NZ718686B2 - Muco-adhesive, controlled release formulations of levodopa and/or esters of levodopa and uses thereof - Google Patents

Abstract

The invention provides a controlled release oral solid formulation comprising (a) a controlled release component comprising core comprising levodopa and/or an ester of levodopa or salts thereof, wherein the core is coated with a layer of a muco-adhesive polymer and externally coated with a layer of an enteric coated polymer; and (b) an immediate release component comprising levodopa and optionally a decarboxylase inhibitor. an enteric coated polymer; and (b) an immediate release component comprising levodopa and optionally a decarboxylase inhibitor.

Description

MUCO-ADHESIVE, CONTROLLED RELEASE FORMULATIONS OF LEVODOPA AND/OR ESTERS OF LEVODOPA AND USES THEREOF Throughout this application various publications are referenced. The disclosures of these ations in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this ion pertains.

FIELD OF THE INVENTION The present invention relates to controlled release ceutical compositions of levodopa (LD) and esters of levodopa or salts thereof, formulated with a muco-adhesive polymer and an enteric coating polymer and, optionally, with a rate-controlling polymer, to yield enhanced drug delivery attributes. These formulations are useful for the ent of conditions such as neurological diseases associated with reduced or impaired dopamine levels.

BACKGROUND OF THE INVENTION ts suffering from Parkinson’s disease (PD) frequently have periods in which their mobility s difficult, often resulting in an inability to move. Abnormally low levels of ne, a neurotransmitter that affects mobility and control of the skeletal—muscular system, is commonly believed to be the main cause ofthese motor symptoms in PD patients. However, administration of dopamine is not effective to treat the motor symptoms of Parkinson's e because dopamine does not cross the blood-brain barrier. To resolve this m, PD ts are administered levodopa, the metabolic precursor of dopamine, but levodopa is not without its issues.

Over time patients treated with LD exhibit symptoms of "wearing of ," where a single dose of 3O levodopa no longer lasts as long as in the early days of levodopa therapy (usually 5-10 years after start of levodopa therapy). Such patients may develop motor fluctuations terized by end-of—dose failure, peak dose esia, and akinesia. The advanced form of motor fluctuations (also commonly referred to as the ‘on-ofl’ phenomenon) is characterized by unpredictable swings from mobility to immobility. Although the causes of these motor fluctuations are not completely understood, advanced patients generally benefit from treatment regimens that produce steady plasma levels of LD, such as through intestinal infusion of LD as such delivery method may mimic normally tonic endogenous dopamine. However, inal infiJsion of LD is restrictive, invasive and some. Oral delivery of LD is preferred, but plasma concentration levels remain difficult to control via oral delivery.

Combinations of levodopa (LD) and a decarboxylase tor (typically carbidopa (CD)) to treat Parkinson's disease (PD) are known in the pharmaceutical arts. Currently, several formulations containing a ation of LD and CD are commercially ble, e. g., T®, T® CR, STALEVO®, PARCOPA®, and their corresponding generic products. In addition, a decarboxylase inhibitor approved for use outside of the United States, is benserazide, which may be given in combination with levodopa.

Nonetheless, a need s for an oral LD formulation that provides steadier plasma concentrations of LD with l 'peak-to-trough' fluctuations during daily dosing and that yields a longer duration-of—effect than the commercially available oral dosage forms of LD. In addition, it is desirable for an oral LD formulation to provide therapeutic blood levels of LD quickly, thereby providing a rapid "on" to a PD patient in need thereof.

SUMMARY OF THE INVENTION The current invention provides controlled release/extended absorption oral dosage forms comprising levodopa and/or ester of levodopa or salts thereof for treatment of Parkinson’s disease and dopamine deficiency disorders. More specifically, in some embodiments, the dosage form comprises two types of components, the first component is an immediate release levodopa and/or its ester or salts thereof, and the second component comprises a core containing levodopa and/or ester of levodopa or salts thereof coated with a muco-adhesive polymer and externally coated with an c coating polymer, ally, with a rate—controlling polymer oating the dhesive polymer. The second ent is essential to provide extended absorption, y providing prolonged and steady therapeutic coverage. The dosage form may se additionally a decarboxylase inhibitor, such as carbidopa.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the tic configuration of the enteric-coated, muco-adhesive lled release multi-particulates of this invention.

Figure 2 is a line graph showing the in vitro dissolution s of IPX203 multi-particulate formulations IPX203-C0004, IPX203-C0005 and IPX203-C0006.

Figure 3 shows the plasma profile for IPX203 multi—particulate formulations IPX203-C0004, IPX203-C0005 and IPX203—C0006 in comparison with Sinemet® CR.

Figure 4 are line graphs showing in vitro release profiles of test regimens A—D for IPX203-Bl3- Figure 5 is a line graph showing in vivo levodopa plasma profiles of IPX203 formulations that provide plasma profiles with pa levels maintained at or greater than 1/2 Cmax longer than about 6 hours under fasted conditions.

Figure 6 shows in vitro release profiles of IPX203-C0023, -C0024, —C0025 and —C0026 formulations.

Figure 7 shows in viva levodopa plasma profiles for the formulations tested in IPX203-B14-01 PK study under fasted conditions.

DETAILED DESCRIPTION OF THE INVENTION Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure s. As used herein the following terms have the ing gs: It must be noted that as used herein and in the appended claims, the singular forms ‘4 3, (C a an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a formulation" includes a plurality of compounds.

As used herein, the term " when used before a numerical designation, e.g., temperature, time, amount, tration, and such other, including a range, indicates approximations which mayvaryby(+)or(-)10%,5%orl%.

COMPOSITIONS OF THE INVENTION The invention provides controlled release oral solid formulations of levodopa and/or an ester of levodopa or a salt thereof ing a relatively steady levodopa plasma or serum concentration profile over a prolonged period of time and enhancing absorption of the active agents in the gastrointestinal tract of a subject. Without being limited by any one theory, it is believed that the polymer layers of the controlled e components of the t invention operate as follows.

The outer enteric coat delays release of the active agents until the dosage form has passed through the stomach and into the small intestine. In the small intestine, the muco-adhesive polymer facilitates adhesion to the intestinal mucosa, ng passage of the dosage form through the intestine. It is desirable to retain the dosage form within the small ine where levodopa is absorbed most efficiently. In preferred embodiments, the third rate-controlling polymer further slows the release of active agent from the dosage form, thereby r extending the release and absorption of levodopa. Preferred formulations include an immediate release component to provide fast levodopa release and absorption, which is ant for PD patients in need of a fast "on. 3, As a result, formulations of the present invention can provide levodopa plasma levels that rise quickly and extend for a prolonged period of time.

Decarboxylase inhibitors such as carbidopa are often provided with levodopa formulations in order to inhibit decarboxylation of levodopa, thereby increasing the levodopa bioavailability. In the formulations of the present ion, a decarboxylase inhibitor may be included in both the immediate release component and the controlled e component. Preferably, the decarboxylase inhibitor is carbidopa and is ed only in the immediate release component.

In one embodiment of the invention, the controlled release oral solid formulation contains (1) a controlled release ent comprising a levodopa and/or an ester of levodopa or salts thereof and (2) an immediate e component comprising levodopa and/or an ester of levodopa or salts f and a decarboxylase inhibitor. The immediate release ent may be ated as a mini-tablet, bead or granule. The controlled release ent comprises a core containing levodopa and/or an ester of levodopa or salts thereof coated with a layer of a muco- adhesive polymer and further coated with an outer layer of an enteric coating polymer.

Preferably, the drug-containing core is coated with a further rate-controlling polymer, which undercoats the muco-adhesive polymer layer. In a preferred embodiment, the immediate release ent is in the form of a granule.

In another embodiment of the invention, the controlled release oral solid ation contains (1) a controlled release component comprising a levodopa and/or an ester of levodopa or salts thereof, and (2) a decarboxylase inhibitor component. The decarboxylase inhibitor component may be formulated as a mini-tablet, bead or granule. In this embodiment, the controlled release ent comprises a drug-containing core coated with a layer of a muco-adhesive polymer and further coated with an outer layer of an enteric coating r. ably, the drug- containing core is coated with a further rate-controlling r that undercoats the muco- adhesive polymer layer. Preferably, the decarboxylase inhibitor is carbidopa. The controlled release component may comprise drug-containing cores containing both pa and/or an ester of levodopa or a salt thereof and a decarboxylase inhibitor, or the levodopa and/or ester of levodopa or salt thereof may be in separate controlled release components from that containing the decarboxylase inhibitor. In one embodiment of the invention, the controlled release component comprises a levodopa-containing core free of a decarboxylase inhibitor such as carbidopa. ably, the ation filrther comprises an immediate release component comprising levodopa and/or an ester of levodopa or a salt thereof and a oxylase inhibitor.

In a preferred embodiment of the invention, the controlled release oral solid formulation contains (1) a controlled release component comprising levodopa and (2) an immediate release component comprising levodopa and carbidopa. In this embodiment, the controlled release component comprises a drug-containing core coated with a first layer of a rate-controlling polymer, a second layer of muco-adhesive polymer and r coated with an outer third layer of an enteric g polymer (see, e.g., Figure 1).

In accordance with the practice of the invention, the formulations of the invention may be obtained by a granulation process, including, but not limited to, wet-granulation, fluid bed granulation or dry granulation, as is well-known in the pharmaceutical arts. The controlled e components and/or the immediate release components may r contain a ant, such as talc.

In an embodiment of the invention, the controlled release and/or immediate release components are multiparticulates that are encapsulated. The multiparticulates may be in a form that can be sprinkled directly onto food or liquids for easy ingestion.

The active agents, such as decarboxylase inhibitor, levodopa and/or levodopa ethyl ester, may be combined and dispersed hout the drug-containing core. In another embodiment, the active agents may be present in the center of the drug-containing core or layered on a sugar sphere.

In an embodiment of the invention, the controlled release oral solid formulation of levodopa or ester of levodopa or salts thereof may comprise two controlled release components that release levodopa or ester of pa or salts thereof at different rates.

In this embodiment, the controlled release oral solid formulation of levodopa or ester of levodopa or salts f may se two controlled release components differing in type, number, thickness and/or composition of coating with a rate-controlling polymer, a muco- adhesive polymer and an enteric-coating polymer.

Examples of levodopa include but are not limited to levodopa, L-DOPA, L—3,4- dihydroxyphenylalanine, and amino(3,4-dihydroxyphenyl)propanoic acid.

An example of a decarboxylase inhibitor es, but is not limited to, carbidopa. Additional decarboxylase inhibitors include alpha dopa, benserazide (Ro4-4602), and alpha- difluoromethyl-DOPA (DFMD) or salts thereof. In a preferred embodiment, the decarboxylase inhibitor is carbidopa.

An example of an ester of levodopa is a levodopa ethyl ester (LDEE; ethyl (2S)amino(3,4- oxyphenyl)propanoateg CAS Number: 371783) and having the structure: (levodopa ethyl ester; CAS Number 371783).

Additional examples of esters of levodopa include, but are not limited to: levodopa butyl ester (butyl (ZS)amino(3,4-dihydroxyphenyl)propanoate; CAS : 396383) having the structure: (Bf/ANA HQ levodopa propyl ester; levodopa propyl ester (propyl (ZS)amino(3,4- dihydroxyphenyl)propanoate; CAS : 3963 8-5 1-2) having the structure: and levodopa methyl ester (methyl (2S)—2-amino-3—(3,4-dihydroxyphenyl)propanoate; CAS Number: 71011), having the structure: HO / HO" "’ The ester of levodopa may be a salt, including, for example, a hydrated salt. The salt of levodopa ester may comprise, but is not limited to, any of an octonoate salt, myristate salt, succinate salt, succinate ate salt, fumarate salt, fumarate dihydrate salt, mesylate salt, tartrate salt, and hydrochlorate salt.

For e, the succinate salt of an ester of levodopa or the succinate dihydrate salt may be a levodopa ethyl ester succinate (LDEE—S) or levodopa ethyl ester succinate dihydrate (LDEE-S- dihydrate or LDEE—S(d)).

As used herein, "levodopa equivalence" or "LD equivalence" means that amount of levodopa ester or salts thereof that contain lent amounts of levodopa, based on weight equivalence.

