Patent Description:
Droxidopa is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) and which is used to increase the concentrations of these neurotransmitters in the body and brain. Chemically, droxidopa is (-)-threo-<NUM>-(<NUM>,<NUM>-Dihydroxyphenyl)-L-serine, and has the following structural formula:
<CHM>.

Unlike norepinephrine and epinephrine themselves, droxidopa is capable of crossing the protective blood-brain barrier (BBB). It is metabolized by aromatic L-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC).

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.

The droxidopa dosage form currently approved for use in the United States is immediate release oral capsules comprising <NUM>, <NUM>, or <NUM> droxidopa, with a maximum daily dosage limited to <NUM>. Current dosing regimens are administration of one or two capsules three times daily.

Disclosed, in various embodiments, are oral dosage forms comprising droxidopa, or a pharmaceutically acceptable salt thereof, as defined below.

In some aspects, the disclosure is directed to a pharmaceutical composition comprising droxidopa, or a pharmaceutically acceptable salt thereof, for oral administration, wherein the pharmaceutical composition is an extended release liquid dosage form or solid dosage form as further defined in claims <NUM> or <NUM>. In some embodiments, the liquid dosage form is a suspension. In some embodiments, the solid dosage form comprises a solid composition packaged in a bottle, a sachet, or a packet for suspension in a liquid vehicle.

In a first aspect, the present invention is directed to an extended-release liquid composition for oral administration comprising:.

wherein the first multi-particulate is capable of releasing droxidopa, or a pharmaceutically acceptable salt thereof, at a pH of less than <NUM>, and the second multi-particulate is capable of releasing droxidopa, or a pharmaceutically acceptable salt thereof, at a pH of <NUM>.

In some embodiment, the release controlling agent is a non-polymeric material. In some embodiments, the multi-particulate is in the form of pellets, granulates, or a mini-tablets. The multi-particulate comprises two or more types of pellets, e.g., one type can be immediate release pellets whereas another type can release the drug over an extended period. The multi-particulate comprises two types of extended release pellets with each type having a different release profile. At least one type of the pellets is coated. In some embodiments, all types of of the pellets are coated.

In some embodiments, the liquid vehicle has a pH of less than <NUM>. In some embodiments, the liquid vehicle includes a buffering agent.

In an embodiment, an extended-release suspension or suspension for oral administration includes an extended-release multi-particulate including an effective amount of droxidopa, or a pharmaceutically acceptable salt thereof, and a release-controlling agent; and a suspending vehicle, wherein the suspension has a pH < <NUM>.

In a second aspect, the present invention is directed to a solid pharmaceutical composition for oral administration comprising.

wherein the first multi-particulate is capable of releasing droxidopa, or a pharmaceutically acceptable salt thereof, at a pH of less than <NUM>, and the second multi-particulate is capable of releasing droxidopa, or a pharmaceutically acceptable salt thereof, at a pH of <NUM>. composition for oral administration includes an extended-release multi-particulate including an effective amount of droxidopa, or a pharmaceutically acceptable salt thereof, and a non-polymeric release-controlling agent. In some embodiments, the solid pharmaceutical composition is suitable for suspension in a liquid vehicle.

In an embodiment, a pharmaceutical kit includes a solid pharmaceutical composition disclosed herein and a liquid vehicle. In some embodiments, the pharmaceutical kit comprises a solid pharmaceutical composition disclosed herein in a container such as a sachet or a bottle. In some embodiments, 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. In some embodiments, the pharmaceutical kit comprises (a) an extended-release multi-particulate comprising an effective amount of droxidopa, or a pharmaceutically acceptable salt thereof, and a release-controlling agent; and (b) an immediate-release composition (e.g., a capsule) comprising an effective amount of droxidopa.

Methods of making the dosage form are disclosed but not claimed. Any method of treatment mentioned herein is to be construed as compositions for use in a method of treatment.

In a further aspect, the composition or dosage form of the claimed invention is for use in treating a subject in need of treatment of hypotension, neurogenic orthostatic hypotension (nOH), intradialytic hypotension, a symptom of Parkinson's disease, orthostatic hypotension associated with Parkinson's disease, postural instability associated with Parkinson's disease, postural orthostatic tachycardia syndrome (POTS), Down's syndrome, a demyelinating disease, Alzheimer's disease, an attention deficit disorder, hypersomnia, pain associated with fibromyalgia, motor paralysis, motor aphasia, urinary incontinence, dementia, antidiuresis, postural tachycardia syndrome, tauopathy, fatigue, headaches, neurological deficits or neuronal death induced by brain ischemia, intracranial hypertension or cerebral edema, cancer, a bacterial infection, to induce or facilitate micturition, nasal congestion, acute pain, chronic pain, or any combination thereof.

These and other features and characteristics are more particularly described below.

The following is a brief description of the drawings which are presented for the purposes of illustrating the exemplary embodiments disclosed herein and not for the purposes of limiting the same.

Currently approved dosing regimens for droxidopa are administration of one or two capsules three times daily. Patients typically treated with droxidopa, for example Parkinson's patients, have difficulty with vertical stability and/or difficulty swallowing large capsules. Patients administered capsules can also feel uncomfortable because capsules can stick to their throat. Three times daily dosing is inconvenient and can decrease patient compliance. To address these problems, the inventors have developed alternative oral dosage forms that are easier and more comfortable to swallow, and/or whose release properties permit dosing fewer than three times daily. 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. In some embodiments, the pharmaceutical compositions disclosed herein allow for oral administration only once or twice daily.

Disclosed herein are improved oral dosage forms comprising droxidopa such as, for example, extended-release formulations, which are more easily administered than currently marketed dosage and require fewer dosage forms to be administered daily.

In one aspect, the extended release dosage form is a solid pharmaceutical composition. The composition comprises an extended-release multi-particulate comprising an effective amount of droxidopa, or a pharmaceutically acceptable salt thereof, and optionally a non-polymeric release-controlling agent.

In another aspect, the extended release dosage form is a suspension for oral administration. The suspension can comprise an extended-release multi-particulate comprising an effective amount of droxidopa, or a pharmaceutically acceptable salt thereof, and a release-controlling agent; and a suspending vehicle, wherein the suspension has a pH < <NUM>.

In some embodiments, the suspension has a pH less than <NUM>. In some embodiments, the suspension has a pH of from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>. In some embodiments, the suspension has a pH of about <NUM>.

The compositions or oral dosage forms disclosed herein comprise a first and a second 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. In some embodiments, a desired characteristic of the multi-particulates is particle size, e.g., less than about <NUM>. In another embodiment, 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. At least the second multi-particulate comprises a release controlling agent. In some embodiments, the multi-particulate comprises a wax/lipid matrix (e.g., the multi-particulate are wax/lipid embedded matrix pellets). In some embodiments, the droxidopa is about <NUM>% to about <NUM>% (e.g. about <NUM>% to about <NUM>%) of the total weight of the multi-particulate. In some embodiments, the droxidopa is about <NUM>% 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. Examples of suitable lubricants include sodium stearyl fumarate, stearic acid, magnesium stearate, glyceryl behenate, talc, and combinations comprising one or more of the foregoing lubricants. Examples of 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 suitable fillers include lactose, microcrystalline cellulose, and combinations comprising one or more the foregoing fillers. An example of a glidant is colloidal silicon dioxide (AEROSIL, Evonik). An example of a suitable plasticizer is triethyl citrate, propylene glycol, or polyethylene glycol.

In some embodiments, the extended release multi-particulates have a particle size (e.g., d<NUM>) of less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, or any combination thereof.

In some embodiments, the extended-release multi-particulates can further comprise a pH-controlling agent. The amount of a pH-controlling agent is sufficient to provide pH independent release of droxidopa from the multi-particulate.

