WO2020050863A1 - Méthodes et compositions pour l'administration d'agents actifs d'acide mycophénolique à des mammifères non humains - Google Patents

Méthodes et compositions pour l'administration d'agents actifs d'acide mycophénolique à des mammifères non humains Download PDF

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Publication number
WO2020050863A1
WO2020050863A1 PCT/US2018/050079 US2018050079W WO2020050863A1 WO 2020050863 A1 WO2020050863 A1 WO 2020050863A1 US 2018050079 W US2018050079 W US 2018050079W WO 2020050863 A1 WO2020050863 A1 WO 2020050863A1
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Prior art keywords
dose
subject
mpa
hours following
plasma
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PCT/US2018/050079
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English (en)
Inventor
Michael KLOTSMAN
Padmaja Shivanand
Wayne H. Anderson
Gayatri Sathyan
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Okava Pharmaceuticals, Inc.
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Priority to PCT/US2018/050079 priority Critical patent/WO2020050863A1/fr
Priority to JP2021512709A priority patent/JP2022506007A/ja
Priority to EP18778780.9A priority patent/EP3846798A1/fr
Priority to CA3111908A priority patent/CA3111908A1/fr
Publication of WO2020050863A1 publication Critical patent/WO2020050863A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • Autoimmune diseases represent a heterogeneous family of chronic diseases.
  • the hallmarks of such diseases include activation and/or proliferation of lymphocytes, development of autoantibodies, and dysregulation of the immune system leading to chronic inflammation and tissue damage.
  • autoimmune diseases represent a category of diseases with few viable treatment options.
  • Mycophenolate mofetil has been recognized as a treatment for autoimmune diseases and other conditions in both human and veterinary subjects.
  • compositions and methods for providing a mycophenolic acid (MPA) active agent to a canine subject in a controlled-release manner are provided.
  • MPA mycophenolic acid
  • MPA-containing e.g, mycophenolate mofetil
  • presently disclosed formulations and methods provide controlled-release profiles of a MPA active agent that attain an average plasma [MPA] concentration over about 8 hours in a canine subject such that 2.5, 4, and 8 hours following a first dose of the formulation, lymphocyte proliferation is reduced as compared to a pre-dose amount.
  • the canine subject achieves an average plasma [MPA] of about 250 ng/ml to about 3000 ng/ml over about 8 hours following a first dose of the controlled-release formulation, whereupon at 2.5 hours, 4 hours, and 8 hours following the first dose, a percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced as compared to the percentage of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the first dose, as determined using monoclonal antibody Ki-67.
  • MPA average plasma
  • administration according to the instant disclosure produces a systemic effect such that 24 hours following a second (or more) once-daily dose, and prior to an eighth dose, the amount of proliferating lymphocytes in a whole blood sample from the canine is lower than the amount of proliferating lymphocytes in whole blood obtained from the canine 15 or fewer minutes prior to the dose of the first day.
  • lymphocyte proliferation according to the disclosed controlled-release methods and compositions is reduced by a greater degree and/or for a longer period of time as compared to the reduction attained using an immediate-release formulation comprising a MPA active agent.
  • the percentage of proliferating lymphocytes in a whole blood sample obtained from the subject at 4 hours (and/or at 8 hours) following administration of a first dose of controlled-release formulation of the present disclosure is lower than (ii) the percentage of proliferating lymphocytes in a whole blood sample obtained from a reference canine subject that received an immediate-release formulation comprising a MPA active agent.
  • administration of the instantly disclosed formulations to a canine subject surprisingly provides a reduction (z.e., in the number, in the severity, or both) of adverse gastrointestinal events in the subject as compared to an
  • immediate-release formulation comprising a MPA active agent. This occurs even when the amount of MPA active agent administered using a controlled-release formulation exceeds that administered in the immediate-release form.
  • administering comprises administering a single dose for each of 10 or more (optionally 15 or more) consecutive days, wherein over the 10 days (optionally 15 or more days), the subject exhibits no adverse gastrointestinal events, wherein an adverse gastrointestinal event comprises emesis, diarrhea, soft stool, or any combination thereof.
  • the presently disclosed methods and compositions have utility in, for example, treating an autoimmune disease or disorder in a canine subject, wherein the autoimmune disease or disorder is characterized by aberrant proliferation and/or activation of lymphocytes, as described herein.
  • Autoimmune diseases and disorders treatable using the presently disclosed methods and compositions include atopic dermatitis, arthritis, myasthenia gravis, celiac disease, diabetes mellitus type 1, Grave’s disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, Beh et’s disease, pemphigus vulgaris, refractory incomplete systemic lupus erythematosus, lupus nephritis, immunoglobulin A nephropathy, small vessel vasculitides, scleroderma (systemic sclerosis or SSc), idiopathic thrombocytopen
  • immunobullous diseases cutaneous vasculitis, recurrent erythema multiforme, erythema nodosum, lichen planus, cutaneous Crohn’s disease, sarcoidosis, hepatitis, pyoderma gangrenosum, and any combination thereof.
  • the MPA active agent comprises mycophenolate sodium.
  • the canine subject receives a controlled-release formulation in a fed state, or in a fasted state, as described herein. In certain embodiments, a controlled-release formulation is administered orally.
  • Controlled-release formulations comprising a MPA active agent, and kits comprising the formulations, are also provided.
  • the present disclosure provides uses of the controlled-release compositions to suppress lymphocyte proliferation in a canine subject.
  • a medicament comprising a controlled-release formulation of the present disclosure.
  • FIG. 1 shows a schematic example of a particulate subunit of a controlled-release formulation of the present disclosure.
  • FIG. 2 shows a representation of an embodiment of a further particulate subunit of a controlled-release formulation in accordance with an embodiment hereof.
  • FIG. 3 shows a representation of an embodiment of a controlled-release formulation according of the present disclosure, in the form of a capsule, comprising particulate subunits in accordance with the present disclosure.
  • FIG. 4 shows the release of mycophenolate sodium in biphasic media (pH
  • FIG. 5 shows the release of mycophenolate sodium from additional embodiments of a particulate subunit of a controlled-release formulation in accordance with the present description. Release was measured during incubation in media at pH 6 8
  • FIG. 6 shows the release of mycophenolate sodium from yet another embodiment of a particulate subunit in accordance with the present disclosure, where the particulate subunit was exposed to a 2-hour incubation in acidic media (pH 1.2), followed by pH 6.8 media.
  • FIG. 7 shows release of mycophenolate sodium from another embodiment of a particulate subunit in accordance with the present disclosure.
  • FIG. 8 shows release of mycophenolate sodium from yet another embodiment of a particulate subunit in accordance with the present disclosure that was exposed to a 2-hour incubation in acidic media (pH 1.2), followed pH 6.8 media.
  • FIG. 9 shows release of mycophenolate sodium from an embodiment of a particulate subunit according to the present disclosure, where the particulate subunit comprises a bead with a solvent-based coating and where the particulate subunit was exposed to a 2-hour incubation in acidic media (pH 1.2), followed by 12 hours in pH 6.8 media.
  • acidic media pH 1.2
  • FIG. 11 provides another view of the data shown in FIG. 10 (“Groups” 2 and 3) and further provides mean serum levels (ng/mL) of MPA in fasted canines following administration of the controlled-release composition (“Group 4”).
  • FIG. 12 shows mean serum levels (ng/mL) of the MPA metabolite acyl MPA glucoronide (AcMPAG) measured in the indicated canine treatment groups.
  • FIG. 13 shows mean serum levels (ng/mL) of the MPA metabolite MPA glucoronide (MPAG) measured in the indicated canine treatment groups.
  • FIG. 14 provides a schematic diagram showing the design of a
  • FIG. 15 shows Day 1 serum MPA concentrations over time from the canine“Period 1” and“Period 2” treatment groups depicted in FIG. 14.
  • FIG. 16 shows Day 5 serum MPA concentrations over time from the canine“Period 1” and“Period 2” treatment groups depicted in FIG. 14.
  • FIGS. 17-26 relate to a 15-day open-label study investigating pharmacodynamic (PD) activity of a controlled-release composition of the present disclosure (“OKV-1001”).
  • FIG. 17 shows the design of the l5-day study.
  • male beagle dogs received a“base dose” of the controlled-release composition (270 mg, containing 252 mg MPA; QD); a“low dose” once-daily (180 mg, containing 168 mg MPA; QD); or a“low dose” twice-daily (180 mg, containing 168 mg MPA; BID).
  • n 5 dogs.
  • FIG. 18 illustrates the data capture timeline for the open-label study shown in Figure 17.
  • PD endpoints were collected at Days 1, 8, and 15. On each endpoint collection day, a total of four (4) sampling timepoints were used, as shown in Table 17 herein.
  • FIG. 19 shows the percentage of lymphocytes expressing the Ki-67 antigen, a marker associated with proliferation, in whole blood samples taken from male beagle dogs prior to, or 2.5 hours, 4 hours, or 8 hours following oral administration of a controlled-release formulation of the present disclosure (containing 252 mg MPA, QD) during a 15-day pharmacodynamics study.
  • Ki-67 expression was determined using monoclonal antibody Ki-67 in samples taken at Days 1, 8 and 15 of the study.
  • the indicated percentages on the Y-axis are with reference to baseline (i.e., percent of baseline Ki67+ cells (+/- SD)) such that lower bars represent a reduction in expression as compared to baseline.
  • FIG. 20 shows the overall percentage of lymphocytes expressing the Ki-67 antigen in whole blood samples taken from male beagle dogs prior to, or 2 hours, 4 hours, or 8 hours following a single oral administration of a controlled-release formulation of the present disclosure.
  • FIG. 21 shows the percentage of lymphocytes expressing the Ki-67 antigen in whole blood samples taken from male beagle dogs prior to, or 2.5 hours, 4 hours, or 8 hours following oral administration of a controlled-release formulation (180 mg, containing 168 mg MPA, QD) of the present disclosure. Samples were taken at Days 1, 8, and 15 of the 15-day study. The indicated percentages are with reference to baseline.
  • a controlled-release formulation 180 mg, containing 168 mg MPA, QD
  • FIG. 22 shows the percentage of lymphocytes expressing the Ki-67 antigen in whole blood samples taken from male beagle dogs prior to, or 0.75 hours, 4 hours, or 8 hours following oral administration of an immediate-release mycophenolate mofetil formulation (120 mg MMF; BID). Samples were taken at Days 1, 8, and 15 of the 15-day study. The indicated percentages are with reference to baseline.
  • FIG. 23 shows a comparison of single-dose (Day 1) pharmacodynamics of an immediate-release mycophenolate mofetil formulation (120 mg MMF), BID) and of a controlled-release formulation of the present disclosure (270 mg, containing 252 mg MPA; QD). Ki-67 expression was measured in whole blood samples taken from male beagle dogs at the indicated timepoints. The indicated percentages are with reference to baseline.