For example, based on the molecular weights, 306 mg of levodopa ethyl ester succinate- dihydrate (LDEE-S-dihydrate) is equivalent to 228 mg of levodopa ethyl ester (LDEE) and to 2O 200 mg pa (LD).

Muco-adhesive polymers may be homogenous, i.e., a single type of polymer, or may se multiple types of dhesive polymers. dhesive polymers may possess certain characteristics such as being hydrophilic, hydrophobic, cationic, anionic and/or biocompatible and include multiple hydrogen g groups, hydrophobic surfaces, positively charged groups and/or negatively charged groups for adhesion to a mucosal surface so that the presence of active agent, such as levodopa, can be prolonged at the site of absorption and increase bioavailability.

Further, the muco-adhesive polymer may be natural, synthetic or from a biological source.

Further still, the muco-adhesive polymer may be composed of a single polymer or a combination of two or more different polymers. In one embodiment, the rs may range in size from ,000 daltons to 1,000,000 daltons and more preferably 20,000 daltons to 200,000 s.

An example of a muco-adhesive polymer includes, but is not limited to, a basic rylate mer, such as an amino methacrylate mer. A preferred example of a methacrylate copolymer is a basic butylated methacrylate copolymer, an amino rylate copolymer, or aminoalkyl methacrylate copolymer, such as Eudragit® E100 (poly(buty1 rylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate) 12:]; CAS number: 249387; Evonik Industries). EUDRAGIT® E100 is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate with a ratio of 2: 1 : 1. The monomers are randomly distributed along the copolymer chain. In a preferred embodiment, the average molar weight of EUDRAGIT® E100 is approximately 150,000 g/mol.

Other examples of dhesive polymer include, but are not limited to, a glyceride, steroidal detergent, polycarbophil (CAS Number 9003-97—8; Noveon® AA-l; Lubrizol Corp), carbomer, cellulosics, chitosan OH OH pH HO See HMof"$45M.» HQWOH"LG: «0" ‘3‘"‘9 NHX NHX NHX where X 2: hydrogen (3+) or acetyl {(183%) group r3 : number of D~glucosamine and N-acetyi~D—g¥ucosamine units (CAS Number: 90124; Chitopharm® S with molecular weight range of 50,000 to 1,000,000 daltons), diethylaminodextran, diethylaminoethyldextran, polygalactosamine, polylysine, polyomithine, prolamine, ine, hyaluronic acid, sodium alginate, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (sodium CMC) and alginate (CAS Number: 9005—32-7) or combination thereof. Alginate is a homopolymer or heteropolymer composed of B-D-mannuronate (M) rs, or-L-guluronate (G) monomers, or mixture of B-D-mannuronate and a-L—guluronate monomers C00 ' 0 0 OH OH C00 ' OH 0 OH 0 HO HO B~D-mannuronate (M) uluronate (G) linked through (l—>4) or (l,4)—glycosidic bonds. The (l,4)—glycosidic linkages present in alginates are: B-D-mannuronate-(l,4)-B-D-mannuronate (MM), nnuronate-(l,4)—0t-L- guluronate (MG), OL-L-guluronate-(l,4)-[3-D-mannuronate (GM) and OL-L-guluronate-(l,4)-0t-L- guluronate (GG), as can be seen below: idic linkage: An alginate may be in the form of a polyanion or in the form of an acid, such as alginic acid.

Further, alginate may be in the form of a salt of alginic acid, such as sodium alginate, potassium alginate, ammonium alginate, triethanolamine te, ium alginate or calcium alginate. atively, alginate may be in the form of an ester of alginic acid such as propylene glycol alginate.

The muco-adhesive r may constitute 2%-50% of the mass of the controlled release component, preferably 3%—15% of the mass of the controlled release component, most preferably about .5% of the mass of the controlled release component. Preferably, the muco- adhesive polymer is Eudragit E 100. The muco-adhesive polymer percentages of mass stated above are based on a multiparticulate with a bead size between 0.8 to 1.2 mm. If the bead size is larger or smaller than 0.8 to 1.2 mm, the d artisan will understand that the mass percentage described above should be adjusted accordingly.

Enteric coating polymers are known in the art. In general, enteric coating polymers are designed to prevent drug release from an oral solid dosage form in the low pH environment of the stomach, thereby delaying drug release until the dosage form reaches the small intestine. As such, the controlled release components of the invention have an in vitro release profile with minimal release of the active agent at pH 1.0. In the lled release formulations of the invention, it is believed the outer enteric coating polymer layer provides an additional advantage in preventing agglomeration of the controlled e components. That is, the enteric coat polymer layer prevents the controlled release beads from sticking together in the low pH environment of the h.

The preferred enteric polymers are shellac (esters of aleurtic acid), ose acetate phthalate (CAP), poly(methacrylic o-methyl methacrylate), poly(methacrylic acid-co-ethyl rylate), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinates. The preferred c polymers release at a pH of greater than or equal to pH 5.5.

Examples include Eudragit® L100 or Eudragit® L100-55. The enteric g polymers may constitute 2-20% of the mass of the controlled release component, preferably 3-15%, most preferably 5-12%. The enteric-coated polymer percentages stated above are based on a articulate bead size between 0.8-1.2 mm. If the bead size is r or , the skilled artisan will understand that the mass percentage described above should be adjusted accordingly.

The enteric coating polymer may comprise a methacrylic acid copolymer or multiple types of methacrylic acid copolymers. The methacrylic copolymer may comprise any of Eudragit® L 30 D-55 (poly(methacrylic acid-co—ethyl acrylate) 1:1; CAS Number 25212—88-8; Evonik Industries), Eudragit® L 100—55 (poly(methacrylic acid-co-ethyl acrylate) 1:1; CAS Number 252128; Evonik Industries), Eudragit® L 100 (poly(methacrylic acid-co—methyl methacrylate) 1:1; CAS Number 25086-15—1; Evonik Industries), Eudragit® L 12,5 (poly(methacry1ic acid-co-methyl Number 250861; Evonik Industries); Eudragit® s 100 (poly(methacry1ic acid-co-methyl methacrylate) 1:2; CAS Number 250861; Evonik Industries), Eudragit® S 12,5 (poly(methacrylic acid-co-methyl methacrylate) 1:2; CAS Number 15-1; Evonik Industries), and Eudragit® FS 30 D methy1 acrylate-co-methyl methacrylate-co-methacry1ic acid) 7:3:1; CAS Number 26936- 24-3; Evonik Industries) or a combination thereof.

In a preferred embodiment of present ion, the controlled release component comprises a further rate—controlling polymer coat over the drug—containing core, undercoating the muco- adhesive polymer. Examples of rate-controlling rs useful in the present invention include, but are not limited to, ellulose, cellulose acetate, Eudragit® E, Eudragit® RS, Eudragit® RL, and Eudragit® NE, or mixtures f. Preferably, the rate-controlling polymers are not soluble in water at neutral pH. Preferably, the rate-controlling polymer is ose acetate. The rate-controlling polymer can also e a flux enhancer to adjust the release rate.

Preferably, the flux enhancer is copovidone, PEG 3350, or low molecular weight HPMC.

Lubricants useful in pharmaceutical formulations are known in the art. Examples of a suitable ant include, but are not limited to, stearic acid, lauric acid, myristic acid, palmitic acid, fatty acid, magnesium te, calcium stearate, zinc stearate, sodium stearate, Stear-O-Wet®, sodium stearyl fumarate, salt of a fatty acid, metallic salt of fatty acid, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, Cornpritol® 888 ATO, glyceride ester, sorbitan monostearate, sucrose monopalmitate, sugar ester, fatty acid ester, talc, hydrated magnesium silicate, PEG 4000, boric acid, Carbowax (PEG) 000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, Sterotex, wax, or mixture thereof.

In accordance with the practice of the invention, a surfactant may be included, such as sodium lauryl sulfate. Other surfactants may be suitable and are well known in the art.

In an embodiment of the ion, the carbidopa and the levodopa or levodopa equivalence are present in the formulation of the invention in a weight ratio of about 1:1 to about 1:10, preferably about 1:4.

For example, useful amounts of levodopa or levodopa equivalence and carbidopa include: (a) 200 mg:3l.25 mg; (b) 200 mgz50 mg; (c) 255.6 mgz50 mg; (d) 360 mg:50 mg; (e) 95 mg:23.75 mg; (f) 145 mg:36.25 mg; (g) 195 mg:48.75 mg; (h) 245 mg:6l.25 mg; or (i) 390 5 mg; with each value capable of varying by i10%. Further examples e amounts of levodopazcarbidopa or levodopa equivalencezcarbidopa as follows: (a) 95 mg:23.75 mg; (b) 145 mg:36.25 mg; (c) 195 mg:48.75 mg; or (d) 245 mg:61.25 mg; with each value capable of varying by i10%.

In an embodiment of the invention, the immediate release component may comprise less levodopa or levodopa equivalence dosage than the controlled release ent. For e, the ratio of levodopa or levodopa equivalence in the immediate release component to that in the controlled release component can be in the range of 0.15 to 0.65. For example, a ratio in weight of levodopa equivalence in the controlled release component:immediate release component is at least about 2: 1, most preferably 3:1.

In one embodiment of the invention, the controlled release component is a bead having a size that passes h 12, 14, or 16 mesh but may be retained on 18, 24 or 25 mesh s.

Further, the bead may have a size that passes through 14 mesh but may be retained on 18 or 24 mesh screens.

The controlled release component will have an in vitro dissolution profile showing minimal release of the levodopa and/or ester of the levodopa or a salt thereof at pH 1.0 and extended release of the ester of levodopa or a salt f near neutral pH, for example at or near pH 7.

For example, l release may entail less than 20% release of levodopa, preferably less than %, most preferably less than 5% using USP I dissolution method at agitation speed of 75 rpm in Simulated Gastric Fluid (pH 1.0, t enzyme) for 2 hrs. Further, extended release may e release at over at least four and up to an additional 8 hours at or near pH 7, upon changing to Simulated Intestinal Fluid (pH 7.0, without enzyme) after first 2 hrs in Simulated Gastric Fluid (pH 1.0, t enzyme) using USP I dissolution method at agitation speed of 75 rpm. Further still, as used here, at or near pH 7 includes a pH at or about pH 6.5, 6.6, 6.7, 6.8 6.9, 7.1, 7.2, 7.3, 7.4, 7.5 or 7.6.

The levodopa and/or ester of levodopa or a salt thereof released from the controlled release component may produce an in viva levodopa plasma profile (e.g., mean in vivo levodopa plasma profile) sing a peak ing not before about two hours after administration to a subject and provides at least three hour duration for pa plasma concentration above 50% the maximum value of the peak concentration (Cmax). In another embodiment, in the plasma profile, the peak occurs after about one and a half hours after administration to the subject and exhibits at least a four-hour duration for pa plasma concentration at or above 50% of Cmax. By way of example, the profile may be achieved under fasting conditions.

When the formulation of the invention comprises an immediate release component and a controlled release component, the in vivo levodopa plasma profile following administration of an oral dosage form of the formulation to a t may comprise time of administration of an oral dosage form; a levodopa plasma concentration corresponding to Cmax occurring within about 6 hours or 7 hours after administration of the dosage form; a mean time to reach 50% of Cmax within one hour of administration, more preferably within 30 minutes. The time to 50% of Cmax is less than one hour and 50% Cmax is maintained for at least 5.0 hours. The time after administration of the dosage form when the maximum plasma concentration is d (Tmax) is between 30 minutes and 7 hours. Preferably, the LD plasma level is ined at or above 50% of Cmax for at least 5.5 hours, more preferably, for at least 6.0 hours, even more preferably, for at least 6.5 hours, and most preferably for at least 7.0 hours.

In one embodiment, the formulations of the invention may have a ratio of said Cmax to the mass of levodopa or levodopa equivalence. The concentration may be ed in units of ng/mL, to the mass of levodopa or levodopa equivalence in the formulation, where said mass is measured in mg, of between 2:1 and 6:1. The ratio may be n 2.521 and 55:], preferably, greater than or equal to about 3:1.

