U.S. patent application number 12/173493 was filed with the patent office on 2008-11-06 for compositions and methods for treating nocturnal acid breakthrough and other related disorders.
This patent application is currently assigned to The Curators of the University of Missouri. Invention is credited to Jeffrey Owen Phillips.
Application Number | 20080275091 12/173493 |
Document ID | / |
Family ID | 37494955 |
Filed Date | 2008-11-06 |
United States Patent
Application |
20080275091 |
Kind Code |
A1 |
Phillips; Jeffrey Owen |
November 6, 2008 |
COMPOSITIONS AND METHODS FOR TREATING NOCTURNAL ACID BREAKTHROUGH
AND OTHER RELATED DISORDERS
Abstract
The present invention relates to, inter alia, pharmaceutical
compositions comprising an acid labile proton pump inhibitor and a
buffering agent; to methods for manufacture of such compositions,
and to use of such compositions in treating and preventing diseases
and/or disorders.
Inventors: |
Phillips; Jeffrey Owen;
(Ashland, MO) |
Correspondence
Address: |
MAYER BROWN LLP
P.O. BOX 2828
CHICAGO
IL
60690
US
|
Assignee: |
The Curators of the University of
Missouri
Columbia
MO
|
Family ID: |
37494955 |
Appl. No.: |
12/173493 |
Filed: |
July 15, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11380177 |
Apr 25, 2006 |
|
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12173493 |
|
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60675123 |
Apr 26, 2005 |
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Current U.S.
Class: |
514/338 |
Current CPC
Class: |
A61P 1/04 20180101; A61K
31/4439 20130101; A61K 31/4745 20130101 |
Class at
Publication: |
514/338 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61P 1/04 20060101 A61P001/04 |
Claims
1. A method for treating and/or preventing nocturnal acid
breakthrough in a subject in need thereof, the method comprising:
administering to the subject a solid pharmaceutical composition
comprising an acid labile proton pump inhibitor and a buffering
agent, wherein: (a) the proton pump inhibitor is not enteric
coated; (b) the proton pump inhibitor is present in the composition
in an amount of about 5 mg to about 60 mg; (c) the buffering agent
is present in the composition in an amount of about 200 mg to about
3500 mg; and (d) the administration step is performed between about
8:00 pm and about 12:00 am, inclusive.
2. The method of claim 1, wherein the administration step is
performed between about 9:00 pm and about 12:00 am, inclusive.
3. The method of claim 1, wherein the administration step is
performed between about 9:30 pm and about 11:30 pm, inclusive.
4. The method of claim 1 wherein the proton pump inhibitor is of
Formula (I): ##STR00002## wherein R.sup.1 is hydrogen, alkyl,
halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl,
carbamoylalkyl, hydroxy, alkoxy which is optionally fluorinated,
hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy,
aryl, aryloxy, alkylthio, or alkylsulfinyl; R.sup.2 is hydrogen,
alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy,
carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl,
alkoxycarbonylmethyl, or alkylsulfonyl; R.sup.3 and R.sup.5 are the
same or different and each is hydrogen, alkyl, alkoxy, amino, or
alkoxyalkoxy; R.sup.4 is hydrogen, alkyl, alkoxy which may
optionally be fluorinated, or alkoxyalkoxy; Q is nitrogen, CH, or
CR.sup.1; W is nitrogen, CH, or CR.sup.1; y is an integer of 0
through 4; and Z is nitrogen, CH, or CR.sup.1; or a free base,
salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug,
polymorph, or derivative thereof.
5. The method of claim 1 wherein the proton pump inhibitor is
omeprazole, tenatoprazole, lansoprazole, rabeprazole, esomeprazole,
pantoprazole, pariprazole, leminoprazole and nepaprazole or a free
base, a free acid, or a salt, hydrate, ester, amide, enantiomer,
isomer, tautomer, polymorph, prodrug, or derivative of such
compounds.
6. The method of claim 1 wherein the proton pump inhibitor is
omeprazole or lansoprazole.
7. The method of claim 1 wherein the proton pump inhibitor is
omeprazole.
8. The method of claim 1 wherein the proton pump inhibitor is
present in an amount of about 10 mg to about 40 mg on a dry weight
basis.
9. The method of claim 1 wherein the buffering agent is present in
an amount of about 400 mg to about 3000 mg on a dry weight
basis.
10. The method of claim 1 wherein the buffering agent is present in
an amount of about 500 mg to about 2500 mg on a dry weight
basis.
11. The method of claim 1 wherein the composition further comprises
at least one pharmaceutically acceptable excipient.
12. The method of claim 1 wherein the composition is a dosage form
is selected from a tablet, a suspension tablet, a bite suspension
tablet, a rapid dispersion tablet, a chewable tablet, an
effervescent tablet, a bilayer tablet, a caplet, a capsule, a
powder, a lozenge, a sachet, a cachet, a troche, a pellet, a
granule and a microgranule.
13. A method for treating and/or preventing nocturnal acid
breakthrough in a subject in need thereof, the method comprising:
administering to the subject a solid pharmaceutical composition
comprising an acid labile proton pump inhibitor and a buffering
agent, wherein: (a) the proton pump inhibitor is not enteric
coated, (b) the proton pump inhibitor is present in the composition
in an amount of about 5 mg to about 60 mg; (c) the buffering agent
is present in the composition in an amount of about 200 mg to about
3500 mg; and (d) the administration step is performed prior to
12:00 am and at such a time so as to result in a blood serum
concentration of the proton pump inhibitor of at least about 0.1
micromolar at any time point from about 12:00 am to about 6:00 am
following administration.
14. The method of claim 13 wherein the administration step is
performed at such a time so as to result in a blood serum
concentration of the proton pump inhibitor of at least about 0.9
micromolar at any time point from about 1:00 am to about 5:00 am
following administration.
15. The method of claim 13 wherein the proton pump inhibitor is of
Formula (I): ##STR00003## wherein R.sup.1 is hydrogen, alkyl,
halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl,
carbamoylalkyl, hydroxy, alkoxy which is optionally fluorinated,
hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy,
aryl, aryloxy, alkylthio, or alkylsulfinyl; R.sup.2 is hydrogen,
alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy,
carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl,
alkoxycarbonylmethyl, or alkylsulfonyl; R.sup.3 and R.sup.5 are the
same or different and each is hydrogen, alkyl, alkoxy, amino, or
alkoxyalkoxy; R.sup.4 is hydrogen, alkyl, alkoxy which may
optionally be fluorinated, or alkoxyalkoxy; Q is nitrogen, CH, or
CR.sup.1; W is nitrogen, CH, or CR.sup.1; y is an integer of 0
through 4; and Z is nitrogen, CH, or CR.sup.1; or a free base,
salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug,
polymorph, or derivative thereof.
16. The method of claim 13 wherein the proton pump inhibitor is
omeprazole, tenatoprazole, lansoprazole, rabeprazole, esomeprazole,
pantoprazole, pariprazole, leminoprazole and nepaprazole or a free
base, a free acid, or a salt, hydrate, ester, amide, enantiomer,
isomer, tautomer, polymorph, prodrug, or derivative of such
compounds.
17. The method of claim 13 wherein the proton pump inhibitor is
omeprazole or lansoprazole.
18. The method of claim 13 wherein the proton pump inhibitor is
omeprazole.
19. The method of claim 13 wherein the proton pump inhibitor is
present in an amount of about 10 mg to about 40 mg on a dry weight
basis.
20. The method of claim 13 wherein the buffering agent is present
in an amount of about 400 mg to about 3000 mg on a dry weight
basis.
21. The method of claim 13 wherein the buffering agent is present
in an amount of about 500 mg to about 2500 mg on a dry weight
basis.
22. The method of claim 13 wherein the composition further
comprises at least one pharmaceutically acceptable excipient.
23. The method of claim 13 wherein the composition is a solid
dosage form is selected from a tablet, a suspension tablet, a bite
suspension tablet, a rapid dispersion tablet, a chewable tablet, an
effervescent tablet, a bilayer tablet, a caplet, a capsule, a
powder, a lozenge, a sachet, a cachet, a troche, a pellet, a
granule and a microgranule.
24. A method for treating and/or preventing nocturnal acid
breakthrough in a subject in need thereof, the method comprising:
administering to the subject a solid pharmaceutical composition
comprising an acid labile proton pump inhibitor and a buffering
agent, wherein: (a) the proton pump inhibitor is not enteric
coated; (b) the proton pump inhibitor is present in the composition
in an amount of about 5 mg to about 60 mg; (c) the buffering agent
is present in the composition in an amount of about 200 mg to about
3500 mg; and (d) the administration step is performed prior to 2:00
am and at such a time so as to result in a blood serum
concentration of the proton pump inhibitor of at least about 1
micromolar at any time point from about 2:00 am to about 4:00 am
following administration.
25. A method for treating and/or preventing nocturnal acid
breakthrough in a subject in need thereof, the method comprising
the steps of: (a) determining the subject's typical period of
nocturnal acid breakthrough; and (b) providing the subject with a
pharmaceutical composition comprising an acid labile, substituted
benzimidazole H.sup.+, K.sup.+-ATPase proton pump inhibitor and a
buffering agent at a time such that the subject exhibits a blood
serum concentration of the proton pump inhibitor of at least about
0.1 micromolar at any time point during the subject's determined
typical period of nocturnal acid breakthrough.
26. A method for treating and/or preventing nocturnal acid
breakthrough in a subject in need thereof, the method comprising
the steps of: (a) determining the subject's typical period of
nocturnal acid breakthrough; and (b) providing the subject with a
pharmaceutical composition comprising an acid labile, substituted
benzimidazole H.sup.+,K.sup.+-ATPase proton pump inhibitor and a
buffering agent at a time such that the subject exhibits a blood
serum concentration of the proton pump inhibitor of at least about
1 micromolar at any time point during the subject's determined
typical period of nocturnal acid breakthrough.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to, inter alia, pharmaceutical
compositions comprising an acid labile proton pump inhibitor and a
buffering agent; to methods for manufacture of such compositions,
and to use of such compositions in treating and preventing diseases
and disorders including but not limited to nocturnal acid
breakthrough and nighttime heartburn.
BACKGROUND OF THE INVENTION
[0002] Gastrointestinal disorders such as active duodenal ulcers,
gastric ulcers, gastroesophageal reflux disease (GERD), nocturnal
acid breakthrough, severe erosive esophagitis, poorly responsive
symptomatic GERD, and pathological hypersecretory conditions such
as Zollinger Ellison syndrome represent a major health concern
impacting millions of people globally. In fact, it is estimated
that as many as 60 million Americans alone experience acid reflux
at least once a month, while approximately 19 million Americans
suffer from GERD.
[0003] In the past, the above-described (and other related)
gastrointestinal disorders and their associated symptoms have been
treated with H.sub.2 histamine antagonists and antacids.
Unfortunately, many such available treatments are not very
effective in ameliorating the disorders themselves or their
symptoms; additionally, many produce adverse side effects
including, among others, constipation, diarrhea, and
thrombocytopenia. Moreover, H.sub.2 antagonists such as ranitidine
and cimetidine are relatively costly modes of therapy generally
requiring multiple daily doses to produce some control of acid
secretion. In addition, tolerance to H.sub.2 antagonists increases
with continued use thus prohibiting clinical utility in chronic
dosing settings.
