Parenteral formulations of dopamine agonists

Abstract

This invention relates to stable pharmaceutical compositions for parenteral administration comprising dopamine agonists and peripheral acting agents useful for treatment of metabolic disorders or key elements thereof. The parenteral dosage forms exhibit long stable shelf life and distinct pharmacokinetics.

1 . A stable parenteral dosage form comprising at least one dopamine agonist and a pharmaceutically acceptable excipient, and exhibiting a pharmacokinetic profile comprising:
 a) a T max  at about 1 to about 90 minutes after administration of the parenteral dosage form;   b) a plasma drug concentration plateau of at least 50% C max  for a duration of about 90 to about 360 minutes.   
   
   
       2 . The parenteral dosage form of  claim 1  exhibiting a pharmacokinetic profile wherein at least about 90% of the dopamine agonist is cleared from plasma within about 240 to about 480 minutes of said plasma drug concentration plateau. 
   
   
       3 . The parenteral dosage form of  claim 1  wherein said T max  is about 5 to about 90 minutes after administration of the parenteral dosage form. 
   
   
       4 . The parental dosage form of  claim 1  exhibiting a pharmacokinetic profile wherein said T max  is about 5 to about 90 minutes after administration of the dosage form and said plateau comprises a post-C max  level comprising about one-half C max  within about 30 to about 150 minutes of T max . 
   
   
       5 . The parental dosage form of  claim 1  exhibiting a pharmacokinetic profile wherein said T max  is about 5 to about 90 minutes after administration of the dosage form and said plateau comprises a post-C max  level comprising about one-half C max  within about 90 to about 360 minutes of T max . 
   
   
       6 . The parenteral dosage form of  claim 1  comprising a D 1  dopamine agonist, a D 2  dopamine agonist, or a combination of a D 1  dopamine agonist and a D 2  dopamine agonist. 
   
   
       7 . The parenteral dosage form of  claim 1  wherein said at least one dopamine agonist comprises at least one of an ergot derivative or a non-ergot derivative. 
   
   
       8 . The parenteral dosage form of  claim 6  wherein said D 2  dopamine agonist is selected from the group consisting of bromocriptine, lisuride, terguride, dihydroergotoxine (hydergine), ropinorole, piribedil, apomorphine, quinelorane, talipexole, ergot alkaloid derivatives, and ergoline derivatives. 
   
   
       9 . The parenteral dosage form of  claim 8  wherein said ergot alkaloid derivatives are selected from the group consisting of dihydro-alpha-ergocriptine, dihydro-alpha-ergotoxine, ergocornine, and 9,10-dihydroergocornine. 
   
   
       10 . The parenteral dosage form of  claim 1 , wherein said one or more dopamine agonists comprises bromocriptine. 
   
   
       11 . The parenteral dosage form of  claim 6  wherein said D 1  agonist is selected from the group consisting of dopamine, apomorphine, fenoldapam, SKF38393, SKF 75670, SKF 82957, SKF 81297, SKF 82958, SKF 82598, A77636, A68930, and benzazepine analogs. 
   
   
       12 . The parenteral dosage form of  claim 1  in the form of a nasal, sublingual, buccal, transdermal, or subcutaneous dosage form. 
   
   
       13 . The parenteral dosage form of  claim 1  comprising a total of about 0.02 to about 50.0 mg of said at least one dopamine agonist. 
   
   
       14 . A method of treating a metabolic disorder or key element thereof, comprising administering to a subject in need of such treatment the parenteral dosage form of  claim 1 , to treat said metabolic disorder or key element thereof. 
   
   
       15 . The method of  claim 14  wherein said metabolic disorder or key element thereof is selected from the group consisting of type 2 diabetes, prediabetes, metabolic syndrome, insulin resistance, hyperinsulinemia, cardiovascular disease, obesity, elevated plasma norepinephrine, elevated cardiovascular-related inflammatory factors or potentiators of vascular endothelial dysfunction, hyperlipoproteinemia, atherosclerosis, hyperphagia, hyperglycemia, hyperlipidemia, hypertension, high blood pressure, metabolic syndrome, elevated plasma norepinephrine, elevated cardiovascular-related inflammatory factors, and hypertension. 
   