The combination of immediate release components and controlled e components of the invention provide the near infusion-like profile as evident from the plateau in the LD plasma profile (see, e.g., Fig. 5). The LD Cmax itself is not clinically relevant. What is clinically relevant is the time to reach a therapeutic level of LD (e.g., an LD level of 50% Cmax) and the time maintained at or above the therapeutic level (e.g., 50% Cmax). The short time to reach a therapeutic LD level is associated with a faster "on" time for PD patients, whereas the prolonged period at or above therapeutic levels es the desired steady "infusion-like" profile.

It is an advantage of the present invention to provide a sustained levodopa plasma concentration for a duration greater than 5 hrs and a more consistent duration with t coefficient of variation (CV) of mean duration of levodopa plasma concentrations > 50% Cm,X of less than %, preferrably less than 30%.

The skilled artisan will iate that daily dosages having an amount of active agent sufficient or effective to treat diseases associated with reduced or impaired dopamine levels may generally contain from about 25 mg to about 6000 mg of levodopa or levodopa equivalence dose in ation with from about 5 mg to about 1500 mg of carbidopa.

Dosage forms may contain 25-750 mg of pa or levodopa equivalence. Further, dosage forms may contain carbidopa ranging from 25-300 mg. For example, the controlled e oral solid formulation of the invention may comprise from about 25 mg to about 1000 mg levodopa or pa equivalence. Further, the controlled release oral solid formulation of the invention may comprise from about 10 mg to about 300 mg carbidopa. Further still, the controlled release oral solid ation of the invention may comprise from about 10 mg to about 150 mg carbidopa.

By way of example, the total daily dose of levodopa from the formulations of the ion may be less than about 2500 mg. For e, the total daily levodopa dose may be between 800 mg to 2500 mg. In a further example, the total daily levodopa dose may be about 855 mg, 1140 mg, 1170 mg, 1305 mg, 1755 mg, 2205 mg, or 2340 mg. In another embodiment, the total daily carbidopa dose may be about 292.5 mg.

The dosing frequency may vary, depending on the need of the subject. For example, the dosing frequency of the formulations of the invention may be three times a day. In another example, the dosing frequency may be a maximum of five times a day.

Actual dosage levels of active ingredient in the compositions of the present invention may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a ular composition. The ations of the invention may be administered as a single dose, or may se of a number of smaller doses to be administered or consumed within a short period of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined using known practices. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person stering or supervising the administration of the formulations of the invention, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the d compositions.

Optimally, after administration to a patient suffering from a condition associated with reduced or impaired ne levels, a pharmaceutical formulation of the invention releases levodopa into the plasma of the patient at a steady or near constant level without significant decrease or fluctuation for an extended amount of time, thereby reducing motor fluctuations.

The invention also provides s for treating a subject with Parkinson’s disease or primary Parkinsonism. The method comprises administering to the subject an effective amount of any of the controlled release oral solid formulations of the invention to treat Parkinson’s disease or y Parkinsonism. In accordance with the practice of this invention, the subject may be a human.

EXAMPLES EXAMPLE 1 1. Development of LDEE-S beads for IPX203-B12-01 Development of core LDEE-S beads ation of Core Beads Required amounts of LDEE-S-Dihydrate, Microcrystalline Cellulose, Fumaric acid, Povidone K29-32, ethanol and Purified Water were dispensed. The alcohol and the d water were charged into a container and stirred using a stir bar. Povidone was slowly added into the l/water mixed solvent. Mixing continued until the Povidone was tely dissolved, and the spray pump was calibrated to the target granulation spray rate.

LDEE-S-Dihydrate, Microcrystalline Cellulose, Fumaric acid, and Povidone were charged into a high shear granulator and dry mixed for 1-5 minutes at impeller speed of 75 rpm and chopper speed of 1000 rpm. The Povidone solution was sprayed into the granulation bowl and granulation continued with either ethanol or water as necessary. The granules were wet mixed for 2 minutes, after the spraying was completed.

The wet granules were extruded using the extruder (MG 55 Multi Granulator) equipped with a 0.8 mm hole size screen at er speed of 55 rpm. The extrudates were collected into double polyethylene lined bags. The ted extrudate was d and adjusted in the quantities ranging from 170-210 g per load.

One load of the weighed extrudate was charge into a spheronizer equipped with a 3mm cross hatch disc. The extrudate was spheronized at a spheronisation speed of 1400 rpm for 1-10 mins.

The spheronized beads were discharge into double polyethylene bags. The remaining extrudate were spheronized until all the double polyethylene-lined bags are completed.

The wet beads were dried in a fluid bed drier (Glatt GPCP-l) at an Inlet temperature of 35 i °C until Loss on Drying was not more than 5.0%. The steps above were repeated until additional sub loads had been processed.

The dried beads were passed through a mechanical sieve (Vibroscreen) equipped with a 24—MG mesh screen at the bottom, 18-MG mesh screen in the middle, and 16-MG mesh screen at the top. The beads that remained on 18-US mesh and 24-MG mesh screens were collected into double polyethylene lined bags.

Muco-adhesive/Rate—controlling Sub-layer Coating The batch yield was ined. The required amounts of Amino Methacrylate Copolymer (Eudragit® E100) and Talc were calculated and dispensed. Purified Water, Acetone and Isopropyl Alcohol were dispensed into a ess steel container and stirred using stir bar.

While stirring, Amino Methacrylate mer (Eudragit® E100) was slowly added into the vortex of the mixed solvent. Mixing continued until the copolymer completely dissolved. While stirring, Talc was slowly disperse into the vortex of the solution. Mixing continued until the material was completely dispersed. The suspension was continually stirred throughout the g s.

The spray pump was calibrated to the target coating spray rate of the altic pump using the suspension solution above. The core beads were coated using Glatt GPCG l equipped with a Wurster insert at Inlet air temperature of 35 i 10°C, Atomization air pressure of 1.0 — 2.0 bars and Wurster partition height of 15-30 mm. During coating, the inlet air temperature, exhaust flap, and spray rate were ed to maintain the exhaust air temperature between 30 i 5°C.

After the target amount of coating solution was sprayed, the coated beads were dried at an inlet air temperature of 40 i 10°C for 90 minutes. The dried beads were passed through a mechanical sieve (Vibroscreen) ed with a pan at the bottom, l4-MG mesh screen in the middle, and 12-MG mesh screen at the top. The beads that remained in the pan and 14-MG mesh screens were collected into double polyethylene lined bags.

The batch yield was determined. Based on the batch yield, the ed amounts of yl Citrate, Talc and an enteric copolymer, either Methacrylic Acid Copolymer, Type A, (Eudragit® L100)/Methacrylic Acid mer, Type B, (Eudragit® S) at 1/2 weight ratio for IPX203- C0006 or Eudragit® L100-55 for IPX203-C0004 and IPX203-C0005 were calculated and dispensed. Acetone and Isopropyl Alcohol for IPX203-C0006 or Acetone, Isopropyl Alcohol and purified water for IPX203-C0004 and IPX203-C0005 were dispensed into a stainless steel container and stirred using stir bar. While stirring, the enteric copolymer and yl Citrate were added slowly into the vortex of the mixed solvent. Mixing continued until the copolymer was completely dissolved.

While stirring, Talc was added slowly into the vortex of the solution. Mixing continued until the material was completely dispersed. The suspension was continually stirred throughout the coating process. The spray pump was calibrated to the target coating spray rate of the peristaltic pump using the suspension solution.

Eudragit® E-coated beads were coated with the enteric composition using Glatt GPCG 1 equipped with a Wurster insert at Inlet air temperature of 35 i 10°C, Atomization air re of 1.0 — 2.0 bars and Wurster partition height of m. During coating, the inlet air temperature, exhaust flap, and spray rate were adjusted to maintain the exhaust air temperature between 30 i 5°C.

After the target amount of g solution was d, the enteric-coated beads were dried at an inlet air temperature of 40 i 10°C for 120 minutes. The dried beads were passed through a mechanical sieve (Vibroscreen) equipped with a pan at the bottom, 14-MG mesh screen in the middle, and 12-MG mesh screen at the top. The beads that remained in the pan and 14-MG mesh screens were collected into double polyethylene lined bags.

Encapsulation The batch yield was determined. Based on the batch yield, the required amounts of the enteric coated beads (also referred to herein as beads having an outer enteric coating polymer layer) and talc were calculated and dispensed. The Enteric Coated Beads and Talc were placed in an appropriated sized plastic bag and were manually blended by shaking the plastic bag with the beads and Talc for 10 s. The blend was encapsulated with 00 size gelatin capsules, using MG Flexalab Encapsulator at the target fill weight of 482mg, 537mg and 472 mg for - C0004, IPX203-C0005 and IPX203-C0006 tively, so that the target LDEE dose/2 capsules was 228mg, equivalent to LD dose of 200mg.

Rationale for components and coatings in formulation The core bead formulation was developed utilizing microcrystalline cellulose (MCC) as filler since the wetted MCC has the d rheological properties, cohesiveness, and plasticity to yield strong beads. An MCC level at 30% was selected and it was found to provide beads with acceptable sphericity and support a robust manufacturing process. Because LDEE-S is more stable in acidic environment, in order to reduce the LDEE degradation inside the beads during the long release duration, a 5% c acid is added in the formulation to lower the microenvironment pH. An extra binder povidone at 1% level is also added to the formulation with the intent to provide a more robust extrusion process. The ution profile of the core beads is fast, with the te e within 30 min, as measured in a USP tus l with basket speed of 75 rpm in pH 7 phosphate buffer.

To control the release of LDEE-S, the core LDEE-S beads are coated with different release polymers. Eudragit® E100 is swellable and permeable above pH 5. It is used as an inner coating to slowly release drug at intestinal pH. As such, the use of Eudragit® E100 coating results in a lled release of LDEE-S. Furthermore, to protect the Eudragit® E layer as well as to direct the release of LDEE-S to the more alkaline region (i.e., intestinal region and not the stomach region), an enteric coating is applied as an outer coat.

Develogment 0: Eudragit® E100 coated LDEE-S beads Prototype ations with different Eudragit® E100 coating content were ped and evaluated based on the in vitro dissolution profiles in pH 7 phosphate buffer solution. Analysis of the effect of coating ess on LDEE e indicates that increasing the coating level decreases the in vitro release of active pharmaceutical ingredient (API) and although polymer has the sustained-release effect, its permeability is relatively large, thus a thick coating is required to prepare formulations with longer release duration (T90 > 5 hr).

In the final polymer coating formulation, talc was also added as a lubricant to facilitate the fluid bed coating process at a ratio of Eudragit® E100/talc at 10/1.

Develogment of enteric coating 01Eudragit® E100 coated LDEE-S beads Initially, the enteric coating chosen at the development stage was Eudragit® $100 and L100 at a ratio of 2:1, and the ratio among polymer and other components was Eudragit® polymer: triethyl citrate (TEC): Talc ratio of 7:2: 1.

The in vitro ution s of ype c coated beads (already coated with Eudragit® E100 at a coating level of 65% w/w) coated with different levels of enteric film. The results showed that a g level of 23% provides an adequate acid protection with less than 5% LDEE released in acidic medium. Further, with less enteric coating level (5 10%), there is ~ 20% LDEE released in acidic medium, and no significant difference in drug release profiles when coated at 5% or 10%.

When the dissolution was done in pH 1 solution for 2 hr and then switch to pH 7 buffer, even with outer enteric coating layer, the permeability of inner Eudragit® E100 layer may se after 2 hr in pH 1.0 medium, since T90 was around 6.5 hr in pH 7 buffer for Eudragit® E coated beads but shortened to ~ 4.5 hr in pH 7 buffer for enteric coated beads after switch over of dissolution medium.

For IPX203-B12-01, enteric polymer coatings that can dissolve at lower pH were also developed, in which Eudragit® L100-55 (dissolve above pH 5.5) was used d of Eudragit® S100 and L100. The ratio among polymer and other ents in the coating formulation was Eudragit® 5: TEC: Talc of6:1 :3.

Dissolution medium QH eZZect on LDEE release Zrom enteric coated beads The effect of pH on the release of LDEE from the LDEE-S core beads coated with Eudragit® E (65% w/w) and enteric coat (Eudragit® S100/L100 at 2/1) was conducted at pH 1.0 solution for 2 hr and then switch to pH 6.6, 6.8, 7.0 buffer solutions.

