Delayed release methylphenidate compositions

11547,670

17/431868

March 05, 2020

The present disclosure provides programmable osmotic-controlled oral compositions providing delayed extended release of a therapeutically acceptable amount of methylphenidate hydrochloride. The programmable osmotic-controlled compositions of the disclosure provide a lag time that is independent of the presence or absence of food, type of food, pH, gastric emptying, and volume of gastric fluid. The compositions of the disclosure can be programmed to provide a desired and precise lag time, and release drug, after the lag time, at a rhythm that matches the circadian rhythm of an individual being treated to optimize therapeutic outcome and minimize side effects.

Amneal Complex Products Research LLC (Bridgewater, NJ, US)

Amneal Complex Products Research LLC (Bridgewater, NJ, US)

1. An osmotic-controlled oral pharmaceutical composition providing delayed release of a therapeutically effective amount of methylphenidate or a pharmaceutically acceptable salt thereof, the composition comprising: a) a multilayered core comprising a placebo layer, an active layer, and a push layer, wherein: (i) the placebo layer comprises at least one polyethylene oxide polymer having an average molecular weight of from about 600,000 Da to about 900,000 Da, (ii) the active layer comprises methylphenidate or a pharmaceutically acceptable salt thereof, and at least one polyethylene oxide polymer having an average molecular weight of from about 100,000 Da to about 300,000 Da, (iii) the push layer comprises at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1000,000 Da, and at least one osmogen; and b) a semipermeable membrane comprising at least one orifice and surrounding the core, wherein the layers in the multilayer core are placed in the following order: the placebo layer in fluid communication with the orifice in the semipermeable membrane; the active layer; and the push layer facing away from the orifice.

2. The composition of claim 1 , wherein the semipermeable membrane comprises a water-insoluble polymer and a pore former.

3. The composition of claim 2 , wherein the water-insoluble polymer and the pore former are present in a polymer to pore former ratio of between about 80:20 and about 99.5:0.5.

4. The composition of claim 2 , wherein the water-insoluble polymer in the semipermeable membrane comprises polymers selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate, and combinations thereof.

5. The composition of claim 2 , wherein the pore former is selected from the group consisting of polyethylene glycol, hydroxypropyl cellulose, polyvinyl pyrrolidone sucrose, glucose, fructose, lactose, mannose, mannitol, sorbitol, methyl cellulose, poloxamers, triethyl citrate, triacetin, hydroxypropyl methylcellulose, glycerol, and combinations thereof.

6. The composition of claim 2 , wherein the semipermeable membrane further comprises at least one plasticizer selected from the group consisting of polyethylene glycols, triethyl citrate, triacetin, diethyl tartrate, dibutyl sebacate, and combinations thereof.

7. The composition of claim 1 , wherein the polyethylene oxide polymer in the placebo layer has an average molecular weight of about 600,000 Da or about 900,000 Da, and the polyethylene oxide polymer in the active layer has an average molecular weight of about 200,000 Da.

8. The composition of claim 1 , wherein any of the placebo layer, the active layer, and the push layer further comprise a binder, a stabilizer, and/or a lubricant.

9. The composition of claim 1 , wherein the polyethylene oxide polymer in the push layer has an average molecular weight of about 1000,000 Da, about 2000,000 Da, about 4000,000 Da, about 5000,000 Da, about 7000,000 Da, or intermediate values therein.

10. The composition of claim 1 , wherein the osmogen in the push layer is selected from the group consisting of sodium chloride, potassium chloride, potassium sulfate, lithium sulfate, sodium sulfate, lactose, dextrose, sucrose, mannitol, fructose, sorbitol, xylitol, dibasic sodium phosphate, and combinations thereof.

11. The composition of claim 1 , wherein the osmogen in the push layer is present in an amount of between about 5 wt % and about 40 wt %, based on the total weight of the push layer.

12. The composition of claim 1 , wherein the semipermeable membrane is applied at a coating weight gain of about 1 wt % to 50 wt %, based on the total weight of the uncoated tablet core.

13. The composition of claim 1 , wherein the composition provides a lag time of at least about 6 hours, during which the composition releases no more than 10 wt % of the methylphenidate or a pharmaceutically acceptable salt thereof, measured in 900 ml of 0.01N HCl, using USP II (sinkers) at 50 rpm and 37° C.