  • FIG. 24 shows a comparison of pharmacodynamics of an immediate-release mycophenolate mofetil formulation (120 mg MMF, BID) and a controlled-release formulation of the present disclosure (270 mg, containing 252 mg MPA; QD) on days 8 and 15 of the 15-day study. Ki-67 expression was measured in whole blood samples taken from male beagle dogs at the indicated timepoints. The indicated percentages are with reference to baseline.
  • FIG. 25 shows an eight-hour pharmacokinetic profile (mean plasma MPA concentration) in male beagle dogs administered a controlled-release formulation of the present disclosure (270 mg, containing 252 mg MPA) measured following 8 days of administration (QD) in the presently disclosed 15-day study.
  • N 5 male beagle dogs.
  • FIG. 26 shows eight-hour pharmacokinetic profiles (mean plasma MPA concentration) in male beagle dogs administered a controlled-release formulation of the present disclosure (180 mg, containing 168 mg MPA; administered BID or QD) measured following 8 days of administration in the presently disclosed 15-day study.
  • N 5 male beagle dogs per treatment group.
  • FIG. 27 compares 8-hour pharmacokinetic profiles (mean plasma MPA concentration) of male beagle dogs administered a controlled-release formulation of the present disclosure (270 mg, containing 252 mg MPA; QD) on Day 8 of the 15-day study with average pharmacokinetic profiles from“Group A” and“Group C” treatment groups on Day 5 of the 5 -day repeat dosing study illustrated in Figure 14.
  • the present disclosure provides methods and compositions for controlled delivery of mycophenolic acid active agents, including mycophenolate sodium, in veterinary subjects.
  • the methods and compositions disclosed herein are useful for, among other applications, suppressing lymphocyte proliferation (e.g ., reducing the number of proliferating lymphocytes) in a veterinary subject, and for treating autoimmune diseases, blood disorders associated with aberrant lymphocyte proliferation and/or activation, and immune rejection related to transplant or graft procedures.
  • any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness are to be understood to include any integer within the recited range, unless otherwise indicated.
  • the term“about” means ⁇ 20% of the indicated range, value, or structure, unless otherwise indicated. It should be understood that the terms“a” and“an” as used herein refer to“one or more” of the enumerated components.
  • GI tract refers to an organ system in veterinary subjects which takes in food, digests the food to extract and absorb energy and nutrients, and expels the remaining waste.
  • the GI tract is commonly considered to comprise two subparts: the upper GI tract (also“upper GI” herein) includes the buccal cavity, pharynx, esophagus, stomach, and duodenum, and the lower GI tract (also“lower GI” herein) includes the small and large intestines, the jejeunum, the ileum, the colon, the cecum, the rectum, the anal canal, and the anus.
  • MPA active agent and“mycophenolic acid active agent” may be used interchangeably herein and refer to MPA or a MPA-based ingredient ( e.g ., of a veterinary composition of the present disclosure) that exerts a physiological or pharmacodynamic effect on a subject.
  • MPA active agents comprise MPA and pharmaceutically acceptable salts, esters, prodrugs, homologs, hydrates or solvates thereof.
  • a MPA active agent comprises mycophenolate sodium.
  • a MPA active agent comprises MMF.
  • Bioavailability refers to the fraction of a drug that is absorbed and therefore available to produce a physiological effect. Bioavailability may be measured by quantifying the AUC, by, for example, plotting serum concentration over time plots using labeled drugs and mass spectroscopy. Bioavailability can be measured in terms of“absolute bioavailablity” or“relative bioavailablity”
  • Absolute bioavailability relates to bioavailability when administered in a non-intravenous dosage form (e.g., oral tablet) compared with the same drug administered intravenously. Absolute bioavailability may be determined by comparing the AUC of the non-z.v. and i.v. forms, and correcting for the respective doses:
  • Relative bioavailability compares the bioavailability of two different dosage forms of a drug.
  • the relative AUCs for each dosage form are compared and relative doses are used to normalize the calculation:
  • PD Pharmacodynamics
  • PD refers to the biochemical or physiological effect or effects of a drug on a subject.
  • PD may be described in the context of a dose-response relationship or a concentration-response relationship, and may encompass a range of desirable, undesirable, or neutral effects through mechanisms such as stimulating or depressing action through receptor agonism and downstream effects, blocking or antagonizing action (e.g, of a signaling pathway, or catalytic activity of an enzyme, or the like), stabilizing action, exchanging, replacing, or accumulating substances (e.g, glycogen storage), conferring a direct beneficial chemical reaction, or conferring a direct harmful chemical reaction (e.g ., cytotoxicity, mutagenesis, or irritation).
  • stimulating or depressing action through receptor agonism and downstream effects
  • blocking or antagonizing action e.g, of a signaling pathway, or catalytic activity of an enzyme, or the like
  • stabilizing action e.g, exchanging, replacing, or accumulating
  • PD values described herein with respect to MPA compositions and related methods include, for example, adverse effects on a canine subject administered an MPA active agent (e.g., adverse gastrointestinal events such as diarrhea, soft stools, emesis, or the like), autoantibody levels or activity, cytokine release rate or levels, inflammation, and B or T lymphocyte count(s) or functionality(ies), including proliferation, e.g, as determined by the presence of the proliferation-associated marker antigen Ki-67.
  • Other markers and assays for determining proliferation of lymphocytes are known in the art and are contemplated herein.
  • Suppression of lymphocyte proliferation may be measured by a reduction in the percentage of proliferating lymphocytes in a whole blood sample, and can be reported as a reduction relative to a baseline level, as a raw percentage, or by other accepted means.
  • Ki-67 expression can be measured using monoclonal antibody Ki-67 (“mAb-Ki-67”).
  • a“canine” refers to any member of the family Canidae, and includes domestic dogs (including any breed or any variant thereof, as well as any combination of two or more breeds or variants, and combinations thereof), wolves, foxes, jackals, and coyotes.
  • Autoimmune disease and“autoimmune disorder” may be used interchangeably herein and refer to conditions in which the immune system of a subject recognizes the subject’s own cell(s) or tissue(s) as antigenic and produces an
  • an autoimmune disease or disorder is associated with 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, relative 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.
  • 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.
  • compositions and methods according to the present disclosure are useful to treat an (i.e., one or more) autoimmune disease, such as, for example, atopic dermatitis, rheumatoid arthritis, celiac disease, diabetes mellitus type 1, Grave’s disease, inflammatory bowel disease, multiple sclerosis, psoriasis, systemic lupus erythematosus, Behqet’s disease, pemphigus vulgaris, refractory incomplete systemic lupus erythematosus, lupus nephritis, immunoglobulin A nephropathy, small vessel vasculitides, scleroderma (systemic sclerosis or SSc), idiopathic
  • autoimmune disease such as, for example, atopic dermatitis, rheumatoid arthritis, celiac disease, diabetes mellitus type 1, Grave’s disease, inflammatory bowel disease, multiple sclerosis, p
  • IPP thrombocytopenic purpura
  • myasthenia gravis myasthenia gravis
  • psoriasis pernicious anemia
  • vitiligo autoimmune hemolytic disease
  • glomerulonephritis autoimmune hemolytic disease
  • immune cytopenias meningoencephalomyelitis, subepidermal blistering autoimmune disease
  • Immunobullous diseases cutaneous vasculitis, recurrent erythema multiforme, erythema nodosum, lichen planus, cutaneous Crohn’s disease, sarcoidosis, immune reactions associated with veterinary transplant or implant procedures (e.g., tissue transplants, grafts, and device implants), including host-versus-graft disease (HvGD) and other forms of implant rejection, hepatitis, and pyoderma gangrenosum.
  • Blood disorders or diseases treatable according to the presently disclosed methods and compositions include, but are not limited to, aplastic anemia, immune mediated hemolytic anemia, and immune-mediated thrombocytopenia.
  • compositions and methods are useful in providing immunosuppression (e.g, by suppressing proliferation and/or activation of lymphocytes) in a canine subject that has undergone, is undergoing, or will undergo an organ transplant and/or an artificial implant (e.g, a corneal implant, an artificial implant or replacement of a joint, a ligament, a bone, or the like).
  • an artificial implant e.g, a corneal implant, an artificial implant or replacement of a joint, a ligament, a bone, or the like.
  • “Treat,”“treatment,” and“ameliorate,” as used herein, refer to the prevention, lessening of the likelihood of, or medical management of a disease, disorder, or condition of a subject (e.g ., a canine having a an autoimmune disease or disorder associated with aberrant lymphocyte proliferation, or a surgical graft or transplant).
  • a canine subject according to the presently disclosed methods and compositions may, but need not necessarily, be evaluated, diagnosed, or treated by a veterinarian or other veterinary care professional).
  • a dose or treatment regimen comprising a controlled-release veterinary composition of the present disclosure is administered to the canine subject in an amount sufficient to elicit a therapeutic or prophylactic benefit.
  • Therapeutic or prophylactic/preventive benefits include, but are not limited to: improved clinical outcome; lessening or alleviation of symptoms associated with a disease; reduced frequency of occurrence of symptoms; improved quality of life; longer disease-free status; diminishment of extent of disease, stabilization of disease state; delay of disease onset, progression; remission; survival; prolonged survival; or any combination thereof.
  • A“therapeutically effective amount” or“effective amount” of a MPA active agent or a controlled-release formulation of the present disclosure refers to an amount sufficient to result in a therapeutic effect, including: improved clinical outcome; lessening or alleviation of symptoms associated with a disease; decreased occurrence of symptoms; improved quality of life; longer disease-free status; diminishment of extent of disease; stabilization of disease state; delay of disease progression; remission; survival; or prolonged survival in a statistically significant manner.
  • a therapeutically effective amount of a MPA active agent according to the compositions and methods of the present disclosure may be an amount sufficient to reduce or delay proliferation and/or activation of B or T lymphocytes, to prevent, reduce, or ameliorate an inflammatory response in a canine subject; to treat an autoimmune disease or disorder; or to prevent, reduce the severity of, or delay the onset of a rejection occurring in the course of a cell, organ, or tissue transplant or graft.
  • a therapeutically effective amount refers to the effects of that ingredient alone.
  • a therapeutically effective amount refers to the combined amounts of active ingredients that result in a therapeutic effect, whether administered sequentially, contemporaneously, or simultaneously.
  • modulating means reducing, raising, hastening, delaying, or preventing an occurrence, or increasing or decreasing the intensity or efficiency of the occurrence being modulated, through either direct or indirect means.
  • controlled-release is used to describe products that alter the timing and/or the rate of release of the drug substance in a way that deviates from immediate-release following administration.
  • a controlled-release dosage form is a formulation in which the drug-release characteristics of time, course, and/or location are chosen to accomplish therapeutic or convenience objectives not offered by
  • immediate-release dosage forms such as immediate-release tablets or suspensions or other promptly dissolving or releasing dosage forms.
  • Controlled-release oral drug formulations include, for example, extended-release formulations (which allow a reduction in dosage frequency as compared to the same drug presented as an
  • immediate-release (conventional) dosage form e.g., sustained-release and long-acting formulations
  • delayed-release formulations which release an identifiable portion or portions of drug at a time other than promptly after administration, e.g. , enteric-coated aspirin and other NS AID products
  • targeted-release formulations which release the drug at or near the intended physiologic site of action, and may have either immediate- or extended-release characteristics
  • ODT orally disintegrating tablets
  • controlled-release “controlled-release,”“modified-release,”“sustained-release,”“extended-release,” “long-acting,”“targeted-release,” and“delayed-release” may be used interchangeably herein to refer to the release of an administered MPA active agent in a way that deviates from immediate release following administration.
