1. A method of improving bioavailability of a pharmaceutical composition comprising, administering a therapeutically effective amount of at least one compound according to the following formula:
to a mammal, wherein R3 and R4 are each independently selected from the group consisting of lower alkyl, phenyl and lower alkyl substituted phenyl, and R1 and R2 are each independently either a hydrogen atom or a radical of the formula
wherein R5 and R6 are each independently selected from the group consisting of H, lower alkyl, phenyl and lower alkyl substituted phenyl, its pharmaceutically acceptable salts and prodrugs thereof and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is administered from about 4 hours prior to ingestion of food to about 4 hours after ingestion of food.
2. The method of claim 1 wherein, the food is ingested from about 2 hours to about 5 minutes before administration of the pharmaceutical composition.
3. The method of claim 2 wherein, the food is ingested from about 30 minutes to about 5 minutes before administration of the pharmaceutical composition.
4. The method of claim 1 wherein, the food is ingested from about 5 minutes to about 2 hours after administration of the pharmaceutical composition.
5. The method of claim 4 wherein, the food is ingested from about 5 minutes to about 30 minutes after administration of the pharmaceutical composition.
6. The method of claim 1 wherein, the fastingfed ratios for the geometric mean AUC0-t, of DMMDPB is at least about 30%.
7. The method of claim 1 wherein, the fastingfed ratios for the geometric mean AUC0-t of MMMDPB is at least about 30%.
8. The method of claim 1 wherein, the fastingfed ratios for the geometric mean AUC0-t of DPB is at least about 60%
9. The method of claim 1 wherein the fastingfed ratios for the geometric mean AUC0-t for DMMDPB is at least about 35.0%, MMMDPB is at least about 36% and DPB is at least about 65%.
10. The method of claim 9 wherein the geometric mean Cmax is at least about 14.0% for DMMDPB, at least about 31.0% for MMMDPB and at least about 62.0% for DPB.
11. The method of claim 1 wherein, R5 and R6 are each independently H or lower alkyl.
12. The method of claim 1 wherein, R3 and R4 are each independently phenyl.
13. The method of claim 1 wherein, at least one of R1 and R2 is defined by the formula
wherein R5 and R6 are each independently selected from H or lower alkyl.
14. The method of claim 1 wherein, at least one of R1 and R2 is \u2014CH2OCH3.
15. The method of claim 1 wherein, both R5 and R6 are phenyl, R1 is \u2014CH2OCH3 and R2 is H.
16. The method of claim 1 wherein, both R5 and R6 are phenyl and both R1 and R2 are \u2014CH2OCH3.
17. The method of claim 1 wherein, the pharmaceutical composition comprises a tablet.
18. The method of claim 1 wherein, the pharmaceutical composition comprises a capsule.
19. The method of claim 1 wherein, the mammal is a human.
20. An item of manufacture comprising, a container containing a pharmaceutical composition of a therapeutically effective amount of at least one
compound according to the following formula:
wherein R3 and R4 are each independently selected from the group consisting of lower alkyl, phenyl and lower alkyl substituted phenyl, and R1 and R2 are each independently either a hydrogen atom or a radical of the formula
wherein R5 and R6 are each independently selected from the group consisting of H, lower alkyl, phenyl and lower alkyl substituted phenyl, its pharmaceutically acceptable salts and prodrugs thereof and at least one pharmaceutically acceptable excipient, wherein the container is associated with printed labeling advising that food should be ingested from about 2 hours prior to administration of the pharmaceutical composition to about 2 hours after administration of the pharmaceutical composition.
