Sustained release pharmaceutical dosage forms with minimized ph dependent dissolution profiles

Abstract

A pharmaceutical composition comprising at least one pharmaceutically active agent that is pH dependent, at least one non-pH dependent sustained release agent, and at least one pH dependent agent that increases the dissolution rate of the at least one pharmaceutically active agent at a pH in excess of 5.5. Such compositions have minimized pH-dependent dissolution profiles or pH-independent dissolution profiles.

What is claimed is:  
     
         1 . A pharmaceutical composition, comprising: 
 (a) at least one pharmaceutically active agent that is pH dependent:    (b) at least one non-pH dependent sustained release agent; and    (c) at least one pH dependent agent that increases the rate of release of said at least one pharmaceutically active agent from the tablet at a pH in excess of 5.5.    
     
     
         2 . The composition of  claim 1  wherein said at least one pH dependent agent is at least one polymer that swells at a pH in excess of 5.5.  
     
     
         3 . The composition of  claim 1  wherein said at least one pH dependent agent is at least one enteric agent.  
     
     
         4 . The composition of  claim 1  wherein said at least one pH dependent agent is at least one agent that increases the solubility of said at least one pharmaceutically active agent at a pH of greater than 5.5.  
     
     
         5 . The composition of  claim 1  wherein said at least one pharmaceutically active agent is selected from the group consisting of guanfacine, anagrelide, guanethidine monosulfate, quanadrel sulfate, resirpine, propanolol, metoprolol, atenolol, timolol, erythromycin, clonidine, chlorpheniramine, bromopheniramine, diltiazem, and scopolamine.  
     
     
         6 . The composition of  claim 5  wherein said at least one pharmaceutically active agent guanfacine.  
     
     
         7 . The composition of  claim 5  wherein said at least one pharmaceutically active agent guanfacine hydrochloride.  
     
     
         8 . The composition of  claim 5  wherein said at least one pharmaceutically active agent is anagrelide.  
     
     
         9 . The composition of  claim 5  wherein said at least one pharmaceutically active agent is anagrelide hydrochloride.  
     
     
         10 . The composition of  claim 1  wherein said non-pH dependent sustained release agent is selected from the group consisting of ethylcellulose, cellulose acetate, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate copolymers, polyethylene oxide, hydroxypropyl methylcellulose, carageenan, alginic acid and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, acacia gum, trgacanth gum, locust bean gum, guar gum, sodium carboxymethyl cellulose, methyl cellulose, beeswax, carnauba wax, cetyl alcohol, hydrogenated vegetable oils, and stearyl alcohol.  
     
     
         11 . The composition of  claim 2  wherein said at least one polymer that swells at a pH in excess of 5.5 is selected from the group consisting of acrylic acid copolymers, sodium alginate, carrageenan, alginic acid, pectin, and sodium carboxymethyl cellulose.  
     
     
         12 . The composition of  claim 3  wherein said at least one enteric agent is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polvinyl acetate phthalate, methacrylic acid copolymers, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate, succinate, shellac, and zein.  
     
     
         13 . The composition of  claim 4  wherein said at least one agent that increase the solubility of said at least one pharmaceutically active agent at a pH greater than 5.5 is at least one organic acid.  
     
     
         14 . The composition of  claim 13  wherein said at least one organic acid is selected from the group consisting of citric acid, fumaric acid, tartaric acid, adipic acid, glucono delta-lactone, and malic acid.  
     
     
         15 . The composition of claim I wherein said pH-dependent agent that increases the rate of release of the at least one pharmaceutically active agent from the tablet at a pH in excess of 5.5 is an agent that maintains an acidic microenvironment in the composition.  
     
     
         16 . The composition of  claim 14  wherein said organic acid is fumaric acid.  
     
     
         17 . The composition of  claim 1  and further comprising a binding agent.  
     
     
         18 . The composition of  claim 17  wherein said binding agent is selected from the group consisting of polyvinyl pyrrolidone, starch, methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sucrose solution, dextrose solution, acacia, tragacanth, and locust bean gum.  
     
     
         19 . The composition of  claim 18  wherein said binder is hydroxypropyl methylcellulose.  
     
     
         20 . The composition of  claim 1  wherein said pharmaceutically active agent is present in the composition in an amount of from about 0.1 wt. % to about 70 wt. %.  
     
     
         21 . The composition of  claim 20  wherein said pharmaceutically active agent is present in the composition in an amount of from about 1 wt. % to about 40 wt. %.  
     