  • an“immediate release” dosage refers to any dosage form that is formulated to release or make available the active ingredient immediately upon administration.
  • a controlled-release formulation according to the present disclosure may, in certain embodiments, be formulated or administered to achieve one or more of the following characteristics: release of a MPA active agent at or within a certain time following administration; release of a MPA active agent under specific physiological conditions (e.g ., pH, temperature); release of a MPA active agent within a particular part of the body based on known, estimated, or predicted digestive, circulatory, or metabolic rates; release of a MPA active agent with, upon, or following administration with another reagent; in a predetermined amount; release of a MPA active agent for a predetermined amount of time; release of a MPA active agent according to particular release profile; or any combination thereof.
  • Certain embodiments of the presently disclosed controlled-release formulations comprise a means for controlling release of the MPA active agent so that the MPA active agent is released from the formulation in vivo such that a canine subject administered the MPA active agent at a single dose achieves a desired PK effect and a desired PD effect, as described herein.
  • cellulose polymers acrylate polymers, cellulose acetates, cellulose acetate butyrates, ethyl celluloses, hydroxypropyl methyl celluloses, methyl cellulose polymers, ethyl celluloses, hydroxypropyl methyl celluloses, methyl cellulose polymers, EUDRAGIT® polymers for controlled release, poly(vinyl acrylate) (PVA) polymers (e.g.,
  • Means for controlling release of a MPA active agent also comprise layers comprising one or more of the herein-described materials (optionally combined with one or more other materials), which layers can be present in any number, type, and thickness as appropriate to achieve a desired controlled-release. Examples of such layers include
  • a pharmaceutically acceptable carrier refers to non-active biologically compatible vehicles, which are described in greater detail herein, that are suitable for administration to a human or other non-human mammalian (e.g, canine) subject and generally recognized as safe or not causing a serious adverse event.
  • a pharmaceutically acceptable carrier includes food items or liquids to be administered to the subject.
  • a controlled-release formulation of the present disclosure can be sprinkled on, sprayed on, or otherwise added to, or combined with, food (including“treats”) or water to be consumed by a canine subject.
  • a MPA composition of the present disclosure may be carried by (i.e., contained within, combined with, or coated on) a food item such as a dry dog food, a treat, a bone, or the like. Feeding regimes useful for practicing such embodiments are described herein.
  • “statistically significant” refers to a p value of 0.050 or less when calculated using the Students t-test and indicates that it is statistically unlikely that a particular event or result being measured has arisen by chance.
  • Mycophenolic acid (Ci 7 H 2 o0 6 ;“MPA”) is a nonnucleoside, noncompetitive, reversible inhibitor of the enzyme inosine 5 '-monophosphate dehydrogenase (IMPDH), which catalyzes the synthesis of xanthine monophosphate (XMP) from inosine-5 '-monophosphate (IMP).
  • IMPDH inosine 5 '-monophosphate dehydrogenase
  • XMP xanthine monophosphate
  • IMP- XMP is the rate-limiting step in the de novo synthesis of guanine nucleotides required for nucleic acid synthesis, proliferation, and differentiation cells, including B and T lymphocytes.
  • MPA acts as an immunosuppressive agent. See, e.g ., Ams, W., Transplantation Proceedings 39: 88-93 (2007), the disclosure and methods of which are herein incorporated by reference in their entirety.
  • IMPDH has two isoenzymes, IMPDH 1 and IMPDH2.
  • the former is expressed in most cell types, while the latter predominates in activated lymphocytes (see, e.g., Winnicki et al., Pharmacogenomics J I0( ⁇ ):70-6 (2009)).
  • MPA inhibits IMPDH2 up to 4- to 5-fold more than IMPDH1, and therefore has a more potent cytostatic effect on activated lymphocytes than on other cells.
  • MPA has been prepared for use in humans as an adjunctive immunosuppressant as a mycophenolate mofetil ester (MMF; approved for human use in the U.S. as CellCept®) and as Na.MPA (Myfortic®).
  • MMF mycophenolate mofetil ester
  • Myfortic® Na.MPA
  • Adverse drug reactions (>l% of human patients) associated with mycophenolate therapy (i.e., any single-dose or multi-dose therapeutic regimen involving use of MPA or an active agent thereof, as defined herein) include diarrhea, nausea, loose stools, emesis, joint pain, infections, leukopenia, and anemia.
  • MMF Mycophenolate sodium is also commonly associated with fatigue, headache, cough and/or breathing issues.
  • IV Intravenous
  • MMF mycophenolate sodium 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.
  • CMV invasive cytomegalovirus
  • pulmonary fibrosis or various neoplasia occur, such as, for example, melanoma, lymphoma, and other malignancies, which MMF-related neoplasias 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.
  • MMF-related neoplasias 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.
  • PRCA pure red cell aplasia
  • compositions and methods according to the present disclosure may be described in pharmacological terms, including pharmacokinetics (“PK”) and
  • PK pharmacodynamics
  • C max the maximum serum concentration of a drug in a specified compartment or test area of the body
  • T max the time at which the C max is observed
  • C min minimum or trough concentration
  • T mm time at which C min is observed
  • Ti /2 half-life of the drug or metabolite, i.e., the time taken for the drug concentration to fall to one half of its original value, which may be calculated using one or more points along the terminal phase of the elimination
  • elimination rate constant“k” the slope calculated using one or more concentrations in the log domain the terminal phase
  • AUC area under the curve”; the definite integral in a plot of concentration of a drug in blood plasma over time).
  • AUC represents the total drug exposure over time in a given dose or dosing regimen, and may be computed starting at the time of administration and ending when the plasma concentration is minimal, or may be measured at chosen points in time and calculated therefrom. It will be appreciated that certain PK values, such as C maX and C mm, may be reported with respect to particular timeframes herein, e.g ., a particular time window, or a particular number of hours, following administration of a controlled-release formulation.
  • PK values described herein with respect to MPA compositions and related methods include, for example, [MPA] (concentration of mycophenolic acid drug),
  • [MPAG], and [Acyl-MPAG] Serum or plasma concentrations of a drug or metabolite may be reported in any appropriate unit, such as, for example, ng/mL, mg/kg, pg/mL, pg/L, and so on. Concentrations over time may be reported in any appropriate unit, such as, for example, pg*h/L or ng*h/mL.
  • the AUC may be used to report the concentration over a given time interval (AUC t ) or unbound by a particular time interval (AUC mf ).
  • MPA PK Other measures of MPA PK include, for example, drug:metabolite ratios, e.g. , drug:metabolite ratios obtainable following administration of a MPA-containing agent (e.g, an immediate-release formulation or a controlled-release formulation of the present disclosure).
  • drug:metabolite ratios e.g. , drug:metabolite ratios obtainable following administration of a MPA-containing agent (e.g, an immediate-release formulation or a controlled-release formulation of the present disclosure).
  • presently disclosed methods and compositions may, in some embodiments, possess desired MPA pharmacodynamics.
  • presently disclosed methods and compositions of the present disclosure may be used for e.g, , reducing lymphocyte proliferation, providing immunosuppression, modulating an inflammatory response in a canine subject, and providing MPA-based therapies with improved safety profiles.
  • controlled-release formulations wherein the formulations comprise: about 3 mg to about 2.2 g of a MPA active agent; and (ii) a means for controlling release of the MPA active agent so that the MPA active agent is released from the formulation in vivo such that a canine subject administered the MPA active agent at a single dose of about 21 mg/kg achieves a plasma [MPA] Cmax of up to about 3000 ng/ml ( e.g ., about 1000, 1500, 2000, 2500, or about 3000 ng/ml) over about 8 hours following the single dose, and a plasma [MPA] Cmin of no less than about 250 ng/mL from about 2.5 to about 8 hours following the first dose, and the subject achieves an average plasma [MPA] of 250 ng/ml to about 2000 ng/ml for about 8 hours following the single dose, and whereupon at 2.5 hours, 4 hours, and 8 hours following the single dose, a percentage of proliferating lymphocytes in a whole
  • the total amount of the MPA active agent present in the controlled-release formulation is about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
  • the MPA active agent comprises mycophenolate sodium.
  • the formulation comprises about 180 mg of mycophenolate sodium. In other embodiments, the formulation comprises about 270 mg of mycophenolate sodium.
  • a delivery system may be used to deliver a formulation of the instant disclosure, such as, for example: (i) a multiparticulate drug delivery system (MDDS) containing a plurality of particulate subunits that each comprise the MPA active agent; (ii) a tablet; (iii) a suspension; (iv) a dragee; (v) a minitablet; or (vi) any combination thereof.
  • MDDS multiparticulate drug delivery system
  • a capsule 300 includes a plurality of subunits 100, 200, dispersed or mixed within the capsule 300.
  • MDDS multi-particulate drug delivery system
  • a multi-unit drug dosage form comprising a plurality of discrete particulate subunits (e.g ., granules, beads, microspheres, spheroids, pellets, and minitablets) that contain or otherwise carry the drug to be delivered.
  • MDDS of the present disclosure are controlled-release oral compositions that release a MPA active agent in vivo along a desired release profile, and include, for example, tablets (including minitablets), capsules, dragees, sachets, and suspensions that comprise particulate subunits.
  • A“particulate subunit,” as described herein, refers to a drug-containing subunit of a MDDS, and can take the form of, for example, a bead, a granule, a microsphere, a spheroid, a pellet, or the like, as described further herein.
  • a formulation comprises a MDDS that is prepared for delivery via a capsule, a sachet, a tablet, or any combination thereof.
  • a MDDS comprises a single type of a particulate subunit. In other embodiments, a MDDS comprises multiple types of the particulate subunits.
  • a MDDS may comprise a mixture of particulate subunits having different release characteristics so as to achieve a desired drug release profile in a canine subject.
  • a plurality of particulate subunits having cores of different sizes, or the presence or absence of a protective layer (described herein), or other characteristics may be present in a MDDS of the present disclosure.
  • this flexibility advantageously permits selecting or calibrating a MDDS for a specific canine subject (e.g., an individual canine) or for a population or sub-population of canine subjects (e.g, a breed or species of canine) as may be warranted by characteristics such as the specific size, activity, level, responsiveness to a pending or prior treatment, general health, metabolic rate or function, and other specific
  • Particulate subunits include, for example, beads, granules, microspheres, spheroids, pellets, and minitablets.
  • a particulate subunit (e.g., FIG. 1, 100) includes a core and a MPA active agent.
  • a core (e.g., FIG. 1, 102) of a particulate subunit 100 comprises a solid support core, such as, for example, a sugar bead, a sugar sphere, a nonpareil bead, a microcrystalline cellulose bead, a silica bead, a calcium carbonate bead, a tartaric acid bead, a mannitol bead, a lactose bead, a starch bead, or another pharmaceutically acceptable core onto which an MPA active agent and other layers described herein can be disposed.
