U.S. patent application number 12/772770 was filed with the patent office on 2010-12-30 for orally disintegrating tablet compositions comprising combinations of high and low-dose drugs.
Invention is credited to James Clevenger, Michael Gosselin, Jin-Wang Lai, Gopi Venkatesh.
Application Number | 20100330150 12/772770 |
Document ID | / |
Family ID | 43032597 |
Filed Date | 2010-12-30 |
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United States Patent
Application |
20100330150 |
Kind Code |
A1 |
Venkatesh; Gopi ; et
al. |
December 30, 2010 |
Orally Disintegrating Tablet Compositions Comprising Combinations
of High and Low-Dose Drugs
Abstract
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.
Inventors: |
Venkatesh; Gopi; (Vandalia,
OH) ; Gosselin; Michael; (Springboro, OH) ;
Clevenger; James; (Vandalia, OH) ; Lai; Jin-Wang;
(Springboro, OH) |
Correspondence
Address: |
Cooley LLP
ATTN: Patent Group, 777 6th Street, N.W., Suite 1100
Washington
DC
20001
US
|
Family ID: |
43032597 |
Appl. No.: |
12/772770 |
Filed: |
May 3, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61174780 |
May 1, 2009 |
|
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61174788 |
May 1, 2009 |
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Current U.S.
Class: |
424/439 ;
424/490; 424/494; 424/495; 424/497; 427/2.14; 514/226.5;
514/255.04; 514/255.06; 514/275; 514/279; 514/282; 514/290;
514/315; 514/317; 514/329; 514/342; 514/369; 514/617; 514/653 |
Current CPC
Class: |
A61K 9/5084 20130101;
A61P 3/06 20180101; A61P 3/10 20180101; A61K 45/06 20130101; A61K
9/5073 20130101; A61K 31/415 20130101; A61K 31/00 20130101; A61K
9/2081 20130101; A61K 31/4415 20130101; A61P 29/00 20180101; A61P
9/00 20180101; A61K 31/407 20130101; A61K 31/5415 20130101; A61K
31/4468 20130101; A61P 25/04 20180101; A61K 31/405 20130101; A61K
31/40 20130101; A61P 37/08 20180101; A61P 11/00 20180101; A61P
43/00 20180101; A61K 31/485 20130101; A61K 31/196 20130101; A61K
9/5047 20130101; A61P 9/10 20180101; A61K 31/60 20130101; A61K
9/5078 20130101; A61K 31/192 20130101; A61K 31/00 20130101; A61K
2300/00 20130101; A61K 31/192 20130101; A61K 2300/00 20130101; A61K
31/196 20130101; A61K 2300/00 20130101; A61K 31/40 20130101; A61K
2300/00 20130101; A61K 31/405 20130101; A61K 2300/00 20130101; A61K
31/407 20130101; A61K 2300/00 20130101; A61K 31/415 20130101; A61K
2300/00 20130101; A61K 31/4415 20130101; A61K 2300/00 20130101;
A61K 31/4468 20130101; A61K 2300/00 20130101; A61K 31/485 20130101;
A61K 2300/00 20130101; A61K 31/5415 20130101; A61K 2300/00
20130101; A61K 31/60 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/439 ;
424/490; 424/497; 424/494; 424/495; 514/282; 514/329; 514/279;
514/226.5; 514/255.06; 514/315; 514/342; 514/617; 514/369; 514/275;
514/317; 514/255.04; 514/290; 514/653; 427/2.14 |
International
Class: |
A61K 9/62 20060101
A61K009/62; A61K 9/50 20060101 A61K009/50; A61K 9/56 20060101
A61K009/56; A61K 9/58 20060101 A61K009/58; A61K 31/445 20060101
A61K031/445; A61K 31/4355 20060101 A61K031/4355; A61K 31/5415
20060101 A61K031/5415; A61K 31/4965 20060101 A61K031/4965; A61K
31/4453 20060101 A61K031/4453; A61K 31/4436 20060101 A61K031/4436;
A61K 31/165 20060101 A61K031/165; A61K 31/427 20060101 A61K031/427;
A61K 31/505 20060101 A61K031/505; A61K 31/495 20060101 A61K031/495;
A61K 31/4545 20060101 A61K031/4545; A61K 31/137 20060101
A61K031/137; B05D 3/00 20060101 B05D003/00; A61P 3/10 20060101
A61P003/10; A61P 9/10 20060101 A61P009/10; A61P 11/00 20060101
A61P011/00 |
Claims
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.RTM. E100
Eudragit.RTM. EPO, polyvinylacetal diethylaminoacetate, AEA.RTM.,
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.sub.maxof 80-125% of 6115 ng/mL, a
hydrocodone bitartrate C.sub.max of 80-125% of 20.14 ng/mL, an
acetaminophen AUC of 80-125% of 19920 nghr/mL, and a hydrocodone
bitartrate AUC of 80-125% of 141 nghr/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.sub.max of 80-125% of 3915
ng/mL, a hydrocodone bitartrate C.sub.max of 80-125% of 40.53
ng/mL, an acetaminophen AUC of 80-125% of 12794 nghr/mL, and a
hydrocodone bitartrate AUC of 80-125% of 280 nghr/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 .mu.m, the rapidly dispersing granules have an
average particle size of less than about 300 .mu.m, and the
disintegrant and sugar alcohol and/or saccharide have an average
particle size of less than about 30 .mu.m.
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 .mu.m, thereby forming
rapidly-dispersing microgranules having an average particle size of
less than about 300 .mu.m; 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.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. Provisional
Application Nos. 61/174,780 and 61/174,788, both filed May 1,
2009.
BACKGROUND OF THE INVENTION
[0002] Moderate to severe pain can be effectively treated with
opioid analgesics such as hydrocodone. However since many opioids
are habit forming, the risk of abuse can be moderated by combining
the opioid with a non-opioid analgesic such as acetaminophen,
aspirin, ibuprofen, etc., thereby allowing effective pain
management at lower doses of the opioid analgesic. Other medical
conditions such as diabetes (hyperglycemia), cardiovascular
disease, and schizophrenia are also effectively treated with drug
combinations. However, the need to administer multiple dosage forms
can result in problems such as patient compliance issues or dosage
administration errors.
[0003] One approach to preventing such problems is to combine
multiple drugs into a single dosage form in order to minimize the
number of different dosage forms to be administered, and to ensure
that the combination of drugs are administered in the correct
relative dosages. For example, Vicodin.RTM. is an immediate-release
(IR) tablet containing 5 mg of hydrocodone bitartrate and 500 mg of
acetaminophen, intended for the management of severe pain. However,
it is very difficult to reproducibly prepare homogeneous blends of
hydrocodone and acetaminophen at the required 1:100 weight ratio
(e.g., with a content uniformity having an RSD of 6% or less, as
required by regulatory agencies worldwide). Thus, there is a need
for methods for uniformly and reproducibly combining a high-dose
drug and a low-dose drug in a single dosage form.
[0004] The two most widely used types of oral dosage forms are
tablets and capsules. However, such dosage forms have several
disadvantages. For example, it is estimated that 50% of the
population have problems swallowing tablets (see Seager, Journal of
Pharmacol. and Pharm. 50, pages 375-382, 1998). It is especially
hard for the elderly or for children to swallow tablets or
capsules, or to medicate patients who are unable or unwilling to
swallow tablets or capsules. Furthermore, conventional tablets or
capsules usually must be administered with water, which is not
always possible or convenient. This leads to poor or even
non-compliance with the treatment which consequently has a negative
impact on the efficacy of the treatment. Orally disintegrating
tablet (ODT) dosage forms have been introduced to address such
problems, because ODTs rapidly dissolve or disintegrate in the
buccal cavity and the resulting slurry or suspension of the drug is
more readily swallowed by the patient. Such dosage forms are also
more convenient because they need not be administered with
water.
[0005] Because the ODT dosage form disintegrates in the oral cavity
of the patient, the disintegrated ODT must be palatable. For
example, if one or more of the drugs in the ODT are bitter tasting,
the drug-containing particles comprising the ODT must be
taste-masked, e.g., by coating the drug-containing particles with a
polymeric membrane to prevent release of the drug in the oral
cavity. However, the main drawback of taste-masking is slower
dissolution of the drug(s) from effectively taste-masked
microparticles. The more bitter the drug, the thicker the
taste-masking coating required and hence, the slower the drug
release from the taste-masked drug-containing particles. Thus the
very process of effectively taste-masking the drug-containing
particles results in a substantially slower drug release, with
concomitant slower systemic absorption of the drug in the
gastrointestinal tract.
[0006] In some cases, slower drug release is a particular problem
for ODT dosage forms which are intended to be bioequivalent to a
reference listed immediate-release (IR) dosage form of the drug,
for example bioequivalent to conventional tablet or effervescent
tablet based IR dosage forms having a T.sub.max of less than an
hour, and rapid-onset of action. For such bioequivalent immediate
release ODT products, it is essential that the taste-masking layer
should not substantially lower the release rate of the drug. For
ODT compositions containing combinations of two or more drugs
(e.g., a high-dose/low-dose drug formulation) this problem is
particularly acute, because the different drug components of the
combination ODT may require different levels of taste-masking
depending on the degree of bitterness of the drugs (i.e., drugs
with low bitterness levels may require little or no taste-masking,
while highly bitter drugs may require substantial taste-masking
layers). Adding further complication, taste-masking layers reduce
the release rate of poorly soluble drugs more than for more soluble
drugs. In certain cases, an ODT composition comprising taste-masked
low-dose drug particles combined with sustained release coated
high-dose drug particles may be more desirable.
[0007] In addition, ODTs must rapidly disintegrate on contact with
the saliva in the oral cavity while also providing sufficient
tablet hardness and strength sufficient to withstand attrition
during packaging, storage, transportation, distribution, and end
use, and also provide acceptable organoleptic properties (e.g., be
palatable as described above, and exhibit a smooth (non-gritty)
mouthfeel), and acceptable pharmacokinetic properties (i.e., rapid
onset, C.sub.max, AUC properties similar to the reference listed
drugs). Achieving all of these properties is often quite difficult
because thicker taste-masking layers may be required for adequate
taste-masking of more soluble and/or more bitter drugs, which may
make it difficult to obtain the required rapid drug release.
[0008] Thus, the preparation of clinically effective pharmaceutical
compositions comprising at least a high-dose and a low-dose drug,
particularly in the form of an ODT, is quite difficult and requires
the balancing of many different and often competing
requirements.
SUMMARY OF THE INVENTION
[0009] In one embodiment, the present invention is directed to a
pharmaceutical composition comprising a plurality of
modified-release coated high-dose/low-dose drug-containing
microparticles, wherein the drug-containing microparticles
comprise: [0010] (a) a core comprising a high-dose drug; [0011] (b)
a first coating comprising a low-dose drug disposed over the core;
and [0012] (c) a second coating disposed over the core,
modified-release coating (e.g., a taste-masking or sustained
release coating to achieve taste-masking and/or extended/sustained
release properties), comprising a comprising a water-insoluble
polymer.
[0013] In another embodiment, the present invention is directed to
a pharmaceutical composition comprising a plurality of taste-masked
non-opioid analgesic drug/opioid analgesic drug-containing
microparticles, wherein the drug-containing microparticles
comprise: [0014] (a) a core comprising a high dose drug such as a
non-opioid analgesic drug; [0015] (b) a layer comprising a low dose
drug such as an opioid analgesic drug disposed over the high-dose
drug-containing core; and [0016] (c) at least one modified-release
coating layer (e.g., a taste-masking or sustained release coating
layer) disposed over the high-dose drug core as well as the
high-dose/low-dose drug-containing core, wherein the at least one
taste-masking or sustained release coating layer comprises a
water-insoluble polymer, or the combination of a water-insoluble
polymer with one or more of a water-soluble polymer, an enteric
polymer, or a gastrosoluble pore-former.
[0017] In still another embodiment, the present invention is
directed to a pharmaceutical composition comprising a plurality of
high-dose/low-dose drug-containing microparticles in combination
with high-dose drug-containing microparticles, wherein the
drug-containing microparticles comprise: [0018] (a) a core
comprising a high-dose drug; [0019] (b) an optional sealant coat
disposed over the high-dose drug-containing core; [0020] (c) a
sustained-release coating layer disposed over the high-dose
drug-containing core; [0021] (d) a low-dose drug layer disposed
over the sustained-release coating layer; [0022] (e) a sealant coat
disposed over the low-dose drug layer; and [0023] (f) a
taste-masking layer disposed over the sealant coat;
[0024] wherein the sustained-release coating layer comprises a
water-insoluble polymer optionally in combination with one or more
of a water soluble or enteric polymer; thereby imparting
taste-masking and/or sustained release properties to the high-dose
drug-containing microparticles; and the taste-masking layer
disposed over the low-dose drug-containing microparticles comprises
a water-insoluble polymer optionally in combination with a
gastrosoluble polymer or a gastrosoluble pore-former.
[0025] In yet another embodiment, the present invention is directed
to a pharmaceutical composition comprising a plurality of
modified-release coated high-dose/low-dose drug-containing
microparticles, wherein the drug-containing microparticles
comprise: [0026] (a) a core comprising a high-dose drug; [0027] (b)
an optional sealant coat disposed over the high-dose
drug-containing core; [0028] (c) a taste-masking coating layer
disposed over the sealant coating layer; [0029] (d) a low-dose drug
layer disposed over the taste-masking coating layer; [0030] (e) a
sealant coat disposed over the low-dose drug layer; and [0031] (f)
a flavorant layer disposed over the sealant coat.
[0032] In still yet another embodiment, the present invention is
directed to an ODT dosage form comprising the combination of one of
the pharmaceutical compositions of the present invention, rapidly
dispersing microgranules, and optionally a second population of
high-dose drug containing particles comprising a high-dose
drug-containing core coated with a modified-release coating
layer.
[0033] In a further embodiment, the present invention is directed
to a method for preparing the pharmaceutical compositions disclosed
herein, comprising: [0034] (1) preparing cores comprising a
high-dose drug; [0035] (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 [0036] (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 coating layer comprising a water-insoluble polymer, thereby
forming taste-masked and sustained-release high-dose/low-dose
drug-containing microparticles.
[0037] In a further embodiment, the present invention is directed
to a method for preparing an ODT pharmaceutical composition as
disclosed herein, further comprising: [0038] (1) preparing rapidly
dispersing microgranules comprising a sugar alcohol, a saccharide,
or a mixture thereof with an average particle size of not more than
30 .mu.m and a super disintegrant; [0039] (2) preparing a blend
comprising high-dose/low-dose drug-containing microparticles with
high-dose drug-containing microparticles and rapidly dispersing
microgranules [0040] (3) compressing the blend into orally
disintegrating tablets.
[0041] In a further embodiment, the present invention is directed
to a method of treating a patient subject to a disease or
condition, comprising administering a therapeutically effective
amount of the high-dose drug and low-dose drug-containing
compositions of the present invention to the patient in need
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] FIG. 1 illustrates a schematic of one embodiment of a
modified release coated microparticle comprising a high-dose
drug-containing core, as well as a taste-masked low-dose/high-dose
drug-containing microparticle.
[0043] FIG. 2 illustrates the plasma concentration-time profiles
for acetaminophen of hydrocodone bitartrate/acetaminophen tablets
observed in the pilot PK (pharmacokinetics) study.
