Dosage forms comprising mycophenolic acid and methods of their use

Abstract

Pharmaceutical formulations comprising mycophenolic acid or pharmaceutically acceptable salts or prodrugs thereof are disclosed. Methods of making the formulations and methods of using them to treat, manage or prevent disease and disorders associated with undesired immune response are also disclosed. The formulations include a core comprising mycophenolic acid, microcrystalline cellulose, povidone, and talc surrounded by a seal coat comprising a polymer, plasticizer and talc which is surrounded by a sustained release layer comprising cellulose, dibutyl sebacate, and talc.

Description

01599.004W01DOSAGE FORMS COMPRISING MYCOPHENOLIC ACID AND METHODS OF THEIR USECROSS-REFERENCE TO RELATED APPLICATIONSThis application claims priority to U. S. provisional patent application no. 63 / 738,603, filed December 24, 2024, the entirety of which is incorporated herein by reference.1. BACKGROUND OF THE INVENTIONMycophenolic acid (MPA) is an immunomodulating agent that inhibits inosine 5'-monophosphate dehydrogenase, an enzyme necessary for the de novo synthesis of guanine nucleotides. See. e.g., Klotsman M., et al., “Mycophenolic acid in patients with immune-mediated inflammatory diseases: From humans to dogs” Journal of Veterinary Pharmacology and Therapeutics 2019:42(2): 127-38; Allison AC and Eugui EM “My cophenolate mofetil and its mechanisms of action” Immunopharmacology 2000;47:85-118. This inhibition of IMPDH leads to the selective arrest of T and B-lymphocyte proliferation. MPA may also have antifibrotic effects and has been shown to induce apoptosis of T-lymphocytes, suppress dendritic cell maturation and reduce monocytes, which may contribute to its efficacy in treating immune-mediated diseases. Id.Mycophenolate mofetil (MMF), which is an ester prodrug of MPA, is sold in the United States for use as an adj unctive immunosuppressant under the tradename CellCept®. The sodium salt of MPA (MPNa) is sold under the tradename Myfortic®. Unfortunately, both compositions are associated with significant side effects, have uneven pharmacodynamic activity' and require frequent dosing to sustain desired activity.The MPA-based product most commonly used in dogs is an immediate release formulation containing MMF that has a suboptimal pharmacokinetic (PK) profile. Klostsman, supra. The PK profile of MMF is characterized by a sharp spike in maximum plasma concentration (Cmax) that can cause gastrointestinal (GI) side effects, a short-half life that necessitates frequent administration to maintain therapeutic drug concentration levels, and high intra- and inter-dog PK variability. Klotsman M, et al., “Single-dose pharmacokinetics of mycophenolic acid following administration of immediate-release mycophenolate mofetil in healthy Beagle dogs” J Vet Pharmacol Then 2021;44(4):650-6. Because MMF has a narrow therapeutic index, the complex and highly variable MMF dose-concentration relationship coupled with high inter-and intra-dog PK variability complicate its use, placing patients at risk of underexposure and treatment failure or over-exposure and toxicity. Abd Rahman AN, et al., “Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease” Clin Pharmacokinet. 2013;52(5):303-31. Improved dosage forms of MPA and its salts and prodrugs are sorely needed.01599.004W012. SUMMARY OF THE INVENTIONThis invention is directed to pharmaceutical formulations comprising mycophenolic acid (MPA), pharmaceutically acceptable salts thereof, such as mycophenolate sodium (MPNa), or pharmaceutically acceptable prodrugs thereof, such as mycophenolate mofetil (MMF). Particular formulations are controlled release formulations of MPA or pharmaceutically acceptable salts and prodrugs thereof.This invention encompasses sustained-release (SR) beads, delayed-release (DR) beads, mixtures of SR and DR beads (SR / DR mixtures), pharmaceutical dosage forms comprising them, and methods of their preparation and use.One embodiment of the invention is directed to an SR bead which contains an API) and comprises (e.g., consists essentially of):(i) a core comprising the API, microcrystalline cellulose, and a binder;(ii) a seal coat layer disposed over the core; and(iii) a sustained-release layer disposed over the seal coat layer;wherein the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof. In preferred embodiments, the sustained-release layer comprises a matrix polymer, a pore-former, and a plasticizer.Another embodiment is directed to a DR bead comprises a delayed-release layer disposed over any of the SR beads described herein. Thus, one embodiment of the invention is directed to a DR bead comprising (e.g., consisting essentially of):(i) a core comprising API, m icrocrystall ine cellulose, and a binder;(ii) a seal coat layer disposed over the core;(iii) a sustained-release layer disposed over the seal coat layer; and(iv) a delayed-release layer disposed over the sustained-release layer;wherein the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof. In preferred embodiments, the sustained-release layer comprises a matrix polymer, a pore-former, and a plasticizer.Another embodiment is directed to a pharmaceutical formulation comprising a mixture of SR and DR beads.Another embodiment is directed to methods of making SR and DR beads and the products of those methods.Other embodiments are directed to methods of suppressing inflammatory response (e.g., lymphocyte proliferation) and treating autoimmune diseases and conditions in patients, which comprise administering pharmaceutical formulations comprising SR and / or DR beads.3. BRIEF DESCRIPTION OF THE DRAWINGSSome aspects of this invention may be understood with reference to the figures.FIG. 1 show s a schematic example of a sustained-release (SR) bead and a delayed-release (DR) bead of a controlled-re lease formulation of the present disclosure.01599.004W01FIG. 2 shows dissolution profiles for four different SR bead formulations.FIG. 3 provides a flow diagram showing the process used to prepare particular pellets, or beads, of the invention.FIG. 4 provides dissolution profiles of SR and DR beads used to prepare Formulation 3. Here, the target profile was the dissolution profile provided by DR beads containing an IR bead with a drug layer and a DR layer consisting of 62.5% Eudragit S 100, 31.2% talc, and 6.3% TEC.FIG. 5A shows the MPA plasma concentrations over time in dogs that received a dose of 300 mg MPA delivered in a capsule containing only the SR beads used to provide Formulation 1. FIG. 5B shows the average MPA plasma concentrations over time in dogs that received a dose of 300 mg MPA delivered in a capsule containing only the DR beads used to provide Formulation 1. FIG. 5C shows the average MPA plasma concentrations over time in dogs that received a dose of 300 mg MPA in a capsule containing SR / DR Formulation 1.FIG. 6 shows the average pharmacokinetic data from healthy beagle dogs that received SR / DR Formulation 1 (diamonds), 50% of the average PK from dogs receiving a composition of SR beads (squares), 50% of the average PK from dogs receiving a composition of DR beads (circles), and a theoretical curve of the sum of the SR and DR curves combined (triangles).FIGS. 7A-D show pharmacokinetic data obtained from a second set of in vivo experiments in healthy beagle dogs. FIG. 7 A shows the average MPA plasma concentrations over time of dogs that recei ved a dose of 300 mg MPA delivered in a capsule containing the SR beads used to prepare Formulation 1. FIG. 7B shows the average MPA plasma concentrations over time in dogs that received a dose of 300 mg MPA delivered in a capsule containing the DR beads used to prepare Formulation 1, FIG.7C shows the average MPA plasma concentrations over time in dogs that received a dose of 300 mg MPA in a capsule containing SR / DR Formulation 1. FIG. 7D shows a comparison of the average MPA plasma concentration over time for groups of dogs that received the SR compositions (i.e., compositions made of SR beads), DR compositions (i. e., compositions made of DR beads), and SR / DR combinations (i. e., compositions made of both SR and DR beads).FIG. 8 A shows the mean plasma concentration of MPA following oral administration of 30 mg / kg dose of SR beads versus time. FIG. 8B shows the mean plasma concentration of MPA following oral administration of a 20 mg / kg dose of SR beads versus time.FIG. 9A shows the mean plasma concentration of MPA following oral administration of a 30 mg / kg dose of DR beads versus time. FIG. 9B shows the mean plasma concentration of MPA following oral administration of a 20 mg / kg dose of DR beads versus time, The means shown here were calculated from the data obtained for dog numbers 7-10.FIG. 10 shows the mean plasma concentration of MPA following oral administration of a 20 mg / kg dose of SR / DR Formulation 2 versus time.FIG. 11 shows plasma concentrations of MPA as a function of time in individual male Beagle dogs in Group 3 following administration of DR beads used in dual-bead Formulation 3 (20 mg / kg).FIG. 12 shows plasma concentrations of MPA as a function of time in individual male Beagle dogs in Group 4 following administration of SR beads used in dual-bead Formulation 3 (20 mg / kg).01599.004W01FIG. 13 shows plasma concentrations of MPA as a function of time in individual male Beagle dogs in Group 5 following administration of dual-bead Formulation 3 comprising SR beads (6 mg / kg MPA) and DR beads (14 mg / kg MPA).FIG. 14 shows plasma concentrations of MPA as a function of time in individual male Beagle dogs in Group 6 following administration of another embodiment of dual-bead Formulation 3 comprising SR beads (20 mg / kg MPA) and DR beads (20 mg / kg MPA).4. DETAIL DESCRIPTION OF THE INVENTIONAlthough mycophenolic acid (MPA) is widely used as an immunosuppressant, current dosage forms of the drug are associated with a wide range of adverse effects. Adverse drug effects associated with mycophenolate therapy include gastrointestinal effects (e.g,, diarrhea, nausea, loose stools, emesis), joint pain, infections, leukopenia and anemia. Mycophenolate sodium is also commonly associated with fatigue, headache, cough and / or breathing issues. Intravenous (IV) administration of the prodrug MMF is also commonly associated with thrombophlebitis and thrombosis. Adverse effects associated with MMF use include esophagitis, gastritis, diarrhea, loose stools, emesis, gastrointestinal tract hemorrhage, and / or invasive cytomegalovirus (CMV) infection. Less frequently, pulmonary’ fibrosis or various neoplasia occur, such as, for example, melanoma, lymphoma, and other malignancies, which MMF-related neoplasia can occur at frequencies of 1 in 20 to 1 in 200, depending on the type, with neoplasia in the skin being the most common site. Cases of pure red cell aplasia have also been reported.Attempts to alleviate adverse reactions associated with the pharmacokinetics of existing dosage forms of MPA have been made. For example, U. S. patent nos. 11,786,505 and 11,633,378 are directed to formulations comprising beads of MPA. Unfortunately, these formulations can be difficult to prepare on a large scale, afford low yields of consistently sized beads, and do not alleviate the large peak-to-trough variations associated with MPA exposure characteristic of commercially-available forms of the drug.The present invention is directed to dosage forms comprising mycophenolate that provide a slow rate of drug release in order to minimize peaks and troughs in circulating drug concentration, extend the duration of therapeutically efficacious drug concentrations and minimize concentration-dependent GI side effects. Advantageously, dosage forms of the invention exhibit remarkable and unexpected pharmacokinetic (PK) properties that may increase the efficacy of the MPA they contain while avoiding adverse effects associated with existing dosage forms of the drug.4.1. DEFINITIONSSome terms used herein are defined in this section. Other terms may be defined elsewhere herein. Unless otherwise indicated, the term “about” means ± 10% of the indicated range.The term “active pharmaceutical ingredient” (API) refers to a compound that has a pharmacological effect when administered to a patient.Unless otherwise indicated, the term “adult”, when used to describe a dog (e.g., a beagle), means a dog at least one year of age.01599.004W01Unless otherwise indicated, the term “average” refers to a mean.Unless otherwise indicated, the terms “bead”, “granule” and “pellet” are used interchangeably herein. The terms generally refer to a particle that is spherical or approximately spherical (e.g., appear spherical or oval to the eye when examined under a microscope).The terms “coat”, “coating” and “layer” are used interchangeably when used to describe components of beads described herein. A layer typically coats the entirety of the surface upon which it sits (e.g,, a seal coating disposed about a core typically coats tire entire core), although this may not always be the case.The term “combination thereof’ when used at the end of a list of items (e.g., excipients) means a combination of at least two items from the list.Tire terms “comprises” and “comprising”, when used to describe a composition or method, should be construed to mean “comprises, consists essentially of, or consists of’ and “comprising, consisting essentially of, or consisting of’.Unless otherwise indicated, when a pharmaceutical formulation “consists essentially of’ certain ingredients, that formulation may contain additional ingredients that do not materially affect the in vivo pharmacokinetic properties of the formulation.The term “controlled-release” is used to a pharmaceutical formulation that releases its API(s) in a controlled fashion. Controlled-release formulations include sustained-release and delayed-release formulations.lire tern “delayed-release” is used to refer to a pharmaceutical formulation that releases most or all of its API(s) at some meaningful (e.g., therapeutically relevant) time after administration. This may be achieved, for example, with tire use of coatings that dissolve or otherwise allow release of API(s) in at a neutral or basic pH.The term “immediate-release” is used herein to describe a pharmaceutical formulation that releases its API(s) promptly upon administration (e.g., upon entering an acidic environment, such as a patient’s stomach).Unless otherwise indicated, the terms “include” and “including” should be construed to mean “include but are not limited to” and “including but not limited to”.Unless otherwise indicated, the term “fasted” when referring to a patient means that the patient did not consume food at least eight hours (e.g., overnight) prior to dosing.The terms “manage,” “managing” and “management” mean preventing the recurrence of the specified disease or disorder in a patient who has already suffered from the disease or disorder, and / or lengthening the time that a patient who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and / or duration of the disease or disorder or changing the way that a patient responds to the disease or disorder.lire terns “patient” and “subject” are used interchangeably. lypical patients are mammals (e.g., humans, dogs and cats).01599.004W01The tern “pharmaceutically acceptable salt” refers to a salt that is generally recognized as safe to administer to a subject. Examples of pharmaceutically acceptable salts include acetate, chloride, diphosphate, hydrochloride, maleate, phosphate, potassium, sodium, and sulfate.The terms “prevent,” “preventing” and “prevention” contemplate an action that occurs before a patient begins to suffer from the specified disease or disorder, which inhibits or reduces the severity of tire disease or disorder. The terms encompass prophylaxis.A “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease or condition, or one or more symptoms associated with the disease or condition, or prevent its recurrence. A “prophylactically effective amount” of a compound means an amount, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.As used herein, the term “substantially all” means at least about 95, 96, 97, 98, or 99 percent. The term “sustained-release” is used to refer to a pharmaceutical formulation that releases its API(s) at a slower rate than a comparable immediate-release formulation.A “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition. A “therapeutically effective amount” of a compound means an amount, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of the disease or condition, lire term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.The terms “treat,” “treating” and “treatment” contemplate an action that occurs while a patient is suffering from a specified disease or disorder, which reduces the severity of the disease or disorder or retards or slows the progression of the disease or disorder.Tire terms “weight percent”, “%w / w” and “%weight” are used interchangeably to refer to the amount of an ingredient or a component in a composition (e.g., a solution, suspension, material, mixture, layer or bead) as measured by the weight of that ingredient or component versus the total weight of the composition.Unless otherwise indicated, ranges of values are closed intervals. For example, the phrase “X is an integer ranging from 1 to 3” means that X may be 1, 2, or 3.Each of the references, including patents and patent applications, cited herein is incorporated herein in its entirety by reference.4.2. FORMULATIONSThis invention is directed to pharmaceutical formulations comprising an active pharmaceutical ingredient (API), which API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt thereof,01599.004W01such as mycophenolate sodium (MPNa), or pharmaceutically acceptable prodrugs thereof, such as mycophenolate mofetil (MMF).In particular, the invention is directed to dosage forms suitable for oral administration to a patient, which dosage forms comprise at least two different formulations of the API. Preferred dosage forms comprise a plurality of “sustained-release” (SR) beads and a plurality of “delayed-release” (DR) beads, which are discussed in detail below and represented in FIG. 1. Compositions (e.g., formulations, dosage forms) comprising mixtures of SR and DR beads are referred to herein as “SR / DR” compositions.As described further below, it has been found that SR / DR formulations of the inventi on have dramatically better pharmacokinetic (PK) properties than currently available dosage forms of the API. Moreover, these formulations exhibit in vivo AUC profiles that are dramatically better than — and wholly unexpected in view of --the PK profiles of formulations made up of only of SR or DR beads.While the SR / DR formulations of the invention provide dramatically different PK profiles than existing forms of MPA, their refinement resulted in SR and DR beads that even when administered alone exhibit far better drug release profiles and less interpatient variability than prior forms of the drug. This means that even formulations comprised only of SR or DR beads may avoid the dose-limiting toxicities associated with existing forms of MPA.An object of this invention was to provide dosage forms comprising MPA or salts or prodrugs thereof that release the API in a manner that avoids toxicities associated with existing, commercial formulations of the drug. Thus, the bioavailability of the drug was a key consideration during their design. As described in detail below, it has been found that particular SR / DR compositions of the invention exhibit unexpectedly advantageous in vivo pharmacokinetic (PK) properties that could not be predicted from the PK properties of the formulations’ individual components.The DR beads used to provide formulations of the invention are preferably, but need not be, prepared from SR beads, which themselves are prepared from what are referred to herein as “immediate-release” (IR) beads.The composition of individual beads are often described in terms of the weight percent of their individual parts and / or ingredients. While the composition of an individual bead may be determined by direct examination of the bead, it easier to extrapolate these values from the ratio of components and / or ingredients used to make a plurality of beads. For example, if a layer is added to a plurality of beads such that their collective weight after drying is increased by five weight percent, it is reasonable — particularly- given the high size and shape consistency of preferred beads of the invention -to assume that an individual coated bead contains that layer in a corresponding amount, which in this case would be about five weight percent of the uncoated bead,4.2.1. EXCIPIENTSExcipients used to provide the beads and formulations of this invention may be classified by function. See, e.g., Rowe, RR et al.. Handbook of Pharmaceutical Excipients, Pharmaceutical Press 2003 (4th ed).01599.004W01Examples of anti-tacking (also referred to as “anti-caking”) agents include calcium phosphate, calcium silicate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, and talc. A preferred anti -tacking agent is talc.Examples of binders include ethyl cellulose, hydroxyethyl cellulose, hydroxy ethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMA, hypromellose), maltose, methylcellulose, polydextrose, polymethacrylates, povidone, starch and sucrose. Preferred binders are hypromellose and povidone.Examples of materials that may be used to provide enteric coatings include methacrylate-based polymers, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose (HPMC) phthalate, HPMC acetate succinate, sodium alginate, zein, polyvinyl acetate phthalate (PVAP), shellac, methacrylic acid-ethyl acrylate copolymer, and combinations thereof. Particular examples of materials used to provide enteric coatings are EUDRAGIT® polymers, poly(vinyl acrylate) (PVA) polymers (e.g,, KOLLIDON® polymers), and combination thereof, A preferred material is a polymethacrylate that dissolves in water at a pH > 5.5 (e.g., pH > 6, 6.5, or 7), such as an anionic polymer of methacrylic acid (e.g., Eudragit L30) or an anionic copolymer of methacrylic acid and methyl methacrylate (e.g., Eudragit S100).Examples of lubricants include calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, magnesium lauryl sulfate, magnesium stearate, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, and talc. A particular lubricant is magnesium stearate.Examples of plasticizers include acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerin, mannitol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, and triethyl citrate. Particular plasticizers include dibutyl sebacate and triethyl citrate.Examples of stabilizers (e.g., to prevent phase separation) include albumin, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cyclodextrins, glycerol monostearate, guar gum, propylene glycol, sodium alginate, sodium stearyl fumarate, sorbitol, and xanthan gum. A particular stabilizer is glycerol monostearate.4.2.2, IMMEDIATE-RELEASE FORMULATIONSImmediate release (IR) beads contain API in the form of MPA or a pharmaceutically acceptable salt or prodrug thereof. Two approaches to preparing these beads yvere investigated. One allows for the use of pre-made, commercially available inert cores (e.g., made from microcrystalline cellulose); the other begins with the manufacture of cores by combining dry' ingredients with a solvent (e.g., water, alcohol) and extruding the wet mass through an orifice selected to provide extrudate of the desired diameter, which is then chopped, spherized and dried.Typical cores comprise microcrystalline cellulose and a binder and an optional lubricant or anti¬ tacking agent. In some embodiments, the core is inert (i.e., contains no API), in which case the core is01599.004W01covered with a drug layer, which contains the API. In other embodiments, the core some API and an enveloping drug layer is applied to add more API to the bead. In preferred embodiments, the core contains API in an amount as high as about 90 weight percent, and a drug layer is not used.When used, the drug layer comprises API, a binder, and optionally one or more excipients added to aid in processing (e.g., an anti-tacking agent).Whether the API is located only in the core of an IR bead or in a layer coating the core, the amount of API contained in an IR bead can range from about 5 to about 90 weight percent of the bead, e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90 weight percent.IR beads are preferably made by applying a seal coat over the drug layer or over the extruded core in cases where a drug overcoat is not applied. Tire seal coat is applied to improve the stability and utility (e.g., by increasing their flowability) of the resulting IR beads during subsequent manufacturing steps. The application of a seal coat can be accomplished using techniques well known in the art, such as by spraying a solution or suspension containing the seal coat ingredients on the beads.A variety of polymers known in the art may be used to provide the seal coat, such as polyethylene glycol (PEG), hydroxypropyl ethylcellulose, and hydroxypropyl methylcellulose (also known as hypromellose). Preferred seal coats comprise a cellulose-based polymer (e.g., HPC), a plasticizer (e.g., triethyl citrate), and an optional de-tacking agent (e.g., talc).Seal coats may be applied in a range of thicknesses, but preferably are done so in a manner that provides an effective coating without materially affecting API release from the underlying layers (i.e., the extruded core and / or its drug overcoat). The average thickness of a seal coat layer may be determined from the average weight gain exhibited by the beads upon coating (e.g., after drying).The average size of IR beads can be controlled by the manufacturing process (e.g., extruder orifice size) as well with the use of appropriately-sized meshes or screens. Sizes of IR beads are determined with an eye towards the desired sizes of the final SR and DR beads, but in general may range from about 0.8 mm to about 4 mm (e.g., from about 1 to about 3.5 mm, or from about 1.5 to about 3 mm) in diameter.4,2.3, SUSTAINED-RELEASE FORMULATIONSSustained-release (SR) beads are prepared by coating IR beads with an SR layer. Tire purpose of the layer is to regulate the release of the API so that its administration to a patient does not result in an immediate spike in exposure.Sustained release beads were prepared by applying a sustained release layer to the various IR beads disclosed above. The sustained release layer is typically comprised of a matrix polymer (also referred to as a “release retardant”), which is poorly or not soluble in water and not readily biodegradable in vivo, a water-soluble or biodegradable pore former, and a plasticizer.Examples of matrix polymers include ethylcellulose, polytetrafluoroethylene (PTFE), polypropylene (PP), poly(methyl methacrylate) (PMMA), poly(vinyl chloride) (PVC),01599.004W01polydimethylsiloxane (PDMS), cellulose acetate butyrate (CAB), and modified versions of cellulose such as aminated lignin. A particular water-insoluble polymer is ethylcellulose.Examples of water-soluble pore formers include polyvinylpyrrolidone (PVP) (e.g,, Kollidon®, Plasdone®), polyethylene glycol (PEG) (e.g., Carbowax®), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) (e.g., Methocel®), and polyvinyl alcohol (PVA) (e.g., Mowiol®). Examples of biodegradable pore formers include polylactic acid (PLA) and polyglycolic acid (PGA). A particular pore former is HPC.One embodiment of the invention is directed to an SR bead which contains an API) and comprises (e.g., consists essentially of):(i) a core comprising the API, microcrystalline cellulose, and a binder;(ii) a seal coat layer disposed over the core; and(iii) a sustained-release layer disposed over the seal coat layer, which sustained-release layer comprises a matrix polymer, a pore-former, and a plasticizer;wherein the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof In some embodiments, the core contains microcrystalline cellulose in an amount ranging from about 5 to about 25 weight percent (e.g., from about 10 to about 22, from about 12 to about 18, or about 15 weight percent) of the core.In some embodiments, the binder constitutes from about 1 to about 7 weight percent (e.g., from about 2 to about 6, from about 3 to about 5, or about 4 weight percent) of the core.In some embodiments, the binder is ethylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMA, hypromellose), maltose, methylcellulose, polydextrose, polymethacrylates, povidone, starch, sucrose, or a combination thereof. Preferred binders are povidone or hypromellose.In some embodiments, the core further comprises an anti-tacking agent.In some embodiments, the core contains the anti -tacking agent in an amount ranging from about 0.25 to about 3 weight percent (e.g., from about 0.5 to about 2, from about 0.75 to about 1.5, or about 1 weight percent) of the core.In some embodiments, the anti-tacking agent is calcium phosphate, calcium silicate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, or a combination thereof. A preferred antitacking agent is talc.In some embodiments, the SR bead comprises a drug layer disposed between the core and the seal coat layer, which drug layer comprises API and a binder. However, in preferred embodiments, all or substantially all (e.g., greater than about 96, 97, 98, or 99 weight percent) of the API contained in the bead is located in the core (e.g., the bead does not contain a drug layer).In some embodiments, the seal coat has a weight that ranges from about I to about 10 percent (e.g., from about 2 to about 8, from about 3 to about 7, or about 5 percent) of the weight of the core.In some embodiments, the seal coat layer comprises a cellulose-based polymer, a plasticizer, and an anti-tacking agent.01599.004W01In some embodiments, the cellulose-based polymer in an amount ranging from about 60 to about 90 weight percent (e.g., from about 65 to about 85, from about 70 to about 80, or about 73 weight percent) of the seal coat layer.In some embodiments, the cellulose-based polymer is polyethylene glycol, hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose, or a combination thereof. A preferred cellulose-based polymer is hydroxypropyl methylcellulose.In some embodiments, the seal coat layer contains the plasticizer in an amount ranging from about 2 to about 12 (e.g., from about 4 to about 10, from about 6 to about 8, or about 7 weight percent) of the seal coat layer. In some embodiments, the plasticizer is acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerin, mannitol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, triethyl citrate, or a combination thereof. A preferred plasticizer is triethyl citrate.In some embodiments, the seal coat layer contains the anti-tacking agent in an amount ranging from about 5 to about 30 weight percent (e.g., from about 10 to about 25, from about 14 to about 24, or about 21 weight percent) of the seal coat layer. In some embodiments, the anti-tacking agent is calcium phosphate, calcium silicate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, or a combination thereof. In some embodiments, tire anti-tacking agent is talc.In some embodiments, the sustained-release layer has a weight that ranges from about 2 to about 25 percent (e.g., from about 5 to about 20, from about 7 to about 17, from about 8 to about 15 weight percent, or about 10 weight percent) of the sum of the weights of the core and seal coat.In some embodiments, the sustained-release layer contains the matrix polymer (insoluble polymer) in an amount ranging from about 50 to about 85 weight percent (e.g., from about 55 to about 80, from about 65 to about 75, or about 69 weight percent) of the sustained-release layer. In some embodiments, the matrix polymer is ethylcellulose, polytetrafluoroethylene (PTFE), polypropylene (PP), poly(methyl methacrylate) (PMMA), poly (vinyl chloride) (PVC), polydimethylsiloxane (PDMS), cellulose acetate butyrate (CAB), or a modified version of cellulose such as aminated lignin. In some embodiments, tire matrix polymer is ethylcellulose.In some embodiments, the sustained-release layer contains the pore-former in an amount ranging from about 3 to about 15 weight percent (e.g., from about 4 to about 12, from about 6 to about 10, or about 8 weight percent) of the sustained-release layer. In some embodiments, the pore-former is polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polylactic acid, polyglycolic acid, or a combination thereof. A particular pore-former is hydroxypropyl cellulose.In some embodiments, the sustained-release layer contains the plasticizer in an amount ranging from about 3 to about 15 weight percent (e.g., from about 4 to about 12, from about 6 to about 10, or about 8 weight percent) of the sustained-release layer. In some embodiments, the plasti cizer is acetyltributyl citrate, acetyl triethyl citrate, benzyl benzoate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerin, mannitol, palmitic acid, polyethylene01599.004W01glycol, polyvinyl acetate phthalate, propylene glycol, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, triethyl citrate, or a combination thereof. A particular plasticizer is dibutyl sebacate.In some embodiments, the sustained-release layer further comprises an anti-tacking agent. In some embodiments, the sustained-release layer contains the anti-tacking agent in an amount ranging from about 8 to about 20 weight percent (e.g., from about 10 to about 18, from about 12 to about 16, or about 15 weight percent) of the sustained-release layer. In some embodiments, the anti -tacking agent is calcium phosphate, calcium silicate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, or a combination thereof. A preferred anti-tacking agent is talc.A particular embodiment of the invention encompasses a sustained-release (SR) bead which contains an active-pharmaceutical ingredient (API) and comprises:(i) a core comprising the API, microcrystalline cellulose, povidone, and talc, wherein the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof and constitutes about 75 to about 85 weight percent of the core; the microcrystalline cellulose constitutes from about 10 to about 20 weight percent of the core; the povidone constitutes from about 2 to about 6 weight percent of the core; and the talc constitutes from about 0.5 to about 2 weight percent of the core;(ii) a seal coat layer disposed over the core, which seal coat layer comprises hydroxypropyl methylcellulose, triethyl citrate, and talc, wherein the hydroxypropyl methylcellulose constitutes from about 65 to about 85 weight percent of the seal coat; the triethyl citrate constitutes from about 4 to about 10 weight percent of the seal coat; and the talc constitutes from about 13 to about 27 weight percent of the seal coat; and(iii) a sustained-release layer disposed over the seal coat layer, which sustained-release layer comprises ethylcellulose, hydroxypropyl cellulose, dibutyl sebacate, and talc, wherein the ethylcellulose constitutes from about 65 to about 75 weight percent (e.g., about 69 weight percent) of the sustained-release layer; the hydroxypropyl cellulose constitutes from about 5 to about 12 weight percent (e.g., about 8 weight percent) of the sustained-release layer; the dibutyl sebacate constitutes from about 4 to about 12 weight percent (e.g., about 8 weight percent) of the sustained-release layer; and the talc constitutes from about 10 to about 18 weight percent (e.g., about 15 weight percent) of the sustained-release layer;wherein the seal coat has a weight that ranges from about 3 to about 7 percent (e.g., about 5 percent) of the weight of the core; the sustained-release layer has a weight that ranges from about 8 to about 15 percent (e.g., about 10 percent) of the sum of the weights of the core and seal coat; and all or substantially all (e.g., greater than about 95, 96, 97, 98, or 99 percent) of the API in the bead is located in the core.In some embodiments of the invention, the SR bead has a diameter of less than about 5 mm (e.g., has a diameter of about 1, 2, 3, 4 or 5 mm).Particular embodiments (e.g., dosage forms) of the invention comprise a plurality of SR beads.01599.004W014.2.3. I. Methods of ManufactureTliis invention encompasses processes for manufacturing SR beads and tire products of those processes. One embodiment encompasses a method of preparing a plurality of beads, which method comprises:extruding a first mixture comprised of a dry blend and water to provide an extrudate; chopping, spherizing, and drying the extrudate to provide a plurality of inner cores;coating the plurality of inner cores with a sealant to provide a plurality of sealed cores, which plurality of sealed cores weighs about 3 to about 8 percent more than the plurality of inner cores; and coating the plurality of sealed cores with a sustained-release mixture to provide the plurality of SR beads, which plurality of SR beads weighs from about 5 to about 20 percent more than the plurality of sealed cores; wherein:the dry blend comprises about 50 to about 90 weight percent of an active pharmaceutical ingredient (API), about 10 to about 40 weight percent microcrystalline cellulose, about 2 to about 7 weight percent binder, and optionally about 0.25 to about 2 weight percent anti-tacking agent, wherein the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof;the sealant, when dried, contains about 70 to about 95 weight percent cellulose -based polymer, optionally from about 4 to about 10 weight percent plasticizer, and optionally from about 13 to about 27 weight percent anti-tacking agent;the sustained-release mixture, when dried, contains from about 50 to about 85 weight percent matrix polymer, from about 4 to about 12 weight percent pore former, from about 4 to about 12. weight percent plasticizer, and optionally from about 10 to about 18 weight percent anti -tacking agent.In particular embodiments of the invention, the binder is povidone or hypromellose. In some embodiments, the sealant cellulose -based polymer is hydroxypropyl methylcellulose. In some embodiments, the sealant plasticizer is triethyl citrate. In some embodiments, the sealant anti -tacking agent is talc.In some embodiments, the matrix polymer is ethylcellulose, polytetrafluoroethylene (PTFE), polypropylene (PP), poly(methyl methacrylate) (PMMA), poly(vinyl chloride) (PVC),polydimethylsiloxane (PDMS), cellulose acetate butyrate (CAB), or a modified version of cellulose such as aminated lignin. A particular matrix polymer is ethylcellulose.In some embodiments, the pore former is polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polylactic acid, polyglycolic acid, or a combination thereof. A particular pore-former is hydroxypropyl cellulose.In some embodiments, the plasticizer is acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerin, mannitol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, triethyl citrate, or a combination thereof. A particular plasticizer is dibutyl sebacate.01599.004W01In some embodiments, the anti-tacking agent is calcium phosphate, calcium silicate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, or a combination thereof. In some embodiments, tire anti -tacking agent is talc.In some embodiments, the first mixture further comprises an alcohol (e.g., ethanol).In some embodiments, the sustained-release mixture is combined with a solvent comprising water and an optional alcohol (e.g., ethanol, isopropanol) prior to coating the plurality of seal sealed cores.Some embodiments further comprise blending at least some of the sealed cores with an anti¬ tacking agent (e.g., talc) before they are coated with the sustained-release mixture.4.23.1. Dissolution and Pharmacokinetic PropertiesThis invention encompasses pluralities of the various SR beads disclosed herein. One embodiment of the invention encompasses a plurality of SR beads, which, when exposed to dissolution conditions that consist of an acid stage and a buffer stage, releases about 40 percent of the API they contain at a time of 3 hours, about 60 percent the API at a time of 4 hours, about 80 percent at a time of 6 hours, about 85 percent at a time of 8 hours, and about 90 percent at a time of 12 hours, which times are measured from when the SR beads are first exposed to the dissolution conditions; wherein: the acid stage lasts for two hours and comprises simulated gastric fluid and the buffer phase lasts from the end of the acid phase to at least 12 hours and comprises a pH 6.8 phosphate buffer.In some embodiments, the plurality of SR beads when orally administered to healthy adult fasted beagle dogs at a dose of 30 mg / kg, provides plasma concentrations of MPA with an average Cmaxof 4400 ± 1900 ng / mL and a median Tmaxof about 2 hours.In some embodiments, the plurality, when orally administered to healthy adult fasted beagle dogs at a dose of 30 mg / kg, provides plasma concentrations of MPA with an average AUC of 26600 ± 12100 ng*hr / mL, which AUCiast is calculated from concentration measurements taken 1, 1.5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours after administration,In some embodiments, the plurality, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average Cmaxof 2600 ± 500 ng / mL and a median Tmaxof about 2 hours.In some embodiments, the plurality, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average AUCiast of 18300 ± 5100 ng*hr / mL, which AUCiast is calculated from concentration measurements taken 1, 1.5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours after administration.4.2.4. DELAYED-RELEASE FORMULATIONSDelayed-release (DR) beads may be prepared directly from IR beads (or their extruded cores), but are preferably prepared by applying a DR coating to SR beads. While the SR coating described above controls the rate of API release, the DR coating ensures that the majority of that release does not occur until a meaningful time after administration (e.g, when the beads enter the colon).01599.004W01In general, a DR bead comprises a delayed-release layer disposed over any of the SR beads described herein. Thus, one embodiment of the invention is directed to a DR bead comprising (e.g., consisting essentially of):(i) a core comprising API, microcrystalline cellulose, and a binder;(ii) a seal coat layer disposed over the core;(ni) a sustained-release layer disposed over the seal coat layer; and(iv) a delayed-release layer disposed over the sustained-release layer;wherein the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof.In some embodiments of the invention, the delayed-release layer has a weight that ranges from about 5 to about 40 percent (e.g., from about 10 to about 40, from about 15 to about 35, or from about 20 to about 30 percent) of the SR bead.In some embodiments, the delayed-release layer comprises a polymethacrylate, a plasticizer, and an optional anti -tacking agent (e.g., talc), wherein tire polymethacrylate dissolves in water at a pH > 5.5 (e.g., pH > 6, 6.5, or 7).In some embodiments, the delayed-release layer contains the polymethacrylate in an amount ranging from about 45 to about 80 weight percent (e.g., from about 55 to about 70, from about 60 to about 65, or about 63 weight percent) of the delayed-release layer, in some embodiments, the polymethacrylate is an anionic polymer of methacrylic acid (e.g., Eudragit L30) or an anionic copolymer of methacrylic acid and methyl methacrylate e.g., Eudragit S100).In some embodiments, the delayed-release layer contains the plasticizer in an amount ranging from about 1 to about 15 weight percent (e.g., from about 2 to about 12, from about 4 to about 10, or about 6 weight percent) of tire delayed-release layer. In some embodiments, the plasticizer is triethyl citrate.In some embodiments, the delayed-release layer contains the anti-tacking agent in an amount ranging from about 15 to about 50 weight percent (e.g., from about 20 to about 40, from about 25 to about 35, or about 31 weight percent) of the delayed-release layer.In some embodiments, the delayed-release layer further contains a stabilizer (e.g., glycerol monostearate). In some embodiments, the delayed-release layer comprises a mixture of the plasticizer, anti-tacking agent, and a stabilizer in an amount ranging from about 5 to about 35 weight percent (e.g., from about 10 to about 30, from about 1 to about 25, or about 20 weight percent) of the delayed-release layer.A typical DR bead has a diameter of less than about 7 mm (e.g., about 3, 4, 5, or 6 mm).A particular embodiment of the invention encompasses a DR bead that contains an active¬ pharmaceutical ingredient (API) and comprises:(i) a core comprising the API, microcrystalline cellulose, povidone, and talc, wherein the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof and constitutes about 75 to about 85 weight percent of the core; the microcrystalline cellulose constitutes from about 1001599.004W01to about 20 weight percent of the core; the povidone constitutes from about 2 to about 6 weigh t percent of the core; and the talc constitutes from about 0.5 to about 2 weight percent of the core;(ii) a seal coat layer disposed over the core, which seal coat layer comprises hydroxypropyl methylcellulose, triethyl citrate, and talc, wherein the hydroxypropyl methylcellulose constitutes from about 65 to about 85 weight percent of the seal coat; the triethyl citrate constitutes from about 4 to about 10 weight percent of the seal coat; and the talc constitutes from about 13 to about 27 weight percent of the seal coat;(iii) a sustained-release layer disposed over the seal coat layer, which sustained-release layer comprises ethylcellulose, hydroxypropyl cellulose, dibutyl sebacate, and talc, wherein the ethylcellulose constitutes from about 65 to about 75 weight percent (e.g., about 69 weight percent) of the sustained-release layer; the hydroxypropyl cellulose constitutes from about 5 to about 12 weight percent (e.g., about 8 weight percent) of the sustained-release layer; the dibutyl sebacate constitutes from about 4 to about 12 weight percent e.g., about 8 weight percent) of the sustained-release layer; and the talc constitutes from about 10 to about 18 weight percent (e.g., about 15 weight percent) of the sustained-release layer; and (iv) a delayed-release layer disposed over the sustained-release layer, which delayed-release layer comprises an anionic copolymer of methacrylic acid and methyl methacrylate (e.g., Eudragit S100), triethyl citrate, and talc, wherein: the anionic copolymer constitutes from about 60 to about 65 weight percent of the delayed-release layer; the triethyl citrate constitutes from about 4 to about 10 weight percent of the delayed-release layer; and the talc constitutes from about 25 to about 35 weight percent (e.g., about 31 weight percent) of the delayed -release layer; andwherein the seal coat has a weight that ranges from about 3 to about 7 percent (e.g., about 5 percent) of the weight of the core; the sustained-release layer has a weight that ranges from about 8 to about 15 percent (e.g., about 10 percent) of the sum of the weights of the core and seal coat; the delayed- release layer has a weight that ranges from about 15 to about 30 percent (e.g., from about 20 to about 25 percent) of the sum of the weights of the core, the seal coat, and the sustained-release layer; and all or substantially all (e.g., greater than about 95, 96, 97, 98, or 99 percent) of the API in the bead is located in the core.4.2.4. I. Methods of ManufactureThe invention encompasses pluralities of the DR beads disclosed herein and methods of their preparation. Preferred methods comprise coating a plurality’ of SR beads with a delayed-release coating.One embodiment of the invention encompasses a method of preparing a plurality of beads, which method comprises:extruding a first blend comprised of a dry' blend and water to provide an extrudate; chopping, spherizing and drying the extrudate to provide a plurality of inner cores;coating the plurality of inner cores with a sealant to provide a plurality of sealed cores, which plurality of sealed cores weighs about 3 to about 8 percent more than the plurality of inner cores;01599.004W01coating the plurality of sealed cores with a sustained-release mixture to provide the plurality of SR beads, which plurality of SR beads weighs from about 5 to about 20 percent more than the plurality of sealed cores; andcoating the plurality of SR beads with a delayed-release mixture to provide a plurality of DR beads, which plurality of DR beads weighs from about 5 to about 40 percent more than the plurality of SR beads wherein:the dry blend comprises about 50 to about 90 weight percent of an active pharmaceutical ingredient (API), about 10 to about 40 weight percent microcrystalline cellulose, about 3 to about 5 weight percent binder, and optionally about 0.25 to about 2 weight percent anti -tacking agent, wherein the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof;the sealant, when dried, comprises about 70 to about 95 weight percent cellulose -based polymer and optionally from about 8 to about 20 weight percent anti-tacking agent;the sustained-release mixture, when dried, contains from about 50 to about 90 weight percent pore former, from about 4 to about 12 weight percent plasticizer, and optionally from about 8 to about 20 weight percent anti-tacking agent; andthe delayed-release mixture, when dried, contains from about 45 to about 80 weight percent polymethacrylate, from about 1 to about 15 weight percent plasticizer, and about 15 to about 50 weight percent anti-tacking agent, wherein the polymethacrylate dissolves in water at a pH ≥ 5.5 (e.g., pH ≥ 6, 6.5, or 7).In some embodiments, the binder is povidone. In some embodiments, the cellulose -based polymer is hydroxypropyl methylcellulose as in an Opadry® formulation such as Opadry® Clear.In some embodiments, the pore former is a mixture of ethylcellulose and hydroxypropyl cellulose. In some embodiments, the plasticizer is dibutyl sebacate. In some embodiments, the antitacking agent is talc.In some embodiments, the first blend further comprises ethanol. In some embodiments, the sustained-release mixture is combined with a solvent comprising water and an optional alcohol (e.g., ethanol, isopropanol) prior to coating the plurality of seal sealed cores.Some embodiments of the method further comprises blending at least some of the sealed cores with an anti -tacking agent (e.g., talc) before they are coated wdtli the sustained-release mixture.In some embodiments, the polymethacrylate is an anionic polymer of methacrylic acid (e.g., Eudragit L30) or an anionic copolymer of methacrylic acid and methyl methacrylate (e.g., Eudragit S100).In some embodiments, the plasticizer is triethyl citrate. In some embodiments, the anti-tacking agent is talc.In some embodiments, the delayed-release mixture is combined with a solvent comprising water prior to coating the plurality of SR beads. In some embodiments, the solvent comprises water, an alcohol (e.g., ethanol, isopropanol), and optionally acetone.01599.004W014.2.4.2. Dissolution and Pharmacokinetic PropertiesThis invention encompasses pluralities of the various DR beads disclosed herein. One embodiment of the invention encompasses a plurality of DR beads, which, when exposed to dissolution conditions that consist of an acid stage and a buffer stage, releases about 15 to about 20 percent of the API they contain at a time of 3 hours, about 40 percent the API at a time of 4 hours, about 60 to about 70 percent at a time of 6 hours, about 85 to about 90 percent at a time of 8 hours, and / or about 90 percent at a time of 12 hours, which times are measured from when the SR beads are first exposed to the dissolution conditions; wherein: the acid stage lasts for two hours and comprises simulated gastric fluid and the buffer phase lasts from the end of the acid phase to at least 12 hours and comprises a pH 6.8 phosphate buffer.In some embodiments, the plurality of DR beads, when orally administered to healthy adult fasted beagle dogs at a dose of 30 mg / kg, provides an average plasma Cmaxof about 3817 ± 1500 ng / mL and a Tmaxof about 4 hours.In some embodiments, the plurality of DR beads, when orally administered to healthy adult fasted beagle dogs at a dose of 30 mg / kg, provides plasma concentrations of MPA with an average AUClastof 31500 ± 16100 ng*hr / mL, which AUClastis calculated from concentration measurements taken 1, 1.5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours after administration.In some embodiments, the plurality of DR beads, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average Cmaxof 1400 ±

