Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions

Abstract

Disclosed are methods of intravenous administration of nanoparticulate drug formulations to a mammal to avoid adverse hemodynamic effects: by reducing the rate and concentration of the nanoparticles in the formulations; or by pre-treating the subject with histamine; or by pretreating the subject with a desensitizing amount of the nanoparticulate drug formulations.

1. A method of administering a nanoparticulate composition to a mammal without eliciting adverse hemodynamic effects comprising intravenously administering to said mammal an effective amount of a nanoparticulate drug composition at an infusion rate not exceeding  a solids dose rate of less than 10 mg/min, wherein said drug composition comprises:
 (a) particles consisting essentially of from about 0.1 to about 99.9% by weight of a crystalline organic drug substance having a solubility in water of less than 10 mg/ml;  
 (b) a surface modifier adsorbed on the surface of the drug substance in an amount of from about 0.1 to about 99.9% by weight and sufficient to maintain an effective average particle size of from about 50 nm to about 1000 nm; and  
 (c) a pharmaceutically acceptable carrier therefor.  
 
     
     
       2. The method of  claim 1  wherein the effective average particle size of said drug is from about 50 to about 400 nm. 
     
     
       3. The method of  claim 1  wherein said drug is an organic therapeutic substance. 
     
     
       4. The method of  claim 1  wherein said drug is a diagnostic agent. 
     
     
       5. A method of administering a nanoparticulate composition to a mammal without eliciting adverse hemodynamic effects comprising:
 (a) intravenously administering to said mammal an antihistamine in the amount of from about 5 to about 10 mg/kg of body weight; and  
 (b) subsequently intravenously administering to said mammal an effective amount of a nanoparticulate drug composition comprising: (1) particles consisting essentially of from about 0.1 to about 99.9% by weight of a crystalline drug substance having a solubility in water of less than 10 mg/ml; and (b  2 ) a surface modifier adsorbed on the surface of the drug substance in an amount of from about 99.9 to about 0.1% by weight and sufficient to maintain an effective average particle size of less than about 1000 nm.  
 
     
     
       6. The method of  claim 5  wherein the effective average particle size of said drug is of  from about 50 to about 400 nm. 
     
     
       7. The method of  claim 5  wherein said drug is an organic therapeutic substance. 
     
     
       8. The method of  claim 5  wherein said drug is a diagnostic agent. 
     
     
       9. A method of administering a nanoparticulate composition to a mammal without eliciting adverse hemodynamic effects comprising:
 (a) intravenously administering to said mammal a desensitizing amount of a nanoparticulate drug composition at an infusion rate not exceeding  a solids dose rate of less than 10 mg/min; and  
 (b) intravenously administering an effective amount of said nanoparticulate composition comprising: (1) particles consisting essentially of from about 0.1 to about 99.9% by weight of a crystalline organic drug substance having a solubility in water of less than 10 mg/ml; (2) a surface modifier adsorbed on the surface of the drug substance in an amount sufficient to maintain an effective average particle size of from about 100 to about 1000 nm; and (3) a pharmaceutically acceptable carrier therefor.  
 
     
     
       10. The method of  claim 9  wherein said drug is an organic therapeutic substance. 
     
     
       11. The method of  claim 9  wherein said drug is a diagnostic agent. 
     
     
       12. The method of  claim 9  wherein the effective average particle size of said drug is of  from about 100 to about 400 nm. 
     
     
       13. A method of administering a nanoparticulate composition to a mammal without eliciting adverse hemodynamic effects comprising intravenously administering to said mammal an effective amount of a nanoparticulate drug composition at an infusion rate not exceeding  a solids dose rate of less than 10 mg/min, wherein said drug composition comprises:
 (a) particles having an effective average particle size of from about 50 to about 1000 nm and consisting essentially of from about 0.1 to about 99.9% by weight of an organic drug substance entrapped in from about 99.9 to about 0.1% by weight of liposome or a colloidal polymeric material; and  
 (b) a pharmaceutically acceptable carrier therefor.  
 
     
     
       14. The method of  claim 13  wherein the effective average particle size of said drug is of  from about 50 to about 400 nm. 
     