[0044] FIG. 3 illustrates the plasma concentration-time profiles
for hydrocodone bitartrate of hydrocodone bitartrate/acetaminophen
tablets observed in the pilot PK (pharmacokinetics) study.
[0045] FIG. 4 illustrates the plasma concentration-time profiles
for acetaminophen of Acetaminophen ODTs versus Panadol.RTM.
observed in the pilot PK (pharmacokinetics) study.
DETAILED DESCRIPTION OF THE INVENTION
[0046] All documents cited herein are incorporated by reference in
their entirety for all purposes. The citation of any document is
not to be construed as an admission that it is prior art with
respect to the present invention.
[0047] The present invention is directed to pharmaceutical
compositions comprising a plurality of modified-release coated
high-dose/low-dose drug-containing microparticles as described
herein. The compositions of the present invention provide
combination high-dose drug/low-dose drug-containing oral dosage
forms meeting one or more of the following specifications: [0048]
Taste-masked and/or sustained release coated microparticles wherein
the low-dose drug is layered onto high-dose drug-containing
microparticles having a blend homogeneity meeting United States
Pharmacopoeia requirements; [0049] effectively taste-masked
microparticles, irrespective of the differences in solubility and
bitterness of the high-dose and low-dose drugs; [0050] in some
embodiments further comprising rapidly dispersing granules so as to
provide an ODT dosage form which rapidly disintegrates on contact
with saliva in the oral cavity, and form a smooth, easy-to-swallow
suspension containing taste-masked drug particles; [0051] drug
particles with an average particle diameter of not more than about
400 .mu.m to provide a smooth mouthfeel leaving no aftertaste
(i.e., little or minimal drug release with a non-gritty or
non-chalky taste) until swallowed; [0052] providing rapid,
substantially-complete release of the dose from the taste-masked
immediate-release drug particles upon arrival in the stomach,
thereby enhancing the probability of being bioequivalent to the
corresponding immediate-release reference-listed-drug product(s) or
providing a target release profile of the high-dose drug to be
suitable for a once- or twice-daily dosing regimen; and [0053]
providing robust tablet formulations exhibiting acceptable tablet
hardness and friability suitable for packaging in HDPE bottles,
and/or transportation in bulk or as packaged tablets for commercial
distribution and end use.
[0054] The term "drug", "active" or "active pharmaceutical
ingredient" as used herein includes a pharmaceutically acceptable
and therapeutically effective compound, pharmaceutically acceptable
salts, stereoisomers and mixtures of stereoisomers, solvates
(including hydrates), polymorphs, and/or esters thereof. When
referring to a drug in the descriptions of the various embodiments
of the invention, the reference encompasses the base drug,
pharmaceutically acceptable salts, stereoisomers and mixtures of
stereoisomers, solvates (including hydrates), polymorphs, and/or
esters thereof, unless otherwise indicated.
[0055] The terms "layer" or "coating" as used herein are
synonymous. For example, the terms sealant layer, drug layer, etc.,
are synonymous with sealant coating, drug coating, etc.
[0056] The terms "orally disintegrating tablet" or "ODT" refers to
a tablet which disintegrates rapidly in the oral cavity of a
patient after administration, without the need for chewing. The
rate of disintegration can vary, but is faster than the rate of
disintegration of conventional solid dosage forms (e.g., tablets or
capsules) which are intended to be swallowed immediately after
administration, or chewable solid dosage forms. Orally
disintegrating compositions of the present invention can contain
pharmaceutically acceptable ingredients which swell, dissolve or
otherwise facilitate the disintegration or dissolution of the ODT
composition. Such ingredients can include pharmaceutical
disintegrant such as crospovidone, water-soluble sugar alcohol such
as mannitol, a saccharide such as lactose, or a mixture thereof, a
water-soluble binder such as povidone, a meltable solid (e.g., a
hydrophobic wax such as polyethylene glycol, glyceryl behenate,
stearic acid, hydrogenated castor oil, etc.) which can release the
drugs upon entering the stomach. Orally disintegrating compositions
of the present invention may be in the form of a tablet, a
minitablet, a capsule or a monodose sachet, or a dry powder for
reconstitution.
[0057] The term "about", as used herein to refer to a numerical
quantity, includes "exactly". For example, "about 60 second"
includes 60 seconds, exactly, as well as values close to 60 seconds
(e.g., 50 seconds, 55 seconds, 59 seconds, 61 seconds, 65 seconds,
70 seconds, etc.).
[0058] Unless stated otherwise, the amount of the various coatings
or layers described herein (the "coating weight") is expressed as
the percentage weight gain of the particles or beads provided by
the dried coating, relative to the initial weight of the particles
or beads prior to coating. Thus, a 10% coating weight refers to a
dried coating which increases the weight of a particle by 10%.
[0059] As used herein, the term "immediate-release" or IR refers to
release of greater than or equal to about 50%, or greater than
about 75%, or greater than about 90%, or greater than about 95% of
the drug within about 2 hours, more particularly within about one
hour following administration of the dosage form.
[0060] The term "substantially disintegrates" means a level of
disintegration amounting to disintegration of at least about 50%,
at least about 60%, at least about 70%, at least about 80%, at
least about 90%, or about 100% disintegration of the ODT
composition.
[0061] As used herein, the term "modified-release" coating
encompasses coatings that delay release, sustain release, extend
release, prevent release, and/or otherwise prolong the release of a
drug relative to formulations lacking such coatings which release a
drug relatively quickly (i.e., "immediate release" compositions).
The term "controlled-release" encompasses "sustained release,"
"extended release," "delayed release," and "timed, pulsatile
release."The term "lag-time" coating refers to a particular type of
"controlled release" coating in which the lag time coating delays
release of a drug after administration. The term "controlled
release" is also used interchangeably with "modified release." The
term "controlled-release particle" refers to a particle showing one
or more controlled-release properties, as described herein. The
term "controlled-release particle" also refers to a drug-containing
particle coated with one or more controlled-release coatings, as
described herein.
[0062] The term "substantially masks the taste" in reference to the
taste-masking layer of the IR particles (when present) refers to
the ability of the taste-masking layer to substantially prevent
release of a bitter tasting drug in the oral cavity of a patient. A
taste-masking layer which "substantially masks" the taste of the
drug typically releases less than about 10% of the drug in the oral
cavity of the patient, in other embodiments, less than about 5%,
less than about 1%, less than about 0.5%, less than about 0.1%,
less than about 0.05%, less than about 0.03%, less than about 0.01%
of the drug. The taste-masking properties of the taste-masking
layer of the compositions of the present invention can be measured
in vivo (e.g., using conventional organoleptic testing methods
known in the art) or in vitro (e.g., using dissolution tests as
described herein). The skilled artisan will recognize that the
amount of drug release associated with a taste-masking layer than
"substantially masks" the taste of a drug is not limited to the
ranges expressly disclosed herein, and can vary depending on other
factors, such as the perceived the bitterness of the drug and the
presence of other flavoring agents in the composition.
[0063] The term "substantially modifies release" in reference to a
layer refers to the ability of the layer to provide modified
release properties, i.e., delay release, sustain release, extend
release, prevent release, and/or otherwise prolong the release of a
drug relative to formulations lacking such coatings which release a
drug relatively quickly (i.e., "immediate release" compositions),
as described herein.
[0064] As used herein, the term "sustained-release" (SR) refers to
the property of slow release of a drug from a drug-containing core
particle, without an appreciable lag time. The term
"sustained-release coating" or "SR coating" refers to a coating
showing sustained-release properties. The term "sustained-release
particle" refers to a drug-containing particle showing
sustained-release properties. In one embodiment, a
sustained-release coating comprises a water-insoluble polymer and
optionally a water-soluble polymer. An SR coating can optionally
contain a plasticizer or other ingredients that do not interfere
with the "sustained-release" properties of the coating.
[0065] As used herein, the term "timed, pulsatile release" (TPR)
refers to the property of modified release of a drug after a
pre-determined lag time. The term "timed, pulsatile-release
coating" or "TPR coating" refers to a coating showing timed,
pulsatile-release properties. The term "timed, pulsatile-release
particle" refers to a drug-containing particle showing timed,
pulsatile-release properties. In some embodiments, a lag time of
from at least about 2 to about 10 hours is achieved by coating the
particle with, e.g. a combination of at least one water-insoluble
polymer and at least one enteric polymer (e.g., a combination of
ethylcellulose and hypromellose phthalate). A TPR coating can
optionally contain a plasticizer or other ingredients which do not
interfere with the "timed, pulsatile release" properties of the
coating.
[0066] The term "modified-release coated drug-containing
microparticles" refers generally to drug-containing microparticles
(e.g., crystals, granules, pellets produced by controlled
spheronization, or drug layered particles/beads) coated with one or
more functional polymers to achieve effective taste-masking and/or
extended/sustained release properties. With respect to
high-dose/low-dose drug-containing microparticles, this term refers
to modified-release coated high-dose/low-dose drug containing
microparticles as described herein.
[0067] The terms "plasma concentration-time profile", "C.sub.max",
"AUC", "T.sub.max", and "elimination half life" have their
generally accepted meanings as defined in the FDA Guidance to
Industry: Bioequivalence.
[0068] Unless otherwise indicated, all percentages and ratios are
calculated by weight based on the total composition.
[0069] The term "disposed over" means that a second material is
deposited over a first material, wherein the second material may or
may not be in direct physical contact with the first material. Thus
it is possible, but not necessary, that an intervening material
lies between the first and second materials.
[0070] Combination drug therapies are increasingly useful in
treating diseases or conditions which are advantageously treated by
the administration of two or more drugs. For example, pain
treatments benefit from the administration of low doses of opioid
analgesics combined with relatively high-doses of non-opioid
analgesics (e.g., an NSAID), which effectively treat moderate to
severe pain, yet reduce the amount of potentially habit forming
opioid drug administered. For other indications (e.g., diabetes),
the combination of drugs can interact synergistically to provide
greater clinical benefits compared to either drug administered
individually. However, the need to administer multiple dosage
forms, each containing a single drug, can result in problems such
as reduced patient compliance, errors in administering the proper
doses of each drug, etc. It is therefore beneficial in such
situations to prepare a single dosage form combining the two (or
more) drugs, thereby permitting the administration of a single
dosage form rather than two (or more) dosage forms. However, it can
be difficult to prepare such combination pharmaceutical
formulations, when one of the drugs is present in a relatively high
concentration compared to one or more of the other drugs; as a
practical matter it is difficult to obtain a uniform mixture of a
high-dose drug and a low-dose drug, such that the high-dose drug
and the low-dose drug are both reproducibly provided at their
respective correct dosages.
[0071] The present invention is directed to pharmaceutical
compositions comprising a plurality of taste-masked
high-dose/low-dose drug-containing microparticles, each containing
both the high-dose drug (or drugs) and the low-dose drug (or
drugs). The core of the taste-masked high-dose/low-dose
drug-containing microparticles comprises the high-dose drug, and
the low-dose drug is provided in a low-dose drug layer disposed
over the high-dose drug-containing core.
[0072] Suitable core compositions include particles of the
high-dose drug itself (e.g., formed by recrystallization or
precipitation of the high-dose drug from solution, or by milling
and sieving the high-dose drug, etc., such that high-dose
drug-containing particles of a desired particle size and particle
size distribution are obtained). Alternatively, the core can
comprise a granulate comprising particles of the high-dose drug in
combination one or more pharmaceutically acceptable excipients
(e.g., lactose, mannitol, microcrystalline cellulose, etc.) and an
optional binder, prepared by wet or dry granulation. In still other
embodiments, the core can comprise extruded and spheronized
particles comprising the high-dose drug (e.g., in combination with
suitable pharmaceutically acceptable excipients as described
herein) or high-dose drug pellets are produced by controlled
spheronization in a Granurex VEC-35 or VEC-40 from Vector
Corporation, and these pellets are coated with polymers or polymer
blends providing target drug release profiles suitable for once- or
twice-daily dosing regimen. In yet other embodiments, the core
comprises drug layered beads--i.e., an inert core (e.g., sugar
spheres, microcrystalline cellulose, mannitol-microcrystalline
cellulose, silicon dioxide, etc.) layered with the high-dose drug
and an optional binder. In further embodiments, the core can
comprise the high-dose drug in combination with pharmaceutically
acceptable excipients, compressed into "minitabs" having a particle
diameter in the range of about 2-5 mm. In a particular embodiment,
the core comprises particles of the high-dose drug. In many
embodiments, the core has an average particle size of less than
about 500 .mu.m, or less than about 400 .mu.m, or less than about
300 .mu.m, or less than about 200 .mu.m.
[0073] Any pharmaceutically acceptable high-dose/low-dose drug
combination that is efficacious in the treatment of disease states
or conditions including, for example, cardiovascular diseases,
diabetes, moderate to severe pain, gastrointestinal disorders, etc.
can be selected in accordance with certain embodiments of the
present invention to create pharmaceutical compositions comprising
one or more populations of modified release coated
high-dose/low-dose drug-containing microparticles exhibiting
desired in vitro/in vivo drug release profiles.
[0074] Any pharmaceutically acceptable polymeric binder which is
compatible with the high-dose drug and/or other components of the
composition may be used in preparing the high-dose drug-containing
cores (e.g., a binder used in forming a granulate, in forming
drug-layered beads, etc.). Suitable polymeric binders include for
example, polymers selected from the group consisting of
hydroxypropylcellulose, povidone, methylcellulose, hydroxypropyl
methylcellulose, carboxyalkylcelluloses, polyethylene oxides,
polysaccharides, acacia, alginic acid, agar, calcium carrageenan,
sodium carboxymethylcellulose, microcrystalline cellulose, dextrin,
ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl
methylcellulose, methylcellulose, pectin, PEG, povidone,
pregelatinized starch, etc.
[0075] The high-dose drug-containing core can be coated directly
with the low-dose drug layer, or can be first coated with a sealant
layer. Suitable sealant layers comprise a hydrophilic water-soluble
polymer. Non-limiting examples of suitable hydrophilic polymers
include hydrophilic hydroxypropyl cellulose (e.g., Klucel.RTM. LF),
hydroxypropyl methylcellulose or hypromellose (e.g., Opadry.RTM.
Clear or Pharmacoat.TM. 603), vinylpyrrolidone-vinylacetate
copolymer (e.g., Kollidon.RTM. VA 64 from BASF), and
ethylcellulose, e.g. low-viscosity ethylcellulose. In many
embodiments, particularly when the high-dose drug-containing core
is particles of the high-dose drug, the compositions of the present
invention do not require a sealant layer coated directly over the
core.
[0076] The sealant layer can be applied at a coating weight of
about 1% to about 10%, for example about 1%, about 2%, about 3%,
about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or
about 10%, inclusive of all ranges and subranges therebetween.
[0077] In some embodiments, the compositions of the present
invention are intended to disintegrate in the oral cavity of the
patient upon administration (e.g., the ODT dosage form as described
herein). In such embodiments, when the high-dose drug and/or the
low-dose drug has unpleasant sensory properties (e.g., is bitter
tasting), the high-dose drug-containing core and/or the low-dose
drug-containing layer is taste-masked to prevent the patient from
tasting the high-dose and/or low dose drug, e.g. by coating the
high-dose drug-containing core and/or the low-dose drug-containing
layer with a taste-masking layer. For example, the compositions of
the present invention can include a single taste-masking layer as
described herein disposed between the high-dose drug-containing
core and the low-dose drug-containing layer, a single taste-masking
layer as described herein disposed over the low-dose
drug-containing layer, or two taste-masking layers disposed
respectively between the high-dose drug-containing core and the
low-dose drug-containing layer and over the low-dose
drug-containing layer. The taste-masking layer can be coated
directly onto the high-dose drug-containing core and/or the
low-dose drug-containing layer, or the high-dose drug-containing
core and/or low-dose drug-containing layer can be first coated with
a sealant layer (e.g., as described herein) for example to minimize
or prevent static charging and/or particle attrition, followed by
the taste-masking polymer coating. When the compositions of the
present invention comprise two or more taste-masking layers, the
taste-masking layers can be independently selected from any of the
taste-masking layer compositions described herein.