14. The composition of claim 1 , wherein the composition further comprises an immediate release layer containing a sedative and placed over the semipermeable membrane.

15. The composition of claim 14 , wherein the sedative is selected from the group consisting of clonidine, guanfacine, diphenhydramine, melatonin, and pharmaceutically acceptable salts thereof.

16. A method for treating attention deficit hyperactivity disorder (ADHD) in a subject, the method comprising orally administering to the subject an osmotic-controlled oral pharmaceutical composition providing delayed release of methylphenidate or a pharmaceutically acceptable salt thereof, the composition comprising: a) a multilayered core comprising a placebo layer, an active layer, and a push layer, wherein: (i) the placebo layer comprises at least one polyethylene oxide polymer having an average molecular weight of from about 600,000 Da to about 900,000 Da, (ii) the active layer comprises methylphenidate or a pharmaceutically acceptable salt thereof, and at least one polyethylene oxide polymer having an average molecular weight of from about 100,000 Da to about 300,000 Da, (iii) the push layer comprises at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1000,000 Da, and at least one osmogen, and b) a semipermeable membrane, comprising at least one orifice and surrounding the core, wherein the layers in the multilayer core are placed in the following order: the placebo layer in fluid communication with the orifice in the semipermeable membrane; the active layer; and the push layer facing away from the orifice.

17. A method for treating attention deficit hyperactivity disorder in a subject, the method comprising orally administering to the subject, in the night before bedtime, an osmotic-controlled oral pharmaceutical composition providing delayed release of methylphenidate or a pharmaceutically acceptable salt thereof, wherein the composition comprises: a) a multilayered core comprising a placebo layer, an active layer, and a push layer, wherein: (i) the placebo layer comprises at least one polyethylene oxide polymer having an average molecular weight of from about 600,000 Da to about 900,000 Da, (ii) the active layer comprises methylphenidate or a pharmaceutically acceptable salt thereof, and at least one polyethylene oxide polymer having an average molecular weight of from about 100,000 Da to about 300,000 Da, (iii) the push layer comprises at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1000,000 Da, and at least one osmogen, and b) a semipermeable membrane comprising at least one orifice and surrounding the core, wherein the layers in the multilayer core are placed in the following order: the placebo layer in fluid communication with the orifice in the semipermeable membrane; the active layer; and the push layer facing away from the orifice, wherein the composition provides a therapeutic amount of methylphenidate throughout the following day.

18. A method for making an osmotic-controlled oral pharmaceutical composition providing delayed release of methylphenidate or a pharmaceutically acceptable salt thereof, the method comprising: i) making placebo layer blend comprising at least one polyethylene oxide polymer having an average molecular weight of from about 600,000 Da to about 900,000 Da; ii) making an active layer blend comprising methylphenidate or a pharmaceutically acceptable salt thereof, and at least one polyethylene oxide polymer having an average molecular weight of from about 100,000 Da to about 300,000 Da; iii) making a push layer blend comprising at least one polyethylene oxide polymer having an average molecular weight of greater than or equal to 1000,000 Da, and at least one osmogen; iv) filling the placebo layer blend, the active layer blend, and the push layer blend into a tablet dye and compressing into a trilayer tablet core; v) coating the trilayer tablet core with a semipermeable membrane coat comprising a water-insoluble polymer and a pore former at a polymer to pore former ratio of between about 80:20 and about 99.5:0.5; and vi) drilling of an orifice in the semipermeable membrane coating.

5156850 October 1992 Wong et al.
6368626 April 2002 Bhatt
7521067 April 2009 Greerke et al.
20010012847 August 2001 Lam et al.
20100112052 May 2010 Chen et al.
20100260844 October 2010 Scicinski
0768867 April 1997
WO 99/62496 December 1999

Kurlan R, et al., Clonidine and methylphenidate were effective for attention deficit hyperactivity disorder in children with comorbid tics, Evidence-based medicine, BMJ Group, UK, US, vol. 7, No. 5, Sep. 1, 2002, p. 157 XP002724188, ISSN: 1356-5524, DOI: 10.1136/EBM.7.5.157. cited by applicant
Robinson, et al., The osmotic coefficients of some organic compounds in relation to their chemical constitution, Trans. Faraday Soc., vol. 38, Jan. 1, 1942, pp. 63-70, XP5589305, Figure 1, table V. cited by applicant
International Search Report. cited by applicant

edspgr.11547670