# US 10,864,166 B2 · Drug delivery systems comprising solid solutions of weakly basic drugs

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- Number: US 10,864,166 B2
- Document ID: US10864166B2
- Status: Granted
- Kind: B2
- Application number: 13/911,961
- Filed: 2013-06-06
- Published: 2014-02-20
- Granted: 2020-12-15
- Earliest claimed: 2006-08-31
- Assignees: Adare Pharmaceuticals, Inc.
- Applicants: Adare Pharmaceuticals, Inc.
- Inventors: Gopi Venkatesh; Luigi Boltri; Italo Colombo; Jin-Wang Lai; Flavio Fabiani; Luigi Mapelli
- Web page: https://patentgrep.com/patent/US10864166B2

## CPC

- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5005: {Wall or coating material}
- A61K 9/5042: {Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose}
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- A61K 9/5078: {with drug-free core}
- A61K 9/5089: {Processes}
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/4422: 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/5513: 1,4-Benzodiazepines, e.g. diazepam {or clozapine}
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to pharmaceutical compositions and dosage forms comprising TPR beads, wherein said TPR beads comprise a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer, and a TPR coating comprising a water insoluble polymer and an enteric polymer, wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8.

## Claims

### Claim 1

A pharmaceutical composition comprising timed pulsatile release (TPR) beads and rapidly dispersing microgranules wherein said TPR beads comprise:
a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8;
a TPR coating comprising a water insoluble polymer and an enteric polymer;
said rapidly dispersing microgranules comprising particles of at least one disintegrant, and a sugar alcohol and/or saccharide, wherein said particles of the disintegrant and sugar alcohol and/or saccharide have an average particle size of not more than 30 μg/mL;
wherein the average particle size of the TPR beads and rapidly dispersing microgranules is not more than 400 μg/mL; and
wherein the composition provides a therapeutically effective plasma concentration of the active pharmaceutical ingredient over a period of at least about 18 hours.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the ratio of water-insoluble polymer to enteric polymer in the TPR coating ranges from about 9:1 to about 1:9.

### Claim 3 (depends on 2)

The pharmaceutical dosage form of claim 2, wherein the TPR coating further comprises about 3% to about 30% by weight of a plasticizer (compared to the total weight of the TPR coating).

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein the solid dispersion of the active pharmaceutical ingredient and solubility-enhancing polymer is deposited on an inert core.

### Claim 5 (depends on 4)

The pharmaceutical composition of claim 4, wherein the solubility-enhancing polymer is selected from the group consisting of polyvinylpyrrolidone, vinyl acetate/vinyl pyrrolidone copolymers, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, polyethylene glycol, and cyclodextrins.

### Claim 6 (depends on 4)

The pharmaceutical composition of claim 4, wherein the solid dispersion further comprises a pharmaceutically acceptable organic acid.

### Claim 7 (depends on 6)

The pharmaceutical composition of claim 6, wherein the ratio of organic acid to active pharmaceutical ingredient ranges from about 4/1 to about 1/9 by weight.

### Claim 8 (depends on 4)

The pharmaceutical composition of claim 4, wherein the water-insoluble polymer is selected from the group consisting of polymers or copolymers of methacrylic acid esters having quaternary ammonium groups, polyvinyl acetate polymers or copolymers, cellulose acetate, cellulose acetate butyrate, ethyl cellulose, and mixtures thereof.

### Claim 9 (depends on 4)

The pharmaceutical composition of claim 4, wherein the TPR beads comprise IR beads coated with the TPR coating; and
the IR beads comprise inert cores coated with the solid dispersion.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, wherein the ratio of active pharmaceutical ingredient to solubility-enhancing polymer ranges from about 6:1 to about 1:9.

### Claim 11 (depends on 9)

The pharmaceutical composition of claim 9, wherein the TPR beads further comprise an enteric coating applied over the solid dispersion;
the enteric coating is up to about 40% of the total weight of the TPR beads; and
the TPR beads provide a lag time of about 1-4 hours.

### Claim 12 (depends on 9)

The pharmaceutical composition of claim 9, wherein the TPR beads further comprise an enteric coating applied over the TPR coating;
the enteric coating is up to about 40% of the total weight of the TPR beads; and
the TPR beads provide a lag time of up to about 4 hours.

### Claim 13 (depends on 9)

The pharmaceutical composition of claim 9, wherein the TPR beads further comprise a first enteric coating applied over the solid dispersion; and
a second enteric coating applied over the TPR coating;
the first and second enteric coatings are each up to about 40% of the total weight of the TPR beads; and
the TPR beads provide a lag time of up to about 4 hours.

### Claim 14 (depends on 10)

The pharmaceutical composition of claim 10, comprising a combination of IR and TPR beads, wherein the ratio of IR to TPR beads is 1:9 to 5:5.

### Claim 15 (depends on 9)

The pharmaceutical composition of claim 9 comprising TPR beads, rapidly dispersing microgranules, and IR beads, wherein the ratio of IR beads to TPR beads ranges from about 10:90 to about 50:50.

### Claim 16 (depends on 15)

The pharmaceutical composition of claim 15, wherein the IR beads further comprise a taste-masking layer coated over the solid dispersion; and
wherein the taste-masking layer comprises a water-insoluble polymer or a water-insoluble polymer in combination with a water-soluble or gastrosoluble pore former.

### Claim 17 (depends on 1)

The pharmaceutical composition of claim 1, wherein the one or more active pharmaceutical ingredients are selected from the group consisting of analgesics, anticonvulsants, anti-diabetic agents, anti-infective agents, anti-neoplastic agents, anti-Parkinsonian agents, anti-rheumatic 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.

### Claim 18 (depends on 17)

The pharmaceutical composition of claim 17, wherein the active pharmaceutical ingredient is lercanidipine, or pharmaceutically acceptable salts, solvates, and/or esters thereof.

### Claim 19 (depends on 15)

The pharmaceutical composition of claim 15, wherein:
the IR beads further comprise a seal coating comprising hypromellose applied over the solid dispersion;
the solubility-enhancing polymer comprises a vinylpyrrolidone-vinyl acetate copolymer or polyvinyl pyrrolidone;
the TPR coating comprises a pharmaceutically acceptable methacrylate ester/methylmethacrylate ester copolymer and a pH-sensitive methacrylic acid-methylmethacrylate copolymer at a ratio of 9:1 to 1:9;
the weight of the TPR coating is up to about 50% of the weight of the TPR beads; and
the active pharmaceutical ingredient is selected from the group consisting of nifedipine, nicorandil, lercanidipine, iloperidone, clonazepam, and pharmaceutically acceptable salts, solvates and/or esters thereof.