Patent Application
20230172866
The present invention relates to an oral pharmaceutical composition of a peptide amide compound. The present invention further relates to a method for preparing the oral pharmaceutical composition and the use thereof.
Polypeptide drugs can be used for treating various diseases due to its wide indications, high safety, remarkable selectivity and effectiveness. With the development of biotechnology, a large number of peptide drugs have entered the market. Currently, the commercially available peptide preparations are mainly in the form of injections and nasal sprays, which bring great inconvenience to patients. For patients, the oral administration is simpler and does not directly damage the skin or mucous membranes, thereby reducing patients' pain and improving patient compliance. However, the oral administration of polypeptide drugs is limited by a series of barriers, specifically, the polypeptide drugs are easily degraded and destroyed by proteolytic enzymes in the digestive tract, and are difficult to pass through the epithelial cell layer of the inner wall of the small intestine due to the large molecular weight, resulting in low oral bioavailability and limiting the clinical use thereof. For example, the absolute bioavailability of the listed semaglutide tablets is only 0.4%-1%. In order to achieve the blood concentration required for the onset of action, the oral dose is relatively high, and it is difficult to achieve oral administration of some polypeptide drugs with a high cost or a narrow therapeutic window. Therefore, improving the oral bioavailability of polypeptide drugs is the key to achieving the oral administration of polypeptide drugs.
Most polypeptide drugs are susceptible to degradation by a protease activated by gastric acid, resulting in a decrease in the activity thereof. Enteric coating technology is usually used to protect polypeptides, which, however, requires complicated process and is of high cost.
WO 2019/015644 discloses a class of peptide amide compounds with novel structure and good analgesic effect, and the general formula thereof is as follows:
Such compounds have a significant agonizing effect on human κ-opioid receptors. Specifically, compound A is disclosed therein:
with a chemical name of 7-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)-2-acetyl-2,7-diazaspiro[3.5]nonane.
The present invention provides an oral polypeptide pharmaceutical composition, which is prepared by combining a polypeptide drug with a specific absorption enhancer and other non-active ingredients, thereby promoting the permeability of the polypeptide drug in the gastrointestinal tract, improving the oral bioavailability of the polypeptide drug, and achieving the oral administration so as to improve patient compliance.
The present invention provides a simple intragastric administration technology, which greatly simplifies the technological process and can greatly improve the oral bioavailability of the polypeptide compound A.
One object of the present invention is to provide an oral pharmaceutical composition of compound A:
The present invention significantly improves the oral bioavailability of compound A, and is more favorable to develop a drug with the compound A.
Another object of the present invention is to provide a method for preparing the oral pharmaceutical composition.
Another object of the present invention is to provide the use of the oral pharmaceutical composition.
In one aspect, the present invention provides an oral pharmaceutical composition comprising:
a) compound A:
and
b) an absorption enhancer.
In some embodiments of the present invention, the absorption enhancer is selected from one or more of N-[8-(2-hydroxybenzoyl)amino]octanoic acid or a pharmaceutically acceptable salt thereof, 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof, lauroyl-L-carnitine or a hydrochloride thereof, sodium caprylate, sodium caprate, capric acid, caprylocaproyl macrogolglyceride; preferably, the pharmaceutically acceptable salt is selected from sodium salt, potassium salt or calcium salt.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) an absorption enhancer selected from N-[8-(2-hydroxybenzoyl)amino]octanoic acid or a pharmaceutically acceptable salt thereof.
In some embodiments of the present invention, the weight ratio of compound A to N-[8-(2-hydroxybenzoyl)amino]octanoic acid or a pharmaceutically acceptable salt thereof is 1:20-1:80, preferably 1:40-1:60, further preferably 1:40.
In some embodiments of the present invention, the weight ratio of compound A to N-[8-(2-hydroxybenzoyl)amino]octanoic acid or a pharmaceutically acceptable salt thereof is 1:20.
In some embodiments of the present invention, the weight ratio of compound A to N-[8-(2-hydroxybenzoyl)amino]octanoic acid or a pharmaceutically acceptable salt thereof is 1:30.
In some embodiments of the present invention, the weight ratio of compound A to N-[8-(2-hydroxybenzoyl)amino]octanoic acid or a pharmaceutically acceptable salt thereof is 1:40.
In some embodiments of the present invention, the weight ratio of compound A to N-[8-(2-hydroxybenzoyl)amino]octanoic acid or a pharmaceutically acceptable salt thereof is 1:80.