  • a core 102 comprises an active agent layer (e.g, FIG. 1, 104) disposed over at least a portion of the core 102 (e.g, disposed over a portion, or all, of the core 102).
  • the MPA active agent may be disposed over core 102 using methods known in the art, such as, for example, spray coating, extrusion, suspension layering, dry powder layering, spray granulation, direct pelletizing, dip coating, layering, painting, deposition methods, and the like (see, e.g, methods outlined by Glatt GmbH, Binzen, Germany, www.glatt.com).
  • a core 202 is an extruded core, in which the MPA active agent is contained.
  • Extruded cores can be prepared as described, for example, in U.S. Patent Nos. 4,808,413 and 5,049,394 (the disclosures of each of which are incorporated by reference herein in their entireties), and may include a binder-plasticizer (e.g, a non-lipophilic binder-plasticizer (such as microcrystalline cellulose)), an excipient (e.g, a starch-based excipient) or a binder.
  • a binder-plasticizer e.g, a non-lipophilic binder-plasticizer (such as microcrystalline cellulose)
  • excipient e.g, a starch-based excipient
  • extruded cores can be prepared as described in Missaghi et al., “Investigation of Venlafaxine HC1 Release from Extruded and Spheronized Beads Coated with Ethylcellulose ETsing Organic or Aqueous Coating Systems,” Controlled Release Society Annual Meeting July 2008, the disclosure of which is incorporated by reference herein in its entirety for all purposes.
  • extruded core 202 includes a MPA active agent (e.g, mycophenolate sodium) from about 50 wt% to about 90 wt%, an extrusion/spheronization aid, such as microcrystalline cellulose, from about 10 wt% to about 30 wt%, or from about 15 wt% to 20wt%.
  • a MPA active agent e.g, mycophenolate sodium
  • an extrusion/spheronization aid such as microcrystalline cellulose
  • the amount of a substance in a composition may be described“by weight,” by“percent weight,” or “wt%,” meaning the weight of a substance relative to the weight of an individual composition (e.g, a single particulate subunit) rather than relative to the total weight of the MDDS comprising the plurality of the particulate subunits).
  • an extruded core 202 further comprises one or more of: a binder (e.g, hydroxypropyl cellulose, hydroxyl propyl methyl cellulose, pregelatinized starch, ethyl cellulose or poly vinyl pyrrolidone) from about 1 wt% to about 10 wt%, preferably from about 2 wt% to about 5 wt%; a release excipient, such as, for example, hydroxpropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), acrylic polymers, hydroxyethyl cellulose (HEC), ethyl cellulose (EC), which can be incorporated into the beads or applied as coating; a filler, such as, for example, lactose, maltodextrin, mannitol, sorbitol, dicalcium phosphate, and the like; and a superdisintegrant, such as, for example, crosslinked poly(vinyl pyrrolidone)
  • At least a portion of the MPA active agent can be dispersed, dissolved, mixed in, or otherwise distributed throughout the core.
  • the MPA active agent may be co-dissolved with the various polymers and other excipients for producing the extruded cores, and then passed through an extruder to form the desired size beads, prior to drying.
  • an extruded core 202 of the present disclosure may also have an active layer (i.e., of MPA active agent) disposed partially or fully thereover.
  • an active layer i.e., of MPA active agent
  • the size of the core 102, 202 of a particulate subunit can be important to ensure sufficient delivery of a MPA active agent to a canine subject.
  • a particulate subunit core can have a diameter of about 0.5 mm to about 10 mm.
  • a diameter of a core is from about 0.5 mm to about 9 mm, about 1 mm to about 8 mm, about 1 mm to about 7 mm, about 1 mm to about 6 mm, about 1 mm to about 5 mm, about 2 mm to about 5 mm, about 2 mm to about 4 mm, or about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, or about 10 mm in diameter.
  • the diameter of the core is about 5 mm or less, or is about 2 mm to about 4 mm.
  • a core diameter of less than about 5 mm allows the particulate subunit, once freed or dispersed from an administered MDDS, to move readily through the stomach of a canine subject, in particular, through a canine stomach and into the upper and then lower gastrointestinal tract for delivery of the MPA active agent.
  • particulate subunit with cores having a diameter of greater than about 5 mm may remain in the stomach for an undesirably long period of time, thereby impacting the targeted delivery of the MPA active agent.
  • the crushing strength of the stomach of certain canines can be significantly higher than the crushing strength of a human stomach (about 1.5N (human) vs. about 3.2N (canine); (see, e.g., Kamba et al, Int. J. Pharmaceutics 228( ⁇ -2): 209-217 (2001)).
  • smaller-sized cores such as cores having diameters of less than about 5 mm, may prevent a particulate subunit from being crushed in the stomach, which may cause premature (and therefore less effective and possibly adverse) release of a MPA active agent in the stomach of the canine subject.
  • particulate subunits (100, 200) of the present disclosure include a controlled-release layer 108, 208 disposed over at least a portion of core 102 or 202.
  • a“controlled-release layer” refers to a layer of material that provides release of a MPA active agent over a pre-determined time or period of time, or at a pre-determined rate, or otherwise along a release profile that does not include immediate release of a MPA active agent following administration.
  • Non-limiting examples of materials suitable for forming a controlled-release layer include various polymers, such as cellulose polymers or acrylate polymers, cellulose acetates, cellulose acetate butyrates, ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose polymers, EUDRAGIT® polymers for modified release (e.g, one or both of
  • EUDRAGIT RS100 and RL100 which if both present can be in any ratio
  • PVA poly(vinyl acrylate)
  • a controlled-release layer comprises from about 15 wt% to about 35 wt% of the composition. In certain embodiments, a
  • controlled-release layer may comprise ethyl cellulose, such as in the form of an aqueous ethyl cellulose rate-controlling polymer.
  • a controlled-release layer may be applied in any way that provides an appropriate rate controlling membrane.
  • a powder coating may be used as a deposition vehicle for the controlled-release layer.
  • Any suitable dispersion product may be used, such as, for example, Surelease (Colorcon, Harleysville, PA, ETSA) or other products and materials known in the art.
  • Any desired polymer ratio, using any polymer blend, may be employed using known techniques to produce a composition having a desired release profile.
  • a controlled-release layer 108, 208 includes a polymer as described herein at about 5 wt% to about 50 wt%, or about 10 wt% to about 40 wt%, or about 20 wt% to about 30 wt%, or about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, or about 40 wt%.
  • the polymer may be an organic or polymer as described herein at about 5
  • controlled-release layer 108, 208 may include a soluble component to modulate the permeability thereof. Release of a MPA active agent may be further adjusted by varying the thickness of one or more polymer layers utilized to form a controlled -release layer (i.e., by varying the weight of the polymer layer) or by adding pore forming-agents to affect the permeability of the controlled-release layer.
  • the controlled-release layer can be applied as a single layer.
  • a controlled-release layer includes multiple layers, optionally (in the case of spherical, circular, round, or ovular subunits) concentrically disposed on one another.
  • the controlled -release layer 108 can be disposed over at least a portion of the active layer 104.
  • core 202 is an extruded core comprising at least a portion of the active agent
  • a controlled-release layer 208 is disposed over at least a portion of core 202.
  • a particulate subunit 100, 200 may further include a protective layer 110, 210 disposed over at least a portion of controlled-release layer 108, 208.
  • protective layer refers to a layer of material that provides protection from degradation or dissolution to an ingested composition (e.g ., a particulate subunit of the present disclosure) as it travels through the stomach.
  • the protective layer 110, 210 is selected or designed to delay release of at least a portion of the MPA active agent until the formulation reaches the a desired site within the canine, such as the lower GI tract.
  • one or more polymers of the Eudragit L series (Evonik, Essen, DE), such as L100, may be used to form a protective layer.
  • the protective layer comprises from about 8wt% to about l5wt% of the composition.
  • a protective layer 1 10, 210 may be a pH sensitive layer that can maintain integrity at the pH of stomach acid (e.g., roughly pH 1.2 to pH 4.5 in canines), but at least partially degrades once it reaches the small or large intestine (having a pH of about 4 to about 8 in canines).
  • protective layer 110, 210 dissolves at a pH above about 6.0. It will be understood that the pH sensitivity of the protective layer, as well as the overall strength and release characteristics of the particulate subunit or formulation, may vary in accordance with the physiological characteristics of the canine subject to be treated (e.g., large canine versus small canine).
  • suitable materials for forming protective layer 110, 210 include enteric polymers, such as methacrylate-based polymers including EUDRAGIT® L or
  • EUDRAGIT® S polymers cellulose acetate phthalate, cellulose acetate succinate, HPMC phthalate, HPMC acetate succinate, sodium alginate, zein, polyvinyl acetate phthalate (PVAP), shellac, methacrylic aid-ethyl acrylate copolymer (Kollicoat MAE), and mixtures thereof.
  • controlled-release layer 108, 208 and protective layer 110, 210 can be designed so as to provide a timed release, rather than a pH-dependent release, of the MPA active agent, so that they enable the compositions to pass through the stomach intact and release (at least a portion of) the MPA active agent in the small and/or large intestine, as desired.
  • particulate subunits of the present disclosure may include a seal coat 106, 206.
  • seal coat 106 separates core 102 and active agent layer 104 from controlled-release layer 108.
  • a particulate subunit 200 includes a seal coat 206 that separates controlled-release layer 208 from core 202, which is an extruded core containing at least some (i.e., all or less than all) of the MPA active agent.
  • a seal coat 106, 206 may be useful to separate, partially or fully, a MPA active agent from controlled-release layer 108, 208 so as to reduce or eliminate interactions and degradation of the
  • compositions for use in seal coat 106, 206 include various cellulose polymers, including hydroxypropyl methylcellulose, poly(vinyl alcohol) (Opadry AMB, Kollicoat), hydroxypropyl methylcellulose, methyl cellulose, hydroxyethylcellulose, Opadry series, and the like.
  • a controlled-release formulation may further comprise a buffering agent or buffer to protect a MPA active agent from degradation by gastric acid.
  • a buffer can be added to core 102, 202 or to active agent layer 104 surrounding core 102.
  • the buffer may be added to core 202 or added to a layer 206, 208, 210 surrounding core 202 to provide buffering and to maintain the integrity and activity of the MPA active agent.
  • Exemplary buffers for use in the formulations and particulate subunites described herein include, but are not limited to, phosphate buffers, citrate buffers and acetate buffers.
  • a particulate subunit may further comprise a buffer to affect stability or release of the MPA active agent under certain pH conditions.
  • Kits are also provided herein that comprise a controlled-release formulation of the instant disclosure, and optionally further comprise instructions for administering the formulation to a canine subject.
  • the kit further comprises a companion delivery piece.
  • a companion delivery piece can be, for example, an irrigation syringe, a syringe, a tube, a transdermal patch, a mixing flask for producing a solution containing the formulation; or a food item to be provided to the veterinary subject with the formulation.