[0004] More recently, at least some of the above-described
gastrointestinal disorders have been treated with proton pump
inhibitors (also called PPIs). PPIs are believed to reduce gastric
acid production by inhibiting H.sup.+, K.sup.+-ATPase of the
parietal cell--the final common pathway for gastric acid secretion.
One particular class of PPIs includes substituted benzimidazole
compounds that contain a sulfinyl group bridging substituted
benzimidazole and pyridine rings.
[0005] At neutral pH, these PPIs are chemically stable,
lipid-soluble compounds that have little or no inhibitory activity.
It is believed that the neutral PPIs reach parietal cells from the
blood and diffuse into the secretory canaliculi where they become
protonated and thereby trapped. The protonated agent is then
believed to rearrange to form a sulfenic acid and a sulfenamide.
The sulfenamide, in turn, is thought to interact covalently with
sulfhydryl groups at critical sites in the extracellular (luminal)
domain of the membrane-spanning H.sup.+, K.sup.+-ATPase. See,
Hardman et al., Goodman & Gilman's The Pharmacological Basis of
Therapeutics, p. 907, 9.sup.th ed. (1996).
[0006] Unfortunately, most commercially available PPIs are unstable
at neutral or acidic pH and undergo decomposition in
gastrointestinal fluid upon oral administration, thereby resulting
in loss of therapeutic activity. To overcome this acid instability,
such compounds are typically formulated for oral delivery as
enteric coated solid dosage forms, for example enteric coated
tablets; the enteric coating protects the drug from contact with
acidic stomach secretions. An undesirable consequence of such
enteric coating is that therapeutic onset time is significantly
delayed by comparison with non-enteric coated dosage forms. Such
prolonged time to therapeutic onset is particularly undesirable for
patients in need of rapid relief from one or more of the above
described disorders or symptoms.
[0007] For example, U.S. Pat. No. 4,786,505 to Lovgren et al.
discloses that a pharmaceutical oral solid dosage form of
omeprazole must be protected from contact with acidic gastric juice
by an enteric coating to maintain its pharmaceutical activity. That
patent describes an enteric coated omeprazole preparation
containing an alkaline core comprising omeprazole, a subcoating
over the core, and an enteric coating over the subcoating.
[0008] Patients with GERD are typically given a once-daily dose of
enteric coated PPI, administered in the morning, to manage daytime
meal-induced gastric acid secretion. However, normal gastric acid
secretion follows a circadian rhythm, with gastric acid secretion
being most pronounced in the evening and early night. This results
in a surge of gastric acidity around 2:00 am, with acid secretion
decreasing toward the later morning. See e.g. Moore, J. G., Englert
E., Circadian rhythm of gastric acid secretion in man. Nature 1970;
226: 1261-2 and Prewett, E. J., Smith, J. T., Nwokolo, C. U., et
al., Twenty-four hour intragastric acidity and plasma gastrin
concentration profiles in female and male subjects. Clin. Sci.
(Lond) 1991; 80:619-24. Unfortunately, it is recognized that
commercially available enteric coated proton pump inhibitors fail
to adequately control nighttime gastric acid secretion and
nighttime GERD symptoms in many patients, regardless of when
administered. For example, according to Tutuian R, et al.,
"[n]octurnal acid breakthrough occurs on any dosing regimen of oral
proton pump inhibitors." Alimentary Pharmacology & Therapeutics
2002; 16(3): 473-477. Furthermore, according to Katz P O, et al.,
"[n]octurnal acid breakthrough is frequently seen on proton pump
inhibitors twice daily and is often accompanied by oesophageal
reflux. This has important implications for medical therapy in
patients with severe gastro-esophageal reflux and Barrett's
oesophagus." Gastro-oesophageal reflux associated with nocturnal
gastric acid breakthrough on proton pump inhibitors. Alimentary
Pharmacology & Therapeutics 1999; 12(12): 1231-1234.
[0009] Moreover, prolonged nocturnal esophageal acid exposure has
been shown to contribute to the development of erosive esophagitis.
See, e.g. Orr, W. C., Allen, M. L., Robinson, M. The pattern of
nocturnal and diurnal esophageal acid exposure in the pathogenesis
of erosive mucosal damage Am J Gastroenterol. 1994 April;
89(4):509-12 and Hatlebakk, J. G., Berstad, A. Endoscopic grading
of reflux oesophagitis: what observations correlate with
gastroesophogeal reflux? Scand. J. Gastroenterol. 1997;
32:760-5.
[0010] Clearly, therefore, an unmet medical need exists for new
formulations of proton pump inhibitors that can treat nighttime
acid breakthrough and/or nighttime heartburn and other acid related
disorders.
SUMMARY OF THE INVENTION
[0011] In various embodiments, the present invention provides
pharmaceutical compositions comprising at least one acid labile
proton pump inhibitor and at least one buffering agent. Also
provided are methods of treating and/or preventing acid related
gastrointestinal disorders by administering to a subject one or
more compositions of the invention. In one embodiment, methods are
provided for treating and/or preventing nighttime acid breakthrough
and/or nighttime heartburn and related symptoms thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0012] While the present invention is capable of being embodied in
various forms, the description below of several embodiments is made
with the understanding that the present disclosure is to be
considered as an exemplification of the invention, and is not
intended to limit the invention to the specific embodiments
illustrated. Headings are provided for convenience only and are not
to be construed to limit the invention in any way. Embodiments
illustrated under any heading may be combined with embodiments
illustrated under any other heading.
[0013] The use of numerical values in the various ranges specified
in this application, unless expressly indicated otherwise, are
stated as approximations as though the minimum and maximum values
within the stated ranges were both preceded by the word "about." In
this manner, slight variations above and below the stated ranges
can be used to achieve substantially the same results as values
within the ranges. As used herein, the terms "about" and
"approximately" when referring to a numerical value shall have
their plain and ordinary meanings to one skilled in the art of
pharmaceutical sciences or the art relevant to the range or element
at issue. The amount of broadening from the strict numerical
boundary depends upon many factors. For example, some of the
factors to be considered may include the criticality of the element
and/or the effect a given amount of variation will have on the
performance of the claimed subject matter, as well as other
considerations known to those of skill in the art. Thus, as a
general matter, "about" or "approximately" broaden the numerical
value. For example, in some cases, "about" or "approximately" may
mean .+-.5%, or .+-.10%, or .+-.20%, or .+-.30% depending on the
relevant technology. Also, the disclosure of ranges is intended as
a continuous range including every value between the minimum and
maximum values recited as well as any ranges that can be formable
thereby.
[0014] It is also to be understood that any ranges, ratios and
ranges of ratios that can be formed by any of the numbers or data
present herein represent further embodiments of the present
invention. This includes ranges that can be formed that do or do
not include a finite upper and/or lower boundary. For example, by
way of illustration and not limitation, in one embodiment, a proton
pump inhibitor is present in a composition of the invention in an
amount of about 1 to about 3000 mg; in another embodiment, a
buffering agent is present in a composition of the invention in an
amount of about 200 mg to about 3500 mg. One of skill in the art
will therefore recognize, for example, that additional embodiments
include situations where a composition has a PPI:buffering agent
weight ratio of less than or greater than 1:200, less than or
greater than about 1:3500, less than or greater than 15:1
(3000/200), or less than or greater than about 0.85 (3000:3500), or
in ranges of about 1:200 to about 1:3500, about 1:3500 to about
15:1, etc. Accordingly, the skilled person will appreciate that
many such ratios, ranges, and ranges of ratios can be unambiguously
derived from the data and numbers presented herein and all
represent embodiments of the present invention.
Proton Pump Inhibitors
[0015] Compositions of the invention comprise at least one
pharmaceutically acceptable acid labile PPI, for example a
substituted imidazole, tetrabenzimidazole, or benzimidazole
H.sup.+,K.sup.+-ATPase PPI. The term proton pump inhibitor or PPI
means any acid labile pharmaceutical agent possessing
pharmacological activity as an inhibitor of H+/K+-ATPase. A PPI
may, if desired, be in the form of free base, free acid, salt,
ester, hydrate, anhydrate, amide, enantiomer, isomer, tautomer,
prodrug, polymorph, derivative, or the like, provided that the free
base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer,
prodrug, or any other pharmacologically suitable derivative is
therapeutically active or undergoes conversion within or outside of
the body to a therapeutically active form.
[0016] In one embodiment, illustrative PPIs are those compounds of
Formula (I):
##STR00001##
wherein
[0017] R.sup.1 is hydrogen, alkyl, halogen, cyano, carboxy,
carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy,
alkoxy which is optionally fluorinated, hydroxyalkyl,
trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy,
alkylthio, or alkylsulfinyl;
[0018] R.sup.2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino,
aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl;
[0019] R.sup.3 and R.sup.5 are the same or different and each is
hydrogen, alkyl, C.sub.1-4 lower alkyl (e.g. methyl, ethyl, etc.),
alkoxy, amino, or alkoxyalkoxy;
[0020] R.sup.4 is hydrogen, alkyl, C.sub.1-4 lower alkyl (e.g.
methyl, ethyl, etc.), alkoxy which may optionally be fluorinated,
or alkoxyalkoxy;
[0021] Q is nitrogen, CH, or CR.sup.1;
[0022] W is nitrogen, CH, or CR.sup.1;
[0023] y is an integer of 0 through 4; and
[0024] Z is nitrogen, CH, or CR.sup.1;
or a free base, salt, ester, hydrate, amide, enantiomer, isomer,
tautomer, prodrug, polymorph, or derivative thereof.
[0025] Specific examples of suitable PPIs include esomeprazole
(also referred to as S-omeprazole), ilaprazole (U.S. Pat. No.
5,703,097), lansoprazole, omeprazole, pantoprazole, pariprazole,
rabeprazole, tenatoprazole, leminoprazole and nepaprazole or a free
base, a free acid, or a salt, hydrate, ester, amide, enantiomer,
isomer, tautomer, polymorph, prodrug, or derivative of such
compounds.
[0026] Other proton pump inhibitors include but are not limited to:
soraprazan (Altana); AZD-0865 (AstraZeneca); YH-1885 (PCT
Publication WO 96/05177) (SB-641257) (2-pyrimidinamine,
4-(3,4-dihydro-1-methyl-2(1H)-isoquinolinyl)-N-(4-fluo-rophenyl)-5,6-dime-
thyl-monohydrochloride) (YuHan); BY-112 (Altana); SPI-447
(Imidazo[1,2-a]thieno(3,2-c)pyridin-3-amine,
5-methyl-2-(2-methyl-3-thieny-1) (Shinnippon);
3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano(2,-3-c)-imidazo[1-
,2-a]pyridine (PCT Publication WO 95/27714) (AstraZeneca);
Pharmaprojects No. 4950
(3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-1-pyrano(2,3-c-
)-imidazo[1,2-a]pyridine) (AstraZeneca, ceased) WO 95/27714;
Pharmaprojects No. 4891 (EP 700899) (Aventis); Pharmaprojects No.