Examples of a pH controlling agent (term used interchangeably wiht a pH modifier or a buffering agent) include pharmaceutically acceptable buffering systems, acids having suitable pKa 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.

In some embodiments, the pH modifier is not in direct contact with droxidopa, or a pharmaceutically acceptable salt thereof of the multi-particulate. In some embodiments, the liquid vehicle comprises a pH modifier (e.g., monosodium citrate or sodium bitartarate) <NUM>% w/v to <NUM>% w/v of the liquid dosage (e.g., suspension) volume.

In some embodiments, a multi-particulate disclosed herein is combined with a liquid vehicle. In some embodiments, the liquid vehicle comprises a pH modifier. In some embodiments, 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 < <NUM>, for example, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>. In some embodiments, the liquid dosage form has a pH of about <NUM>.

In other embodiments, the liquid dosage form comprising a multi-particulate has a pH above <NUM>, such as about <NUM> to about <NUM>, or about <NUM> to about <NUM>. In some liquid dosage forms, droxidopa is protected from degradation by a protective layer that prevents exposure of the drug to the high pH.

In some embodiments, the multi-particulate does not comprise a pH-controlling agent.

The multi-particulate can also be coated with a protection layer. In some embodiments, the protection layer prevents drug release from the multi-particulates reconstituted or suspended into a liquid dosage form or into the food on which it is sprinkled. Examples of a protection layer include, for example, a moisture protection layer, a light protection layer, an integrity protection layer to prevent friable dosage forms from crumbling, a taste masking protective layer, and protective layers that increase ease of swallowing. Examples of materials that may be used in a moisture protection layer include a cationic methacrylate copolymer, for example EUDRAGIT E100, 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 comprises 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. These and other suitable waxes are known to those of skill in the art. A cetyl esters wax, for example, preferably has a molecular weight of about <NUM> to about <NUM> 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 <NUM> wt % to about <NUM> wt%, <NUM> wt % to about <NUM> wt%, about <NUM> wt% to about <NUM> wt%, about <NUM> wt% to about <NUM> wt%, about <NUM> wt% to about <NUM> wt% of the total weight of the multi-particulate. When a combination of wax is used, 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 <NUM> to about <NUM> parts carnauba wax and from <NUM> to about <NUM> parts glyceryl behenate. In formulations that have a combination of carnauba wax and castor wax, for example, the wax component may have about <NUM> to about <NUM> parts carnauba wax and <NUM> to about <NUM> parts castor wax. When carnauba wax, glyceryl behenate and castor wax are present, the carnauba wax can comprise at least about <NUM> 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 <NUM> to about <NUM> 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. Examples of the fully or partially hydrogenated vegetable oil or fat include hydrogenated palm fat and oil, hydrogenated castor oil, hydrogenated rape oil, hydrogenated cottonseed oil, hydrogenated soybean oil, and hardened soybean oil. Examples of a mono-, di-, or triglyceride include glyceryl monolaurate; glyceryl dilaurate; glyceryl monomyristate; glyceryl dimyristate; glyceryl monopalmitate; glyceryl dipalmitate; glyceryl monostearate; glyceryl distearate; glyceryl monooleate; glyceryl dioleate; glyceryl monolinoleate; glyceryl dilinoleate; glyceryl monoarachidate; glyceryl diarachidate; and glyceryl dibehenate, glycerol behenate, glyceryl palmitostearate, trilaurin, trimyristan, tripalmitin, tristearin, and tribehenin. The lipophilic compound can be used in amounts of up to about <NUM> wt% of the total weight of the multi-particulate, or about <NUM> wt% to about <NUM> wt%, or about <NUM> wt% to about <NUM> wt%, or from about <NUM> wt% to about <NUM> wt%, or from about <NUM> wt% to about <NUM> wt% of the total weight of the multi-particulate.

In some embodiments, the oral dosage form disclosed herein comprises immediate release multi-particulates and extended release multi-particulates. In some embodiments, the oral dosage form disclosed herein comprises fast release multi-particulates and extended release multi-particulates. In certain embodiments, the oral dosage form comprises two or more types of extended-release multi-particulates comprising droxidopa, or a pharmaceutically acceptable salt thereof. Each type of extended-release multi-particulate can have a different extended release profile for droxidopa, or the pharmaceutically acceptable salt thereof.

In certain embodiments, the droxidopa, or the pharmaceutically acceptable salt thereof, is released from a first multi-particulate at a pH of about <NUM> to about <NUM> (e.g., about pH <NUM>) and the droxidopa, or the pharmaceutically acceptable salt thereof, is released from a second multiparticulate at a pH of <NUM>. In some embodiments, the first multi-particulate and the second multi-particulate are pellets, granulates, or mini-tablets. In a further embodiment, 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. In some embodiments, the release controlling agent (e.g., the first and/or second release controlling agent) is non-polymeric release controlling agent. In some embodiments, the release controlling agent (e.g., the first and/or second release controlling agent) comprises a wax or a wax/lipid matrix. In some embodiments, the compostion or suspension further comprises a liquid vehicle.

In some embodiments, 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 E100); and (ii) a second multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, and a release controlling agent. In one embodiment, the second multi-particulate comprises a wax/lipid matrix (e.g., hydrogenated castor oil). The second multi-particulate is coated with an enteric protective layer (e.g., EUDRAGIT <NUM>-D55).

In some embodiments, the composition or suspension disclosed herein comprises (i) a first multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, in fast release form, and a moisture protective layer (e.g., EUDRAGIT E100); and (ii) a second multiparticulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, and a release controlling agent. In one embodiment, the second multi-particulate comprises a wax/lipid matrix (e.g., hydrogenated castor oil). The second multi-particulate is coated with an enteric protective layer (e.g., EUDRAGIT <NUM>-D55).

In some embodiments, 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. In one embodiment, the first multi-particulate comprises a wax or a wax/lipid matrix (e.g., glyceryl dibehenate). In one embodiment, the first multi-particulate does not comprise a protective layer. In one embodiment, the second multi-particulate comprises a wax or a wax/lipid matrix (e.g., hydrogenated castor oil). The second multi-particulate is coated with an enteric protective layer (e.g., EUDRAGIT <NUM>-D55).

In some embodiments, the composition or suspension disclosed herein comprises (i) a first multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, and a first non-polymeric release controlling agent (e.g., a wax); and (ii) a second multi-particulate comprising droxidopa, or a pharmaceutically acceptable salt thereof, and a second non-polymeric release controlling agent (e.g., a wax). In some embodiments, the composition or suspension further comprises an aqueous liquid vehice comprising a pH modifier (e.g., monosodium citrate and/or sodium bitartarate) and a suspending agent (e.g., xantham gum). In some embodiments, the first multi-particulate comprises <NUM> to <NUM> (e.g., about <NUM>) of droxidopa and the second multi-particulate comprises <NUM> to <NUM> (e.g., about <NUM>) of droxidopa. In some embodiments, the wax is glyceryl dibehanate. The second multiparticulate is coated with an enteric protective layer (e.g. EUDRAGIT <NUM>-D55). In some embodiments, the liquid vehicle further comprises a preservative, a filler, a sweetener, a flavoring agent, a coloring agent, a pH modifier, or any combination thereof. In some embodiments, the aqueous liquid vehice has a pH of less than <NUM>, e.g., about <NUM> to <NUM>, preferably about <NUM>.

In some embodiments, the first and/or second multi-particulate can comprise a pH controlling agent, such as a citrate, a tartrate, or combinations thereof (e.g., sodium bitartarate, monosodium citrate).

In some embodiments, the multi-particulate are pellets. In some embodiments, the pellets are formed by direct pelletization. In some embodiments, the pellets have a particle size of less than <NUM>.