   
       16 . The method of  claim 14 , wherein said key element is selected from the group consisting of impaired fasting glucose, impaired glucose tolerance, increased waist circumference, increased visceral fat content, increased fasting plasma glucose, increased fasting plasma triglycerides, increased fasting plasma free fatty acids, decreased fasting plasma high density lipoprotein level, increased systolic or diastolic blood pressure, increased plasma postprandial triglyceride or free fatty acid levels, increased cellular oxidative stress or plasma indicators thereof, increased circulating hypercoagulative state, arteriosclerosis, coronary artery disease, peripheral vascular disease, congestive heart failure, renal disease including renal insufficiency, hepatic steatosis and cerebrovascular disease. 
   
   
       17 . The method of  claim 14 , wherein the subject is suffering from at least one condition selected from type 2 diabetes, obesity, prediabetes, metabolic syndrome, and elevated cardiovascular-related inflammatory factors. 
   
   
       18 . The method of  claim 14  which comprises administering said parental dosage form to reduce elevated cardiovascular-related inflammatory factors or cardiovascular disease or key elements of cardiovascular disease. 
   
   
       19 . The method of  claim 14 , wherein the parenteral dosage form is administered as a single daily dose comprising a total of about 0.02 to about 50.0 mg of said at least one dopamine agonist. 
   
   
       20 . The method of  claim 14  wherein the parenteral dosage form is administered at a pre-determined time of day. 
   
   
       21 . The method of  claim 20  wherein said pre-determined time of day is at about the natural daily peak in the circadian rhythm of central dopaminergic neuronal activity in the circadian rhythm of plasma prolactin level in a healthy individual of the same species and sex as said subject in need. 
   
   
       22 . The method of  claim 21 , wherein the parental dosage form is administered from about 0400 to about 1200 hours. 
   
   
       23 . The method of  claim 14 , wherein said dosage form comprises bromocriptine. 
   
   
       24 . A method of reducing elevated plasma norepinephrine levels comprising administering to a subject in need thereof the parenteral dosage form of  claim 1 , to reduce said elevated plasma norepinephrine levels. 
   
   
       25 . The parenteral dosage form of  claim 1  further comprising an anti-hypertensive agent, anti-inflammatory agent, anti-coagulative agent, anti-hypercholesterolemic agent, anti-hypertriglyceridemic agent, anti-hyperglycemic agent or HMGCoA reductase inhibitor. 
   
   
       26 . A method of treating a metabolic disorder or key element thereof, comprising administering to a subject in need of such treatment the parenteral dosage form of  claim 25 , to treat said metabolic disorder or key element thereof. 
   
   
       27 . The method of  claim 26  wherein the parenteral dosage form is administered at a pre-determined time of day. 
   
   
       28 . The method of  claim 27  wherein said pre-determined time of day is at about the natural daily peak in the circadian rhythm of central dopaminergic neuronal activity in the circadian rhythm of plasma prolactin level in a healthy individual of the same species and sex as said subject in need. 
   
   
       29 . The method of  claim 28 , wherein the parental dosage form is administered from about 0400 to about 1200 hours. 
   
   
       30 . The method of  claim 25 , wherein said dosage form comprises bromocriptine. 
   
   
       31 . A sublingual tablet dosage form comprising by weight:
 0.5-20% active agent,   3-50% release matrix,   0.5-10% glidant,   a solubility enhancer in an amount up to 70%,   a bioadhesion enhancer in an amount up to 25%,   a permeation enhancer in an amount up to 30%,   a disintegrant in an amount up to 95%,   a filler in an amount up to 95%, and   an effervescent in an amount up to 65%.   
   
   
       32 . The sublingual tablet dosage form of  claim 31 , comprising by weight:
 0.5-10% active agent,   3-20% release matrix,   0.5-5% glidant,   a solubility enhancer in an amount up to 30%,   a bioadhesion enhancer in an amount up to 10%,   a permeation enhancer in an amount up to 20%,   a disintegrant in an amount up to 85%,   a filler in an amount up to 80%, and   a effervescent in an amount up to 45%.   
   
   
       33 . The sublingual tablet dosage form of  claim 31 , comprising by weight:
 0.5-5% active agent,   7-15% release matrix,   0.5-2.5% glidant,   2-20% solubility enhancer,   2-8% bioadhesion enhancer,   a permeation enhancer in an amount up to 15%,   a disintegrant in an amount up to 82%,   a filler in an amount up to 75%, and   an effervescent in an amount up to 45%.   
   