In some embodiments of the present invention, the absorption enhancer is N-[8-(2-hydroxybenzoyl)amino]sodium caprylate.
In some embodiments of the present invention, the absorption enhancer is N-[8-(2-hydroxybenzoyl)amino]potassium caprylate.
In some embodiments of the present invention, the absorption enhancer is N-[8-(2-hydroxybenzoyl)amino]calcium caprylate.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) an absorption enhancer selected from N-[8-(2-hydroxybenzoyl)amino]octanoic acid or a pharmaceutically acceptable salt thereof;
c) one or more non-active ingredients selected from:
(1) a filler, which is preferably selected from one or more of microcrystalline cellulose, lactose, mannitol, anhydrous calcium hydrogenphosphate, pregelatinized starch, calcium hydrogenphosphate dihydrate;
(2) a binder, which is preferably selected from one or more of povidone, copovidone, a cellulose derivative, wherein the cellulose derivative is selected from one or more of hydroxypropylcellulose, hypromellose, methyl cellulose;
(3) a disintegrant, which is preferably selected from one or more of crospovidone, low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch;
(4) a pH regulator, which is preferably selected from one or more of citric acid, anhydrous citric acid, tartaric acid, fumaric acid, sodium citrate, calcium hydrogenphosphate, calcium carbonate;
(5) a surfactant, which is preferably selected from one or more of polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium dodecyl sulfate;
(6) a lubricant, which is preferably selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
and
b) an absorption enhancer selected from 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof.
In some embodiments of the present invention, the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:20-1:200, preferably 1:40-1:80, further preferably 1:40.
In some embodiments of the present invention, the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:20.
In some embodiments of the present invention, the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:40.
In some embodiments of the present invention, the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:80.
In some embodiments of the present invention, the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:100.
In some embodiments of the present invention, the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 1:200.
In some embodiments of the present invention, the weight ratio of compound A to 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof is 3:200.
In some embodiments of the present invention, the absorption enhancer is 4-[(4-chloro-2-hydroxy-benzoyl)amino]sodium butyrate.
In some embodiments of the present invention, the absorption enhancer is 4-[(4-chloro-2-hydroxy-benzoyl)amino]potassium butyrate.
In some embodiments of the present invention, the absorption enhancer is 4-[(4-chloro-2-hydroxy-benzoyl)amino]calcium butyrate.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) an absorption enhancer selected from 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
c) one or more non-active ingredients selected from:
(1) a filler, which is preferably selected from one or more of microcrystalline cellulose, lactose, mannitol, anhydrous calcium hydrogenphosphate, pregelatinized starch, calcium hydrogenphosphate dihydrate;
(2) a binder, which is preferably selected from one or more of povidone, copovidone, a cellulose derivative, wherein the cellulose derivative is selected from one or more of hydroxypropylcellulose, hypromellose, methyl cellulose;
(3) a disintegrant, which is preferably selected from one or more of crospovidone, low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch;
(4) a pH regulator, which is preferably selected from one or more of citric acid, anhydrous citric acid, tartaric acid, fumaric acid, sodium citrate, calcium hydrogenphosphate, calcium carbonate;
(5) a surfactant, which is preferably selected from one or more of polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium dodecyl sulfate;
(6) a lubricant, which is preferably selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate.
In some embodiments of the present invention, the lubricant is magnesium stearate.
In some embodiments of the present invention, the filler is microcrystalline cellulose and/or anhydrous calcium hydrogenphosphate.
In some embodiments of the present invention, the binder is povidone.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
b) 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
c) a lubricant.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:the lubricant is 1:(20-200):(0.2-2).
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:the lubricant is 1:200:2.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
b) 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
c) magnesium stearate.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:magnesium stearate is 1:(20-200):(0.2-2).
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:magnesium stearate is 1:200:2.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
b) 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
c) a filler;
d) a binder.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:the filler:the binder is 1:(20-200):200:5.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:the filler:the binder is 1:200:200:5.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
b) 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
c) microcrystalline cellulose;
d) povidone.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:microcrystalline cellulose:povidone is 1:(20-200):200:5.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:microcrystalline cellulose:povidone is 1:200:200:5.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
b) 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
c) a filler;
d) a binder;
e) a lubricant.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:the filler:the binder:the lubricant is 1:(20-200):200:5:(1-5).
