1. A process for producing a pharmaceutical composition comprising the steps:
(a) forming a feed solution comprising a drug, a concentration-enhancing polymer and a solvent;
(b) directing said feed solution to a spray-drying apparatus comprising
(i) a drying chamber having a volume Vdryer and a height H,
(ii) atomizing means for atomizing said feed solution into droplets,
(iii) a source of heated drying gas for drying said droplets, said source delivering said drying gas to said drying chamber at a flow rate of G, and
(iv) gas-dispersing means for dispersing said drying gas into said drying chamber, said gas-dispersing means causing organized plug flow of said drying gas,
wherein Vdryer is measured in m3,
H is at least 1 m,
G is measured in m3sec,
and wherein the following mathematical relationship is satisfied
10
V
dryer
G
10
seconds
;
(c) atomizing said feed solution into droplets in said drying chamber by said atomizing means, said droplets having an average diameter of at least 50 m and a D10 of at least 10 m;
(d) contacting said droplets with said heated drying gas to form particulates of a solid amorphous dispersion of said drug and said concentration-enhancing polymer; and
(e) collecting said particulates,
wherein said concentration-enhancing polymer is present in said solution in an amount sufficient that said solid amorphous dispersion provides concentration enhancement of said drug in a use environment relative to a control composition consisting essentially of an equivalent amount of said drug alone.
2. The process of claim 1 wherein said gas-dispersing means is a perforated plate.
3. The process of claim 2 wherein said perforated plate has perforations occupying about 1% of its surface area.
4. The process of claim 3 wherein the density of said perforations near the center of said plate is about 25% the density of said perforations in the outer part of said plate.
5. The process of claim 1 wherein said drying gas has an inlet temperature of from about 60 to about 300 C.
6. The process of claim 5 wherein said drying gas has an outlet temperature of from about 0 to about 100 C.
7. The process of claim 1 wherein said droplets have a D10 of at least 15 m.
8. The process of claim 7 wherein said droplets have a D10 of at least 20 m.
9. The process of claim 1 wherein said droplets have a Span of less than about 3.
10. The process of claim 1 wherein said droplets have a Span of less than about 2.
11. The process of claim 1 wherein at least 80 vol % of said particulates have diameters of greater than 10 m.
12. The process of claim 11 wherein at least 90 vol % of said particulates have diameters of greater than 10 m.
13. The process of claim 1 wherein said drug in said dispersion is substantially amorphous and said dispersion is substantially homogeneous.
14. The process of claim 1 wherein said composition provides a maximum drug concentration of said drug in said use environment that is at least about 1.25-fold that provided by said control composition.
15. The process of claim 1 wherein said composition provides in said use environment an area under the drug concentration versus time curve for any 90-minute period from the time of introduction to about 270 minutes following introduction to said use environment that is at least 1.25-fold that provided by said control composition.
16. The process of claim 1 wherein said composition provides a relative bioavailability of said drug that is at least 1.25-fold that of said control composition.
17. The process of claim 1 wherein said drug is selected from the group consisting of antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, anti-atherosclerotic agents, cholesterol-reducing agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer’s disease agents, antibiotics, anti-depressants, antiviral agents, glycogen phosphorylase inhibitors, and cholesterol ester transfer protein inhibitors.
18. The process of claim 17 wherein said drug is selected from the group consisting of R-(R*S*)-5-chloro-N-2-hydroxy-3-methoxymethylamino-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamide; 5-chloro-1H-indole-2-carboxylic acid (1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropylamide; 2R,4S-4-acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; 2R,4S 4-(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; and 2R,4S 4-(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.
19. The process of claim 1 wherein said concentration-enhancing polymer is selected from the group consisting of ionizable cellulosic polymers, non-ionizable cellulosic polymers, ionizable non-cellulosic polymers, non-ionizable non-cellulosic polymers, neutralized acidic polymers and blends thereof.
20. The process of claim 19 wherein said polymer is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl alcohols that have at least a portion of their repeat units in hydrolyzed form, polyvinyl pyrrolidone, poloxamers and blends thereof.
21. The product of the process of any of claims 1-20.
22. A composition comprising a plurality of solid amorphous dispersion particles comprising a drug and a polymer wherein said particles have an average diameter of at least 40 m and a bulk specific volume of less than 5 mLg, and wherein at least 80 vol % of said particles have diameters of greater than 10 m.
