COMPOSITIONS FOR TREATING PARKINSON’S DISEASE AND QUALITATIVE ASSESSMENT THEREOF
The present disclosure provides compositions comprising Compound 1 uses thereof, and methods of manufacture thereof.
1 . A composition comprising greater than about 0.15% by weight of Compound 1:
or a pharmaceutically acceptable salt thereof.
2 . The composition of claim 1 , comprising greater than or equal to about 50% by weight of Compound 1.
3 . The composition of claim 1 or 2 , comprising greater than or equal to about 75% by weight of Compound 1.
4 . The composition of claim 1 , comprising greater than or equal to about 85% by weight of Compound 1.
5 . The composition of claim 1 , comprising greater than or equal to about 90% by weight of Compound 1.
6 . The composition of claim 1 , comprising greater than or equal to about 95% by weight of Compound 1.
7 . The composition of claim 1 , wherein the composition comprises less than 10% by weight of an organic solvent.
8 . The composition of claim 1 , wherein the composition comprises less than 5% by weight of an organic solvent.
9 . The composition of claim 7 or 8 , wherein the organic solvent is selected from the group consisting of methanol, dichloromethane, acetone, ethanol, isopropanol, ethyl acetate, acetaldehyde, heptane, and acetaldehyde.
10 . The composition of claim 1 , wherein the composition comprises less than or equal to about 4% by weight of water.
11 . The composition of claim 1 , wherein the composition comprises less than or equal to about 2% by weight of water.
12 . The composition of claim 1 , wherein the composition comprises less than or equal to about 1.5% by weight of water.
13 . The composition of claim 10 or 12 , wherein a weight of water is determined by Karl Fisher analysis.
14 . A pharmaceutical composition comprising, carbidopa, entacapone, and greater than 0.15% by weight of Compound 1:
or a pharmaceutically acceptable salt thereof.
15 . The pharmaceutical composition of claim 14 , further comprising levodopa.
16 . The pharmaceutical composition of claim 14 or 15 , characterized in that the pharmaceutical composition is stable for 16 weeks or longer when stored at about 5° C.
17 . The pharmaceutical composition of claim 14 or 15 , characterized in that the pharmaceutical composition is stable for 16 weeks or longer when stored at 5° C.±3° C.
18 . The pharmaceutical composition of claim 14 , characterized in that the pharmaceutical composition is stable for 16 hours or longer at physiological temperature (e.g., 37° C.).
19 . The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition comprises:
about 1-15% by weight of levodopa;
about 0.1-2% by weight of carbidopa; and
about 1-7.5% by weight of entacapone.
20 . The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition comprises:
about 2% by weight of levodopa;
about 0.5% by weight of carbidopa; and
about 2% by weight of entacapone.
21 . The pharmaceutical composition of claim 14 , further comprising one or more pharmaceutical carriers.
22 . The pharmaceutical composition of claim 21 , wherein the one or more pharmaceutical carriers is a polysaccharide.
23 . The pharmaceutical composition of claim 22 , wherein the polysaccharide is sodium carboxymethyl cellulose.
24 . The pharmaceutical composition of claim 22 , wherein the pharmaceutical composition comprises about 2-3% by weight of the sodium carboxymethyl cellulose.
25 . The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is in the form of a gel.
26 . The pharmaceutical composition of claim 25 , wherein the pH of the gel is less than about 5.7.
27 . The pharmaceutical composition of claim 25 or 26 , wherein the pH of the gel is about 4.5 to about 5.5.
28 . The pharmaceutical composition of claim 25 , wherein the pH of the gel is about 5.0.
29 . The pharmaceutical composition of claim 25 , wherein the viscosity of the gel is from about 3000 to about 5000 CPS.
30 . The pharmaceutical composition of claim 25 , wherein the viscosity of the gel is from about 3500 to about 4500 CPS.
31 . The pharmaceutical composition of claim 25 , wherein the gel is formulated to be administered intestinally.
32 . The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is in the form of an oral dosage.
