1. A pharmaceutical formulation having a masked taste comprising from about 15 to about 30% (ww) of EDP-182 mixed with from about 60% to about 80% (ww) of an ester of glycerol or of a fatty acid, to which a wax is optionally added, and to which a surfactant is added, wherein the pharmaceutical formulation is prepared by a spray-cooling process which can produce a particle size of less than about 350 microns.
2. A pharmaceutical formulation having a masked taste, comprising a therapeutically effective amount of EDP-182 in the form of a suspension in an aqueous vehicle, and further comprising a) at least one cellulosic polymer which is soluble in organic solvents and substantially insoluble in water at any pH; b) a methacrylic polymer which is soluble in an acid medium and substantially insoluble at a neutral or alkaline pH wherein EDP-182 is distributed in a homogeneous manner and in the molecular state in the mixture, which is in the form of an atomized matrix; c) a pharmaceutically acceptable alkaline agent of an organic nature or an alkaline salt; and d) an adsorbent agent.
3. A pharmaceutical formulation of claim 2 comprising about 40% to about 45% by weight of cellulosic polymer, about 15% to about 20% by weight of methacrylic polymers, wherein the maximum amount of the EDP-182 in the matrix is about 30% by weight.
4. A capsule for oral administration comprising a formulation selected from the group consisting of:
% Composition
Blend
for 100 mg Strength capsule
#1) EDP-182 API
28.6
Pregelatinized Starch
55.9
Microcrystalline Cellulose
15.0
Magnesium Stearate
\u20020.5
Hard Shell capsule
Size 1
Full Weight
350 mg
#2) EDP-182 API
40.0
Microcrystalline Cellulose
57.0
Crospovidone
\u20022.0
Magnesium Stearate
\u20020.5
Hard Shell capsule
Size 1
Full Weight
250 mg
#3) EDP-182 API
28.6
Lactose Monohydrate
68.9
Croscarmellos Sodium
\u20022.0
Magnesium Stearate
\u20020.5
Hard Shell capsule
Size 1
Full Weight
350 mg
#4) EDP-182 API
16.2
Lactose
81.2
Sodium Starch Glycolate
\u20021.9
Magnesium Stearate
\u20020.7
#5) EDP-182 API
16.2
Starch 1500
81.2
Sodium Starch Glycolate
\u20021.9
Magnesium Stearate
\u20020.7
#6) EDP-182 API
16.2
Mannitol
81.2
Sodium Starch Glycolate
\u20021.9
Magnesium Stearate
\u20020.7
#7) EDP-182 API
16.2
CaHPO4
81.2
Sodium Starch Glycolate
\u20021.9
Magnesium Stearate
\u20020.7
#8) EDP-182 API
16.2
Advicel 102 (Mcc PH102)
81.2
Sodium Starch Glycolate
\u20021.9
Magnesium Stearate
\u20020.7
5. A pharmaceutical formulation comprising a therapeutically effective amount of EDP-182, an alginate matrix consisting of a water soluble alginate salt, a complex salt of alginic acid, and an inorganic salt, characterized in that the inorganic salt is capable of donating a proton and has a pKa value in water of 4.0-9.0.
6. A pharmaceutical formulation for a fast melt lozenge or tablet comprising: a non-compressed, free flowing plurality of particles comprising a therapeutically effective amount of EDP-182, and a water-soluble excipient, the particles having a mean diameter of greater than 10 microns to about 1 mm, the particles comprising at least about 50% of EDP-182, and the formulation dissolving in the patients mouth within 1 minute after administration without the co-administration of fluid.
7. A pharmaceutical formulation for a soft-bite gelatin capsule for transmucosal administration comprising about 0.01-85% by weight of EDP-182, about 4-99.99% by weight of a non-polar solvent, and about 0-20% by weight of emulsifier.
8. A pharmaceutical formulation for a propellant-free buccal spray formulation for transmucosal administration comprising a therapeutically effective amount of EDP-182 and a polar or non-polar solvent in an amount between about 30-99%.
9. A pharmaceutical formulation for a buccal spray formulation for transmucosal administration comprising a therapeutically effective amount of EDP-182, a polar or non-polar solvent in an amount between abut 30-99% by weight, and a propellant in the amount of about 2-10% by weight.
10. A pharmaceutical formulation for pulmonary delivery formulation comprising a therapeutically effective amount of EDP-182 in a nebulized formulation.
11. A pharmaceutical formulation for pulmonary delivery formulation comprising a therapeutically effective amount of EDP-182 in an aerosolized formulation.
12. An oral dosage form of EDP-182 which is in the form of a tablet made by wet granulation, which is administrable to a mammal that has eaten, which comprises EDP-182 and an excipient, said dosage form effecting at least about 90% dissolution of EDP-182 within about 30 minutes when an amount of the dosage form equivalent to 200 mg of EDP-182 is tested as set forth in USP test <711> in a USP-2 dissolution apparatus under conditions at least as stringent as the following: 900 ml sodium phosphate buffer pH 6.0, 37\xb0 C., with paddles turning at 100 rpm, provided that said dosage form contains less than a taste-masking amount of an alkaline earth metal oxide or hydroxide.
13. A dosage form as defined in claim 12, further comprising a flavoring agent.
14. An oral dosage form of EDP-182 which is in the form of a powder for oral suspension containing water and Simple Syrup.
