U.S. patent application number 13/758821 was filed with the patent office on 2014-01-16 for methods and medicaments for administration of ibuprofen.
This patent application is currently assigned to HORIZON PHARMA USA, INC.. The applicant listed for this patent is HORIZON PHARMA USA, INC.. Invention is credited to Barry L. Golombik, Puneet Sharma, George F. Tidmarsh.
Application Number | 20140017321 13/758821 |
Document ID | / |
Family ID | 46329015 |
Filed Date | 2014-01-16 |
United States Patent
Application |
20140017321 |
Kind Code |
A1 |
Tidmarsh; George F. ; et
al. |
January 16, 2014 |
METHODS AND MEDICAMENTS FOR ADMINISTRATION OF IBUPROFEN
Abstract
A method for administration of ibuprofen to a subject in need of
ibuprofen treatment is provided, in which an oral dosage form
comprising a therapeutically effective amount of ibuprofen and a
therapeutically effective amount of famotidine is administered
three times per day.
Inventors: |
Tidmarsh; George F.;
(Portola Valley, CA) ; Golombik; Barry L.;
(Incline Village, NV) ; Sharma; Puneet; (Yardley,
MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HORIZON PHARMA USA, INC.; |
|
|
US |
|
|
Assignee: |
HORIZON PHARMA USA, INC.
Deerfield
IL
|
Family ID: |
46329015 |
Appl. No.: |
13/758821 |
Filed: |
February 4, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12491199 |
Jun 24, 2009 |
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13758821 |
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11779204 |
Jul 17, 2007 |
8067451 |
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12491199 |
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11489705 |
Jul 18, 2006 |
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11779204 |
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11489275 |
Jul 18, 2006 |
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11489705 |
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11489272 |
Jul 18, 2006 |
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11779204 |
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11489269 |
Jul 18, 2006 |
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11489272 |
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60897371 |
Jan 24, 2007 |
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60700481 |
Jul 18, 2005 |
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Current U.S.
Class: |
424/490 ;
427/2.14; 514/370 |
Current CPC
Class: |
A61K 31/192 20130101;
A61K 31/19 20130101; A61K 9/2059 20130101; A61K 9/2054 20130101;
A61P 19/02 20180101; A61K 31/426 20130101; A61K 31/425 20130101;
A61K 9/5084 20130101; A61P 15/00 20180101; A61P 43/00 20180101;
A61P 29/00 20180101; A61K 31/192 20130101; A61K 2300/00 20130101;
A61K 31/426 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/490 ;
514/370; 427/2.14 |
International
Class: |
A61K 31/426 20060101
A61K031/426; A61K 31/192 20060101 A61K031/192 |
Claims
1. A method for treating a patient with an ibuprofen-responsive
condition comprising: administering to said patient a first dose of
an oral dosage form comprising from 775 mg to 825 mg ibuprofen and
from 25 mg to 28 mg famotidine, the ibuprofen and famotidine being
present in a weight ratio in the range 29:1 to 31:1, wherein the
ibuprofen and the famotidine are formulated for immediate release;
administering to said patient a second dose of the oral dosage
form; administering to said patient a third dose of the oral dosage
form, wherein the first dose, the second dose, and the third dose
are administered within a 24 hour dosing cycle, wherein the
ibuprofen and the famotidine are in separate compartments in the
oral dosage form, and wherein the patient does not suffer at the
times of administering from a condition characterized by
hypersecretion of gastric acid and/or from active severe
oesophagitis and/or Barrett's ulceration, and/or from
gastroesophageal reflux disease.
2.-5. (canceled)
6. An oral dosage form comprising from 775 mg to 825 mg ibuprofen
and from 25 mg to 28 mg famotidine, the ibuprofen and famotidine
being present in a weight ratio in the range 29:1 to 31:1, wherein
the ibuprofen and the famotidine are formulated for immediate
release and wherein the ibuprofen and the famotidine are in
separate compartments in the oral dosage form.
7. The oral dosage form of claim 6 comprising a first portion
containing ibuprofen and a second portion containing famotidine,
wherein the famotidine is in the form of barrier-coated particles
distributed in the ibuprofen portion.
8. (canceled)
9. (canceled)
10. The method of claim 1 wherein the oral unit dosage form
comprises about 800 mg ibuprofen and about 26.67 mg famotidine and
the total daily dose is about 2400 mg ibuprofen and about 80 mg
famotidine.
11. (canceled)
12. The oral dosage form of claim 6 wherein the oral unit dosage
form comprises about 800 mg ibuprofen and about 26.6 mg famotidine
and the total daily dose is about 2400 mg ibuprofen and about 80 mg
famotidine.
13. A method for manufacturing an oral dosage form of claim 6
wherein the method comprises the steps of: providing granules
comprising ibuprofen, at least one binder, at least one
disintegrant, and at least one glidant; blending the granules with
at least one binder, at least one disintegrant, at least one
glidant, and at least one lubricant; compressing the blend to form
a core; optionally coating the core with a barrier coat; applying a
layer comprising famotidine to said core; and optionally applying
an overcoating layer to yield the oral dosage form.
14. The method of claim 13 wherein the oral dosage form has a
content uniformity of at least about 95%.
15. The method of claim 13 wherein the oral dosage form has a
content uniformity of at least about 97%.
16. A container comprising a plurality of oral dosage forms of
claim 6 and instructions to take the oral dosage form three times
daily to treat an ibuprofen-responsive condition, wherein the
instructions are affixed to the container or packaged with the
container.
17. A method comprising: manufacturing a plurality of oral dosage
forms of claim 6, and selling the oral dosage form to pharmacies or
hospitals with instructions to take the oral dosage form three
times daily to treat an ibuprofen-responsive condition.