[0520] ng / mL and a median Tmaxof about 2 hours.In some embodiments, the plurality of DR beads, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average AUClastof 14300 ±

[6000] ng*hr / mL, which AUClastis calculated from concentration measurements taken 1, 1.5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours after administration.Based on the data described herein and without being limited by theory, it is believed that formulation s that contain SR beads with a Tmaxof from about 1.5 to about 2 hours and DR beads with a Tmaxof from about 4 to about 5 hours provide particularly consistent patient-to-patient pharmacokinetic profiles (e.g., plasma MPA concentration versus time).4.2.5. INDIVIDUAL DOSAGE FORMSIndividual dosage forms of the invention are suitable for oral administration to a patient and comprise a plurality of SR, a plurality of DR beads, or a mixture of SR and DR beads (referred to herein as “SR / DR” mixtures or formulations). Typical dosage forms are capsules comprising the beads, although other dosage forms suitable for oral deliver}' (e.g., tablet, caplet) may be used. The beads may also be delivered to a patient without encapsulation (e.g, mixed with food).Atypical single unit dosage form of the invention contains at least 100 mg API (e.g., at least 150, 200, 250, 300 or 350 mg).01599.004W01The ratio of DR to SR beads may be varied to affect tire pharmacokinetic profile of the resulting dual SR / DR formulation. Thus, one embodiment of the invention encompasses a method of identifying an optimal pharmaceutical formulation, which method comprises:(i) determining the in vivo pharmacokinetic profile of plurality of test formulations; and (ii) identifying which of the plurality of test formulations provides the smallest Cmax(e.g, relative to AUC), the largest AUCiast, the largest AU Cmf, and / or the least pharmacokinetic variability between test subjects to which the plurality of test formulations were administered;wherein: each of the plurality of test formulations comprises a plurality of SR beads and a plurality of DR beads in an SR: DR ratio determined by the amount of API contained within each plurality of beads.Particular formulations of the invention contain a plurality of SR beads and a plurality of DR beads in a ratio (SR: DR) of from about 1: 10 to about 10: 1 (e.g, 1:10, 1:5, 1:3, 1: 1, 3:1, 5: 1, or 10: 1), which ratio is determined by the amount of API contained within each plurality. In particular formulations, the SR: DR ratio is about 1:1.A particular SR / DR formulation, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average Cmaxof 3100 ± 730 ng / mL and a median Tmaxof about 2 hours.A particular SR / DR formulation, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average AUClastof 22000 ± 2600 ng*hr / mL, which AUClastis calculated from concentration measurements taken 1, 1.5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours after administration.Formulations of the invention, whether made up of only' SR or DR beads or whether a mixture of both, may be included in kits. Kits comprise an SR, DR, or SR / DR formulation or a dosage form comprising it and instructions for administering the formulation or dosage form to a subject. In certain embodiments, the kit further comprises a companion delivery article (e.g, an irrigation syringe, a syringe, a tube, a transdermal patch or a mixing flask for producing a solution containing the formulation). In one embodiment, the kit comprises a sealed package housing individually sealed unit dosage foims comprising the formulation (e.g, as capsules), instructions for use and an optional companion delivery' piece.4.3. METHODS OF USESingle and dual-bead formulations of this invention are useful for suppressing inflammatory response (e.g,, lymphocyte proliferation) and in treating diseases and conditions in patients in need thereof. Consequently, this application encompasses methods of treating, managing or preventing a disease or condition in a patient, which comprises administering to the patient a therapeutically or prophylactically effective amount of a formulation disclosed herein. Administration is preferably oral.01599.004W01In one embodiment, the patient is in a fasted state. In another, the patient has recently eaten food. In one embodiment, the patient is a human, in another, the patient is a non-human mammal (e.g., dog or cat).In one embodiment, the formulation is administered once, twice or three times daily for a period of time (e.g., a week, a month or several months) determined by the clinician.In some embodiments, the patient has been diagnosed with an autoimmune disease or disorder associated with aberrant lymphocyte proliferation and / or activation and / or has undergone or is scheduled to undergo an organ transplant and / or artificial implant (e.g., a corneal implant, an artificial implant or replacement of a joint, a ligament, a bone, or the like).Examples of autoimmune diseases and disorders that may be treated, managed or prevented using formulations disclosed herein include aberrant lymphocyte proliferation and / or activation. Aberrant proliferation of lymphocytes includes, for example, increased proliferation (e.g., an increase in the overall percentage of lymphocytes in a population that are proliferating; an increase in the rate of proliferation of a single lymphocyte or of a population of lymphocytes; or an increase in the speed of one or more cycles of cell division by a lymphocyte or population of lymphocytes, relati ve to a normal baseline; proliferation induced exposure to healthy cells or tissues, rather than, for example, a mitogen, a cancer antigen, or an antigen associated with an infection) and proliferation that results in abnormal and / or dysfunctional lymphocytes, including lymphocytes with a decreased native functionality' and lymphocytes with an acquired undesirable functionality, such as autoreactivity. Aberrant activation of lymphocytes refers to one or more aberration in a functionality of a lymphocyte that typically occurs following contact with an antigen or mitogen, such as the production of lymphokines, the enlargement of cytoplasm, the synthesis of macromolecules (e.g, antibodies) and differentiation into memory and effector cell types.Specific diseases and disorders that may be treated, managed or prevented using formulations disclosed herein include: aplastic anemia; atopic dermatitis; autoimmune hemolytic disease; Behçet's disease; celiac disease; cutaneous Crohn’s disease; cutaneous vasculitis; diabetes mellitus type 1; erythema nodosum; Grave’s disease; glomerulonephritis; hepatitis; idiopathic thrombocytopenic purpura; immune-mediated hemolytic anemia; immune reactions associated with transplant or implant procedures (e.g., tissue transplants, grafts, and device implants) including host-versus-graft disease and other forms of implant rejection; immunobullous disease; immunoglobulin A nephropathy; immune cytopenias; inflammatory- bowel disease; lichen planus; lupus erythematosus; lupus nephritis; meningoencephalomyelitis; multiple sclerosis; myasthenia gravis; pemphigus vulgaris; pyoderma gangrenosum recurrent erythema multiforme; rheumatoid arthritis; pernicious anemia; psoriasis; sarcoidosis; scleroderma; small vessel vasculitis; subepidermal blistering autoimmune disease, or vitiligo. Particular disease and conditions are atopic dermatitis and immunes reaction associated with transplant or implant.Formulations of this invention are suitable for oral delivery to a patient, preferably in a fasted state. In humans, methods of treatment may comprise oral administration of a formulation of the invention sufficient to provide an acceptable dose of MPA, which may vary by condition. For example, when used for organ transplant rejection prophylaxis, the dosage for adults is 400 mg per square meter (m2) twice a01599.004W01day, up to a maximum dose of 720 mg twice a day. Suitable doses for the treatment of other conditions are well documented.In dogs, when used to treat atopic dermatitis, for example, a typical dose will range from about 10 to about 40 mg / kg (e.g., from about 15 to about 35, or from about 20 to about 30 mg / kg), As described below, SR / DR dosage forms of the invention may be effective at lower doses (e.g., 20 mg / kg) than prior forms. Dosage forms of the invention also exhibit dramatically less pharmacokinetic variability than prior forms. Particular dosage forms, when administered to a fasted, healthy beagle dog at a dose of 20 mg / kg, maintain an AUC ≥ 500 ng for at least 12 hours after administration.A dosage form of the invention is typically administered to a patient once or twice daily for as long as necessary to yield its desired therapeutic or prophylactic effect.4.4. EXAMPLESThe examples provided below describe the manufacture of various forms of SR and DR beads and their use to provide SR / DR formulations useful in treating, managing and preventing diseases and disorders in humans and other mammals.Extensive work was done to optimize the materials and methods used to prepare IR, SR and DR beads in order to minimize capsule size and / or the number of capsules that would need to be used to provide a therapeutically effective dose of the API, to improve manufacturing yields, decrease product variability, optimize product stability, and optimize the formulations’ PK and therapeutic profiles.4.4.1. IMMEDIATE RELEASE FOR ULATIONSTwo types of IR beads were prepared: those with a drug layer surrounding a core and those without a drug layer.4.4.1.1. Formulations With a Drug LayerImmediate release beads were prepared using both inert cores and cores composing different amounts of API. Both types of cores were then coated with a drug layer, which itself comprised different amounts of API. The drug layer was then coated with a seal coat to provide an IR bead useful for the preparation of SR and DR beads.Embodiments of IR beads containing an inert core were prepared using Cellets® 700 microcrystalline cellulose pellets (700 - 1000 um in size) coated with a drag layer containing MPNa and hypromellose, over which a seal coat (e.g., Opadry clear) was applied. Ingredients used to provide a DR bead containing this inert core are listed below:01599.004W01Table 1. Exemplary DR BeadSR Beads DR / SR BeadsLayer Material % weight gain % weight gainInert Core Cellets 700 (MCC) n / a n / aMy cophenolate SodiumIR Layer 60 60HvpromelloseSeal Coat Opadry® Clear 3 3Ethylcellulose N10Hydroxypropvl celluloseSR Layer 10 10TalcDibutyl sebacateEudragit S 100DR Layer Talc n / a 20Triethyl citrateTotal n / a n / aOpadry* Clear (Colorcon, Harleysville, PA, USA) comes in different grades and comprises a polymeric film former (e.g., hydroxypropyl methylcellulose) and a plasticizer (e.g., polyethylene glycol, propylene glycol).To increase drug loading, the inert cores were replaced by drug loaded cores that were manufactured by an extrusion and spheronization process. The drug-loaded sphere formulations were prepared by dry blending the ingredients in a high shear granulator bowl to uniformly blend the materials. Wet massing was then initiated by slowly adding solvent (e.g., water) to the bowl to granulate the excipients. Once properly wetted, the wet mass was extruded through a dome-faced screw extruder at a speed of 25 - 40 RPM. The extrudate was collected and added to the spheronizer equipped with a 2 mm die face. The extrudate was processed at 1350 RPM until sphere-like particles were produced. The spheres were then tray-dried in a convection oven at 50 °C to a target loss on drying (LOD) value ofNMT 2.0%.Instruments and equipment used to prepare these formulations include those listed below:01599.004W01Table 2. InstrumentationDescription Model ManufacturerHigh shear granulator GMX.01 VectorDome extruder DG-L1 FujiSpheronizer QJ-230 FujiMechanical oven Isotemp Fisher ScientificFluid bed processor FL-M-1 VectorFluid bed processor FL-M-3 VectorSemi-manual encapsulator ProFill 100 TorpacV-blender Blend-Master Patterson-KelleyAnalytical Balances Various Mettler ToledoPeristaltic Pump Various MasterFlexInduction sealer AM-75 Automate TechnologiesA large number of different formulations and processing conditions were tested to provide optimal cores, including those listed in below:Table 3. Various IR Bead FormulationsComponent (%)PEG Mg HPMCBatch # MPNa MCC Mannitol 8000 Stearate SiOi 603 Water STV02-122 50 50 — - ---- 27.5 STV02-124 50 50 — - ---- 31.5 STV02-125 50 50 ---- ---- 37 TB04-054 50 50 — — — — — — — 35 TB04-056 50 48.5 — — — — 1.5 — — — — 40 TB04-058 50 34 14.5 1.5 —— ---- 28.1 TB04-060 46.3 46.3 5.7 1.74 ----- ---- 39 TB04-063 45.2 45.2 5.7 1.7 2.2 ---- 40 TB04-064 50 43 — — 5 — — 2 — — 29 TB04-071 50 47.5 — - 2.5 ---- 38 TB04-073 50 45 ---- 5 ---- 44 TB04-075 40 58 — — 7 — — — — 59 TB04-076 30 68 — — — — 2 — — — — 59 TB04-078- 29.5 66.7 2 1.9 62 01TB04-079 30 67 2 ----- 1 50 TB04-081 40 57 2 1 34TB04-125 30 63 — — — — 5 2 3901599.004W01A particular IR core composition is described below:Table 4. Drug-Loaded Core FormulationComponent Trade Name % w / wMPNa n / a 30Microcrystalline Cellulose Avicel PH-101 63Magnesium Stearate n / a 5Hypromellose Pharmacoat 603 2Total 100Sieves with different mesh sizes were used to provide cores with a desired size range. In many formulations, the dried cores were screened with 20 and 30 mesh sieves to provide a range of sizes of from about 600 - 850 pm. These cores were then coated with a drug layer, which in most cases was applied in an amount sufficient to increase the weight of the beads by about 60% using a suspension formulated from the ingredients listed below:Table 5. Drug Layering FormulationComponent Function %w / w, film %w / w, suspension MPNa API 89 13.4Hypromellose (HPMC 606) Film former 11 1.6Treated Water Solvent — 85.0Total 100.0 100.0To optimize the conditions used to apply the drug layer, a variety of fluid bed process parameters were evaluated, including those listed below:Table 6. Exemplary Process ParametersTemperature (°C)Weight Gain (%) Substrate (g) Spray Rate (g / min) Process Air (CFM)Inlet Exhaust44 1,000 19 -21 73 - 77 56 - 58 70 - 7644 500 9 - 12 80 - 82 58 - 62 70 - 754.4.1.2. Formulations Without a Drug LayerWhile the use of a drug layer allows for IR beads having an inert core — or a core containing some API — it can make manufacturing difficult. To minimize manufacturing complexity and cost, extensive work focused on preparing cores with drug loads high enough to avoid having to use a drug coating layer. Different ingredients, ingredient ratios and processing conditions were tested with the goal of providing cores with high drug loads (e.g., greater than or equal to about 50, 60, 70, 80, or 90 weight percent of the core). This work utilized the ingredients and equipment described below:01599.004W01Table 7. IngredientsIngredients Grade Function Mycophenolate sodium - Drug Substance Microcrystalline cellulose Avicel PH101 DiluentMicrocrystalline cellulose + Na CMC Avicel RC 591 DiluentMicrocrystalline cellulose + Na CMC Avicel CL 611 DiluentMicrocrystalline cellulose Avicel PH 301 DiluentMicrocrystalline cellulose Ceolus 702 DiluentMicrocrystalline cellulose Ceolus PH 301 Diluent Lactose Monobydrate Impalpable 313 Diluent Hydroxy propyl methyl cellulose Pharmacoat 603 Binder Magnesium stearate, vegetable source Hyqual Lubricant Magnesium stearate MF2V Lubricant Magnesium Aluminum silicate Neusilin UFL2 Diluent Hydroxy’ propyl cellulose Klucel LF Binder Hydroxy propyl methyl cellulose Methocel E15 premium Binder Sodium Lauiyl Sulphate Kolliphor SLS Surfactant Povidone K30 Binder Povidone K 90 BinderTalc (micronized) Luzenac pharma M Anti-Tacking agent Ethanol Commercial grade SolventPurified water Not Applicable Solvent Table 8. EquipmentEquipment Manufacturer Model Weighing Balance - 100 Kg Mettler Toledo Spider 1 Weighing Balance - 15 Kg Sartorius Midrics 2 Weighing Balance - 220 g Sartorius BT 423 SRapid Mixer Granulator Bowman & Archer 250 ml-2000 ml Rapid Mixer Granulator Sainath boilers and Pneumatics TAP-HSMG-R2T-10 Extruder Fuji pandal MG-SS-2 Spheronizer Fuji pandal QJ-230T-2 Rapid drier Retsch TG 200Sieve shaker Electrolab - Overhead stirrer Remi Elektrotechnik Ltd ROG-1261D Friabilator Sievewell Instruments Pvt Ltd EF 2Moisture Analyzer Sartorius MA 100 Compression Machine Rimek Minipress 1101599.004W01With a goals of optimizing both API loads and manufacturing yield, multiple variables were evaluated to determine their effects on core shape, batch yield, manufacturability and product stability. From an ingredient standpoint, these included different amounts of API and different amounts, types and grades of granulating fluid, fillers, binders, lubricants and anti-tacking agents. From a process perspective, variable such as the quantity and kinds of solvent, type of extruder, extruder aperture size, spheronization plate aperture, spheronization time and spheronization speed were evaluated.Multiple combinations of ingredients were dry-blended, combined with a solvent or solvent system to provide a wet mass, and extruded to provide pellets that were spherized and dried for further processing. Some of those combinations are described in the tables below.01599.004W0Table 9Batch No. SF23000623 SF23000600 SF23000624 SF23000631 SF23000651 SF23000663 SF23000776 SF23000791A Material (%w / w)MPNa 32 61 67 80 80 80 80 80 Avicel PH 101 61 32 28 4 16 16 — — Avicel PH 301 — — — — — — 15 — Ceolus UF 702 — — — — — 15 Ceolus PH 301 — — — — — — — — Neusilin — — — 10 — — — Pharmacoat 603 2 2 2 3 4 4 — — Magnesium Stearate 5 5 3 3 -- — —Povidone PVP K30 — — 3 3 Povidone PVP K90 — — — — — — 1 1 HPC Klucel LF ““ ““ 4 — ““ Talc1'■■■ -■ 1 1 MCC and CMC sodium2— — 16 16 16 — - — H2O339 25 15 25 — — — — EtOH: H2O3— — 50 50 50 50 EtOH:H2O ratio -- -- 80:20 70:30 80:20 80:20 RMG Batch Size 195 g 195 g 195 g 195 g 195 g 195 g 195 g 195 g1(micronized) Luzenac pharma M.2Avicel RC591.3Percent of dry mix.01599.004W0Table 10Batch No. SF23000791B SF23000791D SF23000698 SF23000699 SF23000700 SF23000719 SF23000723 SF23000748A Material (%w / w)MPNa 80 80 80 80 80 80 80 80 Avicel PH 101 — 15 — — — — — Avicel PH 301 — — -- — — 18 16 14 Ceolus UF 702 — — — — — — — — Ceolus PH 301 15 — — — — — — — Neusilin — — — — — — — Pharmacoat 603 — — — — 4 — — — Magnesium Stearate — — — — — — — — Povidone P VP K30 3 3 ““ — 2 4 6 Povidone PVP K90 1 1 4 -■ -- — -■ HPC Klucel LF — — 4 — — — Talc11 1 — — — — — — MCC and CMC sodium2— ““ 16 16 16 — ““ H2O3— -■ -- — — EtOH: H2O350 50 50 50 50 50 50 50 EtOH: H2O ratio 80:20 80:20 80:20 80:20 80:20 80:20 80:20 80:20 RMG Batch Size 195 g 195 g 195 g 195 g 195 g 195 g 195 g 195 g1(micronized) Luzenac pharma M.2Avicel RC591.3Percent of dry mix.01599.004W0Table 11Batch No. SF23000748B SF23000776 SF23000737A SF23000737B SF23000737C SF23000737D Material (%w / w)MPNa 80 80 80 80 80 80 Avicel PH 101 — — — — — Avicel PH 301 16 15 16 16 16 16 Ceolus UF 702 — — — — — — Ceolus PH 301 — — — — — — Neusilin — — — — — Pharmacoat 603 — — — -- — -- Magnesium Stearate — — — — — — Povidone PVP K30 3 3 4 4 4 4 Povidone PVP K90 1 1 -- -■ — -■ HPC Klucel LF — — — — — Talc1— 1 — — — — MCC and CMC — ““ ““ ““ sodium2H2O3-- — — — — EtOH: H2O350 50 50 50 50 50 EtOH: H2O ratio 80:20 80:20 80:20 80:20 80:20 80:20 RMG Batch Size 195 g 195 g 195 g 195 g 195 g 195 g1(micro nized) Luzenac pharma M.2Avicel RC591.3Percent of dry mix.01599.004W01The various combination were tested fortheir effect on particle size distribution, since large size distributions can decrease processing yield: narrow distributions are often necessary to provide a final dosage form with predicable pharmacokinetic and in vivo properties.Different binders and binder amounts were found to affect particle size distribution, as well as the stability and uniformity of drug-loaded cores. This may be due, in part, to the binders’ different viscosities, which can affect the plasticity of the wet mass that is extruded to form the cores. In this regard, compositions containing different concentrations (e.g,, from about 2. to about 6 weight percent) and combinations of PVP K30 and PVP K90 were evaluated in the manufacture of IR cores.During spherization of the extruded cores, inner wall sticking was observed in many instances. Considering the suitability of process to operate on large scale equipment and from GMP batches perspective, talc (micronized) was introduced in the formulation, and it was added in binder solution to improve its efficiency as anti-tacking agent. Hie talc typically constituted from about 0.5 to about 2 weight percent (e.g., about 1 weight percent) of the resulting core.Study results show that batches processed at spheronizer speeds of from about 1400 to 1700 RPMs yielded as much as about 80% of pellets of target size. Speeds were varied to maximize the number of spherical cores produced, as opposed to dumbbell-shaped cores, for example. Spheronization times were also varied to optimize yields, and a range of from about 8 to about 12 minutes (e.g., about 9 or 10 minutes) was found to be optimal.The solvent used to provide a wet mass for extrusion can play a large role in the efficacy of that process, and considerable effort was made to identify solvents that provide high yields of spherical cores. A solvent system that was found to work well is an ethanokwater (v / v) mixture in a ratio of about 70 to 90 ethanol to about 30 to about 10 w ater, preferably in a ratio of about 80:20. This allowed bulk yields of greater than 80% is some cases. Attempts to prepare cores of this invention using water as granulating agent tended to produce agglomerates instead of spheroids,A particular API-loaded IR core of the invention was made using tire ingredients set forth below:Table 12. Exemplary Core FormulationMaterial Name Mg per unit %w / w My cophenolate Sodium API 1500.00 80.00 Microcrystalline cellulose (Avicel PH 301) 281.25 15.00 Povidone PVP K30 56.25 3.00Povidone PVP K90 18.75 1.00Talc Micronized (Talc Luzenac Pharma M) 18.75 1.00Ethanol: Water (80:20) of dry mix 50% of dry mix - Total 1875.00 100.0This formulation provided spherical cores with an MPNa load of 80 weight percent with a bulk yield greater than 80%. The resulting cores were spherical in shape and appeared to maintain their integrity after further processing. These cores were then coated with a seal coat.01599.004W014.4.1.3. Seal CoatInert and drug-loaded cores - including those with a drug layer over the inner core - -were coated with a seal coat. A seal coat can increase the stability of the IR beads (e.g., by reducing hygroscopicity and / or MPA degradation) and aid in their flowability.Seal coats used in this invention typically comprise a cellulose-based polymer, a plasticizer, and an anti-tacking agent. For example, Opandry® Clear contains HPC, triethyl citrate, and talc. Spray coating was used to apply seal coats to dried, extruded and spherized cores. Typical seal coats, when applied, constituted from about 2 to about 6 weight percent (e.g., about 3, 4, or 5 weight percent) of the resulting coated bead.In some instances, an aqueous suspension containing about 10 weight percent Opandry® Clear and optionally from about 0.5 to about 1.5 weight percent talc was applied by spray coating with an inlet temperature of NMT 60°C, a product temperature of from about 40-50°C, a spray rate of from 0.5 to about 3.5 g / minute, atomization air pressure of 1.2 bar, process air (CFM) of 30-50, nozzle diameter of 1.0 mm, and a column height of 25-30 mm. The coated granules were then dried using an inlet temperature of 60°C, product temperature of from about 40-50°C, process air (CFM) of 10-30, and a column height of 25-30 mm. In another process, the seal coat was applied by spray coating the formulation with a product temperature of from about 44-46°C, a spray rate of from 0.4 to about 3.2 g / minute, atomization air pressure of 0.9 - 1.1 bar 1.2, process air flow (CFM) of 26-39, nozzle diameter of 1.0 mm, and a column height of 15-19 mm. After drying, the resulting IR beads were blended with micronized talc and sifted through sieves and / or screens of the desired size e.g., #16 sieve and #30 mesh screen). Particular seal-coated IR beads of the invention were prepared from the ingredients listed below:Table 13. Exemplary Seal-Coated IR Bead FormulationIngredient name Mg / unit %w / wIR CoresMycophenolate Sodium API 1500.00 80.00 Microcrystalline cellulose (Avicel PH 301) 281.25 15.00Povidone PVP K30 56.25 3.00Povidone PVP K90 18.75 1.00Talc Micronized (Talc Luzenac Pharma M) 18.75 1.00Ethanol: Water (80:20) of dry mix 50% of dry mix - Total 1875.00 100.00Seal Coated PelletsIR cores 1875.00 95.24Opadry Clear 03K19229 81.00 4.11Talc Micronized (Talc Luzenac Pharma M) 12.75 0.65Water Q.s, -01599.004W01Total 1968.75 100.00BlendingSeal Coated pellets 1968.75 99.75Talc Micronized (Talc Luzenac Pharma M) 4.92 0.25Total 1973.67 100.004.4.2. SUSTAINED RELEASE FORMULATIONSSustained release beads were prepared by applying a sustained release layer to the various IR beads disclosed above.4.4.2.1. Formulations With a Drug LayerIR beads comprising a core with a 30 weight percent drug load were loaded into an FLM-1 fluid bed processor