauryl sulfate, sodium coconut monoglyceride sulfonate, sodium lauryl sarcosinate, sodium lauryl isoethionate, sodium laureth carboxylate and sodium dodecyl benzenesulfonate, dioctyl sodium sulfosuccinate and mixtures thereof.
• Suitable nonionic surfactants include xpoloxamers, polyoxyethylene sorbitan esters, fatty alcohol ethoxylates, alkylphenol ethoxylates, tertiary amine oxides, tertiary phosphine oxides, dialkyl sulfoxides, and mixtures thereof.
• Suitable amphoteric surfactants include derivatives of C 8-20 aliphatic secondary and tertiary amines having an anionic group such as carboxylate, sulfate, sulfonate, phosphate or phosphonate.
• a suitable example is cocoamidopropylbetaine.
• One or more surfactants are optionally present in a total amount of about 0.01% to about 10%.
• stabilizing agents acting as thickeners are also deemed suitable and include tragacanth, xanthan gum, bentonite, starch, acacia, and/or lower alkyl ethers of cellulose (including the hydroxy and carboxy derivatives of the cellulose ethers).
• celluloses include, e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy methylcellulose, microcrystalline cellulose (MCC), and MCC with sodium carboxyl methyl cellulose.
• thickening agents may also function as suspending agents which can be used alone or in combinations.
• Exemplary suspending agents may include starch instant clearjel and xanthan gum.
• Starch instant clearjel may be used in the amount of from about 0.1 to about 10% w/v and preferably about 2 to about 3% w/v.
• Xanthan gum is used in the amount of from about 0.01 to about 5% w/v and preferably about 0.1-0.3% w/v.
• particularly desirable bulking agents include mannitol and microcrystalline cellulose.
• stabilizers include hypromellose that is ordinarily used as an excipient (coating and/or dispersing agent) in oral tablet and capsule formulations, where, depending on the grade, it functions as controlled release agent to delay the release of a medicinal compound into the digestive tract.
• Hypromellose is also used as a binder and as a component of tablet coatings, and notably form in solution non-Newtonian fluids and increases viscosity.
• Suitable suspending agents for use in the aqueous suspensions according to the present invention are cellulose derivatives, e.g.
• hypromellose methyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose, alginates, gelatin, chitosan, dextrans, polyvinylpyrrolidone, polyethylene glycols, polyoxyethylene- and polyoxypropylene ethers. While numerous polymer forms/lengths of hypromellose are known in the art, especially preferred forms of hypromellose include those having a viscosity grade of E3 to E15, which translates to a viscosity of 2.4 Cps to 18 Cps of a 2.0% solution of the polymer.
• Further contemplated agents include bulking agents that are known in the art. Bulking agents may be used alone or in combination in an amount of about 5% w/w to a total amount of up to about 90% w/w, preferably about 10% w/w to a total amount of up to about 70% w/w, more preferably about 10% w/w to about 50% w/w, most preferably about 10% to about 30% w/w.
• mannitol and/or microcrystalline cellulose may be used in an amount of about 10% w/w to about 15% w/w. When used in combination, they may be present in a ratio of 1:1 w/v or one more be present in a higher amount than another.
• Flavorants among those useful herein include any material or mixture of materials operable to enhance the taste of the composition. Any orally acceptable natural or synthetic flavorant can be used, such as flavoring oils, flavoring aldehydes, esters, alcohols, similar materials, and combinations thereof.
• Flavorants include vanillin, sage, marjoram, parsley oil, spearmint oil, cinnamon oil, oil of wintergreen (methylsalicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, citrus oils, fruit oils and essences including those derived from lemon, orange, lime, grapefruit, apricot, banana, grape, apple, strawberry, cherry, pineapple, etc., bean- and nut-derived flavors such as coffee, cocoa, cola, peanut, almond, etc., adsorbed and encapsulated flavorants, and mixtures thereof. Also encompassed within flavorants herein are ingredients that provide fragrance and/or other sensory effect in the mouth, including cooling or warming effects.
• Such ingredients include methol, menthyl acetate, menthyl lactate, camphor, eucalyptus oil, eucalyptol, anethole, eugenol, cassia, oxanone, .alpha.-irisone, propenyl guaiethol, thymol, linalool, benzaldehyde, cinnamaldehyde, N-ethyl-p-menthan-3-carboxamine, N,2,3-trimethyl-2-isopropylbutanamide, 3-1-menthoxypropane-1,2-diol, cinnamaldehyde glycerol acetal (CGA), methone glycerol acetal (MGA), and mixtures thereof.
• One or more flavorants are optionally present in a total amount of about 0.01% to about 5%, optionally in various embodiments from about 0.05 to about 2%, from about 0.1% to about
• Sweeteners among those useful herein include orally acceptable natural or artificial, nutritive or non-nutritive sweeteners.
• Such sweeteners include dextrose, polydextrose, sucrose, maltose, dextrin, dried invert sugar, mannose, xylose, ribose, fructose, levulose, galactose, corn syrup (including high fructose corn syrup and corn syrup solids), partially hydrolyzed starch, hydrogenated starch hydrolysate, sorbitol, mannitol, xylitol, maltitol, isomalt, aspartame, neotame, saccharin and salts thereof, sucralose, dipeptide-based intense sweeteners, cyclamates, dihydrochalcones, and mixtures thereof.
• One or more sweeteners are optionally present in a total amount depending strongly on the particular sweetener(s) selected, but typically at levels of from about 0.005% to about 5%
• Colorants among those useful herein include pigments, dyes, lakes and agents imparting a particular luster or reflectivity such as pearling agents.
