Large-scale manufacturing process for the production of pharmaceutical compositions
Methods for manufacturing pharmaceutical compositions with a predetermined surface tension or other properties are provided. Also provided are pharmaceutical compositions with a predetermined surface tension or other properties, articles of manufacture containing the pharmaceutical compositions and systems for preparation of the compositions.
1 . A method of manufacturing a composition with a predetermined surface tension, comprising:
formulating at a manufacturing scale and under conditions that reduce or inhibit the formation of non-equilibrium aggregates, a pharmaceutical composition that contains an agent, whereby the composition has a predetermined surface tension.
2 . The method of claim 1 , wherein:
the composition comprises one or more surfactants; and
the concentration of the surfactant is near the critical micelle concentration (cmc).
3 . The method of claim 1 , wherein the composition comprises the agent in monomeric form.
4 . A method of manufacturing a composition, comprising:
formulating at a manufacturing scale a pharmaceutical composition that has a predetermined surface tension, wherein:
the composition comprises an agent and a surfactant; and
the concentration of the surfactant is near the critical micelle concentration, whereby the manufactured composition has a predetermined surface tension.
5 . The method of claim 4 , wherein the concentration of the surfactant is below the critical micelle concentration.
6 . The method of claim 4 , wherein the concentration of the surfactant is about or equal to the critical micelle concentration.
7 . The method of claim 4 , wherein the concentration of the surfactant is within 2 fold or 3 fold below or above the critical micelle concentration.
8 . The method of claim 4 , wherein the predetermined surface tension is between 30-50 dynes/cm.
9 . The method of claim 8 , wherein the predetermined surface tension is between 35-45 dynes/cm.
10 . The method of claim 4 , wherein the agent is selected from the group consisting of an anti-infective agent, an anti-inflammatory agent, an antihistamine, an antileukotriene, a decongestant, an antiviral agent and an anesthetic.
11 . The method of claim 10 , wherein the anti-infective is selected from the group consisting of an aminoglycoside, a macrolide, a penicillin, a quinolone, a cephalosporin, an amphotericin B, a polyene, a pyrimidine analog and an azole agent.
12 . The method of claim 10 , wherein the anti-inflammatory agent is selected from the group consisting of a steroid and a non-steroidal anti-inflammatory (NSAID) agent.
13 . The method of claim 4 , wherein the method includes reducing energy input into the manufacturing process.
14 . The method of claim 13 , wherein energy input is reduced at a step selected from the group consisting of mixing, transferring, filtering and filling.
15 . The method of claim 13 , wherein the formation of non-equilibrium aggregates of the agent is reduced or eliminated.
16 . The method of claim 4 , wherein the composition is formulated for direct administration.
17 . The method of claim 4 , wherein manufactured composition is a solution, an emulsion or a suspension.
18 . The method of claim 4 , further comprising the step of assessing the surface tension of the manufactured composition.
19 . The method of claim 13 , wherein energy input is reduced at a step of filtering by reducing the pressure differential across the filter or reducing the turbulence during filtration.
20 . A method of manufacture, comprising:
formulating at a manufacturing scale a pharmaceutical composition that has a predetermined surface tension, wherein:
the composition comprises tobramycin and a surfactant; and
the concentration of surfactant is near the critical micelle concentration, whereby the manufactured composition has a predetermined surface tension between about 30 to about 50 dynes/cm.
21 . The method of claim 20 , wherein the manufacturing process includes a reduced pressure differential during filtration or during filling.
22 . A composition produced by the method of claim 4 .
23 . The composition of claim 22 , wherein the volume manufactured is at least ten liters.
24 . A manufactured composition, comprising:
a pharmaceutical agent; and
a surfactant at a concentration near or at the critical micelle concentration, whereby the manufactured composition has a predetermined surface tension; and
the volume of the manufactured composition is ten liters or greater.
25 . The composition of claim 24 , wherein the surfactant is a non-ionic surfactant.
26 . The composition of claim 25 , wherein the non-ionic surfactant is polysorbate-20.
27 . The composition of claim 24 , wherein the agent is an anti-infective agent or an anti-inflammatory agent.
28 . The composition of claim 24 , wherein the predetermined surface tension is between 30-50 dynes/cm.
29 . The composition of claim 24 , wherein the predetermined surface tension is between 35-45 dynes/cm.
30 . An article of manufacture, comprising:
a pharmaceutical composition in a sterile container; wherein:
the composition comprises a pharmaceutical agent and a surfactant;
the surfactant is at a concentration near or at the critical micelle concentration;
the composition is sterile and has a predetermined surface tension; and
the composition is packaged aseptically.
31 . The article of manufacture of claim 30 , wherein the composition is packaged hermetically.
32 . The article of manufacture of claim 30 , wherein the composition is packaged in a container selected from the group consisting of a heat-sealed container, a vacuum-sealed container and a safety-sealed container.
33 . The article of manufacture of claim 30 , wherein the composition is packaged in a vial or ampoule.
34 . The article of manufacture of claim 30 , wherein the composition is packaged in a plastic or glass container.
35 . The article of manufacture of claim 30 , wherein the predetermined surface tension is between 30-50 dynes/cm.
36 . The article of manufacture of claim 30 , wherein the container is a unit dose or multi-dose container.
37 . The article of manufacture of claim 30 , wherein the composition is for direct administration.
38 . The article of manufacture of claim 30 , wherein the agent is an anti-infective or an anti-inflammatory agent.
39 . The article of manufacture of claim 30 , wherein the agent is an agent effective for the treatment of sinusitis.