equipped with a Wurster tube in a bottom spray configuration. The beads were fluidized from below and traveled upward through the Wurster tube. A solution containing the sustained release polymers was sprayed through a 1.2 mm orifice nozzle, upwards through the tube, coating the bead particles. The beads exited the tube and traveled outward towards the wall of the fluid bed. They subsequently fell back down into the down bed region, where they were re-directed back into the Wurster tube. This process was continued until the desired quantity of polymer has been applied as determined by the beads’ weight gain. At that point, the spray was terminated and the inlet heater was turned off.Fluidization continued for approximately 10 minutes to dry the beads and remove residual solvent. In another process, the beads were dried in an oven.In some instances, the SR coating was applied using a formulation made from the ingredients listed below:Table 14. Exemplary SR Coating FormulationComponent Function % w / w, film % w / w, suspension Ethylcellulose N10 Insoluble Polymer 69.2 4.2Klucel LF Soluble Polymer 7.7 0.5Talc Detackifier 15.4 0.9Dibutyl sebacate Plasticizer 7.8 0.5Treated water Solvent 9.4Ethanol Solvent 84.6Total 100.0 100.0Other SR coating formulations were prepared using 68.9 weight percent Ethocel™, 8.2 weight percent HPC, 8.2 weight percent dibutyl sebacate, 14.8 weight percent talc, and an ethanol / water solvent.01599.004W01Representative fluid bed processing parameters used to apply the SR coating formulation include: spray rate (g / min) of 12-13; inlet temperature of 49-53°C; exhaust temperature of 41-53°C; process air (CFM) 60-70; and atomizing air (PSI) 30.Beads were prepared by varying the amount the weight percentage of the SR layer, and the resulting SR beads were subjected to dissolution tests using the detection parameters and dissolution conditions described in the tables below:Table 15. Detection ParametersColumn: Phenomenex Luna C8, 4.6 x 150 mm, 5 micron particle size, or equivalentDetection: UV at 250 nmColumn temperature: 45°CFlow rate: 1.0 mL / minInjection volume: 10.0 µLMobile phase: Mobile phase A: 22 mmol / L Triethylamine Buffer, pH 5.3Mobile phase B: AcetonitrileGradient program: Isocratic 60% A 40% B Run time: 7 minRetention time of the main peak: 4.0 - 4.6 minutesTable 16. Dissolution ConditionsApparatus: USP I (Baskets)Rotation Speed: 100 RPMDissolution Bath Temperature: 37.0 ± 0.5°CDissolution Vessel Volume: 900 mL SGF for Acid Stage;900 mL 0.05 mol / L NasPOi, pH 6.8, for Buffer Stage Sampling ’limes, Acid Stage: 30, 45, 60, 120 minutesSampling Times, Buffer Stage: 180, 240, 360, 480, 600, 720, 1440 minutesSample Volume: 1.5 mL AutosamplerFilter: 10 micron in-lineDrug dissolution testing for the various compositions described herein was conducted using the USP Type 1 (basket) apparatus, using 900 ml of dissolution media, which was heated to 37.0°C ± 0.5°C. A basket filled with the test samples rotates at 100 RPM inside the vessel of dissolution media. The total dissolution test time was 24 hours. The samples were tested in Simulated Gastric Fluid (SGF) media for the first two hours, then in the buffered media (pH~7) for an additional 22 hours. Some samples tested using this protocol were contained in gelatin or HPMC capsules.4.4.2.2. Formulations Without a Drug LayerUsing IR beads without a drug layer and seal-coated with Opadry® Clear to a 5 weight-percent gain, a range of different sustained-release (SR) beads were prepared by varying the ingredients used to01599.004W01provide the SR layer, the conditions under which the coating occurred and the amount of coating. To obtain desired dissolution profiles, a range of SR formulations and coating process parameters were evaluated, including the ratio of polymer to pore former, plasticizer level, coating parameters (spray rate, bed temperature, atomization pressure), and curing conditions (temperature and time). In most examples, hydroxypropyl cellulose (HPC) was used as the pore former and dibutyl sebacate was used as the plasticizer.Beads with SR layers ranging from 8 to 15 weight percent of the resulting SR beads were prepared. Studies to evaluate the effects of product temperature (e.g., 30 - 32°C, 40 - 45°C) and curing / drying times on dissolution properties and / or residual drug content were performed. Tire solid content within the suspensions used to apply the sustained-release coatings was also varied (e.g., 5, 7.5 weight percent) and its effect on the manufacturing process (e.g., yield) evaluated. Another variable studied was the how the amount of anti -tacking agent (talc, in these examples) (e.g., from about 10 to about 21 weight percent) used in the coating itself and in subsequent processing of dried beads affected manufacturing yield and the beads’ drug release profile. This work was done with the object of obtaining a stable SR formulation that will reproducibly release the API from about 2 to about 14 hours after dosing.SR beads were prepared from IR beads with a seal coat fixed at 5% weight gain using suspensions comprising various amounts of the ingredients listed below:Table 17. Exemplary SR Layer IngredientsIngredients Grade FunctionEthocel STD 10 premium orEthyl cellulose Matrix polymer (release retardant) Ethocel STD 4 CPS premiumHydroxypropyl cellulose Klucel EF Pore formerDibutyl sebacate Not applicable PlasticizerTalc (micronized) Luzenac pharma M Anti-Tacking agentEthanol Commercial grade SolventPurified water Not Applicable SolventSeveral batches were processed using these ingredients, each of which was coated with SR layer to provide a weight gain of 8, 10, 11.25, 12.5 or 15 percent. Formulation details and manufacturing conditions used to prepare the batches are provide in tables 18 and 19, below.Formulations were also prepared with different amount of the pore former and plasticizer used to provide the delayed-release coating. Examples are provided in table 20.01599.004W0Table 18. Exemplary FormulationsBatch No SF23000850A1 SF23000850B2 SF23000750B1 SF23000826 SF23000750A2 %SR Coating 8% w / w 10% w / w 11.25% w / w 12.5% w / w 15% w / w Ingredient Mg / unit %w / w Mg / unit %w / w Mg / unit %w / w Mg / unit %w / w Mg / unit %w / w IR PelletsCores 1875.00 100.00 1875.00 100.00 1875.00 100.00 1875.00 100.00 1875.00 100.00 Seal Coated Cores 1968.75 100.00 1968.75 100.00 1968.75 100.00 1968.75 100.00 1968.75 100.00 Blending (0.25% of Seal Coated Pellets)Seal Coated Pellets 1973.67 100.00 1973.67 100.00 1973.67 100.00 1973.67 100.00 1973.67 100.00 SR CoatingSeal Coated Pellets 1973.67 92.59 1973.67 90.91 1973.67 89.89 1973.67 88.89 1973.67 86.96 Ethocel STD 10 Prem. 108.71 5.10 135.89 6.26 152.88 6.96 169.87 7.65 203.84 8.98 HPC (Klucel EF Pharma) 12.94 0.61 16.18 0.75 18.20 0.83 20.22 0.91 24.27 1.07 Dibutyl sebacate 12.94 0.61 16.18 0.75 18.20 0.83 20.22 0.91 24.27 1.07 Talc Micronized 23.30 1.09 29.12 1.34 32.76 1.49 36.40 1.64 43.68 1.92 Ethanol* Q.s. Q.s. - Q.s. Q.s. Q.s. - Water* Q.s. - Q.s. - Q.s. - Q.s. - Q.s. - Total 2131.56 100.00 2171.04 100.00 2195.71 100.00 2220.38 100.00 2269.73 100.00*Ethanol and water were used as solvent and not present in final product except traces. The ethanol:water ratio used was 85:15 and solid content of SR coating dispersion was kept 5% constant.01599.004W0Table 19. Exemplary Manufacturing ConditionsSF23000850A SF23000850B SF23000750BBatch No SF23000826 SF23000750A21 2 1%SR Coating 8% w / w 10% w / w 11.25% w / w 12.5% w / w 15% w / w Process parameters Observed ValueSprayingInitial Load (g) 450 300 300 370 300Inlet Temp (°C) 53 - 67 53 - 57 52 - 57 53 - 57 54 - 59 Product Temp (°C) 43 - 48 42 - 47 42 - 45 42 - 44 43 - 48 Spray rate (g / min) 0.87 - 3.0 1.2 - 3.3 0.8 - 2.8 1.16 - 3.06 1.1 - 2.8 Air pressure (bar)11.2 1.2 1.2 1.2 1.2 Process air (CFM) 28 - 36 34 - 38 29 - 36 29 - 32 31 - 49 Nozzle (mm)21.0 1.00 1.00 1.00 1.00 Column (mm)320 17 17 - 20 20 20 CuringInlet Temp (°C) 50 58 56 60 - 63 50 Product Temp (°C) 50 44 - 48 45 - 49 45 - 51 50 Curing time (min) 30 30 30 30 301Atomization air pressure;2nozzle diameter;3column height.01599.004W0Table 20. Exemplary FormulationsBatch No SF23000850C2 SF23000850C3 SF23000750D1 SF23000850D2 SF23000850D3 %Pore Fonner 21.90% 11.90% 21.90% 16.90% 11.90% %Plasticizer 21.90% 21.90% 11.90% 16.90% 11.90%%SR Coating 10% SR CoatingTarget Bed Temp 35-39 °CIngredient Mg / unit Mg / unit Mg / unit Mg / unit Mg / unitIR Pellets 1875 1875 1875 1875 1875Seal Coated Pellets 1968.75 1968.75 1968.75 1968.75 1968.75 Blending of Seal Coated Pellets 1973.67 1973.67 1973.67 1973.67 1973.67SR CoatingSeal Coated Pellets (#16P-#30R) 1973.67 1973.67 1973.67 1973.67 1973.67 Ethocel STD 10FP Prem 135.54 135.54 135.54 135.54 135.54HPC (Klucel EF Pharma) 29.68 16.14 29.68 22.90 16.14Dibutyl sebacate 29.86 29.86 16.14 22.90 16.14Talc M 29.04 29.04 29.04 29.04 29.04Ethanol Q.s. Q.s. Q.s. Q.s. Q.s.P. Water Q.s. Q.s. Q.s. Q.s. Q.s.Total 2171.04 2171.04 2171.04 2171.04 2171.04*Ethanol and water was used as solvent and will not be present in final product except in trace. Note that an ethanol:water ratio of 85:15 was used and solid content of SR coating dispersion was kept 5% in all trials. Spraying was stopped after achieving 10%w / w SR coating.01599.004W01Particular SR pellet compositions, calculated for 1500 mg dose of MPNa, were prepared using the ingredients listed below:Table 21Ingredient Weight (%) Weight (nig)IR PelletsMPNa API 80.0 1500MCC (Avicel PH 301) 15.0 281Povidone PVP K30 3.0 56Povidone PVP K90 1.0 19Talc Micronized 1.0 19Total 100.0 1875Overcoat (Seal Coat)Opadiy Clear 03K19229 86.4 81Talc Micronized 13.6 13Total 100.0 94Talc Blended (SO wt. 0.25%)Total Blended 100.0 5Four compositions were prepared using this formulation, which differed only in the percent weight gain for the SR layer and / or the viscosity of the Ethocel™ used:Table 22. SR Coating IngredientsComposition1 2 3 4 SR Layer Weight Gain, % 10 12.5 15 10 Seal Coated Pellet Weight (mg) 1974 1974 1974 1974 Ingredient Wt. % in layer Weight (mg) Ethocel™ STD 10 cps Prem. 68.9 136 170 204 — Ethocel™ STD 4 cps Prem. n / a — — — 136 HPC (Klucel™ EF Pharma) 8.2 16 20 25 16 Dibutyl sebacate 8.2 16 20 25 16 Talc Micronized 14.8 29 36 44 29 Total 100.0 197 247 296 197 Seal coated pellet + SR layer weight* 2171 2220 2270 2171 % MPNa in Pellets 69.09 67.56 66.09 69.10* calculated for 1500 mg dose MPNa.01599.004W01Dissolution profiles of these four formulations are shown in FIG. 2.4.4.3. DELAYED RELEASE FORMULATIONSDelayed-release (DR) beads were prepared by applying a delayed release layer to SR beads, A multitude of different SR beads were used in this regard, including those made from IR beads having only an extruded drug-loaded core, from IR beads having a drug-loaded core coated with a drug layer, from IR beads having a drag-loaded core coated with a drug layer and further coated with a seal coat, and from IR beads having a drag-loaded core coated with a seal coat,4.4.3.1. Formulations With a Drug LayerDifferent coatings were tested to provide DR coated beads. For some, a coating was selected to dissolve at a pH of 5.5, an example of which is Eudragit L30 D55. In others, a coating that dissolves at a pH of 7.0 was used, an example of which is Eudragit S100. In each case, a suspension containing the coating material was used to apply the coating to SR beads.A particular delayed-release formulation was prepared from the ingredients listed below:Table 23. Exemplary Ingredients of a DR CoatingComponent Function %w / w, film % w / w, suspension Eudragit L30D-55 DR polymer system (enteric coat) 80 57.0Plasacryl HTP20 Detackifier and Plasticizer 20 14.55Treated water Solvent 28.45Total 100 100.0Another formulation was prepared using these ingredients:Table 24. Exemplary Ingredients of Another DR CoatingComponent Function %w / w, suspensionEudragit S100 Sustained Release 6.25Talc Anti-tacking 3.125Triethyl citrate Plasticizer 0.625Acetone Solvent 34.29Isopropanol Solvent 51.42Treated water Solvent 4.29Total 100Processing conditions used to prepare beads using these formulations include those described in in the table below, wherein the DR coating was applied to provide a 20 percent weight gain.01599.004W01Table 25. Exemplary Processing ConditionsBatch No. Substrate Spray Rate Inlet Temp. Exhaust Process Air Quantity (g) (g / min.) (°C) Temp. (°C) (CFM)TB03-146 1,420 10 - 12 33 - 35 28 65TB03-156 750 12 40 - 42 28 70The composition of a DR bead formulation comprising a core with approximately 30 weight percent MPNa and a drug layer comprising about 25 weight percent MPNa is summarized below:Table 26. Exemplary DR Bead FormulationLayer Material %weight gain % w / wMPNa 13.8 microcrystalline cellulose 29.0IR Core n / aMagnesium stearate 2.3 Hypromellose 0.9MPNa 24.5IR Drug Layer 60Hypromellose 3.0Seal Coat Opadry Clear 3 2.2Ethylcellulose N10 5.2 Hydroxypropyl cellulose 0.6SR Layer 10Talc 1.1Dibutyl sebacate 0.6DR Layer Eudragit S 100 10.5Talc 20 5.2Triethyl citrate 1.0Total 1004.4.3.2. Formulations Without a Drug LayerDR beads were also prepared from SR beads with cores that contained enough API (e.g., greater than about 70 weight percent) to avoid having to use a drug layer. In this case, DR pellets were prepared with different coating thicknesses (as determined by their relative weight gains) from a sprayed solution having the ingredients listed below':01599.004W01Table 27. Exemplary Spray FormulationIngredient Grade FunctionMethacrylic acid-methyl methacrylatecopolymer (1: 2) Eudragit S100 Release retardant Triethyl citrate Not applicable PlasticizerTalc (micronized) Luzenac pharma M Anti-Tacking agent Acetone Macron SolventIsopropyl alcohol Finar SolventPurified water Not Applicable SolventPellets were prepared using the process represented in the flow diagram shown in FIG. 3. Beads with DR coatings of 10, 15, 20 and 30 weight percent were prepared with an initial load of 300 g, a spray inlet temperature of from 32-36 °C, a product temperature of 27-32 °C a spray rate of 2.6 - 5.0; atomization air pressure 1.2 bar; process air (CFM) of 51 - 60; nozzle diameter of 1.2 mm, column height of 18 mm, a curing inlet temperature of 33 - 47 °C, and a curing time of about 30 minutes. Beads were also coated using low temperature bed of 22-24 °C, a spray inlet temperature of from 24-27 °C, a product temperature of 22-25 °C a spray rate of 2.6 - 5.0; atomization air pressure 1.2 bar; process air of 56-60 CFM; nozzle diameter of 1.2 mm, column height of 18 mm, a curing inlet temperature of 26-49 °C, a product temperature of 24 -41 °C and a curing time of about 30 minutes.Bead formulations prepared by these processes and with varying amounts of DR coating are described in table 28.The effect of the amount of DR coating on the dissolution profiles of beads was examined.Results for beads processed at high product temperatures are presented in Table 29. Beads coated with a 10 percent DR layer weight gain, exhibited faster drug release relative to their SR coated counterparts Those prototypes coated with 15 and 20 percent DR layer weight gains exhibited similar dissolution profiles compared to their SR coated counterparts. Beads coated to 30 percent DR layer weight gain exhibited much slower drug release compared to their SR coated counterparts. (These 30 percent DR coated prototypes were originally coated with 10 percent DR layer weight gain and then re-processed to apply additional DR layer for a total of 30 percent weight gain. Tire pellets were dried for a total of one hour: 30 minutes after the application of 10 percent DR layer weight gain and 30 minutes after coating of the additional 20 percent DR layer weight gain.)Results for beads processed at low product temperatures are presented in table 30. In general, the rate of MPNa drug dissolution trended lower with increased DR coating weight gain (10%, 1 %, 20%, 25% and 30%). Beads with DR layers that added 20 to 25 weight percent to the underlying SR beads exhibited dissolution profiles similar to those exhibited by preferred formulations containing a drug layer over a core with 30 weight percent MPNa.01599.004W0Table 28. Exemplary Bead FormulationsBatch No SYFD240017-86 SYFD240017-88 SYFD240017-85 SYFD240017-86%DR Coating 10%w / w 15%w / w 20%w / w 30%w / wIngredient Mg / unit %w / w Mg / unit %w / w Mg / unit %w / w Mg / unit %w / w IR Pellets 1875.00 100.00 1875.00 100.00 1875.00 100.00Seal Coated Pellets 1968.75 100.00 1968.75 100.00 1968.75 100.00 Additional 20% DR coating wa Seal Coated Pellets (Blended) 1973.67 100.00 1973.67 100.00 1973.67 100.00 performed on 10%DR coated pellets of Batch NoSeal Coated Pellets (Blended) 1973.67 100.00 1973.67 100.00 1973.67 100.00 SYFD240017-86SR Coated Pellets 2171.04 90.91 2171.04 86.96 2171.04 83.34Eudragit S100 135.66 5.68 203.48 8.15 271.31 10.41 271.31 11.89 Talc (micronized) 67.83 2.84 101.74 4.08 135.65 5.21 135.65 5.94 Triethyl citrate 13.57 0.57 20.35 0.82 27.13 1.04 27.13 1.19 Acetone* Q.s. Q.s. - Q.s. - Q.s,Isopropyl alcohol* Q.s. - Q.s. - Q.s. - Q.s. - Water* Q.s. Q.s. Q.s. Q.s.Total 2388.10 100.00 2496.61 100.00 2605.13 100.00 2822.19 100.0001599.004W0Table 29. Dissolution DataBatch No SYFD240017-86 SYFD240017-88 SYFD240017-85 SYFD240017-86PTP%DR Coating 10%w / w 15%w / w 20%w / w 30%w / w Time points Avg Avg %RSD AVG %RSD AVG %RSD AVG %RSD Acid Stage: SGF without enzyme, 900 mL, 100 RPM, USP 1 (Basket)0.5 0 0 NA 0 NA 0 NA 0 NA 1 - 0 NA 0 NA 0 NA 0 NA 2 0 1 0.0 1 0.0 0 NA 0 173.2Buffer Stage: pH6.8 phosphate buffer, 900 mL, 100 RPM, USP 1 (Basket)3 22.5 58 1.7 40 1.5 45 1.3 16 12.5 4 40 72 0.8 63 0.9 64 1.6 30 8.6 6 60 81 0.7 83 0.7 76 1.3 56 4.6 8 70 90 0.7 90 0.6 88 1.3 73 2 9 10 80 93 0.7 93 0.0 92 0.0 82 1.5 12 85 94 0.6 94 0.6 94 0.7 86 1.3 14 - 94 0.0 95 0.6 95 0.0 88 1.4 16 - 95 0.7 95 0.0 95 0.6 90 1.2 18 - 95 0.7 95 0.0 95 0.6 90 0.7 20 94 0.7 96 0.0 95 0.1 90 1.4 24 100 94 0.7 96 0.0 95 0.7 90 1.2 Infinity - 94 0.6 95 0.0 95 0.6 90 1.2 Assay (%) 89.7 93.7 95.1 94.5NAWater (%) 3.13 3.57 3.53 3.6401599.004W0Table 30. Dissolution DataBatch No Proposed SYFD240017-87 SYFD240017-90 SYFD240017-91%DR target20%w / w 25%w / w 30%w / w 10%w / w 15%w / w 20%w / w 20%w / w 25%w / w 30%w / w Coating ProfileTime Avg Avg %RSD AVG %RSD AVG %RSD AVG %RSD Avg %RSD AVG %RSD AVG %RSD AVG %RSD Avg %RSD pointsAcid Stage: SGF without enzyme, 900 mL, 100 RPM, USP 1 (Basket)0.5 0 0 NA 0 NA 0 NA 0 NA 0 NA 0 NA 0 NA 0 NA 0 NA 1 - 0 NA 0 NA 0 NA 0 NA 0 NA 0 NA 0 NA 0 NA 0 NA 2 0 0 NA 0 NA 0 NA 1 0.0 0 NA 0 NA 0 NA 0 NA 0 NA Buffer Stage: pH6.8 phosphate buffer, 900 mL, 100 RPM, USP 1 (Basket)3 22.5 26 2.2 19 8.2 17 5.9 40 2.5 37 1.6 30 0.0 30 1.9 24 2.4 19 3.1 4 40 51 1.1 42 4.1 41 3.8 63 0.9 60 0.0 55 1.1 54 1.1 48 2.1 41 1.4 6 60 78 0.8 72 2.2 72 2.2 84 0.7 82 1.2 80 0.0 79 0.7 76 0.8 71 0.8 8 70 87 0.7 85 0.7 85 1.4 91 0.0 90 1.1 89 0.0 88 0.6 87 0.7 85 0.7 10 80 91 0.7 90 0.7 91 2.0 94 0.0 93 0.7 93 0.0 92 0.0 91 0.7 91 0.6 12 85 92 1.3 92 0.7 94 0.7 95 0.0 94 1.1 95 0.0 93 0.6 93 0.7 93 0.6 14 - 93 1.3 93 0.7 95 0.7 96 0.6 95 0.7 95 0.0 94 0.6 94 0.6 94 1.1 16 - 94 1.1 94 0.7 95 1.9 96 0.0 95 1.1 95 0.6 94 0.6 95 1.1 94 1.1 18 - 94 1.3 94 0.7 96 1.7 96 0.6 95 1.3 96 0.0 94 0.6 95 0.7 95 1.7 20 - 94 1.3 94 0.7 95 1.9 96 0.0 95 1.3 96 0.6 95 1.1 95 0.6 95 1.7 24 100 94 1.3 94 0.7 96 1.7 96 0.6 95 1.1 96 0.6 95 1.2 95 0.7 95 1.9 Infinity - 93 2.0 94 0.7 95 1.2 96 0.0 95 1.3 96 0.6 94 1.7 94 1.1 95 1.701599.004W01Based on these data, a preferred DR pellet formulation is made from the ingredients listed below:Table 31. Exemplary DR Pellet FormulationComponents Weight %IR PelletsMPNa API 80.0MCC (Avicel PH 301) 15.0Povidone (PVP K30) 3.0Povidone (PVP K90; dissolved in solvent) 1.0Talc, micronized (added to solvent) 1.0Granulation solvent: ethanol / water (80:20)Solution sprayed:1. Solvent only (20% w / w of dry components)2. PVP K90, talc, solvent (30% w / w of dry components)Seal Coat (5% wt. gain of IR pellets)Opadry Clear 86.3Talc, micronized 13.7Coating solution: 10% solids (w / w)Water: 100%Talc Blending (0.25% of seal-coated pellets)Talc, micronized 100.0SR Coat (10% of blended seal coated pellets)Ethocel 68.9HPC 8.2Dibutyl sebacate 8.2Talc, micronized 14.8Coating solution: 5% solid contentSolvent: ethanol / water (85:15)DR Coat (16% of SR coated pellets)Eudragit S 100 58.8Talc, micronized 29.4Triethyl citrate 11.7Coating Solution, 10% solid dispersionAcetone / IPA / Water: 38.11 / 57.11 / 4.78 (%w / w / w)A particular form of Opadry Clear used to prepare the beads was Opadry Clear 03O190001. which contains hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG).Dissolution profiles of SR and DR beads using this formulation are among those shown in FIG. 4 (identified as “Prototype 4” and “Prototype 7”, respectively). In addition to their desirable dissolution and pharmacokinetic properties (described below), these DR beads exhibited good shelf stability. Test results showed that drag dissolution from these beads were not significantly changed after storage at 40°C / 75%RH for 1 month.01599.004W014.4.4. SR / DR FORMULATION 1Dissolution profiles of various SR and DR beads were used to arrive a test formulation. Table 32 provides a summan' of some of tire tests, from which it was determined that an SR layer that provides a 12.5 percent weight gain best matched a target profile established for the SR beads. Dissolution studies preformed with DR beads having various amounts of DR layer recommended those with about 20 or 25 weight percent DR layer for further study. Dissolution studies of SR / DR combinations were evaluated to obtain data provided in Table 33. Based on these data, mixtures of SR / DR beads were encapsulated for in vivo testing.01599.004W0Table 32. Dissolution DataReference% SR,wg % DR, wg 30 120 180 240 360 480 600 720 1440 Number- Target SR 0 0 32.5 45 65 75 80 85 100Target DR 0 0 22.5 40 60 70 80 85 100 PF09-03 12.5 - 0.1 1.8 31.9 45 61.9 71.9 78.4 82.5 92.3 PF09-05 12.5 20 0 0 22 42.3 63.7 75.4 82.9 87.4 97.1 PF09-40 12.5 - 0 0 32.6 48 65.7 75.1 80.8 84.7 92.4 JH01-136 10 20 0 0 27.9 51.8 74 83.4 88.4 90.9 96.5Table 33. Dissolution DataDissolution, % dissolved (min)Reference Type SR DR 30 120 180 240 360 480 600 720 1440Reference ReferenceTarget 0.0 0.0 25.0 40.0 60.0 70.0 80.0 85.0 100.0 PF09-16 Size 000 PF09-03 PF09-05 0.0 0.0 31.3 46.5 63.2 71.5 76.6 79.9 86.7Capsulen / a Lab Blend PF09-03 PF09-05 0 0 18.7 30.3 50.6 64.2 73.2 79.2 91.5 PF09-16 Size 000 PF09-03 PF09-05 0.11 1.5 24.3 38.6 56.9 67.5 74.0 78.4 89.0CapsulePF08-175 Size 000 PF08-149 PF08-157 0.55 3.0 48.3 63.8 79.1 85.5 89.3 91.2 96.4Capsule01599.004W01Formulations used to prepare SR and DR beads are provided below. These beads were combined in a 1:1 mixture - --measured by the amount of MPA --to provide capsules containing a total dose of 300 mg MPA. The formulation contained in these capsules (referred to herein as “Formulation 1”) was used for in vivo testing, described below.Table 34. Bead FormulationsSR Beads DR BeadsLayer Material% weight gain % w / w % weight gain % w / w Mycophenolate Sodium 16.2 13.8 MCC 34.0 29.0 IR Core n / a n / aMagnesium Stearate 2.7 2.3 Hypromellose 1.1 0.9 IRDrug Mycophenolate Sodium 28.8 24.560 60Layer Hypromellose 3.6 3.0 Seal Coat Opadry Clear 3 2.6 2.2Ethylcellulose N 10 7 7 5.2 Hydroxypropyl cellulose 0.9 0.6 SR Layer 12.5 10Talc 1.7 1.2 Dibutyl sebacate 0.9 0.6 Eudragit S100 — 10.7 DR Layer Talc n / a — 20 5.3Triethyl citrate — 1.0Total 100 1004.4.5. SR / DR FORMULATION 2A second pharmaceutical formulation was prepared using SR and DR beads without a layer of API surrounding the core. The formulations used to prepare SR and DR beads are provided below.Table 35. SR Bead FormulationIngredient name Mg / unit %w / w IR PelletsMycophenolate Sodium API 1500.00 80.00 Microcrystalline cellulose (Avicel PH 301) 281.25 15.00 Povidone PVP K30 56.25 3.00 Povidone PVP K90 18.75 1.00 Talc Micronized (Talc Luzenac Pharma M) 18.75 1.00 Ethanol: Water (80:20) of dry mix 50% of dry mix - Total 1875.00 100.00 Seal Coated Pellets (coated to 5% weight gain of IR pellets)IR pellets 1875.00 95.24 Opadry Clear 03K19229 81.00 4.11 Talc Micronized (Talc Luzenac Pharma M) 12.75 0.65 Water Q.s. - Total 1968.75 100.00 Talc Blending (0.25% of sea! coated pellets)Seal Coated pellets 1968.75 99.75Talc Micronized (Talc Luzenac Pharma M) 4.92 0.2501599.004W01Total 1973.67 100.00 SR Coated Pellets (10% of sea! coated pellets blended with Talc)Seal Coated Pellets #16P-#30R (Blended) 1973.67 90.91 Ethocel STD 10 Prem. 135.54 6.24 HPC (Klucel EF Pharma) 16.14 0.74 Dibutyl Sebacate 16.14 0.74 Talc Micronized 29.04 1.34 Ethanol* Q.s. - Water* Q.s. -Total 2170.53 100.00Table 36. DR Bead FormulationIngredient name Mg / unit %w / w IR PelletsMycophenolate Sodium API 1500.00 80.00 Microciystalline cellulose (Avicel PH 301) 281.25 15.00 Povidone PVP K30 56.25 3.00 Povidone PVP K90 18.75 1.00 Talc Micronized (Talc Luzenac Pharma M) 18.75 1.00 Ethanol: Water (80:20) of dry mix 50% of dry mix - Total 1875.00 100.00 Seal Coated Pellets (coated to 5% weight gain of IR pellets)IR pellets 1875.00 95.24 Opadiy Clear 03K19229 81.00 4.11 Talc Micronized (Talc Luzenac Pharma M) 12.75 0.65 Water Q.s. - Total 1968.75 100.00 Talc Blending (0.25% of sea! coated