In some embodiments, 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. In one embodiment, 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.

Pulsatile release multi-particulates for each pulse can have the same or different extended release periods. In some embodiments, pulsatile release multi-particulates for each pulse have the same extended release period, such as about <NUM> hours. In some embodiments, pulsatile release multi-particulates for each pulse have the same or a different extended release period, e.g., an extended release period of about <NUM> hour, <NUM> hours, <NUM> hours, <NUM> hours, <NUM> hours, <NUM> hours, <NUM> hours, <NUM> hours, or any combination thereof.

A daily dosage amount of droxidopa, or a pharmaceutically acceptable salt thereof, in the oral dosage form is about <NUM> to about <NUM> or about <NUM> to about <NUM>. In some embodiments, the composition comprising droxidopa, or a pharmaceutically acceptable salt thereof, is administered at a dose of about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, or about <NUM> to about <NUM> once or twice daily. In some embodiments, the composition comprising droxidopa, or a pharmaceutically acceptable salt thereof, is administered at a dose of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM> once or twice daily.

In some embodiments, the composition or suspension disclosed herein provides for a daily dosage of about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, or about <NUM> to about <NUM> of droxidopa, or a pharmaceutically acceptable salt thereof.

In some embodiments, the composition or suspension disclosed herein provides for a one time daily dosage of about about <NUM> to about <NUM> of droxidopa, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition or suspension disclosed herein provides for a twice daily dosage of about about <NUM> to about <NUM> of droxidopa, or a pharmaceutically acceptable salt thereof.

The extended release oral dosage form can provide a droxidopa plasma level in a subject of about <NUM>µg/mL to <NUM>µg/mL for a duration of about <NUM> to <NUM> hours or about <NUM> to <NUM> hours after oral administration of the composition to the subject.

The composition can be packaged to provide a single dose or multiple doses, for example <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or more doses. The composition can be packaged to provide a single daily dosage amount or the daily dosage amount for multiple days, for example at least <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> days.

In certain embodiments, the composition can be in the form of a capsule filled with the extended-release multi-particulate. In yet other embodiments, the composition is in the form of a compressed tablet comprising the multiparticulate. Alternatively, the composition can be in the form of a sealed package, such as a sachet, a two compartment sachet or the cap of a bottle, into which the multi-particulate has been filled. In another embodiment, the composition can be in the form of a suspension comprising one or more types of multi-particulates and a suspending vehicle.

In some embodiments, a solid pharmaceutical composition disclosed herein (e.g., a multi-particulate) is suitable for being reconstituted or suspended as a liquid dosage form (e.g., a suspension) or to be sprinkled on food or in a drink.

Some aspects of the application are directed to an extended-release suspension for oral administration comprising (a) first and second multi-particulates as defined in the claims, and (b) a liquid vehicle.

In another aspect, the application is directed to a solid composition comprising an extended-release multi-particulate of the application, which is suitable for reconstitution or suspension in a liquid vehicle. In some embodiments, the solid composition is packaged in a sachet, a bottle or a packet. In some embodiments, the solid composition is combined with a liquid vehicle, e.g., water, for oral administration.

The liquid vehicle can be an aqueous vehicle or a nonaqueous vehicle. Examples of aqueous vehicles include water and a buffered solution. Examples of nonaqueous vehicles include glycerin and propylene glycol.

The liquid vehicle can comprise excipients such as a stabilizer, a suspending agent, a flavoring agent, or a combination thereof. The liquid vehicle can be a suspending vehicle. In some embodiments, the suspending vehicle can comprise excipients such as suspending agent, a filler, a sweetener, a viscosity modifier, a flowing aid, a pH modifier, a preservative, a surfactant, a flavoring agent, a coloring agent, or a combination thereof.

In some embodiments, the liquid vehicle comprises a suspending agent. In some embodiments, the suspending agent is <NUM>% w/v to <NUM>% w/v of the liquid vehicle (e.g., suspension) volume. In some embodiments, the suspending agent is xanthan gum, guar gum, sodium carboxymethycellulose, hydroxypropyl cellulose, hypromellose, or any combination thereof.

In some embodiments, the liquid vehicle comprises a preservative. In some embodiments, the preservative is up to <NUM> per unit. In some embodiments, the preservative is <NUM>% w/v to <NUM>% w/v of the liquid vehicle (e.g., suspension) volume. In some embodiments, the preservative is sodium benzoate, potassium sorbate, sodium propionate, methylparaben, propylparaben, benzoic acid, sorbic acid, boric acid, or any combination thereof.

In some embodiments, the liquid vehicle, solution, suspension, or emulsion has a pH < <NUM>. In some embodiments, the pH is from <NUM> to <NUM>, or from <NUM> to <NUM>. In some embodiments, the pH is less than <NUM>. In some embodiments, the pH is from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>. In some embodiments, the pH is about <NUM>.

In some embodiments, the liquid vehicle has a pH of less than <NUM>. In some embodiments, the liquid vehicle includes pH modifier. In some embodiments, the liquid vehicle does not include a pH modifier.

Examples of a pH modifier include pharmaceutically acceptable buffering systems, acids having suitable pKa 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.

The liquid vehicle can further comprise a polymer that forms an in situ gel in the gastrointestinal tract. The liquid vehicle for reconstituting a solid droxidopa multi-particulate into a liquid dosage form may comprise materials which are in solution or suspension form before administration to the subject, but once administered undergo gelation in situ in the body to form a gel from which the drug is released in a sustained and controlled manner. The formation of a gel depends on various factors such as temperature modulation, pH change, and the presence of ions. Examples of 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.

In some embodiments, the volume of the liquid dosage form (e.g., suspension) to be administered to a subject is about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, or about <NUM> to about <NUM>). In some embodiments, the liquid dosage form is administered once or twice daily. In some embodiments, a dose of about <NUM> to about <NUM> or about <NUM> to about <NUM> of droxidopa, or a pharmaceutically acceptable salt thereof, in a liquid dosage from is administered to a subject in need thereof.

In some embodiments, 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 <NUM> for at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> days after reconstitution or suspension of the droxidopa, or the pharmaceutically acceptable salt there, in a liquid vehicle. In some embodiments, the droxidopa, or the pharmaceutically acceptable salt there, present in the liquid vehicle or the suspending vehicle is stable at room temperature or <NUM> for at least <NUM> days, at least <NUM> days, at least <NUM> days, or at least <NUM> days (e.g., at least one week, at least two weeks, or at least three weeks) after reconstitution or suspension. The stability of droxidopa is measured by the level of the major degradant (i.e., dihydroxybenzaldehyde) and the total degradation. In some embodiments, the droxidopa in the liquid vehicle or the suspending vehicle is stable when the level of dihydroxybenzaldehyde is below <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or <NUM>%. In some embodimnts, the droxidopa in the liquid vehicle or the suspending vehicle is stable when the level of the total degradation is below <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or <NUM>%.

In certain embodiments, the oral dosage form further comprises droxidopa, or a pharmaceutically acceptable salt thereof, in an immediate release form. The composition or suspension can include ≤ <NUM>% or ≥ <NUM>% of the total amount of droxidopa, or a pharmaceutically acceptable salt thereof, in the dosage form in an immediate release form. In some embodiments, the amount of droxidopa, or a pharmaceutically acceptable salt thereof, in an immediate release form is <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>% or less than <NUM>% of the total weight of droxidopa in the composition or suspension.

In some embodiments, the composition or suspension disclosed herein can comprise droxidopa, or a pharmaceutically acceptable salt thereof, in an immediate release form, in an amount of <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, or <NUM>% to <NUM>% of the total weight of droxidopa in the composition or suspension.