The results indicated that with less enteric layer coated (10%) or thinner enteric outer coating, drug release was earlier, and conversely, with a thicker enteric outer coating (23%), drug release was d at all pH’s compared to the thinner enteric outer coated LDEE-S core beads.

Further, with less or thinner enteric outer coating, there was no effect on drug release when pH changed from 6.6 to 6.8, and the drug release was slower when pH changed to 7.0. However, when thicker c coat layer was applied (23%), there was no effect on drug release when pH d from 6.8 to 7.0, but the drug release was much slower when pH changed to 6.6.

Additionally, the pH value in ution medium can affect drug release s through its effect on both enteric coating layer dissolution and Eudragit® E layer permeability. When enteric coat layer is thin, its dissolution is fast and the pH effect on Eudragit® E is more a rate-limiting factor. Since it® E permeability decreases with increasing pH, slower release was observed in pH 7.0 medium. However, with a thicker enteric coat, the dissolution of the enteric layer is much slower and become a rate-limiting step. With a combination of Eudragit® S100 and L100 at a ratio of 2/1, its dissolution at lower pH (pH 6.6) is much slower than at pH above 6.8.

Thus the drug release is much slower in pH 6.6 medium with a thicker enteric coating.

Final formulation of LDEE-S beads (or IPX203-Bl2-01 The test formulations for IPX203-Bl2-01 are ized in Table 1. The composition of the formulations of LDEE-S beads (IPX203-C0004, IPX203-C0005 and IPX203-C0006) is summarized in Table 2. Figure 2 shows the in vitro dissolution profiles of those formulations.

IPX203-C0006 was coated with 10% (w/w) enteric coat git® S100/L100 at 2/ 1), which released ~ 20% drug in the first 2 hr in pH 1.0 solution. After dissolution medium switch to pH 7 buffer, drug was controlled released over a period T90 ~ 3hr. A better acidic protection for IPX203-0004 and 1PX203-C0005 was observed due to their thicker enteric coat layer (25% w/w, Eudragit® 5). Formulations IPX203-C0004 has a r Eudragit® E100 layer of g compared to IPX203-C0005, and has T90 ~ 3hr in pH 7 buffer. IPX203-C0005 provided longer release duration (T90 ~ 5hr in pH 7 buffer).

Table 1: Test ations of IPX203 Prototype Capsule in Single Dose Relative Bioavailability (BA) Studies IPX203-B12-01*.

Test Study LDEE (mg/2 capsules) Formulation IPX203-C0004 IPX203-C0005 1px203- IPX203-C0006 B 12-01 dopa was dosed as commercial product n® 25 mg/tablet with the dosing regimen: 25 mg at T=0 and 6.25mg (1/4 tablet) at T=4 hr.

Table 2: Composition of Final Formulation of LDEE-S Beads for IPX203-B12-01 Composition (w/w%) Ingredient - IPX203- IPX203- C0004 C0005 C0006 Levodopa Ethyl Ester Succinate, 31.76 28.50 32.39 Dihydrate Microcrystalline Cellulose, NF 14.66 13.15 14.95 Fumaric Acid, NF 2.44 2.19 2.49 Povidone, USP (Plasdone, K- 0.49 0.44 0.50 29/32) Amino Methacrylate Copolymer, 27.14 31.74 36.08 NF (Eudragit® E100) Methacrylic Acid Copolymer, "‘88 "'88 " Type c, NF (Eudragit® L100-55) Methacrylic Acid Copolymer, __ __ 2 10 Type A, NF (Eudragit® L 100) ‘ Methacrylic Acid Copolymer, __ __ 4 20 Type B, NF (Eudragit® s 100) ‘ Composition (w/w%) Ingredient - IPX203- IPX203- C0004 C0005 C0006 1'98 1'98 1'80 Triethyl Citrate, NF Talc, USP 9.64 10.12 5.50 Total 100.0 100.0 100.0 II. In vivo results of -BlZ-0l The in vivo performance of the prepared formulations IPX203-C0004, IPX203-C0005 and IPX203-C0006 has been evaluated in healthy volunteers in a relative bioavailability analysis of IPX203-B12-01. The study design was a randomized, single-dose, crossover study in 15 normal, healthy volunteers under fasting ion.

Figure 3 shows the plasma profile for the multi—particulate formulations -C0004, IPX203-C0005 and IPX203-C0006 in comparison with Sinemet® CR. All the IPX 203 multi- particulate formulations comprise Eudragit® E coating. The relative bioavailability parameters are provided in Table 3. Comparison of the LD plasma concentration profile of the tested formulations to the reference product Sinernet® CR indicate that both IPX203-C0005 and IPX203-C0006 showed sufficient AUC but more extended effect than Sinernet® CR. Further, the difference of Tmax between —C0004 and -C0005 ponds well with their ence in in vitro dissolution profiles. Also, although the in vitro release profiles for IPX203- C0004 and IPX203—C0006 showed similar T90 (~3hr) after switch to pH 7 buffer, IPX203- C0006 showed more delayed effect in viva. Additionally, the results show that IPX203-C0006 has Cmax and AUC comparable to those of Sinemet® CR.

Table 3: Relative LD Bioavailability Parameters of IPX203 es Tested in Bioavailability Analysis of IPX203-B12—01 (n= 15).

Test CD-LDEE % Ratio of Duration LD Formulation (mg) a Test/Sinemet® CR Concentration>50% LDEE 1 CD AUC0_000_ Cmax Cmax (h)b IPX203- C0004 228 31.25 C0005 3.15 325 C0006 325 3.25 a LDEE 228 mg is equivalent to LD 200 mg. 'Sineme1t04CR tablet tmax—— 2.5 hr EXAMPLE 2 1. Processing procedures for Levodopa ethyl ester succinate (LDEE-S)/Carbidopa (CD) es for IPX203 B13-01 Preparation of Core Beads for IPX203-C0012, -C0013 and IPX203-C0016 Required amounts of LDEE-S-Dihydrate, Microcrystalline Cellulose, Fumaric acid, Povidone K29-32, ethanol and Purified Water were dispensed. The alcohol and the purified water were charged into a container and stirred using stir bar, Povidone was slowly added into the ethanol/water mixed solvent. Mixing continued until the Povidone was completely dissolved, and the spray pump was calibrated to the target ation spray rate.

LDEE-S-Dihydrate, Microcrystalline Cellulose, c acid, and Povidone were charged into a high shear ator and dry mixed for 1-5 minutes at impeller speed of 75 rpm and chopper speed of 1000 rpm. The Povidone solution was d into the granulation bowl and granulation continued with either ethanol or water as necessary. The es were wet mixed for 2 minutes, after the spraying was completed.

The wet granules were extruded using the extruder (MG 55 Multi Granulator) equipped with a 0.8 mm hole size screen at extruder speed of 55 rpm. The extrudates were collected into double polyethylene-lined bags. The collected extrudate was weighed and adjusted in the quantities ranging from 180-240 g per load.

One load of the weighed extrudate was charge into a spheronizer equipped with a 3mm cross hatch disc. The extrudate was spheronized at a spheronisation speed of 1400 rpm for 1-10 mins.

The nized beads were discharge into double PE bags. The remaining extrudate were spheronized until all the double hylene-lined bags are completed.

The wet beads were dried in a fluid bed drier (Glatt GPCP-l) at an Inlet temperature of 35 i °C until Loss on Drying is not more than 5.0%. The steps above were repeated until additional sub loads have been processed.

The dried beads were passed through a mechanical sieve (Vibroscreen) equipped with a 24—MG mesh screen at the bottom, 18-MG mesh screen in the middle, and 16-MG mesh screen at the top. The beads that remained on 18-US mesh and 24-MG mesh screens were ted into double polyethylene-lined bags.

Rate-controlling membrane coating for IPX203-C0012 and IPX203-C0013 IPX203-C0012 Beads Batch yield was determined. Based on the batch yield, the required amounts of Cellulose Acetate (CA) and Polyethylene Glycol 3350 (PEG3350) at weight ratio (CA/PEG) of 95/5 and Acetone/Purified Water (95/5 w/w) were calculated and dispensed. The Acetone was dispensed into a stainless steel container and d using stir bar. While stirring, ose Acetate (CA) was added slowly into the vortex of the solvent and mixing was continued until the copolymer completely dissolved.

The Purified Water was dispensed into another stainless steel container and was stirred using a stir bar. While stirring, Polyethylene Glycol 3350 (PEG3350) was added slowly into the vortex of the purified water solvent and mixing was ued until the copolymer completely dissolved. While ng, PEG solution was added quickly into the CA solution and mixing was continued until the solution was clear. Spray pump was calibrated to the target coating spray rate of the peristaltic pump using the clear solution and the core beads were coated using Glatt GPCG 1 equipped with a Wurster insert at Inlet air temperature of 33 i 10°C, Atomization air pressure of 1.0 — 2.0 bars and Wurster partition height of 20-40 mm. During coating, the inlet air temperature, exhaust flap, and spray rate were ed to maintain the exhaust air temperature between 30 i 5°C.

After the target amount of coating solution was sprayed, the coated beads were dried at an inlet air ature of 35 i 10°C for 40 - 60 minutes. The dried beads were passed through a mechanical sieve (Vibroscreen) equipped with a pan at the bottom and a 14—MG mesh screen at the top. and collected the beads that passed h the 14-MG mesh screen were collected in double polyethylene-lined bags. Oversized beads that remained on the 14-MG mesh screen were rej ected.

IPX203-C0013 Beads The procedure for preparing the coating solution and the coating conditions are identical to those for 1PX203-C0012 coating. However, the ontrolling polymer is Cellulose Acetate (CA), and the solvent is Acetone.

Muco-adhesive Coating for IPX203-C0012, IPX203-C0013 and IPX203-C0016 The batch yield was determined. The required amounts of Amino Methacrylate Copolymer (Eudragit® E100) and Talc were calculated and dispensed at weight ratio of 91/9. Purified Water, Acetone and Isopropyl Alcohol were dispensed at weight ratio of 12/68/20 into a stainless steel container and stirred using stir bar. While stirring, Amino rylate Copolymer (Eudragit® E100) was slowly added into the vortex of the mixed t. Mixing continued until the copolymer tely dissolved. While stirring, Talc was slowly dispersed into the vortex of the solution. Mixing continued until the material was completely dispersed. The suspension was ually stirred throughout the coating s.

The spray pump was calibrated to the target coating spray rate of the altic pump using the suspension solution above. The rate-controlling membrane-coated beads for IPX203—C0012 and IPX203-C0013, or the core beads for IPX203-C0016 were coated with the muco-adhesive coating composition Glatt GPCG 1 ed with a Wurster insert at Inlet air ature of 35 i 10°C, Atomization air pressure of 1.0 — 2.0 bars and Wurster partition height of 15-40mm.

During coating, the inlet air temperature, exhaust flap, and spray rate were adjusted to maintain the exhaust air temperature between 30 i 10°C.

After the target amount of coating solution was sprayed, the coated beads were dried at an inlet air temperature of 40 i 10°C for 60-120 minutes. The dried beads were passed through a mechanical sieve (Vibroscreen) equipped with a pan at the bottom and a 14—MG mesh screen at the top. The beads that passed through 14-MG mesh screen were collected into double polyethylene-lined bags and the zed beads that remained on the 14-MG mesh screen were rejected.

Enteric Coating for IPX203-C0012, IPX203-C0013 and IPX203-C0016 The batch yield was determined. Based on the batch yield, the required amounts of yl Citrate, Talc and an enteric copolymer, either Methacrylic Acid mer, Type A, (Eudragit® L100)/Methacrylic Acid Copolymer, Type B, (Eudragit® S) at 1/2 weight ratio for IPX203- C0012 and IPX203-C0016 or Eudragit® L100 for IPX203-C00013 were calculated and dispensed. Acetone and Isopropyl Alcohol were dispensed at weight ratio of 40/60 into a stainless steel container and stirred using stir bar. While stirring, the enteric copolymer and Triethyl e (TEC) were added slowly into the vortex of the mixed solvent and mixing was continued until the c copolymer tely dissolved. While stirring, Talc was slowly dispensed into the vortex of the solution and mixing was continued until the material was completely dispersed. The suspension was continuously stirred throughout the coating process.