pellets)Seal Coated pellets 1968.75 99.75 Talc Micronized (Talc Luzenac Pharma M) 4.92 0.25 Total 1973.67 100.00 SR Coated Pellets (10% of seal coated pellets blended with Talc)Seal Coated Pellets #16P-#30R (Blended) 1973.67 90.91 Ethocel STD 4 CPS Prem. 135.54 6.24 HPC (Klucel EF Pharma) 16.13 0.74 Dibutyl Sebacate 16.13 0.74 Talc Micronized 29.04 1.34 Ethanol* Q.s.Water* Q.s. = Total 2170.53 100.00 DR Coated Pellets (30% of SR coated pellets)SR Coated pellets 2171.04 76.93 Eudragit S100 406.98 14.42 Talc (micronized) 203.48 7.21Triethyl citrate 40.70 1.4401599.004W01Acetone* Q.s. - Isopropyl alcohol* Q.s. - Water* Q.s.Total 2822.20 100.00The SR and DR beads were combined in a 1:1 mixture — measured by the amount of MPA — and loaded in capsules. The formulation contained in these capsules (referred to herein as “Formulation 2”) was used for in vivo testing. The tables below provide dissolution data for the SR and DR beads used in this formulation.Table 37. SR Bead Dissolution DataTarget Initial Test Repeat Test Media Time AVG AVG %RSD AVG %RSD 0.5 0 0 NA 0 NA Acid Stage: SGF without enzyme,1 - 0 NA 0 NA 900 mL, 100 RPM, USP 1 (Basket)2 0 1 0.0 1 0.0 3 40 43 2.3 46 1.2 4 60 60 1.7 64 0.9 6 80 80 1.3 83 0.7 8 85 88 1.2 89 0.6 10 92 1.1 93 1.0 Buffer Stage: pH6.8 phosphate12 90 95 0.6 95 1.5 buffer, 900 mL, 100 RPM, USP 114 - 96 0.6 95 1.1 (Basket)16 97 0.6 96 1.6 18 98 0.1 96 1.0 20 - 98 0.7 96 1.0 24 100 99 0.7 97 1.6Infinity - 98 0.7 96 1.6Table 38. DR Bead Dissolution DataTarget Initial Test Repeat Test Media Time AVG AVG %RSD AVG %RSD 0.5 0 0 NA 0 NA Acid Stage: SGF without enzyme,1 0 0 NA 0 NA 900 mL, 100 RPM, USP 1 (Basket)2 0 0 NA 0 NA 3 22.5 16 3.7 15 10.0 4 40 38 4.6 37 5.7 6 60 70 1.7 70 2.5 8 70 84 0.7 84 1.4 10 80 89 1.2 90 1.4 Buffer Stage: pH6.8 phosphate12 85 92 1.3 92 1.3 buffer, 900 mL, 100 RPM, USP 114 - 94 0.7 93 1.2 (Basket)16 94 1.1 94 1.3 18 95 1.3 94 1.2 20 - 94 1.2 94 1.4 24 100 95 0.7 94 1.2Infinity - 95 1.3 94 1.401599.004W014.4.6. SR / DR FORMULATION 3This pharmaceutical formulation (“Formulation 3”) contained SR and DR beads without a layer of API surrounding the core, The beads were prepared using the formulations described above in table 31.In particular, the IR pellets used to provide SR and DR beads were formulated with 80% MPNa 15% microcrystalline cellulose (MCC), 3% povidone K30 (PVP K30), povidone K90 (PVP K90), and 1% talc. The seal coat consisted of 86% Opadry Clear and 14% talc. The ingredients in the SR layer were 69% ethyl cellulose 4cps (Ethocel or EC), 8% hydroxy propyl cellulose (HPC), 8% dibutyl sebacate, and 15% talc. The SR layer was coated to a 10% weight gain of the seal coated pellets. Tire DR layer consisted of Eudragit S100, talc, and triethyl citrate (TEC), with the ratio of TEC to Eudragit at 20%. The DR layer was coated to a 16% weight gain.Two different embodiments of Formulation 3 were tested in vivo. The first contained SR beads in an amount sufficient to release 6 mg / kg MPA and DR beads in amount sufficient to release 14 mg / kg of the drug. The second embodiment consisted of a 1: 1 mixture — measured by the amount of MPA — of the tw o types of beads, and loaded into capsules.4.4.7. A FIRST PK STUDYThe in vivo pharmacokinetics (PK) of dual bead Formulation 1 w'ere investigated in parallel, 24-hour open-label studies in dogs. The studies were directed at measuring the exposure of MPA follow ing the oral administration of a single-dose of each formulation.Throughout this study, in the study data, and in the data tables, the day of the first dosing of study animals was designated as Day (D) 0. Days preceding Day 0 are be referred to by negative numbers (e. g., Day -1, Day -2). Days subsequent to Day 0 are counted forward (e.g., Day 1, Day 2, Day 3). Study data may refer to either the study day or the study date or both.4.4.7. I. DogsHealthy male beagle dogs with a minimum age of 18 months and an initial body weight of approximately 8-12 kg ere used. Dogs were housed one per cage in a single room. Dogs were identified by unique microchip number and ear tattoo. The animals w'ere acclimated for at least 3 days prior to treatment in the room where they were housed during the study. Animals were in good physical health as determined by physical examinations performed during the acclimation phase.Animals w'ere fed a pelleted diet appropriate for their nutritional needs via feed bowls. Fresh feed was provided once daily. All animals were fasted overnight before dosing then offered feed after collection of the 4 hour sample was complete. Fresh potable water was offered ad libitum via water nipples. Daily health observations were performed once daily to assess general health, behavior, and all GI intolerance (e.g., vomiting and diarrhea) starting at the beginning of acclimation and continuing through Day 1.Animals w ere blocked by body w eight according to body w eights measured on approximately Day -3. Within each block, animals were randomized to either Group 1, Group 2, or Group 3 according to01599.004W01a random number generator. To reduce possible confounding of treatment effects, a treatment order was randomly allocated. The order of animals for dosing (and thus for blood sampling) was based on this order number.4.4.7.2. Drug AdministrationControlled-release MPA formulations were administered as outlined below. Capsules were given orally per dog. Capsule were administered orally by placing the capsule in the back of the throat followed by an approximately 10 mL flush with water.Table 39. Dosing ScheduleTreatment Group Number of Animals Dose Level1 5 300 mg MPA (SR)2 5 300 mg MPA (DR)5 300 mg MPA (SR / DR)All animals were fasted prior to dosing and then fed after the 4 hours sample collection was complete.4.4.7.3. Sample CollectionBlood samples were collected via direct puncture using a sterile needle connected to a vacutainer containing chilled K2-EDTA anticoagulant. Suitable superficial veins (jugular and cephalic veins) were used for sampling. After collection, blood samples were gently rocked to mix with anti-coagulant and then placed on ice until centrifugation.Each specimen (collected blood samples and plasma aliquots) were labeled with a pre-printed frost-proof label and will be identified with the study number, animal identification (treatment order number / microchip number), specimen type, and the target time and Study Day of sampling (pre-dose or minutes / hours post-treatment). The plasma tubes were additionally identified with the aliquot identity (A or B),Blood tubes were centrifuged within 60 minutes of samples collection. Samples were centrifuged at approximately 3000 rpm for 10 min at approximately 4°C. The resultant plasma was divided into 2 aliquots (A and B) in appropriately labelled polypropylene tubes. Aliquots A and B contained 30 pL of a 10% formic acid solution in water ( 1: 10 of concentrated, e.g., 88%, formic acid, final concentration is technically 8.8%). Once plasma was added to the 10% formic acid solution, the samples were capped and mixed. The volumes of the aliquots were: A: 300 pL; B: 300 pL. Plasma specimens were frozen at about - 80°C immediately after distribution into aliquots until shipped for analysis.4.4.7.4. AnalysisPlasma concentration profiles for MPA were collected over time to provide the data shown in FIGS. 5A-C. The data shown in FIG. 5A were obtained from dogs (Group 1) that received a dose of 30001599.004W01mg MPA delivered in a capsule of the SR beads used to provide Formulation 1. FIG. 5B shows the average MPA plasma concentrations overtime in dogs (Group 2) that received a dose of 300 mg MPA delivered in a capsule of the DR beads used to provide Formulation 1. FIG. 5C shows the average MPA plasma concentrations over time in dogs (Group 3) that received a dose of 300 mg MPA in a capsule containing SR / DR Formulation 1.Following a single administration of a SR, DR, or SR / DR formulation, the peak mean concentration were observed at 2 -hours (SR), 5 -hours (DR), and 2 -hours (SR / DR) post-dose, as shown below:Table 40. Mean Single Dose PKGroup Cmax (ng / mL) Tmax (h) AUC0-24h(h*ng / mL) AUCinf(h*ng / mL) Thalf (h)1 1,860 ± 728 2 (2-2) 15,363 ± 9086 16,699 ± 10896 4.89 ± 0.79 2 1,339 ± 734 5 (4-12) 11,915 ± 9278 11,210 ± 10565 4.63 ± 1.24 3 3,162 ± 1981 2 (1.5-5) 25,257± 8099 30,132 ± 10194 6.76 ± 2.18The area under the curve (AUC0-24h) for the individual SR and DR formulations were 15,363 ± 9,086 and 11,915 ± 9,278, respectively. In comparison, the AUC0-24hfor the SR / DR formulation was markedly higher (25,257 ± 8,099). In addition, the SR / DR exhibited dramatically less variation than prior formulations. For example, with the group of five dogs here, the ratio of the AUCinfstandard deviation to AUCinfis about half that of what was observed from the administration of SR or DR beads alone.FIG. 6 shows the average pharmacokinetic data from healthy beagle dogs that received SR / DR Formulation 1 (diamonds), 50% of the average PK from dogs receiving a composition of SR beads (squares), and 50% of the average PK from dogs receiving a composition of DR beads (circles). The triangles represent the sum of the SR and DR curves combined. It is immediately apparent that the mean plasma concentration / time profile of Formulation 1 is dramatically higher than what one would have expected based on the plasma profiles of its constituents. The actual data has a Cmaxthat is about twice that of the anticipated value. Further, if one were to combine the sum of the expected AUC for combining the SR compositions and the DR compositions into a 300 mg MPA dose, one would expect the AUCmf to be about 13,954 (h*ng / mL). Instead, the AUCinffor the SR / DR combination composition was about 16,699 (h*ng / mL). This synergistic effect provided by Formulation 1 was unexpected and prompted further study which, as described below, confirmed these unexpected results.4.4.8. A SECOND PK STUDYThis second study -was carried out as described above using SR / DR Formulation 1 and its component SR and DR beads. Dogs (n=5 per group) were administered a single dose of SR, DR or SR / DR formulations as shown below:01599.004W01Table 41. Dosing ScheduleTreatment Group Number of Animals Dose LevelA 5 30 mg / kg MPA (SR)B 5 ~ 30 mg / kg MPA (DR) C 5 ~ 30 mg / kg MPA (SR / DR)Each of the dogs weighed about 10 kgs. A dose of approximately 30 mg / kg was administered using dosage forms containing 346 mg MPNa.4.4.8.1. AnalysisPlasma concentration profiles over time for MPA were collected and pharmacokinetic data obtained for individual animals in each treatment group are provided in Tables 42-44. Table 42 provides MPA plasma concentration data for Group A; Table 43 provides MPA plasma concentration data for Group B; and Table 44 provides MPA plasma concentration data for Group C, wherein “MR” means not reported due to R2 <0.80 (improper elimination phase) and AUCinfextrapolated (%) is >20%.Table 42Plasma Concentration (ng / mL)Animal IDDog 2 Dog 5 Dog 8 Dog 11 Dog 13 Mean SD Time (h)0.0 0.00 0.00 0.00 0.00 0.00 0.00 NA 0.50 1388.93 818.19 442.04 3244.81 271.83 818.19 1203 1.00 3584.60 4762.72 5194.20 2654.10 4569.59 4569.59 1025 1.50 3151.44 3026.12 4284.78 1603.70 2121.96 3026.12 1032 2.00 2608.97 2187.96 3306.22 938.90 1866.68 2187.96 879 4.00 654.92 878.14 809.36 326.78 629.64 654.92 213 5.00 1142.12 924.17 712.86 798.36 650.81 798.36 195 6.00 1051.00 999.54 731.29 528.36 630.74 731.29 229 8.00 875.45 848.18 931.36 454.34 458.39 848.18 237 12.00 686.42 383.44 668.00 460.57 369.66 460.57 153 16.00 223.84 192.39 271.36 373.49 198.26 223.84 75 20.00 133.92 135.30 278.87 612.92 173.08 173.08 202 24.00 58.09 60.21 520.10 118.29 139.59 118.29 194 Cmax (ng / mL) 3584.6 4762.72 5194.2 3244.81 4569.59 4271.18 822.72 Tmax (hr) 1 1 1 0,5 1 1.00 0.5-1.0 AUClast17943.95 16288.64 20824.32 14393.52 12974.77 16485.04 3069.72 (ng*hr / niL)AUCinf18237.25 16674.59 26764.29 15929.43 16157.49 18752.61 4568.25 (ng*hr / mL)T1 / 2(hr) 3.5 4.44 NR NR 15.8 7.91 6.85MRTlast(hr) 6.24 5.77 7.12 8.89 6.42 6.89 1.2201599.004W01 Ciast (ng / mL) 58.09 60.21 520.1 118.29 139.59 179.26 193.85 Tiast (hr) 24 24 24 24 24 24.00 24.00 Rsq 0.98 0.99 NR NR 0.98 0.98 0.01 AUCinfextrapolated 1.61 2.31 22.19 9.64 19.7 11.09 9.57 (%)Table 43Plasma Concentration (ng / mL)Animal IDDog 6 Dog 10 Dog 14 Dog 17 Dog 19 Mean SD Time (h)0.0 0.00 0.00 0.00 0.00 0.00 0.00 NA 0.50 176.65 1730.84 741.16 456.86 1924.49 741.16 779 1.00 108.10 1396.55 560.27 255.02 1035.74 560.27 539 1.50 124.95 1365.38 1247.91 1623.93 3101.98 1365.38 1067 2.00 211.17 1408.01 1749.83 1584.98 3081.91 1584.98 1023 4.00 401.86 1506.03 611.74 2489.32 1623.60 1506.03 842 5.00 504.38 1820.51 565.22 1826.73 1918.51 1820.51 725 6.00 504.04 966.53 409.97 583.58 1553.13 583.58 469 8.00 744.73 612.89 602.76 705.45 1134.32 705.45 218 12.00 569.19 306.84 226.41 587.53 786.21 569.19 227 16.00 466.45 123.43 658.97 227.70 451.40 451.40 212 20.00 259.09 56.94 1145.98 148.63 249.73 249.73 440 24.00 133.07 29.71 314.82 502.65 203.12 203.12 181 Cmax (ng / mL) 744.73 1820.51 1749.83 2489.32 3101.98 1981.27 883.54 1 max (hr) 8 5 2 4 1.5 4.00 1.5-8.0 AUClast10011.29 13382.68 16123.1 16562.3 23325.66 15881.01 4915.30 (ng*hr / mL)AUCinf10860.04 13534.63 19532.66 NR 25011.46 17234.70 6326.81 (ng*hr / mL)T1 / 2(hr) 4.42 3.55 NR NR 5.75 4.57 1.11 MRTlast(hr) 11.22 5.67 11.8 7.88 7.2 8.75 2.65 Clast(ng / mL) 133.07 29.71 314.82 502.65 203.12 236.67 181.34 Tlast(hr) 24 24 24 24 24 24.00 0.00 Rsq 1 1 NR NR 0.99 1.00 0.01 AUCinfextrapolated 7.82 1.12 17.46 28.57 6.74 12.34 10.81 (%)01599.004W01Table 44Plasma Concentration (ng / mL)Animal IDDog 1 Dog 3 Dog 7 Dog 15 Dog 18 Mean SD Time (h)0.0 0.00 0.00 0.00 0.00 0.00 0.00 NA 0.50 221.90 1563.56 1252.13 1472.56 499.59 1252.13 604 1.00 1904.76 2037.71 2337.36 5206.61 2952.07 2337.36 1358 1.50 2716.00 3969.29 1505.36 5582.30 3974.32 3969.29 1530 2.00 2957.77 4122.16 1806.66 5771.66 3903.10 3903.10 1470 4.00 983.54 1335.64 1051.41 677.92 1158.92 1051.41 243 5.00 781.05 1275.09 923.00 859.66 911.23 911.23 190 6.00 478.01 1216.92 862.45 1287.28 1190.56 1190.56 338 8.00 650.35 805.13 1250.95 1023.18 1445.56 1023.18 323 12.00 426.45 374.69 1146.47 361.86 664.03 426.45 332 16.00 288.35 163.61 699.04 280.04 262.23 280.04 208 20.00 211.68 175.26 409.97 1149.15 113.25 211.68 427 24.00 178.18 109.60 334.20 789.20 52.75 178.18 297 Cmax (ng / mL) 2957.77 4122.16 2337.36 5771.66 3974.32 3832.65 1310.05 Tmax (hr) 2 2 1 2 1.5 2.00 1.0-2.0 AUClast15105.25 19530.74 22042.71 28964.91 21627.54 21454.23 5019.86 (ng*hr / mL)AUCinf17271.67 20337.79 25201.7 NR 21879.02 21172.55 3298.83 (ng*hr / mL)T1 / 2(hr) 8.43 5.1 6.55 NR 3.3 5.85 2.18 MRTiast (hr) 6.92 5.48 9.27 7.98 6.08 7.15 1.51 Ciast (ng / mL) 178.18 109.6 334.2 789.2 52.75 292.79 296.84 Tiast (hr) 24 24 24 24 24 24.00 24.00 Rsq 0.98 0.95 0.97 NR 1 0.98 0.02 AUCinfextrapolated 12.54 3.97 12.53 69.77 1.15 19.99 28.29 (%)Graphical representations of these results are shown in FIGS. 7A, 7B, and 7C, which show the mean plasma concentrations as a function of time for groups A, B, and C, respectively. As shown in FIG.7D, the in vivo characteristics of Formulation 1 is not a simple sum of the properties of its SR and DR components.Following a single administration of a SR, DR, or SR / DR formulation, the peak mean concentration were observed at 2 -hours (SR), 5-hours (DR) and 2 -hours (SR / DR) post-dose. The area under the curve (AUCo-24h) for the individual SR and DR formulations were 16,485 ± 3,070 and 15,881 ± 4,915, respectively. In comparison, the AUCo-24h for tire SR / DR formulation was markedly higher (21,454± 5,020). This data confirms the unexpected and synergistic results observed in the first study.01599.004W01Table 45. Mean Single Dose PKGroup Cmax (ng / mL) Tmax (h) AUC0-24h(h*ng / mL) AUCinf(h*ng / mL) Thalf(h) A 4,271 ± 823 1 (0.5-1) 16,485 ± 3,070 18,752 ± 4,568 7.91 ± 6.85 B 1,981 ± 883 4 (1.5-8) 15,881 ± 4,915 17,245 ± 6,327 4.57 ± 1.11 C 3,832 ± 1,310 2 (1-2) 21,454 ± 5,020 21,172 ± 3,299 5.85 ± 2.18Another benefit conferred by the SR / DR formulation is the low coefficient of variability exhibited by its AUCmf profile as compared to that of the individual beads. The coefficient of variability (CV), which is defined as the standard deviation of a value as a percentage of the mean, of each of the Cmax, AUCu-24hr and AUCmf values in the above table are shown below:Table 46. Coefficients of VariabilityGroup Cmax CV AUC0-24hCV AUCmf CVA 19.27 18.62 24.36B 44.57 30.95 36.69C 34.19 23.40 15.584.4.9. A THIRD PK STUDYThis study utilized SR and DR beads, and a dual-bead formulation comprising them, without a drug layer. In particular, the in vivo pharmacokinetics of SR / DR Formulation 2 and the SR and DR beads used in it were investigated in parallel, 24-hour open-label studies in dogs. The studies were directed at measuring the exposure of MPA following the oral administration of a single-dose of each formulation.Throughout this study, in tire study data, and in the data tables, the day of the first dosing of study animals was designated as Day (D) 0. Days preceding Day 0 will be referred to by negative numbers (e.g., Day -1, Day -2). Days subsequent to Day 0 will be counted forward (e.g., Day 1, Day 2, Day 3). Study data may refer to either the study day or the study date or both.4.4.9.1, DogsHealthy beagle dogs with a minimum age of one year and an initial body weight of approximately 9-12 kg were used. Dogs were housed one per cage in a single room. Dogs were identified by unique microchip number and ear tattoo. Tlie animals were acclimated for at least 3 days prior to treatment in the room where they were housed during the study. Animals were in good physical health as determined by physical examinations performed during the acclimation phase.Animals were fed a pelleted diet appropriate for their nutritional needs via feed bowls. Fresh feed was provided once daily. All animals were fasted overnight before dosing then offered feed after collection of tire 4 hour sample was complete. Fresh potable water was offered ad libitum via water nipples. Daily health observations were performed once daily to assess general health, behavior, and all01599.004W01GI intolerance (e.g., vomiting and diarrhea) starting at the beginning of acclimation and continuing through Day 1.4.4.9.2. Drug AdministrationDrug formulations were orally administered to dogs in capsules, which were placed at the back of each dog’s throat followed by an approximately 10 mL flush with water. All animals were fasted prior to dosing and then fed after the sample collection at 4 hours post-dosing.Formulations consisting of SR beads and formulations consisting of DR beads w ere administered as single capsules that provided a dose of 300 mg MPA. Similarly, SR / DR Formulation 2 was administered as a single capsule providing a total dose of 300 mg MPA. lire treatment groups w'ere as shown below:Table 47. Dosing ScheduleTreatment Group Number of Animals Dose Level1 5 300 mg MPA (SR)2 5 300 mg MPA (DR)3 5 300 mg MPA (SR / DR)4.4.9.3. Sample CollectionBlood samples w'ere collected via direct puncture using a sterile needle connected to a vacutainer containing chilled K2EDTA anticoagulant. Suitable superficial veins (jugular and cephalic veins) were used for sampling. After collection, blood samples were gently rocked to mix with anti-coagulant and then placed on ice until centrifugation.Samples were collected pre-dose, 0.5, 1, 1.5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours post dose. Approximately 1.5 mL of blood sample w ere collected in K2EDTA vacutainer tubes at each sample time point.The collected blood samples were immediately transferred on wet ice prior to centrifugation and centrifuged at 5000 rpm for 10 min at 4°C within 20 minutes of collection for initial timepoints (till 2 hours) and w ithin 10 minutes of collection for later timepoints (post 2 hours). Plasma was separated in the pre-labeled cryovials tubes. Upon harvesting of plasma, 1 volume of 10% formic acid in w ater was mixed with 10 parts of K2EDTA plasma (for example, 10 pL of 10% formic acid in water was quenched with 100 pL of K2EDTA plasma), acidified plasma was transferred in a labelled vial and stored below -70 °C.4.4.9.4. AnalysisPlasma concentration profiles over time for MPA were collected and analyzed as in the studies described above. These data demonstrated that the unexpected synergies observed for SR / DR Formulation 1 extend to SR / DR Formulation 2, which was prepared from SR and DR beads that had different ingredients and different ratios of ingredient that those in Formulation 1.01599.004W01These data also revealed that the SR and DR beads used in Formulation 2, which do not contain a drug layer but instead contain cores with approximately 80 weight percent MPNa, provide dramatically better in vivo pharmacokinetics than earlier versions of those beads. In fact, serum levels measured following administration of these beads alone were so high that further studies employed a 20 mg / kg dose, instead of the 30 mg / kg dose used for the Formulation 1 studies and in reports of other MPA dosage forms.Table 48 provides pharmacokinetic data obtained from healthy beagle dogs to which a 30 mg / kg dose of the SR beads used to prepare Formulation 2 was orally administered. Table 49 provides data regarding the plasma concentration of MPA obtained using a 20 mg / kg dose of the SR beads.Table 48. SR Beads at 30 mg / kgPlasma Concentration (ng / mL)Animal IDDog-1 Dog-2 Dog-3 Dog-4 Dog-5 Mean SD Time (h)Predose 0.00 0.00 0.00 0.00 0.00 0.00 0 0.5 197.36 274.18 113.48 231.10 70.90 177.40 84 1.0 637.62 2943.79 171.94 2754.33 660.92 1433.72 1308 1.5 1298.54 5521.77 4393.15 6316.82 1716.48 3849.35 2249 2.0 1263.44 5385.90 4823.15 6181.31 4022.95 4335.35 1890 4.0 598.69 1335.65 4332.75 4883.55 878.93 2405.91 2037 5.0 1236.16 667.91 4555.30 3553.34 572.44 2117.03 1821 6.0 1457.96 679.31 2637.46 1805.11 489.29 1413.83 873 8.0 1035.48 543.29 2651.85 1802.16 502.10 1306.98 916 12.0 797.24 569.11 1010.81 1219.51 865.32 892.40 243 16.0 426.73 162.31 807.69 593.79 460.61 490.23 237 20.0 267.00 120.80 320.34 155.48 257.04 224.13 83 24.0 121.92 71.66 112.26 67.50 181.99 111.07 46 Cmax(ng / mL) 1457.96 5521.77 4823.15 6317 4023 4429 1864Tmax(hr) 6 1.5 2 1.5 2 2.00 (1.5-6) AUClast16281.36 19974.67 40114.27 39381 17080 26566.15 12113.83 (ng*hr / mL)AUCinf17080.53 20486.4 40715.11 39650.09 18463.5 27279.13 11847.30 (ng*hr / mL)TI / 2 (hr) 4.54 4.95 3.71 2.77 5.27 4.25 1.01 MRTlast(hr) 8.91 5.03 7.05 6.1 8 7.02 1.53 Ciast (ng / mL) 121.92 71.66 112.26 67.5 181.99 111.07 46.37 Tlast(hr) 24 24 24 24 24 24.00 (24-24) Rsq 0.99 0.92 0.97 0.99 0.98 0.97 0.03 AUCinf4.68 2.5 1.48 0.68 7.49 3.37 2.66 extrapolated (%)01599.004W01Table 49. SR Beads at 20 mg / kgPlasma Concentration (ng / mL)Animal IDDog-1 Dog-2 Dog-3 Dog-4 Dog-5 Mean SD Time (h)Predose 0.00 0.00 0.00 0.00 0.00 0.00 0 0.5 28.78 195.14 155.08 154.50 0.00 106.70 86 1.0 194.43 1992.33 1050.88 953.28 171.85 872.55 749 1.5 762.62 2275.19 1829.52 2681.03 750.66 1659.80 878 2.0 2324.42 2041.22 3493.36 1416.77 1784.04 2211.96 790 4.0 1006.02 1856.97 2545.43 663.27 2489.63 1712.26 854 5.0 517.67 1010.74 1283.11 988.32 1801.39 1120.25 470 6.0 892.05 889.86 1077.55 801.96 1285.10 989.30 193 8.0 556.51 754.70 1109.24 892.89 475.30 757.73 256 12.0 451.67 873.71 848.69 1123.53 487.96 757.11 284 16.0 251.10 359.57 513.23 629.36 291.29 408.91 159 20.0 371.16 247.17 418.04 383.63 186.36 321.27 99 24.0 179.06 202.34 1762.04 335.53 200.27 535.85 688 Cmax(ng / mL) 2324.42 2275.19 3493.36 2681 2490 2653 496Tmax(hr) 2 1.5 2 1.5 4 2.00 (1.5-4) AUClast12758.97 18285.64 26363.5 18479 15629 18303.26 5071.68 (ng*hr / mL)AUCinf15036.14 21101 45475.84 21735.97 18606.1 24391.01 12077.07 (ng*hr / mL)TI / 2 (hr) 8.82 9.64 7.52 6.73 10.3 8.60 1.47 MRTiast (hr) 8.82 7.88 9.91 10 7.57 8.84 1.12 Clast(ng / mL) 179.06 202.34 1762.04 335.53 200.27 535.85 688.26 Tlast(hr) 24 24 24 24 24 24.00 (24-24) Rsq 0.87 0.97 0.87 0.94 0.86 0.90 0.05 AUCinf15.14 13.34 42.03 14.98 16 20.30 13.65 extrapolated (%)Graphical representations of the dogs’ average MPA plasma concentration versus time at 30 mg / kg and 20 mg / kg are shown in FIGS. 8A and 8B, respectively.Table 50 provides pharmacokinetic data obtained from healthy beagles to which a 30 mg / kg dose of the DR beads used to prepare Formulation 2 was orally administered. Table 51 provides data regarding the plasma concentration of MPA obtained using a 20 mg / kg dose of the DR beads.01599.004W01Table 50. DR Beads at 30 mg / kgPlasma Concentration (ng / mL)Animal IDDog-6 Dog-7 Dog-8 Dog-9 Dog-10 Mean SD Time (h)Predose 0.00 0.00 0.00 0.00 0.00 0.00 0 0.5 0.00 14.02 7.98 33.21 26.31 16.30 13 1.0 22.07 63.17 61.93 602.21 154.93 180.86 241 1.5 95.94 18.48 318.38 2101.54 1020.80 711.03 872 2.0 958.87 323.29 692.19 5394.30 1796.04 1832.94 2063 4.0 2396.73 3641.53 1071.95 6307.91 3285.44 3340.71 1932 5.0 2235.26 3185.26 3453.79 1130.38 2640.74 2529.09 914 6.0 1965.53 2671.71 2320.44 3128.46 2281.15 2473.46 443 8.0 1842.87 1655.89 1800.25 2503.73 1574.62 1875.47 367 12.0 875.17 1011.14 539.08 1728.50 778.91 986.56 449 16.0 484.04 314.37 466.15 4203.11 651.58 1223.85 1670 20.0 816.60 179.63 328.00 1024.29 