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:the filler:the binder:the lubricant is 1:200:200:5:(4-5), for example 1:200:200:5:4.06.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:the filler:the binder:the lubricant is 3:200:200:5:1.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:the filler:the binder:the lubricant is 3:200:200:5:4.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
b) 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
c) microcrystalline cellulose;
d) povidone;
e) magnesium stearate.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:microcrystalline cellulose:povidone:magnesium stearate is (1-3):(20-200):200:5:(1-5).
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:microcrystalline cellulose:povidone:magnesium stearate is 1:200:200:5:(4-5), for example 1:200:200:5:4.06.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:microcrystalline cellulose:povidone:magnesium stearate is 3:200:200:5:4.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
b) 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
c) povidone;
d) anhydrous calcium hydrogenphosphate;
e) magnesium stearate.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:povidone:anhydrous calcium hydrogenphosphate:magnesium stearate is (1-3):(20-200):5:200:(1-5).
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:povidone:anhydrous calcium hydrogenphosphate:magnesium stearate is 3:200:5:200:4.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
b) 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
c) a surfactant;
d) a filler;
e) a lubricant.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:the surfactant:the filler:the lubricant is (1-3):(20-200):(3-9):200:(1-5), for example 3:200:6:200:1.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
b) 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
c) propylene glycol monolaurate and/or polyethylene glycol (for example polyethylene glycol 300);
d) anhydrous calcium hydrogenphosphate;
e) magnesium stearate.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
b) 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof;
c) propylene glycol monolaurate;
d) polyethylene glycol 300;
e) anhydrous calcium hydrogenphosphate;
f) magnesium stearate.
In some embodiments of the present invention, the weight ratio of compound A:4-[(4-chloro-2-hydroxy-benzoyl)amino]butyric acid or a pharmaceutically acceptable salt thereof:propylene glycol monolaurate:polyethylene glycol 300:anhydrous calcium hydrogenphosphate:magnesium stearate is (1-3):(20-200):(3-9):(3-9):200:(1-5), for example 3:200:3:3:200:1.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
and
b) an absorption enhancer selected from lauroyl-L-carnitine or a hydrochloride thereof.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine or a hydrochloride thereof is 1:10-1:150, for example 1:10, 1:15, 1:20, 1:30, 1:50, 1:75, 1:100 or 1:150.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) an absorption enhancer selected from lauroyl-L-carnitine.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine is 1:10-1:50, preferably 1:10-1:20, further preferably 1:10.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine is 1:10.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine is 1:20.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine is 1:50.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
and
b) an absorption enhancer selected from lauroyl-L-carnitine hydrochloride.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:15-1:150, preferably lauroyl-L-carnitine hydrochloride is used in an amount of 75-150 mg, further preferably lauroyl-L-carnitine hydrochloride is used in an amount of 75 mg.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:15.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:20.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:30.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:75.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:100.
In some embodiments of the present invention, the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:150.
In some embodiments of the present invention, when the absorption enhancer in the oral pharmaceutical composition is selected from lauroyl-L-carnitine or a hydrochloride thereof, the pharmaceutical composition does not comprise enteric coated excipients.
In some embodiments of the present invention, when the absorption enhancer in the oral pharmaceutical composition is selected from lauroyl-L-carnitine or a hydrochloride thereof, the pharmaceutical composition is not in the form of an enteric coated tablet or an enteric coated capsule.
In some embodiments of the present invention, when the absorption enhancer in the oral pharmaceutical composition is selected from lauroyl-L-carnitine or a hydrochloride thereof, the pharmaceutical composition is in the form of a gastric coated capsule, gastric coated tablet or gastric coated granule.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) an absorption enhancer selected from lauroyl-L-carnitine or a hydrochloride thereof;
c) one or more non-active ingredients selected from:
(1) a filler, which is preferably selected from one or more of microcrystalline cellulose, lactose, mannitol, anhydrous calcium hydrogenphosphate, pregelatinized starch, calcium hydrogenphosphate dihydrate;
(2) a binder, which is preferably selected from one or more of povidone, copovidone, a cellulose derivative, the cellulose derivative is selected from one or more of hydroxypropylcellulose, hypromellose, methyl cellulose;
(3) a disintegrant, which is preferably selected from one or more of crospovidone, low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch;
(4) a pH regulator, which is preferably selected from one or more of citric acid, anhydrous citric acid, tartaric acid, fumaric acid, sodium citrate, calcium hydrogenphosphate, calcium carbonate;
(5) a surfactant, which is preferably selected from one or more of polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium dodecyl sulfate;
(6) a lubricant, which is preferably selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) lauroyl-L-carnitine;
c) a pH regulator.
