Pharmaceutical delivery system

Abstract

A pharmaceutical formulation to treat vaginal conditions in a human patient comprises: at least one active agent; a modified release dosage form which provides extended release of the anti-infective agent upon vaginal administration to the patient; and wherein the formulation, when containing a total dose of the anti-infective agent of about 25 μg to about 500 mg based on the active agent will produce a plasma concentration versus time curve (ng/mL versus hours) having an area under the curve (AUC) of less than about 600 ng/mL.hr.

1 . A pharmaceutical formulation to treat vaginal conditions in a human patient comprising: 
 an effective amount of at least one active agent;    a modified release dosage form which provides modified release of said active agent or agents upon vaginal administration to said patient; and    wherein said formulation, when containing a total dose of each active agent of about 25 μg to about 500 mg based on said active agent will produce a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) of less than about 600 ng./mL.hr; and    wherein the at least one active agent is selected from the group consisting of antibacterial agents, antiviral agents, spermicides, hormone agents, growth enhancing agents, cytokines, antitrichomonial agents, antiprotozoan agents, antimycoplasm agents, antiretroviral agents, nucleoside analogues, reverse transcriptase inhibitors, protease inhibitors, contraceptive agents, sulfadrugs, sulfonamides, sulfones, hygiene agents, probiotic agents, vaccine agents, antibody agents, peptide agents, protein agents, polysaccharide agents, nucleic acids, plasmids, liposomes, carbohydrate polymers, transgenic bacteria, yeast, chemotherapeutic agents, steroid agents, growth enhancing agents, libido enhancers, androgenic substances, chitin derivatives, environment modifying agents such as pH modifiers, and mixtures and combinations thereof.    
     
     
         2 . The pharmaceutical formulation as recited in  claim 1 , wherein said formulation when containing an antimicrobial agent as the active agent, and when containing a total dose of said antimicrobial agent of about 100 mg, will produce a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) between about 25 to about 350 ng/mL.hr.  
     
     
         3 . The pharmaceutical formulation as recited in  claim 1 , wherein said dosage form is comprised of: 
 a. an emulsion comprising at least two phases, one phase comprises an external lipoidal phase and the other phase comprising an internal non-lipoidal phase wherein said lipoidal phases is continuous and the said non-lipoidal phase comprises at least 70% by volume of said emulsion;    b. one or more primary stabilizing surfactants selected from the group consisting of phospholipid, non-ionic ester and mixtures thereof; and    c. when said stabilizing surfactants is a phospholipid then one or more auxiliary stabilizing surfactants are added and when said stabilizing surfactants is non-ionic ester then optionally one or more auxiliary stabilizing surfactants are added.    
     
     
         4 . The pharmaceutical formulation as recited in  claim 1 , wherein said active agent is an antimicrobial agent selected from the group consisting of clindamycin, clindamycin phospate, clindamycin hydrochloride, salts thereof, complexes of clindamycin base and mixtures thereof.  
     
     
         5 . The pharmaceutical formulation as recited in  claim 4 , wherein said antimicrobial agent is clindamycin phosphate.  
     
     
         6 . The pharmaceutical formulation as recited in  claim 4 , wherein said antimicrobial agent is present in an amount of less than about 5% weight/weight based on said clindamycin.  
     
     
         7 . The pharmaceutical formulation as recited in  claim 4 , wherein said antimicrobial agent is present in an amount equal to or less than about 2% weight/weight based on said clindamycin.  
     
     
         8 . The pharmaceutical formulation as recited in  claim 4 , wherein said antimicrobial agent is present in an amount equal to or less than about 1% weight/weight based on said clindamycin.  
     
     
         9 . The pharmaceutical formulation as recited in claims  1 ,  3  or  4 , wherein said active agent has properties of a surface active agent.  
     
     
         10 . The pharmaceutical formulation as recited in  claim 9  wherein said surface active agent is selected from the group consisting of Erythromycin, Clarithromycin, Azithromycin, Penicillins, Cephalosporins, Bacitracins, Polymyxins, Metronidazoles and Streptomycins.  
     
     
         11 . The pharmaceutical formulation as recited in  claim 1  having at least one anti-bacterial agent and further comprising and antifungal agent.  
     
     
         12 . The pharmaceutical formulation as recited in  claim 1 ,  3 ,  4  or  10  further comprised of an acid buffered phase.  
     
     
         13 . The pharmaceutical formulation as recited in  claim 12  wherein said acid buffer phase is isotonic, hypertonic or hypotonic.  
     