33 . A method of treating Parkinson's Disease (PD) in a patient comprising administering to the subject a pharmaceutical composition of claim 14 .
34 . The method of claim 33 , wherein the Parkinson's Disease is Advanced Parkinson's Disease.
35 . The method of claim 33 or 34 , wherein the pharmaceutical composition is administered to the patient over a 16 hour course.
36 . The method of claim 33 , wherein about 25% of a total daily dose of the pharmaceutical composition is administered to the patient in the morning.
37 . The method of claim 33 , wherein the pharmaceutical composition is administered to the patient once daily.
38 . The method of claim 33 , wherein the pharmaceutical composition is administered directly to the intestine.
39 . The method of claim 38 , wherein the pharmaceutical composition is administered by a PEG-J tube.
40 . A method of treating Parkinson's Disease (PD) in a patient comprising administering to the subject a pharmaceutical composition of claim 32 .
41 . The method of claim 40 , wherein the Parkinson's Disease is Advanced Parkinson's Disease.
42 . A method of manufacturing a composition comprising Compound 1
comprising contacting Compound 2
with Compound 3
in the presence of an organic solvent and a sulfate salt.
43 . The method of claim 42 , wherein the sulfate salt is sodium sulfate, potassium sulfate, magnesium sulfate, calcium sulfate, or ammonium sulfate.
44 . The method of claim 42 or 43 , wherein the sulfate salt is sodium sulfate.
45 . The method of claim 42 , wherein the organic solvent comprises at least one of methanol, ethanol, propanol, isopropanol, and butanol.
46 . The method of claim 42 , wherein the organic solvent is ethyl acetate.
47 . The method of claim 45 , wherein the organic solvent is methanol.
48 . The method of claim 42 , further comprising suspending Compound 1 in an organic solvent, and filtering a solid form of Compound 1, to thereby provide a composition comprising Compound 1 that is greater than 90% by weight free from impurities.
49 . The method of claim 48 , wherein the composition comprising Compound 1 is greater than 95% by weight free from impurities.
50 . The method of claim 49 , wherein the composition comprising Compound 1 is greater than 99% by weight free from impurities.
51 . The method of claim 50 , wherein the composition comprising Compound 1 is substantially free from impurities.
52 . The method of claim 42 , wherein the organic solvent is dichloromethane.
53 . A method of characterizing the purity of a pharmaceutical composition comprising levodopa, carbidopa, and entacapone, the method comprising determining a quantity of Compound 1:
in the pharmaceutical composition by comparison of a sample of the pharmaceutical composition to a reference standard, wherein the reference standard comprises a known quantity of Compound 1.
54 . The method of claim 53 , wherein the pharmaceutical composition is characterized as being high purity if the pharmaceutical composition comprises less than about 0.15% by weight of Compound 1.
55 . The method of claim 53 or 54 , wherein the reference standard is a composition comprising 95% or greater by weight of Compound 1.
56 . The method of claim 53 , wherein the purity of the pharmaceutical composition is assessed by high pressure liquid chromatography (HPLC) using:
a Waters SunFire C18 Column, 150×4.6 mm, 3.5 um, UV/Vis detector;
a mobile phase A that is 0.06% triflouroacetic acid (TFA) in water; and
a mobile phase B that is 0.04% TFA in (80:20 MeOH;H 2 O).
57 . A method of using a reference standard comprising a known quantity of Compound 1:
to determine a level of purity of a pharmaceutical composition, the method comprising comparing a quantity of Compound 1 in the reference standard to a quantity of Compound 1 in the pharmaceutical composition.
58 . The method of claim 57 , wherein the purity of the pharmaceutical composition is assessed by high pressure liquid chromatography (HPLC) using:
a Waters SunFire C18 Column, 150×4.6 mm, 3.5 um, UV/Vis detector;
a mobile phase A that is 0.06% triflouroacetic acid (TFA) in water; and
a mobile phase B that is 0.04% TFA in (80:20 MeOH;H 2 O).