The weight ratio of enteric mer/TEC/Talc was 70/20/10.

The spray pump was calibrated to the target coating spray rate of the peristaltic pump using the solution, and the Eudragit® E-coated beads were coated using Glatt GPCG l ed with a Wurster insert at Inlet air temperature of 35 i 10°C, Atomization air pressure of 1.0 — 2.0 bars and Wurster partition height of 15-30mm. During coating, the inlet air temperature, exhaust flap, and spray rate were adjusted to maintain the exhaust air temperature between 30 i 5°C. After the target amount of coating solution was sprayed, the coated beads were dried at an inlet air temperature of 40 i 10°C for 60 - 120 minutes and the dried beads were passed h a mechanical sieve (Vibroscreen) equipped with a pan at the bottom and a 14—MG mesh screen at the top. The beads that passed through 14-MG mesh screen were collected into double polyethylene-lined bags, and oversized beads that remained on the 14-MG mesh screen were rej ected.

Immediate Release Granules (CD/LDEE-S) The required amount of 27% Carbidopa USP, 49.9% pa Ethyl Ester Succinate-Dihydrate, 12.2% Dibasic Calcium Phosphate Anhydrous, 7.0% Hydroxypropyl Cellulose (Klucel-EXF), and 2.0% Croscarmellose Sodium, (Ac-Di-Sol) were dispensed and charged into the granulation bowl of a high shear granulator. The components were dry-mixed for 1 — 3 mins at impeller speed between 150 — 250 rpm and Chopper Speed of 1000 rpm. Purified Water was sprayed at a desired flow rate into the granulation bowl until consistent wet mass was d. The dry blend weight ratio was between 0.20 - 0.40. The granules were wet- mixed for onal 1 — 5 minutes, after the spraying was completed. The wet granules were d into the top spray product bowl of GPCGl and dried using GPCG 1 at inlet air temperature of 50°C until the LOD is less than 6.0%. Inlet air flow was adjusted to maintain the fluidization of the wet granules.

The dried granules from the bowl were transferred into clean, double polyethylene-lined containers, and the granules were passed through the Fitzmill equipped with a stainless steel #24 mesh screen at Knife Mode and speed of 2000 — 3000 rpm. The required amount of Talc was calculated based on the weight of the milled granules and 2% Talc of the immediate release granules. The milled granules and Talc were charged into Pharrnatech Miniblender and blended for 5 s. The blend was discharged into clean, double polyethylene-lined containers.

Encapsulation The batch yield was determined. Based on the batch yield, the required s of the Enteric Coated Beads and Talc (at weight ratio of 99/1) were ated and dispensed. The Enteric Coated Beads and Talc were charged into an appropriated sized plastic bag and manually blended by shaking the plastic bag for 10 minutes. The blend and Immediate Release Granules (CD/LDEE-S) were encapsulated with 00 size gelatin capsules, using MG Flexalab Encapsulator. For -C0016, the blend was encapsulated but the Immediate e Granules (CD/LDEE-S) were not. Table 4 shows the target fill weight for IPX203-C0012, IPX203-C0013 and IPX203-C0016 and Table 5 lists the composition of IPX203-C0012, IPX203-C0013 and —C0016.

Table 4: Target Fill Weight of IPX203-C0012, IPX203-C0013 and IPX203-C0016 Target Fill Weight (mg/Capsule) Enteric-coated Beads Immediate release Granules IPX203-C0012 IPX203-C0013 IPX203-C0016 Table 5: Formulation Composition of IPX203—C0012, IPX203-C0013 and IPX203-C0016 IPX203-C0012 IPX203-C0013 IPX203-C0016 Ingredient Amount Amount Amount (mg/capsule) (w/w) (mg/capsule) (W/w) (mg/capsule) (w/w) L‘FVOdOPa Ethyl Esra m’ 306.4 52.0 306.4 50.1 81.8 32.4 D1h drate Microcrystalline Cellulose, NF 3 7.7 14.9 Amino Methacrylate Copolymer, NF git® E100) Fumaric Acid NF (Fine Granules) 2.7 15.9 2.6 Talc, USP 13.1 2.2 15.2 2.5 Methacrylic Acid Copolymer, Type B NF (Eudragit® SlOO) ----_A,NF(Eudragit®L100) ———m-— povidonwsp400011613932) 1.3 0.5 c Calcium Phosphate, Anh drous ---— Hydroxypropyl Cellulose, NF 14.0 2.4 14.0 2.3 Klucel-EXF IPX203-C0012 IPX203-C0013 IPX203-C0016 Ingredient Amount Amount Amount (mg/capsule) (mg/capsule) (mg/capsule) Croscarmellose Sodium, NF (Ac- Di-Sol) *54mg of Carbidopa, USPIS equivalent to 50mg of Carbidopa anhydrate. **306 mg of LevodOpa Ethyl Ester Succinate- Dihydrate is equivalent to 228 mg of LeVOdopa Ethyl Ester and to 200 mg LeVOdopa.

II. Processing procedures for Manufacturing Entacapone Capsules for IPX203 Bl3-01 Preparation of Core Beads for IPX203-C0014 Capsule The required amount of Entacapone, rystalline Cellulose, Povidone K29-32 and Purified Water were dispensed. The purified water was charged into a container and stirred using a stir bar, the Povidone (1.0% of the solid blend) slowly added into the water at Povidone/Water weight ratio of 6/ 133.2 and mixing continued until the Povidone was completely dissolved. The spray pump was calibrated to the target granulation spray rate (23 , and 84.0% Entacapone and 15.0% rystalline Cellulose were charged into a high shear granulator and were dry mixed for 1-5 minutes at er speed of 200 - 300 rpm and r speed of 1400 - 1600 rpm.

The solution was sprayed into the ation bowl until all the solution was sprayed, and granulation was continued with Purified Water as necessary. The granules were wet—mixed for 2 minutes, after the spraying was completed. Then the wet granules were ed using the extruder (MG 55 Multi Granulator) equipped with a 0.8 mm hole size screen at extruder speed of 50 rpm. The extrudates were collected into double polyethylene-lined bags. Further, the collected extrudate were weighed and adjusted in the quantities ranging from 200-210 g per load.

One load of the weighed extrudate was charged into a spheronizer ed with a 3 mm cross hatch disc and spheronized at spheronisation speed of 1000 rpm for 1—2 mins. The spheronized beads were rged into double PE bags. The wet beads were dried in a fluid bed drier (Glatt GPCP-l) at an Inlet temperature of 35 i 10°C until Loss on Drying was not more than 5.0%.

The dried beads were passed through a mechanical sieve (Vibroscreen) equipped with a pan at the bottom, 24-MG mesh screen in the middle, and 16-MG mesh screen at the top. The beads that were retained on 24-MG mesh were collected into double polyethylene-lined bags, and the beads on the pan and l6-MG mesh screen were ed. c g for IPX203-C0014 The required amounts of Triethyl Citrate, Talc, Methacrylic Acid Copolymer Dispersion, NF (Eudragit® L30D-55) and Water were calculated and dispensed. The Purified Water was dispensed into a ess steel container and stirred using a stir bar. While stirring, Triethyl Citrate (TEC), Talc and the c copolymer sion were slowly added into the vortex of Purified Water, and mixing was continued until the material was completely dispersed. The suspension was stirred hout the coating process. The weight ratio of enteric copolymer/Talc/TEC was 63.0/30.7/6.3.

The spray pump was calibrated to the target coating spray rate of the peristaltic pump using the solution, and the core beads were coated using Glatt GPCG 1 equipped with a Wurster insert at Inlet air temperature of 35 i 10°C, Atomization air pressure of 1.0 — 2.0 bars and Wurster partition height of 15-30mm. During coating, the inlet air temperature, exhaust flap, and spray rate were ed to maintain the exhaust air temperature between 30 i 5°C.

After the target amount of coating solution was sprayed, the coated beads were dried at an inlet air temperature of 30 i 10°C until the moisture level was below 5%. The dried beads were passed through a mechanical sieve (Vibroscreen) equipped with a pan at the bottom and a 12- MG mesh screen at the top. The beads that passed through the 12—MG mesh screen were collected into double polyethylene-lined bags, and the oversized beads that remained on the 12- MG mesh screen were rejected.

Encapsulation for IPX203-C0014 The required amounts of the Enteric Coated Beads and Talc (at weight ratio of 99/1) were calculated and sed, and the Enteric Coated Beads and Talc were charged into an appropriate sized plastic bag. The beads and Talc were manually blended by shaking the plastic bag for at least 5 minutes. The blend was encapsulated with 00 size gelatin capsules, using MG Flexalab Encapsulator. The target fill weight was 505mg. Table 6 lists the composition of IPX203-C0014.

Table 6: ation Composition of Entacapone Capsule (IPX203-C0014) Ingredient % (W/W) (mg/12:55:19 Entacapone 400.0 M‘icrocrystallme Cellulose,‘ NF 1 4.1 714 (AVicel PH-101) Povidone, USP one, K-29/32) 1.0 4.8 Methacrylic Acid Copolyrner Dispersion, 3 0' NF git® L30D-55) Talc, USP Triethyl Citrate, NF 100-0 5050 III. In Vitro e Profiles of Final LDEE-S-Dihydrate Dosage Forms for Pharmacokinetic (IPX203-B13-01) Table 7 lists the test regimen for the S-arm cross—over PK analysis (IPX203 B13-01).

Table 7: Dosing Regimen for IPX203 B13-01 Reimen Dosa_eForm CD/casule LD/casule Entacannone/casule Re _imen A IPX203-C0012 200m_* N/A IPX203-C0012 + IPX203- Regimen B C0014 200mg"< 400mg IPX203-C0013 + IPX203- Regimen C C0014 200mg"< 400mg -C0013 + IPX203- Reimen D C0016 + -C0014 255.6m"< 400m: Re_imen E Stalevo® 150m; 37.5mg 150m: 200m; *LD equivalent dose based on total amount of LDEE-S-Dihydrate1n the formulation The in vitro release profiles of the regimen A-D were measured using USP 1 ution method at agitation speed of 75 rpm in Simulated Gastric Fluid (pH 1.0) for first 2 hrs and followed by in Simulated Intestinal Fluid (pH 7.0). Figure 4 shows the release profiles of these test regimens.

The T90 (time duration for 90% of LDEE-S-Dihydrate released) is approximately 3hr, 4.5h and 6hrs for Regimen B, C and D, respectively. The LDEE-S-Dihydrate e (C0012) was used in both Regimen A and Regimen B.

IV. In Vivo tion (IPX203-Bl3—01) The in viva performance of the prepared dosage forms IPX203-C00012, IPX203-C00013 and IPX203-C00014 and IPX203-C0016 has been evaluated in 12 healthy volunteers under fasted condition in a relative bioavailability analysis of IPX203-Bl3-01. The four test treatments were: Regimen A: C0012 Regimen B: C0012+C0014 Regimen C: C0013+C0014 Regimen D: C0013+C0016+C0014 n E: Stalevo 150 (Reference) Where C0012 ned 228mg LDEE ER beads with T90~3 hrs and 50mg CD C0013 contained 228mg LDEE ER beads with T90~5 hrs and 50mg CD C0014 contained 400 mg enteric-coated entacapone C0016 contained 77 mg LDEE ER beads with T90~12 hrs Figure 5 shows the levodopa plasma profiles for all these regimens. Based on the in vivo plasma profiles depicted in Figure 5, the in vivo plasma profiles correlates well with the in vitro dissolution s depicted in Figure 4. Figure 5 demonstrates that Regimen D has the longest therapeutic coverage and a constant plasma profile.

EXAMPLE 3 Prepared Carbidopa Beads The core beads of CD beads were ated based on the granulation-extrusion-spheronisation technology. 30 w/w% MCC was used in the core seed formulation. No controlled release coating layer was needed. CD core beads was c-coated with the enteric coating formulation comprising EUDRAGIT® 8100 and L100 at a ratio of 2:1. The enteric coating level was 5%.

Table 8 ized the composition of final formulation of CD beads.