   
       34 . The sublingual tablet dosage form of  claim 31 , wherein the dosage form comprises by weight:
 0.5-5% dopamine agonist,   2-15% polyvinylpyrrolidone,   3-20% hydroxypropylmethylcellulose,   3-25% sodium starch glycolate and sodium carboxymethyl starch,   3-25% ProSolv,   0.5-10% citric acid,   0.5-5% steric acid,   40-80% mannitol, and   optionally 5-30% cyclodextrin type molecules.   
   
   
       35 . The sublingual tablet dosage form of  claim 31 , wherein the dosage form comprises by weight:
 0.5-4.5% dopamine agonist,   2-6.5% polyvinylpyrrolidone,   3-10% hydroxypropylmethylcellulose,   1-6% citric acid,   0.5-5% steric acid,   60-90% Pharmaburst, and   optionally 5-30% cyclodextrin type molecules.   
   
   
       36 . The sublingual tablet dosage form of  claim 31 , wherein the dosage form comprises by weight:
 1-6% dopamine agonist,   2-10% polyvinylpyrrolidone,   3-10% hydroxypropylmethylcellulose,   1-10% citric acid,   0.5-5% steric acid,   60-90% Pharmaburst, and   optionally 5-30% cyclodextrin type molecules.   
   
   
       37 . The sublingual tablet dosage form of  claim 31 , wherein the dosage form comprises by weight:
 0.5-5.0% dopamine agonist,   5-25% polyvinylpyrrolidone,   5-35% hydroxypropylmethylcellulose,   10-40% citric acid,   0.5-5% steric acid,   3-25% Pharmaburst, and   10-65% sodium bicarbonate.   
   
   
       38 . A transdermal gel dosage form comprising by weight:
 1-3% active agent,   5-95% solvents,   1-30% thickener,   0.5-10% stabilizer, and   a bioadhesive in an amount up to 35%.   
   
   
       39 . The transdermal gel dosage form of  claim 38 , wherein the dosage form comprises by weight:
 0.5-10% dopamine agonist,   5-40% polyethylene glycol,   45-85% glycerol,   3-25% silica, and   0.5-5% citric acid.   
   
   
       40 . The transdermal gel dosage form of  claim 38 , wherein the dosage form comprises by weight:
 0.5-10% dopamine agonist,   5-40% polyethylene glycol,   45-85% glycerol,   3-25% silica,   0.5-5% citric acid,   1-15% hydroxypropylmethylcellulose,   0.5-15% polyvinylpyrrolidone.   
   
   
       41 . A transmucosal film dosage form comprising by weight:
 5-20% active agent,   1-10% film forming agent,   5-20% stabilizing enhancer,   10-95% bioadhesion enhancers,   0-50% solubility enhancers, and   optionally 1-10% oleic acid.   
   
   
       42 . The transmucosal film dosage form of  claim 41 , wherein the dosage form comprises by weight:
 2-20% dopamine agonist,   10-55% Kollidon 90F,   0.5-10% Kollidon VA64,   0.3-5% polyethylene glycol,   10-55% hydroxypropylcellulose,   0.5-10% glycerol,   3-30% cyclodextrin,   2-20% citric acid, and   optionally 1-5% oleic acid.   
   
   
       43 . A subcutaneous dosage form comprising by weight:
 0.01-0.10% active agent,   5-20% emulsifying agent, and   80-95% oil.   
   
   
       44 . The subcutaneous dosage form of  claim 43 , wherein the dosage form comprises by weight:
 0.01-0.1% bromocriptine,   5-10% polysorbate 80, and   90-95% sesame seed oil.   
   
   
       45 . The dosage form of any of  claims 31 - 33 ,  38 ,  41 , or  43 , wherein the active agent is one or more dopamine agonists. 
   
   
       46 . (canceled) 
   
   
       47 . (canceled) 
   
   
       48 . The dosage form of any of  claims 31 - 44 , further comprising a cholesterol-lowering agent or an anti-hypertensive agent. 
   
   
       49 . (canceled) 
   
   
       50 . (canceled) 
   
   
       51 . (canceled) 
   
   
       52 . A method of treating a metabolic disorder or key element thereof, comprising administering to a subject in need of such treatment the dosage form of any of  claims 31 - 44 , to treat said metabolic disorder or key element thereof. 
   
   
       53 - 62 . (canceled)