     
         14 . The pharmaceutical formulation as recited in  claim 12  wherein said acid buffered phase is hypertonic.  
     
     
         15 . The pharmaceutical formulation as recited in  claim 12  wherein said acid buffered phase comprises a member selected from the group consisting of a weak acid and it's conjugate base, citric acid, acetic acid, a salt of citric acid or acetic acid and mixtures thereof.  
     
     
         16 . The pharmaceutical formulation as recited in  claim 12 , wherein said pharmaceutical formulation has a pH between about 3 and about 6.  
     
     
         17 . The pharmaceutical formulation as recited in  claim 16 , wherein said pharmaceutical formulation has a pH between about 4 and about 5.  
     
     
         18 . The pharmaceutical formulation as recited in claims  16  or  17 , wherein said pharmaceutical formulation has a pH of about 4.5.  
     
     
         19 . The pharmaceutical formulation as recited in  claim 12  wherein said pharmaceutical formulation has a pH of about 4.5.  
     
     
         20 . The pharmaceutical formulation as recited in  claim 1 , wherein said plasma concentration versus time curve has a maximum concentration (Cmax) of about 0.4 to about 100 ng/mL.  
     
     
         21 . The pharmaceutical formulation as recited in  claim 20 , wherein the time to reach said Cmax is about 0.5 to about 90 hours.  
     
     
         22 . The pharmaceutical formulation as recited in  claim 21 , wherein said time is about 20 to about 30 hours.  
     
     
         23 . The pharmaceutical formulation as recited in  claim 22 , wherein said time is an average time of about 26 hours.  
     
     
         24 . The pharmaceutical formulation as recited in  claim 1 ,  2 , or  21  wherein said active agent will produce plasma concentration versus time curve of less than about 10 ng/mL.  
     
     
         25 . The pharmaceutical formulation as recited in  claim 3 , wherein said phospholipid is selected from the group consisting of lecithin, refined lecithin and mixtures thereof.  
     
     
         26 . The pharmaceutical formulation as recited in claims  3  or  25  wherein said primary stabilizing surfactant contains less than about 95% phosphatidylcholine.  
     
     
         27 . The pharmaceutical formulation as recited in claims  3  or  25  wherein said primary stabilizing surfactant contains about 90% phosphatidylcholine.  
     
     
         28 . The pharmaceutical formulation as recited in  claim 3 , wherein said auxliary stabilizing surfactants are selected from the group consisting of polyglycerol-3-oleate, glycerol monoisostearate and mixtures thereof.  
     
     
         29 . The pharmaceutical formulation as recited in claims  3  or  28 , wherein said auxiliary stabilizing surfactants are present in said pharmaceutical formulation in amounts of about 2 to 15% weight/weight.  
     
     
         30 . The pharmaceutical formulation as recited in claims  1 ,  2 ,  4  or  10  wherein said formulation affects treatment of said vaginal condition in a single dose.  
     
     
         31 . The pharmaceutical formulation as recited in claims  1 ,  2 ,  4  or  10  wherein said formulation affects treatment of said vaginal condition in multiple doses.  
     
     
         32 . The pharmaceutical formulation as recited in claims  1 ,  2 ,  4  or  10  wherein said active agent is released from said pharmaceutical formulation for extended periods of time.  
     
     
         33 . A pharmaceutical formulation comprising: 
 a. an active pharmaceutical having surfactant properties;    b. an emulsion comprising at least two phases, one phase comprises an external lipoidal phase and the other phase comprising an internal non-lipoidal phase wherein said lipoidal phases is continuous and the said non-lipoidal phase comprises at least 70% by volume of said emulsion;    c. one or more primary stabilizing surfactants selected from the group consisting of phospholipid, non-ionic ester and mixtures thereof; and    d. when said stabilizing surfactants is a phospholipid then one or more auxiliary stabilizing surfactants are added and when said stabilizing surfactants is a non-ionic ester then optionally one or more auxiliary stabilizing surfactants are added.    
     
     
         34 . The pharmaceutical formulation of  claim 33  wherein said active pharmaceutical is selected from the group consisting of antifungal agents, antibacterial agents, antimicrobial agents, antiviral agents, spermicides, hormone agents, growth enhancing agents, cytokines, antitrichomonial agents, antiprotozoan agents, antimycoplasm agents, antiretroviral agents, nucleoside analogues, reverse transcriptase inhibitors, protease inhibitors, contraceptive agents, sulfadrugs, sulfonamides, sulfones, hygiene agents, probiotic agents, vaccine agents, antibody agents, peptide agents, protein agents, polysaccharide agents, nucleic acids, plasmids, liposomes, carbohydrate polymers, transgenic bacteria, yeast, chemotherapeutic agents, steroid agents, growth enhancing agents, libido enhancers, androgenic substances, chitin derivatives, environment modifying agents such as pH modifiers, and mixtures and combinations thereof.  
     