[0078] Suitable taste-masking layers can comprise a water-insoluble
polymer or the combination of a water-insoluble polymer and a
gastrosoluble pore-former (e.g., gastrosoluble and pharmaceutically
acceptable organic, inorganic, or polymeric materials.
[0079] The taste-masking layer can be coated onto the high-dose
drug-containing core and/or low-dose drug-containing layer by any
suitable method, e.g., fluid bed coating or coacervation. For
example the taste-masking polymer coating can be deposited in the
core to provide a weight gain (after coating and drying) of from
about 3% to about 50%, including about 3%, about 5%, about 7%,
about 10%, about 12%, about 15%, about 17%, about 20%, about 22%,
about 25%, about 27%, about 30%, about 35%, about 40%, about 45%,
or about 50%, inclusive of all ranges and subranges
therebetween.
[0080] Non-limiting examples of suitable water-insoluble polymers
include ethylcellulose, cellulose acetate, cellulose triacetate,
cellulose acetate butyrate, polyvinyl acetate, neutral methacrylic
acid-methylmethacrylate copolymers (e.g., Eudragit RL, RS, and
NE30D, etc.), and mixtures thereof. In one embodiment, the
water-insoluble polymer comprises ethylcellulose. In another
embodiment, the water-insoluble polymer comprises ethylcellulose
with a mean viscosity of 10 cps (e.g., Ethocel Standard 10 Premium)
or about 100 cps (Ethocel Standard 100 Premium) in a 5% solution in
80/20 toluene/ethanol, measured at 25.degree. C. with an Ubbelohde
viscometer.
[0081] As described herein, in some embodiments the taste-masking
layer(s) independently comprises the combination of a
water-insoluble polymer (as described herein) and a gastrosoluble
pore-former. Pore-formers include polymeric and non-polymeric
pharmaceutically acceptable gastrosoluble materials. Non-limiting
examples of non-polymeric gastrosoluble pore-formers, include
pharmaceutically acceptable inorganic materials such as calcium
carbonate, magnesium carbonate, calcium phosphate, ferric
hydroxide, ferric phosphate, magnesium hydroxide, magnesium
phosphate, etc.; pharmaceutically acceptable non-polymeric organic
materials such as calcium saccharide, calcium succinate, calcium
tartrate, magnesium citrate, ferric acetate, etc.; pharmaceutically
acceptable gastrosoluble polymers including maltrin, aminoalkyl
methacrylate copolymers available under the trade name of
Eudragit.RTM. (type E100 or EPO), polyvinylacetal
diethylaminoacetate e.g., AEA.RTM. available from Sankyo Company
Limited, Tokyo (Japan), and the like; and mixtures thereof. In one
embodiment, the gastrosoluble polymer is a terpolymer based on
dimethylaminoethyl methacrylate, butyl methacrylate, and methyl
methacrylate. In another embodiment, the terpolymer has an average
molecular weight of 150,000 and the ratio of the monomers is 1:2:1
of methyl methacrylate, N,N-dimethylaminoethyl methacrylate, and
butyl methacrylate, and mixtures thereof.
[0082] The ratio of water-insoluble polymer to gastrosoluble
pore-former ranges from about 95/5 to about 50/50 including about
90/10, about 85/15, about 80/20, about 75/25, about 70/30, about
65/35, about 60/40, or about 55/45.
[0083] The coating weight of the taste-masking layer comprising a
water-insoluble polymer and a gastrosoluble pore-former ranges from
about 5% to about 30%, or about 5%-25%, about 5%-20%, about 5%-15%,
about 5%-10%, about 10%-30%, about 10%-25%, about 10%-20%, about
10%-15%, about 15%-30%, about 50%-25%, about 15%-20%, about
20%-30%, about 20%-25%, or about 25%-30%.
[0084] The ratio of the water-insoluble polymer to the
gastrosoluble polymer ranges from about 9/1 to about 1/1, including
the range of about 6/3 to about 2/1. In other embodiments, the
ratio of water-insoluble polymer to gastrosoluble polymer is about
95/5, about 90/10, about 85/15, about 80/20, about 75/25, about
70/30, about 65/35, about 60/40, about 55/45, or about 50/50,
inclusive of all values, ranges, and subranges therebetween.
[0085] In some embodiments, the taste-masking layer comprising the
combination of a water-insoluble polymer and gastrosoluble polymer
has a coating weight of about 10% to about 40% by weight, including
the ranges from about 12% to about 30%, about 15% to about 25%, and
from about 20% to about 30%. In other embodiments, the coating
weight of the taste-masking layer comprising a combination of
water-insoluble and gastrosoluble polymers is about 10%, about
12.5%, about 13%, about 15%, about 17%, about 18%, about 20%, about
22%, about 24%, about 25%, about 27%, about 30%, about 35%, or
about 40%, inclusive of all ranges and subranges therebetween.
[0086] In various embodiments, it is desirable to provide an
extended-release coating layer over the high-dose drug-containing
cores in order to modify the release of the high-dose drug. The
extended-release coating disposed over the high-dose
drug-containing cores can comprise a water-insoluble polymer,
thereby providing a sustained release (SR) coating; a
water-insoluble polymer in combination with an enteric or
water-soluble polymer, thereby providing a timed pulsatile release
(TPR) coating. In still other embodiments, the extended-release
coating comprises an enteric polymer disposed on the high-dose
drug-containing particle, thereby providing a delayed release (DR)
coating.
[0087] In some embodiments, the extended-release coating provides
suitable properties (e.g., extended release characteristics,
mechanical properties, and coating properties) without the need for
a plasticizer. For example, ethylcellulose without a plasticizer is
used for coating drug-containing cores by solvent coacervation via
phase separation for taste-masking, and or can be applied e.g. from
a suitable solvent to provide sustained-release properties. Also,
coatings comprising polyvinyl acetate (PVA), neutral and cationic
copolymers of acrylate/methacrylate esters (e.g., NE30D and EPO),
waxes, etc. can be applied without plasticizers.
[0088] Non-limiting examples of suitable enteric polymers include
cellulose acetate phthalate, hydroxypropyl methylcellulose
phthalate, hydroxypropyl methylcellulose acetate succinate,
polyvinyl acetate phthalate, pH-sensitive methacrylic
acid/methylmethacrylate copolymers (e.g., Eudragit.RTM. L, S and FS
polymers), shellac, and mixtures thereof. In certain embodiments,
non-polymeric enteric materials such as non-polymeric waxes and
fatty acid compositions may be used instead of enteric polymers,
provided they have the pH sensitive solubility associate with
enteric polymers. These enteric polymers may be used as a solution
in a solvent mixture or an aqueous dispersion. Some commercially
available materials that may be used are methacrylic acid
copolymers sold under the trademark Eudragit (L100, S100, L30D)
manufactured by Rohm Pharma, Cellacefate (cellulose acetate
phthalate) from Eastman Chemical Co., Aquateric (cellulose acetate
phthalate aqueous dispersion) from FMC Corp., and Aqoat
(hydroxypropyl methylcellulose acetate succinate aqueous
dispersion) from Shin Etsu K.K.
[0089] The coating weight of the extended-release coating
comprising the combination of a water-insoluble polymer and an
enteric polymer ranges from about 10 to 60%, more particularly from
about 30% to 60%, including about 15%, about 20%, about 25%, about
30%, about 35%, about 40%, about 45%, about 50%, or about 55%,
inclusive of all ranges and sub ranges therebetween. The ratio of
water insoluble polymer to enteric polymer may vary from about 10:1
to 1:2, more particularly from about 2:1 to 1:1, including about
9:1, about 8:1, about 7:1 about 6:1, about 5:1 about 4:1, about
3:1, about 2:1, or about 1:1.
[0090] In other embodiments, the extended-release layer comprises
the combination of a water-insoluble polymer (as described herein)
in combination with a water-soluble polymer. Non-limiting examples
of suitable water-soluble polymers include polyvinylpyrrolidone
(e.g., Povidone K-25), polyethylene glycol (e.g., PEG 400),
hydroxypropyl methylcellulose, and hydroxypropylcellulose.
[0091] The ratio of the water-insoluble polymer to the
water-soluble polymer ranges from about 95/5 to about 50/50,
including ratios of about 95/5, about 90/10, about 85/15, about
80/20, about 75/25, about 70/30, about 65/35, about 60/40, about
55/45, or about 50/50, inclusive of all ranges and subranges
therebetween. In other embodiments, the taste-masking layer
comprising the combination of a water-insoluble polymer and a
water-soluble polymer is deposited over the high-dose
drug-containing core at a coating weight of about 3%, about 5%,
about 7%, about 10%, about 12%, about 15%, about 17%, about 20%,
about 22%, about 25%, about 27%, about 30%, about 35%, about 40%,
about 45%, and about 50% by weight, inclusive of all values,
ranges, and subranges therebetween.
[0092] In some other embodiments, the present invention relates to
a pharmaceutical composition comprising modified-release coated
high-dose drug cores comprising at least one therapeutic agent or a
pharmaceutically acceptable salt, solvate, and/or ester thereof; a
water-insoluble polymer (e.g., ethylcellulose), a second optional
coating disposed over the first coating, comprising an enteric
polymer and optionally a water-insoluble polymer (e.g.,
ethylcellulose and hypromellose phthalate at a ratio of from about
9:1 to about 5:5).
[0093] The modified-release or taste-masking layer can be
unplasticized or plasticized. For example, drug-containing
particles can be taste-masked with ethylcellulose by solvent
coacervation via phase separation without requiring a plasticizer,
or from suitable pharmaceutically acceptable solvent using a fluid
bed coater. Modified-release coatings comprising various polymers
such as Eudragit NE30D or various hydrophobic waxes in a fluid bed
coater typically do not require a plasticizer.
[0094] When it is desirable or convenient to use a plasticizer,
non-limiting examples of suitable plasticizers include glycerol and
esters thereof (e.g., acetylated mono- or diglycerides including
commercially available Myvacet.RTM. 9-45), glyceryl monostearate,
glyceryl triacetate, glyceryl tributyrate, phthalates (e.g.,
dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl
phthalate, etc.), acetylcitric acid tributyl ester, acetylcitric
acid triethyl ester, tributyl citrate, acetyltributyl citrate,
triethyl citrate, glyceroltributyrate; diethyl sebacate, dibutyl
sebacate, dibutyl adipates, dibutyl azelates, dibutyl benzoates,
chlorobutanol, polyethylene glycols, vegetable oils, diethyl
fumarate, diethyl malates, diethyl oxalate, dibutyl succinate,
dibutyl butyrate, cetyl alcohol esters, malonates (e.g., diethyl
malonate etc.), castor oils, polysorbates,
N-butylbenzenesulfonamide, N-methylpyrrolidone, and mixtures
thereof. In some embodiments, it is desirable to use a
non-phthalate plasticizer. In various embodiments of the present
invention, the amount of plasticizer in the taste-masking layer,
relative to the amount of water-insoluble polymer, ranges from
about 3% to about 30% by weight. In another embodiment, the amount
of plasticizer ranges from 10% to about 25% by weight of the
water-insoluble polymer. In still other embodiments, the amount of
plasticizer relative to the weight of the water-insoluble polymer
is about 3%, about 5%, about 7%, about 10%, about 12%, about 15%,
about 17%, about 20%, about 22%, about 25%, about 27%, and about
30%, inclusive of all ranges and subranges therebetween. One of
ordinary skill in the art would know to select the type of
plasticizer based on the polymer or polymers and nature of the
coating system (e.g., aqueous or solvent-based, solution or
dispersion-based and the total solids). In a particular embodiment,
the plasticizer is castor oil.
[0095] In some embodiments, the taste-masking layer can further
comprise an anti-tacky agent to reduce aggregation of the
taste-masked particles. Suitable anti-tacky agents include talc
and/or magnesium stearate.
[0096] In one embodiment, the taste-masking polymer coating
comprises a plasticized water-insoluble polymer, such as
ethylcellulose (EC-10), at a coating weight of about 5-50% by
weight.
[0097] In some embodiments, the modified-release (sustained-release
and/or taste-masked) high-dose drug-containing core is coated with
a sealant layer, for example to minimize attrition or agglomeration
of the taste-masked cores, or alternatively to prevent contact
between the high-dose drug in the core and e.g., the low-dose drug
in the low-dose drug layer. The composition and coating weight of
the sealant layer is as described herein.
[0098] The low-dose drug layer is disposed directly over the
high-dose drug-containing core, or over a sealant coated core,
and/or a taste-masked core. The low-dose drug can be coated onto
the high-dose drug-containing core by any suitable method, e.g.,
pan coating or fluid bed coating using a solution of the low-dose
drug (in a pharmaceutically acceptable solvent), optionally in
combination with a polymeric binder as described herein. For
example, the low-dose drug coating solution can comprise a suitable
solvent (e.g. water, a pharmaceutically acceptable organic solvent
such as acetone or alcohol, or aqueous organic solvents) in which
the low-dose drug and an optionally a binder (e.g.,
hydroxypropylcellulose, polyvinylpyrrolidone, etc.) are
dissolved.
[0099] The resulting high-dose drug/low-dose drug-containing
microparticle can then be coated, if needed, with an additional
sealant layer (as described herein), and/or a taste-masking layer
(also as described herein). Thus, in some embodiments, the ultimate
high-dose drug/low-dose drug-containing microparticles comprise a
high-dose drug-containing core (as described herein), coated with
an optional sealant coating, a taste-masking layer (e.g.,
comprising a water-insoluble polymer or a water insoluble polymer
in combination with a water-soluble or gastrosoluble polymer), a
low-dose drug layer, a second optional sealant layer, and a second
taste-masking layer (e.g., comprising a water-insoluble polymer or
a water insoluble polymer in combination with a water-soluble or
gastrosoluble polymer).
[0100] The high-dose drug/low-dose drug-containing microparticles
can optionally comprise one or more sealant layers, wherein the
sealant layers can have the same composition or different
compositions, and can be coated at the same coating weight or
different coating weights. Similarly, if the high-dose
drug/low-dose drug-containing microparticles comprise two
taste-masking layers, the two taste-masking layers can have the
same composition or a different composition and/or the same coating
weight or different coating weights. For example, the inner
taste-masking layer can comprise a water-insoluble polymer, and the
outer taste-masking layer can comprise the combination of a
water-insoluble polymer and a water-soluble polymer and/or
gastrosoluble polymer, etc.
[0101] In other embodiments, a flavorant coating layer (which can
include a sweetener and/or a flavoring agent as described herein)
can be disposed over the low-dose drug-containing layer (e.g.,
instead of a taste-masking layer), such that the high-dose
drug/low-dose drug-containing microparticles comprise, for example
a high-dose drug-containing core (as described herein), coated with
an optional sealant coating, a taste-masking layer (e.g.,
comprising a water-insoluble polymer or a water insoluble polymer
in combination with a water-soluble or gastrosoluble polymer), a
low-dose drug layer, a second optional sealant layer, and the
flavorant coating layer.