In some embodiments of the present invention, the weight ratio of compound A:lauroyl-L-carnitine:the pH regulator is 1:(10-50):24.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) lauroyl-L-carnitine;
c) citric acid.
In some embodiments of the present invention, the weight ratio of compound A:lauroyl-L-carnitine:citric acid is 1:(10-50):24.
In some embodiments of the present invention, the weight ratio of compound A:lauroyl-L-carnitine:citric acid is 1:50:24.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) an absorption enhancer selected from sodium caprate.
In some embodiments of the present invention, the weight ratio of compound A to sodium caprate is 1:50-1:200, preferably 1:100-1:200, most preferably 1:100.
In some embodiments of the present invention, the weight ratio of compound A to sodium caprate is 1:50.
In some embodiments of the present invention, the weight ratio of compound A to sodium caprate is 1:100.
In some embodiments of the present invention, the weight ratio of compound A to sodium caprate is 1:200.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) an absorption enhancer selected from sodium caprate;
c) one or more non-active ingredients selected from:
(1) a filler, which is preferably selected from one or more of microcrystalline cellulose, lactose, mannitol, anhydrous calcium hydrogenphosphate, pregelatinized starch, calcium hydrogenphosphate dihydrate;
(2) a binder, which is preferably selected from one or more of povidone, copovidone, a cellulose derivative, wherein the cellulose derivative is selected from one or more of hydroxypropylcellulose, hypromellose, methyl cellulose;
(3) a disintegrant, which is preferably selected from one or more of crospovidone, low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch;
(4) a glyceride, which is preferably selected from one or more of monocaprylin, tricaprylin.
(5) a surfactant, which is preferably selected from one or more of caprylocaproyl macrogolglyceride, polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium dodecyl sulfate;
(6) a lubricant, which is preferably selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate.
In some embodiments of the present invention, the binder is povidone.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) sodium caprate;
c) povidone.
In some embodiments of the present invention, the weight ratio of compound A:sodium caprate:povidone is 1:(50-200):50, for example 1:50:50, 1:100:50 or 1:200:50.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
and
b) an absorption enhancer selected from capric acid;
c) one or more non-active ingredients selected from:
(1) a filler, preferably the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, anhydrous calcium hydrogenphosphate, pregelatinized starch, calcium hydrogenphosphate dihydrate;
(2) a binder, which is preferably selected from one or more of povidone, copovidone, a cellulose derivative, wherein the cellulose derivative is selected from one or more of hydroxypropylcellulose, hypromellose, methyl cellulose;
(3) a disintegrant, which is preferably selected from one or more of crospovidone, low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch;
(4) a glyceride, which is preferably selected from one or more of monocaprylin, tricaprylin. (5) a surfactant, preferably the surfactant is selected from one or more of caprylocaproyl macrogolglyceride, polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium dodecyl sulfate;
(6) a lubricant, which is preferably selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) an absorption enhancer selected from caprylocaproyl macrogolglyceride.
In some embodiments of the present invention, the weight ratio of compound A to caprylocaproyl macrogolglyceride is 1:600-1:3600, preferably 1:2400-1:3600, most preferably 1:2400.
In some embodiments of the present invention, the weight ratio of compound A to caprylocaproyl macrogolglyceride is 1:600.
In some embodiments of the present invention, the weight ratio of compound A to caprylocaproyl macrogolglyceride is 1:1200.
In some embodiments of the present invention, the weight ratio of compound A to caprylocaproyl macrogolglyceride is 1:1800.
In some embodiments of the present invention, the weight ratio of compound A to caprylocaproyl macrogolglyceride is 1:2400.
In some embodiments of the present invention, the weight ratio of compound A to caprylocaproyl macrogolglyceride is 1:3600.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) an absorption enhancer selected from caprylocaproyl macrogolglyceride;
c) one or more non-active ingredients selected from:
(1) a hydrophobic medium, which is preferably selected from one or more of coconut oil, castor oil, olive oil;
(2) a surfactant, which is preferably selected from one or more of polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium dodecyl sulfate;
(3) a glyceride, which is preferably selected from one or more of monocaprylin, tricaprylin.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) an absorption enhancer selected from caprylocaproyl macrogolglyceride;
c) one or more non-active ingredients selected from:
(1) a hydrophobic medium, which is preferably selected from one or more of coconut oil, castor oil, olive oil;
(2) a surfactant, which is preferably selected from one or more of polyethylene glycol, poloxamer, phospholipid, Tween 80, Span 40, propylene glycol monolaurate, sodium dodecyl sulfate;
(3) a glyceride other than caprylocaproyl macrogolglyceride, preferably the glyceride is selected from one or more of monocaprylin, tricaprylin.
