Timed, pulsatile release systems

• US 20060246134A1
• Filed: 05/02/2005
• Published: 11/02/2006
• Est. Priority Date: 05/02/2005
• Status: Active Grant

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Adare Pharmaceuticals, Inc.
• Inventors: Venkatesh, Gopi M.
• Granted Patent: US 9,161,918 B2
• Time in Patent Office: Days
• US Class Current: 424/469
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

A unit multiparticulate dosage form for delivering one or more basic, active pharmaceutical ingredients into the body in need of such medications to achieve target PK (pharmacokinetics) profiles is described. The dosage form comprises one or more multicoated drug particles (beads, pellets, mini-/micro-tablets) having a barrier coating and a lag-time coating. Each Timed Pulsatile Release (TPR) bead population exhibits pre-determined lag-time followed by differing release characteristics. The composition and thickness of the barrier coating, composition and thickness of the lag-time coating, ratio of IR beads to one or more TPR bead populations and total dose may be varied depending on the alkalinity, pH-dependent solubility and elimination half-life of the active ingredients to achieve target PK profiles (suitable for a once or twice daily dosing regimen) in patients in need of such medications.

Claims

1. A pharmaceutical multiparticulate dosage form comprising a mixture of immediate release (IR) beads and timed, pulsatile release (TPR) beads, wherein said TPR beads comprise:

a) a core particle comprising one or more basic, active pharmaceutical ingredients or pharmaceutically acceptable salts thereof;

b) an inner barrier coating surrounding said core particle, said barrier coating comprising;

i) an enteric polymer, or ii) a water-insoluble polymer alone or in combination with a water-soluble pore-forming polymer; and

c) an outer lag-time coating comprising a water-insoluble polymer in combination with an enteric polymer, said outer membrane providing a lag time of at least about 5 hours before onset of drug release.

2. A pharmaceutical multiparticulate dosage form claim 1 wherein the active pharmaceutical ingredient is selected from the group consisting of analgesics, anticonvulsants, antidiabetic agents, anti-infective agents, antineoplastics, antiParkinsonian agents, antirheumatic agents, cardiovascular agents, CNS (central nervous system) stimulants, dopamine receptor agonists, anti-emetics, gastrointestinal agents, psychotherapeutic agents, opioid agonists, opioid antagonists, anti-epileptic drugs, histamine H₂ antagonists, anti-asthmatic agents, and skeletal muscle relaxants.

3. A pharmaceutical multiparticulate dosage form in accordance with claim 1 comprising two or more bead populations to provide target pharmacokinetic profiles suitable for a once or twice-daily dosing regimen, wherein each population exhibits a predetermined (target) drug-release profile when dissolution tested using USP Apparatus 1 or 2 and a two-stage dissolution media (first two hours in 700 mL of 0.1N HCl and thereafter in 900 mL at pH 6.8).

4. A pharmaceutical multiparticulate dosage form in accordance with claim 1 comprising at least an IR bead population, a first TPR bead population and a second TPR bead population wherein the ratio of IR bead to the first and second TPR bead populations varies from about 10/20/70 to about 30/60/10, respectively, depending on the alkalinity, pH-dependent solubility and/or elimination half-life of the active ingredient.

5. A pharmaceutical multiparticulate dosage form in accordance with claim 1, wherein said core particle comprises:

i) an inert particle coated with an active ingredient and a polymeric binder;

or

ii) a pellet or mini- or micro-tablet containing the active ingredient, a polymeric binder and a diluent/filler, prepared by rotogranulation, granulation-extrusion-spheronization or granulation-tableting.

6. A pharmaceutical multiparticulate dosage form in accordance with claim 5 wherein said polymeric binder is selected from the group consisting of polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, corn starch, pregelatinized starch and mixtures thereof.

7. A pharmaceutical multiparticulate dosage form in accordance with claim 1 wherein said particle barrier coating comprises an enteric polymer selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methylmethacrylate copolymers, shellac, derivatives thereof, and mixtures thereof.

8. A pharmaceutical multiparticulate dosage form in accordance with claim 7 wherein the barrier coating comprises from about 5 to 20% by weight of the barrier coated bead.