[0102] The flavorant coating layer comprises a combination of a
flavorant and a binder. Suitable binders include those described
herein. The flavorant includes water soluble sweeteners such as
sucralose, saccharine, aspartame, neotame, acesulfame K, sodium
saccharinate, neohesperidine, lactitol, maltitol, sorbitol, and
mixtures thereof, or alternatively flavoring agents such as
strawberry cherry, peppermint, strawberry and mixtures thereof. In
one embodiment, the binder is hydroxypropyl cellulose and the
flavorant is sucralose.
[0103] The coating weight of the flavorant coating layer can range
from about 1% to about 10% by weight, including the ranges from
about 3.0% to about 8%, about 5% to about 7.5%, and from about 5%
to about 10%, of the weight of the coated core, or about 1%, about
2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%,
about 9%, or about 10%, inclusive of all ranges and subranges
therebetween.
[0104] As described herein, the taste-masked high-dose/low-dose
drug-containing microparticles can include various layers in
addition to the taste-masking layer (e.g. optional sealant layers,
etc.). Thus, the taste-masking layer can be disposed directly over
the high-dose drug-containing core, or a sealant layer can be
interposed between the high-dose drug-containing core and a
taste-masking layer. In other embodiments, the low-dose
drug-containing layer is coated with a taste-masking layer
comprising a water-insoluble polymer combined with a gastrosoluble
polymer such as a cationic dimethylaminoethyl methacrylate
copolymer. In another embodiment, the taste-masking layer disposed
over the low-dose drug layer comprises a water-insoluble polymer
and no water-soluble or gastrosoluble polymer. In an alternative
embodiment, a flavorant coating layer (e.g., at coating weight of
about 1% to about 10%) comprising a water-soluble sweetener is
disposed directly over the low-dose drug layer, or over a sealant
layer (e.g., hydroxypropyl cellulose at a coating weight of about
1% to about 10%) disposed over the low-dose drug layer. The
high-dose drug/low-dose drug-containing microparticles of the
present invention provide rapid dissolution of the high-dose and
low-dose drugs when dissolution tested using USP Apparatus 1
(baskets@ 100 RPM) or USP Apparatus 2 (paddles@ 50 RPM) in 900 mL
media (pH 1.2, pH 5.8, pH 6.8, or pH 7 (water)) at 37.degree.
C.
[0105] As described herein, the pharmaceutical compositions
comprising the modified-release coated high-dose drug/low-dose
drug-containing microparticles of the present invention provide
blend homogeneity as well as uniformity of dosage units as per the
USP requirements which are difficult to achieve by other methods
(e.g., by blending particles comprising the high-dose drug with a
second population of particles comprising the low-dose drug),
particularly when the ratio of the high-dose drug to the low-dose
drug is about 20/1 or higher (e.g., about 20/1, about 25/1, about
30/1, about 35/1, about 40/1, about 45/1, about 50/1, about 60/1,
about 70/1, about 80/1, about 90/1, about 100/1, etc.).
[0106] The high-dose drug and the low-dose drug can comprise any
drugs which are intended to be used in combination to treat a
condition or disease in a patient. For example, pharmaceutical
compositions of the present invention can include combinations of
high-dose and low-dose drugs such as non-opioid analgesics (e.g.,
acetaminophen and non-steroidal anti-inflammatory drugs such as
aspirin, ibuprofen, ketoprofen, meloxicam, diclofenac potassium,
etodolac, sulindac, indomethacin, celecoxib, etc.) in combination
with one or more opioid analgesics (hydrocodone bitartrate,
oxymorphone, buprenorphine, fentanyl, hydromorphone) for the
treatment of moderate-to-severe pain. Similarly, an anti-diabetic
combination of high-dose and low-dose drugs suitable for the
treatment of diabetes mellitus (by lowering glucose levels in the
blood) include at least one biguanide (e.g., metformin) in
combination with at least one sulfonylurea (e.g., glipizide,
gliclazide, glyburide, gliquidone, glyclopyamide, glimepiride),
meglitinide (e.g. repaglinide, nateglinide) or thiazolidinedione
(e.g., roseglitazone, pioglitazone, troglitazone). Alternatively, a
high-dose drug (e.g., nicotinic acid) in combination with a
low-dose drug (e.g., lovastatin, fluvastatin, atorvastatin,
cerivastatin, simvastatin, mevastatin, rosuvastatin, pravastatin)
is useful for lowering cholesterol (very low density lipoproteins)
and triglycerides levels in people with, or at risk of
cardiovascular disease. Combinations of a high-dose drug such as
pseudoephedrine hydrochloride, pseudoephedrine sulfate, or
fexofenadine and a low-dose drug such as cetirizine, loratidine,
and phenylephrine are useful for treating indoor and outdoor
allergies.
[0107] In a particular embodiment, the low-dose drug is a
therapeutically effective amount of hydrocodone bitartrate and the
high-dose drug is a therapeutically effective amount of
acetaminophen for treating pain. In another particular embodiment,
the high-dose drug is a therapeutically effective amount of
metformin and the low-dose drug is a therapeutically effective
amount of roseglitazone for treating hyperglycemia.
[0108] In one embodiment, the pharmaceutical compositions of the
present invention can comprise niacin (nicotinic acid) as the
high-dose drug, formulated as taste-masked high-dose drug particles
with an immediate-release (IR) profile, layered with a statin and
taste-masking coating. Alternatively, the niacin can be formulated
as sustained-release (SR) coated high-dose drug particles to
produce modified-release pharmaceutical compositions.
[0109] The pharmaceutical compositions of the present invention
comprise high-dose/low-dose drug-containing microparticles. In an
alternative embodiment, the pharmaceutical compositions of the
present invention can further comprise a second population of
high-dose drug containing microparticles. The high-dose
drug-containing microparticles comprise, for example, a high-dose
drug-containing core (as described herein) coated with a
water-insoluble polymer, e.g., at a coating weight of about 15% to
about 35%, thereby providing sustained-release (SR) high-dose
drug-containing particles. The combination of high-dose/low-dose
drug-containing microparticles and SR high-dose drug-containing
particles exhibit rapid low-dose drug release profiles and
prolonged high-dose drug release (modified release) profiles.
[0110] The pharmaceutical compositions of the present invention can
be used to prepare oral dosage forms such as tablets, capsules, and
ODTs. Tablets can be prepared by combining the pharmaceutical
compositions of the present invention with suitable
pharmaceutically acceptable excipients, and then compressing the
resulting mixture to form tablets. Alternatively, capsules can be
filled with the pharmaceutical compositions of the present
invention (and optional excipients).
[0111] In a particular embodiment, the pharmaceutical compositions
of the present invention can be combined with rapidly dispersing
microgranules to form an orally disintegrating tablet (ODT). An ODT
is a tablet designed to substantially disintegrate in the oral
cavity after administration (without chewing) within about 60
seconds after contact with saliva (i.e., in the oral cavity) or
with simulated saliva fluid (e.g., tested according to the USP
<701> Disintegration Test). In particular embodiments, the
ODT substantially disintegrates within about 30 seconds. The
disintegration of the ODT in the oral cavity of the patient
provides a smooth, easy-to-swallow suspension having no gritty
mouthfeel or aftertaste, while still providing pharmacokinetic
profiles for the drugs contained in the ODT (e.g., plasma
concentration vs. time profiles) which are bioequivalent to the
respective reference listed drugs (RLDs).
[0112] The ODTs of the present invention comprise the
pharmaceutical compositions of the present invention combined with
rapidly dispersing microgranules. Rapidly dispersing microgranules
can be prepared as described in US Publication Nos. 2006/0078614,
2006/0105038, 2005/0232988 or 2003/0215500 (each of which is herein
incorporated by reference in its entirety for all purposes) by
granulating a disintegrant with a sugar alcohol and/or saccharide
having an average particle size of not more than about 30 .mu.m.
The granulation can be carried out, for example, in a high shear
granulator with approximately 20-25% water as the granulating
fluid, and if needed wet milled and dried to produce rapidly
dispersing microgranules, for example having an average particle
size of not more than about 300 .mu.m (e.g., about 175-300
.mu.m).
[0113] The ratio of the disintegrant to the sugar alcohol,
saccharide, or mixture thereof in the rapidly dispersing
microgranules ranges from about 90/10 to about 99/01, for example
about 90/10, about 91/9, about 92/8, about 93/7, about 94/6, about
95/5, about 96/4, about 97/3, about 98/2, about 99/1, inclusive of
all values, ranges, and subranges therebetween.
[0114] The ratio of the rapidly dispersing microgranules to
taste-masked drug-containing particles ranges from about 5/1 to
about 1/1, including about 5/1, 4/1, 3/1, 2/1, 1/1, inclusive of
all values, ranges, and subranges therebetween.
[0115] The taste-masked high-dose/low-dose drug-containing
microparticles incorporated into the ODT dosage form should also
have a small enough particle size such that after disintegration of
the ODT in the oral cavity of the patient, a smooth,
easy-to-swallow suspension results. In most embodiments in which
the pharmaceutical compositions of the present invention as
provided as an ODT dosage form, the average particle size of the
taste-masked high-dose/low-dose drug-containing microparticles is
not more than about 400 .mu.m, or in some embodiments not more than
about 300 .mu.m.
[0116] The ODT dosage form, as described herein, may also include
pharmaceutically acceptable excipients typically used in
disintegrating tablet formulations such as microcrystalline
cellulose and spray dried mannitol (compressible diluents),
croscarmellose sodium or crospovidone (super disintegrant),
coloring agents, and optionally magnesium stearate or sodium
stearyl fumarate (lubricant intragranularly mixed or used
externally to lubricate die and punch surfaces).
[0117] Tablet dosage forms, including ODT dosage forms, comprising
the pharmaceutical composition of the present invention have a low
friability, e.g., less than about 1%, (e.g., less than about 0.9%,
less than about 0.8%, less than about 0.7%, less than about 0.6%,
less than about 0.5%, less than about 0.4%, less than about 0.3%,
etc., inclusive of all ranges and subranges therebetween) in order
to have sufficient durability to withstand handling, shipping,
and/or packaging in push-through blister packaging.
[0118] A non-limiting list of suitable disintegrants for the
rapidly dispersing microgranules includes crospovidone
(cross-linked PVP), sodium starch glycolate, cross-linked sodium
carboxymethylcellulose, calcium silicate, and low substituted
hydroxypropyl cellulose. The amount of disintegrant in the ODT is
typically in the range of about 1% to about 10% by weight,
including about 1%, about 2%, about 3%, about 4%, about 5%, about
6%, about 7%, about 8%, about 9%, or about 10%, inclusive of all
ranges and subranges therebetween. In a particular embodiment, the
disintegrant for the rapidly dispersing microgranules is selected
from the group consisting of crospovidone, cross-linked sodium
carboxymethylcellulose, and low substituted hydroxypropyl
cellulose. In a more particular embodiment, the disintegrant for
the rapidly dispersing microgranules is crospovidone.
[0119] A non-limiting list of suitable sugar alcohols includes
mannitol, sorbitol, xylitol, maltitol, arabitol, ribitol, dulcitol,
iditol, isomalt, lactitol, erythritol and combinations thereof. In
a particular embodiment, the sugar alcohol is mannitol. A
non-limiting list of suitable saccharides includes lactose,
sucrose, maltose, and combinations thereof. In a particular
embodiment, the saccharide is lactose. The amount of sugar alcohol
and/or saccharide in the ODT ranges from about 30% to about 70% by
weight, including, for example, about 30%, about 35%, about 40%,
about 45%, about 50%, about 55%, about 60%, about 65%, or about
70%, inclusive of all ranges and subranges therebetween.
[0120] Pharmaceutically acceptable excipients include fillers,
diluents, glidants, disintegrants, binders, lubricants etc. Other
pharmaceutically acceptable excipients include acidifying agents,
alkalizing agents, preservatives, antioxidants, buffering agents,
chelating agents, coloring agents, complexing agents, emulsifying
and/or solubilizing agents, flavors and perfumes, humectants,
sweetening agents, wetting agents etc. Examples of suitable
fillers, diluents and/or binders include lactose (e.g. spray-dried
lactose, .alpha.-lactose, .beta.-lactose, Tabletose.RTM., various
grades of Pharmatose.RTM., Microtose.RTM. or Fast-Flo.RTM.),
microcrystalline cellulose (various grades of Avicel.RTM.,
Ceolus.RTM., Elcema.RTM., Vivacel.RTM., Ming Tai.RTM. or
Solka-Floc.RTM.), hydroxypropylcellulose, L-hydroxypropylcellulose
(low substituted), low molecular weight hydroxypropyl
methylcellulose (HPMC) (e.g. Methocel E, F and K from Dow Chemical,
Metolose SH from Shin-Etsu, Ltd), hydroxyethylcellulose, sodium
carboxymethylcellulose, carboxymethylhydroxyethylcellulose and
other cellulose derivatives, sucrose, agarose, sorbitol, mannitol,
dextrins, maltodextrins, starches or modified starches (including
potato starch, maize starch and rice starch), calcium phosphate
(e.g. basic calcium phosphate, calcium hydrogen phosphate,
dicalcium phosphate hydrate), calcium sulfate, calcium carbonate,
sodium alginate, collagen etc.
[0121] Examples of suitable diluents include e.g. calcium
carbonate, dibasic calcium phosphate, tribasic calcium phosphate,
calcium sulfate, microcrystalline cellulose, powdered cellulose,
dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol,
sorbitol, starch, pregelatinized starch, sucrose, sugar etc.
[0122] Examples of suitable disintegrants include e.g. alginic acid
or alginates, microcrystalline cellulose, hydroxypropyl cellulose
and other cellulose derivatives, croscarmellose sodium,
crospovidone, polacrillin potassium, sodium starch glycolate,
starch, pregelatinized starch, carboxymethyl starch (e.g.
Primogel.RTM. and Explotab.RTM.) etc.
[0123] Specific examples of glidants and lubricants include stearic
acid, magnesium stearate, calcium stearate or other metallic
stearates, talc, waxes and glycerides, light mineral oil, PEG,
glyceryl behenate, colloidal silica, hydrogenated vegetable oils,
corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl
sulfates, sodium benzoate, sodium acetate etc.
[0124] Other excipients include e.g. flavoring agents, coloring
agents, taste-masking agents, pH-adjusting agents, buffering
agents, preservatives, stabilizing agents, anti-oxidants, wetting
agents, humidity-adjusting agents, surface-active agents,
suspending agents, absorption enhancing agents, agents for modified
release etc.
[0125] The present invention is also directed to methods of
preparing the pharmaceutical compositions and dosage forms
described herein. In one embodiment, the high-dose/low-dose
drug-containing microparticles are prepared by a method comprising:
[0126] (a) preparing a core comprising a high-dose drug as
described herein (e.g., a non-opioid analgesic such as
acetaminophen, diclofenac potassium, etc.; [0127] (b) coating a
low-dose drug layer (e.g., comprising a low-dose drug as described
herein, such as hydrocodone bitartrate) over the high-dose
drug-containing core; [0128] (c) coating the high-dose
drug-containing core of step (a) with at least one taste-masking
and/or modified-release coating layer and the high-dose/low-dose
drug-containing particles of step (b) with at least one
taste-masking layer or flavorant layer.
