Classifications

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Definitions

• Droxidopa is used to treat neurogenic orthostatic hypotension.
• Neurogenic orthostatic hypotension has a variety of causes and is also a common symptom of Parkinson's disease.
• Droxidopa is thought to work by increasing the levels of norepinephrine and epinephrine in the peripheral nervous system (PNS), which induces tachycardia or increased heart rate and hypertension or increased blood pressure, thus enabling the body to maintain blood flow upon and while standing.
• PNS peripheral nervous system
• the liquid vehicle has a pH of less than 7.0. In some embodiments, the liquid vehicle includes a buffering agent.
• a pharmaceutical kit includes a solid pharmaceutical composition disclosed herein and a liquid vehicle.
• the pharmaceutical kit comprises a solid pharmaceutical composition disclosed herein in a container such as a sachet or a bottle.
• the disclosure is directed to a pharmaceutical kit comprising: (a) a solid composition comprising: (i) a first multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, and optionally, a first release controlling agent and (ii) a second multiparticulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, and a second release controlling agent; and (b) a liquid vehicle.
• FIG. 1 provides flow-charts for six different processes to manufacture extended release multi-particulates: hot-melt extrusion, melt-granulation, extrusion-spheronization, direct pelletization, and spray drying/spray congealing.
• This applicaton discloses extended release droxidopa dosage forms, e.g., a solid dosage form that can be reconstituted to a liquid dosage form or a ready-to-use liquid dosage form.
• the pharmaceutical compositions disclosed herein allow for oral administration only once or twice daily.
• the suspension has a pH less than 5.0. In some embodiments, the suspension has a pH of from about 2.0 to about 5.0, or from about 3.0 to about 5.0. In some embodiments, the suspension has a pH of about 4.0.
• the compositions or oral dosage forms disclosed herein comprise a multi-particulate (used interchangeably herein with "multi-particulates”), e.g., an extended release multi-particulate.
• Multi-particulates are discrete, small drug units, exhibiting a desired characteristic, that make up a multiple unit drug delivery system.
• the multi-particulates can be in the form of, for example, a drug particle, a granule, a pellet, a bead, a sphere, or a mini-tablet. Any of these multi-particulate forms can be coated or uncoated.
• a desired characteristic of the multi-particulates is particle size, e.g., less than about 400 ⁇ .
• a desired characteristic of the multi-particulates is controlled release (e.g., extended release) of the drug (e.g., droxidopa or a pharmaceutically acceptable salt thereof) over a period of time.
• the multi-particulate comprises droxidopa or a pharmaceutically acceptable salt thereof.
• the multi-particulate comprises a release controlling agent.
• the multi-particulate comprises a coating.
• the multi-particulate comprises a wax/lipid matrix (e.g., the multi-particulate are wax/lipid embedded matrix pellets).
• the droxidopa is about 10% to about 70% (e.g. about 15% to about 35%) of the total weight of the multi-particulate. In some embodiments, the droxidopa is about 20% of the total weight of the multi-particulate.
• the extended release multi-particulate can further comprise an excipient, e.g., a lubricant, a binder, a filler, a glidant, a plasticizer, or a combination thereof.
• a lubricant include sodium stearyl fumarate, stearic acid, magnesium stearate, glyceryl behenate, talc, and combinations comprising one or more of the foregoing lubricants.
• suitable binders include water-soluble polymer, such as modified starch, gelatin, polyvinyl alcohol, and combinations comprising one or more of the foregoing binders.
• Another suitable binder includes hydroxyproply cellulose alone or in combination with another binder.
• Examples of a pH controlling agent include pharmaceutically acceptable buffering systems, acids having suitable pK a and/or their salts, for example citric acid, citrate salts, tartaric acid, tartarate salts, succinic acid, succinate salts, acetic acid, acetate salts, fumaric acid, and fumarate salts.
• acids having suitable pK a and/or their salts for example citric acid, citrate salts, tartaric acid, tartarate salts, succinic acid, succinate salts, acetic acid, acetate salts, fumaric acid, and fumarate salts.
• Inorganic acids can also be used, including hydrochloric or sulfuric acid.
• a multi-particulate disclosed herein is combined with a liquid vehicle.
• the liquid vehichle can comprises a pH modifier.
