Oral pharmaceutical dosage forms

Abstract

Controlled release oral dosage forms suitable for administration of methylphenidate are provided. Abuse-resistant controlled release oral dosage forms suitable for administration of methylphenidate are also provided. Methods of treating ADD and ADHD using the oral dosage forms are also provided.

1 . An oral controlled release dosage form comprising methylphenidate and a controlled release carrier system, wherein said dosage form is characterized by providing:
 (i) an initial increasing in vivo rate of release of methylphenidate from the controlled release system suitable to provide an initial increasing-rate phase of less than or equal to about 2 hours, and sufficient to provide a therapeutically effective amount of methylphenidate for a rapid onset of action;   (ii) a second, non-ascending in vivo rate of release of methylphenidate from the controlled release system that provides a subsequent non-ascending phase sufficient to provide a therapeutically effective amount of methylphenidate through at least about 11 to 12 hours post administration; and   (iii) a single T max  of about 5.5 to 7.5 hours post administration.   
     
     
         2 . The controlled release oral dosage form of  claim 1 , wherein the initial increasing-rate phase is sufficient to provide an onset of action within about 1 to 1.5 hours post administration. 
     
     
         3 . The controlled release oral dosage form of  claim 1 , wherein the single T max  occurs at about 6 to 7 hours post administration. 
     
     
         4 . The controlled release oral dosage form of  claim 1 , wherein the subsequent non-ascending phase is sufficient to provide a therapeutically effective amount of methylphenidate through at least about 12 to 14 hours post administration 
     
     
         5 . The controlled release oral dosage form of  claim 1 , wherein the dosage form is further characterized by having a food effect. 
     
     
         6 . The controlled release oral dosage form of  claim 5 , wherein the oral bioavailability of the methylphenidate from the dosage form is increased upon co-administration with food. 
     
     
         7 . The controlled release oral dosage form of  claim 6 , wherein the rate of absorption of methylphenidate is decreased and the extent of absorption of methylphenidate is increased upon co-administration with food. 
     
     
         8 . The controlled release oral dosage form of  claim 1 , wherein the controlled release (CR) carrier system is selected from an Osmotic CR carrier system, a Liquid CR carrier system, a Particulate CR carrier system, a CR Matrix carrier system, or a CR Melt-Extrusion Matrix carrier system. 
     
     
         9 . The controlled release oral dosage form of  claim 1 , wherein the dosage form is abuse-resistant. 
     
     
         10 . The abuse-resistant controlled release oral dosage form of  claim 9 , wherein the controlled release carrier system provides a decreased risk of misuse or abuse. 
     
     
         11 . The abuse-resistant controlled release oral dosage form of  claim 10 , wherein said decreased risk of misuse or abuse is characterized by a low in vitro solvent extractability value of the methylphenidate from the dosage form. 
     
     
         12 . The abuse-resistant controlled release oral dosage form of  claim 10 , wherein said decreased risk of misuse or abuse is characterized by the absence of any significant effect on absorption of the methylphenidate from the dosage form upon co-ingestion of the dosage form and alcohol by a subject. 
     
     
         13 . The abuse-resistant controlled release oral dosage form of  claim 10 , wherein said decreased risk of misuse or abuse is characterized by a low injectability potential. 
     
     
         14 . The abuse-resistant controlled release oral dosage form of  claim 9 , wherein said dosage form is not susceptible to common forms of abuse comprising injection, inhalation (crushing and sniffing) and volatilization (smoking). 
     
     
         15 . The abuse-resistant controlled release oral dosage form of  claim 9 , wherein the controlled release carrier system comprises a high viscosity liquid carrier material (HVLCM). 
     
     
         16 . The controlled release oral dosage form of  claim 1 , wherein the initial increasing-rate phase and subsequent non-ascending phase are sufficient to provide the methylphenidate in vivo PK profile depicted in  FIG. 7  when the dosage form is administered to a subject. 
     
     
         17 . A method of treating Attention Deficit Disorder (ADD) or Attention Deficit Hyperactivity Disorder (ADHD) in a subject, said method comprising administering the controlled release oral dosage form of  claim 1  to the subject on a once-day (QD) basis. 
     