4697 (PCT Publication WO 95/32959) (AstraZeneca); H-335/25
(AstraZeneca); T-330 (Saitama 335) (Pharmacological Research Lab);
Pharmaprojects No. 3177 (Roche); BY-574 (Altana); Pharmaprojects
No. 2870 (Pfizer); AU-1421 (EP 264883) (Merck); AU-2064 (Merck);
AY-28200 (Wyeth); Pharmaprojects No. 2126 (Aventis); WY-26769
(Wyeth); pumaprazole (PCT Publication WO 96/05199) (Altana);
YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publication WO
97/32854) (Dainippon); BY-686 (Altana); YM-020 (Yamanouchi);
GYKI-34655 (Ivax); FPL-65372 (Aventis); Pharmaprojects No. 3264 (EP
509974) (AstraZeneca); nepaprazole (To a Eiyo); HN-11203 (Nycomed
Pharma); OPC-22575; pumilacidin A (BMS); saviprazole (EP 234485)
(Aventis); SK and F-95601 (GSK, discontinued); Pharmaprojects No.
2522 (EP 204215) (Pfizer); S-3337 (Aventis); RS-13232A (Roche);
AU-1363 (Merck); SK and F-96067 (EP 259174) (Altana); SUN 8176
(Daiichi Pharma); Ro-18-5362 (Roche); ufiprazole (EP 74341)
(AstraZeneca); and Bay-p-1455 (Bayer); or a free base, free acid,
salt, hydrate, ester, amide, enantiomer, isomer, tautomer,
polymorph, prodrug, or derivative of these compounds.
[0027] Still other proton pump inhibitors contemplated by the
present invention include those described in the following U.S.
Pat. Nos. 4,628,098; 4,689,333; 4,786,505; 4,853,230; 4,965,269;
5,021,433; 5,026,560; 5,045,321; 5,093,132; 5,430,042; 5,433,959;
5,576,025; 5,639,478; 5,703,110; 5,705,517; 5,708,017; 5,731,006;
5,824,339; 5,855,914; 5,879,708; 5,948,773; 6,017,560; 6,123,962;
6,187,340; 6,296,875; 6,319,904; 6,328,994; 4,255,431; 4,508,905;
4,636,499; 4,738,974; 5,690,960; 5,714,504; 5,753,265; 5,817,338;
6,093,734; 6,013,281; 6,136,344; 6,183,776; 6,328,994; 6,479,075;
6,559,167.
[0028] Proton pump inhibitors as well as their salts, hydrates,
esters, amides, enantiomers, isomers, tautomers, polymorphs,
prodrugs, and derivatives may be prepared using standard procedures
known to those skilled in the art of synthetic organic chemistry.
See, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms
and Structure, 4th Ed. (New York: Wiley-Interscience, 1992);
Leonard et al., Advanced Practical Organic Chemistry (1992);
Howarth et al., Core Organic Chemistry (1998); and Weisermel et
al., Industrial Organic Chemistry (2002).
[0029] "Pharmaceutically acceptable salts," or "salts," include the
salt of a proton pump inhibitor prepared from formic, acetic,
propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,
citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic,
glutamic, benzoic, anthranilic, mesylic, stearic, salicylic,
p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic,
ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic,
2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic,
algenic, beta.-hydroxybutyric, galactaric and galacturonic
acids.
[0030] In one embodiment, acid addition salts are prepared from the
free base forms using conventional methodology involving reaction
of the free base with a suitable acid. Suitable acids for preparing
acid addition salts include both organic acids, e.g., acetic acid,
propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic
acid, malonic acid, succinic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid, and the like, as well as inorganic acids,
e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like.
[0031] In other embodiments, an acid addition salt is reconverted
to the free base by treatment with a suitable base. In a further
embodiment, the acid addition salts of the proton pump inhibitors
are halide salts, which are prepared using hydrochloric or
hydrobromic acids. In still other embodiments, the basic salts are
alkali metal salts, e.g., sodium salt.
[0032] Salt forms of proton pump inhibitors include, but are not
limited to: a sodium salt form such as esomeprazole sodium,
omeprazole sodium, rabeprazole sodium, pantoprazole sodium; or a
magnesium salt form such as esomeprazole magnesium or omeprazole
magnesium, described in U.S. Pat. No. 5,900,424; a calcium salt
form; or a potassium salt form such as the potassium salt of
esomeprazole, described in U.S. Pat. No. 6,511,996. Other salts of
esomeprazole are described in U.S. Pat. Nos. 4,738,974 and
6,369,085. Salt forms of pantoprazole and lansoprazole are
discussed in U.S. Pat. Nos. 4,758,579 and 4,628,098,
respectively.
[0033] In one embodiment, preparation of esters involves
functionalizing hydroxyl and/or carboxyl groups that may be present
within the molecular structure of the drug. In another embodiment,
the esters are acyl-substituted derivatives of free alcohol groups,
e.g., moieties derived from carboxylic acids of the formula
RCOOR.sub.1 where .sub.1 is a lower alkyl group. Esters can be
reconverted to the free acids, if desired, by using conventional
procedures such as hydrogenolysis or hydrolysis.
[0034] "Amides" may be prepared using techniques known to those
skilled in the art or described in the pertinent literature. For
example, amides may be prepared from esters, using suitable amine
reactants, or they may be prepared from an anhydride or an acid
chloride by reaction with an amine group such as ammonia or a lower
alkyl amine.
[0035] "Tautomers" of substituted bicyclic aryl-imidazoles include,
e.g., tautomers of omeprazole such as those described in U.S. Pat.
Nos. 6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020;
6,326,384; 6,369,087; and 6,444,689.
[0036] An exemplary "isomer" of a substituted bicyclic
aryl-imidazole is the isomer of omeprazole including but not
limited to isomers described in: Oishi et al., Acta Cryst. (1989),
C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S. Patent Publication
No. 02/0156284; and PCT Publication No. WO 02/085889.
[0037] Exemplary "polymorphs" include, but are not limited to,
those described in PCT Publication No. WO 92/08716, and U.S. Pat.
Nos. 4,045,563; 4,182,766; 4,508,905; 4,628,098; 4,636,499;
4,689,333; 4,758,579; 4,783,974; 4,786,505; 4,808,596; 4,853,230;
5,026,560; 5,013,743; 5,035,899; 5,045,321; 5,045,552; 5,093,132;
5,093,342; 5,433,959; 5,464,632; 5,536,735; 5,576,025; 5,599,794;
5,629,305; 5,639,478; 5,690,960; 5,703,110; 5,705,517; 5,714,504;
5,731,006; 5,879,708; 5,900,424; 5,948,773; 5,997,903; 6,017,560;
6,123,962; 6,147,103; 6,150,380; 6,166,213; 6,191,148; 5,187,340;
6,268,385; 6,262,086; 6,262,085; 6,296,875; 6,316,020; 6,328,994;
6,326,384; 6,369,085; 6,369,087; 6,380,234; 6,428,810; 6,444,689;
and 6,462,0577.
[0038] In one embodiment, no portion of the proton pump inhibitor
is enteric coated. In another embodiment, at least a portion of the
proton pump inhibitor is not enteric coated. In another embodiment,
at least a therapeutically effective portion of the proton pump
inhibitor is not enteric coated. In another embodiment, at least
about 5%, about 15%, about 20%, about 30%, about 40%, about 50% or
about 60% of the proton pump inhibitor is not enteric coated.
[0039] In one embodiment, the proton pump inhibitor has a D.sub.90,
D.sub.80, D.sub.70 or D.sub.50 particle size, by weight or by
number, of less than about 500 .mu.m, less than about 400 .mu.m,
less than about 300 .mu.m, less than about 200 .mu.m, less than
about 150 .mu.m, less than about 100 .mu.m, less than about 80
.mu.m, less than about 60 .mu.m, less than about 40 .mu.m, less
than about 35 .mu.m, less than about 30 .mu.m, less than about 25
.mu.m, less than about 20 .mu.m, less than about 15 .mu.m, or less
than about 10 .mu.m.
[0040] In another embodiment, compositions are provided wherein the
micronized proton pump inhibitor is of a size which allows greater
than about 90% or greater than about 75% of the proton pump
inhibitor to be released from the dosage unit within about 1 hour,
within about 50 minutes, within about 40 minutes, within about 30
minutes, within about 20 minutes, within about 10 minutes, or
within about 5 minutes after placement in a standard dissolution
test.
[0041] In another embodiment, compositions of the invention
comprise one or more PPIs in a total amount of about 1 mg to about
3000 mg, about 1 mg to about 2000 mg, about 1 mg to about 1000 mg,
about 5 mg to about 750 mg, about 5 mg to about 500 mg, about 5 mg
to about 250 mg, about 5 mg to about 100 mg, about 5 mg to about
100 mg, or about 5 mg to about 50 mg, for example about 7.5 mg,
about 10 mg, about 15 mg, about 20 mg or about 40 mg.
[0042] Compositions of the invention can be in the form of an
orally deliverable dosage unit. The terms "oral administration" or
"orally deliverable" herein include any form of delivery of a
therapeutic agent or a composition thereof to a subject wherein the
agent or composition is placed in the mouth of the subject, whether
or not the agent or composition is swallowed. Thus "oral
administration" includes buccal and sublingual as well as
esophageal administration.
Buffering Agent
[0043] Compositions of the invention comprise one or more
pharmaceutically acceptable buffering agents. Buffering agents
useful in the present invention include agents possessing
pharmacological activity as a weak or strong base. In one
embodiment, the buffering agent, when formulated with or
administered substantially simultaneously with a PPI, functions to
raise the pH of gastrointestinal fluid and thereby to substantially
prevent or inhibit acid degradation of the PPI by gastrointestinal
fluid for a period of time. In one embodiment, the period of time
is a time sufficient to protect at least a therapeutic portion of
the PPI from acid degradation in GI fluid.
[0044] In another embodiment, buffering agents useful in accordance
with the present invention comprise a salt of a Group IA metal
including, for example, a bicarbonate salt of a Group IA metal, a
carbonate salt of a Group IA metal, an alkaline earth metal
buffering agent, an amino acid, an alkaline salt of an amino acid,
an aluminum buffering agent, a calcium buffering agent, a sodium
buffering agent, or a magnesium buffering agent. Other suitable
buffering agents include alkali (sodium and potassium) or alkaline
earth (calcium and magnesium) carbonates, phosphates, bicarbonates,
citrates, borates, acetates, phthalates, tartrates, succinates and
the like, such as sodium or potassium phosphate, citrate, borate,
acetate, bicarbonate and carbonate.