Table 8: Composition of Formulation of CD Beads Ingredient Composition (w/W%) Carbidopa 66.44 Microcrystalline Cellulose, NF 28.47 Methacrylic Acid Copolymer, Type A, 1'14 NF (Eudragit® L 100) Methacrylic Acid Copolymer, Type B, 2'35 NF (Eudragit® s 100) Triethyl Citrate, NF 1.00 Talc, USP 0.60 Total 100.0 EXAMPLE 4 The preparation procedure in Example 1 was repeated in this example, except the coating compositions. The core beads were coated first with either ose acetate polymer or a combination of Hypromellose and ethylcellulose. The coated beads were fiarther coated with chitosan or polycarbophil or it® E100. After the second layer coating, the beads were further coated with Eudragit® L100-55. Table 9 shows the composition of four formulations -C0007, IPX203—C0008, IPX203-C0009 and IPX203—C0010.

Table 9: Composition of Formulations of LDEE-S Beads Using Chitosan or Polycarbophil as Muco-adhesive rs Composition (w/w%) Ingredient IPX203- IPX203- IPX203- IPX203- C0007 C0008 C0009 C0010 Levodopa Ethyl Ester ate, Dihydrate 39.45 45.18 31.14 45.30 Microcrystalline Cellulose, NF 18.21 20.85 14.37 20.91 Fumaric Acid, NF 3.03 3.48 2.40 3.48 ition (w/w%) Ingredient IPX203- IPX203- IPX203- IPX203- C0007 C0008 C0009 C0010 Povidone, USP (Plasdone, K-29/32) 0.61 0.70 0.48 0.70 Hypromellose, Type 2910, USP 2'82 __ 2‘23 4'22 (Pharmacoat 606, 6cps) ellulose, NF (Ethocel, Standard-10 FP 11.28 __ 8.90 16.89 Premlum) Polycarbophil, USP (Noveon® AA-l) 3.77 —— —— 4.57 Cellulose Acetate, NF (CA10 NF) -- 4.21 -- -- Chitosan, NF (ChitoPharm® S) (Material __ 3 74 __ __ 178) ' Glacial Acetic Acid, USP -- 1.01 -- -- Amino Methacrylate Copolymer, NF (Eudragit® E 1 00) __ __ 17 86 __ Methacrylic Acid Copolymer, Type C, NF (Eudragit®L100-55) 11.91 11.91 11.90 1.76 Triethyl Citrate, NF (PG) 1.99 1.99 1.98 0.29 Talc, USP 6.94 6.93 8.73 1.87 Total 100.0 100.0 100.0 100.0 EXAMPLE 5 I. Formulations for -Bl4-01 Biostudy Four test formulations were evaluated in biostudy IPX203-B14-01. For IPX203-C0023, , and -C0025 formulations, there were two components in one capsule. For IPX203-C0026, there were three components in one capsule. Table 10 below showed the formulation information for each product, and Tables 11-13 showed formulation composition for each component.

Table 10: Test ations for Relative Bioavailability Study IPX203-B14-01 Test Component 1: IR Component II: Entacapone Formulation LD ER (ENT) Component CD (mg) Prototype/LD (mg) ENT (mg) IPX203-C0023 50 Prototype 1/280 IPX203-C0024 Prototype 111/280 IPX203-C0025 Prototype 11/280 1PX203C0026 Prototype 11/280 o® 100 CD/LD/ENT (25/100/200 mg) (Reference) Table 11: Composition of Prototype Formulations of IPX203 Component II Ingredient Composition (%) Prototype I Prototype 11 Prototype 111 Core bead CA/Copovidone layer (1St layer) Cellulose Acetate 1.89 1.85 done 2.31 2.27 Eudragit® E100 layer (2nd layer) Eudragit® E100 6.42 6.41 3.93 Talc 0.63 0.65 0.40 Enteric layer (3rd layer) —m-—— Table 12: Composition for ent I Formulation Carbidopa 35-86 7-00 3-00 1-00 100-0 Table 13: ation Composition for Entacapone ent Entacapone 73. 15 Microcrystalline Cellulose, NF 14 25 (Avicel PH-101) ' Povidone, USP (Plasdone, K-29/32) 1.90 Sodium Starch Glycolate 3.80 Sodium Lauryl Sulfate, NF 1.90 Methacrylic Acid Copolymer, Type A, 3 50' NF (Eudragit® L100) Talc, USP 0.50 Triethyl Citrate, NF 1.00 100.0 11. Processing procedures for Manufacturing IPX203 Capsules for IPX203 Bl4-01 Biostudy Preparation of Component I Povidone was dissolved in the purified water completely, and then the spray pump with pOVidone on was calibrated to the target granulation spray rate (40mL/min). CD, LD, Croscarmellose Sodium were charged into a high shear granulator and dry mixed for 1-5 minutes at impeller speed of 150 rpm and chopper speed of 1800 rpm. While continue mixing, the solution from Step 1 was sprayed into the ation bowl until all the solution is sprayed, and granulation was continued with purified water if necessary. The granules were collected, and the wet es were dried in a fluid bed drier (Glatt GPCP-l) at an Inlet temperature of 65°C until Loss on Drying is not more than 2.5%. The dried granules were passed through Fitzmill, and the al that passes h 30 mesh screen was collected. The collected material was blended with magnesium stearate.

Alternative Preparation of Carbidopa-Containing Granules or Beads In order to avoid potential opa degradation during wet granulation process, a dry granulation process by roller compaction was developed. In this formulation, shown in Table 14, the procedures are described as below.

Appropriate amount of carbidopa, levodopa, microcrystalline cellulose, and croscarmellose sodium were charged into a suitable mixer. The materials were dry mixed for an appropriate time and then charged into roller compactor at the controlled speed to start the roller compaction process. After roller tion, the collected compacted sheets of materials were blended with colloidal silicon dioxide for appropriate time, and then milled into dried granules using a suitable mill. Finally the milled granules were d with magnesium stearate in the blender.

Table 14: Composition for Levodopa/Carbidopa IR Granules by Dry ation Method Ingredient Composition (w/w%) Carbidopa 37-0 Levodopa 35-0 Microcrystalline Cellulose 20-0 Croscarmellose Sodium 4-0 Colloidal Silicon Dioxide 3-0 Magnesium Stearate 1.0 Total The amount and ratio of carbidopa and levodopa may be adjusted as desired, so long as performance of the dried granules or beads are not compromised.

Similarly, controlled release beads containing carbidopa may be prepared by a dry granulation method as provided h the incorporation of rate-controlling excipient, muco-adhesive polymer, and/or enteric coat. Entacapone—containing beads or granules may also be prepared by a dry granulation method.

Preparation of Component II Pregaration of Core Beads [0r Comgonent II Povidone was dissolved in the purified water completely, and then calibrate the spray pump with povidone on to the target granulation spray rate (18 mL/min). LD, Microcrystalline Cellulose, Mannitol and Sodium Lauryl Sulfate were charged into a high shear granulator and dry mixed for 1-5 minutes at impeller speed of 250 rpm and r speed of 1800 rpm. The solution from Step 1 was sprayed into the granulation bowl until all the solution is sprayed, and granulation with purified water was continued as necessary. The wet granules were extruded using the extruder (MG 55 Multi Granulator) equipped with a 0.9 mm hole size screen at extruder speed of 75 rpm. The extrudates were collected, and the ates so collected were charged into a spheronizer ed with a 3 mm cross hatch disc. The extrudates were spheronized at speed of 800 rpm for 1—2 mins. The wet beads were dried in a fluid bed drier (Glatt ) at an Inlet temperature of 65 i 10°C until Loss on Drying is not more than 2.5%.

The dried beads were passed through a mechanical sieve screen) equipped with a 24-MG mesh screen at the , and 16—MG mesh screen at the top. The beads that remained on the 24-MG mesh screens were collected into double polyethylene-lined bags, and the oversized and undersized beads were discarded CA/Cogovidone Layer Coating (for Prototme II and III [or Comgonent II) Cellulose acetate and copovidone (Kollidon VA64) were dissolved into the e of acetone and isopropyl alcohol (IPA) solution (acetone/IPA at weight ratio of 4/1) completely. The pump was calibrated and set at the target spray rate of 15 g/min for the coating. The core beads from above were coated using Glatt GPCG 2 equipped with a r insert at Inlet air temperature of °C, Atomization air re of 2.0 bars and Wurster partition height of 30 mm. During coating, the inlet air temperature and spray rate were ed to maintain the exhaust air temperature between 25::50C. After the target amount of g solution was sprayed, the coated beads were dried at an inlet air temperature of 35°C for 30 minutes. The dried beads were passed through a mechanical sieve (Vibroscreen) equipped with a pan at the bottom and a 14- MG mesh screen at the top. The beads that passed through l4-MG mesh screen were collected and the oversized beads were rejected.

Eudmgit® E100 Larger Coating e, IPA and purified water (at weight ratio acetone/IPA/water of 68/20/12) were dispensed into a stainless steel container and begin ng using stir bar. While stirring, Triethyl citrate, Amino Methacrylate mer (Eudragit® E100) were slowly added into the vortex of the mixed solvent. The mixing was continued until the copolymer tely dissolved. While stirring, Talc was slowly dispersed into the vortex of the on. Mixing was continued until the material completely dispersed. The suspension was stirred throughout the coating process.

The spray pump was calibrated to the target coating spray rate (10 g/min) using the solution above. The beads (from Prototype I, and Prototype 11 and III) were coated using Glatt GPCG 2 equipped with a Wurster insert at Inlet air temperature of 33°C, Atomization air pressure of 2.0 bars and Wurster partition height of 30 mm. During coating, the inlet air temperature and spray rate were adjusted to maintain the exhaust air temperature between 26 : 5°C. After the target amount of g solution was sprayed, the coated beads were dried at an inlet air temperature of 35°C for 30 minutes. The dried beads were passed through a mechanical sieve (Vibroscreen) equipped with a pan at the bottom and a l4-MG mesh screen at the top. The beads that passed through 14-MG mesh screen were collected, and the oversized beads were rejected.

Enteric (Eudragit® L100; Coating e and Isopropyl Alcohol were dispensed at weight ratio of 40/60 into a stainless steel container and stirred using a stir bar. While stirring, the enteric copolymer Eudragit® L100 and Triethyl Citrate (TEC) were slowly added into the vortex of the mixed solvent. Mixing was continued until the enteric copolymer completely dissolved. While stirring, Talc was slowly dispersed into the vortex of the solution. Mixing continued until the al was completely dispersed. The suspension was continually d throughout the coating process. The spray pump was calibrated to the target at a g spray rate (9 g/min) using the solution above. The Eudragit® E—coated beads were coated using Glatt GPCG 2 equipped with a Wurster insert at Inlet air temperature of 35°C, Atomization air pressure of 2.0 bars and Wurster partition height of 30 mm. During g, the inlet air temperature, and spray rate was adjusted to maintain the exhaust air temperature between 27 i 5°C. After the target amount of coating solution was d, the coated beads were dried at an inlet air temperature of 38°C for 30 minutes. The dried beads were passed through a mechanical sieve (Vibroscreen) ed with a pan at the bottom and a 14-MG mesh screen at the top. The beads that passed through l4-MG mesh screen were collected, and the oversized beads were rejected.