In some embodiments of the present invention, the oral pharmaceutical composition comprises:
a) compound A:
and
b) caprylocaproyl macrogolglyceride;
c) capric acid.
In some embodiments of the present invention, the weight ratio of compound A:caprylocaproyl macrogolglyceride:capric acid is 1:(3000-6000):(50-200), for example 1:3000:(50-100) or 1:(4000-6000):200, for example 1:3000:50, 1:3000:75, 1:3000:100, 1:4000:200 or 1:6000:200.
In some embodiments of the present invention, the oral pharmaceutical composition is in the form of a solution, a suspension, a granule, a powder, a capsule, a tablet or other oral dosage forms.
In some embodiments of the present invention, the oral pharmaceutical composition is in the form of a gastric coated capsule, a gastric coated tablet or a gastric coated granule.
In some embodiments of the present invention, compound (A) is present in the oral pharmaceutical composition at a therapeutically effective amount or unit dose. In some embodiments of the present invention, compound (A) is present in the oral pharmaceutical composition at a does of less than 1 mg, 1-3 mg, 3-5 mg, 5-10 mg, 10-25 mg, 25-32 mg, 32-100 mg, or more than 100 mg.
In some embodiments of the present invention, the above-mentioned oral pharmaceutical composition is prepared as follows: compound A, the absorption enhancer and other non-active ingredients are mixed directly, and then filled into capsules or compressed into tablets.
In some embodiments of the present invention, the above-mentioned oral pharmaceutical composition is prepared as follows: compound A, the absorption enhancer and other non-active ingredients are wet granulated and then filled into capsules or compressed into tablets.
In some embodiments of the present invention, the above-mentioned oral pharmaceutical composition is prepared as follows: compound A, the absorption enhancer and the hydrophilic non-active ingredients are wet granulated, then dispersed in a hydrophobic medium, and filled into capsules.
In the present invention, the oral pharmaceutical composition can also be prepared as a solution, a suspension, a granule, a powder or other oral dosage forms using a conventional preparation process.
In the present invention, the capsule may be a hard capsule or a soft capsule.
The present invention also provides the use of the oral pharmaceutical composition in preparing a drug for treating diseases or conditions related to the κ-opioid receptor.
The present invention also provides a method for treating diseases or conditions related to the κ-opioid receptor in a subject, comprising administering the oral pharmaceutical composition of any one of the foregoing embodiments to the subject.
In some embodiments of the present invention, the diseases or conditions related to the κ-opioid receptor are selected from pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma.
In some embodiments of the present invention, the pain is selected from neuropathic pain, somatic pain, visceral pain and skin pain.
In some embodiments of the present invention, the diseases or conditions are selected from arthritis pain, kidney stone pain, hysterotrismus, dysmenorrhea, endometriosis, dyspepsia, pain after surgery, pain after medical treatment, ocular pain, otitis pain, breakthrough cancer pain, and pain associated with GI disorders (gastrointestinal disorders).
In one embodiment of the present invention, the oral pharmaceutical composition can be used for treating acute and chronic pain and itching.
In certain embodiments, the oral pharmaceutical composition is administered to the subject 1, 2, or 3 times daily.
In certain embodiments, the subject is a mammal, such as a bovine, an equine, a porcine, a canine, a feline, a rodent, a primate animal, wherein, particularly preferred subjects are humans.
Unless stated to the contrary, the terms used in the description and claims have the following meanings.
(1) SNAC: sodium N-[8-(2-hydroxybenzoyl)amino]octanoate.
(2) 4-CNAB: sodium 4-[(4-chloro-2-hydroxy-benzoyl)amino]butyrate.
The implementation process and beneficial effects of the present invention are described in detail below through specific examples, which are intended to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of the present invention.
The raw materials/reagents used in the examples are commercially available or self-prepared, and the formulations in the examples are all at single preparation dosage.
Unless otherwise specified, “0 #capsule” in the following examples refers to the shell that can be used to prepare gastric coated hard capsules with the specification of 0 #.
Compound A was prepared with reference to the method disclosed in WO 2019/015644.
3 mg of compound A was dissolved in physiological saline to prepare 0.06 mg/ml physiological saline solution.
5 mg of compound A and 150 mg of SNAC were mixed uniformly and then filled into 0 #capsules.
5 mg of compound A and 100 mg of SNAC were mixed uniformly and then filled into 0 #capsules.
