DOSAGE FORMS FOR ORAL ADMINISTRATION AND METHODS OF TREATMENT USING THE SAME

• US 20150250744A1
• Filed: 03/18/2015
• Published: 09/10/2015
• Est. Priority Date: 06/28/2011
• Status: Active Grant

• Current Assignee: NEOS Therapeutics Incorporated
• Original Assignee: NEOS Therapeutics Incorporated
• Inventors: Tengler, Mark, McMahen, Russell
• Granted Patent: US 9,265,737 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/585 Ion exchange resins, e.g. polystyrene sulfonic acid resin
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• 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 9/5084 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: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C12N 9/2402 hydrolysing O- and S- glycosyl compounds (3.2.1)

Abstract

The invention relates to dosage forms that provide prolonged therapy. In particular, the invention relates to dosage forms including various pluralities of drug-containing resin particles. The invention also relates to methods of making these dosage forms and methods of treating using these dosage forms.

Claims

1. A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug-resin particles, wherein 30 to 50% by weight of said amphetamines are present in a first plurality of immediate release drug-resin particles and 50 to 70% by weight of said amphetamines are present in a second plurality of drug-resin particles that are coated with a delayed release coating.

2. The composition of claim 1, wherein the second plurality of drug resin particles comprises a triggered-release coating triggered by a pH change.

3. The composition of claim 2, wherein the triggered-release coating is cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, co-polymerized methacrylic acid/acrylic acid ethyl esters, or mixtures thereof.

4. The composition of claim 1, wherein the resin particles are strong acidic cation exchange resins, selected from the group consisting of polistirex, polacrilex, cholestyramine, polacrilin or mixtures thereof.

5. The composition of claim 1, wherein 40%-50% by weight of said amphetamines are present in the first plurality of drug-resin particles and 50%-60% by weight of said amphetamines are present in the second plurality of drug-resin particles.

6. The composition of claim 5, wherein about 45% by weight of said amphetamines are present in the first plurality of drug-resin particles and about 55% by weight of said amphetamines are present in the second plurality of drug-resin particles.

7. The composition of claim 1, wherein the composition is a liquid suspension, chewable composition, or an orally disintegrating tablet composition.

8. The composition of claim 1, wherein said amphetamines in said drug-resin particles comprise 25% levo-amphetamine and 75% dextro-amphetamine.

9. The composition of claim 1, wherein the amount of ADHD effective agent is 2-60 mg.

10. The composition of claim 1, wherein 40-45% of the ADHD effective agent is released within the first 45 minutes after the drug-resin particles are introduced into an in vitro dissolution assay, followed by a period of substantially no ADHD effective agent release from 45 minutes to 2 hours, and concluding with period of from 2 to 8 hours during which substantially all of the remaining ADHD effective agent is released, wherein the conditions of the dissolution assay are an initial dissolution medium of 0.1 N HCL, and after 2 hours, the medium is adjusted to a pH of about 6.8;

and the dissolution assay is performed using a USP Apparatus 2.

11. The composition of claim 1, wherein the delayed release coating releases substantially all of the ADHD effective agent in the second plurality of drug-resin particles within about 60 minutes after initiation of the delayed release.

15. The composition of claim 1, wherein the amount of said amphetamines is equivalent to the total amount of dextro- and levo-amphetamines present in a 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg reference composition without resin particle which comprises a mixture of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate.

12. (canceled)

13. (canceled)

14. A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein a mammal receiving said composition, in the presence of ethanol, is exposed to a reduced amount of amphetamines compared to when said mammal receives a composition without resin particles in the presence of ethanol, said composition comprising a mixture of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate.