Preparation of Entacapone ent (for IPX203-C0026) Povidone was completely dissolved in the purified water. pone, Sodium Starch Glycolate, Sodium Lauryl Sulfate and Microcrystalline ose were charged into a high shear granulator and dry mix for 1-5 minutes at impeller speed of 200 - 300 rpm and chopper speed of 1400 - 1600 rpm. The solution was sprayed into the granulation bowl at the spray rate of 19 ml/min until all the solution is used, and granulation continued with Purified Water as necessary. The wet granules were extruded using the extruder (MG 55 Multi Granulator) equipped with a 0.9 mm hole size screen at extruder speed of 55 rpm. The extrudates were collected, and charged into a spheronizer equipped with a 3mm cross hatch disc. The extrudate were spheronized at a spheronization speed of 650 rpm for 2 mins. The wet beads were dried in a fluid bed drier (Glatt GPCP-l) at an Inlet temperature of 40 i 5°C until Loss on Drying is not more than 5.0%. The dried beads were passed through a mechanical sieve (Vibroscreen) equipped with a pan at the bottom, 24-MG mesh screen in the middle, and 16-MG mesh screen at the top. The beads that were retained on 24-MG mesh were collected and the beads on the pan and 16-MG mesh screen were rejected. e and Isopropyl Alcohol were dispensed at weight ratio of 40/60 into a stainless steel container and stirred using a stir bar. While stirring, the enteric copolymer Eudragit® L100 and TEC were slowly added into the vortex of the mixed solvent. Mixing ued until the enteric copolymer completely dissolved. While stirring, Talc was slowly dispersed into the vortex of the solution. Mixing continued until the material was completely dispersed. The suspension was d throughout the coating process. The spray pump was calibrated to the target coating spray rate (8 g/min) using the solution. The core beads were coated using Glatt GPCG 1 ed with a Wurster insert at Inlet air temperature of 35 i 10°C, Atomization air pressure of 1.5 bars and Wurster partition height of 15-30mm. During g, the inlet air temperature, exhaust flap, and spray rate were adjusted to maintain the exhaust air temperature between 27 i 5°C. After the target amount of coating solution was sprayed, the coated beads were dried at an inlet air temperature of 40°C for 20 minutes. The dried beads were passed h a mechanical sieve (Vibroscreen) equipped with a pan at the bottom and a 14- MG mesh screen at the top. The beads that passed through 14-MG mesh screen were collected and the oversized beads were rejected.

Encapsulation The required amounts of the Component 1, and Component II Beads and Talc were dispensed.

For formulation IPX203-C0026, also Entacapone component beads were also sed. Talc was weighed at the weight ratio of beads/Talc at 99/ 1, and Component II beads and Talc were blended thoroughly. For —C0026 product, Talc was also weighed at the weight ratio of ENT beads/Talc at 99/1, and Entacapone beads and Talc were blended thoroughly. The Component I granules and Component II beads (from encapsulation section) were encapsulated into size 00 hard gelatin capsules, using MG Flexalab Encapsulator at the target fill weight for IPX203 products 1PX203-C0023, -C0024, and -C0025. The Component 1 es, Component II beads (from encapsulation section), and entacapone beads (from encapsulation section) were ulated into size 00 hard gelatin capsules, using MG Flexalab Encapsulator at the target fill weight for IPX203 products -C0026.

III. In Vitro LD Release Profiles of Four Formulations for Pharmacokinetic Study (IPX203-B14-01) The in vitro release profiles of the formulations IPX203-C0023, -C0024, -C0025, and —C0026 were measured using USP I dissolution method at agitation speed of 75 rpm in Simulated Gastric Fluid (pH 1.0, without enzyme) for first 2 hrs and followed by in Simulated Intestinal Fluid (pH 7.0, without enzyme). Figure 6 shows the e profiles of these four formulations.

Formulation IPX203-C0025 and IPX203-C0026 contain the same Component II beads thus having same dissolution profiles. The T90 (time duration for 90% of LD released) is approximately 4hr, 5h and 7hrs for —C0023, -C0025 and —C0026, and —C0024, respectively.

IV. In Vivo Evaluation (Biostudy -B14-01) The in viva mance of the prepared products IPX203-C0023, -C0024, -C0025, and —C0026 has been evaluated in 19 healthy volunteers in a relative bioavailability study IPX203-Bl4-01.

IPX203-B4-01 was a single-center, open-label, randomized, single-dose, five-sequence, five- treatment ver study. During each treatment period ts received a single dose of the assigned study treatment. There was a minimum 5-day washout between treatments. Blood samples were obtained predose and following dosing for approximately 12 hours for measurement of plasma concentrations. Thirty healthy male and female subjects, 18 to 45 years of age at the time of dosing with a body mass index of 18.0 to 30.0 kg/mz, inclusive, were enrolled. All treatments were administered with 240 mL of room-temperature water to ts in a fasted state. Subjects were instructed to swallow the study drugs intact without ng or g. Figure 7 shows the levodopa plasma profiles for all these regimens, and Table 15 shows the PK parameters relative to Stalevo®.

Table 15: PK Parameters for All the Regimens Tested in IPX203 B13-01 Study (n=19) Formulation % of IPX203 Test Formulation / % of IPX203 Test Formulation Stalevo® / Stalevo® (normalized by LD dose) IPX203-C0023 277.3 179.4 IPX203-C0024 199.1 121.4 IPX203-C0025 226.9 134.0 63.0 37.2 IPX203-C0026 265.9 141.6 73.9 39.3 Table 16 shows the duration of time above 50% Cmax for IPX203-C0023, -C0024, -C0025 and —C0026 and tional formulations.

Table 16: Duration of Time Above 50% Cmax IPX203-C0023, -C0024, -C0025 and —C0026 and Conventional ations % Coefficient of ation N Median Mean Variation SD/Mean Isz03-C0023 29.88 Isz03-Cooz4 35.94 -C0025 29.30 IPX203-C0026 19 4.88 5.23 36.32 Cmax values normalized to allow comparison Comparison of the LD plasma concentration profile of the tested formulations to the nce product Stalevo® indicates that: (1) the IPX203 regimens, based on IPX203-C0023, -C0024, -C0025 and —C0026 formulations, showed more extended effect than Stalevo® (Table 16 and Figure 7); in addition, the IPX203 formulations showed more extended effect than Sinemet® or Sinemet® CR (Table 16 and Figure 3; for Sinemet® CR (N = 11), T>50% Cmax is N 3.41 hrs); (2) the IPX203 formulations, namely IPX203-C0023, -C0024, —C0025 and —C0026 formulations, showed relatively flat plasma profiles for LD compared to Stalevo® (Figure 7); (3) the time duration between 50% of Cmax to Cmax for IPX203-C0023, -C0024, -C0025 and —C0026 formulations are much longer than Stalevo®, (aPproximately 4.1-5.2 hrs for test formulations, compared to 2.3 hrs for Stalevo®; and (4) the variation of the time duration n 50% Cmax to Cmax for IPX2003-C0023, , -C0025 and —C0026 formulations is less than Stalevo®.

I/

Claims (85)

WE CLAIM :

1. A controlled release oral solid formulation comprising: (a) a controlled release component comprising a core comprising levodopa and/or an ester of levodopa or salts f, wherein the core is coated with a layer comprising a muco-adhesive amino methacrylate copolymer, and ally coated with a layer comprising an enteric coating polymer; and (b) an immediate release component comprising levodopa and/or an ester of levodopa or salts f.

2. The controlled release oral solid formulation of claim 1 further comprising a ratecontrolling polymer which undercoats the muco-adhesive polymer layer within the controlled release component.

3. The controlled release oral solid formulation of claim 1 or claim 2, wherein the controlled release ent (a) is ated as a bead.

4. The controlled e oral solid formulation of claim 3 wherein the controlled release bead size is between 0.8 to 1.2 mm.

5. The lled release oral solid formulation of claim 3 wherein the controlled release bead is a size that passes through 12, 14, or 16 mesh but may be retained on 18, 24, or 25 mesh screens.

6. The controlled release oral solid ation of claim 3 wherein the controlled release bead is a size that passes through 14 mesh but may be retained on 18 or 24 mesh screens.

7. The controlled release oral solid formulation of any one of claims 1 to 6, further comprising carbidopa. AH26(28029224_1):JIN

8. The controlled release oral solid formulation of any one of claims 1 to 7, wherein the amino methacrylate copolymer comprises poly(butyl methacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1.

9. The controlled release oral solid ation of any one of claims 1 to 8, wherein the muco-adhesive polymer layer also comprises an additional polymer selected from the group consisting of polycarbophil, carbomer, cellulosics, chitosan, diethylaminodextran, diethylaminoethyldextran, polygalactosamine, sine, polyornithine, prolamin, polyimine, hyaluronic acid, sodium alginate, sodium carboxymethylcellulose m CMC) and alginate, or a ation thereof.

10. The controlled release oral solid formulation of claim 2, wherein the rate-controlling polymer comprises cellulose e or ethylcellulose.

11. The controlled release oral solid formulation of claim 1, comprising: (a) a controlled release component comprising a core comprising levodopa, wherein the core is coated with (a) a ontrolling polymer layer, (b) the mucoadhesive r layer applied to the rate-controlling polymer layer, and (c) the enteric coating polymer layer; and (b) an immediate release component comprising levodopa and carbidopa.

12. The controlled release oral solid formulation of claim 1 or 2, n the ester of levodopa is selected from the group consisting of ethyl (2S)amino(3,4- dihydroxyphenyl)propanoate (levodopa ethyl ester), levodopa butyl ester, and levodopa methyl ester.

13. The controlled release oral solid formulation of any one of claims 1 to 12, wherein the controlled release ent (a) has an in vitro dissolution e with less than 20% release of the levodopa or ester of levodopa within two hours of testing using a United States Pharmacopeia Type I dissolution apparatus with a dissolution media of about pH 1.0. AH26(28029224_1):JIN

14. The controlled release formulation of claim 13, wherein the lled release component (a) has an in vitro dissolution profile with less than 10% release of the levodopa or ester of pa at about pH 1.0 within two hours.

15. The controlled release oral solid formulation of claim 13 or 14 wherein the controlled release component es the levodopa or ester of pa over at least 4 to 8 hours upon changing the dissolution media to media with a pH of 6.5 to 7.6.

16. The controlled e oral solid formulation of any one of claims 1 to 15, having an in vivo levodopa plasma profile following oral administration of the controlled release oral solid formulation to a subject under g conditions, comprising: (a) a time of administration; (b) a levodopa plasma concentration corresponding to maximum levodopa plasma concentration (Cmax) occurring within 6 hours after administration of the dosage form; (c) a time to reach 50% Cmax of less than one hour; and (d) wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 5.0 hours.

17. The controlled release formulation of claim 16, wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 5.5 hours.

18. The controlled release ation of claim 16, wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 6.0 hours.

19. The controlled release formulation of claim 16, wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 6.5 hours.

20. The controlled release formulation of claim 16, wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 7.0 hours. AH26(28029224_1):JIN

21. The controlled release formulation of any one of claims 1 to 20 wherein the enteric coating polymer comprises shellac, cellulose acetate phthalate, poly(methacrylic acid-comethyl rylate), poly(methacrylic acid-co-ethylmethacrylate), cellulose acetate litate, poly(vinyl acetate phthalate), hydroxpropyl methylcellulose phthalate or hydroxypropyl methylcellulose e succinate.

22. The controlled release formulation of any one of claims 1 to 20, wherein the enteric coating polymer layer ves at a pH of greater than or equal to 5.5.

23. The controlled release oral solid formulation of claim 21 or 22, wherein the enteric coating polymer comprises one or more methacrylic acid mers.

24. The lled release oral solid formulation of any one of claims 1 to 23, wherein the levodopa, and/or ester of levodopa, and/or salts thereof are dispersed throughout the core or layered on a sugar sphere.

25. The controlled release oral solid formulation of any one of claims 1 to 24, wherein the core of the controlled e component is a spheronized core.

26. The lled release oral solid formulation of claim 25, wherein the core of the controlled release component is an extruded and spheronized core.

27. The controlled e oral solid ation of any one of claims 1 to 26, wherein the controlled release component is free of carbidopa.

28. The controlled release oral solid formulation of any one of claims 1 to 27, wherein the ratio of levodopa in the immediate release component to the controlled release component is about 1:3.

29. The controlled release oral solid formulation of any one of claims 1 to 28, wherein immediate release component comprises carbidopa and levodopa in ratio of about 1:1. AH26(28029224_1):JIN

30. Use of a lled release oral solid formulation of any one of claims 1 to 29 for the manufacture of a medicament effective in the treatment of Parkinson’s disease or primary parkinsonism.