     
         35 . The pharmaceutical formulation as recited in  claim 34 , wherein said active agent is an antimicrobial agent.  
     
     
         36 . The pharmaceutical formulation as recited in  claim 35  wherein said antimicrobial agent is selected from the group consisting of clindamycin, clindamycin phospate, clindamycin hydrochloride, salts thereof, complexes of clindamycin base and mixtures thereof.  
     
     
         37 . The pharmaceutical formulation as recited in  claim 36 , wherein said antimicrobial agent is clindamycin phosphate.  
     
     
         38 . The pharmaceutical formulation as recited in  claim 35 , wherein said antimicrobial agent is present in an amount of less than about 5% weight based on clindamycin.  
     
     
         39 . The pharmaceutical formulation as recited in  claim 38 , wherein said antimicrobial agent is present in an amount of less than about 2% weight based on clindamycin.  
     
     
         40 . The pharmaceutical formulation as recited in  claim 33  or  37  wherein the active agent will produce a plasma concentration versus time curve of less than 50 ng/mL.  
     
     
         41 . The pharmaceutical formulation as recited in claims  33 ,  35  or  37 , wherein said active agent is a surface active agent.  
     
     
         42 . The pharmaceutical formulation as recited in claims  33 , wherein said pharmaceutically acceptable carrier is further comprised of an acid buffered phase, which is isotonic, hypertonic or hypotonic.  
     
     
         43 . The pharmaceutical formulation as recited in  claim 42 , wherein said buffered phase comprises a member selected from the group consisting of a salt of citric acid, an ester of citric acid, acetic acid, a salt of citric acid or acetic acid, an ester of acetic acid and mixtures thereof.  
     
     
         44 . The pharmaceutical formulation as recited in  claim 33  or  42 , wherein the active agent is metronidazole.  
     
     
         45 . The pharmaceutical formulation as recited in  claim 44 , wherein the pharmaceutical formulation has a pH of about 4.5.  
     
     
         46 . The pharmaceutical formulation as recited in  claim 42 , wherein the pharmaceutical formulation has a pH between about 3 and about 6.  
     
     
         47 . The pharmaceutical formulation as recited in  claim 46 , wherein the pharmaceutical formulation has a pH between about 4 and about 5.  
     
     
         48 . The pharmaceutical formulation as recited in claims  42  or  47 , wherein the pharmaceutical formulation has a pH of about 4.5.  
     
     
         49 . The pharmaceutical formulation as recited in  claim 33 , wherein the plasma concentration versus time curve has a maximum concentration (Cmax) of about 0.4 to about 100 ng/mL.  
     
     
         50 . The pharmaceutical formulation as recited in  claim 49 , wherein the time to reach said Cmax is about 0.5 to about 90 hours.  
     
     
         51 . The pharmaceutical formulation as recited in  claim 50 , wherein said time is about 20 to about 30 hours.  
     
     
         52 . The pharmaceutical formulation as recited in  claim 51 , wherein said time is about 26 hours.  
     
     
         53 . The pharmaceutical formulation as recited in claims  49  or  50 , wherein the formulation has an AUC of about 25.00 to about 600.00 ng/mL.hr.  
     
     
         54 . The pharmaceutical formulation as recited in  claim 49  or  0 . 50 , wherein Cmax is about 75.00 ng/mL.  
     
     
         55 . The pharmaceutical formulation as recited in  claim 33 , wherein said phospholipid or said non-ionic ester is selected from the group consisting of lecithin, refined lecithin and mixtures thereof.  
     
     
         56 . The pharmaceutical formulation as recited in claims  33  or  55 , wherein said primary stabilizing surfactants contain less than about 95% phosphatidylcholine.  
     
     
         57 . The pharmaceutical formulation as recited in claims  33  or  55 , wherein said primary stabilizing surfactants contain less than about 90% phosphatidylcholine.  
     
     
         58 . The pharmaceutical formulation as recited in claims  33  or  55 , wherein said primary stabilizing surfactants contain less than about 75% phosphatidylcholine.  
     