  • a food item is of a recommended meal size for the veterinary subject.
  • a food item may be useful in accompanying the formulation for oral ingestion as a separate item or as a coating, filling, or mixture with the formulation.
  • a controlled-release formulation (e.g ., powder or microbeads) may also be mixed with water or another liquid so that the formulation is ingested when the canine subject takes a drink. If the subject is not drinking or resists drinking, the irrigation syringe may be useful to deliver the formulation to the subject.
  • the kit comprises a sealed package housing individually sealed unit dosage forms comprising the formulation, e.g., MDDS, capsules, tablets, or the like, along with instructions for use and an optional companion delivery piece.
  • Controlled-release MPA formulations including the formulations described herein, may be useful for suppressing lymphocyte proliferation and in treating diseases and conditions in which such suppression may be desired.
  • the present disclosure provides, for the first time, a pharmacokinetic“window” of MPA which advantageous pharmacodynamic effects are achieved in a canine subject using controlled-release formulations.
  • a method for suppressing lymphocyte proliferation in a canine subject comprises administering to the subject a controlled-release formulation comprising a MPA active agent such that the subject achieves an average plasma [MPA] of about 250 ng/mL to about 3000 ng/mL (e.g ., about 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or about 3000 ng/mL) over about 8 hours following a first dose of the controlled-release formulation, whereupon at 2.5 hours, 4 hours, and 8 hours following the first dose, a percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced as compared to the percentage of proliferating lymphocytes in a whole blood sample
  • the subject achieves an average plasma [MPA] of about 250 ng/mL to about 2500 ng/mL for about 8 hours following a first dose.
  • the subject achieves an average plasma [MPA] of about 350 ng/mL to about 2000 ng/mL for about 8 hours following a first dose.
  • MPA average plasma
  • the pharmacokinetics of a controlled-release MPA formulation may depend on whether the canine subject receiving the formulation is in a fed state, or is in a fasted state, as described herein.
  • a canine subject is
  • the canine subject is administered a first dose of the controlled-release formulation when in a fed state, wherein the subject achieves an average plasma [MPA] of about 500 ng/mL to about 2500 ng/mL for about 8 hours following a first dose.
  • the canine subject is administered a first dose of the controlled-release formulation when in a fasted state, wherein the subject achieves an average plasma [MPA] of about 500 ng/mL to about 3000 ng/mL for about 8 hours following the first dose.
  • a fasted state may comprise a state in which the canine subject was fed no later than about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 14, 16, 18, 20, 24, or more hours prior to administration, and then optionally not fed again until about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, or 24 hours following administration.
  • a fed state may comprise a state in which the canine subject has been fed immediately prior to, or no more than 1 hour prior to, administration.
  • the subject achieves an average plasma [MPA] of about 500 ng/mL to about 1700 ng/mL for about 8 hours following a first dose.
  • the subject achieves an average plasma [MPA] of about 650 ng/mL to about 1500 ng/mL for about 8 hours following a first dose.
  • subject achieves an average plasma [MPA] of about 250 ng/mL to about 600 ng/mL for about 8 hours following a first dose.
  • MPA average plasma
  • the subject achieves a plasma [MPA] Cmax of about 2000 ng/mL over about 8 hours following a first dose, and a plasma [MPA] Cmin of no less than about 500 ng/mL from about 2.5 to about 8 hours following the first dose.
  • the subject achieves a plasma [MPA] Cmax of about 2500 ng/mL over about 8 hours following a first dose, and a plasma [MPA] Cmin of no less than about 250 ng/mL from about 2.5 to about 8 hours following the first dose.
  • the subject achieves a plasma [MPA] Cmax of about 1500 ng/mL over about 8 hours following a first dose, and a plasma [MPA] Cmin of no less than about 600 ng/mL from about 2.5 to about 8 hours following the first dose.
  • the subject achieves a plasma [MPA] Cmax of about 700 ng/mL over about 8 hours following a first dose, and a plasma [MPA] Cmin of no less than about 250 ng/mL from about 2.5 to about 8 hours following the first dose
  • the subject achieves a plasma [MPA] Cmax of about 600 ng/mL from about 1 to about 8 hours following a first dose, and a plasma [MPA] Cmin of no less than about 250 ng/mL from about 2.5 to about 8 hours following the first dose.
  • PK profiles are believed to provide a desirable MPA PD in a canine subject administered a controlled-release formulation.
  • the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by at least about 35%, 40%, 45%, 50%, 55%, 60 %, 65%, 70%, 75%, 80%, or more, relative to the percentage of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the first dose.
  • the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by at least about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more, relative to the percentage of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the first dose.
  • the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by at least about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more, relative to the amount of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the first dose.
  • the reduction in the percentage of proliferating lymphocytes may be achieved at 2.5, 4, or 8 hours following a first dose, or may be achieved at any two or all three of the indicated timepoints (i.e., at 2.5 and 4, at 2.5 and 8, at 4 and 8, or at 2.5, at 4, and at 8 hours following a first dose).
  • a dose may be administered at any time, though generally in the morning or evening.
  • administering comprises administering a single dose of the controlled-release composition per day for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more, consecutive days.
  • administering a once-daily dose according of the presently disclosed methods for multiple (i.e., two or more) consecutive days provides a systemic effect.
  • administering comprises administering a single dose for two or more consecutive days (e.g, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more), whereupon 24 hours after the dose of the second day, and prior to any subsequent dose, the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more, relative to the amount of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the dose of the first day.
  • consecutive days e.g, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more
  • administering is performed for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more days, and whereupon 24 hours after the dose of each of the second, third, fourth, fifth, sixth, seven, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, and fifteenth days, and prior to any subsequent dose, the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more, relative to the amount of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the dose of the first day.
  • administering comprises administering a single dose for seven or more consecutive days, whereupon 24 hours following the seventh dose, and prior to any subsequent dose, the percentage of proliferating lymphocytes in a whole blood sample from the canine subject is reduced (e.g, by any amount, including and up to at least about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more) as compared to the amount of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the dose of the first day.
  • administering is performed for 8, 9, 10, 11, 12, 13, 14, 15, or more days, whereupon 24 hours after the dose of each of the eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, and fifteenth days, and prior to any subsequent dose, the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more, relative to the amount of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the dose of the first day.
  • a single dose of a controlled-release formulation has improved activity, both in degree and duration, over immediate-release (IR) formulations that comprise an MPA active agent (e.g, mycophenolate mofetil), including when the IR formulation is administered twice daily.
  • MPA active agent e.g, mycophenolate mofetil
  • the percentage of proliferating lymphocytes in a whole blood sample obtained from the subject at 4 hours following administration of a single dose is lower than (ii) the percentage of proliferating lymphocytes in a whole blood sample obtained from a reference canine subject that received an immediate-release formulation comprising a MPA active agent.
  • the amount of proliferating lymphocytes in a whole blood sample obtained from the subject at 8 hours following administration of a single dose is lower than (ii) the amount of proliferating lymphocytes in a whole blood sample obtained from a reference canine subject that received an immediate-release formulation comprising a MPA active agent.
  • A“reference canine subject,” as referred to herein, is a comparator canine of a similar or same age, size, gender, breed, and disease state as the canine subject receiving the controlled-release formulation.
  • a reference canine subject receives, in one or more doses of the immediate-release formulation, a total daily intake of an MPA active agent that is present in in a standard-of-care treatment such as CellCept® (Genentech) (e.g, 10 mg/kg BID; MPA dose-equivalent of approximately 7.4 mg/kg for each dose for an approximately lOkg canine).
  • a reference canine subject receives a total daily intake of a MPA active agent that is about 40%, 45%, 50%, 55%, 60%, 65%, 70%, or up to about 100% of the amount present in the controlled-release formulation administered to the canine subject.
  • a reference male beagle dog weighing approximately 12 kg may receive two daily administrations of an immediate-release formulation, each administration containing about 88.5 mg MPA and totaling about 177 mg MPA, while a male beagle dog weighing approximately l2kg may receive a once-daily administration of a controlled-release formulation of the instant disclosure containing about l68mg MPA or about 252 mg MPA, or any amount therebetween.
  • administering comprises administering the dose for 10 or more days, wherein over the 10 days, the subject exhibits no adverse gastrointestinal events, wherein an adverse gastrointestinal event comprises emesis, diarrhea, soft stool, or any combination thereof.
  • administering comprises administering the dose for 15 or more days, and wherein over the 15 days, the canine subj ect exhibits no adverse gastrointestinal events.
  • administering comprises administering a dose for 10 or more days, wherein over the 10 days, the subject exhibits a reduced number, a reduced severity, or both, of an adverse gastrointestinal event as compared to a reference canine subject that received an immediate-release formulation comprising a MPA active agent, wherein an adverse gastrointestinal event comprises emesis, diarrhea, soft stool, or any combination thereof.
  • administering comprises administering a dose for 15 or more days, wherein over the 15 days, the canine subject exhibits a reduced number, a reduced severity, or both, of an adverse gastrointestinal event as compared to the reference canine subj ect.
  • administration can comprise oral administration.
  • a method comprises use of any one or more of a controlled-release formulation as described herein, such as, for example, (i) a multiparticulate drug delivery system (MDDS) containing a plurality of particulate subunits that each comprise the MPA active agent; (ii) a tablet; (iii) a suspension; (iv) a dragee; or (v) any combination thereof.
  • a controlled-release formulation comprises a MDDS comprising a plurality of particulate subunits each having a diameter of than about 5 mm.
  • a formulation comprises a MDDS that is prepared for delivery to the subject via a capsule, a sachet, a tablet, or any combination thereof.
  • each of the plurality of particulate subunits of the MDDS comprises a core, wherein: (i) the MPA active agent is contained in an active layer disposed over at least a portion of the core; or (ii) the MPA active agent is contained within the core.
  • each particulate subunit of the plurality further comprises a controlled-release layer, wherein the controlled-release layer is disposed over the MPA active layer of the core of (i), or is disposed over at least a portion of the core of (ii).
  • each particulate subunit of the plurality comprises a seal coat layer, wherein the seal coat layer is disposed between the MPA active layer of the core of (i) and the controlled-release layer, or disposed between the core of (ii) and the controlled-release layer.
  • each particulate subunit of the plurality further comprises a protective layer disposed over the controlled-release layer.
  • a first dose comprises the MPA active agent at about 3 mg/kg to about 35 mg/kg.
  • a first dose comprises the MPA active agent at about 15 mg/kg to about 30 mg/kg.
  • a first dose comprises from about 3mg to about 2200 mg of the MPA active agent.
  • a first dose comprises about 168 mg of the MPA active agent. In some embodiments, a first dose comprises about 252 mg of the MPA active agent. In any of the presently disclosed embodiments, the MPA active agent can comprise mycophenolate sodium. In some embodiments, the controlled-release composition is administered to the subject with food, and may in any embodiment be administered in a fed state or a fasted state.