[0045] Non-limiting examples of suitable buffering agents include
aluminum, magnesium hydroxide, aluminum hydroxide/magnesium
hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate
co-precipitate, aluminum glycinate, calcium acetate, calcium
bicarbonate, calcium borate, calcium carbonate, calcium citrate,
calcium gluconate, calcium glycerophosphate, calcium hydroxide,
calcium lactate, calcium phthalate, calcium phosphate, calcium
succinate, calcium tartrate, dibasic sodium phosphate, dipotassium
hydrogen phosphate, dipotassium phosphate, disodium hydrogen
phosphate, disodium succinate, dry aluminum hydroxide gel,
L-arginine, magnesium acetate, magnesium aluminate, magnesium
borate, magnesium bicarbonate, magnesium carbonate, magnesium
citrate, magnesium gluconate, magnesium hydroxide, magnesium
lactate, magnesium metasilicate aluminate, magnesium oxide,
magnesium phthalate, magnesium phosphate, magnesium silicate,
magnesium succinate, magnesium tartrate, potassium acetate,
potassium carbonate, potassium bicarbonate, potassium borate,
potassium citrate, potassium metaphosphate, potassium phthalate,
potassium phosphate, potassium polyphosphate, potassium
pyrophosphate, potassium succinate, potassium tartrate, sodium
acetate, sodium bicarbonate, sodium borate, sodium carbonate,
sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium
hydroxide, sodium lactate, sodium phthalate, sodium phosphate,
sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate,
sodium succinate, sodium tartrate, sodium tripolyphosphate,
synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium
pyrophosphate, tripotassium phosphate, trisodium phosphate, and
trometarnol. (Based in part upon the list provided in The Merck
Index, Merck & Co. Rahway, N.J. (2001)). In addition, due to
the ability of proteins or protein hydrolysates to react with
stomach acids, they too can serve as buffering agents in the
present invention. Furthermore, combinations or mixtures of the
above mentioned buffering agents can be used in the pharmaceutical
formulations described herein.
[0046] Buffering agents useful in the present invention also
include buffering agents or combinations of buffering agents that
interact with HCl (or other acids in the environment of interest)
faster than the proton pump inhibitor interacts with the same
acids. When placed in a liquid phase such as water, these buffering
agents produce and maintain a pH greater than the pKa of the proton
pump inhibitor.
[0047] In various other embodiments of the present invention, the
buffering agent is present in a total amount of about 0.1 mEq/mg to
about 5 mEq/mg of the proton pump inhibitor, about 0.5 mEq/mg to
about 3 mEq/mg of the proton pump inhibitor, about 0.6 mEq/mg to
about 2.5 mEq/mg of the proton pump inhibitor, about 0.7 mEq/mg to
about 2.0 mEq/mg of the proton pump inhibitor, about 0.8 mEq/mg to
about 1.8 mEq/mg of the proton pump inhibitor, about 1.0 mEq/mg to
about 1.5 mEq/mg of the proton pump inhibitor. In another
embodiment, the buffering agent is present in an amount of at least
about 0.5 mEq/mg of the proton pump inhibitor, at least about 0.75
mEq/mg of the proton pump inhibitor, or at least about 1 mEq/mg of
the proton pump inhibitor on a dry weight basis.
[0048] In another embodiment, one or more buffering agents are
present in a total amount of about 0.5 mEq to about 160 mEq, about
1 mEq to about 150 mEq, about 10 mEq to about 150 mEq, about 10 mEq
to about 75 mEq, about 10 mEq to about 60 mEq, or about 10 mEq to
about 50 mEq. Illustratively, a composition of the invention can
comprise about 1 mEq, or about 5 mEq, or about 10 mEq, or about 15
mEq, or about 20 mEq, or about 25 mEq, or about 30 mEq, or about 35
mEq, or about 40 mEq, or about 45 mEq, or about 50 mEq, or about 60
mEq, or about 70 mEq, or about 80 mEq, or about 90 mEq, or about
100 mEq, or about 110 mEq, or about 120 mEq, or about 130 mEq, or
about 140 mEq, or about 150 mEq, or about 160 mEq of buffering
agent.
[0049] In yet another embodiment, one or more buffering agents are
present in a total amount of at least about 10 mEq, at least about
11 mEq, at least about 12 mEq, at least about 13 mEq, at least
about 14 mEq, or at least about 15 mEq.
[0050] In still another embodiment, one or more buffering agents
and the PPI are present in a weight ratio of at least about 5:1, at
least about 7:1, at least about 10:1, at least about 20:1, greater
than 20:1, at least about 21:1, at least about 22:1, at least about
23:1, at least about 25:1, at least about 30:1, at least about
35:1, at least about 40:1, greater than 40:1, or at least about
45:1.
[0051] In another embodiment, the amount of buffering agent present
in a composition of the invention ranges from about 200 to about
3500 mg, about 300 to about 3000 mg, about 400 to about 2500 mg, or
about 500 to about 2200 mg. In other embodiments, the amount of
buffering agent present in a composition of the invention is about
200 mgs, or about 300 mgs, or about 400 mgs, or about 500 mgs, or
about 600 mgs, or about 700 mgs, or about 800 mgs, or about 900
mgs, or about 1000 mgs, or about 1100 mgs, or about 1200 mgs, or
about 1300 mgs, or about 1400 mgs, or about 1500 mgs, or about 1600
mgs, or about 1700 mgs, or about 1800 mgs, or about 1900 mgs, or
about 2000 mgs, or about 2100 mgs, or about 2200 mgs, or about 2300
mgs, or about 2400 mgs, or about 2500 mgs, or about 2600 mgs, or
about 2700 mgs, or about 2800 mgs, or about 2900 mgs, or about 3000
mgs, or about 3200 mgs, or about 3500 mgs.
[0052] In another embodiment, one or more buffering agents are
present in a composition of the invention in a total amount that is
greater than 800 mg, for example at least about 920 mg or at least
about 1000 mg.
[0053] In still another embodiment, particularly where the
composition is other than a dosage form selected from the group
consisting of a suspension tablet, a chewable tablet, an
effervescent powder, an effervescent tablet, lozenge and/or a
troche, the buffering agent and PPI are present in a weight ratio
greater than 20:1, not less than about 21:1, not less than about
22:1, not less than about 23:1, not less than about 24:1, not less
than about 25:1, not less than about 26:1, not less than about
27:1, not less than about 28:1, not less than about 29:1, not less
than about 30:1, not less than about 31:1, not less than about
32:1, not less than about 33:1, not less than about 34:1, not less
than about 35:1, not less than about 36:1, not less than about
37:1, not less than about 38:1, not less than about 39:1, not less
than about 40:1, not less than about 41:1, not less than about
42:1, not less than about 43:1, not less than about 44:1, not less
than about 45:1, not less than about 46:1, not less than about
47:1, not less than about 48:1, not less than about 49:1, or not
less than about 50:1.
[0054] In another embodiment, a composition is provided that
comprises a combination of at least two non-amino acid buffering
agents, wherein the combination of at least two non-amino acid
buffering agents comprises substantially no aluminum
hydroxide-sodium bicarbonate co-precipitate. In a related
embodiment, if such a composition comprises a
poly[phosphoryl/sulfon]-ated carbohydrate, the weight ratio of
poly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is
less than 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05).
Alternatively, the poly[phosphoryl/sulfon]-ated carbohydrate is
present in the composition, if at all, in an amount less than 50
mg, less than 25 mg, less than 10 mg or less than 5 mg.
[0055] In other embodiments, if the pharmaceutical composition
comprises an amino acid buffering agent, the total amount of amino
acid buffering agent present in the pharmaceutical composition is
less than about 5 mEq, or less than about 4 mEq, or less than about
3 mEq.
[0056] The phrase "amino acid buffering agent" as used herein
includes amino acids, amino acid salts, and amino acid alkali salts
including: glycine, alanine, threonine, isoleucine, valine,
phenylalanine, glutamic acid, asparagininic acid, lysine, aluminum
glycinate and/or lysine glutamic acid salt, glycine hydrochloride,
L-alanine, DL-alanine, L-threonine, DL-threonine, L-isoleucine,
L-valine, L-phenylalanine, L-glutamic acid, L-glutamic acid
hydrochloride, L-glutamic acid sodium salt, L-asparaginic acid,
L-asparaginic acid sodium salt, L-lysine and L-lysine-L-glutamic
acid salt. The term "non-amino acid buffering agent" herein
includes buffering agents as defined hereinabove but does not
include amino acid buffering agents.
[0057] In another embodiment, a composition of the invention
comprises at least one non-amino acid buffering agent wherein the
non-amino acid buffering agent is present in the composition in a
total amount greater than 800 mg. In a related embodiment, if such
a composition comprises a poly[phosphoryl/sulfon]-ated
carbohydrate, the weight ratio of poly[phosphoryl/sulfon]-ated
carbohydrate to buffering agent is less than 1:5 (0.2), less than
1:10 (0.1) or less than 1:20 (0.05). Alternatively, the
poly[phosphoryl/sulfon]-ated carbohydrate is present in the
composition, if at all, in an amount less than 50 mg, less than 25
mg, less than 10 mg or less than 5 mg.
[0058] In still another embodiment, a composition is provided which
comprises at least one buffering agent in a total amount of at
least about 10 mEq. In a related embodiment, if an amino acid
buffering agent is present in the composition, at least one of the
following conditions is met: (1) the weight ratio of amino acid
buffering agent:proton pump inhibitor is greater than 20:1; (2) the
composition comprises at least two non-amino acid buffering agents;
(3) the composition comprises at least one non-amino acid buffering
agent wherein the weight ratio of the at least one non-amino acid
buffering agent:proton pump inhibitor is greater than 20:1; and/or
(4) the weight ratio of total buffering agent:proton pump inhibitor
is greater than 40:1.
[0059] In other embodiments, where two or more buffering agents are
present, the two or more buffering agents comprise at least two
non-amino acid buffering agents, wherein the combination of at
least two non-amino acid buffering agents comprises substantially
no aluminum hydroxide-sodium bicarbonate co-precipitate.
[0060] In still another embodiment, the buffering agent comprises a
mixture of sodium bicarbonate, calcium carbonate, and magnesium
hydroxide, wherein the sodium bicarbonate, calcium carbonate, and
magnesium hydroxide are each present in an amount of about 0.1
mEq/mg proton pump inhibitor to about 5 mEq/mg of the proton pump
inhibitor.
[0061] Also provided herein are pharmaceutical compositions
comprising at least one soluble buffering agent. The term "soluble
buffering agent" as used herein refers to an antacid that has a
solubility of at least about 500 mg/mL, or at least about 300
mg/mL, or at least about 200 mg/mL, or at least about 100 mL/mL in
gastrointestinal fluid or simulated gastrointestinal fluid.
[0062] In some embodiments of the present invention, the buffering
agent has a defined particle size distribution. For example, in one
embodiment, the D.sub.50, D.sub.70, D.sub.80, or D.sub.90 particle
size of the buffering agent, by weight or by number, is no greater
than about 20 .mu.m, no greater than about 30 .mu.m, no greater
than about 40 .mu.m, no greater than about 50 .mu.m, no greater
than about 60 .mu.m, no greater than about 70 .mu.m, no greater
than about 80 .mu.m, no greater than about 90 .mu.m, no greater
than about 100 .mu.m in diameter, no greater than about 200 .mu.m
in diameter, no greater than about 300 .mu.m in diameter, no
greater than about 400 .mu.m in diameter, or no greater than about
100 .mu.m in diameter.
Pharmaceutical Excipients
[0063] Compositions of the invention can, if desired, include one
or more pharmaceutically acceptable excipients. The term
"excipient" herein means any substance, not itself a therapeutic
agent, used as a carrier or vehicle for delivery of a therapeutic
agent to a subject or added to a pharmaceutical composition to
improve its handling or storage properties or to permit or
facilitate formation of a dose unit of the composition. Excipients
include, by way of illustration and not limitation, diluents,
disintegrants, binding agents, adhesives, wetting agents,
lubricants, glidants, surface modifying agents, substances added to
mask or counteract a disagreeable taste or odor, flavors, dyes,
fragrances, and substances added to improve appearance of the
composition. Any such excipients can be used in any dosage forms of
according to the present invention, including liquid, solid or
semi-solid dosage forms.