5 mg of compound A and 200 mg of SNAC were mixed uniformly and then filled into 0 #capsules.
5 mg of compound A and 400 mg of SNAC were mixed uniformly and then filled into 0 #capsules.
5 mg of compound A, 50 mg of lauroyl-L-carnitine and 120 mg of citric acid were mixed uniformly and then filled into 0 #capsules.
5 mg of compound A and 100 mg of 4-CNAB were mixed uniformly and then filled into 0 #capsules.
5 mg of compound A and 200 mg of 4-CNAB were mixed uniformly and then filled into 0 #capsules.
5 mg of compound A and 400 mg of 4-CNAB were mixed uniformly and then filled into 0 #capsules.
1 mg of compound A and 200 mg of 4-CNAB were mixed uniformly and then filled into 0 #capsules.
1 mg of compound A, 200 mg of 4-CNAB and 2 mg of magnesium stearate were mixed uniformly and then compressed into tablets.
1 mg of compound A, 200 mg of 4-CNAB, 200 mg of microcrystalline cellulose, and 5 mg of povidone were mixed uniformly and then filled into 0 #capsules.
1 mg of compound A, 200 mg of 4-CNAB, 200 mg of microcrystalline cellulose, 5 mg of povidone, and 4.06 mg of magnesium stearate were mixed uniformly and then compressed into tablets.
1 mg of compound A, 200 mg of 4-CNAB, 200 mg of microcrystalline cellulose, and 5 mg of povidone were weighed; compound A and 4-CNAB were dissolved in water, subjected to rotary evaporation, dried, ground and pulverized; and same were mixed with the other non-active ingredients uniformly and then filled into 0 #capsules.
1 mg of compound A, 200 mg of 4-CNAB, 200 mg of microcrystalline cellulose, 5 mg of povidone, and 4.06 mg of magnesium stearate were weighed; compound A and 4-CNAB were dissolved in water, subjected to rotary evaporation, dried, ground and pulverized; and same were mixed with the other non-active ingredients and then compressed into tablets.
2 mg of compound A and 200 mg of 4-CNAB were mixed uniformly and then filled into 0 #capsules.
3 mg of compound A and 200 mg of 4-CNAB were mixed uniformly and then filled into 0 #capsules.
10 mg of compound A and 200 mg of 4-CNAB were mixed uniformly and then filled into 0 #capsules.
3 mg of compound A, 200 mg of 4-CNAB, 5 mg of povidone, 200 mg of microcrystalline cellulose, and 4 mg of magnesium stearate were mixed uniformly and then filled into 0 #capsules.
3 mg of compound A, 200 mg of 4-CNAB, 5 mg of povidone, 200 mg of anhydrous calcium hydrogenphosphate, and 4 mg of magnesium stearate were mixed uniformly and then filled into 0 #capsules.
{circle around (1)} 3 mg of compound A and 200 mg of 4-CNAB were mixed uniformly.
{circle around (2)} 3 mg of propylene glycol monolaurate and 3 mg of polyethylene glycol 300 were absorbed by and dispersed with 200 mg of anhydrous calcium hydrogenphosphate.
{circle around (3)} The samples from the above two steps were mixed uniformly.
{circle around (4)} 1 mg of magnesium stearate was added, and the mixture was mixed uniformly and then filled into 0 #capsules.
100 mg of compound A, 5 g of povidone K12 and 5 g of sodium caprate were completely dissolved in 100 g of purified water, then freeze-dried and passed through a 120-mesh sieve and then filled into 0 #capsules.
100 mg of compound A, 5 g of povidone K12 and 10 g of sodium caprate were completely dissolved in 100 g of purified water, then freeze-dried and passed through a 120-mesh sieve and then filled into 0 #capsules.
25 mg of compound A, 1.25 g of povidone K12 and 5 g of sodium caprate were completely dissolved in 100 g of purified water, then freeze-dried and passed through a 120-mesh sieve and then filled into 00 #capsules.
1 mg of compound A and 0.6 g of caprylocaproyl macrogolglyceride were completely dissolved in purified water to obtain a 10 ml solution.
1 mg of compound A and 1.2 g of caprylocaproyl macrogolglyceride were completely dissolved in purified water to obtain a 10 ml solution.
1 mg of compound A and 1.8 g of caprylocaproyl macrogolglyceride were completely dissolved in purified water to obtain a 10 ml solution.
1 mg of compound A and 2.4 g of caprylocaproyl macrogolglyceride were completely dissolved in purified water to obtain a 10 ml solution.
