# US 10,500,162 B2 · Methods and compositions particularly for treatment of attention deficit disorder

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- Number: US 10,500,162 B2
- Document ID: US10500162B2
- Status: Granted
- Kind: B2
- Application number: 16/185,730
- Filed: 2018-11-09
- Published: 2019-03-14
- Granted: 2019-12-10
- Earliest claimed: 2014-10-31
- Assignees: Purdue Pharma L.P.
- Applicants: Purdue Pharma L.P.
- Inventors: Ricardo Alberto Vargas Rincon; Joseph Reiz
- Web page: https://patentgrep.com/patent/US10500162B2

## CPC

- A61K 9/5078: {with drug-free core}
- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- 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)}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5036: {Polysaccharides, e.g. gums, alginate; Cyclodextrin}
- 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)}
- A61K 31/4458: only substituted in position 2, e.g. methylphenidate
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/26: Psychostimulants, e.g. nicotine, cocaine
- 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

There is described, inter alia, a coated bead comprising: (a) a granule; (b) a first layer coated over the granule, the first layer comprising a first amount of an active pharmaceutical ingredient comprising a central nervous system stimulant; and (c) a second layer coated over the first layer, the second layer being present in an amount sufficient to substantially delay release of the active pharmaceutical ingredient in the first layer until after the coated bead reaches a distal intestine portion of a subject to whom the coated bead is administered; and (d) the third layer coated over the second layer, the third layer comprising a second amount of the active pharmaceutical ingredient, the third layer being configured to permit substantially immediate release of the active pharmaceutical ingredient comprised therein. Embodiments related to a solid oral pharmaceutical composition are also described.

## Claims

### Claim 1

A method of treating Attention Deficit Hyperactivity Disorder (ADHD) in a subject in need thereof, the method comprising administering to the subject an oral solid pharmaceutical composition comprising an immediate release methylphenidate hydrochloride component and a controlled/delayed release methylphenidate hydrochloride component, wherein the immediate release methylphenidate component and the controlled/delayed release methylphenidate component, together, provide 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride; and wherein
the oral solid pharmaceutical composition, when administered to the subject in a fed state, provides a pharmacokinetic profile comprising:
an average ±standard deviation methylphenidate AUC0-4 of 21160.21±6420.56 pg·hr/mL;
an average ±standard deviation methylphenidate AUC8-12 of 29392.15±8453.72 pg·hr/mL; and
an average ±standard deviation methylphenidate AUC12-16 of 36653.88±11521.14 pg·hr/mL
when the oral solid pharmaceutical composition provides 100 mg of methylphenidate hydrochloride, or dose proportional AUC values thereof, when the oral solid pharmaceutical composition provides 25, 35, 45, 55, 70, or 85 mg methylphenidate hydrochloride;
and further wherein the oral solid pharmaceutical composition provides efficacious treatment of ADHD for 16 hours after a single oral administration; and further wherein the oral solid pharmaceutical composition has the following in vitro methylphenidate dissolution profile:
Time
Methylphenidate
(hours)
(% dissolved)
1
NLT 15%
4
18-38%
8
35-55%
12
68-98
16
NLT 68
when tested according to the USP paddle method, 100 rpm, at 37° C.; (i) starting with 900 ml simulated gastric fluid for 2 hours, (ii) followed by 900 ml phosphate buffer pH 6.0 for 4 hours, and (iii) for the 7th hour onwards, 900 mL of phosphate buffer pH 7.4; USP <711> Acceptance Table 2.

### Claim 2 (depends on 1)

The method of claim 1, wherein the oral solid pharmaceutical composition provides, in a fed state, an in vivo methylphenidate Tmax0-4 of about 3 hours and a methylphenidate Tmax8-16 of about 13.5 hours.

### Claim 3 (depends on 1)

The method of claim 1, wherein the controlled/delayed release methylphenidate hydrochloride component and the immediate release methylphenidate component are provided via a plurality of coated beads.

### Claim 4 (depends on 3)

The method of claim 3, wherein each bead comprises a portion of the controlled/delayed release methylphenidate hydrochloride component and a portion of the immediate release methylphenidate component.

### Claim 5 (depends on 4)

The method of claim 4, wherein each bead in the plurality of beads comprises a core comprising a first amount of methylphenidate hydrochloride corresponding to the portion of the delayed/controlled release methylphenidate hydrochloride component.

### Claim 6 (depends on 5)

The method of claim 5, wherein the core comprises a granule coated with the first amount of methylphenidate hydrochloride or wherein the granule comprises a granule substrate in admixture with the first amount of methylphenidate hydrochloride.

### Claim 7 (depends on 6)

The method of claim 6, wherein the core comprises the granule coated with the first amount of methylphenidate hydrochloride.

### Claim 8 (depends on 7)

The method of claim 7, wherein the first amount of methylphenidate hydrochloride is coated with an inner controlled release coating and an outer delayed release coating coated over the inner controlled release coating.

### Claim 9 (depends on 8)

The method of claim 8, wherein a second amount of methylphenidate hydrochloride, corresponding to the portion of the immediate release methylphenidate component, is coated over the outer delayed release coating.

### Claim 10 (depends on 8)

The method of claim 8, wherein the delayed/controlled release methylphenidate hydrochloride component comprises about 70 weight percent to about 99 weight percent of the 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride in the pharmaceutical composition.

### Claim 11 (depends on 9)

The method of claim 9, wherein the delayed/controlled release methylphenidate hydrochloride component comprises about 78 weight percent to weight about 82 percent of the 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride in the pharmaceutical composition.