[0064] Excipients optionally employed in compositions of the
invention can be solids, semi-solids, liquids or combinations
thereof. Compositions of the invention containing excipients can be
prepared by any known technique of pharmacy that comprises admixing
an excipient with a drug or therapeutic agent.
[0065] Compositions of the invention optionally comprise one or
more pharmaceutically acceptable diluents as excipients. Suitable
diluents illustratively include, either individually or in
combination, lactose, including anhydrous lactose and lactose
monohydrate; starches, including directly compressible starch and
hydrolyzed starches (e.g., Celutab.TM. and Emdex.TM.); mannitol;
sorbitol; xylitol; dextrose (e.g., Cerelose.TM. 2000) and dextrose
monohydrate; dibasic calcium phosphate dihydrate; sucrose-based
diluents; confectioner's sugar; monobasic calcium sulfate
monohydrate; calcium sulfate dihydrate; granular calcium lactate
trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose;
celluloses including microcrystalline cellulose, food grade sources
of .alpha.- and amorphous cellulose (e.g., Rexcel.TM.) and powdered
cellulose; calcium carbonate; glycine; bentonite;
polyvinylpyrrolidone; and the like. Such diluents, if present,
constitute in total about 5% to about 99%, about 10% to about 85%,
or about 20% to about 80%, of the total weight of the composition.
The diluent or diluents selected preferably exhibit suitable flow
properties and, where tablets are desired, compressibility.
[0066] The use of extragranular microcrystalline cellulose (that
is, microcrystalline cellulose added to a wet granulated
composition after a drying step) can be used to improve hardness
(for tablets) and/or disintegration time.
[0067] Compositions of the invention optionally comprise one or
more pharmaceutically acceptable disintegrants as excipients,
particularly for tablet formulations. Suitable disintegrants
include, either individually or in combination, starches, including
sodium starch glycolate (e.g., Explotab.TM. of PenWest) and
pregelatinized corn starches (e.g., National.TM. 1551, National.TM.
1550, and Colocorn.TM. 1500), clays (e.g., Veegum.TM. HV),
celluloses such as purified cellulose, microcrystalline cellulose,
methylcellulose, carboxymethylcellulose and sodium
carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-Sol.TM.
of FMC), alginates, crospovidone, and gums such as agar, guar,
xanthan, locust bean, karaya, pectin and tragacanth gums.
[0068] Disintegrants may be added at any suitable step during the
preparation of the composition, particularly prior to a granulation
step or during a lubrication step prior to compression. Such
disintegrants, if present, constitute in total about 0.2% to about
30%, about 0.2% to about 10%, or about 0.2% to about 5%, of the
total weight of the composition.
[0069] Croscarmellose sodium is a preferred disintegrant for tablet
or capsule disintegration, and, if present, typically constitutes
about 0.2% to about 10%, about 0.2% to about 7%, or about 0.2% to
about 5%, of the total weight of the composition.
[0070] Compositions of the invention optionally comprise one or
more pharmaceutically acceptable binding agents or adhesives as
excipients, particularly for tablet formulations. Such binding
agents and adhesives preferably impart sufficient cohesion to the
powder being tableted to allow for normal processing operations
such as sizing, lubrication, compression and packaging, but still
allow the tablet to disintegrate and the composition to be absorbed
upon ingestion. Suitable binding agents and adhesives include,
either individually or in combination, acacia; tragacanth; sucrose;
gelatin; glucose; starches such as, but not limited to,
pregelatinized starches (e.g., National.TM. 1511 and National.TM.
1500); celluloses such as, but not limited to, methylcellulose and
carmellose sodium (e.g., Tylose.TM.); alginic acid and salts of
alginic acid; magnesium aluminum silicate; PEG; guar gum;
polysaccharide acids; bentonites; povidone, for example povidone
K-15, K-30 and K-29/32; polymethacrylates; HPMC;
hydroxypropylcellulose (e.g., Klucel.TM.); and ethylcellulose
(e.g., Ethocel.TM.). Such binding agents and/or adhesives, if
present, constitute in total about 0.5% to about 25%, about 0.75%
to about 15%, or about 1% to about 10%, of the total weight of the
composition.
[0071] Compositions of the invention optionally comprise one or
more pharmaceutically acceptable wetting agents as excipients.
Non-limiting examples of surfactants that can be used as wetting
agents in compositions of the invention include quaternary ammonium
compounds, for example benzalkonium chloride, benzethonium chloride
and cetylpyridinium chloride, dioctyl sodium sulfosuccinate,
polyoxyethylene alkylphenyl ethers, for example nonoxynol 9,
nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and
polyoxypropylene block copolymers), polyoxyethylene fatty acid
glycerides and oils, for example polyoxyethylene (8)
caprylic/capric mono- and diglycerides (e.g., Labrasol.TM. of
Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene
(40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for
example polyoxyethylene (20) cetostearyl ether, polyoxyethylene
fatty acid esters, for example polyoxyethylene (40) stearate,
polyoxyethylene sorbitan esters, for example polysorbate 20 and
polysorbate 80 (e.g., Tween.TM. 80 of ICI), propylene glycol fatty
acid esters, for example propylene glycol laurate (e.g.,
Lauroglycol.TM. of Gattefosse), sodium lauryl sulfate, fatty acids
and salts thereof, for example oleic acid, sodium oleate and
triethanolamine oleate, glyceryl fatty acid esters, for example
glyceryl monostearate, sorbitan esters, for example sorbitan
monolaurate, sorbitan monooleate, sorbitan monopalmitate and
sorbitan monostearate, tyloxapol, and mixtures thereof. Such
wetting agents, if present, constitute in total about 0.25% to
about 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of
the total weight of the composition.
[0072] Compositions of the invention optionally comprise one or
more pharmaceutically acceptable lubricants (including
anti-adherents and/or glidants) as excipients. Suitable lubricants
include, either individually or in combination, glyceryl behapate
(e.g., Compritol.TM. 888); stearic acid and salts thereof,
including magnesium (magnesium stearate), calcium and sodium
stearates; hydrogenated vegetable oils (e.g., Sterotex.TM.);
colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium
acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g.,
Carbowax.TM. 4000 and Carbowax.TM. 6000); sodium oleate; sodium
lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if
present, constitute in total about 0.1% to about 10%, about 0.2% to
about 8%, or about 0.25% to about 5%, of the total weight of the
composition.
[0073] Suitable anti-adherents include talc, cornstarch,
DL-leucine, sodium lauryl sulfate and metallic stearates. Talc is a
anti-adherent or glidant used, for example, to reduce formulation
sticking to equipment surfaces and also to reduce static in the
blend. Talc, if present, constitutes about 0.1% to about 10%, about
0.25% to about 5%, or about 0.5% to about 2%, of the total weight
of the composition.
[0074] Glidants can be used to promote powder flow of a solid
formulation. Suitable glidants include colloidal silicon dioxide,
starch, talc, tribasic calcium phosphate, powdered cellulose and
magnesium trisilicate. Colloidal silicon dioxide is particularly
preferred.
[0075] Compositions of the present invention can comprise one or
more anti-foaming agents. Simethicone is an illustrative
anti-foaming agent.
[0076] Compositions of the present invention can comprise one or
more flavoring agents, sweetening agents, and/or colorants.
Flavoring agents useful in the present invention include, without
limitation, acacia syrup, alitame, anise, apple, aspartame, banana,
Bavarian cream, berry, black currant, butter, butter pecan,
butterscotch, calcium citrate, camphor, caramel, cherry, cherry
cream, chocolate, cinnamon, citrus, citrus punch, citrus cream,
cocoa, coffee, cola, cool cherry, cool citrus, cyclamate, cylamate,
dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,
glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit,
honey, isomalt, lemon, lime, lemon cream, MagnaSweet.RTM., maltol,
mannitol, maple, menthol, mint, mint cream, mixed berry, nut,
orange, peanut butter, pear, peppermint, peppermint cream,
Prosweet.RTM. Powder, raspberry, root beer, rum, saccharin,
safrole, sorbitol, spearmint, spearmint cream, strawberry,
strawberry cream, stevia, sucralose, sucrose, Swiss cream,
tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut,
watermelon, wild cherry, wintergreen, xylitol, and combinations
thereof, for example, anise-menthol, cherry-anise, cinnamon-orange,
cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint,
etc.
[0077] Sweetening agents that can be used in the present invention
include, for example, acesulfame potassium (acesulfame K), alitame,
aspartame, cyclamate, cylamate, dextrose, isomalt, MagnaSweet.RTM.,
maltitol, mannitol, neohesperidine DC, neotame, Prosweet.RTM.
Powder, saccharin, sorbitol, stevia, sucralose, sucrose, tagatose,
thaumatin, xylitol, and the like.
[0078] The foregoing excipients can have multiple roles as is known
in the art. For example, starch can serve as a filler as well as a
disintegrant. The classification of excipients above is not to be
construed as limiting in any manner.
Pharmaceutical Dosage Forms
[0079] Compositions of the present invention can be formulated as
solid, liquid or semi-solid dosage forms. In one embodiment, such
compositions are in the form of discrete dose units or dosage
units. The terms "dose unit" and/or "dosage unit" herein refer to a
portion of a pharmaceutical composition that contains an amount of
a therapeutic agent suitable for a single administration to provide
a therapeutic effect. Such dosage units may be administered one to
a small plurality (i.e. 1 to about 4) of times per day, or as many
times as needed to elicit a therapeutic response. A particular
dosage form can be selected to accommodate any desired frequency of
administration to achieve a specified daily dose. Typically one
dose unit, or a small plurality (i.e. up to about 4) of dose units,
provides a sufficient amount of the active drug (e.g. benzimidazole
moiety) to result in the desired response or effect.
[0080] Alternatively, compositions of the invention can also be
formulated for rectal, topical, or parenteral (e.g. subcutaneous,
intramuscular, intravenous and intradermal or infusion)
delivery.
[0081] In one embodiment, compositions of the invention are
suitable for rapid onset of therapeutic effect, particularly with
respect to the PPI component. In another embodiment, upon oral
administration of a composition of the invention to a subject, at
least a therapeutically effective amount of the PPI is available
for absorption in the stomach of the subject. As discussed above,
most commercially available PPIs require enteric coating to prevent
exposure of the PPI to gastrointestinal fluids (and consequent drug
degradation) by way of pH dependent coatings. Such coating, in
turn, prevents rapid PPI absorption and therapeutic onset of
action. Compositions of the present invention, by contrast, do not
require enteric coating to maintain drug stability in
gastrointestinal fluids and thereby provide for rapid absorption
and onset of therapeutic effect. In fact, in one embodiment, a
composition comprises at least a therapeutically effective amount
of PPI that is not enteric coated.
[0082] In one embodiment, a single dosage unit, be it solid or
liquid, comprises a therapeutically effective amount or a
therapeutically and/or prophylactically effective amount of PPI.