  • the subject (i) has, or is suspected of having, an autoimmune disease or disorder associated with aberrant lymphocyte proliferation;
  • the canine subject has or is suspected of having an autoimmune disease or disorder comprising atopic dermatitis, arthritis, myasthenia gravis, celiac disease, diabetes mellitus type 1, Grave’s disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, Belief s disease, pemphigus vulgaris, refractory incomplete systemic lupus
  • an autoimmune disease or disorder comprising atopic dermatitis, arthritis, myasthenia gravis, celiac disease, diabetes mellitus type 1, Grave’s disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, Belief s disease, pemphigus vulgaris, refractory incomplete systemic lupus
  • erythematosus erythematosus, lupus nephritis, immunoglobulin A nephropathy, small vessel vasculitides, scleroderma (systemic sclerosis or SSc), idiopathic thrombocytopenic purpura (ITP), psoriasis, apernicious anemia, vitiligo, autoimmune hemolytic disease, glomerulonephritis, immune cytopenias, meningoencephalomyelitis, subepidermal blistering autoimmune disease, immunobullous diseases, cutaneous vasculitis, recurrent erythema multiforme, erythema nodosum, lichen planus, cutaneous Crohn’s disease, sarcoidosis, hepatitis, pyoderma gangrenosum, or any combination thereof.
  • the subject achieves an average plasma [MPA] of about 250 ng/mL to about 2500 ng/mL for about 8 hours following a first dose.
  • the subject achieves an average plasma [MPA] of about 350 ng/mL to about 2000 ng/mL for about 8 hours following a first dose.
  • the subject achieves an average plasma [MPA] of about 500 ng/mL to about 1700 ng/mL for about 8 hours following a first dose.
  • the subject achieves an average plasma [MPA] of about 650 ng/mL to about 1500 ng/mL for about 8 hours following a first dose.
  • the subject achieves a plasma [MPA] Cmax of about 2500 ng/mL over about 8 hours following a first dose, and a plasma [MPA] Cmin of no less than about 250 ng/mL from about 2.5 to about 8 hours following a first dose.
  • the subject achieves a plasma [MPA] Cmax of about 2000 ng/mL over about 8 hours following a single dose, and a plasma [MPA] Cmin of no less than about 500 ng/mL from about 2.5 to about 8 hours following the single dose.
  • the subject achieves a plasma [MPA] Cmax of about 1500 ng/mL over about 8 hours following a single dose, and a plasma [MPA] Cmin of no less than about 600 ng/mL from about 2.5 to about 8 hours following the single dose.
  • the subject achieves a plasma [MPA] Cmax of about 700 ng/mL over about 8 hours following a single dose, and a plasma [MPA] Cmin of no less than about 250 ng/mL from about 2.5 to about 8 hours following the single dose.
  • the subject achieves a plasma [MPA] Cmax of about 600 ng/mL from about 1 to about 8 hours following the first dose, and a plasma [MPA] Cmin of no less than about 250 ng/mL from about 2.5 to about 8 hours following the first dose.
  • the administering comprises administering a single dose for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more, consecutive days.
  • administering comprises administering a single dose for two or more consecutive days (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more), whereupon 24 hours after the dose of the second day, and prior to any subsequent dose, the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more, relative to the amount of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the dose of the first day.
  • consecutive days e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more
  • the administering is performed for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more days, and whereupon 24 hours after the dose of each of the second, third, fourth, fifth, sixth, seven, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, and fifteenth days, and prior to any subsequent dose, the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more, relative to the amount of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the dose of the first day.
  • the administering comprises administering a single dose for seven or more consecutive days, whereupon 24 hours after the dose of the seventh day, and prior to any subsequent dose, the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more, relative to the amount of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the dose of the first day.
  • the administering comprises administering a single dose for 10 or more days, wherein over the 10 days, the subject exhibits no adverse gastrointestinal events, wherein an adverse gastrointestinal event comprises emesis, diarrhea, soft stool, or any combination thereof.
  • the autoimmune disease or disorder comprises atopic dermatitis, arthritis, myasthenia gravis, celiac disease, diabetes mellitus type 1, Grave’s disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, Beh et’s disease, pemphigus vulgaris, refractory incomplete systemic lupus erythematosus, lupus nephritis, immunoglobulin A nephropathy, small vessel vasculitides, scleroderma (systemic sclerosis or SSc), idiopathic thrombocytopenic purpura (ITP), psoriasis, apernicious anemia, vitiligo, autoimmune hemolytic disease, glomerulonephritis, immune cytopenias,
  • Grave’s disease inflammatory bowel disease, multiple sclerosis, ps
  • immunobullous diseases cutaneous vasculitis, recurrent erythema multiforme, erythema nodosum, lichen planus, cutaneous Crohn’s disease, sarcoidosis, hepatitis, pyoderma gangrenosum, or any combination thereof.
  • a method comprises administering to a canine subject that has undergone, is undergoing, or will undergo an organ transplant and/or artificial implant, a controlled-release composition comprising a MPA active agent, at a dose of about 3 mg/kg to about 35 mg/kg of the MPA active agent, wherein the subject receives a single dose of the controlled-release composition per day, such that the subject achieves a plasma [MPA] Cmax of about 3000 ng/mL over about 8 hours following a single dose , and a plasma [MPA] Cmin of no less than about 250 ng/mL from about 2.5 to about 8 hours following the single dose, and the subject achieves an average plasma [MPA] of 250 ng/mL to about 2500 ng/ml for about 8 hours following the single dose, and
  • the subject achieves a plasma [MPA] Cmax of about 2500 ng/mL over about 8 hours following the first dose, and a plasma [MPA] Cmin of no less than about 250 ng/mL from about 2.5 to about 8 hours following the single dose.
  • the subject achieves a plasma [MPA] Cmax of about 2000 ng/mL over about 8 hours following the single dose, and a plasma [MPA] Cmin of no less than about 500 ng/mL from about 2.5 to about 8 hours following the single dose.
  • the subject achieves a plasma [MPA] Cmax of about 1500 ng/mL over about 8 hours following the single dose, and a plasma [MPA] Cmin of no less than about 600 ng/mL from about 2.5 to about 8 hours following the single dose.
  • the subject achieves a plasma [MPA] Cmax of about 700ng/mL over about 8 hours following the single dose , and a plasma [MPA] Cmin of no less than about 250 ng/mL from about 1 to about 8 hours following the single dose.
  • the administering comprises administering the dose for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more, consecutive days.
  • the administering comprises administering the single dose for seven or more consecutive days, whereupon 24 hours after the dose of the seventh day, and prior to any subsequent dose, the percentage of proliferating lymphocytes in a whole blood sample from the canine subject is reduced by about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more, relative to the amount of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the dose of the first day.
  • the administering comprises administering the dose for 10 or more days, wherein over the 10 days, the subject exhibits no adverse gastrointestinal events, wherein an adverse gastrointestinal event comprises emesis, diarrhea, soft stool, or any combination thereof.
  • the canine subject exhibits a reduction in the severity of a symptom associated with the autoimmune disease or disorder.
  • symptoms include, for example, rash, elevated levels of autoantibodies and/or inflammatory cytokine levels, fever, fatigue, stiffness, pain, blisters, itchiness, discharge, eczema, swelling, hair loss, loss of appetite, asthma, and foul odor.
  • the present disclosure provides uses of a controlled-release MPA formulation for suppressing lymphocyte proliferation and/or activation in a canine subject.
  • a use comprises administering to the subject a controlled-release formulation comprising a mycophenolic acid (MPA) active agent such that the subject achieves an average plasma [MPA] of about 250 ng/mL to about 3000 ng/mL (e.g., about 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or about 3000 ng/mL)over about 8 hours following a first dose of the controlled-release formulation, wherein the subject achieves a plasma [MPA] Cmax of about 3000 ng/mL, optionally about 2500 ng/mL, optionally about 2000 ng/mL, optionally about 1500 mL, optionally about 700 ng/mL, optionally
  • the subject achieves an average of plasma [MPA] of: (i) about 350 ng/ml to about 2000 ng/mL over 8 hours following the first dose; (ii) about 500 ng/ml to about 1700 ng/mL over 8 hours following the first dose; or (iii) about 650 ng/ml to about 1500 ng/mL over 8 hours following the first dose.
  • MPA average of plasma
  • the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by at least about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more, relative to the percentage of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the first dose.
  • the subject is administered the composition for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more, consecutive days.
  • the subject receives a single dose of the controlled-release composition per day.
  • the administering comprises administering the single dose for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more days, and whereupon 24 hours after the dose of each of the second, third , fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth days, and prior to any subsequent dose, the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more, relative to the amount of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the dose of the first day.
  • the administering comprises administering the single dose for 7 or more consecutive days, whereupon after the dose of the seventh day, the percentage of proliferating lymphocytes in a whole blood sample from the subject is reduced by about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more, relative to the amount of proliferating lymphocytes in a whole blood sample obtained from the subject 15 or fewer minutes prior to the dose of the first day.
  • the percentage of proliferating lymphocytes in a whole blood sample obtained from the subject at 4 hours, optionally at 8 hours, following administration of a first dose is lower than (ii) the percentage of proliferating lymphocytes in a whole blood sample obtained from a reference canine subject ⁇ i.e., a reference canine subject as described herein) that was administered an immediate-release formulation comprising a MPA active agent.
  • the administering comprises administering the single dose for 10 or more days, wherein over the 10 days, the subject exhibits no adverse gastrointestinal events, wherein an adverse gastrointestinal event comprises emesis, diarrhea, soft stool, or any combination thereof.
  • the administering comprises administering the single dose for 15 or more days, wherein over the 15 days, the subject exhibits no adverse gastrointestinal events, wherein an adverse gastrointestinal event comprises emesis, diarrhea, soft stool, or any combination thereof.
  • the administering comprises administering the single dose for 10 or more days, wherein over the 10 days, the subject exhibits a reduced number, a reduced severity, or both, of an adverse gastrointestinal event as compared to a reference canine subject (i.e., a reference canine subject as described herein) that was administered an immediate-release formulation comprising a MPA active agent, wherein an adverse gastrointestinal event comprises emesis, diarrhea, soft stool, or any combination thereof.
  • a reference canine subject i.e., a reference canine subject as described herein
  • an adverse gastrointestinal event comprises emesis, diarrhea, soft stool, or any combination thereof.
  • the immediate-release formulation was administered to the reference canine subject at a twice-daily dose of 7.4 mg/kg MPA, wherein the immediate-release formulation optionally comprises mycophenolate mofetil.
  • the MPA active agent comprises mycophenolate sodium, wherein the mycophenolate sodium is optionally administered to the canine subject orally.