9. A pharmaceutical multiparticulate dosage form in accordance with claim 1 wherein particle core is provided with a barrier coating comprising a water-insoluble polymer alone or in combination with a water soluble polymer at a ratio of from about 9:

1 to 5;

5 wherein said barrier coating is applied for a weight gain of from about 1.5% to 15% by weight based on the weight of the coated bead.

10. A pharmaceutical dosage form in accordance with claim 9 wherein said water-soluble polymer is selected from the group consisting of such as methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone and polyethylene glycol and mixtures thereof.

11. A pharmaceutical dosage form in accordance with claim 1 wherein the outer lag-time coating comprises the water-insoluble polymer and the enteric polymer at a ratio of from about 10:

1 to 1;

2, respectively, for a weight gain of from about 30% to 60% by weight based on the weight of the TPR bead.

12. A pharmaceutical dosage form in accordance with claim 11 wherein said water-insoluble polymer is selected from the group consisting of ethylcellulose, cellulose acetate, polyvinyl acetate, methylmethacrylate ester polymers and mixtures thereof.

13. A pharmaceutical dosage form in accordance with claim 1 wherein at least one of the inner barrier coating and the outer lag-time coating comprises a plasticizer selected from the group consisting of triacetin, tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated mono- and di-glycerides and mixtures thereof.

14. A pharmaceutical dosage form in accordance with claim 1 wherein said lag-time coating comprises water insoluble and enteric polymers at a ratio varying from approximately 3:

1 to approximately 1;

1, respectively.

15. A pharmaceutical dosage form in accordance with claim 1 wherein said dosage form further comprises immediate release (IR) beads, which provide a loading dose by releasing not less than about 90% of the active contained in said IR beads within the first hour after oral administration of the dosage form.

16. A pharmaceutical dosage form in accordance with claim 1 wherein said dosage form comprises at least two timed, pulsatile release (TPR) bead populations, wherein each TPR bead population exhibits upon oral administration of the dosage form a pre-determined lag-time followed by differing release characteristics.

17. A pharmaceutical dosage form in accordance with claim 1 wherein said lag-time coating comprises ethylcellulose and hydroxypropyl methylcellulose phthalate.

22. A method comprising orally administering to a patient a dosage form in accordance with claim 1 containing therapeutically effective amounts of one or more active pharmaceutical ingredients.

23. A method comprising orally administering to a patient a dosage form in accordance with claim 1 wherein the dosage form comprises therapeutically effective amounts of IR and one or more multicoated TPR bead populations of one or more active pharmaceutical ingredients, each multicoated TPR bead population exhibiting a lag-time of at least 5 hours, followed by differing release characteristics.

18. A method for the preparation of a multiparticulate dosage form comprising:

a) preparing IR (immediate-release) beads comprising one or more basic active pharmaceutical ingredients or pharmaceutically acceptable salts thereof;

b) applying a barrier coating on said IR beads, said barrier coating comprising an enteric polymer or a water-insoluble polymer for a weight gain of from about 1.5% to 20% by dry weight of the coated bead;

c) applying an outer lag-time coating comprising a water-insoluble polymer in combination with an enteric polymer at a ratio of from about 10;

1 to 1;

2, respectively, for a weight gain of from about 30% to 60% by dry weight of the coated bead to form a Timed, Pulsatile Release (TPR) bead; and

d) filling into gelatin capsules or compressing into conventional tablets or ODTs (orally disintegrating tablets) one or more TPR bead populations at appropriate amounts to achieve target PK (pharmacokinetics) profiles (suitable for a once- or twice daily dosing regimen) in patients in need of such active pharmaceutical ingredients.

19. A method in accordance with claim 18, wherein said outer lag-time coating is applied from a solution in a pharmaceutically acceptable solvent system or from an aqueous dispersion.

20. A method in accordance with claim 18 wherein said pharmaceutical dosage form is in the form of a hard gelatin capsule, a conventional tablet rapidly disintegrating into coated beads upon entry into the stomach, or an orally disintegrating tablet rapidly disintegrating in the oral (buccal) cavity forming easy-to-swallow suspensions.

21. A method in accordance with claim 18 wherein said pharmaceutical dosage form further comprises IR beads to provide target PK release profiles in patients in need of such a treatment.