403.87 550.48 355 24.0 413.59 97.25 166.20 625.81 854.64 431.50 316 Cmax (ng / mL) 2396.73 3641.53 3453.79 6308 3285 3817 1472 Tmax(hr) 4 4 5 4 4 4.00 (4-5) AUClast25100.79 24289.8 20667.83 59983 27607.31529.68 16098.80 (ng*hr / mL)AUCinf27575.69 24952.89 21957.05 62611.42 38016.98* 34274.26 19030.39 (ng*hr / mL)T1 / 2(hr) 4.15 4.73 5.38 2.91 8.44 5.12 2.07 MRTiast (hr) 9.89 7.83 8.7 10.19 9.02 9.13 0.95 Clast(ng / mL) 413.59 97.25 166.2 625.81 854.64 431.50 315.92 Tiast (hr) 24 24 24 24 24 24.00 (24-24) Rsq 1 1 0.97 0.93 0.94 0.97 0.03 AUCinfextrapolated 8.97 2.66 5.87 4.2 27.38* 5.43 2.70 (%)Table 51. DR Beads at 20 mg / kgPlasma Concentration (ng / mL)Animal IDDog-6 Dog-7 Dog-8 Dog-9 Dog-10 Mean SD Time (h)Predose 0.00 0.00 0.00 0.00 0.00 0.00 0 0.5 50.57 54.04 6.06 38.20 101.06 49.99 34 1.0 73.03 284.15 3.07 176.89 71.92 121.81 110 1.5 111.29 538.51 83.14 956.22 536.31 445.09 361 2.0 526.40 1059.33 182.21 1039.69 1396.82 840.89 48201599.004W014.0 4440.71 2007.45 749.54 1423.92 1480.95 2020.51 1425 5.0 2101.16 1295.49 539.04 913.31 1385.63 1246.93 584 6.0 3826.93 953.21 532.43 960.49 1042.95 1463.20 1336 8.0 4347.86 713.28 362.06 290.99 953.46 1333.53 1706 12.0 1820.61 1091.62 337.59 400.46 961.22 922.30 602 16.0 1720.87 546.03 184.67 240.91 674.14 673.32 620 20.0 849.67 378.51 457.88 171.60 628.32 497.20 256 24.0 376.42 218.77 212.25 83.24 818.42 341.82 286 Cmax(ng / mL) 4440.71 2007.45 749.54 1424 1481 2021 1425 4 4 4 4 4 4.00 (4-4) AUClast(ng*hr / mL) 45438.13 17920.34 8056.87 10462 20779 20531.15 14868.07(ng*hr / mL) 48477.38 19606.88 10316 11120.72 38598.9 25623.97 17113.67 (hr) 5.6 5.34 7.38 5.49 15.09 7.78 4.17 MRTtast (hr) 10.07 9.78 11.84 8.02 11.13 10.17 1.46(ng / mL) 376.42 218.77 212.25 83.24 818.42 341.82 285.98 (hr) 24 24 24 24 24 24.00 (24-24) Rsq 0.92 0.99 0.91 0.98 0.87 0.93 0.05 AUCinfextrapolated 6.27 8.6 21.9 5.93 46.17 17.77 17.18(%)In this particular testing DR beads at 20 mg / kg, tire data obtained for Dog-6 was clearly an outlier, having MPA concentration values vastly different from the other dogs’. Consequently, more realistic values for the average Cmax and other pharmacokinetic parameters may be obtained by excluding Dog-6 data, to provide tire values provided below:Table 52. DR Beads at 20 mg / kgProperty Mean (n=4) SD (n=4)(ng / mL) 1415 516(hr) 4 0AU (ng*hr / mL) 14304 6022AUCmf(ng*br / mL) 19911 13149Tv?, (hr) 8 5(hr) 10 2Ciast (ng / mL) 333 329(hr) 24 0Rsq 1 0AUCmf extrapolated (%) 21 1801599.004W01Graphical representation of the dogs’ average MPA plasma concentration versus time following administration of 30 mg / kg and 20 mg / kg of DR beads is shown in FIGS. 9 A and 9B (excluding the data for the outlier, Dog-6), respectively.Pharmacokinetic data obtained from healthy beagles to which a 20 mg / kg dose of SR / DR Formulation 2 was orally administered is shown below:Table 53. Formulation 2 at 20 mg / kgPlasma Concentration (ng / mL)Animal IDDog-11 Dog-12 Dog-13 Dog-14 Dog-15 Mean SD Time (h)Predose 0.00 0.00 0.00 0.00 0.00 0.00 0 0.5 112.41 46.17 117.99 108.95 64.39 89.98 32 1.0 1078.07 441.75 411.57 581.11 367.36 575.97 292 1.5 2006.34 1704.38 643.53 1895.03 2272.14 1704.28 628 2.0 2088.88 2545.77 1235.17 3800.69 3588.24 2651.75 1064 4.0 1311.48 1290.93 3334.50 1262.06 1485.72 1736.94 897 5.0 1788.60 1279.34 1502.51 1234.35 1111.92 1383.34 267 6.0 1956.38 1448.18 2788.29 1798.00 1084.43 1815.06 640 8.0 1645.85 900.66 438.84 864.42 949.23 959.80 434 12.0 1066.86 596.32 1259.43 957.95 731.76 922.46 264 16.0 522.14 413.08 470.41 412.29 591.40 481.86 76 20.0 920.43 273.59 779.04 288.30 296.60 511.59 313 24.0 373.54 1479.52 100.73 183.06 195.28 466.43 575 Cmax (ng / mL) 2088.88 2545.77 3334.5 3801 3588 3072 726 T (hr) 9 2 4 2 2 2.00 (2-4) AUClast(ng*hr / mL) 26178.94 20192.03 22876.3 20709 20094 22010.12 2588.33 AUCinf(ng*hr / mL) 31185.28 35206.33 23410.74 22512.68 21773.1 26817.62 6021.50 (hr) 9.29 7.03 3.68 6.83 5.96 6.56 2.02 MRTlast(hr) 9.78 10.19 9.27 8 8.2 9.09 0.96 Clast(ng / mL) 373.54 1479.52 100.73 183.06 195.28 466.43 575.01 Tlast(hr) 24 24 24 24 24 24.00 (24-24) Rsq 0.89 1 0.99 1 0.97 0.97 0.05 AUCinfextrapolated 16.05 42.65 2.28 8.01 7.71 15.34 16.04 (%)The 20 mg / kg dose was employed in these experiments because of the unexpectedly high MPA exposure provided by the SR and DR beads used in this formulation. FIG. 10 provides a graphical representation of the dogs’ mean MPA plasma concentration versus time.A comparison of average pharmacokinetic parameters obtained from this experiment is provided below, where G- 1 was the formulation of SR beads at a dose of 20 mg / kg, G-2 was the formulation of DR01599.004W01beads at a dose of 20 mg / kg excluding Dog-6, G-3 was the SR / DR Formulation 1 comprising a dose of 10 mg / kg each of SR and DR beads, G-4 was the formulation of SR beads at a dose of 30 mg / kg, and G-6 was the formulation of DR beads at a dose of 30 mg / kg:Table 54. Mean Pharmacokinetic ParametersForm Dose (mg / kg) Tmax (ti)® Cmax (ng / mL) AUClast(h*ng / mL) (h) MRTiast (h) G-l 20 2 (1.5-4) 2653 ± 496 18303 ± 5072 8.6 ± 1.5 9 ± 1 G-2 20 4 (4-4) 1415 ± 516 14304 ± 6022 8 ± 5 10 ± 2 G-3 10 + 10 2 (2-4) 3072 ± 726 22010 ± 2588 6.6 ± 2 9 ± 1 G-4 30 1.75 (1.5-2) 5171 ± 979 29137 ± 12312 4.2 ± 1.2 7 ± 130 4 (4-5) 3817 ± 1472 31530 ± 16099 5.1 ± 2.1 9 ± 1G-6§The numbers in parenthesis are ranges.These data clearly show that the dual bead SR / DR Formulation 2 exhibits unexpectedly good MPA exposure over 24 hours without the dramatic peaks and troughs exhibited by prior formulations of the drug. CV calculations for the Cmaxand AUC values in the above table are shown below:Table 55. Coefficients of VariabilityGroup Cmax CV AUClastCVG-l 18.69 27.71G-2 36.46 42.10G-3 23.63 11.75G-4 18.93 42.25G-6 38.56 51.064.4.10. A FOURTH PK STUDYThe in vivo pharmacokinetics (PK) of two embodiments of dual bead Formulation 3 and its components were investigated in parallel, 24-hour open-label studies in dogs. As a comparison, one arm of the study was performed using Myfortic®.4.4.10.1. DogsHealthy male beagle dogs aged 1-3 years and an initial body weight of approximately 8-12 kg were used. Dogs were housed one per cage in a single room. Dogs were identified by unique microchip number and ear tattoo. Tire animals were acclimated for at least 3 days prior to treatment in the room where they were housed during the study. Animals were in good physical health as determined by physical examinations performed during tire acclimation phase.Animals were fed a pelleted diet appropriate for their nutritional needs via feed bowls. Fresh feed was provided once daily. All animals were fasted overnight before dosing then offered feed after collection of the 4 hour sample was complete. Fresh potable water was offered ad libitum via water01599.004W01nipples. Daily health observations were performed once daily to assess general health, behavior, and all GI intolerance (e.g., vomiting and diarrhea) starting at the beginning of acclimation and continuing through Day 1.Animals were blocked by body weight according to body weights measured on approximately Day -3. Within each block, animals were randomized to either Group 1, Group 2, or Group 3 according to a random number generator. To reduce possible confounding of treatment effects, a treatment order was randomly allocated. The order of animals for dosing (and thus for blood sampling) was based on this order number.4.4.10.1. Drug AdministrationDrug formulations were orally administered to dogs in capsules, which were placed at the back of each dog’s throat followed by an approximately 10 mL flush with water. All animals were fasted prior to dosing and then fed after the sample collection at 4 hours post-dosing. Each of the treatment groups had eight dogs, and are summarized below:Table 56. Dosing GroupsGroup Drug Dose / RouteG-l My cophenolate Sodium (Myfortic® 180 mg Tablet) 180 mg, POG-2 Mycophenolate Sodium Sustained Release Capsules 20 mg / kg, POG-3 My cophenolate Sodium Delayed Release Capsules 20 mg / kg, POG-4 G4: Mycophenolate Sodium Sustained Release Capsules lOmg / kg + 20 mg / kg, PO Mycophenolate Sodium Delayed Release Capsules 1 Omg / kgG-5 G5: Mycophenolate Sodium Sustained Release Capsules 6 mg / kg + 20 mg / kg, PO Mycophenolate Sodium Delayed Release Capsules 14 mg / kgG-6 G6: Mycophenolate Sodium Sustained Release Capsules 20mg / kg + 40 mg / kg, PO Mycophenolate Sodium Delayed Release Capsules 20mg / kgwherein the sustained release capsules contained SR beads and the delayed release capsules contained DR beads.4.4.10.2. Sample CollectionBlood samples were collected via direct puncture using a sterile needle connected to a vacutainer containing chilled K2EDTA anticoagulant. Suitable superficial veins (jugular and cephalic veins) were used for sampling. After collection, blood samples were gently rocked to mix with anti-coagulant and then placed on ice until centrifugation.Samples were collected pre-dose, 0.5, 1, 1,5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours post dose. Approximately 1.5 mL of blood sample were collected in K2EDTA vacutainer tubes at each sample time point.The collected blood samples were immediately transferred on wet ice prior to centrifugation and centrifuged at 5000 rpm for 10 min at 4°C within 20 minutes of collection for initial timepoints (till 2 hours) and within 10 minutes of collection for later timepoints (post 2 hours). Plasma was separated in the01599.004W01pre-labeled cryovials tubes. Upon harvesting of plasma, 1 volume of 10% formic acid in water -was mixed with 10 parts of K2EDTA plasma (for example, 10 pL of 10% formic acid in water was quenched with 100 pL of K2EDTA plasma), acidified plasma was transferred in a labelled vial and stored below -70 °C.4.4.10.3. AnalysisPlasma concentration profiles over time for MPA were collected and analyzed as in the studies described above. These data demonstrate again the unexpected synergies observed for SR / DR formulations as compared to SR and DR beads alone.MPA plasma measurements and other PK information for each of the groups tested are presented in the tables below. Tables 56-A and 56-B provide raw and summarized PK data for Group 1; tables 57 -A and 57-B provide raw and summarized PK data for Group 2; tables 58-A and 58-B provide raw and summarized PK data for Group 3; tables 59-A and 59-B provide raw and summarized PK data for Group 4; tables 60-A and 60-B provide raw and summarized PK data for Group 5; and tables 61-A and 62-B provide raw and summarized PK data for Group 6, respectively.01599.004W0Table 56-A. Group 1 MPA Plasma ConcentrationsPlasma Concentration (ng / mL)Animal Id Dog-1 Dog-2 Dog-3 Dog-4 Dog-5 Dog-6 Dog-7 Dog-8Mean (n=8) SD (n=8) Time (h) MalePredose 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 0.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 1.0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 1.5 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 2.0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 3.0 0.00 0.00 0.00 0.00 25970.78 0.00 16206.09 0.00 5272.11 10105 4.0 0.00 0.00 0.00 0.00 1177.69 0.00 1533.73 0.00 338.93 635 5.0 4437.59 0.00 0.00 0.00 421.98 0.00 550.74 0.00 676.29 1536 6.0 1122.58 0.00 5616.53 0.00 265.62 0.00 484.17 3694.87 1397.97 2109 8.0 1141.04 0.00 415.96 0.00 397.60 0.00 686.63 436.77 384.75 398 12.0 552.97 1248.01 458.60 0.00 666.95 5.22 747.96 731.15 551.36 411 16.0 379.18 1211.65 499.23 2285.24 547.18 1250.40 496.34 313.25 872.81 676 20.0 289.61 305.71 206.62 1763.91 1245.76 694.65 188.93 182.34 609.69 593 24.0 152.14 225.29 120.46 482.51 611.00 261.02 125.96 138.78 264.65 18401599.004W0Table 56-B. Group 1 MPA PK SummaryDog-1 Dog-2 Dog-3 Dog-4 Dog-5 Dog-6 Dog-7 Dog-8 Mean (n=8) SD (n=8) Cmax (ng / mL) 4437.59 1248.01 5616.53 2285.24 25970.78 1250.40 16206.09 3694.87 7588.69 8861.20 ^max (hr) 5.00 12.00 6.00 16.00 3.00 16.00 3.00 6.00 6.00 3 - 16 AUClast(ng*hr / mL) 14167.73 11100.25 12434.55 16577.90 34436.88 8075.58 24191.41 10813.02 16474.67 8745.02 AUCinf(ng*hr / mL) 15637.33 12171.56 13419.35 NC NC NC 24989.88 11817.52 15607.13 5454.07 TI / 2 (hr) 6.70 3.30 5.67 NC NC NC 4.39 5.02 5.02 1.28 MRTiast (hr) 9.86 15.14 10.08 18.26 8.02 18.08 6.59 10.57 12.08 4.49 Ciast (ng / mL) 152.14 225.29 120.46 482.51 611.00 261.02 125.96 138.78 264.65 184.20 Tiast(hr) 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24 -24 Rsq 0.97 0.88 0.87 NC NC NC 0.97 0.95 0.93 0.05 AUC extrapolated (%) 9.40 8.80 7.34 NC NC NC 3.20 8.50 7.45 2.4901599.004W0Table 57-A. Group 2 MPA Plasma ConcentrationsPlasma Concentration (ng / mL)Animal Id Dog-9 Dog-10 Dog- 11 Dog-12 Dog-13 Dog-14 Dog-15 Dog-16Mean (n=8) SD (n=8) Time (h) MalePredose 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 0.25 0.00 10.35 20.52 0.00 5.33 0.00 21.78 0.00 7.25 9 0.5 5.37 416.33 3017.04 5.76 74.79 17.20 102.77 154.12 474.17 1036 1.0 194.40 6186.80 4264.15 137.09 1841.56 1288.69 574.92 2795.70 2160.41 2151 1.5 1136.07 7058.79 1697.42 220.52 2232.00 5587.11 2682.56 939.14 2694.20 2398 2.0 2855.84 5871.76 767.28 190.71 966.43 9078.59 788.27 3415.65 2991.82 3101 3.0 1000.26 2965.13 256.61 585.71 460.05 2919.36 408.60 1870.87 1308.32 1128 4.0 334.89 1296.15 300.33 2928.41 354.30 360.46 598.39 1385.55 944.81 914 5.0 439.88 2988.94 791.94 2286.30 1352.00 281.91 775.47 1140.04 1257.06 937 6.0 148.21 2991.71 637.34 651.47 519.00 472.43 504.08 800.25 840.56 889 8.0 214.37 1779.45 620.85 731.04 413.38 523.66 320.81 773.88 672.18 488 12.0 157.44 1672.27 354.81 1124.13 158.56 477.31 293.02 596.67 604.28 532 16.0 130.74 1094.47 179.04 492.59 231.80 382.47 398.82 334.99 405.62 303 20.0 63.64 1392.91 148.51 96.00 181.08 381.74 103.82 536.50 363.03 447 24.0 72.60 132.76 99.72 45.45 37.83 199.30 48.86 296.65 116.65 9101599.004W0Table 57-B. Group 2 MPA PK SummaryDog-9 Dog-10 Dog-11 Dog-12 Dog-13 Dog-14 Dog-15 Dog-16 Mean (n=8) SD (n=8) Cmax (ng / mL) 2855.84 7058.79 4264.15 2928.41 2232.00 9078.59 2682.56 3415.65 4314.50 2452.03 ^max (hr) 2.00 1.50 1.00 4.00 1.50 2.00 1.50 2.00 1.75 1 - 4 AUClast(ng*hr / mL) 6733.84 43783.38 11515.42 15665.04 9034.73 20423.26 8763.83 18572.80 16811.54 11951.06 AUCinf(ng*hr / mL) 7679.38 44853.63 12396.27 15826.50 9308.56 24121.72 9054.67 22588.47 18228.65 12406.39 TI / 2 (hr) 9.03 NR 6.12 2.46 5.02 12.86 4.13 9.38 7.00 3.60 MRTiast (hr) 6.31 8.41 6.68 8.94 7.25 6.51 8.19 8.46 7.59 1.03 Ciast (ng / mL) 72.60 132.76 99.72 45.45 37.83 199.30 48.86 296.65 116.65 90.71 Tiast(hr) 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24 -24 Rsq 0.89 NR 0.97 0.98 0.81 0.82 0.81 0.82 0.87 0.08 AUC extrapolated (%) 12.31 2.39 7.11 1.02 2.94 15.33 3.21 17.78 7.76 6.5101599.004W0Table 58-A. Group 3 MPA Plasma ConcentrationsPlasma Concentration (ng / mL)Animal Id Dog-17 Dog-18 Dog-19 Dog-20 Dog-21 Dog-22 Dog-23 Dog-24Mean (n=8) SD (n=8) Time (h) MalePredose 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 0.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 0.5 0.00 11.87 11.88 0.00 27.85 0.00 0.00 0.00 6.45 10 1.0 16.39 94.38 48.44 0.00 13.04 99.87 104.48 79.43 57.00 43 1.5 144.24 702.71 151.48 0.00 172.74 330.08 436.64 186.13 265.50 220 2.0 350.92 909.03 239.53 43.64 255.04 225.16 2012.70 140.40 522.05 656 3.0 299.86 1576.25 356.02 262.18 812.59 306.11 1988.56 128.88 716.31 696 4.0 368.47 917.37 498.31 258.53 694.41 399.62 1299.64 277.67 589.25 363 5.0 439.95 1113.43 254.48 621.72 804.66 339.54 1426.97 651.94 706.59 399 6.0 798.74 713.56 336.41 482.56 646.46 221.09 1148.99 333.49 585.16 305 8.0 398.31 476.35 211.39 459.50 803.94 169.47 1389.45 644.54 569.12 391 12.0 374.46 437.05 97.42 444.49 743.57 175.00 730.56 405.05 425.95 229 16.0 619.90 109.41 55.79 548.05 263.03 74.67 681.42 221.98 321.78 256 20.0 214.32 75.65 31.09 481.77 489.72 49.86 558.33 160.58 257.67 218 24.0 114.87 25.00 20.65 148.79 533.64 33.04 312.73 144.01 166.59 17701599.004W0Table 58-B. Group 3 MPA PK SummaryDog-17 Dog-18 Dog-19 Dog-20 Dog-21 Dog-22 Dog-23 Dog-24 Mean (n=8) SD (n=8) Cmax (ng / mL) 798.74 1576.25 498.31 621.72 812.59 399.62 2012.70 651.94 921.48 568.25 ^max (hr) 6.00 3.00 4.00 5.00 3.00 4.00 2.00 5.00 4.00 2 - 6 AUCiast (ng*hr / mL) 8700.56 9499.14 3243.92 9338.67 12870.34 3490.59 20667.68 7069.96 9360.11 5577.27 AUCinf (ng*hr / mL) 9245.69 9634.62 3410.13 10251.62 NR 3814.77 23879.95 8538.50 9825.04 6794.90 TI / 2 (hr) 3.29 3.76 5.58 4.25 NR 6.80 7.12 7.07 5.41 1.64 MRTiast (hr) 11.57 7.13 7.60 12.93 11.76 8.47 9.87 10.93 10.03 2.12 Ciast (ng / mL) 114.87 25.00 20.65 148.79 533.64 33.04 312.73 144.01 166.59 176.78 Tiast(hr) 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24 -24 Rsq 0.98 0.92 0.99 0.82 NR 1.00 0.93 0.95 0.94 0.06 AUC extrapolated (%) 5.90 1.41 4.87 8.91 59.04* 8.50 13.45 17.20 8.61 5.3301599.004W0Table 59-A. Group 4 MPA Plasma ConcentrationsPlasma Concentration (ng / mL)Animal Id Dog-1 Dog-2 Dog-3 Dog-4 Dog-5 Dog-6 Dog-7 Dog-8Mean (n=8) SD (n=8) Time (h) MalePredose 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 0.25 0.00 85.58 53.09 66.05 38.79 7.83 166.90 0.00 52.28 56 0.5 185.80 282.61 202.15 419.50 322.33 87.12 8413.96 10.05 1240.44 2901 1.0 918.86 630.14 718.11 807.95 2287.10 780.03 995.66 790.79 991.08 536 1.5 2145.89 1608.47 2438.45 1459.11 2659.05 641.46 1902.91 2478.15 1916.69 668 2.0 2358.58 1141.96 1709.66 1480.24 2809.75 1966.73 2515.13 1809.23 1973.91 557 3.0 2452.04 831.46 1592.50 3851.07 1572.83 2126.99 2959.80 1277.10 2082.97 982 4.0 1933.24 980.45 1440.60 3099.44 1211.25 4992.38 2332.41 955.89 2118.21 1375 5.0 2326.76 1290.68 1044.70 2934.75 1552.69 5083.28 2286.19 700.20 2152.41 1398 6.0 1388.79 1616.15 2073.10 1324.69 989.41 2858.79 2154.91 548.79 1619.33 728 8.0 1696.81 1230.32 830.81 1219.51 625.19 2020.69 1337.09 805.16 1220.70 472 12.0 920.63 812.52 547.19 848.20 643.06 274.81 974.88 310.43 666.47 270 16.0 1653.86 1229.94 1828.50 649.98 418.60 169.18 608.28 181.50 842.48 648 20.0 429.50 537.07 260.50 379.91 1817.60 485.81 301.56 136.62 543.57 531 24.0 552.36 237.73 428.43 238.55 597.10 264.22 157.91 99.33 321.95 18301599.004W0Table 59-B. Group 4 MPA PK SummaryDog-1 Dog-2 Dog-3 Dog-4 Dog-5 Dog-6 Dog-7 Dog-8 Mean (n=8) SD (n=8) Cmax (ng / mL) 2452.04 1616.15 2438.45 3851.07 2809.75 5083.28 8413.96 2478.15 3642.86 2200.92 ^max (hr) 3.00 6.00 1.50 3.00 2.00 5.00 0.50 1.50 2.50 0.5 - 6 AUCiast (ng*hr / mL) 29635.41 21754.88 22822.34 25684.05 24526.65 27712.95 28319.45 11652.27 24013.50 5684.66 AUCinf (ng*hr / mL) NR 22912.01 NR 27587.95 NR 29848.03 29256.17 12970.50 24514.93 7003.71 TI / 2 (hr) NR 3.37 NR 5.53 NR NR 4.11 9.20 5.55 2.59 MRTiast (hr) 9.81 10.60 10.11 8.11 11.18 7.18 7.27 7.09 8.92 1.69 Ciast (ng / mL) 552.36 237.73 428.43 238.55 597.10 264.22 157.91 99.33 321.95 182.83 Tiast(hr) 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24 -24 Rsq NR 1.00 NR 1.00 NR NR 1.00 1.00 1.00 0.00 AUC extrapolated (%) 21.18* 5.05 21.94* 6.90 47.53* 7.15 3.20 10.16 6.49 2.6001599.004W0Table 60-A. Group 5 MPA Plasma ConcentrationsPlasma Concentration (ng / mL)Animal Id Dog-9 Dog-10 Dog-11 Dog-12 Dog-13 Dog-14 Dog-15 Dog-16Mean (n=8) SD (n=8) Time (h) MalePredose 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 0.25 18.71 48.04 0.00 41.49 19.64 12.68 13.08 0.00 19.21 18 0.5 124.35 244.52 0.00 28.11 99.85 134.91 156.26 31.02 102.38 81 1.0 1789.41 1713.33 441.96 40.98 603.91 1830.92 619.80 193.86 904.27 749 1.5 3162.49 2376.05 1554.45 29.61 1495.49 2120.87 1479.12 140.34 1544.80 1063 2.0 1205.39 3444.67 2256.71 53.97 1510.00 2211.65 2024.59 1434.70 1767.71 982 3.0 1450.87 2959.86 1528.95 194.85 1905.46 2545.07 2705.44 1400.80 1836.41 899 4.0 1322.09 2023.26 1423.11 162.79 1562.13 1358.62 1328.99 1541.83 1340.35 528 5.0 1149.53 1129.99 1661.62 933.34 1249.39 626.47 1173.84 1941.16 1233.17 408 6.0 749.82 1514.62 1205.12 1235.12 507.20 546.75 379.11 1471.18 951.12 457 8.0 270.95 726.06 961.68 672.76 399.41 314.02 371.97 974.65 586.44 286 12.0 213.88 770.40 458.94 803.20 306.14 465.17 313.05 622.67 494.18 219 16.0 80.11 1228.35 316.62 485.71 212.45 312.87 172.83 342.77 393.96 359 20.0 143.04 1375.56 582.37 439.89 445.07 188.84 267.70 273.98 464.56 396 24.0 111.51 490.36 336.94 72.88 69.19 365.84 555.43 414.42 302.07 19301599.004W0Table 60-B. Group 5 MPA PK SummaryDog-9 Dog-10 Dog-11 Dog-12 Dog-13 Dog-14 Dog-15 Dog-16 Mean (n=8) SD (n=8) Cmax (ng / mL) 3162.49 3444.67 2256.71 1235.12 1905.46 2545.07 2705.44 1941.16 2399.52 719.09 ^max (hr) 1.50 2.00 2.00 6.00 3.00 3.00 3.00 5.00 3.00 1.5 -6 AUCiast (ng*hr / mL) 11037.77 29299.35 17872.24 11998.80 12582.37 14408.34 13461.02 16897.28 15944.65 5885.23 AUCinf (ng*hr / mL) 11869.04 33571.30 22227.42 12398.23 13208.11 NR NR NR 18654.82 9355.79 TI / 2 (hr) 5.17 NR NR 3.80 6.27 NR NR NR 5.08 1.24 MRT|ast(hr) 5.94 10.46 9.09 11.52 7.92 7.60 8.18 9.07 8.72 1.73 Ciast (ng / mL) 111.51 490.36 336.94 72.88 69.19 365.84 555.43 414.42 302.07 192.96 Tiast (hr) 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.90 24 -24 Rsq 0.82 NR NR 0.81 0.70 NR NR NR 0.78 0.07 AUC extrapolated (%) 7.00 12.73 19.59 3.22 4.74 31.19* 45.74* 20.98* 9.46 6.7201599.004W0Table 61-A. Group 6 MPA Plasma ConcentrationsPlasma Concentration (ng / mL)Animal Id Dog-17 Dog-18 Dog-19 Dog-20 Dog-21 Dog-22 Dog-23 Dog-24Mean (n=8) SD (n=8) Time (h) MalePredose 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0 0.25 56.58 238.60 65.14 11.31 19.61 183.82 256.34 121.11 119.06 97 0.5 216.50 430.97 346.05 105.91 142.37 1121.00 447.40 523.76 416.75 322 1.0 2128.89 2381.62 1337.21 645.13 557.54 3266.26 2161.20 4212.58 2086.30 1253 1.5 4889.05 5722.51 844.98 573.83 1366.90 6253.23 4850.09 369.70 3108.79 2536 2.0 6770.54 7860.59 2008.82 2247.18 1359.79 3516.87 7859.71 6994.19 4827.21 2808 3.0 3679.67 6198.24 3974.27 2571.94 2842.72 2168.51 6634.36 4338.45 4051.02 1635 4.0 4457.36 3302.44 4924.25 2677.23 2905.96 2446.14 4976.31 2283.64 3496.67 1120 5.0 4334.41 3908.93 6122.07 4464.96 6078.67 1632.02 5512.45 1778.72 4229.03 1755 6.0 4196.98 2934.54 3542.27 4182.36 3293.59 1281.57 3338.36 1571.18 3042.61 1090 8.0 2083.75 1309.86 2284.50 3817.79 2958.54 808.69 2906.89 1419.42 2198.68 1004 12.0 797.30 999.44 1009.61 1478.40 1444.44 647.64 1477.25 1266.94 1140.13 324 16.0 708.97 265.03 561.34 1054.76 1233.41 320.82 865.50 1422.15 804.00 418 20.0 820.71 163.86 223.29 466.22 753.17 146.91 598.38 771.44 493.00 284 24.0 521.20 86.56 99.38 374.87 210.28 64.95 313.01 763.05 304.16 24401599.004W0Table 61-B. Group 6 MPA PK SummaryDog-17 Dog-18 Dog-19 Dog-20 Dog-21 Dog-22 Dog-23 Dog-24 Mean (n=8) SD (n=8) C'max (ng / mL) 6770.54 7860.59 6122.07 4464.96 6078.67 6253.23 7859.71 6994.19 6550.50 1103.22 I' max (hr) 2.00 2.00 5.00 5.00 5.00 1.50 2.00 2.00 2.00 1.5 -5 AUCiast (ng*hr / mL) 43194.93 36996.83 36522.96 41576.71 41007.62 22705.53 52194.10 37424.35 38952.88 8284.88 AUCinf (ng*hr / mL) 47912.63 37615.67 36982.15 44179.91 42512.97 23030.84 54424.64 NR 40951.26 9923.696.27 4.96 3.20 4.81 4.96 3.47 4.94 NR 4.66 1.03 TI / 2 (hr)MRTiast (hr) 7.57 5.58 7.09 8.81 9.03 5.88 7.16 9.14 7.53 1.38 Ciast (ng / mL) 521.20 86.56 99.38 374.87 210.28 64.95 313.01 763.05 304.16 244.39 Tiast(hr) 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24.00 24 -24 Rsq 0.86 0.99 1.00 0.97 0.93 1.00 0.98 NR 0.96 0.05 AUC extrapolated (%) 9.85 1.65 1.24 5.89 3.54 1.41 4.10 30.14* 3.95 3.11Table 62. PK Summary Across GroupsCmaxGroup Dose Cmax(Study-1) ratio (Study-1) (Study-1) ratioratio ratio ratio (Study-1) ratio MPA mg / kg (h) (h) (ng / mL) (h* ng / mL) (ng / mL) (h* ng / mL) (ng / mL) (h* ng / mL)G-l 20 6.00 5.02 7588.69 NA 16474.67G-l (Study-1) 20 1.00 7.83 NA NA NA NA 10512.00 NA 14357.00 NAG-2 (Study-1) 25 0.50 4.62 NA NA NA NA 5616.00 NA 11722.00 NAG-2 29 1.75 7.00 4314.50 0.57 16811.54 1.02 0.41 1.17 0.77 1.430.57 G-3 20 4.00 5.41 921.48 0.12 0.09 0.65 0.16 0.80 9360.11G-4 20 2.50 5.55 3642.86 0.48 24013.50 1.46 0.35 1.67 0.65 2.0520 3.00 5.08 2399.52 0.32 15944.65 0.97 0.23 1.11 0.43 1.36 G-5G-6 49 2.00 4.66 6550.50 0.86 38952.88 2.36 0.62 2.71 1.17 3.3201599.004W01Table 62 provides a summary of pharmacokinetic data across all six groups. In Group 1, the median time to reach maximum plasma concentration (Tmax) was 6 hours (range: 3-16 h) and the corresponding mean concentration (Cmax) and AUClastvalues were 7588.69 ng / mL and 16474.67 h*ng / mL, respectively. In Group 2, Tmaxwas 1.75 hours (range: 1-4 h) and the corresponding Cmaxand AUClastvalues were 4314.50 ng / mL and 16811.54 h*ng / mL, respectively. In Group 3, Tmaxwas 4 hours (range: 2-6h) and the corresponding Cmaxand AUClastvalues were 921.48 ng / mL and 9360.11 h*ng / mL, respectively. In Group 4, Tmaxwas 2.50 hours (range: 0.5-6h) and the corresponding Cmaxand AUClastvalues were 3642.86 ng / mL and 24013.50 h*ng / mL, respectively. In Group 5, Tmaxwas 3 hours (range: 1.5-6h) and the corresponding Cmaxand AUClastvalues were 2399.52 ng / mL and 15944.65 h*ng / mL, respectively. In Group 6, Tmaxwas 2 hours (range: 1.5-5h) and the corresponding Cmaxand AUClastvalues were 6550.50 ng / mL and 38952.88 h*ng / mL, respectively.For Groups 3-6, graphical representations of their dogs’ MPA plasma concentrations as a function of time are presented in FIGS. 11-14.It is clear from these data that both embodiments of Formulation 3 provide greater exposure to the active pharmaceutical ingredient than what would be provided by a simple sum of their SR and