[0129] The step (a) of preparing the core may be accomplished by
any of the methods known in the art; for example, layering an inert
bead (e.g., sugar, microcrystalline cellulose,
mannitol-microcrystalline cellulose, silicon dioxide, etc.) with a
solution comprising the drug and optionally a polymeric binder
(e.g., by fluid-bed or pan coating). Alternatively, the core may
comprise drug crystals of the desired particle size (e.g., about
50-500 .mu.m, including 100-250 .mu.m), prepared by crystallization
of the drug from a suitable solvent, or by milling drug crystals to
a desired particle size. In still other embodiments, the core can
comprise a pellet prepared by controlled-spheronization.
[0130] In a particular embodiment, the microgranules comprising a
high-dose drug (e.g., a non-opioid analgesic or anti-diabetic drug)
may be prepared by a conventional high-shear or planetary
granulation process or high-dose drug-containing pellets may be
prepared by a conventional granulation-extrusion-spheronization
process comprising e.g. acetaminophen, a polymer binder and one or
more fillers/diluents.
[0131] Step (b) comprises coating the taste-masked high-dose
drug-containing core with the low-dose drug using a drug-layering
solution as described herein (e.g., comprising a solution of the
low-dose drug and optionally a binder). The low-dose drug layer can
be applied using any suitable method, for example fluid bed, pan
coating, coacervation, etc.
[0132] Step (c) comprises coating the high-dose drug-containing
core and/or the low-dose drug containing layer with a taste-masking
layer. In some embodiments, a taste-masking layer is coated
directly over the high-dose-drug containing core, or a sealant
layer is coated onto the high-dose drug-containing core before
coating with the low-dose drug-containing layer and/or a
taste-masking layer. Likewise, a sealant layer may be coated onto
the low-dose drug-containing layer before coating with a
taste-masking layer or a flavorant layer as described herein (e.g.,
comprising a sweetener and/or flavoring agent and an optional
polymeric binder such as hydroxypropylcellulose, applied as a
solution or suspension). The taste-masking layer comprises a
water-insoluble polymer or a water-insoluble polymer combined with
a water-soluble or gastrosoluble polymer (and optionally a binder),
for example any of the compositions described herein such as
ethylcellulose (Ethocel Standard 100 Premium, at a coating weight
of about 10%), or a combination of ethylcellulose with a
gastrosoluble polymer (e.g., Eudragit E100) at coating weight of
about 25%.
[0133] After depositing the low-dose drug layer, the resulting
particles can optionally be coated with a sealant coat (as
described herein) and then coated with a taste-masking layer or
flavorant layer (as described herein). For example, the
taste-masking layer applied over the low-dose drug layer (or over a
sealant coat deposited on the low-dose drug layer) can comprise a
water-insoluble polymer (e.g. ethylcellulose) or the combination of
a water-insoluble polymer and a water soluble or gastrosoluble
polymer (e.g., ethylcellulose in combination with Eudragit E100).
Alternatively, instead of a taste-masking layer, a flavorant
coating can be applied over the low-dose drug layer, or over a
protective sealant layer applied over the low-dose drug layer.
[0134] In particular embodiments, the method comprises coating by
solvent coacervation a taste-masking layer directly over the
high-dose drug-containing core or over a sealant layer disposed on
the high-dose drug-containing core, wherein the taste-masking layer
comprises water-insoluble ethylcellulose (Ethocel Standard 100
Premium) at coating weight of about 6%. In other embodiments, the
method comprises coating water-insoluble ethylcellulose (Ethocel
Standard 10 Premium) in combination with water-soluble
hydroxypropylcellulose at a ratio of 7:3 or gastrosoluble Eudragit
E100 at a ratio of 8:7 at a coating weight of about 20% by fluid
bed coating.
[0135] In another particular embodiment, the method comprises
coating by solvent coacervation a taste-masking layer directly over
the low-dose drug-containing layer or over a sealant layer disposed
on the low-dose drug-containing layer, e.g. with water-insoluble
ethylcellulose (Ethocel Standard 100 Premium) at a coating weight
of about 6%. In other embodiments, the method comprises coating
water-insoluble ethylcellulose (Ethocel Standard 10 Premium) in
combination with water-soluble hydroxypropylcellulose at a ratio of
7:3 or gastrosoluble Eudragit E100 at a ratio of 8:7 at a level of
about 20% by weight based on the total weight of the coated
particles by fluid bed coating. Taste-masking coatings can be
prepared and applied as described, for example in U.S. Patent Publ.
Nos. 2006/0078614 and 2006/0105038.
[0136] In yet another particular embodiment, the method comprises
coating the low-dose drug-containing layer with a sealant layer
comprising hydrophilic hydroxypropylcellulose at a coating weight
of about 5%, then coating with a taste-masking layer comprising a
sweetener such as sucralose at a coating weight of about 5% by
weight.
[0137] The ultimate dosage form comprising the taste-masked
high-dose/low-dose drug-containing microparticles of the present
invention can then be prepared by various methods known in the
pharmaceutical arts, such as filling an appropriate amount of the
taste-masked high-dose/low-dose drug-containing microparticles into
e.g. a gelatin capsule or a container suitable for storing a
suspension, sachet, etc. In other embodiments, the taste-masked
high-dose/low-dose drug-containing microparticles of the present
invention are combined with suitable pharmaceutically acceptable
excipients and compressed to form a tablet. Tablets comprising the
pharmaceutical compositions of the present invention can contain an
internal lubricant (e.g., magnesium stearate), or can be compressed
into tablets using an external lubrication process, in which the
lubricant is sprayed onto the surface of the die and punch
surfaces, rather than incorporated into the compression blend.
External lubrication and compression methods than can be used to
prepare oral dosage forms (e.g., tablets, ODTs) comprising the
pharmaceutical compositions of the present invention are described
for example in U.S. Pat. No. 5,996,902 and U.S. Pat. No.
6,776,361.
[0138] When the ultimate dosage form is an ODT, the method further
comprises preparing rapidly dispersing microgranules comprising a
disintegrant and a sugar alcohol, a saccharide or a mixture
thereof, wherein each of the disintegrant, sugar alcohol and/or
saccharide have an average particle diameter of not more than 30
.mu.m; then combining the rapidly dispersing microgranules with
taste-masked high-dose/low-dose drug-containing microgranules and
optionally other pharmaceutically acceptable excipients, e.g., in a
mixer or V-blender; and finally compressing the blend of rapidly
dispersing microgranules and taste-masked high-dose/low-dose
drug-containing microgranules into an ODT, e.g., using an
externally lubricated tablet press to provide ODTs with desired
tableting characteristics (e.g., adequate hardness, friability of
<0.6%, low disintegration time, and rapid dissolution). Rapidly
dispersing microgranules can be prepared following the procedures
disclosed in US Patent Publ. Nos. 2006/0078614, 2006/0105038,
2006/0105039 and 2005/0232988.
[0139] In particular embodiments, the rapidly dispersing
microgranules and taste-masked drug-containing microparticles may
be present in the ratio of about 4/1 to 2/1 to achieve a smooth
mouthfeel. Rapidly dispersing microgranules may be produced as
described herein by granulating a disintegrant such as Crospovidone
XL-10 with a sugar alcohol or a saccharide, or a combination
thereof, each having an average particle diameter of not more than
about 30 .mu.m, with water or an alcohol-water mixture in a
conventional or high shear granulator and drying in a fluid bed
equipment or a tray drying oven to produce granules with an average
particle size not more than about 400 .mu.m (preferably not more
than about 300 .mu.m).
[0140] The ultimate dosage forms can comprise a single population
of taste-masked high-dose/low-dose drug-containing microparticles
of the present invention in combination with excipients, rapidly
dispersing microgranules, etc, or can include a combination of the
taste-masked high-dose/low-dose drug-containing microparticles in
combination with high-dose drug-containing particles, or
alternatively two or more populations of different taste-masked
high-dose/low-dose drug-containing microparticles. The ratio of the
different populations of high-dose/low-dose drug-containing
microparticles or high-dose/low-dose drug-containing microparticles
and high-dose drug containing particles can be varied to provide
suitable dosages of the high-dose and low-dose drugs.
[0141] Alternately, the ultimate dosage forms can comprise a single
population of taste-masked high-dose/low-dose drug-containing
microparticles of the present invention in combination with
excipients, rapidly dispersing microgranules, etc, or can include a
combination of the taste-masked high-dose/low-dose drug-containing
microparticles in combination with modified release (e.g.,
taste-masked or sustained release) coated high-dose drug-containing
microparticles, or alternatively two or more populations of
different taste-masked high-dose/low-dose drug-containing
microparticles, wherein the sustained release coated high-dose
drug-containing microparticles comprise a water insoluble polymer
optionally in combination with a water soluble or enteric polymer
applied prior to low-dose drug layering. The ratio of the different
populations of high-dose/low-dose drug-containing microparticles or
high-dose/low-dose drug-containing microparticles and taste-masked
or sustained release coated high-dose drug-containing
microparticles can be varied to provide suitable dosages of the
high-dose and low-dose drug components.
[0142] The oral dosage forms of the present invention, prepared by
the methods described herein, provide in vivo plasma concentrations
and release profiles which mimic RLD's. In accordance with certain
embodiments, the pharmaceutical compositions of the present
invention comprise microgranules or extruded/spheronized pellets
comprising acetaminophen, a polymeric binder, which imparts
resilient characteristics to the dried microgranules/pellets, a
hydrophilic filler/diluent, and optionally a flavor, a sweetener
and/or a disintegrant.
[0143] In certain embodiments, the present invention is directed to
compositions of the present invention comprising at least one
population of non-opioid analgesic/opioid analgesic drug-containing
microparticles combined with non-opioid analgesic drug-containing
microparticles with drug release properties suitable for a twice-
or once-daily dosing regimen, wherein the one or more of the
non-opioid analgesic drug-containing microparticle populations
comprise non-opioid analgesic drug-containing microparticles with
one or more coating layers comprising a water-insoluble polymer, an
enteric polymer, or an enteric polymer in combination with a
water-insoluble polymer.
[0144] In most embodiments, the taste-masked pharmaceutical
compositions of the present invention exhibit the following
properties: [0145] 1) acceptable taste-masking leaving no
aftertaste when the composition is placed in the oral cavity for 3
minutes, more particularly for 2 minutes and in certain embodiments
for 60 seconds, and in still other embodiments, until it is
swallowed; [0146] 2) acceptable homogeneity of blends as per United
States Pharmacopoeia requirements; and [0147] 3) rapid
substantially complete release of the dose upon entry into the
stomach, i.e., release of not less than 75% of the total dose in 30
min when tested for dissolution using United States Pharmacopoeia
Apparatus 1 (Baskets @ 100 rpm) or Apparatus 2 (paddles @ 50 rpm in
900 mL of dissolution media at 37.+-.0.5.degree. C.).
[0148] An ODT prepared in accordance with certain embodiments of
the present invention may exhibit the following properties: [0149]
1) exhibits acceptable uniformity of dosage forms as defined in
United States Pharmacopoeia; [0150] 2) disintegrates on contact
with the saliva in the oral cavity forming a smooth,
easy-to-swallow suspension comprising taste-masked microparticles;
[0151] 3) leaves no aftertaste after swallowing (no gritty or
chalky mouthfeel); [0152] 4) provides rapid, substantially-complete
release of the total dose upon entry into the stomach; or [0153] 5)
the ODT when tested for dissolution using United States
Pharmacopoeia Apparatus 1 (baskets @ 100 rpm) or Apparatus 2
(paddles @ 50 rpm) in 900 mL buffer releases not less than 75% of
the total dose in about 30 minutes.
[0154] In another particular embodiment, the pharmaceutical
composition of the present invention comprises acetaminophen as the
high-dose drug and hydrocodone bitartrate as the low-dose drug.
Following oral administration, acetaminophen is rapidly and almost
completely absorbed from the GI tract. Peak plasma concentrations
are attained within 30-60 minutes (binding to serum protein is
about 25% after normal therapeutic dosages) and plasma half-life is
between 1-2.5 hours in normal, healthy patients. After about 8
hours, only traces of the drug are detectable.
[0155] Pharmaceutical compositions of the present invention
comprising therapeutically effective amounts of taste-masked
high-dose/low-dose drug-containing microparticles are effective in
treating various diseases or conditions. For example,
pharmaceutical compositions of the present invention comprising
therapeutically effective amounts of a non-steroidal
anti-inflammatory drug such as aspirin, ibuprofen, ketoprofen,
meloxicam, diclofenac potassium, etodolac, sulindac, indomethacin,
celecoxib, or mixtures thereof, in combination with an opioid
analgesic such as hydrocodone bitartrate, oxymorphone,
buprenorphine, fentanyl, hydromorphone, or mixtures thereof (e.g. a
combination of acetaminophen and hydrocodone) are effective for
relief of mild to moderate pain of acute, chronic, or
post-operative pain, or disabling pain of terminal conditions such
as cancer.
[0156] In a particular embodiment, the pharmaceutical compositions
of the present invention comprise therapeutically effective amounts
of acetaminophen in combination with therapeutically effective
amount of hydrocodone or salts thereof, e.g. hydrocodone
bitartrate. In a specific embodiment, the pharmaceutical
compositions of the present invention comprise 500 mg of
acetaminophen and 5 mg of hydrocodone bitartrate, or 300 mg of
acetaminophen and 100 mg of hydrocodone bitartrate. The
acetaminophen/hydrocodone-containing compositions of the present
invention are bioequivalent to known acetaminophen/hydrocodone
compositions such as Vicodin.RTM., Panadol.RTM., and Xodol.RTM..
Compositions of the present invention comprising 500 mg of
acetaminophen/5 mg of hydrocodone bitartrate have an acetaminophen
C.sub.max of 80-125% of 6115 ng/mL, a hydrocodone bitartrate
C.sub.max of 80-125% of 20.14 ng/mL, an acetaminophen AUC of
80-125% of 19920 nghr/mL, and a hydrocodone bitartrate AUC of
80-125% of 141 nghr/mL. compositions of the present invention
comprising 300 mg acetaminophen/10 mg hydrocodone bitartrate have
an acetaminophen C.sub.max of 80-125% of 3915 ng/mL, a hydrocodone
bitartrate C.sub.max of 80-125% of 40.53 ng/mL, an acetaminophen
AUC of 80-125% of 12794 nghr/mL, and a hydrocodone bitartrate AUC
of 80-125% of 280 nghr/mL.
[0157] Likewise, pharmaceutical compositions of the present
invention comprising therapeutically effective amounts of niacin in
combination with a statin such as atorvastatin, lovastatin,
fluvastatin, cerivastatin, simvastatin, mevastatin, rosuvastatin,
pravastatin or mixtures thereof are effective to lower cholesterol
(very low density lipoproteins) and triglycerides levels in
patients with or at risk of cardiovascular disease.
[0158] Similarly, pharmaceutical compositions of the present
invention comprising therapeutically effective amounts of metformin
in combination with a drug such as glipizide, glyburide,
glimepiride, repaglinide, nateglinide, rosiglitazone, pioglitazone,
troglitazone (e.g., a combination of metformin and rosiglitazone)
are effective to treat hyperglycemia, e.g., in diabetic
patients.
[0159] Finally, pharmaceutical compositions of the present
invention comprising therapeutically effective amounts of
pseudoephedrine hydrochloride, pseudoephedrine sulfate, or
fexofenadine, in combination with a drug such as cetirizine or
loratidine are effective to treat indoor or outdoor allergies.
Example 1
1.A IR Beads
Drug Load: Approximately 5% Hydrocodone Bitartrate
[0160] Hydrocodone bitartrate (81.1 g) was slowly added to an
acetone/water (1453/782) solution of hydroxypropyl cellulose (8.1 g
of Nisso HPC-L-FP) and mixed well to dissolve. 60-80 mesh sugar
spheres (1500 g) were coated with the drug-layering formulation in
a Glatt fluid-bed coater (Glatt GPCG 3, equipped with a 7''
bottom-spray Wurster insert, 7 13/16'' column, 25 mm column height,
`C` air distribution plate, and 200 mesh product retention screen)
under the following conditions--inlet air temperature:
70.+-.5.degree. C.; product temperature: 45.+-.5.degree. C.;
atomization air pressure 2.43 bar; port size: 1.0 mm; flow rate: 2
g/min increased in steps to 15 g/min, air flow: 25% flap. Following
the drug layering, a sealant coating solution of
hydroxypropylcellulose (32.4 g in 457/51 acetone/water) was sprayed
onto the drug layered beads for a coating weight of 2%. The dried
immediate release (IR) beads were sieved through 50 and 80 mesh
screens for a usable total yield of 88.4%.
1.B Taste-Masked Beads
Drug Load: Approximately 3.5% Hydrocodone Bitartrate
[0161] IR beads (140 g) from Example 1.A, above were coated with
ethylcellulose (Ethocel Standard Premium 100 from Dow Chemicals) by
solvent coacervation at a coating weight of 30%. The ethylcellulose
(60 g) and polyethylene (40 g Epolene C-10 from Eastman Chemicals)
were dissolved/suspended in 2000 g cyclohexane at an agitation
speed of 300 RPM. The tank was heated to 80.degree. C. to dissolve
the ethylcellulose, and thereafter, the tank was cooled to below
30.degree. C. to achieve taste-masked hydrocodone bitartrate
microcapsules. The microcapsules were separated by decanting, then
filtered and washed with fresh cyclohexane and air dried in a fume
hood.
1.C Taste-Masked Microparticles by Fluid-Bed Coating
[0162] IR Beads (1001.3 g) prepared as described in Example 1.A,
above were coated with a solution of ethylcellulose (Ethocel
Standard Premium 10 cps, hereafter referred as EC-10)/Eudragit E100
(188.6 g each) plasticized with diacetylated monoglycerides
(Myvacet 9-45; 30.0 g) and kosher magnesium stearate (30.0 g)
dissolved in 80/20 acetone (3086 g)/water (771 g) for a coating
weight of 30%. Samples were pulled during the coating process at
coating weights of about 10%, 15%, 20%, and 25% and dissolution
tested to evaluate the effect of coating level on dissolution and
organoleptic properties. The coated beads were dried/cured at
60.degree. C. for 10 minutes in the Glatt GPCG 3 and sieved to
discard agglomerates.
1.D Standard Acetaminophen Microcapsules (PE004)
[0163] Production of industrial scale acetaminophen microcapsules
using Acetaminophen Granular (Particle size: 45-80 mesh or 177-350
.mu.m) from Covidien were coated using a method similar to that
described above in Example 1.B using a 200-gallon, 500-gallon or
1000-gallon system, and using a computerized recipe for the process
(e.g., quantities for the 200-gallon system at 10%
coating--Acetaminophen: 94.1 kg; Ethocel 100: 10.5 kg, Epolene: 2.1
kg and Cyclohexane: 146.0 gallons or 547.5 L). Upon controlled
cooling to <30.degree. C., the microcapsule bed is subjected to
vacuum filtration and rinsing with cyclohexane to wash off residual
polyethylene. The microcapsules were transferred to a fluid bed
dryer, subjected to a drying procedure, and dried for a period of
4-6 hrs to reduce the cyclohexane level to not more than 1000
ppm.
1.E Rapidly Dispersing Microgranules
[0164] Rapidly dispersing microgranules comprise a sugar alcohol
such as mannitol and/or a saccharide such as lactose and a
disintegrant such as Crospovidone. The sugar alcohol and/or
saccharide and disintegrant will typically be present in the
rapidly dispersing microgranules at a ratio of from about 99:1 to
about 90:10 (sugar alcohol and/or saccharide:disintegrant). For
example, the rapidly dispersing microgranules used in the ODT
formulations disclosed in the various examples in accordance with
the present invention were produced by granulating 95 parts of
D-mannitol with an average particle size of about 15 .mu.m, and 5
parts of crospovidone (Crospovidone XL-10) in a high shear mixer
(e.g., GMX 600 from Vector Corporation) with water as the
granulating fluid, drying the wet mass in a fluid bed dryer (e.g.,
Glatt GPCG 200 or Fluid Air FA0300), and sieving/milling to obtain
granules with an average particle size of less than 400 .mu.m.
Alternately, the wet milled granules are dried in a tray drying
oven for a loss on drying value of less than 1% by weight.
1.F Hydrocodone Bitartrate/Acetaminophen ODTs, 5 mg/500 mg
[0165] Beads (172.4 g) prepared as described in Example 1.B (30%
coating weight), above; standard acetaminophen microcapsules
(PE004, 531.9 g) produced in Example 1D, above, and rapidly
dispersing microgranules (803.4 g) from Example 1E above, were
blended with a pre-blend comprising crospovidone (XL-10, 80.0 g),
sucralose (5.6 g), and strawberry flavor (6.7 g) before compressing
into 5 mg/500 mg hydrocodone bitartrate/acetaminophen orally
disintegrating tablets (19 mm in diameter) weighing approximately
1600 mg using a Carver tablet press at a compression force of 1
metric ton.
Example 2
2.A Hydrocodone Bitartrate/Acetaminophen Microparticles
Drug Load: 3%
[0166] Hydrocodone bitartrate (47.5 g) was slowly added to a 50/50
acetone/water (each 452 g) solution of hydroxypropylcellulose (5.3
g of Nisso HPC-L-FP) and mixed well to dissolve. Acetaminophen
microcapsules (PE004) from Example 1.D with a 6% EC-100 coating
(1500.0 g) were coated with the drug-layering formulation in a
Glatt fluid-bed coater Glatt GPCG 3. Following drug layering, a
sealant coating solution of hydroxypropylcellulose (31.7 g in
447/50 acetone/water) was sprayed onto the drug layered beads at a
coating weight 2%. The dried IR beads were sieved through 35 and 80
mesh screens for a usable total yield of 99.0%.
2.B Taste-Masked Hydrocodone Bitartrate/Acetaminophen
Microparticles
[0167] IR particles (1100.0 g) prepared as described in Example
2.A, above were coated with a solution of ethylcellulose (EC-10;
43%)/Eudragit E100 (43%) plasticized with diacetylated
monoglycerides (Myvacet 9-45 at 7%) and kosher magnesium stearate
(7%) dissolved in 80/20 acetone (3294 g)/water (848 g) for a 30%
weight gain. Samples were pulled during the coating process at
coating weights of about 5%, 10%, 15%, 20%, and 25% and dissolution
tested to evaluate the effect of coating level on dissolution as
well as organoleptic properties. The coated beads were dried at the
same temperature settings in the Glatt GPCG 3 and sieved to discard
agglomerates for a total useable yield of 98.9%.
2.C Hydrocodone Bitartrate/Acetaminophen ODTs, 10 mg/300 mg
[0168] 20% EC-10/E100 coated (10.01% of hydrocodone
bitartrate/Acetaminophen beads at 15% hydrocodone bitartrate load)
from Example 2.B, above; standard acetaminophen microcapsules
(PE004, 35.46%) from Example 1.D, above, and rapidly dispersing
microgranules (48.76%) from Example 1.E above, were blended with a
pre-blend comprising crospovidone (XL-10 at 5.0%), sucralose
(0.35%), and strawberry flavor (0.42%) before compressing into 10
mg/300 mg hydrocodone bitartrate/acetaminophen orally
disintegrating tablets (15 mm in diameter) weighing approximately
900 mg using a Carver tablet press at a compression force of 1
metric ton.
2.D Hydrocodone Bitartrate/Acetaminophen ODTs, 5 mg/500 mg
[0169] 30% coated beads (10.78%) from Example 2.B, above, standard
acetaminophen microcapsules (PE004, 33.24%) from Example 1.D,
above, and rapidly dispersing microgranules (37.71%) from Example
1.E above, were blended with a pre-blend comprising
microcrystalline cellulose (Avicel PH101 at 12.5%), crospovidone
(XL-10 at 5.0%), sucralose (0.35%), and strawberry flavor (0.42%)
before compressing into 5 mg/500 mg hydrocodone
bitartrate/acetaminophen orally disintegrating tablets (17 mm in
diameter) weighing approximately 1600 mg using a rotary Hata tablet
press equipped with an external lubrication system (Matsui Ex-Lub
System) to lubricate the die/punch surfaces by spraying magnesium
stearate prior to each compression.
Example 3
3.A Taste-Masked Acetaminophen Microparticles
[0170] Acetaminophen (Granular grade from Covidien (A100); 2000.0
g) was coated in a Glatt GPCG 3 (7'' bottom spray Wurster insert
and nozzle with 1.00 mm port size) with a solution of
ethylcellulose (10 cps; 114.3 g)/Eudragit E100 (100.0 g)
plasticized with polyethylene glycol (PEG 400; 42.9 g) and kosher
magnesium stearate (28.6 g) homogeneously suspended in acetone
(1359.5 g)/isopropyl alcohol (672.7 g)/water (770.8 g) for a 12.5%
weight gain. The dried particles were sieved with 35 and 80 mesh
screens to discard agglomerates/fines (useable yield: 93.6%).
3.B Low Potency Hydrocodone Bitartrate/Acetaminophen
[0171] Hydrocodone bitartrate was layered onto acetaminophen
(Granular A100) by spraying the drug-layering formulation (see
Table 1--Low Potency for compositions) in a Glatt GPCG 3 fluid-bed
coater. Following the drug layering, the sealant coating solution
was sprayed onto the drug layered particles at a coating weight of
2%, followed by a taste-masking coating with EC-10/E100/PEG 400/Mg
stearate at a ratio of 40/35/15/10 at a coating weight of 22% using
the method disclosed in Example 3.A above.
3.C High Potency Hydrocodone Bitartrate/Acetaminophen
[0172] Hydrocodone bitartrate was layered onto acetaminophen
(Granular A100) by spraying the drug-layering formulation (see
Table 1--High Potency for compositions) in a Glatt GPCG 3 fluid-bed
coater. Following the drug layering, the sealant coating solution
was sprayed onto the drug layered particles at a coating weight of
2%, followed by a taste-masking coating with EC-10/E100/PEG 400/Mg
stearate at a ratio of 40/35/15/10 at a coating weight of 27%.
TABLE-US-00001 TABLE 1 Taste-Masked Low Potency (PE382)/High
Potency ((PE384) Hydrocodone Bitartrate/Acetaminophen (A100)
Percent Quantity Required. (g) Taste-masked
Hydrocodone/Acetaminophen - PE382 (LP)/PE384 (HP) or Acetaminophen
PE380 Low High Low High Ingredients Potency Potency PE380 Potency
Potency LP/HP HCB on Acetaminophen (A100) Acetaminophen Granular
(A100) 96.06 90.22 2500.0 2000.0 Hydrocodone Bitartrate, NF 1.75
7.00 45.5 155.2 Hydroxypropylcellulose, NF 0.196 0.78 5.1 17.2
(Klucel LF) Acetone, NF 432.7 1474.1 Purified Water, USP 432.7
1474.1 Hydroxypropylcellulose 1.70 1.70 44.2 37.7 (Klucel .RTM. LF)
Magnesium Stearate NF 0.30 0.30 7.8 6.7 Acetone NF* 611.6 520.9
Purified Water USP * 203.9 173.6 Total 100.0 100.0 2602.6 2216.8
Taste-masking Coating - (5% Solids) LP/HP Hydrocodone-layered 78.00
73.00 2000.0 1500.0 Acetaminophen Acetaminophen Granular (A100)
2000.0 Ethylcellulose NF 8.80 10.80 114.3 225.6 221.9 (Ethocel
.RTM. Standard 10 Premium) Aminoalkyl Methacrylate 7.70 9.48 100.0
197.4 194.2 Copolymer E (Eudragit .RTM. E 100) Polyethylene Glycol
3.30 4.05 42.9 84.6 83.2 (Carbowax .RTM. 400) Magnesium Stearate NF
2.20 2.70 28.6 56.4 55.5 Acetone NF* Traces Traces 1359.5 2684.1
2639.8 Isopropyl Alcohol USP* Traces Traces 672.7 1328.2 1306.3
Purified Water USP* Traces Traces 770.8 1521.9 1496.8 Total 100.0
100.0 2285.8 2564.0 2054.8
3.D Hydrocodone Bitartrate/Acetaminophen ODTs, 5 mg/500 mg
[0173] 12.5% coated acetaminophen from Example 3A, above, 22%
coated hydrocodone/acetaminophen from Example 3B, above, rapidly
dispersing microgranules from Example 1.E above, were blended with
a pre-blend comprising microcrystalline cellulose (Avicel PH101),
(Parteck M200), crospovidone, sucralose, and strawberry flavor
before compressing into 5 mg/500 mg hydrocodone
bitartrate/acetaminophen orally disintegrating tablets (17 mm in
diameter) weighing approximately 1600 mg using a using a rotary
Hata tablet press equipped with an external lubrication system
(Matsui Ex-Lub System) to lubricate the die/punch surfaces prior to
each compression at a compression force of 18 to 24 kN.
3.E Hydrocodone Bitartrate/Acetaminophen ODTs, 10 mg/300 mg
[0174] 12.5% coated acetaminophen from Example 3.A, above, 27%
coated hydrocodone/acetaminophen from Example 3.C, above, and
rapidly dispersing microgranules from Example 1.E above, were
blended with a pre-blend comprising microcrystalline cellulose
(Avicel PH101), mannitol (Parteck M200), crospovidone, sucralose,
and strawberry flavor before compressing into 5 mg/500 mg
hydrocodone bitartrate/acetaminophen orally disintegrating tablets
(17 mm in diameter) weighing approximately 1000 mg using a using a
rotary Hata tablet press equipped with an external lubrication
system (Matsui Ex-Lub System) to lubricate the die/punch surfaces
prior to each compression at a compression force of 10 to 15 kN
(see Table 2 for details).
TABLE-US-00002 TABLE 2 Hydrocodone Bitartrate/Acetaminophen ODTs, 5
mg/500 mg & 10 mg/300 mg Hydrocodone/Acetaminophen ODTs PF401
(5 mg/500 mg) PF402 (10 mg/300 mg) Item Ingredient %/tablet g/Batch
%/tablet g/Batch 1 Low-potency Taste-masked Hydrocodone 22.89
572.25 Bitartrate/Acetaminophen (PE382) 2 High-potency Taste-masked
15.66 391.5 Hydrocodone/Acetaminophen (PE384) 3 Acetaminophen
Microcapsules (PE380) 16.11 402.75 15.60 390.0 4 Rapidly Dispersing
Granules 40.15 1003.75 49.70 1242.5 5 Mannitol, USP (Parteck .RTM.
M200) 4.25 106.25 5.00 125.0 6 Microcrystalline Cellulose, NF 10.00
250.0 10.00 250.0 7 Crospovidone, NF (XL-10) 5.25 131.25 5.26 131.3
8 Sucralose, NF 0.35 8.75 0.35 8.8 9 Artificial Strawberry Flavor
1.00 25.00 1.00 25.0 10 Magnesium Stearate Traces Traces Traces
Traces Total 100.0 2500.0 100.0 2500.0 Tablet Weight (mg) 1600.0
1250.0
Example 4
4.A Pilot PK Trial Supplies
[0175] Two tablet strengths of hydrocodone bitartrate/acetaminophen
ODTs--5 mg/500 mg and 10 mg/300 mg, and three different
taste-masked particle compositions were used between these two
strengths: 1) acetaminophen crystals (A100--standard particle size,
i.e., 177-350 .mu.m) with a taste-masking coating composition used
in both ODT formulations; 2) acetaminophen crystals (standard
particle size) with a 1.75% w/w drug layer of hydrocodone
bitartrate and a subsequent taste-masking coating, used in the 5
mg/500 mg strength; and 3) acetaminophen crystals (standard
particle size) with a 7% w/w drug layer of hydrocodone bitartrate
and a subsequent taste-masking coating, used in the 10 mg/300 mg
strength. The taste-masking coating was compositionally the same
for all particles, but the amount of coating on a w/w basis varies
from 12.5% on acetaminophen (PE380), 22% on 1.75% hydrocodone
bitartrate/acetaminophen (PE382) used in 5 mg/500 mg ODTs (PF401)
to 27% on 7% hydrocodone bitartrate/acetaminophen (PE384) used in
10 mg/300 mg ODTs (PF402). The compression blend is compressed into
hydrocodone bitartrate/acetaminophen ODTs using an Elizabeth Hata
tablet press equipped with a Matsui Ex-Lub lubricating system that
uses magnesium stearate as an external lubricant. Each of the
dosages has a unique blend and was prepared using different
tableting parameters (see Table 3 below for details). These ODT
batches were prepared as described in Examples 3.A to 3.E (see
Tables 1 and 2 for compositions. The intermediate and finished
products were tested using qualified analytical test methods and
used in the pilot PK study in healthy volunteers.
TABLE-US-00003 TABLE 3 Tableting Parameters for Hydrocodone
Bitartrate/Acetaminophen ODTs: 5 mg/500 10 mg/300 Parameter mg ODT
mg ODT Tooling - round, flat face, radius edge 17 mm 15 mm Target
tablet weight (mg) 1600 1250 Lower target tablet weight .times.
0.985 (mg) 1576 1231 Target tablet weight .times. 1.015 (mg) 1624
1269 Turn table speed with range (rpm) 15 (10-20) 15 (10-20) Fill
depth (mm) 10.94-10.98 5.11 Main position (mm) 10.6-11.1 4.44 Pre.
Position (mm) 6.2-6.4 4.61 Scale on the feed shoe 2 (0-4) 2 (0-4)
Tablet Weight (mg) 1597 1248.6 Hardness with range (n) 6.80
6.92-6.95 Thickness with range (mm) 47-49 40-42 Friability with
range (%) 0.25-0.31 0.24-0.31
4.B Pilot PK (Pharmacokinetics) Study
[0176] Hydrocodone bitartrate/acetaminophen ODTs, 5 mg/500 mg and
10 mg/300 mg dosages were tested in a 4-arm pilot PK
(pharmacokinetics) study involving 16 healthy subjects per arm in
comparison to the corresponding RLDs, Abbott's VICODIN.RTM. 5
mg/500 mg, Mikart's Xodol.RTM., 10 mg/300 mg. Acetaminophen and
hydrocodone bitartrate plasma concentration vs. time profiles for
these ODTs are shown in FIGS. 2 and 3.
TABLE-US-00004 TABLE 4 PK Parameters for Hydrocodone/Acetaminophen
ODTs Ratio Test# ODT RLD IR Active Test ODT RLD Test/RLD Min-Max
C.sub.max (ng/mL) 5/500 mg Vicodin Acetaminophen 5013.86 6115.49
81.99 67.79-99.15 AUC.sub.0.fwdarw.inf (ng hr/mL) 19205.98 19917.76
96.43 79.17-117.4 C.sub.max (ng/mL) 10/300 mg Xodol Acetaminophen
3159.55 3914.16 80.72 67.80-96.10 AUC.sub.0.fwdarw.inf (ng hr/mL)
12196.49 12794.85 95.32 79.55-114.2 C.sub.max (ng/mL) 5/500 mg
Vicodin Hydrocodone 19.708 20.139 97.86 90.44-105.9
AUC.sub.0.fwdarw.inf (ng hr/mL) 141.36 141.40 99.97 93.56-106.8
C.sub.max (ng/mL) 10/300 mg Xodol Hydrocodone 38.719 40.530 95.53
88.87-102.7 AUC.sub.0.fwdarw.inf (ng hr/mL) 286.33 279.06 102.6
96.25-109.4
[0177] FIG. 4 shows the plasma concentration-time profiles for
acetaminophen observed in another 3-arm pilot PK study involving 24
healthy subjects per arm wherein Acetaminophen ODT, 500 mg with or
without water was administered to fasted healthy volunteers in
comparison to the corresponding RLD, GSK's Panadol.RTM. 500 mg.
Acetaminophen of semi-fine grade (A137) with a smaller particle
size distribution of 53-177 .mu.m were taste-masked by solvent
coacervation with Ethocel Standard Premium 100 cps for a coating
weight of 10-12%. To produce orally disintegrating tablets, these
microcapsules were blended with rapidly dispersing microgranules
(PE378 prepared from mannitol 25/crospovidone at 95/5 as disclosed
in Example 1.E, above), crospovidone, microcrystalline cellulose,
aspartame (sweetener) and strawberry flavor in a V-blender and then
compressed on a rotary tablet press equipped with an external
lubrication system. These tablets (see Table 5 for compositions)
released not less than 85% in 15 min when tested using the USP
apparatus 2 (paddles@ 75 rpm in pH 5.8 buffer (see Table 6 for
dissolution data).
TABLE-US-00005 TABLE 5 Compositions of Acetaminophen ODTs Quantity
% per ODT (mg/tablet) (kg)/Batch Ingredients tablet 250 mg 500 mg
250 mg/500 mg Taste-masked (10-12%) 39.68 277.8 555.5 63.5
Acetaminophen (A137) Rapidly Dispersing 42.12 294.8 589.7 67.4
Granules (PE375) Microcrystalline 10.00 70.0 140.0 8.0 Cellulose
(Avicel PH101) Crospovidone NF (XL-10) 5.00 35.0 70.0 16.0
Sucralose NF 1.60 11.2 22.4 2.56 Strawberry Flavor 1.60 11.2 22.4
2.56 Total 100.0 700.0 1400.0 160.0
[0178] The PK parameters for Acetaminophen ODTs in comparison to
Panadol.RTM. are given below: [0179] Regimen T1: Acetaminophen
(P-300) ODT with water [0180] Regimen T2: Acetaminophen (P-300) ODT
without water [0181] Regimen 3: Reference tablet (Panadol.RTM.)
swallowed with water
TABLE-US-00006 [0181] 90% Confidence 90% Confidence Test 1 (ODT)
Test 2 (ODT) Interval Interval PK Parameter With water W/O water
Test T1 vs. RLD Test T2 vs. RLD C.sub.max (ng/mL) 7.240 7.635
90.94-110.25 94.04-114.01 AUC.sub.0-t (ng hr/mL) 21.44 21.00
99.61-106.19 98.06-104.53 AUC.sub.0-INF (ng hr/mL) 22.43 21.69
99.41-106.33 96.82-103.57
[0182] The above results confirm that the test product,
Acetaminophen ODT, 500 mg when administered with and without water
is bioequivalent to the reference product, Panadol.RTM., 500 mg
swallowed with water. Multi-speed (50, 75 and 100 rpm) and multi-pH
in vitro dissolution (water, pH 1.2, 4.5, 5.8, 6.8) data were
generated on batches of 5 mg/500 mg and 10 mg/300 mg ODT tablets of
Example 3 and 4 and 250 mg and 500 mg ODT tablets of Example 4, and
a comparative data set is presented in Table 6. Since different
grades of the drug substance such as Acetaminophen Granular and
Acetaminophen Semi-fine were used to manufacture batches of 5
mg/500 mg-10 mg/300 mg ODT tablets and 250 mg-500 mg ODT tablets,
respectively, the particle size distributions of several lots of
the drug substance and the corresponding batches of microcapsules
were determined. Table 7 shows the mean particle size distribution
data.
TABLE-US-00007 TABLE 6 Dissolution Data for
Hydrocodone/Acetaminophen IR Tablets and ODTs and Acetaminophen ODT
Time PF401EA0001 PF402EA0001 Vicodin* Xodol PF407EA0001A
PF408EA0002A (min) 5 mg/500 mg 10 mg/300 mg 5/500 mg 10/300 mg 250
mg 500 mg 0 0 0 0 0 0 0 5 23 28 49 40 10 53 60 65 87 75 15 75 87 71
84 95 88 30 101 103 76 93 *.fwdarw. Vicodin is released by USP test
2 which is 0.1N HCl media
TABLE-US-00008 TABLE 7 Particle Size Distributions of Acetaminophen
Drug Substance and Microcapsules Acetaminophen Drug Substance
Microcapsules % Particles % Particles % Assay Grade Retained on
Coating Retained (STD) Granular (Mean of >80% <425-180
.mu.m> .sup. 6% (500/1000 gallon) 95% <425-180 .mu.m> 93
.+-. 1.37 multiple batches) Semi-fine Mean of 90% <150-53
.mu.m> 12% (5-gallon) 87% <250-74 .mu.m> 87.9 multiple
batches A13709532 89.5% <150-53 .mu.m> 12% (500-gallon) 90%
<250-74 .mu.m> 86.8 A13709533 86.2% <150-53 .mu.m> 10%
(500-gallon) 89.5% <250-74 mesh 89.7
[0183] Acetaminophen/Hydrocodone ODT tablets (5 mg/500 mg or 10
mg/300 mg ODTs) contain two of three types of microencapsulated
acetaminophen drug particles--granular grade acetaminophen and
granular grade acetaminophen drug particles layered with
hydrocodone at a low or high drug load, all taste-masked with a
coating of ethylcellulose/Eudragit EPO. To improve dissolution and
bioequivalence to the RLDs and to improve the stability of
hydrocodone when directly layered onto acetaminophen particles, it
was decided to use the drug substance with a smaller particle size
distribution (e.g., Acetaminophen Semi-fine) in the tablet
formulation to manufacture "smaller acetaminophen
microcapsules".
[0184] During the evaluation of different taste-masking coatings
applied on microparticles comprising hydrocodone bitartrate for
their ability to impart acceptable organoleptic properties, it was
discovered that a coating comprising a sweetener in combination
with a seal coating layer comprising hydroxypropylcellulose (Klucel
LF) was effective in masking the bitter taste of hydrocodone
bitartrate.
Example 5
5.A Taste-Masked Acetaminophen Microparticles (6%)
[0185] Acetaminophen (Semi-fine grade from Covidien with a particle
size of 80-270 mesh or 53-177 .mu.m (A137); 1800.0 g) was
taste-masked by solvent coacervation in a 5-gallon system. The
5-gallon system filled with 10,000 g of cyclohexane was charged
with ethylcellulose (Ethocel Standard Premium 100 from Dow
Chemicals; 114.9 g), polyethylene (Epolene C-10; 50 g), and the
drug. The system was subjected to a controlled heating cycle to
achieve a temperature of 80.degree. C. to dissolve ethylcellulose
while agitating the contents at a speed of 300 RPM. Thereafter the
system was subjected to a computer controlled cooling cycle to
<28.degree. C. in not less than 45 min to encapsulate the drug
crystals with a smooth coating at a coating weight of 6%, and
avoiding formation of agglomerates. The microcapsules were
separated by decanting, washed with fresh cyclohexane, and dried in
a fume hood. The microcapsules with a size less than 35 mesh were
collected for taste-masking (useable yield: 98.0%).
5.B Taste-Masked Hydrocodone Bitartrate/Acetaminophen
Microcapsules
[0186] Hydrocodone bitartrate (57.4 g), acetaminophen (semi-finer
grade A137; 1742.6 g), ethylcellulose (156.5 g), polyethylene (50.0
g) were suspended in cyclohexane in the 5 gallon system, and
HCB/Acetaminophen microencapsulated particles at an EC-100 coating
of 8% by weight were produced following the procedure of Example
5.A. Hydrocodone bitartrate/Acetaminophen microencapsulated
particles (1518.8 g) were sealant coating with Klucel LF (288.6
g)/magnesium stearate (15.2 g) and further provided with a second
taste-masking membrane comprising ethylcellulose (EC-10)/Eudragit
E100/Myvacet/magnesium stearate at a ratio of 286.6/253.5/31.8/35.7
in a Glatt GPCG 3 for a coating weight of 25% as described in
Example 3.
5.C Taste-Masked Hydrocodone Bitartrate/Acetaminophen
Microcapsules
[0187] Hydrocodone bitartrate (60.0 g and 6.7 g of Klucel LF) was
layered onto acetaminophen microcapsules (Semi-fine A137 with an
EC-100 coating weight of 6% from Example 5.A; 1205.3 g) in the
Glatt GPCG 3 for a coating weight of 8% as described in Example 3.
Following the drug layering, a sealant coating with Klucel LF (28.0
g) was sprayed onto the hydrocodone-layered particles, followed by
a taste-masking coating with EC-10/E100/PEG 400/Myvacet 9-45 at a
ratio of 40/35/15/10 for a coating weight of 35%.
5.D Hydrocodone Bitartrate/Acetaminophen ODTs
[0188] The compression blend comprising taste-masked
Hydrocodone/Acetaminophen microparticles from Example 5.B, above or
taste-masked Hydrocodone/Acetaminophen microparticles from Example
5.C, above was combined with the rapidly dispersing microgranules
from 1.E, above, and a pre-blend comprising microcrystalline
cellulose, crospovidone, sucralose, and strawberry flavor, and
compressed into hydrocodone bitartrate/acetaminophen ODTs, 5 mg/500
mg and 10 mg/300 mg (see Table 8 for compositions) using an
Elizabeth Hata tablet press equipped with a Matsui Ex-Lub
lubricating system that uses magnesium stearate as an external
lubricant.
TABLE-US-00009 TABLE 8 Compositions of Acetaminophen ODTs ODTs, 5
mg/500 mg ODTs 10 mg/300 mg Ingredients (mg/tablet) 1300-086
1300-088 1300-085 1300-087 Taste-masked Hydrocodone/ 287.4 344.8
Acetaminophen (Example 5.B) Taste-masked Hydrocodone/ 172.4 344.8
Acetaminophen (Example 5.C) Acetaminophen Microcapsules (PE378)
378.4 445.4 123.3 123.3 Rapidly Dispersing Granules 496.9 544.9
445.5 445.5 Microcrystalline Cellulose (Avicel 140.0 140.0 110.0
110.0 PH101) Crospovidone NF (XL-10) 70.0 70.0 55.0 55.0 Sucralose
NF 4.9 4.9 3.85 3.85 Strawberry Flavor 22.4 22.4 17.6 17.6 Total
1400.0 1400.0 1100.0 1100.0
[0189] Table 9 presents the dissolution profiles of hydrocodone
bitartrate and acetaminophen from ODTs. A slightly thicker coating
on acetaminophen drug particles by coacervation (EC-100) or a
thicker fluid-bed coating (EC-10/E100) appeared to have little
impact on drug dissolution rates.