40 . The article of manufacture of claim 30 , wherein the surfactant is a non-ionic surfactant.
41 . The article of manufacture of claim 30 , wherein the surfactant is not benzalkonium chloride.
42 . A pharmaceutical composition, comprising:
tobramycin at a concentration of between about or at 15 mg/ml to about or at 60 mg/ml;
polysorbate-20 at a concentration of 0.125 mg/ml or at a concentration between 0.009% and 0.015% by weight;
sodium chloride at a concentration between 2.5 mg/ml and 4.3 mg/ml;
a volume greater than about or at ten liters; and
a predetermined surface tension between about or at 30 dynes/cm to about or at 50 dynes/cm.
43 . An article of manufacture of claim 31 , wherein the composition comprises:
tobramycin at a concentration of between about or at 15 mg/ml to about or at 60 mg/ml;
polysorbate-20 at a concentration of 0.125 mg/ml or at a concentration between 0.009% and 0.015% by weight;
sodium chloride at a concentration between 2.5 mg/ml and 4.3 mg/ml; and
the composition has a surface tension between about or at 30 dynes/cm to about or at 50 dynes/cm.
44 . A system of manufacture for a formulation of at least 10 liters of a pharmaceutical composition, comprising:
an agent and a surfactant, wherein the amount of surfactant is near the critical micelle concentration; and
a filtration apparatus containing a filter, wherein the filter is for sterilization of the pharmaceutical composition and of a configuration that produces low turbulent flow, whereby the resulting composition is produced at a stable predetermined surface tension.
45 . The system of claim 44 , wherein the surfactant is a polysorbate.
46 . The system of claim 44 , wherein the filter has a pore size and/or pore distribution that permits or promotes laminar flow.
47 . The system of claim 44 , further comprising an automated apparatus for aseptically filling and hermetically sealing containers.
48 . The system of claim 44 , further comprising a computer for directing automated operation of the system.
49 . A method of treating chronic sinusitis, comprising:
unsealing the container in the article of manufacture of claim 30;
transferring the composition contained in the container into a nebulizing device; and
nebulizing the composition, wherein the composition comprises an agent effective for treating sinusitis.
50 . The method of claim 49 , wherein the agent is an anti-infective or an anti-inflammatory.
51 . The method of claim 49 , wherein the agent is tobramycin.
52 . The method of claim 49 , wherein the composition comprises a non-ionic surfactant.
53 . The method of claim 49 , wherein the composition has a predetermined surface tension between about or at 30 dynes/cm to about or at 50 dynes/cm.
54 . A method of manufacturing a composition with a predetermined surface tension, comprising:
dispersing or dissolving an active agent in a liquid in a formulation tank;
adding a surfactant to the active agent composition, wherein the final concentration of the surfactant in the composition is near the critical micelle concentration;
mixing the composition;
optionally adjusting the pH of the composition;
optionally adding other components to the composition;
transferring the composition to a filtration unit and filtering the composition under conditions that reduce or inhibit formation of non-equilibrium aggregates; and
packaging the filtered composition.
55 . The method of claim 54 , wherein the concentration of the surfactant is below the critical micelle concentration.
56 . The method of claim 54 , wherein the concentration of the surfactant is within 2 fold or 3 fold below or above the critical micelle concentration.
57 . The method of claim 54 , wherein the predetermined surface tension is between 30-50 dynes/cm.
58 . The method of claim 57 , wherein the predetermined surface tension is between 35-45 dynes/cm.
59 . The method of claim 54 , wherein the agent is selected from the group consisting of an anti-infective agent, an anti-inflammatory agent, an antihistamine, an antileukotriene, a decongestant, an antiviral agent, and an anesthetic.
60 . The method of claim 59 , wherein the anti-infective is selected from the group consisting of an aminoglycoside, a macrolide, a penicillin, a quinolone, a cephalosporin, an amphotericin B, a polyene, a pyrimidine analog and an azole agent.
61 . The method of claim 59 , wherein the anti-inflammatory agent is selected from the group consisting of a steroid and a non-steroidal anti-inflammatory (NSAID) agent.
62 . The method of claim 54 , wherein the method includes reducing energy input into the manufacturing process.
63 . The method of claim 62 , wherein energy input is reduced at a step selected from the group consisting of mixing, transferring, filtering and filling.
64 . The method of claim 54 , wherein the filter is a sterilizing filter having a pore size selected from the group consisting of 0.22, 0.2 or 0.1 micron.
65 . The method of claim 64 , wherein the sterile composition is aseptically packaged.
66 . The method of claim 54 , wherein the composition is packaged hermetically.
67 . The method of claim 54 , wherein the composition is packaged in a container selected from the group consisting of a heat-sealed container, a vacuum-sealed container or a safety-sealed container.
68 . The method of claim 54 , wherein the composition is packaged in a vial or ampoule.
69 . The method of claim 54 , wherein the agent is an agent effective for the treatment of sinusitis.
70 . The method of claim 54 , wherein the surfactant is a non-ionic surfactant.
71 . The method of claim 54 , wherein the agent is tobramycin and the surfactant is polysorbate-20.
72 . The method of claim 71 , wherein
the tobramycin is at a concentration of between about or at 15 mg/ml to about or at 60 mg/ml;
the polysorbate-20 is at a concentration of 0.125 mg/ml or at a concentration between 0.009% and 0.015% by weight; and
the composition has a predetermined surface tension between about or at 30 dynes/cm to about or at 50 dynes/cm.