DR components. Formulation 3 also provides more consistent dog-to-dog plasma concentrations over time as compared to its individual SR and DR components, without the dramatic peaks and troughs exhibited by¬ current, commercially available formulations of the drug. This is apparent from FIGS. 11-14 and is evidenced by the coefficient of variability values shown below.Table 63. Coefficients of VariabilityGroup Cmax CV AUClastCV AUCmf CVG-l 1.17 0.53 0.35G-2 0.57 0.71 0.68G-3 0.62 0.60 0.69G-4 0.60 0.24 0.29G-5 0.30 0.37 0.50G-6 0.17 0.21 0.24While the variability of Cmaxobserved for the SR and DR beads alone is reduced when the two are combined, even the single beads provide dramatically lower variability than the commercially available Myfortic®. The embodimen ts of Formula 3 used in groups 4 and 6 exhibi ted remarkably low coefficients of variability across multiple PK parameters, including Cmax, AUCiast, and AUCmf.4.5. CONCLUSIONIn conclusion, this invention provides pharmaceutical formulations of MPA (and salts and prodrugs thereof) that afford dramatically better pharmacokinetic profiles that those previously known or suggested in the art. This invention also provides methods of manufacturing and tailoring MPA01599.004W01compositions to provide properties optimized for specific kinds of patients (e.g, human, canine) and specific diseases. Particular embodiments of the invention are listed below.4.5.1. SR BEADS1. A sustained-release (SR) bead, which contains an active -pharmaceutical ingredient (API) and comprises:(i) a core comprising the API, microcrystalline cellulose, and a binder;(ii) a seal coat layer disposed over the core; and(iii) a sustained-release layer disposed over the seal coat layer, which sustained-release layer comprises a matrix polymer, a pore-former, and a plasticizer;wherein the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof.2. The SR bead of embodiment 1, wherein the API constitutes from about 50 to about 90 weight percent of the core (e.g., from about 60 to about 90, from about 70 to about 85, or about 80 weight percent) of the core.3. The SR bead of any of embodiments 1-2, wherein the core contains microcrystalline cellulose in an amount ranging from about 5 to about 25 weight percent (e.g., from about 10 to about 22, from about 12 to about 18, or about 15 weight percent) of the core,4. The SR bead of any of embodiments 1-3, wherein the binder constitutes from about 1 to about 7 weight percent (e.g., from about 2 to about 6, from about 3 to about 5, or about 4 weight percent) of the core.5. The SR bead of any of embodiments 1-4, wherein the binder is ethylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMA, hypromellose), maltose, methyl cellulose, polydextrose, polymethacrylates, povidone, starch, sucrose, or a combination thereof.6. The SR bead of embodiment 5, wherein the binder is povidone or hypromellose.7. The SR bead of any of embodiments 1-5, wherein the core further comprises an anti-tacking agent.8. The SR bead of embodiment 7, wherein the core contains the anti -tacking agent in an amount ranging from about 0.25 to about 3 weight percent (e.g., from about 0.5 to about 2, from about 0.75 to about 1.5, or about 1 weight percent) of the core.9. The SR bead of embodiment 7 or 8, wherein the anti-tacking agent is calcium phosphate, calcium silicate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, or a combination thereof.01599.004W0110. The SR bead of any of embodiments 1 -9, which further comprises a drug layer disposed between the core and the seal coat layer, which drug layer comprises API and a binder.11. The SR bead of any of embodiments 1 -9, wherein all or substantially all (e.g., greater than about 96, 97, 98, or 99 weight percent) of the API contained in the bead is located in the core (e.g., the bead does not contain a drug layer),12. The SR bead of any of embodiments 1-11, wherein the seal coat has a weight that ranges from about 1 to about 10 percent (e.g., from about 2 to about 8, from about 3 to about 7, or about 5 percent) of the weight of the core.13. The SR bead of any of embodiments 1-12, wherein the seal coat layer comprises a cellulose-based polymer, a plasticizer, and an anti-tacking agent.14. The SR bead of embodiment 13, wherein the seal coat layer contains the cellulose-based polymer in an amount ranging from about 60 to about 90 weight percent (e.g., from about 65 to about 85, from about 70 to about 80, or about 73 weight percent) of the seal coat layer.15. Tire SR bead of any of embodiments 13-14, wherein the cellulose-based polymer is hydroxypropyl ethylcellulose or hydroxypropyl methylcellulose.16. Tire SR bead of embodiment 15, wherein the cellulose-based polymer is hydroxypropyl methylcellulose.17. The SR bead of embodiment 13, wherein the seal coat layer contains the plasticizer in an amount ranging from about 2 to about 12 (e.g., from about 4 to about 10, from about 6 to about 8, or about 7 weight percent) of the seal coat layer.18. The SR bead of embodiment 13 or 17, wherein the plasticizer is acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerin, mannitol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, triethyl citrate, or a combination thereof.19. Tire SR bead of embodiment 18, wherein the plasticizer is triethyl citrate, polyethylene glycol, or propylene glycol.20. Tire SR bead of any of embodiments 13-19, wherein the seal coat layer contains the anti¬ tacking agent in an amount ranging from about 5 to about 30 weight percent (e.g., from about 10 to about 25, or from about 14 to 21 weight percent) of the seal coat layer.21. The SR bead of any of embodiments 13-20, wherein the anti -tacking agent is calcium phosphate, calcium silicate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, or a combination thereof.22 The SR bead of embodiment 21, wherein the anti-tacking agent is talc.01599.004W0123. The SR bead of any of embodiments 1 -22, wherein the sustained-release layer has a weight that ranges from about 2 to about 25 percent (e.g., from about 5 to about 20, from about 7 to about 17, from about 8 to about 1 weight percent, or about 10 weight percent) of the sum of the weights of the core and seal coat,24. The SR bead of any of embodiments 1-23, wherein the sustained-release layer contains the matrix polymer (insoluble polymer) in an amount ranging from about 50 to about 85 weight percent (e.g., from about 55 to about 80, from about 65 to about 75, or about 69 weight percent) of the sustained- release layer.25. The SR bead of any of embodiments 1-24, wherein the matrix polymer is ethylcellulose, polytetrafluoroethylene (PTFE), polypropylene (PP), poly(methyl methacrylate) (PMMA), poly(vinyl chloride) (PVC), polydimethyl siloxane (PDMS), cellulose acetate butyrate (CAB), or a modified version of cellulose such as aminated lignin.26. Tire SR bead of embodiment 25, wherein the matrix polymer is ethylcellulose.27. Tire SR bead of any of embodiments 1 -26, wherein the sustained-release layer contains the pore-former in an amount ranging from about 3 to about 15 weight percent (e.g., from about 4 to about 12, from about 6 to about 10, or about 8 weight percent) of the sustained-release layer.28. The SR bead of any of embodiments 1-27, wherein the pore-former is polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polylactic acid, polyglycolic acid, or a combination thereof.29. The SR bead of embodiment 28, wherein the pore-former is hydroxypropyl cellulose. 30. The SR bead any of embodiments 1-29, wherein the sustained-release layer contains the plasticizer in an amount ranging from about 3 to about 15 weight percent (e.g., from about 4 to about 12, from about 6 to about 10, or about 8 weight percent) of the sustained-release layer,31. Tire SR bead of any of embodiments 1 -30, wherein the plasticizer is acetyltri butyl citrate, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerin, mannitol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, triethyl citrate, or a combination thereof.32. The SR bead of embodiment 31, wherein the plasticizer is dibutyl sebacate.33. The SR bead of any of embodiments 1-32, wherein the sustained-release layer further comprises an anti-tacking agent,34. The SR bead of embodiment 33, wherein the sustained-release layer contains the antitacking agent in an amount ranging from about 8 to about 20 weight percent (e.g., from about 10 to about 18, from about 12 to about 16, or about 15 weight percent) of the sustained-release layer.01599.004W0135. The SR bead of embodiment 33 or 34, wherein tire anti-tacking agent is calcium phosphate, calcium silicate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, or a combination thereof.36. A sustained-release (SR) bead, which bead comprises:(i) a core comprising an active-pharmaceutical ingredient (API), microcrystalline cellulose, povidone, and talc, wherein:the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof and constitutes from about 75 to about 85 weight percent of the core;the microcrystalline cellulose constitutes from about 10 to about 20 weight percent of the core;the povidone constitutes from about 2 to about 6 -weight percent of the core; and the talc constitutes from about 0.5 to about 2 weight percent of the core;(ii) a seal coat layer disposed over the core, which seal coat layer comprises talc, hydroxypropyl methylcellulose, and a glycol (e.g., polyethylene glycol, propylene glycol), wherein:the talc constitutes from about 10 to about 20 weight percent of the seal coat; and (iii) a sustained-release layer disposed over the seal coat layer, which sustained-release layer comprises ethylcellulose, hydroxypropyl cellulose, dibutyl sebacate, and talc, wherein:the ethylcellulose constitutes from about 60 to about 75 weight percent (e.g., about 69 weight percent) of the sustained-release layer;the hydroxypropyl cellulose constitutes from about 4 to about 12 weight percent (e.g., about 8 weight percent) of the sustained-release layer;the dibutyl sebacate constitutes from about 4 to about 12 -weight percent (e.g., about 8 weight percent) of the sustained-release layer; andthe talc constitutes from about 10 to about 18 weight percent (e.g., about 15 weight percent) of the sustained-release layer;wherein:the seal coat has a weight that ranges from about 3 to about 7 percent (e.g., about 5 percent) of the weight of the core; andthe sustained-release layer has a weight that ranges from about 5 to about 15 percent (e.g,, about 10 percent) of the sum of the weights of the core and seal coat.37. The SR bead of embodiment 36, wherein all of the API in the bead is located within the core.38. The SR bead of any of embodiments 1-37, which bead has a diameter of less than about 5 mm (e.g., has a diameter of about 1, 2, 3, 4 or 5 mm).39. A plurality of SR beads, w hich SR beads are of any of embodiments 1-38.40. A method of preparing a plurality of beads, which method comprises:extruding a first mixture comprised of a dry blend and water to provide an extrudate;01599.004W01chopping, spherizing, and drying the extrudate to provide a plurality of inner cores;coating the plurality of inner cores with a sealant to provide a plurality of sealed cores, which plurality of sealed cores weighs about 3 to about 8 percent more than the plurality of inner cores; and coating the plurality of sealed cores with a sustained-release mixture to provide the plurality of SR beads, which plurality of SR beads weighs from about 5 to about 20 percent more than the plurality of sealed cores; wherein:the dry blend comprises about 50 to about 90 weight percent of an active pharmaceutical ingredient (API), about 10 to about 40 weight percent microcrystalline cellulose, about 2 to about 7 weight percent binder, and optionally about 0.25 to about 2 weight percent anti-tacking agent, wherein the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof;the sealant, when dried, contains about 70 to about 95 weight percent cellulose-based polymer, optionally from about 4 to about 10 weight percent plasticizer, and optionally from about 13 to about 27 weight percent anti -tacking agent;the sustained-release mixture, when dried, contains from about 50 to about 85 weight percent matrix polymer, from about 4 to about 12 weight percent pore former, from about 4 to about 12 weight percent plasticizer, and optionally from about 10 to about 18 weight percent anti -tacking agent.41. The method of embodiment 40, wherein the binder is povidone or hypromellose.42. The method of embodiment 40, wherein the sealant cellulose-based polymer is hydroxypropyl methylcellulose.43. Tire method of embodiment 40, wherein the sealant plasticizer is triethyl citrate.44. Tire method of embodiment 40, wherein the sealant anti-tacking agent is talc.45. Tire method of embodiment 40, wherein the matrix polymer is ethylcellulose, polytetrafluoroethylene (PTFE), polypropylene (PP), poly(methyl methacrylate) (PMMA), poly(vinyl chloride) (PV C), polydimethylsiloxane (PDMS), cellulose acetate butyrate (CAB), or a modified version of cellulose such as aminated lignin,46. The method of embodiment 45, wherein the matrix polymer is ethylcellulose.47. The method of embodiment 40, wherein the pore former is polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polylactic acid, polyglycolic acid, or a combination thereof.48. The method of embodiment 47, wherein the pore-former is hydroxypropyl cellulose. 49. The method of embodiment 40, wherein the plasticizer is acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerin, mannitol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, triethyl citrate, or a combination thereof.01599.004W0150. The method of embodiment 49, wherein the plasticizer is dibutyl sebacate.51. Tire method of embodiment 40, wherein the anti-tacking agent is calcium phosphate, calcium silicate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, or a combination thereof.52. The method of embodiment 51, wherein the anti-tacking agent is talc.53. The method of embodiment 52, wherein the first mixture further comprises an alcohol (e.g., ethanol).54. The method of embodiment 53, wherein the sustained-release mixture is combined with a solvent comprising water and an optional alcohol (e.g., ethanol, isopropanol) prior to coating the plurality of seal sealed cores.55. The method of any of embodiments 40-54, which further comprises blending at least some of the sealed cores with an anti -tacking agent (e.g., talc) before they are coated with the sustained-release mixture.56. A plurality of SR beads prepared according to the method of any of embodiments 40-55.57. The plurality of SR beads of embodiment 39 or 56, which plurality of SR beads, when exposed to dissolution conditions that consist of an acid stage and a buffer stage, releases about 40 percent of the API they contain at a time of 3 hours, about 60 percent the API at a time of 4 hours, about 80 percent at a time of 6 hours, about 85 percent at a time of 8 hours, and about 90 percent at a time of 12 hours, which times are measured from when the SR beads are first exposed to the dissolution conditions;wherein: the acid stage lasts for two hours and comprises simulated gastric fluid and the buffer phase lasts from the end of the acid phase to at least 12 hours and comprises a pH 6.8 phosphate buffer.58. The plurality of SR beads of embodiment 39 or 56, which, when orally administered to healthy adult fasted beagle dogs at a dose of 30 mg / kg, provides plasma concentrations of MPA with an average Cmaxof 4400 ± 1900 ng / mL and a median Tmaxof about 2 hours.59. The plurality of SR beads of embodiment 39 or 56, which, w'hen orally administered to healthy adult fasted beagle dogs at a dose of 30 mg / kg, provides plasma concentrations of MPA with an average AUC of 26600 ± 12100 ng*hr / mL, which AUC is calculated from concentration measurements taken 1, 1.5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours after administration,60. Tire plurality of SR beads of embodiment 39 or 56, which, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average Cmaxof 2600 ± 500 ng / mL and a median Tmaxof about 2 hours.61. The plurali ty of SR beads of embodiment 39 or 56, w hich, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average AUClastof 18300 ± 5100 ng*hr / mL, which AUClastis calculated from concentration measurements taken 1, 1.5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours after administration.01599.004W014.5.2. DR BEADS62. A delayed-release (DR) bead, which comprises a delayed-release layer disposed over the SR bead of any of embodiments 1-38.63. The DR bead of embodiment 62, wherein the delayed-release layer has a weight that is from about 5 to about 40 weight percent (e.g., from about 10 to about 40, from about 12 to about 35, or from about 15 to about 20 weight percent) of the SR bead.64. The DR bead of embodimen t 62 or 63, wherein the delayed-release layer comprises a polymethacrylate and a plasticizer, wherein the polymethacrylate dissolves in water at a pH ≥ 5.5 (e.g., pH ≥ 6, 6.5, or 7).65. The DR bead of embodimen t 64, w herein the delayed-release layer con tains the polymethacrylate in an amount ranging from about 45 to about 80 weight percent (e.g., from about 55 to about 70, from about 60 to about 65, or about 63 weight percent) of the delayed-release layer.66. The DR bead of embodiment 62 or 63, w herein the polymethacrylate is an anionic polymer of methacrylic acid (e.g., Eudragit L30) or an anionic copolymer of methacrylic acid and methyl methacrylate (e.g., Eudragit S100).67. Tire DR bead of any of embodiments 64-66, wherein the delayed-release layer contains the plasticizer in an amount ranging from about 1 to about 15 weight percent (e.g., from about 2 to about 12, from about 4 to about 10, or about 6 weight percent) of the delayed-release layer.68. The DR bead of any of embodiments 64-67, w herein the plasticizer is acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerin, mannitol, palmitic acid, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, triethyl citrate, or a combination thereof.69. The DR bead of embodiment 68, wherein the plasticizer is triethyl citrate.70. The DR bead of any of embodiments 64-69, wherein the delayed-release layer further comprises an anti-tacking agent.71. Tire DR bead of embodiment 70, w herein the delayed-release layer contains the antitacking agent in an amount ranging from about 15 to about 50 weight percent (e.g., from about 20 to about 40, from about 25 to about 35, or about 31 weight percent) of the delayed-release layer.72. Tire DR bead of embodiment 70 or 71, wherein the anti-tacking agent is calcium phosphate, calcium silicate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, or a combination thereof.73. The DR bead of embodiment 72, wherein the anti-tacking agent is talc.01599.004W0174. The DR bead of any of embodiments 64-73, wherein the delayed-release layer further comprises a stabilizer (e.g., glycerol monostearate).75. The DR bead of embodiment 62 or 63, wherein the delayed-release layer comprises a mixture of the plasticizer, anti-tacking agent, and a stabilizer, which mixture is in an amount ranging from about 5 to about 35 weight percent (e.g., from about 10 to about 30, from about 15 to about 25, or about 20 weight percent) of the delayed-release layer.76. The DR bead of any of embodiments 62-75, which bead has a diameter of less than about 7 mm (e.g., about 3, 4, 5, or 6 mm).77. A delayed-release (DR) bead, which bead comprises:(i) a core comprising an active -pharmaceutical ingredient (API), microcrystalline cellulose, povidone, and talc, wherein:the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof and constitutes about 75 to about 85 weight percent of the core;the microcrystalline cellulose constitutes from about 10 to about 20 w eight percent of the core;the povidone constitutes from about 2 to about 6 weight percent of the core; and the talc constitutes from about 0.5 to about 2 weight percent of the core;(ii) a seal coat layer disposed over the core, which seal coat layer comprises talc, hydroxypropyl methylcellulose, and a glycol (e.g., polyethylene glycol, propylene glycol), wherein:the talc constitutes from about 10 to about 20 weight percent of the seal coat;(iii) a sustained-release layer disposed over the seal coat layer, which sustained-release layer comprises ethylcellulose, hydroxypropyl cellulose, dibutyl sebacate, and talc, wherein:the ethylcellulose constitutes from about 65 to about 75 weight percent (e.g., about 69 weight percent) of the sustained-release layer;the hydroxypropyl cellulose constitutes from about 4 to about 12 weight percent (e.g., about 8 weight percent) of the sustained-release layer;the dibutyl sebacate constitutes from about 4 to about 12 weight percent (e.g., about 8 weight percent) of the sustained-release layer; andthe talc constitutes from about 10 to about 18 weight percent (e.g., about 15 weight percent) of the sustained-release layer; and(iv) a delayed-release layer disposed over the sustained-release layer, which delayed-release layer comprises an anionic copolymer of methacrylic acid and methyl methacrylate (e.g., Eudragit S100), triethyl citrate, and talc, wherein:the anionic copolymer constitutes from about 50 to about 65 weight percent of the delayed-release layer (e.g., about 59 weight percent);the triethyl citrate constitutes from about 7 to about 15 weight percent of the delayed- release layer (e.g., about 12 weight percent); and01599.004W01the talc constitutes from about 25 to about 35 weight percent (e.g., about 30 weight percent) of the delayed-release layer; andwherein:the seal coat has a weight that ranges from about 3 to about 7 percent (e.g., about 5 percent) of the weight of the core;the sustained-release layer has a weight that ranges from about 8 to about 15 percent (e.g., about 10 weight percent) of the sum of the weights of the core and seal coat; andthe delayed-release layer has a weight that ranges from about 10 to about 15 percent (e.g., about 16 weight percent) of the sum of the weights of the core, the seal coat, and the sustained-release layer.78. Tire DR bead of embodiment 77, wherein all of the API is located in the core.79. A plurality of DR beads, which DR beads are of any of embodiments 62-78.80. Tire method of any of embodiments 40-55, which method further comprises coating the plurality of SR beads with a delayed-release mixture to provide a plurality of DR beads, which plurality of DR beads weighs from about 5 to about 40 percent (e.g., from about 10 to 20 percent) more than the plurality of SR beads; wherein:the delayed-release mixture, when dried, contains from about 45 to about 80 weight percent polymethacrylate, from about 1 to about 15 weight percent plasticizer, and about 15 to about 50 weight percent anti-tacking agent, wherein the polymethacrylate dissolves in water at a pH ≥ 5.5 (e.g., pH ≥ 6, 6.5, or 7).81. The method of embodiment 80, wherein the polymethacrylate is an anionic polymer of methacrylic acid (e.g-, Eudragit L30) or an anionic copolymer of methacrylic acid and methyl methacrylate (e.g., Eudragit S100).82. The method of embodiment 80 or 81, wherein the plasticizer is triethyl citrate.83. The method of any of embodiments 80-82, wherein the anti-tacking agent is talc.84. The method of any of embodiments 80-83, wherein the delayed-release mixture is combined with a solvent comprising water prior to coating the plurality of SR beads.85. The method of embodiment 84, wherein the solvent comprises water, an alcohol (e.g., ethanol, isopropanol), and optionally acetone.86. A plurality of DR beads, w hich DR beads are prepared according to the method of any of embodiments 80-85.01599.004W0187. The plurality of DR beads of embodiment 79 or 86, which plurality of DR beads, when exposed to dissolution conditions that consist of an acid stage and a buffer stage, releases about 15 to about 20 percent of the API they contain at a time of 3 hours, about 40 percent the API at a time of 4 hours, about 60 to about 70 percent at a time of 6 hours, about 85 to about 90 percent at a time of 8 hours, and / or about 90 percent at a time of 12 hours, which times are measured from when the SR beads are first exposed to the dissolution conditions;wherein: tire acid stage lasts for two hours and comprises simulated gastric fluid and the buffer phase lasts from the end of the acid phase to at least 12 hours and comprises a pH 6.8 phosphate buffer.88. Tire plurality of DR beads of embodiment 79 or 86, which, when orally administered to healthy adult fasted beagle dogs at a dose of 30 mg / kg, provides an average plasma Cmaxof 3800 ± 1500 ng / mL and a Tmaxof about 4 hours.89. The plurality of DR beads of embodiment 79 or 86, which, when orally administered to healthy adult fasted beagle dogs at a dose of 30 mg / kg, provides plasma concentrations of MPA with an average AUClastof 31500 ± 16100 ng*hr / mL, which AUClastis calculated from concentration measurements taken 1, 1.5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours after administration.90. The plurality of DR beads of embodiment 79 or 86, which, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average Cmaxof 1400 ±