1 mg of compound A and 3.6 g of caprylocaproyl macrogolglyceride were completely dissolved in purified water to obtain a 10 ml solution.
1 mg of compound A and 0.6 g of caprylocaproyl macrogolglyceride were mixed and suspended uniformly by ultrasonic dispersion, and then filled into 0 #capsules.
1 mg of compound A and 1.8 g of caprylocaproyl macrogolglyceride were mixed and suspended uniformly by ultrasonic dispersion, and then filled into 0 #capsules.
5 mg of compound A and 3.0 g of caprylocaproyl macrogolglyceride were mixed and suspended uniformly by ultrasonic dispersion, and then filled into 0 #capsules.
1 mg of compound A, 3 g of caprylocaproyl macrogolglyceride and 50 mg of sodium caprate were completely dissolved in purified water to obtain a 10 ml solution.
1 mg of compound A, 3 g of caprylocaproyl macrogolglyceride and 75 mg of sodium caprate were completely dissolved in purified water to obtain a 10 ml solution.
1 mg of compound A, 3 g of caprylocaproyl macrogolglyceride and 100 mg of sodium caprate were completely dissolved in purified water to obtain a 10 ml solution.
1 mg of compound A, 4 g of caprylocaproyl macrogolglyceride and 200 mg of mgcapric acid were completely dissolved in purified water to obtain a 10 ml solution.
1 mg of compound A, 6 g of caprylocaproyl macrogolglyceride and 200 mg of mgcapric acid were completely dissolved in purified water to obtain a 10 ml solution.
5 mg of compound A and 50 mg of lauroyl-L-carnitine were filled into 0 #capsules.
5 mg of compound A and 100 mg of lauroyl-L-carnitine were filled into 0 #capsules.
5 mg of compound A and 250 mg of lauroyl-L-carnitine were filled into 0 #capsules.
5 mg of compound A and 100 mg of lauroyl-L-carnitine were filled into 0 #enteric coated capsules.
5 mg of compound A and 75 mg of lauroyl-L-carnitine hydrochloride were filled into 0 #capsules.
5 mg of compound A and 100 mg of lauroyl-L-carnitine hydrochloride were filled into 0 #capsules.
5 mg of compound A and 150 mg of lauroyl-L-carnitine hydrochloride were filled into 0 #capsules.
1 mg of compound A and 75 mg of lauroyl-L-carnitine hydrochloride were filled into 0 #capsules.
1 mg of compound A and 100 mg of lauroyl-L-carnitine hydrochloride were filled into 0 #capsules.
1 mg of compound A and 150 mg of lauroyl-L-carnitine hydrochloride were filled into 0 #capsules.
1 mg of compound A and 200 mg of sodium caproate were filled into 0 #capsules.
1 mg of compound A and 100 mg of sodium caprylate were filled into 0 #capsules.
1 mg of compound A and 200 mg of sodium laurate were filled into 0 #capsules.
1 mg of compound A and 200 mg of sodium myristate were filled into 0 #capsules.
1 mg of compound A and 200 mg of sodium palmitate were filled into 0 #capsules.
The physiological saline solution of compound A obtained in Example 1 was orally administered at a single dose to male Beagle dogs (3 for each preparation), venous blood was taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
After a single oral administration of the capsules obtained in Example 2 to male Beagle dogs (3 for each preparation) with 5 tablets of the samples for each dog, venous blood was taken at 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
By means of adding 150 mg of SNAC to the formulations, the bioavailability is significantly improved, and the absolute bioavailability is up to 3.46%.
After a single oral administration of the capsules obtained in Examples 3-5 to male Beagle dogs (3 for each preparation) with 1 tablet of the samples for each dog, venous blood was taken at 0, 0.083, 0.25, 0.5, 0.75, 1, 2, 4, 8, 10, 12 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
In the case of the weight ratio of compound A to SNAC being in the range of 1:20-1:80, the bioavailability of compound A can be significantly improved, and the absolute bioavailability is better when the weight ratio thereof is 1:40.
After a single oral administration of the capsules obtained in Example 6 to male Beagle dogs (3 for each preparation) with 5 tablets of the samples for each dog, venous blood was taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 28, 48 and 72 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
Adding 50 mg of lauroyl-L-carnitine and 120 mg of citric acid to the formulations provides a good absorption promoting effect, and the absolute bioavailability of compound A is up to 6.62%.