     
         59 . The pharmaceutical formulation as recited in  claim 33 , wherein said auxiliary stabilizing surfactants are selected from the group consisting of polyglycerol-3-oleate, glycerol monoisostearate and mixtures thereof.  
     
     
         60 . The pharmaceutical formulation as recited in claims  33  or  59 , wherein said auxiliary stabilizing surfactants are present in said pharmaceutical formulation in amounts of about 2 to 15% weight/weight.  
     
     
         61 . The pharmaceutical formulation as recited in claims  33  or  37 , wherein said formulation affects treatment of said vaginal condition in a single dose.  
     
     
         62 . The pharmaceutical formulation as recited in claims  33  or  37 , wherein said formulation affects treatment of said vaginal condition is multiple doses.  
     
     
         63 . The pharmaceutical formulation as recited in claims  33  or  37 , wherein said active agent is released from said pharmaceutical formulation for extended periods of time.  
     
     
         64 . A composition for treating a vaginal infection, comprising: 
 an effective amount of at least one active agent;    a modified release dosage form which provides modified release of said active agent or agents upon vaginal administration to said patient; and    wherein said formulation, when containing a total dose of each active agent of about 25 μg to about 500 mg based on said active agent will produce a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) of less than about 600 ng/mL.hr; and    wherein the at least one active agent is selected from the group consisting of antibacterial agents, antiviral agents, spermicides, hormone agents, growth enhancing agents, cytokines, antitrichomonial agents, antiprotozoan agents, antimycoplasm agents, antiretroviral agents, nucleoside analogues, reverse transcriptase inhibitors, protease inhibitors, contraceptive agents, sulfadrugs, sulfonamides, sulfones, hygiene agents, probiotic agents, vaccine agents, antibody agents, peptide agents, protein agents, polysaccharide agents, nucleic acids, plasmids, liposomes, carbohydrate polymers, transgenic bacteria, yeast, chemotherapeutic agents, steroid agents, growth enhancing agents, libido enhancers, androgenic substances, chitin derivatives, environment modifying agents such as pH modifiers, and mixtures and combinations thereof; and    wherein said composition is administered in a single administration and is statistically equivalent to seven doses of a conventional clindamycin vaginal cream, 2% in the treatment of bacterial vaginosis.    
     
     
         65 . A pharmaceutical formulation to treat vaginal conditions in a human patient comprising: 
 an effective amount of at least one active antibacterial agent;    a modified release dosage form for vaginal administration to said patient;    wherein said active antibacterial agent is not an antifungal agent; and    wherein said formulation, when containing a total dose of each active antibacterial agent of about 25 μg to about 500 mg based on said active agent will produce a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) of less than about 600 ng/mL.hr.    
     
     
         66 . A pharmaceutical formulation to treat vaginal conditions in a human patient comprising: 
 an effective amount of at least one active antibacterial agent;    a modified release dosage form for vaginal administration to said patient;    wherein said active antibacterial agent is not an antifungal agent;    wherein said antifungal agent is not butaconazole; and    wherein said formulation, when containing a total dose of each active antibacterial agent of about 25 μg to about 500 mg based on said active agent will produce a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) of less than about 600 ng/mL.hr.    
     
     
         67 . A method of treating a vaginal infection by administering a therapeutically effective amount of a pharmaceutical formulation to treat said vaginal condition comprising administering to said patient the formulation accomplishes a biologic endpoint of  claim 1 .  
     
     
         68 . The method of  claim 67 , wherein said formulation, when containing a total dose of said antimicrobial agent of about 100 mg based on said active agent will produce a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) between about 25 to about 350 ng/mL.hr.  
     
     
         69 . The method of  claim 67 , wherein said dosage form comprises: 
 a. an emulsion comprising at least two phases, one phase comprises an external lipoidal phase and the other phase comprising an internal non-lipoidal phase wherein said lipoidal phases is continuous and the said non-lipoidal phase comprises at least 70% by volume of said emulsion;    b. one or more primary stabilizing surfactants selected from the group consisting Phospholipid or non-ionic ester; and    c. when said stabilizing surfactants is a Phospholipid then one or more auxiliary stabilizing surfactants and when said stabilizing surfactants is non-ionic ester then optionally one or more auxiliary stabilizing surfactants.    
     
