METHODS OF USE OF PPAR AGONIST COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF
The present disclosure relates to methods of use of an agonist of peroxisome proliferator-activated receptors delta (PPARδ) (e.g., Compound (I) or a pharmaceutically acceptable salt thereof disclosed herein), for example, for treating patients having primary mitochondrial myopathies (PMM). The present disclosure also relates to a pharmaceutical composition comprising an agonist of peroxisome proliferator-activated receptors delta (PPARδ) and croscarmellose sodium.
1 . A method of treating a primary mitochondrial myopathy or primary mitochondrial myopathies comprising administering to a patient in need thereof an amount of 30 mg to 125 mg of Compound (I):
or a pharmaceutically acceptable salt thereof in an amount equivalent to 30 mg to 125 mg of Compound (I) per day.
2 . The method of claim 1 , wherein the patient in need thereof is administered a hemisulfate salt of Compound (I).
3 . The method of claim 1 , wherein the amount of Compound (I) is 30-50 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 30-50 mg/day of Compound (I).
4 . The method of claim 1 , wherein the amount of Compound (I) is 50-75 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 50-75 mg/day of Compound (I).
5 . The method of claim 1 , wherein the amount of Compound (I) is 75-125 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 75-125 mg/day of Compound (I).
6 . The method of claim 1 , wherein the amount of Compound (I) is 30 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 30 mg/day of Compound (I).
7 . The method of claim 1 , wherein the amount of Compound (I) is 50 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 50 mg/day of Compound (I).
8 . The method of claim 1 , wherein the amount of Compound (I) is 75 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 75 mg/day of Compound (I).
9 . The method of claim 1 , wherein the amount of Compound (I) is 125 mg/day, or a pharmaceutically acceptable salt thereof in an amount equivalent to 125 mg/day of Compound (I).
10 . (canceled)
11 . The method of claim 1 , wherein the primary mitochondrial myopathy is Alpers Disease, chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre Syndrome (KSS), Leber Hereditary Optic Neuropathy (LHON), Leigh Syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fiber disease (MERRF), neuropathy-ataxia-retinitis pigmentosa (NARP), or Pearson Syndrome.
12 . The method of claim 1 , wherein the patient in need thereof is previously treated with coenzyme Q10 (CoQ10), carnitine, creatine, or other mitochondrial disease-focused vitamin or supplemental therapy.
13 . The method of claim 1 , comprising administering to the patient a pharmaceutical composition comprising Compound (I), or a pharmaceutically acceptable salt thereof, and croscarmellose sodium.
14 . The method of claim 1 , comprising administering to the patient a pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate.
15 . The method of claim 1 , comprising administering to the patient a pharmaceutical composition comprising Compound (I), wherein the pharmaceutical composition comprises the following components, and the weight percentage of each component, relative to the total weight of the pharmaceutical composition, is as follows:
hemisulfate salt of Compound (I)
12-17%
lactose monohydrate
55-65%
microcrystalline cellulose
5-15%
croscarmellose sodium
8-13%
hydroxypropyl cellulose
2-5%
magnesium stearate
1-3%.
16 . The method of claim 1 , comprising administering to the patient a pharmaceutical composition comprising Compound (I), wherein the pharmaceutical composition comprises the following components, and the weight percentage of each component, relative to the total weight of the pharmaceutical composition, is as follows:
hemisulfate salt of Compound (I)
5-8%
lactose monohydrate
65-72%
microcrystalline cellulose
5-15%
croscarmellose sodium
8-13%
hydroxypropyl cellulose
2-5%
magnesium stearate
1-3%.
17 . The method of claim 1 , comprising administering to the patient a pharmaceutical composition comprising Compound (I), wherein the pharmaceutical composition comprises the following components, and the weight percentage of each component, relative to the total weight of the pharmaceutical composition, is as follows:
hemisulfate salt of Compound (I)
2-4%
lactose monohydrate
69-74%
microcrystalline cellulose
5-15%
croscarmellose sodium
8-13%
hydroxypropyl cellulose
2-5%
magnesium stearate
1-3%.
18 . The method of claim 15 , wherein the pharmaceutical composition further comprises a film-coating agent, and the weight percentage of the film-coating agent, relative to the total weight of the pharmaceutical composition, is 2-4%.
19 . The method of claim 1 , comprising administering to the patient a pharmaceutical composition comprising Compound (I), wherein the pharmaceutical composition comprises the following components, and the weight percentage of each component, relative to the total weight of the pharmaceutical composition, is as follows:
hemisulfate salt of Compound (I)
15.4%
lactose monohydrate
59.1%
microcrystalline cellulose
10%
croscarmellose sodium
10%
hydroxypropyl cellulose
3%
magnesium stearate
2.5%;
or wherein the pharmaceutical composition comprises the following components, and the weight percentage of each component, relative to the total weight of the pharmaceutical composition, is as follows:
hemisulfate salt of Compound (I)
14.9%
lactose monohydrate
57.4%
microcrystalline cellulose
9.7%
croscarmellose sodium
9.7%
hydroxypropyl cellulose
2.9%
magnesium stearate
2.4%
a film-coating agent
2.9%.
20 . The method of claim 1 , comprising administering to the patient a pharmaceutical composition comprising Compound (I), wherein the pharmaceutical composition comprises the following components, and the weight percentage of each component, relative to the total weight of the pharmaceutical composition, is as follows:
hemisulfate salt of Compound (I)
6.1%
lactose monohydrate
68.4%
microcrystalline cellulose
10%
croscarmellose sodium
10%
hydroxypropyl cellulose
3%
magnesium stearate
2.5%;
or wherein the pharmaceutical composition comprises the following components, and the weight percentage of each component, relative to the total weight of the pharmaceutical composition, is as follows:
hemisulfate salt of Compound (I)
6.0%
lactose monohydrate
66.4%
microcrystalline cellulose
9.7%
croscarmellose sodium
9.7%
hydroxypropyl cellulose
2.9%
magnesium stearate
2.4%
a film-coating agent
2.9%.
21 . The method of claim 1 , comprising administering to the patient a pharmaceutical composition comprising Compound (I), wherein the pharmaceutical composition comprises the following components, and the weight percentage of each component, relative to the total weight of the pharmaceutical composition, is as follows:
hemisulfate salt of Compound (I)
3.1%
lactose monohydrate
71.4%
microcrystalline cellulose
10%
croscarmellose sodium
10%
hydroxypropyl cellulose
3%
magnesium stearate
2.5%;
or wherein the pharmaceutical composition comprises the following components, and the weight percentage of each component, relative to the total weight of the pharmaceutical composition, is as follows:
hemisulfate salt of Compound (I)
3.0%
lactose monohydrate
69.3%
microcrystalline cellulose
9.7%
croscarmellose sodium
9.7%
hydroxypropyl cellulose
2.9%
magnesium stearate
2.4%
a film-coating agent
2.9%.
22 .- 24 . (canceled)