16. (canceled)

17. A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein said composition is an orally disintegrating tablet and is effective to provide a mean plasma concentration profile in human ADHD patients which has the following AUC and C_max values for a 30 mg total dose, or respective AUC and C_max values directly proportional thereto for a total dose other than 30 mg:

(a) an AUC_0-4 of 85.8 ng hr/mL −

20%/+25% and a C_max of 44.5 ng/mL −

20%/+25% for dextroamphetamine and/or an AUC_0-4 of 26.3 ng hr/mL −

20%/+25% and a C_max of 14.2 ng/mL −

20%/+25% for levoamphetamine;

(b) an AUC_0-5 of 126.3 ng hr/mL −

20%/+25% and a C_max of 44.5 ng/mL −

20%/+25% for dextroamphetamine and/or an AUC_0-5 of 39.1 ng hr/mL −

20%/+25% and a C_max of 14.2 ng/mL −

20%/+25% for levoamphetamine;

(c) an AUC_4-12 of 291 ng hr/mL −

20%/+25% and a C_max of 44.5 ng/mL −

20%/+25% for dextroamphetamine and/or an AUC_4-12 of 95.1 ng hr/mL −

20%/+25% and a C_max of 14.2 ng/mL −

20%/+25% for levoamphetamine;

(d) an AUC_5-12 of 250.5 ng hr/mL −

20%/+25% and a C_max of 44.5 ng/mL −

20%/+25% for dextroamphetamine and/or an AUC_5-12 of 82.3 ng hr/mL −

20%/+25% and a C_max of 14.2 ng/mL −

20%/+25% for levoamphetamine; and

/or

(e) an AUC_0-24 of 613.3 ng hr/mL −

20%/+25% and a C_max of 44.5 ng/mL −

20%/+25% for dextroamphetamine and/or an AUC_0-24 of 204.9 ng hr/mL −

20%/+25% and a C_max of 14.2 ng/mL −

20%/+25% for levoamphetamine.

18. (canceled)

19. (canceled)

20. (canceled)

21. (canceled)

22. A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein said composition is a liquid suspension and is effective to provide a mean plasma concentration profile in human ADHD patients which has the following AUC and C_max values for a 30 mg total dose, or respective AUC and C_max values directly proportional thereto for a total dose other than 30 mg:

(a) an AUC_0-4 of 104.7 ng hr/mL −

20%/+25% and a C_max of 46.3 ng/mL −

20%/+25% for dextroamphetamine and/or an AUC_0-4 of 31.8 ng hr/mL −

20%/+25% and a C_max of 14.6 ng/mL −

20%/+25% for levoamphetamine;

(b) an AUC_0-5 of 148.6 ng hr/mL −

20%/+25% and a C_max of 46.3 ng/mL −

20%/+25% for dextroamphetamine and/or an AUC_0-5 of 45.7 ng hr/mL −

20%/+25% and a C_max of 14.6 ng/mL −

20%/+25% for levoamphetamine; and

/or

(c) an AUC_4-12 of 300.3 ng hr/mL −

20%/+25% and a C_max of 46.3 ng/mL −

20%/+25% for dextroamphetamine and/or an AUC_4-12 of 96.8 ng hr/mL −

20%/+25% and a C_max of 14.6 ng/mL −

20%/+25% for levoamphetamine.

23. (canceled)

24. (canceled)

25. A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein said composition, when containing about a total amphetamine dose of 30 mg, will produce in a human, a mean plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC_0-∞

) of about 1140 to about 1240 for total amphetamines (dextroamphetamine+levoamphetamine).

26. A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein one or more in vivo pharmacokinetic parameters of the composition selected from the group consisting of C_max, AUC_0-5, AUC_5-12, AUC_5-24, AUC_5-t, AUC_0-12, AUC_0-24, AUC_0-t, and AUC_0-∞

have a 90% confidence interval with upper and lower bounds within a range from 90%-115% of the value of the same parameter(s) for a bioequivalent reference composition.

27. A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein said composition is a liquid suspension and a human receiving said composition substantially contemporaneously with food is exposed to an increased amount of amphetamines in the first 4 hours compared to a human receiving a reference composition comprising a mixture of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate.

28. A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein about 50% by weight of said amphetamines are present in a first plurality of immediate release drug-resin particles and about 50% by weight of said amphetamines are present in a second plurality of drug-resin particles that are coated with a delayed release coating.

29. A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating and wherein said composition has an in vivo fasted serum profile with a first and second peak wherein said first peak occurs between 1 and 3 hours after ingestion of the composition and said second peak occurs between 4 and 7 hours after ingestion and is the C_max.