In some embodiments, the composition or suspension disclosed herein can comprise droxidopa, or a pharmaceutically acceptable salt thereof, in a fast release form, in an amount of <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, <NUM>% to <NUM>%, or <NUM>% to <NUM>% of the total weight of droxidopa in the composition or suspension.

In another aspect, a pharmaceutical kit is disclosed herein. The kit can comprise any of the solid pharmaceutical compositions disclosed 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 suspension. The liquid vehicle can be a suspending vehicle. In some embodiments, the liquid dosage form produced can have a pH < <NUM>. In some embodiments, the liquid dosage form produced can have a pH from <NUM> to <NUM>, or from <NUM> to <NUM>. In some embodiments, the pH is less than <NUM>. In some embodiments, the pH is from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>.

The kit can be in the form of a capped bottle in which the composition is stored in a sealed compartment within the cap of the bottle and the liquid vehicle is stored in the bottle. In some embodiments, the cap of the bottle stores a solid dosage form (e.g., a multi-particulate) comprising droxidopa, or a pharmaceutically acceptable salt thereof, in a sealed compartment within the cap of the bottle. In some embodiments, the liquid vehicle (i.e., a suspending vehicle) is stored in the bottle. In some embodiments, the sealed compartment within the cap of the bottle is unsealed and the solid dosage form is combined with the liquid vehicle. The solid dosage form comprises two or more types of multi-particulate pellets and the liquid vehicle is a suspending vehicle. In some embodiments, some excipients of the liquid vehicle (e.g., a suspending agent or a gel forming polymer) can be stored in a solid form in the kit.

In some embodiments, the solid dosage form (e.g., a multi-particulate) is stored in a container (e.g., a sachet), and a patient can open the container, mix the solid dosage with water or a beverage, or sprinkle the solid dosage on food, for oral consumption.

In certain aspects of the disclosure, the kit comprises a single dose or multiple doses, for example <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or more doses. The kit (e.g., a single bottle) can be prepared to provide a single daily dosage amount or the daily dosage amount for multiple days, for example at least <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> days. In some embodiments, the liquid dosage form is a suspension that is stable at room temperature or <NUM> for at least <NUM> days, <NUM> days, <NUM> days, or <NUM> days.

Active agent release from a pharmaceutical formulation can be analyzed in various ways. One exemplary test is in vitro dissolution. A dissolution profile is a plot of the cumulative amount of active agent released from a formulation as a function of time. A dissolution profile can be measured utilizing the Drug Release Test <<NUM>>, which incorporates standard test USP <NUM> (Test <<NUM>>). A profile is characterized by the test conditions selected such as, for example, apparatus type, shaft speed, temperature, volume, and pH of the dissolution medium. More than one dissolution profile may be measured. For example, a first dissolution profile can be measured at a pH level approximating that of the stomach, and a second dissolution profile can be measured at a pH level approximating that of one point in the intestine or several pH levels approximating multiple points in the intestine.

For example, for the currently marketed droxidopa dosage forms, the U. FDA suggests evaluation of droxidopa release characteristics and dissolution profiles in <NUM> of <NUM> N HCl, equilibrated at <NUM> ± <NUM> using a basket method (USP Apparatus <NUM>) at <NUM> rpm with sampling times of <NUM>, <NUM>, <NUM>, <NUM>, <NUM> minutes. Other conditions, such as different pH, extended dissolution time for up to <NUM> hrs or different apparatus may be used as known in the art. Sample aliquots can be taken at different time intervals and analyzed by high performance liquid chromatography.

Dissolution profile can be measured under other conditions, for example: <NUM> of <NUM> N HCl for <NUM>-<NUM> hours and Phosphate Buffer (pH <NUM>) for <NUM>-<NUM> hours or <NUM>-<NUM> hours using an USP II (Paddle) apparatus.

Alternatively, active agent release from a pharmaceutical formulation can be determined in a pharmacokinetics study. Design of such a pharmacokinetics study is within the skill of practitioners in the art.

The extended release droxidopa dosage forms when orally administered once daily to a subject, provide a droxidopa plasma level in the subject of about <NUM>µg/mL to <NUM>µg/mL for a duration of about <NUM> to <NUM> hour or about <NUM> to <NUM> hours after oral administration to the subject.

In some embodiments, the composition or suspension disclosed herein releases substantially all of the active agent in about <NUM>, <NUM>, or <NUM> hours post administration. In some embodiments, the composition or suspension disclosed herein provides only one Cmax and the Cmax is at about <NUM> to <NUM> hours post administration.

In another aspect, compositions for use in a method of treating a subject are disclosed. The method can comprise orally administering an effective amount of a droxidopa liquid dosage form disclosed herein or a solid droxidopa composition herein to a subject in need of treatment of a disease or disorder. The disease or disorder can be hypotension (for example neurogenic orthostatic hypotension (nOH) or intradialytic hypotension), a symptom of Parkinson's disease (e.g., orthostatic hypotension, postural instability (<CIT>)), Down's syndrome (<CIT>), a demyelinating disease (<CIT>), Alzheimer's disease (<CIT>), an attention deficit disorder (<CIT>), hypersomnia (<CIT>), pain associated with fibromyalgia (<CIT>), motor paralysis (<CIT>), motor aphasia (<CIT>), urinary incontinence (<CIT>), dementia (<CIT>), antidiuresis (<CIT>), postural tachycardia syndrome (<CIT>), tauopathy (<CIT>), fatigue (<CIT>), headaches (<CIT>), neurological deficits or neuronal death induced by brain ischemia (<CIT>), intracranial hypertension or cerebral edema (<CIT>), cancer (<CIT>), a bacterial infection (<CIT>), to induce or facilitate micturition (<CIT>), nasal congestion (<CIT>), or pain (e.g., acute or chronic) (<CIT>). Preferably the disease or disorder is hypotension or a symptom of Parkinson's disease. The administering can be once or twice daily, and can occur with the subject in a supine position. In some embodiments, the total daily dose of droxidopa administered to the subject is <NUM> to <NUM> or about <NUM> to about <NUM>.

The compositions or oral dosage forms of the present disclosure comprising droxidopa, or a pharmaceutically acceptable salt thereof, can be used to treat or reduce the incidence of a disorder including at least one of: orthostatic hypotension; postural orthostatic tachycardia syndrome (POTS); dysautonomia; symptoms of chronic orthostatic hypotension corresponding to autonomic failure associated with Bradbury-Eggleston syndrome, Shy-Drager syndrome, diabetes mellitus disease, and Parkinson's disease; and retrograde ejaculation. In some embodiments, the compositions or oral dosage forms of the present disclosure can be used to treat orthostatic hypotension in a subject suffering from Parkinson's disease. In some embodiments, the oral dosage form, pharmaceutical composition, or formulation of the present disclosure can be used to treat a subject suffering from or at risk of suffering from postural orthostatic tachycardia syndrome (POTS).

In certain aspects, the method is directed to treating a subject suffering from or at risk of suffering from orthostatic hypotension due to autonomic failure comprising administering an effective amount of a composition or oral dosage form disclosed herein to the subject.

In certain aspects, 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.

In some embodiments, the subject is <NUM>-<NUM> years old, <NUM>-<NUM> years old, e.g., <NUM>-<NUM> years old, <NUM>-<NUM> years old, or <NUM>-<NUM> years old. In some embodiments, the subject is male or female. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is female, aged <NUM>-<NUM> years old and suffers from POTS. In some embodiments, the subject suffers from Parkinson's disease. In some embodiments, the subject suffers from early-onset Parkinson's disease (e.g., is <NUM> years old or younger). In some embodiments, the subject is older than <NUM> years.