21. The item of manufacture of claim 20 wherein, the pharmaceutical composition is a tablet unit dosage form.
22. The item of manufacture of claim 20 wherein, the pharmaceutical composition is a capsule unit dosage form.
23. A method of improving bioavailability of a pharmaceutical composition comprising, administering a therapeutically effective amount of at least one compound according to the following formula to a mammal:
wherein R1 and R2 may be the same or different and are independently
lower alkyl, substituted by lower cycloalkyl, acyl, acyloxy, aryl, aryloxy, thioalkyl or thioaryl, amino, alkylamino, dialkylamino, or one or more halogen atoms;
phenyl;
C(O)XR6, wherein X is S or O and R6 is lower alkyl or aryl;
CXR7, wherein X is as defined above and R7 is hydrogen, lower alkyl or aryl; and
CH(XR8)2, wherein X is as defined above and R8 is a lower alkyl group; and
wherein
R3 and R4 may be the same or different and are independently hydrogen;
aryl optionally containing one or more heteroatoms selected from the group consisting of N, S, and O;
lower acyloxy;
phenyl substituted with lower acyl group or derivative thereof or acetamide;
benzyl; benzyl substituted on the ring by one or more halogens, lower alkyl groups or both; cycloalkyl, which optionally contains one or more heteroatoms selected from the group consisting of N, O, and S;
lower alkyl; or lower alkyl substituted with an aromatic moiety;
provided that at least one of R3 and R4 is an aromatic ring or an aromatic ring containing moiety,
and salts thereof,
with the proviso that:
when one of R3 and R4 is benzyl, the other of R3 and R4 is not ethyl, the compound is other than
a) 1-methyl-5-(1-phenylethyl)-5-propionyloxy-barbituric acid,
b) 1,3-diphenyl-5,5-(dibenzyl) barbituric acid,
c) 1,3,5-triphenyl barbituric acid, and
d) 5-benzyl-1,3-dimethyl barbituric acid
and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is administered from about 4 hours prior to ingestion of food to about 4 hours after ingestion of food.
24. A method of improving bioavailability of a pharmaceutical composition comprising, administering a therapeutically effective amount of sodium 5,5-diphenyl barbiturate or a derivative thereof and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is administered from about 4 hours prior to ingestion of food to about 4 hours after ingestion of food.
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 vibration generator, comprising:
a housing including a circumferential wall portion extending along a peripheral edge of the housing;
a vibrating body arranged inside of the circumferential wall portion of the housing in an opposing relationship with a coil and configured to reciprocatingly vibrate in one direction;
a band-like leaf spring arranged between the vibrating body and the circumferential wall portion to support the vibrating body on the circumferential wall portion,
wherein the leaf spring includes a connection portion connected to the vibrating body at one longitudinal end of the leaf spring, an attachment portion attached to the circumferential wall portion at the other longitudinal end of the leaf spring and an intermediate portion extended between the connection portion and the attachment portion around the vibrating body,
the connection portion and the attachment portion are arranged along a direction intersecting a vibration direction of the vibrating body at opposite sides of the vibrating body, and
the intermediate portion is arranged to extend across the vibration direction of the vibrating body in an outside region around the vibrating body.
2. The vibration generator of claim 1, wherein the intermediate portion includes a plurality of curved sections at which the leaf spring extends in a curved shape.
3. The vibration generator of claim 2, wherein the leaf spring is curved to protrude from the vibrating body toward the circumferential wall portion in a region on the side of the connection portion, the leaf spring being obliquely formed in the longitudinal outside region of the vibrating body to go away from the vibrating body and come close to the circumferential wall portion as the leaf spring extends from the side of the connection portion to the side of the attachment portion, the leaf spring being curved from the outside region around the vibrating body toward a central region of the vibrating body on the side of the attachment portion.
4. The vibration generator of claim 1, wherein the leaf spring includes first and second leaf springs respectively arranged at the opposite sides of the vibrating body in the vibration direction of the vibrating body.
5. The vibration generator of claim 4, wherein the first and second leaf springs are formed into a one-piece member.
6. The vibration generator of claim 1, wherein the housing further includes a bottom member to which the coil is attached and a top portion arranged to close a top end of the housing, the vibrating body including an upper surface making contact with an inner surface of the top portion, and the vibration generator further comprises: a sliding member arranged on at least one of the upper surface of the vibrating body and the inner surface of the top portion to smoothly slide the vibrating body with respect to the inner surface of the top portion.
7. The vibration generator of claim 1, wherein the coil is a hollow-core spiral coil formed by spirally winding a wire, the bottom member of the housing having a communication groove interconnecting the inside and the outside of the coil, the coil including a lead wire extending from an inner edge of the coil and passing through the communication groove.