     
         22 . The composition of  claim 1  wherein said non-pH-dependent sustained release agent is present in the composition in an amount of from about 5 wt. % to about 50 wt. %.  
     
     
         23 . The composition of  claim 22  wherein said non-pH-dependent sustained release agent is present in the composition in an amount of from about 10 wt. % to about 30 wt. %.  
     
     
         24 . The composition of  claim 1  wherein said at least one pH-dependent agent is present in the composition in an amount of from about 0.5 wt. % to about 40 wt. %.  
     
     
         25 . The composition of  claim 24  wherein said at least one pH-dependent agent is present in the composition in an amount of from about 1 wt. % to about 20 wt. %.  
     
     
         26 . The composition of  claim 10  wherein said non-pH-dependent sustained release agent is ethyl cellulose.  
     
     
         27 . The composition of  claim 10  wherein said non-pH-dependent sustained release agent is hydroxypropyl methylcellulose.  
     
     
         28 . The composition of  claim 10  wherein said non-pH-dependent sustained release agent is an acrylate/methacrylate copolymer.  
     
     
         29 . The composition of  claim 10  wherein said non-pH-dependent sustained release agent is polyethylene oxide.  
     
     
         30 . The composition of  claim 11  wherein said at least one polymer that swells at a pH in excess of 5.5 is sodium alginate.  
     
     
         31 . The composition of  claim 12  wherein said at least one enteric agent is a methacrylic acid copolymer.  
     
     
         32 . The composition of  claim 1  wherein said composition is in the form of a tablet.  
     
     
         33 . The composition of  claim 6  or  7  wherein said non-pH-dependent sustained release agent is selected from the group consisting of ethylcellulose, cellulose acetate, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate copolymers, polyethylene oxide, hydroxypropyl methylcellulose, carrageenan, alginic acid and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium carboxymethyl cellulose, methyl cellulose, beeswax, carnauba wax, cetyl alcohol, hydrogenated vegetable oils, and stearyl alcohol.  
     
     
         34 . The composition of  claim 6  or  7  wherein said at least one pH-dependent agent is at least one polymer that swells at a pH in excess of 5.5.  
     
     
         35 . The composition of  claim 34  wherein said at least one polymer that swells at a pH in excess of 5.5 is selected from the group consisting of acrylic acid copolymers, sodium alginate, carrageenan, alginic acid, pectin, and sodium carboxymethyl cellulose.  
     
     
         36 . The composition of  claim 6  or  7  wherein said at least one pH-dependent agent is at least one enteric agent.  
     
     
         37 . The composition of  claim 36  wherein said at least one enteric agent is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate, succinate, shellac, and zein.  
     
     
         38 . The composition of  claim 8  or  9  wherein said non-pH-dependent sustained release agent is selected from the group consisting of ethylcellulose, cellulose acetate, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate copolymers, polyethylene oxide, hydroxypropyl methylcellulose, carageenan, alginic acid and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium carboxymethyl cellulose, methylcellulose, beeswax, carnauba wax, cetyl alcohol, hydrogenated vegetable oils, and stearyl alcohol.  
     
     
         39 . The composition of  claim 38  wherein said non-pH-dependent sustained release agent is polyethylene oxide.  
     
     
         40 . The composition of  claim 8  or  9  wherein said at least one pH-dependent agent is at least one enteric agent.  
     
     
         41 . The composition of  claim 40  wherein said at least one enteric agent is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate, succinate, shellac, and zein.  
     
     
         42 . The composition of  claim 41  wherein said at least one enteric agent is a methacrylic acid copolymer.  
     
     
         43 . The composition of  claim 8  or  9  and further comprising a bulking agent.  
     
     
         44 . The composition of  claim 43  wherein said bulking agent is dibasic calcium phosphate.  
     
     
         45 . The composition of  claim 43  wherein said bulking agent is microcrystalline cellulose.  
     
     
         46 . The composition of  claim 8  or  9  and further comprising a lubricant.  
     
     
         47 . The composition of  claim 46  wherein said lubricant is glyceryl behenate.  
     
     
         48 . The composition of  claim 46  wherein said lubricant is magnesium stearate.  
     
     
         49 . A pharmaceutical composition, comprising: 
 (a) anagrelide;    (b) polyethylene oxide;    (c) dibasic calcium phosphate;    (d) microcrystalline cellulose;    (e) a methacrylic acid copolymer;    (f) glyceryl behenate; and    (g) magnesium stearate.    
     