The term "therapeutically effective amount" or "therapeutically
and/or prophylactically effective amount" as used herein refers to
an amount of compound or agent that is sufficient to elicit the
required or desired therapeutic and/or prophylactic response, as
the particular treatment context may require.
[0083] It will be understood that a therapeutically and/or
prophylactically effective amount of a drug for a subject is
dependent inter alia on the body weight of the subject. A "subject"
herein to which a therapeutic agent or composition thereof can be
administered includes a human subject of either sex and of any age,
and also includes any nonhuman animal, particularly a domestic or
companion animal, illustratively a cat, dog or a horse.
Solid Dosage Forms
[0084] In some embodiments, compositions of the invention are in
the form of solid dosage forms or units. Non-limiting examples of
suitable solid dosage forms include tablets (e.g. suspension
tablets, bite suspension tablets, rapid dispersion tablets,
chewable tablets, effervescent tablets, bilayer tablets, etc),
caplets, capsules (e.g. a soft or a hard gelatin capsule), powder
(e.g. a packaged powder, a dispensable powder or an effervescent
powder), lozenges, sachets, cachets, troches, pellets, granules,
microgranules, encapsulated microgranules, powder aerosol
formulations, or any other solid dosage form reasonably adapted for
oral administration.
[0085] Tablets are an illustrative dosage form for compositions of
the invention. Tablets can be prepared according to any of the many
relevant, well known pharmacy techniques. In one embodiment,
tablets or other solid dosage forms can be prepared by processes
that employ one or a combination of methods including, without
limitation, (1) dry mixing, (2) direct compression, (3) milling,
(4) dry or non-aqueous granulation, (5) wet granulation, or (6)
fusion.
[0086] The individual steps in the wet granulation process of
tablet preparation typically include milling and sieving of the
ingredients, dry powder mixing, wet massing, granulation and final
grinding. Dry granulation involves compressing a powder mixture
into a rough tablet or "slug" on a heavy-duty rotary tablet press.
The slugs are then broken up into granular particles by a grinding
operation, usually by passage through an oscillation granulator.
The individual steps include mixing of the powders, compressing
(slugging) and grinding (slug reduction or granulation). Typically,
no wet binder or moisture is involved in any of the steps.
[0087] In another embodiment, solid dosage forms such as tablets
can be prepared by mixing a PPI with at least one buffering agent
as described herein above and, if desired, with one or more
optional pharmaceutical excipient to form a substantially
homogeneous preformulation blend. The preformulation blend can then
be subdivided and optionally further processed (e.g. compressed,
encapsulated, packaged, dispersed, etc.) into any desired dosage
forms.
[0088] Compressed tablets can be prepared by compacting a powder or
granulation composition of the invention. The term "compressed
tablet" generally refers to a plain, uncoated tablet suitable for
oral ingestion, prepared by a single compression or by
pre-compaction tapping followed by a final compression. Tablets of
the present invention may be coated or otherwise compounded to
provide a dosage form affording the advantage of improved handling
or storage characteristics. Preferably, however, any such coating
will be selected so as to not substantially delay onset of
therapeutic effect of a composition of the invention upon
administration to a subject. The term "suspension tablet" as used
herein refers to a compressed tablet that rapidly disintegrates
after placement in water.
[0089] In one embodiment, a composition of the invention comprises
a multi-layer tablet having a core comprising a proton pump
inhibitor; the core is substantially or completely surrounded by
the buffering agent. In one such embodiment, the buffering agent
layer completely surrounds the core. In another embodiment, the
buffering agent layer partially surrounds the core. In yet another
embodiment, the buffering agent layer is in contact with a portion
of or with all of the surface area of the core.
[0090] In another embodiment, one or more intermediate layers
exists in between the core and the buffering agent. The
intermediate layers can comprise any pharmaceutically acceptable
material, preferably inert and non-pH sensitive coating materials
such as polymer based coatings.
[0091] In still another embodiment, compositions of the invention
can be microencapsulated, for example as is described in U.S.
Patent Publication No. 2005/0037070, hereby incorporated by
reference herein in its entirety.
[0092] In another embodiment, a composition of the invention
comprises a proton pump inhibitor and a buffering agent mixed
together in powder form and optionally filled into a capsule, for
example a hard or soft gelatin or HPMC capsule.
Liquid Dosage Forms
[0093] In another embodiment of the invention, compositions can be
in the form of liquid dosage forms or units. Non-limiting examples
of suitable liquid dosage forms include solutions, suspension,
elixirs, syrups, liquid aerosol formulations, etc.
[0094] In one embodiment, a liquid composition comprising water,
PPI and a buffering agent can be prepared. In another embodiment,
compositions of the invention are in the form of a powder for
suspension that can be suspended in a liquid vehicle prior to
administration to a subject. While the powder for suspension
itself, can be a solid dosage form of the present invention, the
powder dispersed in liquid also comprises a liquid embodiment of
the invention.
[0095] Generally, a liquid composition of PPI (without a buffering
agent) would exhibit a very short period of stability, even when
maintained under refrigerated conditions. This is particularly
inconvenient in the hospital setting as fresh batches of suspension
are continually required.
[0096] Suspension compositions of the invention comprise at least
one PPI, a buffering agent, a liquid media (e.g. water, de-ionized
water, etc.) and one or more optional pharmaceutical excipients.
Such compositions, upon storage in a closed container maintained at
either room temperature, refrigerated (e.g. about 5-10.degree. C.)
temperature, or freezing temperature for a period of about 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, or 12 months, exhibit at least about 90%,
at least about 92.5%, at least about 95%, or at least about 97.5%
of the original PPI present therein.
Storage Stability
[0097] In one embodiment, compositions of the invention are in the
form of a powder for suspension that is ultimately to be suspended
in a liquid vehicle prior to administration to a subject. Liquid
compositions comprising an acid labile PPI suspended in a liquid
vehicle, without more, would typically exhibit short periods of
stability, even when maintained under refrigerated conditions. This
is particularly inconvenient in the hospital setting as fresh
batches of suspension are continually required. Suspension
compositions of the invention are believed to exhibit improve
storage stability.
[0098] Illustrative suspension compositions of the invention
comprise at least one PPI, at least one buffering agent, vitamin
B.sub.12, water, and one or more optional pharmaceutical
excipients. Such compositions, upon storage in a closed container
maintained at room temperature, refrigerated (e.g. about 5 to about
5-10.degree. C.) temperature, or frozen for a period of about 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, preferably exhibit at
least about 90%, more preferably at least about 92.5%, still more
preferably at least about 95%, and yet more preferably at least
about 97.5% of the proton pump inhibitor present therein.
Parietal Cell Activators
[0099] In one embodiment, a composition of the present invention
can further include one or more parietal cell activators. Parietal
cell activators are particularly preferred where the benzimidazole
moiety is a PPI. Parietal cell activators such as chocolate,
calcium and sodium bicarbonate and other alkaline substances
stimulate the parietal cells and enhance the pharmacologic activity
of the PPI administered. For the purposes of this application,
"parietal cell activator" or "activator" shall mean any compound or
mixture of compounds possessing such stimulatory effect including,
but not limited to, chocolate, sodium bicarbonate, calcium (for
example, calcium carbonate, calcium gluconate, calcium hydroxide,
calcium acetate and calcium glycerophosphate), peppermint oil,
spearmint oil, coffee, tea and colas (even if decaffeinated),
caffeine, theophylline, theobromine, and amino acids (particularly
aromatic amino acids such as phenylalanine and tryptophan) and
combinations thereof.
[0100] Parietal cell activators, if desired, are typically present
in a composition of the invention in an amount sufficient to
produce the desired stimulatory effect without causing untoward
side effects to patients. For example, chocolate, as raw cocoa, is
administered in an amount of about 5 mg to 2.5 g per 20 mg dose of
omeprazole (or equivalent pharmacologic dose of another proton pump
inhibiting agent). The dose of activator administered to a subject,
for example, a human, in the context of the present invention
should be sufficient to result in enhanced effect of a PPI over a
desired time frame.
[0101] Illustratively, the approximate effective ranges for various
parietal cell activators per 20 mg dose of omeprazole (or
equivalent dose of other PPI) include, Chocolate (raw cocoa)--5 mg
to 2.5 g; Sodium bicarbonate--7 mEq to 25 mEq; Calcium carbonate--1
mg to 1.5 g; Calcium gluconate--1 mg to 1.5 g; Calcium lactate--1
mg to 1.5 g; Calcium hydroxide--1 mg to 1.5 g; Calcium acetate--0.5
mg to 1.5 g; Calcium glycerophosphate--0.5 mg to 1.5 g; Peppermint
oil--(powdered form) 1 mg to 1 g; Spearmint oil--(powdered form) 1
mg to 1 g; Coffee--ml to 240 ml; Tea--20 ml to 240 ml; Cola--20 ml
to 240 ml; Caffeine--0.5 mg to 1.5 g; Theophylline--0.5 mg to 1.5
g; Theobromine--0.5 mg to 1.5 g; Phenylalanine--0.5 mg to 1.5 g;
and Tryptophan--0.5 mg to 1.5 g.
Administration
[0102] Compositions of the present invention are useful for
treating and/or preventing, inter alia, gastrointestinal disorders
and, in particular, acid related gastrointestinal disorders. The
phrase "acid related gastrointestinal disorder" or "acid related
gastrointestinal disease" refers generally to a disease or disorder
that occurs due to an imbalance between acid and pepsin production
on the one hand, so-called aggressive factors, and mucous,
bicarbonate, and prostaglandin production on the other hand,
so-called defensive factors.
[0103] The term "treat" or "treatment" as used herein refers to any
treatment of a disorder or disease associated with a
gastrointestinal disorder, and includes, but is not limited to,
preventing the disorder or disease from occurring in a subject that
may be predisposed to the disorder or disease but has not yet been
diagnosed as having the disorder or disease; inhibiting the
disorder or disease, for example, arresting the development of the
disorder or disease; relieving the disorder or disease, for
example, causing regression of the disorder or disease; or
relieving the condition caused by the disease or disorder, for
example, stopping the symptoms of the disease or disorder.
[0104] The term "prevent" or "prevention," in relation to a
gastrointestinal disorder or disease, means preventing the onset of
gastrointestinal disorder or disease development if none had
occurred, or preventing further gastrointestinal disorder or
disease development if the gastrointestinal disorder or disease was
already present.
[0105] In mammals gastrointestinal disorders include, but are not
limited to, duodenal ulcer, gastric ulcer, acid dyspepsia,
gastroesophageal reflux disease (GERD), severe erosive esophagitis,
poorly responsive symptomatic gastroesophageal reflux disease,
(acid reflux), heartburn, nighttime heartburn symptoms, nocturnal
acid breakthrough (NAB), and gastrointestinal pathological
hypersecretory conditions such as Zollinger Ellison Syndrome.
Illustrative acid-related gastrointestinal disorders including
duodenal ulcer disease, gastric ulcer disease, gastroesophageal
reflux disease (GERD), erosive esophagitis, poorly responsive
symptomatic gastroesophageal reflux disease (acid reflux),
pathological gastrointestinal hypersecretory disease, Zollinger
Ellison Syndrome, acid dyspepsia, heartburn, and/or NSAID induced
ulcer.