TABLE-US-00010 TABLE 9 Dissolution Data for Hydrocodone
Bitartrate/Acetaminophen ODTS Hydrocodone Bitartrate Released (%)
Acetaminophen Released (%) Time ODT (10 mg/300 mg) ODT (5 mg/500
mg) ODT (10 mg/300 mg) ODT (5 mg/500 mg) (min) 1300-085 1300-087
1300-086 1300-088 1300-085 1300-087 1300-086 1300-088 0 0 0 0 0 0 0
0 0 5 90 101 87 98 54 49 47 51 10 94 104 91 101 91 80 81 81 15 94
104 92 101 102 95 93 92 30 95 104 93 102 105 103 98 98
Example 6
6.A Microencapsulation of Acetaminophen
[0190] A 200-gallon solvent coacervation system (146 kg) was
charged with acetaminophen (Semifine grade A137; 75.5 kg),
Ethylcellulose (EC-100; 4.8 kg), Epolene; 2.1 kg) and the
acetaminophen was taste-masked by solvent coacervation in a
200-gallon system while agitating at 80.+-.5 RPM. A computer
controlled "heat to 80.degree. C.- and hold" cycle was used to
achieve a temperature of 80.degree. C. to dissolve the
ethylcellulose in the coacervation system. Thereafter the system
was subjected to a cooling cycle to <28.degree. in not less than
45 min to encapsulate the acetaminophen crystals with a smooth
coating at 6% by weight, and avoiding the formation of
agglomerate's. The microcapsules were vacuum-filtered, washed with
cyclohexane, and dried in a fluid bed dryer using a 3-step
temperature (e.g., 25.degree. C., 35.degree. C., 99.degree. C.) for
4 to 6 hrs to achieve a residual cyclohexane level of less than
1000 ppm. The microcapsules were sieved through a US 35 mesh sieve.
Following the same procedure, several batches of microcapsules
(batch size: 80 kg) were prepared at a coating weight of 6% in the
200 gallon system.
6.B Taste-Masked Hydrocodone/Acetaminophen Microparticles
[0191] Hydrocodone bitartrate (see Table 10 for compositions and
batch quantities) was layered onto acetaminophen microcapsules (6%
EC-100 coating; 3375.0 g) from Example 6.A, above by spraying the
drug-layering formulation comprising hydroxypropylcellulose (10%
solids) in a Glatt GPCG 5 (9'' Wurster, 25 mm partition gap, 200
mesh product retention screen, 1.0 mm nozzle tip diameter, `C`
bottom air distribution plate; product temperature: 37.+-.3.degree.
C.; inlet air volume: 40-45 CFM; spray rate: 8-24 ml/min) for a
hydrocodone bitartrate load of 9.0%. A sealant coating solution of
hydroxypropyl (5.0% or 73.68 g dissolved in 50/50 acetone/water at
10% solids) was sprayed onto the drug-layered particles (1400 g) in
a Glatt GPCG 3, for a coating weight of 5%, followed by a
taste-masking coating with sucralose (5.0%) dissolved in an aqueous
solution of hydroxypropylcellulose (1.24%; at a ratio of 80/20
sucralose/HPC) using the following process conditions: Inlet
temperature: 57.+-.2.degree. C.; product temperature:
37.+-.2.degree. C.; spray rate: 8 mL/min; inlet air volume: 6
CFM.
6.C Taste-Masked Hydrocodone/Acetaminophen Microparticles
[0192] Hydrocodone bitartrate (see Table 10 for compositions and
batch quantities) was layered onto acetaminophen microcapsules (6%
EC-100 coating; 3733.3 g) from Example 6.A, above by spraying a
drug-layering formulation comprising hydroxypropylcellulose (10%
solids) in a Glatt GPCG 5 as described in Example 6.B, above.
Following the coating, the microparticles were sealant coated with
hydroxypropylcellulose at 5% in the same unit, dried for 5 minutes
to reduce residual moisture and sieved through 30 and 80 mesh
sieves to discard over sized particles and fines.
TABLE-US-00011 TABLE 10 5.0% Sucralose/5.0% HPC/Hydrocodone
Bitartrate/Acetaminophen Microparticles Ingredients 5.0%
Sucralose/5.0% HPC Coated Percent Quantity Required (g)
Hydrocodone/Acetaminophen Microcapsules Formula A Formula B Formula
A Formula B Drug Layering - (10% solids) Microcaps APAP (A137) (6%
Coating) 80.16 84.24 3375.0 3733.3 Hydrocodone Bitartrate, NF 8.02
5.41 337.5 240.0 Hydroxypropyl Cellulose, NF (Klucel LF) 0.89 0.60
37.5 26.7 Acetone, NF Traces Traces 2400.0 Purified Water, USP
Traces Traces 3375.0 2400.0 HPC Sealant Coat - (6% solids)
Hydrocodone/Acetaminophen Microcapsules 89.07 90.25 1400.0 4000.0
Hydroxypropyl Cellulose, NF (Klucel LF) 4.69 4.75 73.68 210.5
Acetone, NF Traces Traces 614.0 1649.1 Purified Water, USP Traces
Traces 614.0 1649.1 Sucralose Coat (15% solids) HPC Coated
Hydrocodone/Acetaminophen 93.76 95.00 1300.0 3400.0 Sucralose, NF
5.00 5.00 69.33 179.0 Hydroxypropyl Cellulose, NF (Klucel LF) 1.24
17.19 Purified Water, USP Traces Traces 490.27 1014.0 Total 100.0
100.0 1386.52 3578.9
6.D Hydrocodone/Acetaminophen ODTs
[0193] A compression blend comprising taste-masked
hydrocodone/acetaminophen microparticles from Example 6.B, above or
taste-masked Hydrocodone/Acetaminophen microparticles from Example
6.C, above was combined with the rapidly dispersing microgranules
from 1.E, above, and a pre-blend comprising microcrystalline
cellulose, crospovidone, sucralose, and strawberry flavor, and
compressed into Hydrocodone bitartrate/Acetaminophen ODTs, 10
mg/300 mg and 5 mg/500 mg (see Table 11 for compositions) using an
Elizabeth Hata tablet press. While ODT lot # 1334-JMC-142 was
compressed using magnesium stearate as an external lubricant, ODT
lot # 1198-JMC-046 and 1198-JMC-062 were compressed using Sodium
stearyl fumarate (PRUV) as an internal lubricant. The tableting
properties are listed in Table 12.
TABLE-US-00012 TABLE 11 Hydrocodone Bitartrate/Acetaminophen ODTs,
5 mg/500 mg & 10 mg/300 mg Hydrocodone/Acetaminophen ODTs 10
mg/300 mg 10 mg/300 mg 5 mg/500 mg 1334-JMC-142 1198-JMC-062
1198-046 Item Ingredient (mg/tablet) mg/tablet mg/tablet mg/tablet
1 Sucralose/HPC/9% Hydrocodone/ 123.11 Acetaminophen (from Example
6.B) Sucralose/HPC/5.7% Hydrocodone/ 184.50 92.25 Acetaminophen
(from Example 6.C) 2 Acetaminophen Microcapsules (10%) 225.88
172.33 476.35 3 Rapidly Dispersing Granules 542.01 443.97 454.10 4
Microcrystalline Cellulose, NF 110.00 110.00 140.00 5 Mannitol, USP
(Parteck .RTM. M200) 110.00 140.00 6 Crospovidone 55.00
Croscarmellose Sodium (Ac-Di-Sol) 33.00 42.00 7 Sucralose, NF 13.75
18.70 23.80 8 Artificial Cherry Flavor 19.25 16.50 17.50 9 Citric
Acid 11.00 Magnesium stearate (External) Traces Sodium Stearyl
Fumarate (PRUV) 11.00 14.00 Total 1100.0 1100.0 1400.0
TABLE-US-00013 TABLE 12 Tableting Properties of Hydrocodone
Bitartrate/Acetaminophen ODTs Compression Lot# Force Weight
Thickness Hardness Friability ODTs 10-mg/300-mg 1334-142 13 kN 1102
mg 6.12 mm 41.3 N 0.51% 14 kN 1101 mg 6.03 mm 46.4 N 0.37% 1198-062
12.5 kN 1099 mg 6.09 mm 46.0 N 0.20% ODTs 5-mg/500-mg 1198-046 18
kN 1402 mg 6.11 mm 53 N 0.18% 20 kN 1394 mg 6.03 mm 61 N 0.05% 22
kN 1390 mg 5.97 mm 67 N 0.17%
Example 7
7.A Taste-Masked Metformin Microparticles
[0194] Metformin hydrochloride (1000.0 g) is coated in a Glatt GPCG
3 with a solution of ethylcellulose (Ethocel Standard 10 Premium;
78.5 g)/Eudragit E100 (75.0 g) plasticized with polyethylene glycol
(PEG 400; 25.9 g) and kosher magnesium stearate (15.6 g) dissolved
in 80/20 acetone (1359.5 g)/isopropyl alcohol (672.7 g)/water
(770.8 g) for a coating weight of 17.5%. The dried particles are
sieved using 35 and 80 mesh sieves to discard agglomerates/fines. A
batch of taste-masked metformin microcapsules are also prepared at
a coating weight of 25%. A 5% sealant coating with Klucel LF is
also applied to avoid potential interaction between the cationic
polymer of the taste-masking membrane and low-dose drug (e.g.,
rosiglitazone). Another batch of taste-masked metformin
microparticles is also prepared with the coating formulation at the
same ratio and same % solids for a coating weight of 25%, for
directly incorporating in the ODT formulation.
7.B Taste-Masked Rosiglitazone/Metformin
[0195] Rosiglitazone maleate is layered onto sealant-coated
metformin microcapsules from Example 7.A, above in the Glatt GPCG 3
for a coating weight gain of 2.5%, using a method similar to that
described in Example 5.B, above. Following the drug layering, a
sealant coating of a 2% by weight Klucel LF solution at is sprayed
onto the rosiglitazone-layered particles, followed by coating with
a taste-masking coating of EC-10/E100/PEG 400/Mg stearate at a
ratio of 40/35/15/10 at a coating weight of 20%.
7.C Rosiglitazone/Metformin ODT
[0196] Rosiglitazone maleate/Metformin hydrochloride microparticles
from Example 7.B, above, taste-masked Metformin hydrochloride
microparticles from Example 7.A, above, rapidly dispersing
microgranules from Example 1.E, above and a pre-blend comprising
microcrystallinecellulose, sucralose, strawberry flavor, and
crospovidone are blended together in a V-blender and compressed
into Rosiglitazone/Metformin ODTs, 1 mg/500 mg, 2 mg/500 mg, 4
mg/500 mg, and 4 mg/1 g using an Elizabeth Hata tablet press
equipped with a Matsui Ex-Lub lubricating system that uses
magnesium stearate as an external lubricant to lubricate punch and
die surfaces prior to compression.
[0197] These examples demonstrate that the ODT formulations
comprising microparticles comprising high-dose metformin
HCl/low-dose rosiglitazone maleate (e.g., 500 mg/l mg, 500 mg/2 mg,
or 500 mg/4 mg) exhibit acceptable tableting properties (e.g.,
hardness, friability, uniformity of dosage forms, low in vitro/in
vivo disintegration time, rapid dissolution, acceptable
organoleptic properties which significantly improve
patient-compliance. In addition, the pharmaceutical compositions
(and oral dosage forms prepared therefrom) of the present invention
exhibit acceptable taste-masking and provides rapid,
substantially-complete release of the dose on entry into the
stomach, thereby providing bioequivalence to the appropriate
reference immediate release (IR) product.
Example 8
8.A Niacin Microparticles by Controlled Spheronization
[0198] Povidone (PVP K-30; 50 g) is slowly added to purified water
(500 g) while constantly stirring to prepare a polymer binder
solution at 10% w/w solids. Niacin (or nicotinic acid from Lonza
Corporation; 2000 g) is blended with 10 g of colloidal silica (a
flow aid, Cab-O-Sil M-5P from Cabot Corporation) and povidone (50
g) in a V-blender and charged into the product bowl of Granurex
GX-35 from Vector Corporation (Iowa, USA). The 10% PVP binder
solution is sprayed into the rotating material bed at a controlled
rate. Optimized process parameters during pellet formation--process
air temperature: .about.19-20.degree. C.; product temperature:
16.+-.2.degree. C.; Rotor speed: 425 RPM; External air supply: 150
L/min; Spray rate: 15 RPM (.about.8 mL/min); pressure drop across
slit: 1.3-11 mm in water. Optimized process parameters during
drying of pellets--Process air volume: 30 CFM; Process air
temperature: .about.60.degree. C.; Product temperature: 35.degree.
C. (to stop drying); Rotor speed: 180 RPM; Slit air volume: 10 CFM;
Processing time: 40 min. About 65% of the pellets thus prepared
have a size in the range of 40-80 mesh.
8.B SR Coated Niacin Microparticles
[0199] Niacin microparticles (1600 g) from step 8.A, above are
provided with an SR coating with ethylcellulose (Ethocel Standard
10 Premium; 180 g)/TEC (triethyl citrate, a plasticizer; 20 g)
dissolved in 90/10 acetone/water for a 15% weight gain. Samples are
pulled at a coating of 7.5, 10, 12.5% by weight for drug release
testing. The dried particles are sieved using 30 and 80 mesh sieves
to discard agglomerates/fines. A 2% seal coat with Klucel LF is
also applied to avoid potential interaction between the
polymer/plasticizer and low-dose drug (e.g., atorvastatin).
[0200] Another batch of taste-masked niacin microparticles is also
be prepared with the coating formulation at the same ratio and same
% solids for a weight gain of 15% based on the total weight of the
coated microparticles for directly incorporating in the ODT
formulation.
8.C Atorvastatin Coated Niacin Microparticles
[0201] Atorvastatin calcium is layered onto seal-coated niacin
microcapsules from step 8.B, above in the Glatt GPCG 3 for a weight
gain of 4% as described in Example 1.C, above. Following the drug
layering, a seal coating of Klucel LF at 2% by weight is sprayed
onto the atorvastatin-layered particles, followed by a
taste-masking coating with EC-10/E100/PEG 400/Mg stearate at a
ratio of 40/35/15/10 for a weight gain of 20%.
8.D Atorvastatin/Niacin SR ODT
[0202] Taste-masked Atorvastatin calcium/Niacin microparticles from
step 8.C, above, taste-masked Niacin microparticles from step 8.B,
above, rapidly dispersing microgranules from step 1.E, above and a
pre-blend comprising microcrystalline cellulose, sucralose,
strawberry flavor, and crospovidone are blended together in a
V-blender and compressed into Atorvastatin/Niacin ODTs,
2.5-mg/500-mg, 5-mg/500-mg, and 10-mg/500-mg using an Elizabeth
Hata tablet press equipped with a Matsui Ex-Lub lubricating system
that uses magnesium stearate as an external lubricant to lubricate
punch and die surfaces prior to compression.
[0203] Changes may be made by persons skilled in the art in the
construction and the various components and assembly described
herein or in the steps or the sequence of steps of the method of
manufacture described therein without departing from the spirit and
scope of the invention as described herein.
* * * * *