After a single oral administration of the capsules obtained in Examples 7-9 to male Beagle dogs (3 for each preparation) with 1 tablet of the samples for each dog, venous blood was taken at 0, 0.083, 0.25, 0.5, 0.75, 1, 2, 4, 8, 10, 12 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
2.60 ± 0.49
In the case of the weight ratio of compound A to 4-CNAB being in the range of 1:20-1:80, the bioavailability of compound A can be significantly improved, and the absolute bioavailability is better when the weight ratio thereof is 1:40.
After a single oral administration of the preparation samples prepared in Examples 10-15 by different processes to male Beagle dogs (3 for each preparation) with 1 tablet of the samples for each dog, venous blood was taken at 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 28 and 48 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
By means of adding 4-CNAB to the formulations, the absolute bioavailability of samples at different dosage forms and prepared by different preparation processes is increased significantly.
After a single oral administration of the preparation samples obtained in Examples 22-24 to male Beagle dogs (3 for each preparation) with 1 tablet of the samples for each dog, venous blood was taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
In the formulations, the bioavailability of compound A is improved by sodium caprate in a dose-response manner. When the weight ratio of compound A to sodium caprate is 1:50, the bioavailability does not change significantly, while the weight ratio of compound A to sodium caprate is 1:100 and 1:200, the bioavailability is increased significantly.
After a single oral administration of the preparation samples obtained in Examples 25-29 to male Beagle dogs (3 for each preparation) with 10 ml of the samples for each dog, venous blood was taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
In the formulations, the bioavailability is significantly improved when the weight ratio of compound A to caprylocaproyl macrogolglyceride is 1:600-1:3600, and the absolute bioavailability is better when the weight ratio is 1:2400.
After a single oral administration of the preparation samples obtained in Examples 25, 27 and 30-32 to male Beagle dogs (3 for each preparation), venous blood was taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
Both solutions and capsules obtained by adding caprylocaproyl macrogolglyceride to the formulations can significantly improve the bioavailability of compound A, and the improvement levels of the bioavailability of compound A are similar at the specification of 1 mg and 5 mg.
After a single oral administration of the preparation samples obtained in Examples 33-35 to male Beagle dogs (3 for each preparation) with 10 ml of the samples for each dog, venous blood was taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
In the formulations, the bioavailability of compound A is significantly improved when the weight ratio of compound A:caprylocaproyl macrogolglyceride:sodium caprate is 1:3000:50-100, and the bioavailability is better when the weight ratio is 1:3000:100.
After a single oral administration of the preparation samples obtained in Examples 36-37 to male Beagle dogs (3 for each preparation) with 10 ml of the samples for each dog, venous blood was taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
In the formulations, the bioavailability of compound A is significantly improved when the weight ratio of compound A:caprylocaproyl macrogolglyceride:capric acid is 1:(4000-6000):200, and the bioavailability is better when the weight ratio is 1:6000:200.
After a single oral administration of the preparation samples obtained in Examples 43-45 to male Beagle dogs (3 for each preparation) with 1 tablet of the samples for each dog, venous blood was taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
In the formulations, the bioavailability of compound A is significantly improved when the weight ratio of compound A to lauroyl-L-carnitine is 1:10-1:50, and the bioavailability is better when the weight ratio is 1:20.
When the weight ratio of compound A to lauroyl-L-carnitine is 1:20, the bioavailability of the gastric coated capsule preparation is 4 times that of the enteric coated capsule preparation.
After a single oral administration of the preparation samples obtained in Examples 42-47 to male Beagle dogs (3 for each preparation) 1 tablet of the samples for each dog, venous blood was taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
The bioavailability of compound A is significantly improved when the weight ratio of compound A to lauroyl-L-carnitine hydrochloride is 1:15-1:150, and the bioavailability is better when the weight ratio is 1:15 and 1:75.
After a single oral administration of the preparation samples obtained in Examples 24 and 48-52 to male Beagle dogs (3 for each preparation) 1 tablet of the samples for each dog, venous blood was taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h, and the absolute bioavailability (F %) (relative to intravenous dose of compound A) was calculated from the area under the curve obtained from the points where the plasma concentration of compound A was taken as a function of time.
Fatty acid salts with different aliphatic chain lengths have different effects on bioavailability. Among the fatty acid salts with aliphatic chain lengths of C6-C16, only the fatty acid salts with aliphatic chain length of C10 can significantly increase the bioavailability of compound A.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202010179149.6 | Mar 2020 | CN | national |
| 202110268405.3 | Mar 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/081224 | 3/17/2021 | WO |