[0106] Where the disorder is heartburn, the heartburn can be
meal-related or induced, sleep-related or induced, and/or
nighttime-related or induced heartburn. Sleep-related heartburn
and/or nighttime-related heartburn can be caused, for example, by
breakthrough gastritis between conventional doses of a therapeutic
agent, such as while sleeping or in the early morning hours after a
night's sleep. Treatment of these conditions is accomplished by
administering to a subject a gastrointestinal-disorder-effective
amount (or a therapeutically-effective amount) of a pharmaceutical
composition according to the present invention. A subject may be
experiencing one or more of the above conditions or disorders or
related symptoms.
[0107] Compositions of the invention can be administered to a
subject at any suitable time, for example upon waking, prior to a
meal, during the day, or at night time (e.g. before bed). In one
embodiment, a composition of the invention is useful for treating
and/or preventing nighttime heartburn or nighttime heartburn
symptoms, nocturnal acid breakthrough (NAB), and/or for providing
nighttime pH control. NAB herein refers to intragastric pH less
than 4 for more than 1 hour in the overnight period.
[0108] In another embodiment, a composition of the invention is
administered to a subject between about 6:00 pm and about 1:00 am,
about 7:00 pm and about 1:00 am, about 8:00 pm and about 12:00 am,
about 8:00 pm and about 11: pm, about 8:00 pm and about 10:30 pm,
or about 9:00 pm and about 10:30 pm, for example at about 9:00 pm,
9:15 pm, 9:30 pm, 9:45 pm, 10:00 pm, 10:15 pm or 10:30 pm.
[0109] In another embodiment, a composition of the invention is
administered to a subject within about 3 hours before or after the
subject has eaten dinner, within about 2 hours before or after the
subject has eaten dinner, within about 1 hour before or after the
subject has eaten dinner or within about 30 minutes before or after
the subject has eaten dinner.
[0110] In another embodiment, a composition of the invention is
administered to a subject at such a time to result in a blood serum
concentration of the proton pump inhibitor of at least about 0.1
micromolar, at least about 0.2 micromolar, at least about 0.3
micromolar, at least about 0.4 micromolar, at least about 0.5
micromolar, at least about 0.6 micromolar, at least about 0.7
micromolar, at least about 0.8 micromolar, at least about 0.9
micromolar that occurs at any time during the subject's typical
period of nocturnal acid breakthrough, for example the subject's
next typical period of nocturnal acid breakthrough following
administration.
[0111] The term "the subject's typical period of nocturnal acid
breakthrough" refers to a period of time at night during which a
subject tends to experience intragastric pH not greater than 4 for
a continuous period of about one hour. This can be determined, for
example, by measuring a subject's intragastric pH for 1 to 3 nights
and calculating the beginning and ending times (of pH less than 4),
or the average beginning and ending times if pH is measured during
more than 1 night. For example, if a subject experiences nocturnal
acid breakthrough on a first measured day starting at 1:00 am and
ending at 4:00 am, and on a second measured day that subject
experiences nocturnal acid breakthrough starting at 2:00 am and
ending at 5:00 am, the subject's typical period of nocturnal acid
breakthrough could be characterized as 1:30 am to 4:30 am. Thus, a
composition of the invention could be administered to the subject
at such a time so as to provide a blood serum concentration of the
proton pump inhibitor of at least about 0.1 micromolar, at least
about 0.2 micromolar, at least about 0.3 micromolar, at least about
0.4 micromolar, at least about 0.5 micromolar, at least about 0.6
micromolar, at least about 0.7 micromolar, at least about 0.8
micromolar, or at least about 0.9 micromolar at any time during the
period of about 12:00 am to about 6:00 am, about 12:30 am to about
5:30 am, about 1:00 am to about 5:00 am, or about 2:00 am to about
4:00 am following administration.
[0112] In another embodiment, a composition of the invention is
administered to a subject at such a time to result in a blood serum
concentration of the proton pump inhibitor of at least about 0.1
micromolar, at least about 0.2 micromolar, at least about 0.3
micromolar, at least about 0.4 micromolar, at least about 0.5
micromolar, at least about 0.6 micromolar, at least about 0.7
micromolar, at least about 0.8 micromolar, at least about 0.9
micromolar or at least about 1 micromolar continuously throughout
the subject's typical period of nocturnal acid breakthrough, for
example the subject's next typical period of nocturnal acid
breakthrough after administration.
[0113] In another embodiment, a composition of the invention is
administered to a subject at such a time to result in a blood serum
concentration of the proton pump inhibitor of at least about 0.1
micromolar, at least about 0.2 micromolar, at least about 0.3
micromolar, at least about 0.4 micromolar, at least about 0.5
micromolar, at least about 0.6 micromolar, at least about 0.7
micromolar, at least about 0.8 micromolar, at least about 0.9
micromolar, or at least about 1 micromolar at any time point during
the period of about 12:00 am to about 6:00 am, about 12:30 am to
about 5:30 am, about 1:00 am to about 5:00 am, or about 2:00 am to
about 4:00 am following administration.
[0114] The term "following administration" in the context of timing
of administration means the next relevant time period after
administration. For example, if a composition of the invention is
to be administered to a subject at such a time to result in a blood
serum concentration of the proton pump inhibitor of about 0.1
micromolar to about 5 micromolar at any time point from about 12:00
am to about 6:00 am following administration, that refers to the
next 12:00 am to 6:00 am period following administration. If the
composition was administered at 10:00 pm on Day 1, the period of
about 12:00 am to about 6:00 am following administration refers to
12:0 am to about 6:00 am on the day immediately following Day
1.
[0115] In another embodiment, a composition of the invention is
administered to a subject at such a time to result in a blood serum
concentration of the proton pump inhibitor of at least about 0.1
micromolar, at least about 0.2 micromolar, at least about 0.3
micromolar, at least about 0.4 micromolar, at least about 0.5
micromolar, at least about 0.6 micromolar, at least about 0.7
micromolar, at least about 0.8 micromolar, at least about 0.9
micromolar or at least about 1 micromolar continuously from about
12:00 am to about 6:00 am, from about 12:30 am to about 5:30 am,
from about 1:00 am to about 5:00 am, or from about 2:00 am to about
4:00 am following administration.
[0116] In another embodiment, a composition of the invention is
administered to a subject at such a time to result in a blood serum
concentration of the proton pump inhibitor of about 0.1 micromolar
to about 5 micromolar, about 0.2 micromolar to about 2.5
micromolar, or about 0.3 micromolar to about 2 micromolar
continuously from about 12:00 am to about 6:00 am, from about 12:30
am to about 5:30 am, from about 1:00 am to about 5:00 am, or from
about 2:00 am to about 4:00 am following administration.
[0117] In another embodiment, a composition of the invention is
administered to a subject at such a time to result in a blood serum
concentration of the proton pump inhibitor of about 0.1 micromolar
to about 5 micromolar, about 0.2 micromolar to about 2.5
micromolar, or about 0.3 micromolar to about 2 micromolar from
about 12:00 am to about 6:00 am, from about 12:30 am to about 5:30
am, at any time during the period of about 1:00 am to about 5:00
am, or from about 2:00 am to about 4:00 am following
administration.
[0118] In still another embodiment, a composition of the invention
is administered to a subject at such a time to result in a
C.sub.max of the proton pump inhibitor that occurs during the
subject's typical period of nocturnal acid breakthrough, for
example during the subject's typical period of nocturnal acid
breakthrough following administration.
[0119] In another embodiment, a composition of the invention is
administered to a subject at such a time to result in a C.sub.max
of the proton pump inhibitor that occurs about 0.1 to about 5
hours, about 0.1 to about 4 hours, about 0.1 to about 3 hours, or
about 0.1 to about 2 hours before the subject's typical period of
nocturnal acid breakthrough, for example during the subject's
typical period of nocturnal acid breakthrough following
administration.
[0120] Castell, Donald et al., Zegerid Oral Suspension is More
Effective than Pantoprazole (Protonix) Delayed-Release Capsules in
Reducing Nighttime Gastric Acidity in GERD Patients, American
Journal of Gastroenterology, Vol 99, No. 10 S40 is hereby
incorporated by reference herein in its entirety.
[0121] Compositions of the invention are to be administered and
dosed in accordance with good medical practice, taking into account
the clinical condition of the individual patient, the site and
method of administration, scheduling of administration and other
factors known to medical practitioners. In human therapy, it is
important to provide a dosage form that delivers the required
therapeutic amount of the drug in vivo, and renders the drug
bioavailable in a rapid manner. In addition to the dosage forms
described herein, the dosage forms described by Phillips et al. in
U.S. Pat. No. 6,489,346 are incorporated herein by reference.
[0122] The percent of intact drug that is absorbed into the
bloodstream is not narrowly critical, as long as a
therapeutic-disorder-effective amount, for example a
gastrointestinal-disorder-effective amount of a proton pump
inhibiting agent, is absorbed following administration of the
pharmaceutical composition to a subject. It will be understood that
the amount of proton pump inhibiting agent and/or antacid that is
administered to a subject is dependent on various factors including
the sex, general health, diet, and/or body weight of the
subject.
[0123] Illustratively, when administering a PPI to a young child or
a small animal, such as a dog, a relatively low amount of the
proton pump inhibitor, e.g., about 1 mg to about 30 mg, will often
provide blood serum concentrations consistent with therapeutic
effectiveness. Where the subject is an adult human or a large
animal, such as a horse, achievement of a therapeutically effective
blood serum concentration may require larger dosage units, for
example about 10 mg, about 15 mg, about 20 mg, about 30 mg, about
40 mg, about 80 mg, or about 120 mg dose for an adult human, or
about 150 mg, or about 200 mg, or about 400 mg, or about 800 mg, or
about 1000 mg dose, or about 1500 mg dose, or about 2000 mg dose,
or about 2500 mg dose, or about 3000 mg dose, or about 3200 mg
dose, or about 3500 mg dose for an adult horse.
[0124] In various other embodiments of the present invention, the
amount of proton pump inhibitor administered to a subject is about
1-2 mg/Kg of body weight, illustratively about 0.5 mg/Kg of body
weight, about 1 mg/Kg of body weight, about 1.5 mg/Kg of body
weight, or about 2 mg/Kg of body weight.
[0125] Treatment dosages generally may be titrated to optimize
safety and efficacy. Typically, dosage-effect relationships from in
vitro and/or in vivo tests initially can provide useful guidance on
the proper doses for subject administration. Studies in animal
models generally may be used for guidance regarding effective
dosages for treatment of gastrointestinal disorders or diseases in
accordance with the present invention. In terms of treatment
protocols, it should be appreciated that the dosage to be
administered will depend on several factors, including the
particular agent that is administered, the route chosen for
administration, and the condition of the particular subject.
[0126] In another embodiment of the present invention, the
composition is administered to a subject in an amount sufficient to
achieve a measurable serum concentration of a non-acid degraded or
non-acid reacted proton pump inhibitor greater than about 100 ng/ml
within about 30 minutes or about 15 minutes or about 10 minutes
after administration of the composition.