     
       15. The method of  claim 13  wherein said drug is an organic therapeutic substance. 
     
     
       16. The method of  claim 13  wherein said drug is a diagnostic agent. 
     
     
       17. A method of administering a nanoparticulate composition to a mammal without eliciting adverse hemodynamic effects comprising:
 (a) intravenously administering to said mammal an antihistamine in the amount of from about 5 to about 10 mg/kg of body weight; and  
 (b) subsequently intravenously administering to said mammal an effective amount of a nanoparticulate drug composition comprising: (1) particles having an effective average particle size of from about 50 to bout  about 1000 nm and consisting essentially of from about 0.1 to about 99.9% by weight of an organic drug substance entrapped in from about 99.9 to about 0.1% by weight of liposome or a colloidal polymeric material; and (2) a pharmaceutically acceptable carrier therefor.  
 
     
     
       18. The method of  claim 17  wherein the effective average particle size of said drug is of  from about 50 to about 400 nm. 
     
     
       19. The method of  claim 17  wherein said drug is an organic therapeutic substance. 
     
     
       20. The method of  claim 17  wherein said drug is a diagnostic agent. 
     
     
       21. The method of  claim 13  wherein the organic drug substance is in crystalline phase.  
     
     
       22. The method of  claim 17  wherein the organic drug substance is in crystalline phase.  
     
     
       23. The method of  claim 1  wherein the solids dose rate is  5  mg/min.  
     
     
       24. The method of  claim 9  wherein the solids dose rate is  5  mg/min.  
     
     
       25. The method of  claim 13  wherein the solids dose rate is  5  mg/min.  
     
     
       26. The method of  claim 1  wherein said drug is selected from the group consisting of anti- inflammatory agents, anti - arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobactehal agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, beta - adrenoceptor blocking agents, cardiac inotropic agents, contrast media, corticosteroids, dopaminergics, haemostatics, lipid regulation agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates prostaglandins, anti - allergic agents, anoretics, thyroid agents, vasodilators and xanthines.    
     
     
       27. The method of  claim 5  wherein said drug is selected from the group consisting of anti- inflammatory agents, anti - arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobactehal agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, beta - adrenoceptor blocking agents, cardiac inotropic agents, contrast media, corticosteroids, dopaminergics, haemostatics, lipid regulation agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates prostaglandins, anti - allergic agents, anoretics, thyroid agents, vasodilators and xanthines.    
     
     
       28. The method of  claim 9  wherein said drug is selected from the group consisting of anti- inflammatory agents, anti - arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, beta - adrenoceptor blocking agents, cardiac inotropic agents, contrast media, corticosteroids, dopaminergics, haemostatics, lipid regulation agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, anti - allergic agents, anoretics, thyroid agents, vasodilators and xanthines.    
     
     
       29. The method of  claim 13  wherein said drug is selected from the group consisting of anti- inflammatory agents, anti - arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, beta - adrenoceptor blocking agents, cardiac inotropic agents, contrast media, corticosteroids, dopaminergics, haemostatics, lipid regulation agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, anti - allergic agents, anoretics, thyroid agents, vasodilators and xanthines.    
     
     
       30. The method of  claim 17  wherein said drug is selected from the group consisting of anti- inflammatory agents, anti - arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, beta - adrenoceptor blocking agents, cardiac inotropic agents, contrast media, corticosteroids, dopaminergics, haemostatics, lipid regulation agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, anti - allergic agents, anoretics, thyroid agents, vasodilators and xanthines.    
     
     
       31. The method of  claim 26  wherein said drug is selected from the group consisting of antibiotics, antimicrobials, antineoplastics and immunosuppresants.  
     
     
       32. The method of  claim 27  wherein said drug is selected from the group consisting of antibiotics, antimicrobials, antineoplastics and immunosuppresants. 
     
     
       33. The method of  claim 28  wherein said drug is selected from the group consisting of antibiotics, antimicrobials, antineoplastics and immunosuppresants. 
     
     
       34. The method of  claim 29  wherein said drug is selected from the group consisting of antibiotics, antimicrobials, antineoplastics and immunosuppresants. 
     
     
       35. The method of  claim 30  wherein said drug is selected from the group consisting of antibiotics, antimicrobials, antineoplastics and immunosuppresants.