31. A multiparticulate, controlled release oral solid ation sing: (a) a plurality of controlled release components sing a core comprising levodopa, wherein the core is coated with a layer comprising a muco-adhesive polymer selected from an amino methacrylate copolymer, polycarbophil, carbomer, cellulosics, chitosan, diethylaminodextran, diethylaminoethyldextran, polygalactosamine, polylysine, polyornthine, prolamin, ine, hyaluronic acid, sodium alginate, sodium carboxymethylcellulose (sodium CMC) and alginate, or a combination thereof and externally coated with a layer comprising an c coating polymer and wherein the controlled release components (i) have an in vitro dissolution profile with less than 20% release of the levodopa at pH 1.0 within two hours and (ii) are free of opa; and (b) an immediate release component comprising levodopa and optionally carbidopa; and wherein the oral solid formulation releases at least 90% of the pa in 4 to 7 hours when tested in a United States Pharmacopeia (USP) Type I dissolution apparatus with a rotational speed of 75 rpm in Simulated c Fluid at pH 1.0 without s for the first 2 hours and followed by testing in Simulated Intestinal Fluid at pH 7.0 without enzymes.

32. The multiparticulate controlled e oral solid formulation of claim 31, wherein the controlled release components pass through a 12 mesh screen and are retained on a 25 mesh screen.

33. The controlled release oral solid formulation of claim 31 or 32, wherein the ratio of levodopa in the immediate release component to the controlled release component is about 1:3. AH26(28029224_1):JIN

34. The controlled release oral solid formulation of any one of claims 31 to 33, wherein immediate release component comprises carbidopa and levodopa in ratio of about 1:1.

35. The articulate controlled release oral solid formulation of any one of claims 31 to 34, further comprising a rate-controlling polymer which undercoats the muco-adhesive r layer within the controlled release components.

36. The multiparticulate controlled release oral solid formulation of claim 35, wherein the rate-controlling polymer comprises cellulose acetate or ethylcellulose.

37. The multiparticulate controlled release oral solid formulation of claim 35, wherein the rate-controlling polymer comprises ose acetate and copovidone.

38. The multiparticulate controlled release oral solid formulation of any one of claims 31 to 37, wherein the immediate release component (b) is formulated as a ablet, bead, or granule.

39. The multiparticulate lled release oral solid formulation of any one of claims 31 to 38, wherein the ation is encapsulated in a capsule.

40. The multiparticulate controlled release oral solid formulation of any one of claims 31 to 39, wherein the muco-adhesive polymer is an amino rylate copolymer.

41. The multiparticulate controlled release oral solid formulation of claim 40, n the amino methacrylate copolymer is a dimethylaminoethyl methacrylate copolymer.

42. The multiparticulate controlled release oral solid formulation of claim 41, wherein the amino methacrylate copolymer is a utyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1.

43. The multiparticulate controlled release oral solid formulation of any one of claims 31 to 42, wherein the c coating polymer layer dissolves at a pH of greater than or equal to 5.5. AH26(28029224_1):JIN

44. The controlled release formulation of any one of claims 31 to 43 wherein the enteric coating r comprises shellac, ose acetate ate, poly(methacrylic acid-comethyl methacrylate), poly(methacrylic acid-co-ethylmethacrylate), ose acetate litate, inyl acetate phthalate), propyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate.

45. The multiparticulate controlled release oral solid formulation of claim 43 or claim 44, wherein the enteric g polymer comprises a one or more methacrylic acid copolymers.

46. The multiparticulate controlled release oral solid formulation of any one of claims 31 to 45, wherein the oral solid formulation releases at least 90% of the levodopa in 5 to 7 hours when tested in a United States Pharmacopeia (USP) Type I dissolution apparatus with a rotational speed of 75 rpm in ted Gastric Fluid at pH 1.0 without enzymes for the first 2 hours and followed by testing in Simulated Intestinal Fluid at pH 7.0 without enzymes.

47. The multiparticulate controlled e formulation of any one of claims 31 to 46, wherein the controlled release component (a) has an in vitro dissolution profile with less than 10% release of the levodopa at pH 1.0 within two hours.

48. The multiparticulate controlled release oral solid formulation of any one of claims 31 to 47, having an in vivo levodopa plasma profile following administration of an oral dosage form of the formulation to a subject under fasting conditions comprising (a) a time of administration; (b) a levodopa plasma concentration corresponding to maximum levodopa plasma concentration (Cmax) occurring within 6 hours after administration of the oral dosage form; (c) a time to reach 50% Cmax of less than one hour; and (d) wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 5.0 hours. AH26(28029224_1):JIN

49. The multiparticulate controlled release oral solid formulation of claim 48, n the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 5.5 hours.

50. The multiparticulate controlled release oral solid formulation of claim 48, wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 6.0 hours.

51. The multiparticulate controlled release oral solid formulation of claim 48, wherein the in vivo plasma level of levodopa is ined at 50% Cmax or above for at least 6.5 hours.

52. The multiparticulate controlled release oral solid formulation of claim 48, wherein the in vivo plasma level of levodopa is maintained at 50% Cmax or above for at least 7.0 hours.

53. The multiparticulate controlled release oral solid formulation of any one of claims 31 to 52, wherein the core of the controlled release components is a spheronized core.

54. The multiparticulate controlled release oral solid formulation of claim 53, wherein the core of the lled release components is an extruded and nized core.

55. Use of a multiparticulate lled release oral solid formulation of any one of claims 31 to 54 for the cture of a medicament effective in the treatment of Parkinson’s disease or primary parkinsonism.

56. A multiparticulate controlled release levodopa solid oral dosage form comprising: (i) one or more immediate release components comprising carbidopa and levodopa in a ratio of about 1:1; and (ii) one or more controlled release levodopa particles wherein the one or more lled release levodopa particles comprise: (a) a spheronized core comprising levodopa; (b) a coating surrounding the core comprising a muco-adhesive material selected from the group consisting of amino methacrylate copolymers, polycarbophil, er, cellulosics, an, diethylaminodextran, diethylaminoethyldextran, AH26(28029224_1):JIN polygalactosamine, polylysine, polyornithine, prolamin, ine, hyaluronic acid, sodium alginate, sodium carboxymethylcellulose (sodium CMC) and alginate, or a combination thereof; and (c) a coating sing an c material surrounding the coating comprising the muco-adhesive material.

57. The multiparticulate controlled release levodopa solid oral dosage form of claim 56, wherein the controlled release levodopa particles are free of carbidopa

58. The articulate controlled release levodopa solid oral dosage form of claim 56 or 57, wherein the ratio of levodopa in the immediate release ent to the controlled release levodopa particles is about 1:3.

59. The multiparticulate controlled release levodopa solid oral dosage form of any one of claims 56 to 58, wherein the one or more controlled release pa particles pass through a 12 mesh screen but are ed on a 25 mesh screen.

60. The multiparticulate controlled e levodopa solid oral dosage form of any one of claims 56 to 59, wherein the one or more controlled release particles pass through a 14 mesh screen but are ed on a 24 mesh screen.

61. The multiparticulate controlled release levodopa solid oral dosage form of any one of claims 56 to 60, wherein the solid oral dosage form releases at least 90% of the levodopa in 4 to 7 hours when tested in a United States Pharmacopeia (USP) Type I dissolution apparatus with a rotational speed of 75 rpm in Simulated Gastric Fluid at pH 1.0 without enzymes for the first 2 hours and followed by testing in Simulated Intestinal Fluid at pH 7.0 without enzymes.

62. The multiparticulate controlled release levodopa solid oral dosage form of any of claims 56 to 61, wherein the solid oral dosage form releases at least 90% of the levodopa in 5 to 7 hours when tested in a United States Pharmacopeia (USP) Type I ution apparatus with a rotational speed of 75 rpm in Simulated Gastric Fluid at pH 1.0 without enzymes AH26(28029224_1):JIN for the first 2 hours and followed by testing in Simulated Intestinal Fluid at pH 7.0 without enzymes.

63. The multiparticulate lled release levodopa solid oral dosage form any one of claims 56 to 62, wherein the immediate release levodopa component comprises levodopa and is a mini-tablet, bead or granule.

64. The multiparticulate controlled release levodopa solid oral dosage form of claim 63, wherein the immediate release levodopa component is a granule.

65. The multiparticulate controlled release levodopa solid oral dosage form any one of claims 56 to 64, wherein the muco-adhesive material comprises an amino methacrylate copolymer.

66. The articulate lled release pa solid oral dosage form of claim 65, wherein the amino rylate copolymer is poly(butyl methacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate polymer).

67. The multiparticulate controlled release levodopa solid oral dosage form of any one of claims 56 to 66, wherein the enteric material dissolves at a pH of greater than or equal to 5.5.

68. The controlled release formulation of any one of claims 56 to 67 wherein the enteric coating polymer comprises shellac, cellulose acetate phthalate, poly(methacrylic acid-comethyl methacrylate), poly(methacrylic acid-co-ethylmethacrylate), cellulose acetate trimellitate, poly(vinyl e ate), propyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate ate.

69. The multiparticulate controlled release levodopa solid oral dosage form of any one of claims 56 to 68, wherein the enteric material comprises a methacrylic acid copolymer. AH26(28029224_1):JIN

70. The multiparticulate controlled release levodopa solid oral dosage form of any one of claims 56 to 69, wherein the one or more controlled release particles further comprises a controlled release coating nding the core and wherein the controlled release coating is d prior to coating (b) comprising the dhesive material.

71. The multiparticulate controlled release levodopa solid oral dosage form of any one of claims 56 to 70, wherein the core of the one or more controlled release levodopa les is an extruded and spheronized core.

72. The multiparticulate controlled release levodopa solid oral dosage form of any one of claims 56 to 71 wherein the solid oral dosage form comprises 95 mg to 390 mg of levodopa.

73. Use of a multiparticulate controlled release levodopa solid oral dosage form of any one of claims 56 to 72 for the manufacture of a medicament effective in the treatment of Parkinson’s e or primary parkinsonism.

74. The multiparticulate controlled release levodopa solid oral dosage form as d in any one of claims 56 to 59, comprising: (i) one or more immediate release levodopa components; and (ii) a plurality of controlled release levodopa particles that pass through a 12 mesh screen but are ed on a 25 mesh screen comprising: (a) a spheronized core comprising levodopa; (b) a lled release coating surrounding the spheronized core; (c) a dhesive coating comprising a poly(butyl methacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate) polymer surrounding the controlled release coating; and (d) an enteric coating comprising a methacrylic acid copolymer that dissolves at a pH of 5.5 or greater surrounding the muco-adhesive coating; and wherein the one or more immediate e levodopa components and the ity of controlled e levodopa particles are encapsulated in a capsule and the capsule comprises 95 mg to 390 mg of pa.

75. The capsule of claim 74, n the one or more controlled release les pass through a 14 mesh screen but are retained on a 24 mesh screen.

76. The capsule of claim 74 or 75, wherein the immediate release pa component comprises levodopa and is a mini-tablet, bead, or granule.

77. The capsule of claim 74, where the immediate release levodopa component is a granule.

78. The capsule of claim 77, wherein the granules comprise a mixture of levodopa, carbidopa, croscarmellose sodium, povidone and magnesium stearate.

79. The capsule of any one of claims 74 to 78, wherein the controlled release coating comprises ethylcellulose.

80. The capsule of any one of claims 74 to 78 wherein the controlled release coating comprises cellulose acetate.

81. The capsule of any one of claims 74 to 80, wherein the plurality of lled release levodopa particles pass through a 14 mesh screen but are ed on a 24 mesh screen and comprise: (a) a nized core comprising levodopa, microcrystalline cellulose, mannitol, sodium lauryl sulfate and povidone; (b) a controlled release coating surrounding the spheronized core wherein the controlled release coating comprises cellulose acetate or ethylcellulose; (c) a muco-adhesive coating comprising a poly(butylmethacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate) polymer surrounding the controlled release coating; and (d) an enteric coating comprising a methacrylic acid copolymer that dissolves at a pH of 5.5 or greater surrounding the muco-adhesive coating.

82. The capsule of claim 81 further wherein the one or more immediate e levodopa components comprise one or more immediate release granules comprising a mixture of levodopa, and carbidopa.

83. The e of claim 82 wherein the ate release granules comprise mixture of levodopa, carbidopa, croscarmellose sodium, povidone and magnesium stearate.

84. The capsule of any one of claims 81 to 83 wherein the core of the controlled release levodopa les are extruded and spheronized cores.

85. Use of a capsule of any one of claims 74 to 84 for the manufacture of a ment effective in the treatment of Parkinson’s disease or primary sonism. Impax Laboratories, LLC By the Attorneys for the Applicant SPRUSON & FERGUSON Per: