Orally Disintegrating Tablet Compositions Comprising Combinations of High and Low-Dose Drugs
The present invention is directed to pharmaceutical compositions comprising a plurality of taste-masked high-dose/low-dose drug-containing microparticles, dosage forms comprising such pharmaceutical compositions (such as an orally disintegrating tablet), and methods of making the pharmaceutical compositions and dosage forms of the present invention. Dosage forms comprising the pharmaceutical compositions of the present invention are improved homogeneous blends of high-dose and low-dose drugs which provide for more convenient and palatable administration of drug combinations, for example for treating pain, hyperglycemia, cardiovascular disease, and allergies.
1 . A pharmaceutical composition comprising a plurality of high-dose/low-dose drug-containing microparticles, wherein the drug-containing microparticles comprise:
(a) a core comprising a high-dose drug;
(b) a first coating disposed over the core, comprising a low-dose drug; and
(c) a second coating disposed over the core, comprising a water-insoluble polymer.
2 . The pharmaceutical composition of claim 1 , wherein the weight ratio of high-dose drug to low-dose drug in the pharmaceutical composition is at least about 20:1.
3 . The pharmaceutical composition of claim 1 , wherein the high-dose drug-containing core comprises particles of the high-dose drug, wherein the second coating is a modified release coating comprising a water insoluble polymer.
4 . (canceled)
5 . (canceled)
6 . (canceled)
7 . The pharmaceutical composition of claim 1 , wherein the second coating further comprises a plasticizer.
8 . The pharmaceutical composition of claim 7 , wherein the plasticizer is free of phthalates.
9 . The pharmaceutical composition of claim 7 , wherein the plasticizer is selected from the group consisting of glycerol, glycerol esters, acetylated mono- or diglycerides, glyceryl monostearate, glyceryl triacetate, glyceryl tributyrate, phthalates, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, citrates, acetylcitric acid tributyl ester, acetylcitric acid triethyl ester, tributyl citrate, acetyltributyl citrate, triethyl citrate, glyceroltributyrate, sebacates, diethyl sebacate, dibutyl sebacate, adipates, azelates, benzoates, chlorobutanol, polyethylene glycols, vegetable oils, fumarates, diethyl fumarate, malates, diethyl malate, oxalates, diethyl oxalate, succinates, dibutyl succinate, butyrates, cetyl alcohol esters, malonates, diethyl malonate, castor oil, and combinations thereof.
10 . The pharmaceutical composition of claim 1 , wherein the second coating substantially masks the taste of the high-dose drug and/or the low-dose drug and is disposed below the first coating.
11 . (canceled)
12 . The pharmaceutical composition of claim 10 , wherein the second coating further comprises a gastrosoluble polymer or a gastrosoluble pore-former.
13 . (canceled)
14 . The pharmaceutical composition of claim 12 , wherein the water-insoluble polymer is selected from the group consisting of water-insoluble cellulose ethers, ethylcellulose, water-insoluble cellulose esters, cellulose acetate, cellulose triacetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylic acid-methylmethacrylate copolymers, and mixtures thereof; and the gastrosoluble pore-former is selected from the group consisting of maltrin, aminoalkyl methacrylate copolymers, Eudragit® E100 Eudragit® EPO, polyvinylacetal diethylaminoacetate, AEA®, terpolymers based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, calcium carbonate, calcium phosphate, calcium saccharide, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium phosphate, and mixtures thereof.
15 . (canceled)
16 . The pharmaceutical composition of claim 1 , wherein the second coating further comprises a water-soluble polymer or an enteric polymer.
17 . The pharmaceutical composition of claim 16 , wherein the water-insoluble polymer is selected from the group consisting of water-insoluble cellulose ethers, ethylcellulose, water-insoluble cellulose esters, cellulose acetate, cellulose triacetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylic acid-methylmethacrylate copolymers, and mixtures thereof; the water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; and the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid/methylmethacrylate copolymers, shellac, and mixtures thereof.
18 . The pharmaceutical composition of claim 1 , wherein the second coating is disposed between the core and the first coating.
19 . The pharmaceutical composition of claim 18 , further comprising a third coating disposed over the first coating, wherein the third coating comprises a water-insoluble polymer which is the same as or different from the water-insoluble polymer of the second coating.
20 . The pharmaceutical composition of claim 19 , wherein the third coating substantially masks the taste of the low-dose drug.
21 . The pharmaceutical composition of claim 1 , further comprising a third coating disposed between the core and the first coating, wherein the third coating comprises a water-insoluble polymer which is the same as or different from the water-insoluble polymer and a second coating.
22 . The pharmaceutical composition of claim 21 , wherein the third coating substantially masks the taste of the high-dose drug.
23 . The pharmaceutical composition of claim 22 , wherein the third coating further comprises a gastrosoluble polymer or a gastrosoluble pore-former.
24 . The pharmaceutical composition of claim 1 , further comprising a flavorant coating disposed over the first coating, wherein the flavorant coating comprises a sweetener.
25 . The pharmaceutical composition of claim 24 , wherein the sweetener is selected from the group consisting of sucralose, lactitol, maltitol, sorbitol, and combinations thereof.
26 . The pharmaceutical composition of claim 24 , wherein the second coating is disposed between the core and the first coating.
27 . The pharmaceutical composition of claim 26 , wherein the second coating substantially modifies the release of the high-dose drug, and comprises a water insoluble or hydrophobic wax selected from the group consisting of glyceryl behenate, stearic acid, and hydrogenated castor oil.
28 . The pharmaceutical composition of claim 1 , wherein the high-dose drug comprises a non-opioid analgesic drug and the low-dose drug is comprises an opioid analgesic drug; or the high-dose drug comprises a bisguanidine and the low-dose drug comprises a sulfonylurea; or the high-dose drug comprises nicotinic acid and the low-dose drug comprises a statin; or the high-dose drug comprises a decongestant or a histamine antagonist and the low-dose drug comprises a histamine antagonist or a decongestant.
29 . The pharmaceutical composition of claim 28 , wherein the second coating is disposed between the core and the first coating, and the second coating substantially modifies the release of the high-dose drug.
30 . The pharmaceutical composition of claim 29 , further comprising a third coating disposed over the first coating, wherein the third coating comprises a water-insoluble polymer which is the same as or different from the water-insoluble polymer of the second coating, or the third coating comprises a flavorant coating; and the third coating substantially masks the taste of the low-dose drug.
31 . The pharmaceutical composition of claim 28 , wherein the high-dose drug is a non-steroidal anti-inflammatory drug and the low-dose drug is an opioid analgesic drug.
32 . The pharmaceutical composition of claim 31 , wherein the high-dose drug is selected from the group consisting of acetaminophen, aspirin, ibuprofen, ketoprofen, meloxicam, diclofenac potassium, etodolac, sulindac, indomethacin, and celecoxib; and the low-dose drug is selected from the group consisting of hydrocodone, oxymorphone, buprenorphine, fentanyl, and hydromorphone.
33 . The pharmaceutical composition of claim 32 , wherein the high-dose drug comprises acetaminophen, and the low-dose drug comprises hydrocodone.
34 . The pharmaceutical composition of claim 33 , further comprising a flavorant coating comprising a sweetener disposed over the first coating, wherein the second coating is disposed between the core and the first coating.
35 . The pharmaceutical composition of claim 34 , wherein the second coating comprises ethylcellulose, and the third coating comprises sucralose and an optional binder.
36 . The pharmaceutical composition of claim 28 , wherein the high-dose drug is metformin, and the low-dose drug is selected from the group consisting of glipizide, glyburide, glimepiride, repaglinide, nateglinide, rosiglitazone, pioglitazone, and troglitazone.
37 . The pharmaceutical composition of claim 28 , wherein the high-dose drug is nicotinic acid, and the low-dose drug is selected from the group consisting of lovastatin, fluvastatin, atorvastatin, cerivastatin, simvastatin, mevastatin, rosuvastatin, and pravastatin.
38 . The pharmaceutical composition of claim 28 , wherein the high-dose drug is selected from the group consisting of pseudoephedrine hydrochloride or sulfate, fexofenadine, and the low-dose drug is selected from the group consisting of cetirizine, loratidine, and phenylephrine.
39 . The pharmaceutical composition of claim 1 , further comprising a second population of high-dose drug-containing particles, wherein the second population of drug-containing particles comprises:
(i) a second core comprising the high-dose drug; and
(ii) a fourth coating comprising a water-insoluble polymer disposed over the second core, wherein the water-insoluble polymer of the fourth coating is the same as or different from the water-insoluble polymer of the second coating.
40 . The pharmaceutical composition of claim 39 , wherein the fourth coating further comprises a water-soluble polymer or an enteric polymer, and an optional gastrosoluble pore former.
41 . (canceled)
42 . (canceled)
43 . (canceled)
44 . A dosage form comprising the composition of claim 1 and one or more pharmaceutically acceptable excipients.
45 . (canceled)
46 . (canceled)
47 . The dosage form of claim 44 , wherein the dosage form further comprises rapidly dispersing granules comprising a disintegrant and a sugar alcohol and/or saccharide; wherein the dosage form is an ODT.
48 . (canceled)
49 . The dosage form of claim 47 , wherein the ODT substantially disintegrates within about 30 seconds when tested according to the USP <701> Disintegration Test.
50 . The dosage form of claim 47 , wherein the ODT releases at least about 75% of the total amount of the high-dose drug and at least about 75% of the low-dose drug in 30 minutes, when dissolution tested using USP Apparatus 1 (Baskets @ 100 rpm) or Apparatus 2 (Paddles @ 50 rpm), in 900 mL of a pH 1.2 buffer.
51 . The dosage form of claim 47 in the form of an ODT, comprising 500 mg of acetaminophen and 5 mg of hydrocodone bitartrate, wherein the ODT has an acetaminophen C max of 80-125% of 6115 ng/mL, a hydrocodone bitartrate C max of 80-125% of 20.14 ng/mL, an acetaminophen AUC of 80-125% of 19920 ng·hr/mL, and a hydrocodone bitartrate AUC of 80-125% of 141 ng·hr/mL.
52 . The dosage form of claim 47 in the form of an ODT, comprising 300 mg of acetaminophen and 10 mg of hydrocodone bitartrate, wherein the ODT has an acetaminophen C max of 80-125% of 3915 ng/mL, a hydrocodone bitartrate C max of 80-125% of 40.53 ng/mL, an acetaminophen AUC of 80-125% of 12794 ng·hr/mL, and a hydrocodone bitartrate AUC of 80-125% of 280 ng·hr/mL.
53 . The dosage form of claim 47 , wherein said the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, crosslinked carboxymethyl cellulose of sodium, low-substituted hydroxypropylcellulose and mixtures thereof and the sugar alcohol or saccharide is selected from the group consisting of mannitol, xylitol, maltol, maltitol, sorbitol, lactose, sucralose, maltose, and combinations thereof.
54 . The dosage form of claim 47 , wherein the high-dose/low-dose drug-containing microparticles have an average particle size of less than about 400 μm, the rapidly dispersing granules have an average particle size of less than about 300 μm, and the disintegrant and sugar alcohol and/or saccharide have an average particle size of less than about 30 μm.
55 . A method for preparing the pharmaceutical composition of claim 1 , comprising:
(1) preparing cores comprising a high-dose drug;
(2) coating the high-dose drug-containing cores of step (1) with a low-dose drug layer, thereby forming high-dose/low-dose drug-containing microparticles; and
(3) coating the high-dose drug-containing cores of step (1) and/or the high-dose/low-dose drug-containing microparticles of step (2) with a second coating comprising a water-insoluble polymer.
56 - 65 . (canceled)
66 . A method of preparing the dosage form of claim 44 , comprising:
(1) preparing cores comprising the high-dose drug;
(2) coating the high-dose drug-containing cores of step (1) with a sustained-release coating comprising a water-insoluble polymer, a pharmaceutically acceptable solvent, and an optional plasticizer;
(3) coating the sustained-release coated high-dose drug-containing cores of step (2) with the low-dose drug, a pharmaceutically acceptable solvent, and an optional binder, thereby forming high-dose/low-dose drug containing microparticles;
(4) coating the high-dose/low-dose drug-containing microparticles of step (3) with a taste-masking coating comprising a water-insoluble polymer and a pharmaceutically acceptable solvent; or a flavorant coating comprising a sweetener, a pharmaceutically acceptable solvent, and an optional binder;
(5) mixing the taste-masked or flavorant-coated high-dose/low-dose drug-containing microparticles of step (4) with at least one pharmaceutically acceptable excipient; and
(6) forming a tablet or a capsule.
67 . The method of claim 66 , further comprising:
(i) preparing a second population of cores comprising the high-dose drug, wherein the high-dose drug-containing cores of steps (1) and (i) are the same or different;
(ii) coating the second population of high-dose drug-containing cores of step (i) with a taste-masking layer, thereby forming taste-masked high-dose drug-containing cores;
wherein:
step (5) further comprises mixing the taste-masked or flavorant-coated high-dose/low-dose drug-containing microparticles of step (4) and the taste-masked high-dose drug-containing cores of step (ii).
68 . The method of claim 66 , further comprising:
(i) granulating a disintegrant and a sugar alcohol and/or saccharide each having an average particle size of less than about 30 μm, thereby forming rapidly-dispersing microgranules having an average particle size of less than about 300 μm;
wherein:
step (5) further comprises mixing the taste-masked high-dose/low-dose drug-containing microparticles of step (4) and the rapidly-dispersing microgranules of step (i); and
step (6) comprises compressing the mixture of step (5), thereby forming an ODT.
69 . (canceled)
70 . A method of treating pain comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 32 to a patient in need thereof.
71 . A method of treating hyperglycemia comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 36 to a patient in need thereof.
72 . A method of treating cardiovascular disease comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 37 to a patient in need thereof.
73 . A method of treating hypercholesterolemia comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 37 to a patient in need thereof.
74 . A method of treating indoor or outdoor allergies comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 38 to a patient in need thereof.