     
         18 . An abuse-resistant oral controlled release dosage form comprising methylphenidate and a controlled release carrier system, wherein said dosage form is characterized by providing:
 (i) an initial increasing in vivo rate of release of methylphenidate from the controlled release system suitable to provide an initial increasing-rate phase of less than or equal to about 2 hours, and sufficient to provide a therapeutically effective amount of methylphenidate for a rapid onset of action;   (ii) a second, non-ascending in vivo rate of release of methylphenidate from the controlled release system that provides a subsequent non-ascending phase sufficient to provide a therapeutically effective amount of methylphenidate through at least about 11 to 12 hours post administration; and   (iii) a single T max  of about 5.5 to 7.5 hours post administration, and further wherein said controlled release carrier system comprises an HVLCM, a network former, and at least one viscosity enhancing agent.   
     
     
         19 . The abuse-resistant controlled release oral dosage form of  claim 18 , wherein the initial increasing-rate phase is sufficient to provide an onset of action within about 1 to 1.5 hours post administration. 
     
     
         20 . The abuse-resistant controlled release oral dosage form of  claim 18 , wherein the single T max  occurs at about 6 to 7 hours post administration. 
     
     
         21 . The abuse-resistant controlled release oral dosage form of  claim 18 , wherein the subsequent non-ascending phase is sufficient to provide a therapeutically effective amount of methylphenidate through at least about 12 to 14 hours post administration 
     
     
         22 . The abuse-resistant controlled release oral dosage form of  claim 18 , wherein the dosage form is further characterized by having a food effect. 
     
     
         23 . The abuse-resistant controlled release oral dosage form of  claim 22 , wherein the oral bioavailability of the methylphenidate from the dosage form is increased upon co-administration with food. 
     
     
         24 . The abuse-resistant controlled release oral dosage form of  claim 22 , wherein the rate of absorption of methylphenidate is decreased and the extent of absorption of methylphenidate is increased upon co-administration with food. 
     
     
         25 . The abuse-resistant controlled release oral dosage form of  claim 18 , wherein the viscosity enhancing agent is a synthetic polymer. 
     
     
         26 . The abuse-resistant controlled release oral dosage form of  claim 25 , wherein the synthetic polymer is a cellulose derivative. 
     
     
         27 . The abuse-resistant controlled release oral dosage form of  claim 18 , wherein the controlled release carrier system further comprises a surfactant. 
     
     
         28 . The abuse-resistant controlled release oral dosage form of  claim 18 , wherein the controlled release carrier system further comprises a plurality of hydrophilic excipients. 
     
     
         29 . The abuse-resistant controlled release oral dosage form of  claim 18 , wherein the controlled release carrier system further comprises a second viscosity enhancing agent. 
     
     
         30 . The abuse-resistant controlled release oral dosage form of  claim 29 , wherein the second viscosity enhancing agent comprises a stiffening agent. 
     
     
         31 . The abuse-resistant controlled release oral dosage form of  claim 30 , wherein the second viscosity enhancing agent comprises a SiO 2 . 
     
     
         32 . The abuse-resistant controlled release oral dosage form of  claim 18 , wherein the controlled release carrier system further comprises a plurality of solvents. 
     
     
         33 . The abuse-resistant controlled release dosage form of  claim 32 , wherein the solvents comprise a hydrophobic solvent and a hydrophilic solvent. 
     
     
         34 . The abuse-resistant controlled release oral dosage form of  claim 18 , wherein the controlled release carrier system provides a decreased risk of misuse or abuse. 
     
     
         35 . The abuse-resistant controlled release oral dosage form of  claim 34 , wherein said decreased risk of misuse or abuse is characterized by a low in vitro solvent extractability value of the methylphenidate from the dosage form. 
     
     
         36 . The abuse-resistant controlled release oral dosage form of  claim 34 , wherein said decreased risk of misuse or abuse is characterized by the absence of any significant effect on absorption of the methylphenidate from the dosage form upon co-ingestion of the dosage form and alcohol by a subject. 
     
     
         37 . The abuse-resistant controlled release oral dosage form of  claim 34 , wherein said decreased risk of misuse or abuse is characterized by a low injectability potential. 
     
     
         38 . The abuse-resistant controlled release oral dosage form of  claim 34 , wherein said dosage form is not susceptible to common forms of abuse comprising injection, inhalation (crushing and sniffing) and volatilization (smoking). 
     
