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EP-3934622-B1 - DELAYED RELEASE METHYLPHENIDATE COMPOSITIONS

EP3934622B1EP 3934622 B1EP3934622 B1EP 3934622B1EP-3934622-B1

Inventors

  • THONGSUKMAK, Atsawin
  • VAKA, Siva, Ram, Kiran
  • JARIWALA, Paras
  • VAGHASHIYA, Jaydeep
  • DESAI, DIPEN
  • PHUAPRADIT, WANTANEE
  • SHAH, NAVNIT, H.

Dates

Publication Date
20260506
Application Date
20200305

Claims (14)

  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 an active layer sandwiched between a placebo layer and a push layer, wherein: (i) the placebo layer comprises at least one polyethylene oxide polymer having an average molecular weight of about 600K, about 900K, or intermediate values thereof, (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 300,000Da, (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, containing at least one orifice facing the placebo layer, and surrounding the core.
  2. The composition of claim 1, wherein the semipermeable membrane comprises a pH-independent water-insoluble polymer and a pH-independent pore former at a polymer to pore former ratio of between about 80:20 and about 99.5:0.5.
  3. The composition of claim 2, wherein the pH-independent water-insoluble polymer in the semipermeable membrane comprises one or more of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate.
  4. The composition of any one of the claims 2 or 3, 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.
  5. The composition of any one of the claims 2, 3, or 4, 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.
  6. The composition of any one of the preceding claims, wherein the polyethylene oxide polymer in the placebo layer has an average molecular weight of about 600K or about 900K, and the polyethylene oxide polymer in the active layer has an average molecular weight of about 200K.
  7. The composition of any one of the preceding claims, wherein any of the placebo layer, the active layer, and the push layer further comprise a binder, and/or a lubricant.
  8. The composition of any one of the preceding claims, wherein the polyethylene oxide polymer in the push layer has an average molecular weight of about 1M, about 2M, about 4M, about 5M, about 7M, or intermediate values therein.
  9. The composition of any one of the preceding claims, 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.
  10. The composition of any one of the preceding claims, 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.
  11. The composition of any one of the preceding claims, wherein the semipermeable membrane is applied with a coating weight gain of about 1 wt% to 50 wt%, based on the total weight of the uncoated tablet core.
  12. The composition of any one of the preceding claims, wherein the composition further comprises an immediate release layer containing a sedative, wherein the immediate release layer is placed over the semipermeable membrane, and wherein the sedative is selected from the group consisting of clonidine, guanfacine, diphenhydramine, and melatonin, or pharmaceutically acceptable salts thereof.
  13. A composition as defined in any one of claims 1 to 12 for use in treating Attention Deficit Hyperactivity Disorder (ADHD) in a subject.
  14. A method for making an osmotic-controlled oral pharmaceutical composition providing delayed extended release of a therapeutically effective amount of methylphenidate or a pharmaceutically acceptable salt thereof, the method comprising: i) making a placebo layer blend comprising at least one polyethylene oxide polymer having an average molecular weight of about 600K, about 900K, or intermediate values thereof; 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 300,000Da; 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 pH-independent water-insoluble polymer and a pH-independent 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 coating.

Description

1. RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62/814,237, filed March 5, 2019 and U.S. Provisional Patent Application No. 62/872,492, filed July 10, 2019. 2. TECHNICAL FIELD The presently disclosed subject matter relates to therapeutic compositions and methods for the treatment of attention deficit disorder (ADD), or attention deficit hyperactivity disorder (ADHD). The present disclosure relates to programmable osmotic-controlled oral compositions providing delayed controlled release of stimulants, e.g., methylphenidate or pharmaceutically acceptable salts thereof, and mixed amphetamines. The osmotic-controlled oral compositions of the disclosure can be programmed to provide a desired and precise lag time, and a desired release profile after the lag time to provide therapeutic plasma concentrations of stimulants, e.g., methylphenidate or pharmaceutically acceptable salts thereof, even while releasing the drugs in the lower portions of the GI tract. The compositions of the disclosure provide a precise lag time that is substantially independent of the presence or absence of food, type of food, pH, gastric emptying time, and volume and viscosity of immediate microenvironment of drug release. 3. BACKGROUND Attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD) are two of the most common developmental disorders in children which are characterized by symptoms such as impulsiveness, hyperactivity, and inattentiveness. Hyperactivity is particularly common in children with ADHD. Treatment of these disorders include various stimulate medications. Methylphenidate hydrochloride, and mixed amphetamines are among stimulants that have been approved by FDA. However, treatment of ADHD/ADD, as well as other stimulant-responsive conditions provides challenges associated with delivering and maintaining an effective stimulant concentration in patients, particularly children, throughout the day. This is particularly important during the morning hours when cognitive abilities and concentration are needed for school or work, and during the late afternoon or evening when students often do homework. Furthermore, parents and caregivers of children suffering from ADHD/ADD often experience early morning symptom control as a major obstacle for getting the children ready for school. Stimulant-based medications are typically dosed two hours prior to beginning an early morning routine, with an onset of treatment effect usually about two hours after administration. Such medications require twice-daily administration and cause compliance issues. Commercially available products of methylphenidate have been approved by the FDA for the treatment of ADHD in patients six years and older. Certain methylphenidate formulations are administered in the evening in an attempt to improve ADHD symptoms in the early morning and throughout the day. However, drug release from formulations can be affected by pH, food, and gastric transit time, with a potential for variable drug release during the night and early morning leading to insomnia. There remains a need to develop compositions that can be programmed to control attention disorders, which improve symptoms in the early morning and throughout the day, without the potential for variable drug release during the night and early morning, leading to insomnia. In particular, there remains a need to develop extended release methylphenidate compositions that can be taken, in the evening or before bed time, with or without food, to delay the release of methylphenidate by at least about 6 hours with minimal inter-subject variability, independent of pH, viscosity, and GI transit time, to control symptoms of attention disorder in the early morning and throughout the day. The present disclosure addresses the unmet needs by providing osmotic-controlled, oral, delayed-release methylphenidate compositions that can improve the symptoms of ADHD/ADD in the early morning and throughout the day, without the need for early morning dosing that requires an onset time of about two hours. The compositions of the disclosure provide a precise lag time, with minimal variability in drug release, independent of the presence or absence of food, type of food, pH, gastric emptying, gastric transit time, and volume of fluid in the immediate microenvironment of drug release. In particular, the disclosure provides desired drug bioavailability while releasing the drug in lower portions of the GI tract, e.g., in the colon in a viscous alkaline microenvironment. US 2001/012847 and WO 99/62496 disclose oral dosage forms that release drug within the gastrointestinal tract at an ascending release rate over an extended time period. US7521067 relates to methods and apparatus for determining formulation orientation of multi-layered pharmaceutical dosage forms 4. SUMMARY The purpose and advantages of the disclosed subject matter will be set forth and are apparent from