23. The composition of claim 22 wherein at least 90 vol % of said particles have diameters of greater than 10 m.
24. The composition of claim 22 wherein said particles have an average diameter of at least 50 m.
25. The composition of claim 22 wherein said particles have a bulk specific volume of less than 4 mLg.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A return to neutral mechanism for a hydraulic pump comprising:
a lever configured to cooperate with a control rod of an associated hydraulic pump such that movement of the lever results in rotation of the control rod;
a hub configured to connect fast with the control rod for rotation therewith, the hub being connected to the lever in a manner to allow for adjusting the lever with respect to the hub prior to fixing the hub with respect to the lever so that the hub rotates in response to movement of the lever; and
a biasing member contacting the lever for biasing the control rod toward a neutral position when the control rod has been moved from the neutral position, wherein the biasing member is a curved piece of spring steel.
2. The mechanism of claim 1, wherein the lever includes a fastener slot and the hub includes a fastener opening, wherein the fastener slot is larger than the fastener opening.
3. A method for attaching a return to neutral mechanism to a control arm of a hydraulic pump, the method comprising:
operating a hydraulic pump in neutral;
connecting a hub fast to a control arm of the hydraulic pump such that the hub rotates with the control arm;
placing a lever on the hub;
contacting the lever with a biasing member having a coil axis parallel to a rotational axis of the lever;
allowing the control arm to return to a neutral position so that the hydraulic pump is operating in neutral; and
fixing the lever to the hub so that rotation of the lever results in rotation of the hub and the control arm.
4. The method of claim 3, wherein connecting the hub fast to a control arm further comprises inserting the control arm through an opening of the hub.
5. The method of claim 3, wherein placing a lever on the hub comprises inserting the control arm through an opening of the lever.
6. The method of claim 3, wherein contacting the biasing member with the lever includes connecting a first biasing member to the lever and the pump housing and connecting a second biasing member to the lever and the pump housing, wherein the first biasing member is configured to bias the lever in a first rotational direction and the second biasing member is configured to rotate the biasing member in a second rotational direction.
7. The method of claim 3, wherein fixing the lever to the hub further comprises rotating the lever with respect to the hub to align slots in the lever with openings in the hub, and inserting fasteners into the respective slots and openings.
8. A return to neutral mechanism for a hydraulic pump comprising:
a lever configured to cooperate with a control rod of an associated hydraulic pump such that movement of the lever results in rotation of the control rod;
a hub configured to connect fast with the control rod for rotation therewith, the hub being connected to the lever in a manner to allow for adjusting the lever with respect to the hub prior to fixing the hub with respect to the lever so that the hub rotates in response to movement of the lever;
a first biasing member contacting the lever for biasing the control rod in a first rotational direction toward a neutral position when the control rod has been moved from the neutral position; and
a second biasing member contacting the lever for biasing the control rod in a second rotational direction toward the neutral position when the control rod has been moved from the neutral position,
wherein each biasing member is a helical spring including a central coiled portion and an extension, the extension engages the lever and is substantially parallel to the rotational axis of the hub.
9. The mechanism of claim 8, wherein the lever includes at least three biasing member openings each configured to receive a respective extension.
10. The mechanism of claim 8, wherein the lever includes at least two biasing member openings, each biasing member opening being generally oblong.
11. The mechanism of claim 10, wherein the first biasing member deflects when the lever rotates in a first direction and the second biasing member is relaxed when the lever rotates in the first direction.
12. The mechanism of claim 8, wherein the lever includes a fastener slot and the hub includes a fastener opening, wherein the fastener slot is larger than the fastener opening.
13. The mechanism of claim 12, wherein the hub includes more fastener openings than the lever includes fastener slots.
14. The mechanism of claim 8, wherein the extension is parallel to a coil axis of the spring.
15. A return to neutral mechanism for a hydraulic pump comprising:
a lever configured to cooperate with a control rod of an associated hydraulic pump such that movement of the lever results in rotation of the control rod, the lever including at least two generally oblong biasing member openings;
a hub configured to connect fast with the control rod for rotation therewith, the hub being connected to the lever in a manner to allow for adjusting the lever with respect to the hub prior to fixing the hub with respect to the lever so that the hub rotates in response to movement of the lever;
a first biasing member contacting the lever and received in one of the biasing member openings for biasing the control rod in a first rotational direction toward a neutral position when the control rod has been moved from the neutral position; and
a second biasing member contacting the lever and received in another of the biasing member openings for biasing the control rod in a second rotational direction toward the neutral position when the control rod has been moved from the neutral position.
16. The mechanism of claim 15, wherein the first biasing member deflects when the lever rotates in the first direction and the second biasing member is relaxed when the lever rotates in the first direction.
17. The mechanism of claim 15, wherein each biasing member is a helical spring including a central coiled portion and an extension, the extension engages the lever and is substantially parallel to the rotational axis of the hub.
18. The mechanism of claim 17, wherein each biasing member is a helical spring including a central coiled portion defining a coil axis, which is parallel to the rotational axis of the hub.