The method of treatment can include administering a single dose of a composition or oral dosage form disclosed herein to a subject. In certain embodiments, the composition or oral dosage form comprises droxidopa, or a pharmaceutically acceptable salt thereof, in an amount of about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, or about <NUM> to about <NUM>. In some embodiments, the composition or oral dosage form comprises droxidopa, or a pharmaceutically acceptable salt thereof, in an amount of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>. In some embodiments, the composition or oral dosage form disclosed herein is administered once or twice daily.

In some embodiments, a single dose can be administered to effectively raise blood pressure in a subject and maintain the blood pressure in the subject during an extended release period. A single dose can include the active agent in an amount in milligrams of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or a range between about <NUM> to about <NUM> or about <NUM> to about <NUM>, between about <NUM> to about <NUM>, between about <NUM> to about <NUM>, between about <NUM> to about <NUM>, about <NUM> to about <NUM>, or between about <NUM> to about <NUM>.

In some embodiments, the composition or oral dosage form is a liquid dosage (e.g., a suspension or emulsion) and the dosage can be titrated to an effective level for the subject. A subject can start with an initial dose of the active and the subsequent doses can be adjusted based on the subject's response to the initial dose. Dose titration can be conveniently achieved for the liquid dosage form by adjusting the volume of oral suspension to be administered to the subject. In some embodiments, the volume of the liquid dosage form (e.g., a solution, a suspension, or an emulsion) to be administered to a subject is about <NUM> to about <NUM> (e.g., about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>) per dose.

In some embodiments, the methods of the present application are directed to administereing a composition or oral dosage form disclosed herein to a subject to maintain the subject's blood pressure in a clinically acceptable range throughout the day.

The method can include administering the single dose to the subject according to any aspect of the composition or oral dosage form described herein. For example, the method can include administering the single dose to the subject in the form of extended release multiparticulates suspended in a liquid vehicle.

In some embodiments, the method can include administering the single dose to the subject such that the extended release of the active agent into the subject's plasma over the extended release period is characterized by an extended release rate. The method may include administering the single dose to the subject such that greater than about <NUM>% (w/w) of the active agent in the pharmaceutical composition is released to the subject over the extended release period. The extended release period can be, in hours, at least one of, or at least about one of: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> hours, e.g., about <NUM> hours, or a range between any two of the preceding values, for example, of between about <NUM> hours and about <NUM> hours, between <NUM> hours to <NUM> hours, between <NUM> hours to <NUM> hours, between <NUM> hours to <NUM> hours, or between <NUM> hours to <NUM> hours.

In some embodiments, the composition or oral dosage form described herein is administered once or twice daily to a subject in need thereof. The dose administered can be sufficient to obtain a suitable therapeutic response in the subject.

A variety of processes can be used to produce the extended release multi-particulates comprising droxidopa and the release controlling agent. Exemplary processes include hot melt extrusion, melt granulation, extrusion spheronization, direct pelletization, spray drying, and spray congealing.

Generally, melt-granulation techniques involve melting a normally solid release controlling agent, e.g. a wax or a lipophilic compound, and incorporating a powdered active agent therein. The release controlling agent can be pre-heated to a molten state and then mixed with the dry pre-blend of the remaining matrix ingredients. Alternatively, the release controlling agent can be mixed with the dry pre-blend and the entire mass is then heated to melt the release controlling agent. The mixing should be sufficient to homogenously disperse the dry pre-blend into the molten binder. The mixture is then allowed to cool and the mixture can be ground or milled and screened to the desired size. The ground or milled granulate may be mixed with an optional lubricant or other processing aid. The processing aid can include, for example, hydrophobic colloidal silicon dioxide (such as CAB-O-SIL® M5). Hydrophobic silicon dioxide may be used in amounts of less than or equal to about <NUM> wt%, but individual formulations can be varied as required. The blend of the granulate and the processing aids, if any, may be optionally compressed into mini-tablets and then optionally coated.

The preparation of a suitable melt-extruded matrix according to the present invention may, for example, include the steps of blending the active agent, together with a release-controlling agent and optionally a binder material to obtain a homogeneous mixture. The homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude the same. The resulting homogeneous mixture is then extruded, e.g., using a twin-screw extruder, to form strands. The extrudate is preferably cooled and cut into multiparticulates by any means known in the art. The strands are cooled and cut into multiparticulates. The multiparticulates are then divided into unit doses. The extrudate preferably has a diameter of from about <NUM> to about <NUM> and provides controlled release of the therapeutically active agent for a time period of from about <NUM> to about <NUM> hours or about <NUM> to about <NUM> hours.

Extrusion-spheronization typically begins with damp wet mass which can be extruded with a twin screw extruder in to wet extrudes. The wet extrudes are spheronized in a marumerizer at a predetermined speed. The extruded cylindrically shaped extrudates are gradually transformed into spherical shapes.

There are few techniques available that can be used to directly form pellets. One of the examples of these techniques is rotor granulation. With this advanced technology, pellets with spherical shape, smooth surface and uniform particle size are generated. Physical properties of the pellets can be controlled through ingredients' properties and process parameters.

Spray drying and spray congealing, known as globulation processes, involve atomization of hot melts, solutions, or suspensions to generate spherical particles or pellets. During spray drying, drug entities in solution or suspension is sprayed, with or without excipients, into a hot air stream to generate dry and highly spherical particles. As the atomized droplets come in contact with hot air, evaporation of the application medium is initiated. This drying process continues through a series of stages where the viscosity of the droplets constantly increases until finally almost the entire application medium is driven off and solid particles are formed. Generally, spray-dried pellets tend to be porous.

During spray congealing, a drug substance is allowed to melt, disperse, or dissolve in hot melts of waxes, fatty acids, etc., and sprayed into an air chamber where the temperature is below the melting temperatures of the formulation components, to provide under appropriate processing conditions spherical congealed pellets.

The multiparticulates can optionally be coated with a protection layer, such as a moisture protection layer. The terms "protection layer" and "protective layer" are used interchangeably herein. The most common method used for the application of coating onto multiparticulates is air suspension coating. Other methods include compression coating, solvent evaporation, coacervation, and interfacial complexation.

In some embodiments, the multi-particulate of the disclosure is pepared by direct pelletization, e.g., using rotor granulation. Characteristics of the pellets formed from the direct pelletization process included one or more of spherical shape, smooth surfaces, broad drug load (<<NUM>-<NUM>%), high density, and/or uniform and small particle size (e.g., less than <NUM>).

In another aspect, a method of making an oral liquid dosage form is disclosed. The method comprises mixing any of the solid droxidopa compositions disclosed herein with a liquid vehicle to produce a liquid dosage form. The liquid dosage form can be a suspension or an emulsion. The liquid dosage form can have a pH < <NUM>, < <NUM>, < <NUM>, < <NUM>, or < <NUM>. The method can further comprise breaking a seal of a compartment in a bottle in which the solid droxidopa composition is stored to release the composition into the liquid vehicle.

In this specification and claims that follow, references will be made to a number of terms which shall be defined to have the following meanings.

The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and/or". The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to").

A "dosage form" means a unit of administration of an active agent. Examples of dosage forms include tablets, mini-tablets, capsules, suspensions, solutions, liquids, emulsions, bottles, sachets, or packets, and the like.

An "active agent" means a compound, element, or mixture that when administered to a patient, alone or in combination with another compound, element, or mixture, confers, directly or indirectly, a physiological effect on the patient. The indirect physiological effect may occur via a metabolite or other indirect mechanism. In some embodiments, the active agent is droxidopa.

"Dosing regimen" means the dose of an active agent taken at a first time by a patient and the interval (time or symptomatic) at which any subsequent doses of the active agent are taken by the patient. The additional doses of the active agent can be different from the dose taken at the first time.

A "dose" means the measured quantity of an active agent to be taken at one time by a patient.

