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Details for Patent: 9,089,496

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Details for Patent: 9,089,496

Title:Compositions comprising methylphenidate complexed with ion-exchange resin particles
Abstract: Pharmaceutical compositions of methylphenidate complexed with ion-exchange resin particles to form drug-resin particles are provided. The compositions have a first plurality of drug-resin particles that are uncoated and a second plurality of drug-resin particles that are coated with a delayed release coating.
Inventor(s): Tengler; Mark (Colleyville, TX), McMahen; Russell (Flower Mound, TX)
Assignee: NEOS THERAPEUTICS, LP (Grand Prairie, TX)
Filing Date:Jul 22, 2013
Application Number:13/947,907
Claims:1. A pharmaceutical composition comprising an ADHD effective agent complexed with ion-exchange resin particles to form drug-resin particles, wherein said ADHD effective agent is methylphenidate, wherein said composition comprises a first plurality of drug-resin particles that provide for immediate release of said ADHD effective agent and a second plurality of drug-resin particles that are coated with a delayed release coating, said drug-resin particles of said second plurality being coated with a triggered-release coating triggered by a pH change and a diffusion barrier coating, wherein 20%-30% by weight of said methylphenidate is present-in the first plurality of drug-resin particles and 70-80% by weight of said methylphenidate is present in the second plurality of drug-resin particles, and wherein administration of the composition to a human produces a mean plasma concentration profile for d-methylphenidate in human subjects which has one or more parameters selected from the group consisting of AUC.sub.0-3, AUC.sub.0-5, AUC.sub.0-Tmax, AUC.sub.5-12, AUC.sub.5-24, AUC.sub.Tmax-24, AUC.sub.Tmax-12, AUC.sub.5-t, AUC.sub.Tmax-t, AUC.sub.0-24, and AUC.sub.0-.infin. which is substantially similar to those parameters of at least one of the in vivo serum profiles of the compositions comprising methylphenidate-containing drug-resin particles shown in FIG. 20A.

2. The composition of claim 1, 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.

3. The composition of claim 1, wherein the diffusion barrier coating is a water insoluble, water permeable membrane.

4. The composition of claim 3, wherein the water insoluble, water permeable membrane is ethylcellulose.

5. The composition of claim 1, wherein the triggered-release coating covers the diffusion barrier coating.

6. The composition of claim 5, wherein the diffusion barrier coating is ethylcellulose.

7. 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 and mixtures thereof.

8. The composition of claim 1, wherein about 25% by weight of said methylphenidate is present in a first plurality of drug-resin particles that provide for immediate release of said ADHD effective agent and about 75% by weight of said methylphenidate is present in a second plurality of drug-resin particles that are coated with a trigger-release coating triggered by a pH change and a diffusion barrier coating.

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

10. The composition of claim 1, wherein the amount of said methylphenidate is 10-60 mg.

11. The composition of claim 1, wherein the composition has an in vitro dissolution profile wherein 30-33% by weight of said methylphenidate is released from the drug-resin particles within the first 30 minutes, 34-42% by weight of said methylphenidate is released within 2 hours, 40-80% by weight of said methylphenidate is released within 4 hours, and 80-100% by weight of said methylphenidate is released within 24 hours, wherein the dissolution profile is determined by an in vitro dissolution, 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.

12. The composition of claim 1, wherein the composition has an in vivo serum profile that is statistically similar to at least one profile selected from FIGS. 27A, 27B, 28A, and 28B.

13. The composition of claim 1, wherein the amount of said methylphenidate in said composition is equivalent to the amount present in a 10 mg, 20 mg, 30 mg, 40 mg, 50 mg or 60 mg dose of methylphenidate hydrochloride.

14. The composition of claim 1, wherein said composition is an orally disintegrating tablet and is effective to provide a mean plasma concentration profile in human adult ADHD patients which has an AUC.sub.0-3 of 20.53 ng hr/mL -20%/+25% and a C.sub.max of 20.17 ng/mL -20%/+25% for d-methylphenidate, an AUC.sub.0-3 of 0.62 ng hr/mL -20%/+25% and a C.sub.max of 0.44 ng/mL -20%/+25% for l-methylphenidate, and/or an AUC.sub.0-3 of 21.29 ng hr/mL -20%/+25% and a C.sub.max of 20.60 ng/mL -20%/+25% for total methylphenidate, for a total methylphenidate dose that is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride, or respective AUC and C.sub.max values directly proportional thereto for a total methylphenidate dose other than that which is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride.