[0520] ng / mL and a median Tmaxof about 2 hours.91. The plurality of DR beads of embodiment 79 or 86, which, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average AUCiast of 14300 ±

[6000] ng*hr / mL, which AUCiast is calculated from concentration measurements taken 1, 1.5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours after administration.4.5.3. SR / DR BEAD FORMULATIONS92. A pharmaceutical formulation comprising a plurality of SR beads and a plurality of DR beads, wherein:the plurality of SR beads is of embodiment 39 or 56; andthe plurality of DR beads is of embodiment 79 or 86.93. The pharmaceutical formulation of embodiment 92, wherein the plurality of SR beads and the plurality of DR beads are present in a ratio (SR: DR) of from about l:10to about 10:1 (e.g., 1:10, 1:5, 1:3, 1:1, 3:1, 5:1, or 10:1), which ratio is determined by the amount of API contained within each plurality.94. The pharmaceutical formulation of embodiment 93, wherein the SR: DR ratio is about 1:1.95. The pharmaceutical formulation of any of embodiments 92-94 which, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average Cmaxof 3100 ± 730 ng / mL and a median Tmaxof about 2 hours.01599.004W0196. The pharmaceutical formulation of any of embodiments 92-94 which, when orally administered to healthy adult fasted beagle dogs at a dose of 20 mg / kg, provides plasma concentrations of MPA with an average AUClastof 22000 ± 2600 ng*hr / mL, which AUClastis calculated from concentration measurements taken 1, 1.5, 2, 4, 5, 6, 8, 12, 16, 20, and 24 hours after administration.97. A single unit dosage form suitable for oral administration (e.g., a capsule, caplet) to a patient comprising the pharmaceutical formulation of any of embodiments 92-94.98. The single unit dosage form of embodiment 97, which contains at least 100 mg API (e.g., at least 150, 200, 250, 300 or 350 mg),4.5.4. METHODS OF OPTIMIZING PK99. A method of identifying an optimal pharmaceutical formulation, which method comprises:(i) determining the in vivo pharmacokinetic profile of plurality of test formulations; and (ii) identifying which of the plurality of test formulations provides the smallest Cmax(e.g., relative to AUG), the largest AUClast, the largest AUCinf, and / or the least pharmacokinetic variability between test subjects to which the plurality of test formulations were administered;wherein: each of the plurality of test formulations comprises a plurality of SR beads and a plurality of DR beads in an SR: DR ratio determined by the amount of API contained within each plurality of beads;the plurality of SR beads is of embodiment 39 or 56; andthe plurality of DR beads is of embodiment 79 or 86.4.5.5. METHODS OF USE100. A method of suppressing an immune response in a patient, which comprises administering to a patient in need thereof a pharmaceutical formulation comprised of a plurality of SR beads of embodiment 79 or 86.101. A method of suppressing an immune response in a patient, which comprises administering to a patient in need thereof a pharmaceutical formulation comprised of a plurality of DR beads of embodiment 79 or 86.102. A method of suppressing an immune response in a patient, which comprises administering to a patient in need thereof a pharmaceutical formulation or single unit dosage form of any of embodiments 92-98.103. The method of any of embodiments 100-102, w hich method reduces lymphocyte production.104. A method of treating or managing a disease or condition in a patient, which comprises administering to a patient in need thereof a pharmaceutical formulation or single unit dosage form of any01599.004W01of embodiments 92-98, wherein the disease or condition is: aplastic anemia; atopic dermatitis; autoimmune hemolytic disease; Behcet’s disease; celiac disease; cutaneous Crohn’s disease; cutaneous vasculitis; diabetes mellitus type 1; erythema nodosum; Grave’s disease; glomerulonephritis; hepatitis; idiopathic thrombocytopenic purpura; immune-mediated hemolytic anemia; immune reactions associated with transplant or implant procedures (e.g., tissue transplants, grafts, and device implants) including host-versus-graft disease and other forms of implant rejection; immunobullous disease; immunoglobulin A nephropathy; immune cytopenias; inflammatory bowel disease; lichen planus; lupus erythematosus; lupus nephritis; meningoencephalomyelitis; multiple sclerosis; myasthenia gravis; pemphigus vulgaris; pyoderma gangrenosum recurrent erythema multiforme; rheumatoid arthritis; pernicious anemia; psoriasis; sarcoidosis; scleroderma; small vessel vasculitis; subepidermal blistering autoimmune disease, or vitiligo.105. The method of embodiment 104, wherein the disease or condition is atopic dermatitis.106. The method of embodiment 104, wherein the disease or condition is an immune reaction associated with transplant or implant.107. The method of any of embodiments 100-106, wherein the patient is a human.108. The method of any of embodiments 100-106, wherein the patient is a canine.Each publication (e.g., patent or patent application) cited above is incorporated herein by reference.