     
         70 . The method of  claim 69 , wherein said active agent is selected from the group consisting of antibacterial agents, antiviral agents, spermicides, hormone agents, growth enhancing agents, cytokines, antitrichomonial agents, antiprotozoan agents, antimycoplasm agents, antiretroviral agents, nucleoside analogues, reverse transcriptase inhibitors, protease inhibitors, contraceptive agents, sulfadrugs, sulfonamides, sulfones, hygiene agerts, probiotic agents, vaccine agents, antibody agents, peptide agents, protein agents, polysaccharide agents, nucleic acids, plasmids, liposomes, carbohydrate polymers, transgenic bacteria, yeast, chemotherapeutic agents, steroid agents, growth enhancing agents, libido enhancers, androgenic substances, chitin derivatives, environment modifying agents such as pH modifiers, and mixtures and combinations thereof.  
     
     
         71 . The method  claim 70 , wherein said active agent is an antibacterial agent selected from the group consisting of clindamycin, clindamycin phospate, clindamycin hydrochloride, salts thereof, complexes of clindamycin base and mixtures thereof.  
     
     
         72 . The method of  claim 71 , wherein said antibacterial agent is clindamycin phosphate.  
     
     
         73 . A method of treating a vaginal infection comprising administering to a patient in need thereof a single dose of a therapeutically effective pharmaceutical formulation comprising an active pharmaceutical formulation having surfactant properties, wherein treatment of said vaginal infection is affected with said single dose.  
     
     
         74 . The method of  claim 73 , wherein said vaginal infection is bacterial vaginitis.  
     
     
         75 . A method of stabilizing a clindamycin formulation by adding one or more primary stabilizing surfactants selected from the group consisting of a phospholipid, a non-ionic ester, and mixtures thereof; wherein when said stabilizing surfactant is a phospholipid, then one or more auxiliary stabilizing surfactants are added, and when said stabilizing surfactant is a non-ionic ester, then optionally one or more auxiliary stabilizing surfactants are added.  
     
     
         76 . A method of treating or preventing a reoccurrence of a vaginal infection in a patient comprising administering a single dose of a pharmaceutical formulation comprising an active pharmaceutical having surfactant properties to a patient in need thereof effective to treat said vaginal condition.  
     
     
         77 . A method of treating a vaginal infection by administering a pharmaceutical formulation for vaginal administration comprising: 
 an effective amount of at least one active agent;    a modified release dosage form which provides modified release of said active agent or agents upon vaginal administration to said patient; and    wherein said formulation, when containing a total dose of each active agent of about 25 μg to about 500 mg based on said active agent will produce a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) of less than about 600 ng/mL.hr; and    wherein the at least one active agent is selected from the group consisting of antibacterial agents, antiviral agents, spermicides, hormone agents, growth enhancing agents, cytokines, antitrichomonial agents, antiprotozoan agents, antimycoplasm agents, antiretroviral agents, nucleoside analogues, reverse transcriptase inhibitors, protease inhibitors, contraceptive agents, sulfadrugs, sulfonamides, sulfones, hygiene agents, probiotic agents, vaccine agents, antibody agents, peptide agents, protein agents, polysaccharide agents, nucleic acids, plasmids, liposomes, carbohydrate polymers, transgenic bacteria, yeast, chemotherapeutic agents, steroid agents, growth enhancing agents, libido enhancers, androgenic substances, chitin derivatives, environment modifying agents such as pH modifiers, and mixtures and combinations thereof; and    wherein said administration is a single administration and is statistically equivalent to seven doses of a conventional clindamycin vaginal cream, 2% in the treatment of bacterial vaginosis.    
     
     
         78 . A method for treating vaginal conditions, which comprises: 
 administering topically to a vaginal mucosal tissue site a modified release pharmaceutical formulation comprising at least one active agent, 
 wherein the formulation maintains topical residence in a vaginal cavity for up to 10 days; and  
 wherein systemic absorption of the at least one active agent is minimized.  
   
     
     
         79 . A method for treating vaginal conditions, which comprises: 
 administering topically to a vaginal mucosal tissue site a modified release pharmaceutical formulation comprising at least one active agent, 
 wherein the formulation maintains topical residence in a vaginal cavity for up to 7 days; and  
 wherein systemic absorption of the at least one active agent is minimized.  
   
     
     
         80 . The method of  claim 79  wherein said formulation, when containing a total dose of each active agent of about 25 μg to about 500 mg based on said active agent will produce a plasma concentration versus time curve (ng/ml versus hours) having an area-under the curve (AUC) of less than about 600 ng/mL.hr.  
     
     
         81 . The method of  claim 79 , wherein said formulation when containing an antimicrobial agent as the active agent, and when containing a total dose of said antimicrobial agent of about 100 mg, will produce a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) between about 25 to about 350 ng/mL.hr.