     
         39 . The abuse-resistant controlled release oral dosage form of  claim 18 , wherein the initial increasing-rate phase and subsequent non-ascending phase are sufficient to provide the methylphenidate in vivo PK profile depicted in  FIG. 7  when the dosage form is administered to a subject. 
     
     
         40 . A method of treating Attention Deficit Disorder (ADD) or Attention Deficit Hyperactivity Disorder (ADHD) in a subject, said method comprising administering the abuse-resistant controlled release oral dosage form of  claim 18  to the subject on a once-day (QD) basis. 
     
     
         41 . An abuse-resistant oral controlled release dosage form comprising methylphenidate and a controlled release carrier system, wherein said dosage form is characterized by providing:
 (i) an initial increasing in vivo rate of release of methylphenidate from the controlled release system suitable to provide an initial increasing-rate phase of less than or equal to about 2 hours, and sufficient to provide a therapeutically effective amount of methylphenidate for a rapid onset of action;   (ii) a second, non-ascending in vivo rate of release of methylphenidate from the controlled release system that provides a subsequent non-ascending phase sufficient to provide a therapeutically effective amount of methylphenidate through at least about 11 to 12 hours post administration; and   (iii) a single T max  of about 5.5 to 7.5 hours post administration, and further wherein said controlled release carrier system comprises an HVLCM, a network former, a rheology modifier and a hydrophilic agent.   
     
     
         42 . The abuse-resistant oral controlled release dosage form of  claim 41 , wherein the controlled release carrier system further comprises a viscosity enhancing agent. 
     
     
         43 . The abuse-resistant oral controlled release dosage form of  claim 42 , wherein the hydrophilic agent also serves as a second viscosity enhancing agent. 
     
     
         44 . The abuse-resistant oral controlled release dosage form of  claim 41 , wherein the hydrophilic agent is hydroxyethyl cellulose (HEC). 
     
     
         45 . The abuse-resistant oral controlled release dosage form of  claim 41 , wherein the HVLCM is sucrose acetate isobutyrate (SAIB). 
     
     
         46 . The abuse-resistant oral controlled release dosage form of  claim 41  further comprising a solvent. 
     
     
         47 . The abuse-resistant oral controlled release dosage form of  claim 46 , wherein the solvent is triacetin. 
     
     
         48 . The abuse-resistant oral controlled release dosage form of  claim 42 , wherein the viscosity enhancing agent is a silicon dioxide. 
     
     
         49 . The abuse-resistant oral controlled release dosage form of  claim 41 , wherein the network former is cellulose acetate butyrate (CAB). 
     
     
         50 . The abuse-resistant oral controlled release dosage form of  claim 41 , wherein the rheology modifier is isopropyl myristate (IPM). 
     
     
         51 . The abuse-resistant controlled release oral dosage form of  claim 41 , wherein the controlled release carrier system provides a decreased risk of misuse or abuse. 
     
     
         52 . The abuse-resistant controlled release oral dosage form of  claim 51 , wherein said decreased risk of misuse or abuse is characterized by a low in vitro solvent extractability value of the methylphenidate from the dosage form. 
     
     
         53 . The abuse-resistant controlled release oral dosage form of  claim 51 , wherein said decreased risk of misuse or abuse is characterized by the absence of any significant effect on absorption of the methylphenidate from the dosage form upon co-ingestion of the dosage form and alcohol by a subject. 
     
     
         54 . The abuse-resistant controlled release oral dosage form of  claim 51 , wherein said decreased risk of misuse or abuse is characterized by a low injectability potential. 
     
     
         55 . The abuse-resistant controlled release oral dosage form of  claim 51 , wherein said dosage form is not susceptible to common forms of abuse comprising injection, inhalation (crushing and sniffing) and volatilization (smoking). 
     
     
         56 . The abuse-resistant controlled release oral dosage form of  claim 41 , wherein the initial increasing-rate phase and subsequent non-ascending phase are sufficient to provide the methylphenidate in vivo PK profile depicted in  FIG. 7  when the dosage form is administered to a subject. 
     
     
         57 . A method of treating Attention Deficit Disorder (ADD) or Attention Deficit Hyperactivity Disorder (ADHD) in a subject, said method comprising administering the abuse-resistant controlled release oral dosage form of  claim 41  to the subject on a once-day (QD) basis.