• the pH modifier is chosen such that when supplied as ready-to-use suspension or when the multi-particulates are reconstituted or suspended with a liquid vehicle, such as water, the pH modifier can maintain the pH of the reconstituted liquid dosage form, e.g., at a pH of ⁇ 7.0, for example, from about 6.0 to about 7.0, from about 2.0 to about 5.0, from about 2.0 to about 4.5, from about 2.0 to about 4.0, from about 2.5 to about 5.0, from about 2.5 to about 4.5, from about 2.5 to about 4.0, from about 3.0 to about 5.0, from about 3.5 to about 4.5, or from about 3.5 to about 4.0.
• the liquid dosage form has a pH of about 4.0.
• the multi-particulate does not comprise a pH-controlling agent.
• Examples of materials that may be used in a moisture protection layer include a cationic methacrylate copolymer, for example EUDRAGIT El 00, a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, methyl methacrylate, or a combination of the foregoing.
• Polyvinyl alcohol, ethyl cellulose, and hydroxypropyl methyl cellulose may also be used in moisture protection layers and other types of protection layers. Unless clearly indicated by the context of this disclosure, protection layers do not significantly affect drug release profiles and are not controlled release coatings.
• the extended-release multi-particulate can comprise or be combined with a release-controlling agent.
• the release-controlling agent can comprise a polymer, a non-polymeric material, or a combination thereof.
• Examples of a polymeric release controlling agent include shellacs, ethylcellulose, cellulose acetate phthalate, acrylic resins, methacrylate hydrogels, methylmethacrylate, polymethacrylate, polylactic acid, polyvinyl acetate, polyvinyl chloride, polymethacrylate, hydroxypropylmethylcellulose, polyethylene glycols, carboxymethylcellulose, sodium carboxymethylcellulose, and combinations thereof.
• the non-polymeric release-controlling agent can comprise a wax, a lipophilic compound, or a combination thereof.
• the wax can be, for example, an amorphous wax, an anionic wax, an anionic emulsifying wax, a bleached wax, a carnauba wax, a cetyl esters wax, a beeswax, a castor wax, a cationic emulsifying wax, a cetrimide emulsifying wax, an emulsifying wax, a glyceryl behenate, a microcrystalline wax, a nonionic wax, a nonionic emulsifying wax, a paraffin, a petroleum wax, a spermaceti wax, a white wax, a yellow wax, and combinations comprising one or more of the foregoing waxes.
• an amorphous wax an anionic wax, an anionic emulsifying wax, a bleached wax, a carnauba wax, a cetyl esters wax, a beeswax, a castor wax, a cationic emuls
• a cetyl esters wax for example, preferably has a molecular weight of about 470 to about 490 and is a mixture containing primarily esters of saturated fatty alcohols and saturated fatty acids.
• the wax can comprise a carnauba wax, glyceryl behenates (e.g., glyceryl dibehenate), castor wax, and combinations comprising one or more of the foregoing waxes.
• the wax material can be used at about 10 wt % to about 70 wt%, 13 wt % to about 55 wt%, about 16 wt% to about 40 wt%, about 20 wt% to about 36 wt%, about 24 wt% to about 33 wt% of the total weight of the multi-particulate.
• a combination of wax e.g., carnauba wax and glyceryl behenate
• the component waxes can be used in a suitable ratio.
• Certain formulations include the wax material component from 100 to about 85 parts carnauba wax and from 0 to about 15 parts glyceryl behenate.
• the wax component may have about 100 to about 85 parts carnauba wax and 0 to about 15 parts castor wax.
• the carnauba wax can comprise at least about 85 wt% of the waxy material and the balance of the waxy material is made up of a combination of glyceryl behenate and castor wax, in a suitable relative proportion.
• the lipophilic compound can be, for example, a fatty acid, a fatty acid soap; a fully or partially hydrogenated vegetable oil or fat; or a mono-, di-, or triacylglceride.
• the fatty acids and fatty acid soaps can be those that are generally used in the pharmaceutical industry as tableting lubricants, such as, for example, solid fatty acids (for example fatty acids having from about 16 to about 22 carbon atoms), and the alkaline earth metal salts thereof, particularly the magnesium and calcium salts, and combinations comprising one or more of the foregoing fatty acids.
• the fatty acid can be, for example, stearic acid.
• the lipophilic compound can be used in amounts of up to about 70 wt% of the total weight of the multi-particulate, or about 2.5 wt% to about 55 wt%, or about 2.7 wt% to about 40 wt%, or from about 3 wt% to about 36 wt%, or from about 3.5 wt% to about 33 wt% of the total weight of the multi-particulate.
• the droxidopa, or the pharmaceutically acceptable salt thereof is released from a first multi-particulate at a pH of about 1.0 to about 3.5 (e.g., about pH 1.2) and the droxidopa, or the pharmaceutically acceptable salt thereof, is released from a second multiparticulate at a pH of about 4.0 to about 6.0 (e.g., about pH 5.5).