15. The composition of claim 1, wherein said composition is an orally disintegrating tablet and is effective to provide a mean plasma concentration profile in human adult ADHD patients which has an AUC.sub.0-5 of 50.16 ng hr/mL -20%/+25% and a C.sub.max of 20.17 ng/mL -20%/+25% for d-methylphenidate, an AUC.sub.0-5 of 1.07 ng hr/mL -20%/+25% and a C.sub.max of 0.44 ng/mL -20%/+25% for 1-methylphenidate, and/or an AUC.sub.0-5 of 51.43 ng hr/mL -20%/+25% and a C.sub.max of 20.60 ng/mL -20%/+25% for total methylphenidate, for a total methylphenidate dose that is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride, or respective AUC and C.sub.max values directly proportional thereto for a total methylphenidate dose other than that which is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride.

16. The composition of claim 1, wherein said composition is an orally disintegrating tablet and is effective to provide a mean plasma concentration profile in human adult ADHD patients which has an AUC.sub.5-24 of 103.84 ng hr/mL -20%/+25% and a C.sub.max of 20.17 ng/mL -20%/+25% for d-methylphenidate, an AUC.sub.5-24 of 0.96 ng hr/mL -20%/+25% and a C.sub.max of 0.44 ng/mL -20%/+25% for 1-methylphenidate, and/or an AUC.sub.5-24 of 105.07 ng hr/mL -20%/+25% and a C.sub.max of 20.60 ng/mL -20%/+25% for total methylphenidate, for a total methylphenidate dose that is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride, or respective AUC and C.sub.max values directly proportional thereto for a total methylphenidate dose other than that which is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride.

17. The composition of claim 1, wherein said composition is an orally disintegrating tablet and is effective to provide a mean plasma concentration profile in human adult ADHD patients which has an AUC.sub.0-24 of 156.72 ng hr/mL -20%/+25% and a C.sub.max of 20.17 ng/mL -20%/+25% for d-methylphenidate, an AUC.sub.0-24 of 2.19 ng hr/mL -20%/+25% and a C.sub.max of 0.44 ng/mL -20%/+25% for 1-methylphenidate, and/or an AUC.sub.0-24 of 159.25 ng hr/mL -20%/+25% and a C.sub.max of 20.60 ng/mL -20%/+25% for total methylphenidate, for a total methylphenidate dose that is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride, or respective AUC and C.sub.max values directly proportional thereto for a total methylphenidate dose other than that which is equivalent to the amount present in a 60 mg total dose of methylphenidate hydrochloride.

18. The composition of claim 1, wherein one or more in vivo pharmacokinetic parameters of the composition selected from the group consisting of C.sub.max, AUC.sub.0-3, AUC.sub.0-5, AUC.sub.0-Tmax, AUC.sub.5-12, AUC.sub.5-24, AUC.sub.Tmax-24, AUC.sub.Tmax-12, AUC.sub.5-t, AUC.sub.Tmax-t, AUC.sub.0-24, and AUC.sub.0-.infin. have a 90% confidence interval with upper and lower bounds within a range from 90%415% of the value of the same parameter(s) for a bioequivalent reference composition.

19. A pharmaceutical composition comprising an ADHD effective agent complexed with ion-exchange resin particles to form drug-resin particles, wherein said ADHD effective agent is methylphenidate, wherein said composition comprises a first plurality of drug-resin particles that provide for immediate release of said ADHD effective agent and a second plurality of drug-resin particles that are coated with a delayed release coating, said drug-resin particles of said second plurality being coated with a triggered-release coating triggered by a pH change and a diffusion barrier coating, wherein 20%-30% by weight of said methylphenidate is present-in the first plurality of drug-resin particles and 70-80% by weight of said methylphenidate is present in the second plurality of drug-resin particles, and wherein said composition, would produce, in a human adult, a mean plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC.sub.0-.infin.) of about 160 ng hr/ml to about 180 ng hr/ml for total methylphenidate when said composition contains a total methylphenidate dose that is equivalent to that present in about a 60 mg total dose of methylphenidate hydrochloride.

20. The composition of claim 19, wherein the administration of an amount of said composition containing an amount of said methylphenidate equivalent to that present in an about 60 mg dose of methylphenidate hydrochloride produces a mean C.sub.max greater than 16.55 ng/mL.

21. The composition of claim 19, wherein said composition has a T.sub.max of approximately six hours.

22. The composition of claim 21, wherein said composition has a bimodal profile with two peaks, having a first peak at approximately 3 hours.
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