"Droxidopa" as used herein refers to droxidopa or a pharmaceutically acceptable salt thereof.

"Droxidopa therapy" refers to medical treatment of a symptom, disorder, or condition by administration of droxidopa. Droxidopa therapy can be considered optimal when effective plasma levels are reached when required. In addition, peak plasma values (Cmax) should be as low as possible while still maintaining an effective plasma level throughout the day so as to reduce the incidence and severity of possible side effects.

The term "effective amount" or "therapeutically effective amount" means an amount effective, when administered to a patient, to provide any therapeutic benefit. A therapeutic benefit may be an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of acute gouty arthritis, for example pain associated with an attack of acute gouty arthritis. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent, and the like. Thus, it is not always possible to specify an exact "effective amount. " However, an appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. In certain circumstances a patient may not present symptoms of a condition for which the patient is being treated. A therapeutically effective amount of an active agent may also be an amount sufficient to provide a significant positive effect on any indicium of a disease, disorder, or condition, e.g. an amount sufficient to significantly reduce the severity of hypotension. A significant effect on an indicium of a disease, disorder, or condition is statistically significant in a standard parametric test of statistical significance, for example Student's T-test, where p ≤ <NUM>.

In some embodiments, an effective amount or therapeutically effective amount of droxidopa can be an amount of about <NUM> per day to about <NUM> or about <NUM> to about <NUM> per day, about <NUM> to about <NUM> per day, or about <NUM> to about <NUM> per day.

"Efficacy" means the ability of an active agent administered to a patient to produce a therapeutic effect in the patient.

A "liquid vehicle" as used herein means a solution or a suspension that can be combined with a solid dosage form comprising an active agent for delivery of the active agent to a subject. The liquid vehicle is a suspending vehicle. In some embodiments, the liquid vehicle can be an aqueous vehicle or a nonaqueous vehicle. Examples of aqueous vehicles include, e.g., water and a buffered solution. Examples of nonaqueous vehicles include, e.g., mixture of alcohol with aqueous vehicle.

An "oral dosage form" means a unit dosage form for oral administration.

A "patient" means a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment. In some embodiments the patient is a human patient.

As used herein, the terms "pH controlling agent," "pH modifier," and "buffering agent" are used interchangeably, unless indicated otherwise. Examples of a pH controlling agent, a pH modifier, or a buffering agent include pharmaceutically acceptable buffering systems, acids having suitable pKa 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.

"Pharmaceutically acceptable" means that which is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.

"Pharmaceutically acceptable salts" includes derivatives of droxidopa, wherein the droxidopa is modified by making acid or base addition salts thereof, and further refers to pharmaceutically acceptable solvates, including hydrates, and co-crystals of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues; and the like, and combinations comprising one or more of the foregoing salts. The pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of the droxidopa. For example, non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal salts, such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts. Pharmaceutically acceptable organic salts includes salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, <NUM>-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n-COOH where n is <NUM>-<NUM>, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, and the like; and amino acid salts such as arginate, asparginate, glutamate, and the like; and combinations comprising one or more of the foregoing salts; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N' dibenzylethylenediamine salt, and the like; and amino acid salts such as arginate, asparginate, glutamate, and the like; and combinations comprising one or more of the foregoing salts. All forms of such derivatives of droxidopa are contemplated herein, including all crystalline, amorphous, and polymorph forms.

"Pharmacokinetic parameters" describe the in vivo characteristics of an active agent (or a metabolite or a surrogate marker for the active agent) over time, such as plasma concentration (C), Cmax, Cn, C<NUM>, Tmax, and AUC. "Cmax" is the measured plasma concentration of the active agent at the point of maximum, or peak, concentration. "Cmin" is the measured plasma concentration of the active agent at the point of minimum concentration. "Cn" is the measured plasma concentration of the active agent at about n hours after administration. "C<NUM>" is the measured plasma concentration of the active agent at about <NUM> hours after administration. The term "Tmax" refers to the time at which the measured plasma concentration of the active agent is the highest after administration of the active agent. "AUC" is the area under the curve of a graph of the measured plasma concentration of an active agent vs. time, measured from one time point to another time point. For example AUC<NUM>-t is the area under the curve of plasma concentration versus time from time <NUM> to time t, where t can be the last time point with measurable plasma concentration for an individual formulation. The AUC<NUM>-∞ or AUC<NUM>-INF is the calculated area under the curve of plasma concentration versus time from time <NUM> to time infinity.

The term "subject" includes any human or non-human animal. For example, the methods and compositions disclosed herein can be used to treat a subject having Parkinson's disease. In a particular embodiment, the subject is a human.

The terms "treating" and "treatment" mean implementation of therapy with the intention of reducing in severity or frequency symptoms, elimination of symptoms or underlying cause, prevention of or reducing the risk of the occurrence of symptoms or their underlying cause, and improvement or remediation of damage.

The terms "administer," "administering," "administered" or "administration" refer to any manner of providing an active agent (such as, droxidopa or a pharmaceutically acceptable salt thereof) to a subject or patient. Routes of administration can be accomplished through any means known by those skilled in the art. Such means include oral, buccal, intravenous, subcutaneous, intramuscular, transdermal, and inhalation.

The term "fast release" as used herein refers to a pharmaceutical formulation that releases the active agent contained therein relatively fast, e.g., relase of the drug starts within about <NUM> minutes to <NUM> hours after the start of an in vitro dissolution test. In some embodiments, the fast release pharmaceutical formulation comprises an immediate release delivery system.

The term "immediate-release" refers to a pharmaceutical formulation characterized by conventional or non-modified release of the active agent immediately after drug administration. In some embodiments, immediate release means greater than or equal to about <NUM>% of the active agent is released within two hours of administration, specifically within one hour of administration.

As used herein, the term "extended release" refers to a pharmaceutical formulation that provides for the gradual release of an active agent over an extended period of time. "Extended-release" includes the release of the active agent at such a rate that blood (e.g., plasma) levels are maintained within a therapeutic range for at least about <NUM> hours, for about <NUM> to about <NUM> hours, about <NUM> to about <NUM> hours, or about <NUM> to about <NUM> hours. The term steady-state means that a plasma level for a given active agent has been achieved and which is maintained with subsequent doses of the drug at a level which is at or above the minimum effective therapeutic level for a given active agent.

The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). The notation "± <NUM>%" means that the indicated measurement can be from an amount that is minus <NUM>% to an amount that is plus <NUM>% of the stated value.

"Optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event occurs and instances where it does not. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

The following example are merely illustrative of the compositions and methods disclosed herein and are not intended to limit the scope hereof.

A variety of processes can be used to produce the extended release multi-particulates comprising droxidopa and a non-polymeric release controlling material. Exemplary processes include hot melt extrusion, melt granulation, extrusion spheronization, direct pelletization, spray congealing and wax coating. Schematic flow charts for manufacture of extended release multiparticulates via each of these processes are shown in <FIG>.

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. For example, 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.

Only examples <NUM>, formulation I of example <NUM>, and example <NUM> are according to the claimed invention. The other examples are reference examples.

Example <NUM>. An extended release multi-particulate formulation comprising a lipid matrix with optional moisture protection coating is shown in Table <NUM>.

Example <NUM>. An extended release multi-particulate formulation comprising a lipid matrix is shown in Table <NUM>.

Example <NUM>. An extended release multi-particulate formulation comprising droxidopa granules with a lipid coating is shown in Table <NUM>.

A protective coating may be applied to the above extended release multi-particulates so that there is no drug release for a period of time, e.g., at least <NUM>. An example of the formulation is shown in Table <NUM> below. The multi-particulates can be administered as a suspension.