• colorants are operable to provide a white or light-colored coating on a dental surface, to act as an indicator of locations on a dental surface that have been effectively contacted by the composition, and/or to modify appearance, in particular color and/or opacity, of the composition to enhance attractiveness to the consumer.
• Any orally acceptable colorant can be used, including FD&C dyes and pigments, talc, mica, magnesium carbonate, calcium carbonate, magnesium silicate, magnesium aluminum silicate, silica, titanium dioxide, zinc oxide, red, yellow, brown and black iron oxides, ferric ammonium ferrocyanide, manganese violet, ultramarine, titaniated mica, bismuth oxychloride, and mixtures thereof.
• One or more colorants are optionally present in a total amount of about 0.001% to about 20%.
• compositions of the present invention optionally comprise an antioxidant.
• Any orally acceptable antioxidant can be used, including butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin A, carotenoids, vitamin E, flavonoids, polyphenols, ascorbic acid, herbal antioxidants, chlorophyll, melatonin, and mixtures thereof.
• contemplated compositions and formulations will also include one or more preservative agents and exemplary agents include ethyl alcohol, propylene glycol, glycerin, benzyl alcohol, benzoic acid, sodium benzoate, potassium benzoate, asorbic acid, potassium sorbate, esters of p-hydroxybenzoic acid (parabens), benzalkonium chloride solution NF, and especially sodium benzoate. Suitable quantities of such preservative agents will generally follow those well known in the art.
• contemplated stabilized aqueous suspension of aprepitant for oral administration will be packaged in a sterile single use container that contains a unit dose for administration to a patient.
• suitable containers may contain volumes of between 1-10 ml, 10-20 ml, 20-40 ml, and 40-100 ml, and even more.
• the container will typically comprise aprepitant in an amount of between 20-40 mg, between 40-80 mg, between 80-130 mg, or even more.
• the container may be a multi-use container (i.e., retains at least one more unit dose after a first unit dose is dispensed).
• Examples 1 and 2 were draw to solutions of aprepitant in which an attempt was made to solubilize the active ingredient using non-aqueous solvents and emulsifiers as shown in the examples of Tables 1 and 2.
• the inventors then attempted to formulate aprepitant with a co-solvent as exemplarily described in the examples of Tables 5-8. Once more, aprepitant precipitated out of solution in relatively short time.
• micronized aprepitant at various particle sizes (some data not shown) and unexpectedly discovered that micronized aprepitant when in combination with a cellulosic stabilizer (acting as a coating and/or dispersing agent) and an anionic surfactant formed suspensions that were stable over extended periods at ambient (20-25° C., 60% RH) storage conditions.
• a cellulosic stabilizer acting as a coating and/or dispersing agent
• anionic surfactant formed suspensions that were stable over extended periods at ambient (20-25° C., 60% RH) storage conditions.
• Exemplary compositions and associated stability data are shown in Tables 9-10 below.
• addition of PVA known as a stabilizer for various compounds
• use of a branched-chain surfactant with carbonyl groups appeared to abrogate stability for otherwise similar compositions.
• Slurry Phase Preparation Take purified water, approximately 5% of the target batch weight. Add and dissolve Sodium lauryl sulphate, NF, approximately 8% of the required batch quantity, Sodium benzoate, NF, 100% of the required batch quantity, Sodium citrate dihydrate, USP, 40% of the required batch quantity, Citric acid monohydrate, USP, 3.5% of the required batch quantity, Benecel E5 Pharm hypromellose, 100% of the required batch quantity. Add calculated amount of Aprepitant to the vessel under stirring over the time period of 30 minutes and stir until contents are completely dispersed. Q.S. with Purified water to approximately 8% of the batch weight and stir for NLT 15 minute and ensure there is no visible lump.
• Diluent Phase Preparation Take purified water, approximately 60% of the target batch weight. Add and dissolve the remaining Sodium lauryl sulphate, NF, Sodium citrate dihydrate, USP, Citric acid monohydrate, USP. Add and dissolve the required quantity of Sucrose, USP. Q.S. to about 70.0% of the target batch weight.
• Nano-Milling and preparation of final formulation Set up the nanomill with 270 mL zirconium beads (Bead size: 0.3 mm to 4.0 mm). Add slurry phase to nanomill feeding vessel. Run nanomill with set parameters: pump speed and mill agitator speed. Measure the particle size distribution on the in-process samples and continue milling until the target particle size is reached. Collect the milled slurry in a vessel. Rinse the nanomill with the diluent phase. Collect the rinse in the same vessel as that containing the milled slurry. Q.S the batch to the required weight.
• Example 11 Example 12
• Example 13 Ingredients (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) Aprepitant, USP 15.625 15.625 15.625 16.000 16.000 Benecel E5 Pharm hypromellose 6.000 6.000 6.000 6.000 Polyvinyl alcohol, -/- -/- 2.500 2.500 -/- USP Docusate sodium -/- -/- -/- 1.150 1.150 USP/NF Sodium lauryl 1.500 3.000 3.000 -/- -/- sulphate, NF Sodium benzoate, 1.826 1.826 1.826 1.826 1.826 NF Sodium citrate dihydrate, USP 0.091 0.091 0.091 0.091 0.091 Citric acid 1.369 1.369 1.369 1.369 monohydrate, USP Sucrose, USP 50.00 50.00 50.00 50.00 Purified Water q.s.
• the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.

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