Claims

01599.004W01CLAIMSWhat is claimed is:

1. A pharmaceutical formulation comprising a plurality of sustained-release (SR) beads and a plurality of delayed-release (DR) beads, wherein:each of the SR beads comprises:(i) a core comprising an active-pharmaceutical ingredient (API), microcrystalline cellulose, povidone, and talc, wherein:the API is mycophenolic acid (MPA) or a pharmaceutically acceptable salt or prodrug thereof and constitutes about 75 to about 85 weight percent of the core;the microcrystalline cellulose constitutes from about 10 to about 20 weight percent of the core;the povidone constitutes from about 2 to about 6 weight percent of the core; and the talc constitutes from about 0.5 to about 2 weight percent of the core;(ii) a seal coat layer disposed over the core, which seal coat layer comprises cellulose-based polymer, a plasticizer, and talc, wherein:the talc constitutes from about 10 to about 20 weight percent of the seal coat;(iii) a sustained-release layer disposed over the seal coat layer, which sustained- release layer comprises cellulose, dibutyl sebacate, and talc, wherein:the cellulose constitutes from about 60 to about 90 weight percent of the sustained-release layer;the dibutyl sebacate constitutes from about 4 to about 12 weight percent of the sustained- release layer;the talc constitutes from about 10 to about 18 weight percent of the sustained-release layer; andeach of the DR beads comprises an SR bead over which a delayed-release layer is disposed, which delayed-release layer comprises a polymer that dissolves at a pH ≥ 7.

2. The pharmaceutical formulation of claim 1, wherein the API constitutes about 80 weight percent of the core.

3. The pharmaceutical formulation of claim 1 or 2, wherein the microcrystalline cellulose constitutes about 15 weight percent of the core.

4. The pharmaceutical formulation of any of claims 1-3, wherein seal coat has a weight that ranges from about 3 to about 7 percent e.g., about 5 percent) of the weight of the core.

5. The pharmaceutical formulation of any of claims 1-4, wherein the seal coat cellulose- based polymer is hydroxypropyl cellulose.

6. The pharmaceutical formulation of any of claims 1-5, wherein the seal coat plasticizer is a glycol (e.g., polyethylene glycol or propylene glycol).01599.004W017. The pharmaceutical formulation of any of claims 1-6, wherein the cellulose and plasticizer constitute from about 80 to 90 weight percent of the seal coat.

8. The pharmaceutical formulation of any of claims 1-7, wherein the sustained-release layer has a weight that ranges from about 5 to about 15 percent (e.g., about 10 percent) of the sum of the weights of the core and seal coat.

9. The pharmaceutical formulation of any of claims 1-8, wherein the cellulose in the sustained-release layer comprises ethylcellulose.

10. The pharmaceutical formulation of any of claims 1-9, wherein the cellulose in the sustained sustained-release layer comprises hydroxypropyl cellulose.

11. The pharmaceutical formulation of claim 10, wherein the ethylcellulose constitutes from about 60 to about 75 weight percent of the sustained-release layer and the hydroxypropyl cellulose constitutes from about 4 to about 12 weight percent of the sustained-release layer.

12. The pharmaceutical formulation of any of claims 1-11, wherein the delayed-release layer has a weight that ranges from about 10 to about 25 weight percent (e.g., about 16 weight percent) of the sum of the weights of the core, the seal coat, and the sustained-release layer.

13. The pharmaceutical formulation of any of claims 1-12, wherein the polymer that dissolves at a pH ≥ 7 is a polymethacrylate.

14. The pharmaceutical formulation of claim 13, wherein the polymethacrylate constitutes from about 50 to about 65 weight percent of the DR layer.

15. The pharmaceutical formulation of any of claims 1-14, wherein the DR layer further comprises talc in an amount of from about 20 to about 35 weight percent of the DR layer.

16. The pharmaceutical formulation of any of claims 1-15, wherein the DR layer further comprises triethyl citrate in an amount of from about 5 to about 15 weight percent of the DR layer.

17. The pharmaceutical formulation of any of claims 1-16, wherein the Tmaxof the SR beads is from about 1.5 to about 2 hours when orally administered to healthy adult fasted male beagle dogs at a dose of 20 mg / kg.

18. The pharmaceutical formulation of any of claims 1-17, wherein the Tmaxof the DR beads is from about 4 to 5 about hours when orally administered to healthy adult fasted male beagle dogs at a dose of 20 mg / kg,19. The pharmaceutical formulation of any of claims 1-18, which has a Tmaxof from about 2 to about 2.5, when orally administered to healthy adult fasted male beagle dogs at a dose of 20 mg / kg.

20. A single unit dosage form (e.g., a capsule or tablet) comprising the pharmaceutical formulation of any of claims 1-19.01599.004W0121. A method of suppressing an immune response in a patient, which comprises administering to a patient in need thereof the pharmaceutical formulation of any of claims 1-19 or the single unit dosage form of claim 20.

22. A method of treating or managing a disease or condition in a patient, which comprises administering to a patient in need thereof the pharmaceutical formulation of any of claims 1 -19 or the single unit dosage form of claim 20, wherein the disease or condition is atopic dermatitis or an immune reaction associated with transplant or implant.

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