  • the controlled-release composition comprises a fillable capsule comprising a plurality of particulate subunits that each comprise: (i) a core, wherein (a) the MPA active agent is comprised in an active layer disposed over at least a portion of the core; or (b) the MPA active agent is disposed within the core; (ii) a controlled-release layer disposed over at least a portion of (a) the active layer or (b) the core; (iii) an optional seal coat layer disposed between (a) the active layer and the controlled-release layer, or (b) the core and the controlled-release layer; (iv) an optional protective layer disposed over the controlled-release layer, wherein the MPA active agent comprises mycophenolate sodium and is optionally present in the controlled-release composition from about 3 mg to about 2.2 g (i.e., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
  • the canine (i) has, or is suspected of having, an autoimmune disease or disorder associated with aberrant lymphocyte proliferation and/or activation, wherein the autoimmune disease or disorder optionally comprises atopic dermatitis, arthritis, myasthenia gravis, celiac disease, diabetes mellitus type 1, Grave’s disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, Behçet’s disease, pemphigus vulgaris, refractory incomplete systemic lupus erythematosus, lupus nephritis, immunoglobulin A nephropathy, small vessel vasculitides, scleroderma (systemic sclerosis or SSc), idiopathic thrombocytopenic purpura (ITP), psoriasis, apernicious
  • the veterinary subject exhibits a reduction in the severity of a symptom associated with the autoimmune disease or disorder, wherein the symptom is not aberrant lymphocyte proliferation.
  • symptoms include, for example, rash, elevated levels of autoantibodies and/or inflammatory cytokine levels, fever, fatigue, stiffness, pain, blisters, itchiness, discharge, eczema, swelling, hair loss, loss of appetite, asthma, and foul odor.
  • a variety of dosages of a controlled-release formulation of the present disclosure may be administered to a veterinary subject in accordance with, e.g ., the physiological characteristics of the veterinary subject (e.g ., size, GI length, digestive rate, digestive pH, stomach crushing strength), the state of health of the veterinary subject (e.g., the urgency of the need for treatment and of what strength) and other factors.
  • a dosing regime or schedule comprises a single administration of a single dose of a controlled-release formulation as described herein).
  • a dosage regime or schedule comprises multiple administrations of a single dose over the course of, e.g., a day.
  • a dosage regime or schedule may comprise single or multiple administrations of multiple doses of a controlled-release formulation.
  • the doses may be administered simultaneously, contemporaneously, or sequentially.
  • An appropriate dose will be determined according to any one or more of a variety of factors typically considered when determining an appropriate drug dose; e.g, the size, age, species, gender, and general health of a subject receiving the dose; the type, severity, and stage of a disease condition; known PK parameters of the drug, such as absorption, in vivo half-life, and the like).
  • Table 1 provides non-limiting examples of dosages of a formulation of the present disclosure for canine subjects ranging in size from 2 to 80 kilograms; it will be understood that for subjects larger than 80 kilograms, or smaller than 2 kilograms, or in between the shown sizes, and/or of non-canine species, dosages may be adjusted accordingly.
  • Extrusion/Spheronization Aid Microcrystalline Cellulose: 15 to 20% Binders: Hydroxypropyl cellulose or hydroxyl propyl methyl cellulose or Pregelatinized Starch or Ethyl Cellulose or poly(vinyl pyrrolidone) (2 to 5%)
  • HPMC HPMC
  • HPC HPC
  • acrylic polymers HEC
  • EC - Modified release excipients
  • the drug substance was mixed with microcrystalline cellulose, binder, and disintegrant in a planetary mixer or a high shear mixer for 10 minutes;
  • the resulting wet mass was passed through an extruder to obtain an extrudate (example equipment: Caleva, LCI, Glatt etc.);
  • the extrudate was then spheronized on a spheronizer fitted with a crosshatch plate to form spheronized beads (example equipment: Caleva, LCI, Glatt)
  • the spheronized beads were then dried in a fluid bed dryer till the desired moisture content ( ⁇ l%) was reached;
  • the dried beads were then passed through screens to remove fine beads ( ⁇ 500 pm) and coarse beads (>2500 pm);
  • the dried beads were then loaded into a fluid bed coater and coated with an appropriate amount of a rate-controlling polymer (15 to 30% range);
  • the beads were then dried after all coating steps were completed.
  • Talc was dispersed into the OPADRY ® solution and stirred to obtain a smooth dispersion.
  • SURELEASE ® E-7 19040 aqueous ethylcellulose rate controlling polymer (COLORCON ® , Harleysville, PA) (Other grades of SURELEASE ® can be used if desired)
  • SEIRELEASE® was dispersed in purified water and stirred to obtain a smooth dispersion.
  • the bed was fluidized, the seal coated beads were warmed, and the coating solution prepared as described in Table 4 was sprayed onto the fluidized beads.
  • Coated bead samples were withdrawn at desired weight gain (e.g. : 15%, 22%, 30%).
  • EUDRAGIT® RS (acrylic controlled-release polymer either as powder or premade dispersion - RS 30D)
  • EUDRAGIT®RL (acrylic controlled-release polymer either as powder or premade dispersion - RL 30D)
  • Talc and TEC were dispersed in purified water and homogenized until a smooth dispersion is obtained.
  • the dispersion was filtered through 80 mesh sieve to remove any coarse particles.
  • the bed was fluidized, seal coated beads were warmed and the coating solution prepared as described in Table 4 was sprayed onto the fluidized beads.
  • the drug coated beads were loaded into the fluid bed coater 6.
  • the bed was fluidized, beads were warmed, and the coating solution prepared as described in step 4 was sprayed onto the fluidized beads.
  • EETDRAGIT® L30 D 55 other grades of EEDRAGIT® polymers, or OPADRY® polymers that confer enteric protection can also be used
  • Talc and TEC were dispersed in purified water and homogenized until a smooth dispersion was obtained.
  • the dispersion from Step (1) was dispersed into EUDRAGIT® L30D 55 suspension and mix until a uniform dispersion was obtained.
  • the dispersion was filtered through 80 mesh sieve to remove any coarse particles.
  • the bed was fluidized, controlled-release coated beads were warmed and the coating solution prepared as described in Table 7 is sprayed onto the fluidized beads.
  • Release rate determinations were performed on beads obtained after coating with controlled-release layer(s) and optionally a protective layer. Release rate determinations were conducted as follows:
  • Dissolution Media Volume and Speed 900 mL at 100 rpm
  • a known quantity of beads were weighed (based on assay of coated beads) and placed in the ETSP Type 1 basket apparatus.
  • For a biphasic dissolution profile (biphasic media), beads were exposed to pH 1.2 media for 2 hours. After 2 hours, the basket was moved to buffer media at pH 6.8 and dissolution was continued for an additional 10 hours, 12 hours, 14 hours or 24 hours, as desired. Aliquots were withdrawn at periodic intervals and analyzed for mycophenolate sodium using a UV detection method. Data from representative experiments are shown in FIGS. 6-9 and Table 8, below.
  • FIG. 4 shows the release of sodium mycophenolate from
  • controlled-release beads in biphasic media as noted above.
  • the bead construct is sugar sphere/drug layer/HPMC seal coat/ethyl cellulose (SURELEASE ® ).
  • SURELEASE ® sugar sphere/drug layer/HPMC seal coat/ethyl cellulose
  • the data was generated for beads with only a controlled-release layer.
  • a protective layer was not included.
  • release from beads coated with a 22% by weight ethyl cellulose controlled-release layer was higher than that for beads coated with a 30% by weight ethyl cellulose layer. Both compositions maintained their integrity at pH 1.2 (0-2 hours), with rapid release upon transitioning to pH 6.8 (>2 hours).
  • FIG. 5 shows the release of sodium mycophenolate from
  • the bead construct is sugar sphere/drug layer/HPMC seal coat/acrylic polymer (EUDRAGIT ® RS 100). A protective layer was not included.
  • FIG. 6 shows the release of sodium mycophenolate from
  • the bead construct is sugar sphere/drug layer/HMPC seal coat/EUDRAGIT ® RS 100/EUDRAGIT ® L30D 55.
  • the EUDRAGIT ® RS 100 layer provides the controlled-release characteristics, while the EUDRAGIT ® L30D 55 provides the protective, enteric coating. As noted, little to no release occurred at pH 1.2 (0-2 hours), with release occurring once the pH was raised to 6.8 (>2 hours).
  • FIG. 7 shows the release of sodium mycophenolate from
  • the bead construct is sugar sphere/drug layer/EUDRAGIT ® RS 100 :EUDRAGIT ® RL 100 (90:10).
  • a seal coat and a protective layer were not included. Rapid release is noted occurring around hours 2-6.
  • FIG. 8 shows release of sodium mycophenolate from a particulate subunits (coated beads) comprising 30 wt% Surelease polymer coat and a protective enteric coating. pH was switched from 1.2 to 6.8 following 2h incubation.
  • FIG. 9 shows release of sodium mycophenolate from particulate subunits (coated beads) comprising a solvent-based coating. pH was switched from 1.2 to 6.8 following 2h incubation.
  • Table 7 below provides MPA active agent release data from particulate subunits of two exemplary formulations according to the present disclosure.
  • Two sets of extended-release enteric-coating Na.MPA coated beads were prepared as described above (22 wt% Surelease coating and 30 wt% coating) and placed in acid (2h, pH 1.2) followed by a buffer that raised pH to approximately 6.8.
  • Magnesium Stearate 0.5-5 %, suitably 2% The required quantities of mycophenolate sodium and microcrystalline cellulose were mixed together in a high shear mixer for about 5 minutes.
  • the required quantity of PVP was dissolved in water to form a 10% w/w solution of PVP.
  • the PVP solution was gradually added to the high shear mixer and the blend was mixed until a wet mass was formed.
  • the wet mass was transferred to a fluid bed dryer and dried.
  • the dried granulation was passed through a sieve such that very coarse and very fine particles were removed.
  • the sieved granulation was transferred to a V blender and mixed with the Magnesium stearate for about 3 minutes.
  • the lubricated granules were compressed into mini-tablets using a 2 mm round standard concave multi tip tooling on a compression press.
  • the mini-tablets were coated with a seal coat, a controlled-release layer, and a protective layer, as described herein.
  • mini-tablets can be administered to the veterinary subject, either filled in a capsule, as a slurry, as a sachet, a dragee, etc.
  • EC-ER-Na.MP enteric coated-extended release sodium mycophenolate formulation
  • IC intracolonic
  • 270 mg of an EC-ER-Na.MPA formulation was administered in the both fed and fasted states and pharmacokinetics were compared with oral administration of 10 mg/kg MMF in the fasted state. Both studies were conducted by Absorption Systems (San Diego, CA).
  • MPA was delivered as a solution via an endoscope, and for PO dosing each dog received a single Myfortic® 180 mg enteric coated capsule.
  • blood samples were collected up to 24 hours post-dose. Plasma concentrations of MPA, MPAG, and AcMPAG were determined with a qualified LC-MS/MS method, and pharmacokinetic parameters were determined with WinNonlin v.6.4 software.
  • the t maX for MPAG ranged from 5 to 15 minutes post-dose, and the average AUCi ast was 233 ⁇ 160 hr*ng/mL.
  • the average AUCi ast for MPAG was 28882 hr*ng/mL after PO dosing and 11702 hr*ng/mL after IC dosing.
  • the average AUCi ast for AcMPAG was 529 hr*ng/mL after PO dosing and 233 hr*ng/mL after IC dosing.
  • the mean pharmacokinetic parameters and the drug to metabolite ratios are summarized in Table 9.