### Claim 12 (depends on 10)

The method of claim 10, wherein the delayed/controlled release methylphenidate hydrochloride component comprises about 80 weight percent of the 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride in the pharmaceutical composition and wherein the immediate release methylphenidate component provides about 20 percent by weight of the 25, 35, 45, 55, 70, 85, or 100 mg methylphenidate hydrochloride in the pharmaceutical composition.

### Claim 13 (depends on 7)

The method of claim 7, wherein the granule is selected from the group consisting of: a sugar sphere, a microcrystalline cellulose granule, a silica granule, a starch granule, a lactose granule, a calcium carbonate granule, and a mannitol-polyvinylpyrrolidone granule.

### Claim 14 (depends on 8)

The method of claim 8, wherein the inner controlled release coating is present in an amount of about 3 percent to about 16 percent by weight, of each bead in the plurality of coated beads, and wherein the outer delayed release coating is present in an amount of from about 3 percent to about 20 percent by weight of each bead in the plurality of coated beads.

### Claim 15 (depends on 14)

The composition of claim 14, wherein the inner controlled release coating is present in an amount of about 10.0 percent to about 10.7 percent by weight of each bead in the plurality of coated beads, and wherein the outer delayed release coating is present in an amount of from about 15 percent to about 16 percent by weight of each bead in the plurality of coated beads.

### Claim 16 (depends on 14)

The method of claim 14, wherein the inner controlled release coating is selected from the group consisting of an ethylcellulose polymer, a cellulose ether, a polyethylene oxide, a polyvinyl alcohol derivate, a methacrylic acid copolymer, polyethylene glycol, a polyglycolic acid, a polylactic acid, a polycaprolactone, a poly(n-hydroxybutyrate), a polyamino acid, a poly(amide-enamine), a polyester, an ethylene-vinyl acetate (EVA), a polyvinyl pyrrolidone (PVP), a poly (acrylic acid) (PAA), a poly (methacrylic acid) (PMAA), and mixtures thereof.

### Claim 17 (depends on 15)

The method of claim 15, wherein the inner controlled release coating comprises ammonio methacrylate copolymer, Type B USP/NF.

### Claim 18 (depends on 17)

The method of claim 17, wherein the outer delayed release coating comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1.

### Claim 19

A method of treating Attention Deficit Hyperactivity Disorder (ADHD) in a subject in need thereof, the method comprising administering to the subject an oral solid pharmaceutical composition comprising an immediate release methylphenidate hydrochloride component and a controlled/delayed release methylphenidate hydrochloride component, wherein the immediate release methylphenidate component and the controlled/delayed release methylphenidate component, together, provide 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride; and wherein
the oral solid pharmaceutical composition, when administered to the subject in a fed state, provides a pharmacokinetic profile comprising:
an average ±standard deviation methylphenidate Cmax0-4 of 9248.95±1886.65 pg/mL; and
an average ±standard deviation methylphenidate Cmax8-16 of 10667.64±3017.29 pg/mL;
when the oral solid pharmaceutical composition comprises 100 mg of methylphenidate hydrochloride, or dose proportional Cmax values thereof, when the oral solid pharmaceutical composition comprises 25, 35, 45, 55, 70, or 85 mg methylphenidate hydrochloride;
wherein the oral solid pharmaceutical composition provides efficacious treatment of ADHD for 16 hours after a single oral administration; and further wherein the oral solid pharmaceutical composition has the following in vitro methylphenidate dissolution profile:
Time
Methylphenidate
(hours)
(% dissolved)
1
NLT 15%
4
18-38%
8
35-55%
12
68-98
16
NLT 68
when tested according to the USP paddle method, 100 rpm, at 37° C.; (i) starting with 900 ml simulated gastric fluid for 2 hours, (ii) followed by 900 ml phosphate buffer pH 6.0 for 4 hours, and (iii) for the 7th hour onwards, 900 mL of phosphate buffer pH 7.4; USP <711> Acceptance Table 2.

### Claim 20 (depends on 19)

The method of claim 19, wherein the oral solid pharmaceutical composition provides, in a fed state, an in vivo methylphenidate Tmax0-4 of about 3 hours and a methylphenidate Tmax8-16 of about 13.5 hours.

### Claim 21 (depends on 19)

The method of claim 19, wherein the controlled/delayed release methylphenidate hydrochloride component and the immediate release methylphenidate component are provided via a plurality of coated beads.

### Claim 22 (depends on 21)

The method of claim 21, wherein each bead comprises a portion of the controlled/delayed release methylphenidate hydrochloride component and a portion of the immediate release methylphenidate component.

### Claim 23 (depends on 22)

The method of claim 22, wherein each bead in the plurality of beads comprises a core comprising a first amount of methylphenidate hydrochloride corresponding to the portion of the delayed/controlled release methylphenidate hydrochloride component.

### Claim 24 (depends on 23)

The method of claim 23, wherein the core comprises a granule coated with the first amount of methylphenidate hydrochloride or wherein the granule comprises a granule substrate in admixture with the first amount of methylphenidate hydrochloride.

### Claim 25 (depends on 24)

The method of claim 24, wherein the core comprises the granule coated with the first amount of methylphenidate hydrochloride.

### Claim 26 (depends on 25)

The method of claim 25, wherein the first amount of methylphenidate hydrochloride is coated with an inner controlled release coating and an outer delayed release coating coated over the inner controlled release coating.

### Claim 27 (depends on 26)

The method of claim 26, wherein a second amount of methylphenidate hydrochloride, corresponding to the portion of the immediate release methylphenidate component, is coated over the outer delayed release coating.

### Claim 28 (depends on 27)

The method of claim 27, wherein the delayed/controlled release methylphenidate hydrochloride component comprises about 70 weight percent to about 99 weight percent of the 25, 35, 45, 55, 70, 85, or 100 mg of methylphenidate hydrochloride in the pharmaceutical composition.