• the first multi-particulate and the second multi-particulate are pellets, granulates, or mini-tablets.
• the composition can comprise an immediate release multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof.
• the composition or suspension disclosed herein comprises (i) a first multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, and optionally a first release controlling agent; and (ii) a second multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, and a second release controlling agent.
• the release controlling agent e.g., the first and/or second release controlling agent
• the release controlling agent e.g., the first and/or second release controlling agent
• the release controlling agent comprises a wax or a wax/lipid matrix.
• the compostion or suspension further comprises a liquid vehicle.
• the composition or suspension disclosed herein comprises (i) a first multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, in an immediate release form, and a moisture protective layer (e.g., EUDRAGIT El 00); and (ii) a second multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, and a release controlling agent.
• the second multi-particulate comprises a wax/lipid matrix (e.g., hydrogenated castor oil).
• the second multi-particulate is coated with a protective layer (e.g., EUDRAGIT 30-D55).
• the second multi-particulate is coated with a moisture protective layer (e.g., EUDRAGIT E100).
• the second multi-particulate is coated with a moisture protective layer (e.g., EUDRAGIT E100).
• a moisture protective layer e.g., EUDRAGIT E100.
• the composition or suspension disclosed herein comprises (i) a first multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, and a first release controlling agent; and (ii) a second multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, and a second release controlling agent.
• the first multi-particulate comprises a wax or a wax/lipid matrix (e.g., glyceryl dibehenate).
• the first multi-particulate does not comprise a protective layer.
• the second multi-particulate comprises a wax or a wax/lipid matrix (e.g., hydrogenated castor oil).
• the second multi-particulate is coated with a protective layer (e.g., EUDRAGIT 30-D55).
• the second multi-particulate does not comprise a moisture protective layer.
• the first multi-particulate comprises 200 mg to 400 mg (e.g., about 300 mg) of droxidopa and the second multi-particulate comprises 500 mg to 700 mg (e.g., about 600 mg) of droxidopa.
• the wax is glyceryl dibehanate.
• the second multiparticulate is coated with a protective layer (e.g. EUDRAGIT 30-D55).
• the liquid vehicle further comprises a preservative, a filler, a sweetener, a flavoring agent, a coloring agent, a pH modifier, or any combination thereof.
• the aqueous liquid vehice has a pH of less than 7, e.g., about 3 to 5, preferably about 4.
• the multi-particulate is a pulsatile release multi-particulate.
• the composition or suspension disclosed herein can comprises one or more types of pulsetile release multi-particulates comprising droxidopa, or a pharmaceutically acceptable salt thereof. Each type of pulsetile release multi-particulates releases the drug at a different time.
• the composition or suspension comprises two types of pulsetile release multiparticulates. In another embodiment, the composition or suspension comprises three types of pulsetile release multi-particulates.
• Pulsatile release multi-particulates for each pulse can release the same or different amounts of the active agent. In some embodiments, pulsatile release multi-particulates for each pulse releases the same amount of the active agent. In some embodiments, pulsatile release multi-particulates for each pulse releases a different amount of the active agent.
• the composition comprising droxidopa, or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, or about 3000 mg once or twice daily.
• the composition or suspension disclosed herein provides for a daily dosage of about 330 mg to about 500 mg, about 660 mg to about 1000 mg, about 495 mg to about 1500 mg, about 990 mg to about 1500 mg, about 990 mg to about 3000 mg, or about 100 mg to about 3000 mg of droxidopa, or a pharmaceutically acceptable salt thereof.
• polymers that can be used in the liquid vehicle for formation of an in situ gel after administration include gellan gum (induced by cations), sodium alginate (induced by cations), xyloglucan (induced by temperature), pectin (induced by calcium cation), chitosan, carbomer(induced by pH), poly(DL-lactic acid), poly(DL-lactide-co-glycolide), and poly- caprolactone.
• the liquid composition (e.g., a solution, a suspension, or an emulsion) comprising a multi-particulate comprising droxidopa, or pharmaceutically acceptable salt there, is stable when stored at room temperature or 4 °C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days after reconstitution or suspension of the droxidopa, or the pharmaceutically acceptable salt there, in a liquid vehicle.
• a solution, a suspension, or an emulsion comprising a multi-particulate comprising droxidopa, or pharmaceutically acceptable salt there, is stable when stored at room temperature or 4 °C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days after reconstitution or suspension of the droxidopa, or the pharmaceutically acceptable salt there, in a liquid vehicle.