  • the MPA/MPAG ratio and MPA/ AcMPAG ratio were each observed to be almost 2-fold higher following the IC dosing compared to the oral administration.
  • MMF oral suspension For MMF administration, an MMF oral suspension was prepared according to the instructions for CellCept®. Leftover dosing solutions were stored at room temperature.
  • blood was collected pre-dosing, then at either: 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 9, 12, and 24 hours (processed to obtain plasma); or 1, 2, 3, 4, 6, 8, 12, and 24 hours (processed to PBMC).
  • blood was collected at pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, , 4, 6, 8, 9, 12, and 18 hours (processed to plasma); or at pre-dose, 1, 2, 3, 4, 6, 8, 12, and 18 hours (processed to obtain PBMCs).
  • Plasma concentrations of MPA, MPAG, and AcMPAG were determined with a qualified LC-MS/MS method, and pharmacokinetic parameters were determined with WinNonlin v.6.4 software. Plasma concentration curves are shown in FIGS. 10-13.
  • the mean pharmacokinetic parameters and drug to metabolite ratios are summarized in Table 10. Linder fasted conditions, the MPA/MPAG ratio was 1.5 to 2.0 fold higher with EC-ER-Na.MP compared to the reference oral dosing (Table 10). The MPA/AcMPAG ratio also trended to be higher, although to a lesser extent.
  • Table 10 Mean Pharmacokinetic Parameters of MPA and Metabolites Following Oral MMF and EC-ER-Na.MP Administration
  • Table 1 1 Treatments Received by Each Group in Study 3
  • PK samples were collected after a 12-hour fast, while samples were collected 1 hour after the animals were fed on Day 5. At the time of dosing, any uneaten food was removed, and the amount of food provided and consumed by each animal was recorded. On Days 2-5, animals were fed once daily in the morning, 1 hour prior to administration of the morning dose.
  • the general health of each animal was assessed at every blood sampling time point during the course of the study. On study days with no blood sampling or only one blood sampling time point, the general health was assessed at least twice daily (AM and PM).
  • Standard non compartmental pharmacokinetic parameters (C max , T maX , ti /2 , AUCi ast and A UC m r foil owing the Day 1 dosing; C maX , T maX and AUQ au following the Day 5 dosing where tau is 12 h for MMF and 24 h for OKV-1001) were estimated using Phoenix Winnonlin software 64 (Build 7.0.0.2535) for MPA, MPAG and AcMPAG. MPA plasma concentration levels for each treatment group on Day 1 (fasted;
  • FIG. 15 MPA plasma concentration levels for each treatment group on Day 5 (fed; steady state) are shown in FIG. 16.
  • Calculated drug:metabolite (D:M) ratios for Group C, Group A, and Group B are shown in Tables 12, 13, and 14, respectively. Reference ratio values from Study 2 are also shown.
  • Non-compartmental PK parameter estimates for all treatment groups are provided in Table 15. It should be noted that data from Group B/Period 2/Day 5 was not obtained from 5 of the 7 dogs.
  • Controlled-release MPA compositions (two profiles,“Profile 1” and “Profile 2”) were manufactured as follows.
  • Hypromellose 2910 Required quantities of Hypromellose 2910 and purified water were mixed together in a suitable container until the Hypromellose is completely dissolved. The required amount of sodium mycophenolate was added to the
  • microcrystalline cellulose spheres were loaded into the chamber of an appropriately sized fluid bed coater. The beads were pre- warmed to 48°C.
  • the drug-binder solution prepared in Step 1 was sprayed on to the microcrystalline spheres in the fluid bed coater while the bed was maintained at 50°C.
  • the drug binder solution was sprayed on the spheres until a weight gain of 44% was achieved on the dry beads.
  • a subcoating solution was prepared by mixing Opadry Clear and Purified Water in a suitable mixer until a clear solution was formed.
  • a suitable quantity of drug loaded beads was placed in the chamber of an appropriately sized fluid bed coater. The beads were pre-warmed to 50°C and maintained at 50°C during the subcoating process.
  • the subcoating solution prepared in Step 5 was sprayed on to the drug-coated beads in the fluid bed coater until a weight gain of 7% was achieved on the beads.
  • the beads were dried at ambient temperature for approximately 10 minutes while the airflow is maintained at 90 cfm.
  • the rate control membrane solution was prepared as follows: Required quantities of DI water and ethanol were mixed together in a suitable mixer until homogenous. Dibutyl sebacate was added and mixed to form a homogenous suspension. Ethyl cellulose and Klucel EF were added and mixed to form a homogenous suspension. The required quantity of talc was added and mixed until a uniform suspension was formed.
  • a suitable quantity of sub-coated beads was placed in the chamber of an appropriately sized fluid bed coater. The beads were pre-warmed to 42°C.
  • the rate control membrane prepared in Step 8 was sprayed onto the drug-coated beads in the fluid bed coater.
  • the membrane coating solution was sprayed on the spheres until a weight gain of 30% (Profile 1) or 45% (Profile 2) was achieved on the beads. After completion of coating, beads were dried under ambient temperature for approximately 10 minutes with an air flow volume if 50 cfm.
  • the enteric coat solution was prepared by mixing a required quantity Plasacryl HTP 20 with required quantity of DI water. Eudragit L30D 55 was dispersed and mixed into this solution until a homogenous suspension was obtained.
  • a suitable quantity of membrane-coated beads was placed in the chamber of an appropriately sized fluid bed coater. The beads were pre-warmed to 29°C.
  • the enteric coating solution prepared in Step 11 was sprayed on to the drug-coated beads in the fluid bed coater.
  • the enteric coating solution was sprayed on the spheres until a weight gain of 25% was achieved on the beads for both Profile 1 and Profile 2 formulations.
  • the beads were dried at ambient temperature for approximately 10 minutes after coating was complete.
  • the dried beads were manually filled into a Veterinary Size 13 gelatin capsule.
  • the capsule was filled with beads equivalent to either 180 mg or 270 mg of mycophenolate sodium.
  • the final MDDS product composition containing 270mg of mycophenolate sodium was as shown in Table 16.
  • mice were feed-acclimated to a food schedule (500 g of a 1 : 1 mixture of a dry certified laboratory diet (5006 laboratory canine diet from Lab Diet) and canned wet dog food (AlpoTM) lx daily in the morning).
  • the feeding schedule was maintained throughout the duration of both studies. All food was removed 1 hour prior to administration of the first daily dose.
  • animals received oral capsules comprising either 270 mg or 180 mg MPA QD, or 180 mg MPA BID.
  • QD dosing was performed for Days 1-15.
  • BID dosing was performed for Days 1-14, with a final, single dose on Day 15.
  • the stool of all animals was observed and recorded over the active study duration (Days 1-15). On blood sampling days (Days 1, 8, & 15), the presence or absence of stool was noted at each general health observation timepoint. The time(s) of defecation (post-dose) were recorded. If defecation occurred between observation timepoints, the closest estimation of the time(s) of defecation was recorded. On days with no blood sampling, the stool of animals was observed during general health observations.
  • the stool of each animal was graded using a modified WALTHAM® feces scoring system, as follows:
  • Grade 1 Hard, dry Grade 2: Well-formed and does not leave a trail when picked up.
  • Grade 3 Moist and beginning to lose form. Leaves a mark when picked up.
  • Grade 4 Majority of form is lost, poor consistency; viscous.
  • PK pharmacokinetic
  • PD pharmacodynamic
  • Blood was collected from the jugular vein or other accessible vessel.
  • PK samples 2 mL whole blood was collected via the jugular vein or other accessible vessel directly into 2 mL chilled (purple top) Vacutainers (a needle and
  • Plasma samples were snap frozen on dry ice and stored frozen at -60 to - 80°C.
  • T lymphocyte proliferation was evaluated using a flow cytometry assay as previously described (Bishop KA. Pharmacodynamic assessment of a panel of immunosuppressant drugs in ex-vivo canine T-lymphocyte proliferation (abstract) 2016 Merial NIH National Veterinary Research Scholars Symposium
  • erythrocytes were lysed and leukocytes were stained with eBioscienceTM Fixable Viability Dye eFluor 450 (Thermo Fisher Scientific 65-0863-14), Rat a Dog CD5 APC (Bio-Rad MCA1037APC, clone YKIX322.3), Rat a Dog CD45 RPE (Bio-Rad MCA1037APC, clone YKIX716.13), and Mouse a Human/Dog Ki-67 FITC (Thermo Fisher Scientific 11-5698-80, clone SolAl5).
  • eBioscienceTM Fixable Viability Dye eFluor 450 Thermo Fisher Scientific 65-0863-14
  • Rat a Dog CD5 APC Bio-Rad MCA1037APC, clone YKIX322.3
  • Rat a Dog CD45 RPE Bio-Rad MCA1037APC, clone YKIX716.13
  • Lymphocyte PD data are provided in Figures 19-24.
  • dogs that received OKV-1001 270 mg
  • a similar effect was seen at Day 15.
  • dogs receiving OKV-1001 had similar reduced levels of Ki-67-expressing cells at all timepoints after dosing (decreases of 50% to 85% relative to baseline), indicating that the OKV-1001 formulations provide sustained suppression of lymphocyte proliferation, with little PD variability over the course of an 8-hour period following administration.
  • Similar results were observed in the dogs that received OKV-1001 (180 mg, QD), as shown in Figure 21.
  • the daily MPA load in 270 mg OKV-1001 (252 mg MPA) is 42% higher than that of 120 mg MMF (BID) (177 mg), but the OKV-1001 had fewer GI side effects than MMF.
  • the data from the parallel 15-day pharmacodynamics studies show that MDDS of the present disclosure have a faster onset of systemic action than IR-MMF, have more consistent pharmacodynamics effects (reduced proliferation of lymphocytes) over a 4 and an 8 hour period post-administration, can be advantageously administered once daily as compared to IR-MMF (BID), and are safer than IR-MMF, as determined by the number and severity of gastrointestinal side effects experienced by the dogs.
  • BID IR-MMF

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Abstract

La présente invention concerne des méthodes et des compositions pour l'administration modifiée d'agents actifs d'acide mycophénolique, notamment du mycophénolate de sodium, chez des sujets canins. Les méthodes et compositions selon l'invention sont utiles, par exemple, pour traiter des maladies auto-immunes, des troubles sanguins associés et un rejet immunitaire lié à des interventions de greffe ou de transplantation.
PCT/US2018/050079 2018-09-07 2018-09-07 Méthodes et compositions pour l'administration d'agents actifs d'acide mycophénolique à des mammifères non humains WO2020050863A1 (fr)

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JP2021512709A JP2022506007A (ja) 2018-09-07 2018-09-07 ミコフェノール酸活性剤を非ヒト哺乳動物に送達するための方法および組成物
EP18778780.9A EP3846798A1 (fr) 2018-09-07 2018-09-07 Méthodes et compositions pour l'administration d'agents actifs d'acide mycophénolique à des mammifères non humains
CA3111908A CA3111908A1 (fr) 2018-09-07 2018-09-07 Methodes et compositions pour l'administration d'agents actifs d'acide mycophenolique a des mammiferes non humains

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