15. A dosage form as defined in claim 14, further comprising a flavoring agent.
16. A dosage form as defined in claim 15, wherein said flavoring agent is a flavor system consisting of grape, cherry, vanilla, bubble gum and banana.
17. An oral dosage form of EDP-182 which is in the form of a bead made by wet granulation, which is administrable to a mammal that has eaten, which comprises EDP-182 and an excipient.
18. An oral dosage form of EDP-182 which is in the form of a granulate.
19. A dosage form comprising a formulation selected from the group consisting of:
A
28.6% EDP-182 API
55.9% pregelatinized starch
15.0% microcrystalline cellulose
0.5% magnesium state
B
40.0% EDP-182 API
57.0% microcrystalline cellulose
2.0% crospovidone
0.5% magnesium stearate
C
28.6% EDP-182 API
68.9% lactose monohydrate
2.0% croscarmellos sodium
0.5% magnesium stearate
D
16.2% EDP-182 API
81.2% Lactose
1.9% Sodium Starch Glycolate
0.7% Magnesium Stearate
E
16.2% EDP-182 API
81.2% Starch 1500
1.9% Sodium Starch Glycolate
0.7% Magnesium Stearate
F
16.2% EDP-182 API
81.2% Mannitol
1.9% Sodium Starch Glycolate
0.7% Magnesium Stearate
G
16.2% EDP-182 API
81.2% CaHPO4
1.9% Sodium Starch Glycolate
0.7% Magnesium Stearate
H
16.2% EDP-182 API
81.2% Advicel 102 (Mcc PH102)
1.9% Sodium Starch Glycolate
0.7% Magnesium Stearate
I
5% EDP-182 API
5% sucrose
J
5% EDP-182 API
5% sorbitol
20. A pharmaceutical formulation of claim 19 in a form selected from: capsule, tablet, suspension and elixir.
21. A pharmaceutical composition of claim 19 wherein the composition is coated with a pharmaceutically acceptable coating.
22. A dosage form as defined in claim 19 made as a tablet and coated with:
1-20% cellulosic polymer.
23. A dosage form as defined in claim 19 made as a tablet and coated with:
1-20% methacrylate polymer.
24. A dosage form as defined in claim 17 or 18 coated with:
1-20% cellulosic polymer.
25. A dosage form as defined in claim 17 or 18 made as beads or granulate and coated with:
1-20% methacrylate polymer.
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 process for producing a 2-alkyl-2-cycloalken-1-one represented by general formula (2), comprising dehydrating and isomerizing a 2-(1-hydroxyalkyl)cycloalkan-1-one represented by general formula (1) in the presence of an acid and a platinum group metal catalyst:
wherein n is an integer of 1 or 2; and R1 and R2 are each independently a hydrogen atom or an alkyl group having 1 to 8 carbon atoms with the proviso that R1 and R2 may form a cyclopentane ring or a cyclohexane ring through a carbon atom adjacent thereto; and
wherein n, R1 and R2 are the same as defined above.
2. The process for producing a 2-alkyl-2-cycloalken-1-one according to claim 1, wherein the acid has a first acid dissociation constant (pKa) of 0 or more as measured at 25\xb0 C.
3. The process for producing a 2-alkyl-2-cycloalken-1-one according to claim 1, wherein the acid is a solid acid.
4. The process for producing a 2-alkyl-2-cycloalken-1-one according to claim 3, wherein an amount (mmolg) of acid sites of the solid acid from which NH3 is desorbed at a temperature of from 100 to 250\xb0 C. is larger than an amount (mmolg) of acid sites of the solid acid from which NH3 is desorbed at a temperature higher than 250\xb0 C., as measured by an ammonia temperature-programmed desorption (TPD) method.
5. The process for producing a 2-alkyl-2-cycloalken-1-one according to claim 1, wherein said dehydrating and isomerizing comprises (A) and (B) where (B) is carried out after (A),
(A): dehydrating and isomerizing the 2-(1-hydroxyalkyl)cycloalkan-1-one in an atmosphere in which a concentration of a hydrogen gas is from 5 to 45% by volume; and
(B): dehydrating and isomerizing the 2-(1-hydroxyalkyl)cycloalkan-1-one in an atmosphere in which a concentration of a hydrogen gas is 1% by volume or higher, and is lower, by 2% by volume or more, than the concentration of the hydrogen gas in the atmosphere present in (A).
6. The process for producing a 2-alkyl-2-cycloalken-1-one according to claim 1, wherein the platinum group metal catalyst is a Pd-containing catalyst.
7. The process for producing a 2-alkyl-2-cycloalken-1-one according to claim 5, wherein the reactions of (A) and (B) are carried out at a temperature of from 0 to 300\xb0 C.
8. The process for producing a 2-alkyl-2-cycloalken-1-one according to claim 5, wherein a reaction time of (A) is from 5 to 50% of a total reaction time of (A) and (B).
9. A process for producing an alkyl(3-oxo-alkylcycloalkyl)acetate represented by general formula (4), comprising:
reacting the 2-alkyl-2-cycloalken-1-one represented by general formula (2) which is obtained by the process as defined in claim 1, with a malonic acid diester represented by general formula (3); and
reacting the resulting reaction product with water:
wherein n, R1 and R2 are the same as defined above;
wherein R3 is an alkyl group having 1 to 3 carbon atoms with the proviso that the two R3 groups may be the same or different from each other; and
wherein n, R1, R2 and R3 are the same as defined above.