• the droxidopa in the liquid vehicle or the suspending vehicle is stable when the level of dihydroxybenzaldehyde is below 0.1%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01%. In some embodimnts, the droxidopa in the liquid vehicle or the suspending vehicle is stable when the level of the total degradation is below 1%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%.
• a pharmaceutical kit is disclosed herein.
• the kit can comprise any of the solid pharmaceutical compositions disclose herein (e.g., a multi-particulate packaged in a sachet, a bottle or a packet) and a liquid vehicle for reconstituting or suspending the solid composition into an oral liquid dosage form, e.g., a solution, a suspension, or an emulsion dosage form.
• the liquid vehicle can be a suspending vehicle.
• the liquid dosage form produced can have a pH ⁇ 7.0.
• the liquid dosage form produced can have a pH from 7.0 to 8.0, or from 7.0 to 9.0.
• the pH is less than 5.0.
• the pH is from about 2.0 to about 5.0, or from about 3.0 to about 5.0.
• the kit comprises a single dose or multiple doses, for example 2, 3, 4, 5, 6, 7, 8, or more doses.
• the kit e.g., a single bottle
• the liquid dosage form is a suspension that is stable at room temperature or 4 °C for at least 7 days, 10 days, 14 days, or 21 days.
• the method is directed to treating a subject having Parkinson's disease or postural orthostatic tachycardia syndrome (POTS) who suffers from or is at risk of suffering from orthostatic hypotension comprising administering an effective amount of a composition or oral dosage form disclosed herein to the subject.
• POTS postural orthostatic tachycardia syndrome
• the method of treatment can include administering a single dose of a composition or oral dosage form disclosed herein to a subject.
• the composition or oral dosage form comprises droxidopa, or a pharmaceutically acceptable salt thereof, in an amount of about 100 mg to about 3000 mg, about 200 mg to about 3000 mg, about 300 mg to about 3000 mg, about 400 mg to about 3000 mg, about 500 mg to about 3000 mg, about 600 mg to about 3000 mg, about 700 mg to about 3000 mg, about 800 mg to about 3000 mg, about 900 mg to about 3000 mg, about 1000 mg to about 3000 mg, about 1500 mg to about 3000 mg, about 2000 mg to about 3000 mg, about 100 mg to about 1800 mg, about 200 mg to about 1800 mg, about 300 mg to about 1800 mg, about 400 mg to about 1800 mg, about 500 mg to about 1800 mg, about 600 mg to about 1800 mg, about 700 mg to about 1800 mg, about 800 mg to about 1800 mg, about 900 mg to about 1800 mg, about 500 mg to about 1200 mg
• the extended release period can be, in hours, at least one of, or at least about one of: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 hours, e.g., about 12 hours, or a range between any two of the preceding values, for example, of between about 4 hours and about 12 hours, between 6 hours to 12 hours, between 8 hours to 12 hours, between 8 hours to 14 hours, or between 8 hours to 16 hours.
• Extended release multi-particulates may also comprise non-release controlling agents such as binders, wetting agents, lubricants, protective coating agents, and surfactants. These excipients are not used to control the drug release, but to improve flowability, stabilize the multiparticulates, minimize premature drug release prior to administration.
• extended release multi-particulates may be coated with a protective polymer, which is used to minimize premature drug release in the suspension before administration and will dissolve once it is administered.
• Table 11 shows droxidopa solubility at room temperature at pH 1.2, 3.0, 4.5, 5.5 and 6.8.
• Table 13A summarizes stability data for droxidopa after exposure in solutions of varying different pH.
• E15 The liquid composition of embodiment 13 or 14, wherein the pH controlling agent is a salt of citric acid or tartaric acid.
• liquid composition or the suspension of any of the preceding embodiments, wherein the total amount of droxidopa, or a pharmaceutically-acceptable salt thereof, in a 5 mL dose of the liquid composition or the suspension is about 100 mg to about 1800 mg.
• liquid composition or the suspension of any of the preceding embodiments wherein the liquid composition or the suspension is packaged to provide per package a daily dosage amount of droxidopa, or the pharmaceutically acceptable salt thereof, of about 100 mg to about 3000 mg or about 100 mg to about 1800 mg for n days, preferably n is at least 3, 4, 5, 6, or 7.
• E78 The method of any one of embodiment 74 to 76 or the kit of any one of embodiments 71 to 73, wherein the liquid vehicle is a nonaqueous vehicle.

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