Extended release granules can be blended with excipients such as diluents, lubricants, and flow aids, and compressed into extended release mini-tablets with a diameter ranging between <NUM>-<NUM>. Any of the extended release multi-particulates disclosed herein or exemplified above can be used. Table <NUM> shows an example of extended release multi-particulates.

Extended release droxidopa multi-particulates are packaged in the cap and a suspending vehicle is filled in the bottle. When opening the bottle, the multi-particulates are released from the cap and fall into the bottle with the suspending vehicle. The suspending vehicle may comprise water, suspending agents, sweeteners, stabilizers, preservatives, coloring agents, surfactants, and flavoring agents. Any of the extended release multi-particulates disclosed herein or exemplified above can be used in these dosage forms. An extended release multi-particulate solid formulation and a suspending vehicle formulation, which can be combined in a bottle to form a suspension, is shown in shown in Table <NUM>.

The suspending vehicle may also comprise an alcohol, e.g., ethanol, as shown in Table <NUM>.

The extended release multi-particulates are coated to prevent drug release in a ready-to-use suspension. Any of the extended release multi-particulates disclosed herein or exemplified above can be used in this dosage form.

Example <NUM>. Extended-release multi-particulates for reconstitution or use as a sprinkle is shown in Table <NUM>.

A quantity of extended release multi-particulates suitable for a single dose or for multiple doses are filled into a sachet or packet.

The sachet is opened and the extended release multi-particulates are sprinkled on food or a beverage for oral consumption.

The contents of a single dose sachet is mixed with a suspending vehicle and reconstituted into a suspension at the time of oral administration.

The contents of a multi-dose sachet is mixed with a suitable volume of suspending vehicle including a preservative and reconstituted into a suspension for oral administration over a period of at least a week.

The suspending vehicle is optionally provided with the sachet as shown in Table <NUM>.

Table <NUM> shows droxidopa solubility at room temperature at pH <NUM>, <NUM>, <NUM>, <NUM> and <NUM>.

Droxidopa is stable in acidic solution, but degrades in neutral or alkaline conditions. Saturated droxidopa in citric acid solution (pH <NUM>) or in citrate buffer (pH <NUM>) was found to be stable at room temperature over <NUM> days. When citric acid was present with the drug in solid state, e.g. powder or uncoated granules, droxidopa became unstable under accelerated conditions <NUM>/ <NUM>% RH. When these droxidopa granules/pellets were coated with a protective layer, and blended with citric acid, the drug degradation was reduced.

The effect of pH modifiers or buffering agents on certain liquid dosage forms was tested.

Droxidopa was dissolved in <NUM> diluents at different pH and stored at room temperature for <NUM> or <NUM> hours in sealed glass containers. All solutions were prepared at a nominal concentration of <NUM>/ml. Per cent degradation was determined by ultra-performance liquid chromatography (UPLC) on a Waters ACQUITY UPLC with a photodiode array (PDA) detector using a Waters ACQUITY BEH C18 <NUM> <NUM>. 1x50 mm column. Run conditions for the analyses were as follows:.

Mobile phase A: <NUM> sodium phosphate pH <NUM>
Mobile phase B: Acetonitrile
Detection wavelength: <NUM>
Flow: <NUM>/min
Column temperature: <NUM> C
Injection volume: <NUM>µl
Gradient (linear transitions) are shown in Table 12A:.

Identification of the known components droxidopa and dihydroxybenzaldehyde was confirmed through retention time and spectral match against pure materials of known identity. Degradation results were quantified as a percent area of degradation peaks versus total area of all degradation/droxidopa peaks. Results for pH <NUM> and pH <NUM> samples were estimated at ><NUM>% due to a significant number of peaks present near the retention time of droxidopa.

Table 13A below summarizes stability data for droxidopa after exposure in solutions of varying different pH.

Saturated solutions of droxidopa were prepared in <NUM> diluents at different pH and stored at room temperature for up to <NUM> days in sealed containers. All solutions were prepared with an excess of droxidopa by combining <NUM> droxidopa per ml of diluent. Exposed samples were filtered and degradation as a percent of initial droxidopa amount was determined by ultra-performance liquid chromatography (UPLC) on a Waters ACQUITY UPLC with a photodiode array (PDA) detector using a Waters ACQUITY HSS PFP <NUM> <NUM>. 1x100 mm column. Run conditions for the analyses were as follows:.

Mobile phase A: <NUM> ammonium formate pH <NUM>
Mobile phase B: Acetonitrile
Detection wavelength: <NUM>
Flow: <NUM>/min
Column temperature: <NUM> C
Injection volume: <NUM>µl
Gradient (linear transitions) are shown in Table 12B:.

Table 13B below summarizes stability data for droxidopa after exposure in saturated solutions.

These results show that addition of pH modifiers or buffering agents to the tested liquid dosage forms or one or more components required to reconstitute a solid droxidopa composition to a liquid dosage form can help stabilize the drug.

Examples of suspension formulations with a pH modifier are shown in the Tables <NUM> and <NUM> below.

Alternatively, the pH modifier can be included in the extended release multi-particulate. An example extended release multi-particulate form including a pH modifier is shown in the Table <NUM> below.

The liquid vehicle for reconstituting a solid droxidopa multi-particulate into a liquid dosage form may comprise materials which are in solution form before administration in the body, but once administered undergo gelation in situ to form a gel from which the drug is released in a sustained and controlled manner. The formation of a gel depends on various factors such as temperature modulation, pH change, and the presence of ions. Examples of polymers that can be used in formulations for formation of in situ gels 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.

An exemplary formulation of a dosage form providing in situ gel formation and extended release is shown in Table <NUM> below.

Furthermore, a pH modifier monosodium citrate was used instead of citric acid and blended with droxidopa granules. Droxidopa was stable for <NUM> days under accelerated conditions <NUM>/ <NUM>% RH. Another pH modifier sodium bitartrate monohydrate was used the same way and showed similar results. Thus, salt based pH modifiers can be used to improve the stability of the droxidopa.

Ready-to-use suspensions comprising extended release multi-particulates comprising a polymer matrix and a suspending vehicle having a pH < <NUM> are made.

Extended release multi-particulates are made by dry blending the drug and polymer and then granulated in a fluidized bed granulator using sufficient granulation fluid to produce a wet granulate that is subsequently dried and screened. The multi-particulates optionally include a protection coating. Examples of extended release multi-particulates are show in Tables <NUM>-<NUM>.

Any one of above extended release granule formulations, for example the granules including Hypromellose, is mixed with a suspending vehicle comprising a pH modifier (citric acid or monosodium citrate) to form a ready-to-use suspension having a pH < <NUM>. An example of a ready-to-use suspension is shown in Table <NUM>.

A pH dependence was also observed in drug release from a droxidopa tablet in dissolution tests. The tested tablet formulation is shown in Table <NUM> below.

Droxidopa dissolution from the tablets was tested in <NUM> <NUM>. 1N HCl or water in a USP II apparatus (paddle) at <NUM> and <NUM> rpm. The % drug released over time is shown in Table <NUM>.

An extended release droxidopa suspension containing two different types of pellets, pellets I and pellets II, were prepared as shown in Table 24A.

Pellets I included a release controlling agent. Upon exposure to pH <NUM> in stomach, Pellets I started releasing the drug over a short period of time, e.g. up to about <NUM>-<NUM> hrs.

Pellets II included a release controlling agent and a protective coating, protecting the drug from releasing in stomach pH <NUM>, but allowing release at about pH <NUM>. For example, Eudragit L30-D55 was used to protect the drug from releasing in stomach, and can readily dissolve in small intestine at pH <NUM>.

Hydroxypropyl cellulose (HPC) was used as a binder and is compatible with the drug. No significant degradation was observed when HPC was used as a dry binder or added as a binder in solution form. The quantity of HPC used is less than <NUM>% w/w, so it does not control drug release in this formulation.