     
         50 . A pharmaceutical composition, comprising: 
 (h) Anagrelide hydrochloride;    (i) polyethylene oxide;    (j) dibasic calcium phosphate;    (k) microcrystalline cellulose;    (l) a methacrylic acid copolymer;    (m) glyceryl behenate; and    (n) magnesium stearate.    
     
     
         51 . A method of treating a myeloproliferative blood disorder in a patient, comprising: administering to said patient the composition of anyone of  claims 8  to  50  in an amount effective to treat said myeloproliferative blood disorder in said patient.  
     
     
         52 . The method of  claim 51  wherein said myeloproliferative blood disorder is essential thrombocythemia.  
     
     
         53 . The method of  claim 51  wherein said myeloproliferative blood disorder is chronic myelogenous leukemia.  
     
     
         54 . The method of  claim 51  wherein said myeloproliferative blood disorder is polycythemia vera.  
     
     
         55 . The method of  claim 51  wherein said myeloproliferative blood disorder is agnogenic myeloid metaplasia.  
     
     
         56 . The method of  claim 51  wherein the amount of the active ingredient anagrelide is about 0.01 mg to about 15 mg.  
     
     
         57 . The method of  claim 51  wherein the amount of the active ingredient anagrelide is about 0.1 mg to about 10 mg.  
     
     
         58 . The method of  claim 51  wherein the amount of the active ingredient anagrelide is about 0.1 mg to about 5 mg.  
     
     
         59 . The method of  claim 51  wherein the amount of the active ingredient anagrelide is about 0.5mg to about 2 mg.  
     
     
         60 . A pharmaceutical composition comprising anagrelide as an active agent and characterized in that said composition when administered to a patient produces less of the side effects usually associated with anagrelide.  
     
     
         61 . The pharmaceutical composition of  claim 60  wherein said side effects are chosen from Headache, Asthenia, Somnolence, Dizziness, Tacchycardia, Nausea, Pain Abdominal, Vomit, Infect or Palpitations.  
     
     
         62 . The pharmaceutical composition of  claim 61  wherein said side effects are chosen from Headache and Asthenia.  
     
     
         63 . The pharmaceutical composition of  claim 61  wherein said side effect is Headache.  
     
     
         64 . The pharmaceutical composition of  claim 61  wherein said side effect is Asthenia.  
     
     
         65 . A method of reducing the likelihood of side effects associated with the administration of anagrelide, comprising administering to a patient a therapeutically effective amount of a composition as defined in anyone of  claims 8  to  50 .  
     
     
         66 . The method of  claim 65  wherein said side effects are chosen from Headache, Asthenia, Somnolence, Dizziness, Tacchycardia, Nausea, Pain Abdominal, Vomit, Infect, or Palpitations.  
     
     
         67 . The method of  claim 65  wherein said side effects are chosen from Headache and Asthenia.  
     
     
         68 . The method of  claim 65  wherein said side effect is Headache.  
     
     
         69 . The method of  claim 65  wherein said side effect is Asthenia  
     
     
         70 . A pharmaceutical composition, comprising: 
 (a) guanfacine;    (b) Hydroxypropyl Methylcellulose    (c) Ammonio Methacrylate Copolymer    (d) microcrystalline cellulose;    (e) a methacrylic acid copolymer;    (f) glyceryl behenate; and    (g) Fumaric Acid,    (h) Lactose Monohydrate    (i) Povidone; and    (j) Crospovidone Granulated Blend.    
     
     
         71 . A pharmaceutical composition comprising: 
 (a) Guanfacine hydrochloride;    (b) Hydroxypropyl Methylcellulose    (c) Ammonio Methacrylate Copolymer    (d) microcrystalline cellulose;    (e) a methacrylic acid copolymer;    (f) glyceryl behenate; and    (g) Fumaric Acid,    (h) Lactose Monohydrate    (i) Povidone; and    (j) Crospovidone Granulated Blend.    
     
     
         72 . A method of treating an attention deficit disorder or attention deficit with hyperactivity disorder in a patient, comprising administering to said patient the composition of  claim 6  or  7  in an amount effective to treat said attention deficit disorder or attention deficit with hyperactivity disorder in said patient.  
     
     
         73 . A method of reducing the likelihood of side effects associated with the administration of guanfacine, comprising administering to a patient a therapeutically effective amount of the composition of  claim 6  or  7