[0127] In another embodiment of the present invention, the
composition is administered to a subject in an amount sufficient to
achieve a measurable serum concentration of the proton pump
inhibitor greater than about 150 ng/ml within about 15 minutes and
to maintain a serum concentration of the proton pump inhibitor of
greater than about 150 ng/ml from about 15 minutes to about 1 hour
after administration of the composition. In yet another embodiment
of the present invention, the composition is administered to the
subject in an amount sufficient to achieve a measurable serum
concentration of the proton pump inhibitor greater than about 250
ng/ml within about 15 minutes and to maintain a serum concentration
of the proton pump inhibiting agent of greater than about 150 ng/ml
from about 15 minutes to about 1 hour after administration of the
composition.
[0128] In another embodiment of the present invention, the
composition is administered to the subject in an amount sufficient
to achieve a measurable serum concentration of the proton pump
inhibitor greater than about 350 ng/ml within about 15 minutes and
to maintain a serum concentration of the proton pump inhibitor of
greater than about 150 ng/ml from about 15 minutes to about 1 hour
after administration of the composition. In another embodiment, the
composition is administered to the subject in an amount sufficient
to achieve a measurable serum concentration of the proton pump
inhibiting agent greater than about 450 ng/ml within about 15
minutes and to maintain a serum concentration of the proton pump
inhibiting agent of greater than about 150 ng/ml from about 15
minutes to about 1 hour after administration of the
composition.
[0129] In another embodiment, the composition is administered to
the subject in an amount sufficient to achieve a measurable serum
concentration of the proton pump inhibitor greater than about 150
ng/ml within about 30 minutes and to maintain a serum concentration
of the proton pump inhibitor of greater than about 150 ng/ml from
about 30 minutes to about 1 hour after administration of the
composition. In yet another embodiment of the present invention,
the composition is administered to the subject in an amount to
achieve a measurable serum concentration of the proton pump
inhibitor greater than about 250 ng/ml within about 30 minutes and
to maintain a serum concentration of the proton pump inhibitor of
greater than about 150 ng/ml from about 30 minutes to about 1 hour
after administration of the composition. In another embodiment of
the present invention, the composition is administered to the
subject in an amount sufficient to achieve a measurable serum
concentration of the proton pump inhibitor greater than about 350
ng/ml within about 30 minutes and to maintain a serum concentration
of the proton pump inhibitor of greater than about 150 ng/ml from
about 30 minutes to about 1 hour after administration of the
composition. In another embodiment of the present invention, the
composition is administered to the subject in an amount sufficient
to achieve a measurable serum concentration of the proton pump
inhibitor greater than about 450 ng/ml within about 30 minutes and
to maintain a serum concentration of the proton pump inhibiting
agent of greater than about 150 ng/ml from about 30 minutes to
about 1 hour after administration of the composition.
[0130] In still another embodiment of the present invention, the
composition is administered to the subject in an amount sufficient
to achieve a measurable serum concentration of a non-acid degraded
or non-acid reacted proton pump inhibitor greater than about 500
ng/ml within about 1 hour after administration of the composition.
In yet another embodiment of the present invention, the composition
is administered to the subject in an amount to achieve a measurable
serum concentration of a non-acid degraded or non-acid reacted
proton pump inhibitor greater than about 300 ng/ml within about 45
minutes after administration of the composition.
[0131] Contemplated compositions of the present invention provide a
therapeutic effect as proton pump inhibiting agent medications over
an interval of about 5 minutes to about 24 hours after
administration, enabling, for example, once-a-day, twice-a-day, or
three times a day administration if desired.
[0132] In another embodiment, upon oral administration of a
composition of the invention to a plurality of fasted human
subjects, the subjects exhibit an average T.sub.max of PPI within
about 30 seconds to about 90 minutes, within about 1 minute to
about 80 minutes, within about 5 minutes to about 60 minutes,
within about 10 minutes to about 50 minutes, or within about 15
minutes to about 45 minutes.
[0133] In still another embodiment, upon administration of a
composition of the invention to a plurality of fasted human
subjects, the subjects exhibit an average plasma concentration of
the PPI of at least about 0.1 .mu.g/ml, at least about 0.15
.mu.g/ml, at least about 0.2 .mu.g/ml, at least about 0.3 .mu.g/ml,
at least about 0.4 .mu.g/ml, at least about 0.5 .mu.g/ml, at least
about 0.6 .mu.g/ml, at least about 0.7 .mu.g/ml, at least about 0.8
.mu.g/ml, at least about 0.9 .mu.g/ml, at least about 1 .mu.g/ml,
at least about 1.5 .mu.g/ml, or at least about 2.0 .mu.g/ml at any
time within about 90 minutes, within about 75 minutes, within about
60 minutes, within about 55 minutes, within about 50 minutes,
within about 45 minutes, within about 40 minutes, within about 35
minutes, within about 30 minutes, within about 25 minutes, within
about 20 minutes, within about 17 minutes, within about 15 minutes,
within about 12 minutes, or within about 10 minutes after
administration.
[0134] In yet another embodiment, upon administration of a
composition of the invention to a plurality of fasted human
subjects, the subjects exhibit a plasma concentration of PPI of at
least about 0.1 .mu.g/ml, at least about 0.15 .mu.g/ml, at least
about 0.2 .mu.g/ml, at least about 0.3 .mu.g/ml, at least about 0.4
.mu.g/ml, at least about 0.5 .mu.g/ml, at least about 0.6 .mu.g/ml,
at least about 0.7 .mu.g/ml, at least about 0.8 .mu.g/ml, at least
about 0.9 .mu.g/ml, at least about 1.0 .mu.g/ml, at least about 1.5
.mu.g/ml or at least about 2.0 .mu.g/ml, maintained from at latest
about 15 minutes to at earliest about 60 minutes after
administration, preferably at latest about 15 minutes after
administration to at earliest about 90 minutes after
administration, more preferably at latest about 15 minutes to at
earliest about 120 minutes after administration, and still more
preferably at latest about 15 minutes to at earliest about 180
minutes after administration.
[0135] In another embodiment, upon administration of a composition
of the invention to a plurality of fasted human subjects, the
subjects exhibit at least one of: a mean C.sub.max of PPI of about
500 .mu.g/ml to about 2000 .mu.g/ml, about 600 .mu.g/ml to about
1900 .mu.g/ml, or about 700 ng/ml to about 1800 .mu.g/ml; a mean
T.sub.max of PPI of about 0.15 to about 2 hours, about 0.25 to
about 1.75 hours, or about 0.3 hours to about 1 hour; and/or a mean
AUC.sub.(0-inf) of PPI of about 1000 to about 3000 g*hr/ml, about
1500 to about 2700 .mu.g*hr/ml, or about 1700 to about 2500
.mu.g*hr/ml.
[0136] In another embodiment, upon administration of a composition
of the invention to a plurality of fasted adult human subjects, the
subjects exhibit: a mean C.sub.max of PPI of about 500 .mu.g/ml to
about 2000 .mu.g/ml, about 600 .mu.g/ml to about 1900 .mu.g/ml, or
about 700 .mu.g/ml to about 1800 .mu.g/ml; a mean T.sub.max of PPI
of about 0.15 to about 2 hours, about 0.25 to about 1.75 hours, or
about 0.3 hours to about 1 hour; and a mean AUC.sub.(0-inf) of PPI
of about 1000 to about 3000 ng*hr/ml, about 1500 to about 2700
ng*hr/ml, or about 1700 to about 2500 ng*hr/ml.
[0137] Those skilled in the art will readily appreciate that
numerous other embodiments, modifications and equivalents are
contemplated and encompassed by the disclosure of the present
invention.
[0138] All U.S. patents and published U.S. patent applications
listed herein are hereby incorporated by reference in their
entirety. All patents, patent applications and publications
referenced herein are hereby incorporated by reference herein to
the fullest extent allowed under the law.
EXAMPLES
Example 1
[0139] Enteric coated pantoprazole and an immediate release
omeprazole formulation were compared in a clinical study.
Thirty-two patients with nocturnal GERD symptoms were enrolled in a
crossover trial; subjects were provided 40 mg of enteric coated
pantoprazole (Protonix.RTM.) given at 2200 hours (bedtime) on Day 1
and prior to dinner on Days 2-6 or 40 mg of a non-enteric coated
omeprazole suspension (Zegerid.TM.) given at 2200 hours on Days
1-6. On Day 7, both PPIs were given 1 hour prior to breakfast and
at 2200 hours. Continuous 24-hour gastric pH monitoring (Medtronic)
was performed on Days 1, 6, and 7. Median gastric pH, percent of
time gastric pH was less than 4, and the proportion of patients
with "nocturnal acid breakthrough" (NAB) (>1 hr of continuous
pH<4) were determined for the nighttime period (2200-0600
hours).
[0140] Nighttime median gastric pH on Day 6 is shown below. For
this 8-hr period, median time that pH was >4 was greater for
Zegerid.TM. (55%) than for Protonix.RTM. (27%) (p<0.001); median
pH was 4.7 for Zegerid.TM. and 2.0 for Protonix.RTM. (p<0.001).
Furthermore, NAB occurred in fewer Zegerid.TM.-treated patients
(17/32) than Protonix.RTM.-treated patients (25/32) (p=0.005). For
the 8-hr nighttime period after twice-daily dosing, median % time
that pH was >4 was greater for Zegerid.TM. (40 mg and 20 mg)
than for Protonix.RTM. (92% vs. 37% and 79% vs. 31%, p<0.001,
respectively). Median pH was also higher for Zegerid.TM. (40 mg and
20 mg) than for Protonix.RTM. (6.5 vs. 1.5 and 5.8 vs. 1.9,
p<0.001, respectively). NAB occurred in fewer
Zegerid.TM.-treated patients than Protonix.RTM.-treated patients
(2/17 vs. 12/17 and 7/15 vs. 12/15, p<0.025, respectively). The
above example is as described in Castell., Donald et al., Zegerid
Oral Suspension is More Effective than Pantoprazole (Protonix)
Delayed-Release Capsules in Reducing Nighttime Gastric Acidity in
GERD Patients, American Journal of Gastroenterology, Vol 99, No. 10
S40.
Example 2
[0141] Seventeen healthy subjects were enrolled in an open-label
trial. Single 20-mg doses of Zegerid.TM. suspension (Santarus, San
Diego) were given 1 hr prior to breakfast (qAM) for 7 days. On Day
8, the 20-mg suspension was given b.i.d.: at 0830 hrs (1 hr prior
to a standardized high-fat breakfast) and at 2200 hrs (bedtime). On
Days 7 and 8, standardized lunch and dinner were given at 1300 and
1800 hrs. Gastric pH was continuously monitored (Medtronic) for 24
hrs following the morning doses on Days 7 and 8. The percent time
pH was >4 was assessed for the 8-hr nighttime period (2200-0600
hrs) and for the 24-hr period following the morning dose. The
proportion of subjects with "nocturnal acid breakthrough" (NAB)
(>1 hr of continuous pH<4) was assessed for the 8-hr
nighttime period.
[0142] After the bedtime dose, Zegerid.TM. 20 mg abruptly raised
the gastric pH and sustained this effect for approximately 8 hrs.
The median % time pH was >4 was greater for b.i.d dosing (87%)
than for qAM dosing (39%) (p<0.001). NAB occurred in fewer
subjects dosed b.i.d. (5/17 [29%]) than dosed qAM (13/17 [76%])
(p=0.005).
* * * * *