A pH dependence was observed in drug release in a dissolution test performed with USP Apparatus II (Paddles) at <NUM> rpm in <NUM> of <NUM> N HCl for <NUM> hours at <NUM> and USP Apparatus II (Paddles) at <NUM> rpm in <NUM> of pH <NUM> phosphate buffer for <NUM>-<NUM> hours at <NUM>. The dissolution profile (% release over time) is shown in Table <NUM> and <FIG>.

Alternatively, pellets I were coated with a protective layer which is soluble at pH <NUM> or below and the pH of the suspension can be <NUM> or higher (see Table 24B). The protective layer prevents exposure of the drug to higher pH of the suspension and thus degradation. Upon administration, the protective layer dissolves in stomach and drug is released in the similar manner.

No buffering agent was used for pellet I or pellet II. Instead, the drug release for the formulation was controlled by non-polymeric materials.

Extended release granules with <NUM> droxidopa were prepared by melt granulation process and included the ingredients shown in Table <NUM>.

A dissolution test with the extended release granules was performed with USP Apparatus II (Paddles) at <NUM> rpm in <NUM> of <NUM> N HCl for <NUM> hours at <NUM> and USP Apparatus II (Paddles) at <NUM> rpm in <NUM> of pH <NUM> phosphate buffer for <NUM>-<NUM> hours at <NUM>. The dissolution profile (% release over time) is shown in <FIG>.

Extended release mini-tablets with <NUM> droxidopa were prepared by melt granulation and direct compression process and included the ingredients shown in Tables <NUM> (using wax as the release-controlling agent) and Table <NUM> (no release controlling agent included).

A dissolution test on the mini-tablets was performed with USP Apparatus II (Paddles) at <NUM> rpm in <NUM> of <NUM> N HCl for <NUM> hours at <NUM> and USP Apparatus II (Paddles) at <NUM> rpm in <NUM> of pH <NUM> phosphate buffer for <NUM>-<NUM> hours at <NUM>. No different in dissolution profile was observed for mini-tablets prepared either by melt granulation or by direct compression. The dissolution profile (% release over time) is shown in <FIG>.

Pellets formed by extrusion spheronization process are usually quite limited by the size of the twin-screw screens available. Pellets prepared by extrusion spheronization often have a wide particle size distribution. For an oral extended-release suspension, uniform pellets with a particle size less than <NUM> was desired to avoid a gritty mouth-feel. Further, the four-steps involved in the extrusion spheronization process makes it not economic.

A preferred manufacturing process that could create uniform size pellets with higher drug load was preferred for pellet formation. There were few techniques available that could be used to form such pellets.

An example of a technique for direct pellet formation is rotor granulation. Characteristics of the pellets formed from the direct pelletization process included spherical shape, smooth surfaces, broad drug load (<<NUM>-<NUM>%), high density, uniform and smaller particle size.

An example of direct pelletization manufacturing process is described as follows: droxidopa was blended with microcrystalline cellulose and a rate-controlling agent in a high shear granulator, and water was sprayed to form a damp mass. The damp mass was then fed into a rotary granulator where the loose agglomerates were densified and spheronized by an orbital motion while additional water was sprayed. Small and uniform pellets were produced and then dried in a fluid bed processor. A portion of the pellets was further coated in a fluid bed processor with a protective layer. Optionally, the rest of the pellets were coated with a moisture protective layer, which dissolved at pH <NUM>. These pellets were blended together to form a uniform blend, which can be filled into a sachet or into a cap of a bottle containing a suspending vehicle in the bottle.

As an another example of direct pelletization, droxidopa was blended with microcrystalline cellulose in a high shear granulator, and purified water was sprayed onto the blend to form a damp mass. The damp mass was then fed into a rotary granulator where the loose agglomerates were densified and spheronized by an orbital motion. Small uniform pellets were produced and dried in a fluid bed processor. Extended release pellets were produced by further coating these pellets with a non-polymeric material in a fluid bed processor. Spraying molten wax on drug loaded immediate release pellets formed extended release pellets.

Pulsatile release can be realized by incorporating three different kinds of extended release multi-particulate (e.g., pellets or granules) that each starts releasing the drug at a different time. For example, the first type of multi-particulate (1st pulse) release the drug for a period of about <NUM> hours. The 2nd type of coated multi-particulate (2nd pulse) will not release any drug until about <NUM> hours later, but will start to release the drug about <NUM> hours after the initial administration of the pulsetile release formulation and extends the drug release for <NUM> hours after the 1st pulse release period. The 3rd type of coated multi-particulate (3rd pulse), will not release the drug until about <NUM> hours later, but will start to release the drug <NUM> hours after the initial administration of the pulsetile release formulation and extends the drug relase for <NUM> hours after the 2nd pulse release period and for a total of <NUM> hours extended release following the initial administration of the pulsetile release formulation.

Extended release granules can be prepared by wet granulation process followed by a melt granulation process. Drug, a filler, and a binder are blended and granulated in a high shear granulator forming wet granules, which are dried in a fluid bed processor. The granules are mixed with a wax, e.g. hydrogenated castor oil and heated up to the temperature above melting point of the wax, then granulated to form extended release granules. These granules can be coated with different levels of coating which start releasing the drug at different pH.

Pulsatile drug release can release equal amount of drug during each pulse (see Table <NUM> & <FIG>), or can release different amount of drug during each pulse (see Table <NUM> & <FIG>), or can release for different extended periods during each pulse.

Droxidopa pellet suspensions were prepared and stored at room temperature and at refrigerated temperature for up to <NUM> days in sealed containers. Suspensions included pellets containing <NUM> droxidopa (prepared similarly to pellets I of Formulation II in Example <NUM>: <NUM> droxidopa; <NUM> microcrystalline cellulose; water, q. ) in <NUM> of a suspending vehicle as shown below. A description of the study is shown in Table <NUM>.

For tested samples, the suspension was centrifuged and the supernatant was diluted <NUM> to <NUM> with water. Supernatant of the suspension was analyzed. Degradation as a percentage of droxidopa amount was determined by ultra-performance liquid chromatography (UPLC) on a Waters ACQUITY UPLC with a photodiode array (PDA) detector utilizing <NUM> methods that covered the range of separation characteristics for potential degradation products.

Method <NUM>: Analysis performed using a Waters Acquity HSS PFP <NUM> <NUM>. 1x100 mm column. Run conditions for the analyses were as follows:.

Mobile phase A: <NUM> ammonium formate adjusted to pH <NUM> with formic acid
Mobile phase B: acetonitrile
Detection wavelength: <NUM>
Flow: <NUM>/min
Column temperature: <NUM>
Injection volume: <NUM>µl
Gradient (linear transitions) are shown in Table <NUM>:.

Method <NUM>: Analysis performed using a Waters Acquity BEH Amide <NUM> <NUM>. 1x50 mm column. Run conditions for the analyses were as follows:.

Identification of a known degradation product dihydroxybenzaldehyde was confirmed through retention time and spectral match and quantified against pure material of known identity. Degradation results for unidentified peaks were quantified against a droxidopa standard of known concentration assuming a relative response of <NUM>.

Table <NUM> below summarizes stability data for droxidopa after exposure in suspended solution.

Claim 1:
An extended-release liquid composition for oral administration comprising:
(a)
(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, a second release controlling agent, and an enteric layer; and
(b) a liquid vehicle,
wherein the first multi-particulate is capable of releasing droxidopa, or a pharmaceutically acceptable salt thereof, at a pH of less than <NUM>, and the second multi-particulate is capable of releasing droxidopa, or a pharmaceutically acceptable salt thereof, at a pH of <NUM>