Description
1.0 CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 11/489,705; a continuation-in-part of U.S.
patent application Ser. No. 11/489,272; a continuation-in-part of
U.S. patent application Ser. No. 11/489,269 and a
continuation-in-part of U.S. patent application Ser. No. 11/489,275
(all filed Jul. 18, 2006), and claims benefit under 35 USC
.sctn.119(e) to U.S. provisional application No. 60/897,371 (filed
Jan. 24, 2007). The entire contents of each of these applications
is herein incorporated by reference for all purposes.
2.0 FIELD OF THE INVENTION
[0002] The invention relates to pharmaceutical compositions
containing ibuprofen and famotidine, and finds application in the
field of medicine.
3.0 BACKGROUND OF THE INVENTION
[0003] Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID),
has been used in humans for nearly forty years. While generally
regarded as safe, ibuprofen and other NSAIDs can cause gastritis,
dyspepsia, and gastric and duodenal ulceration. Gastric and
duodenal ulceration is a consequence of impaired mucosal integrity
resulting from ibuprofen-mediated inhibition of prostaglandin
synthesis. This side-effect is a particular problem for individuals
who take ibuprofen for extended periods of time, such as patients
suffering from rheumatoid arthritis and osteoarthritis.
[0004] The risk of developing gastric or duodenal ulceration can be
reduced by cotherapy with the drug famotidine. Famotidine blocks
the action of the histamine type 2 (H2) receptor, leading to a
reduction of acid secretion in the stomach. Reducing stomach acid
with famotidine during treatment with certain nonsteroidal
anti-inflammatory drugs is reported to decrease incidence of
gastrointestinal ulcers (see Taha et al., 1996, "Famotidine for the
prevention of gastric and duodenal ulcers caused by nonsteroidal
anti-inflammatory drugs" N Engl J Med 334:1435-9, and Rostom et
al., 2002, "Prevention of NSAID-induced gastrointestinal ulcers"
Cochrane Database Syst Rev 4:CD002296).
[0005] Famotidine is used for treatment of heartburn, ulcers, and
esophagitis at daily doses from 10 mg to 80 mg. Approved schedules
of famotidine administration include 10 or 20 mg QD or BID (for
treatment of heartburn), 20 mg or 40 mg QD (for healing ulcers,
such as 40 mg HS for 4-8 weeks for healing duodenal ulcers), 20 mg
HS (maintenance dose following healing of ulcer), 20 mg BID for 6
weeks (for treatment of gastroesophageal reflux disease), and 20 or
40 mg BID (for treatment of esophageal erosion). For treatment of
Zollinger-Ellison Syndrome, a disease characterized by
hypersecretion of gastric acid, doses of up to 800 mg/day have been
used.
[0006] Although NSAID plus famotidine cotherapy reduces risk of
developing gastric or duodenal ulceration, present therapies are
not widely used. More effective methods of treatment and
pharmaceutical compositions are needed. The present invention meets
this and other needs.
4.0 BRIEF SUMMARY OF THE INVENTION
[0007] In one aspect the invention provides a method for reducing
gastric acid while treating a patient with an ibuprofen-responsive
condition. The method involves administering a first dose of an
oral dosage form containing from 775 mg to 825 mg ibuprofen and
from 25 mg to 28 mg famotidine, where the ibuprofen and famotidine
are present in a weight ratio in the range 29:1 to 31:1, and where
the ibuprofen and the famotidine are formulated for immediate
release; administering a second dose of the oral dosage form; and
administering a third dose of the oral dosage form, where the first
dose, the second dose, and the third dose are administered within a
24 hour dosing cycle. In one embodiment, the ibuprofen and the
famotidine are admixed in the oral dosage form. In one embodiment,
the ibuprofen and the famotidine are in separate compartments in
the oral dosage form.
[0008] The ibuprofen and the famotidine may be formulated to
release at least 60% of the ibuprofen and the famotidine within
about 20 minutes under neutral pH conditions.
[0009] In one aspect the invention provides an oral dosage form
comprising from 775 mg to 825 mg ibuprofen and from 25 mg to 28 mg
famotidine, the ibuprofen and famotidine being present in a weight
ratio in the range 29:1 to 31:1, where the ibuprofen and the
famotidine are formulated for immediate release. In one embodiment
the oral dosage form comprises a first portion containing ibuprofen
and a second portion containing famotidine, where the famotidine is
in the form of barrier-coated particles distributed in the
ibuprofen portion.
[0010] In one aspect the invention provides a method of reducing
the likelihood that a patient receiving combined
ibuprofen-famotidine therapy will experience a 24-hour median pH
less than 2.5, by administering a oral unit dosage form to the
patient on a TID (three-times-per-day) schedule.
[0011] In one aspect the invention provides a method for reducing
patient-to-patient variability with respect to gastric pH in a
population of patients in need of an ibuprofen-famotidine
combination therapy by administering to patients in the population
an oral unit dosage form containing ibuprofen and famotidine, where
the ibuprofen and famotidine are in a weight ratio in the range of
29:1 to 31:1, and the oral unit dose form is administered
three-times-per-day (TID). In one embodiment the oral unit dosage
form contains about 800 mg ibuprofen and about 26.67 mg famotidine
or about 400 mg ibuprofen and about 13.33 mg famotidine.
[0012] In one aspect the invention provides an improved method for
treating a population of patients in need of an
ibuprofen-famotidine combination therapy and reducing inter-patient
variability with respect to gastric pH in the population. The
method involves administering to patients in the population an oral
unit dosage form containing ibuprofen and famotidine, where the
ibuprofen and famotidine are in a weight ratio in the range of 29:1
to 31:1, and the oral unit dose form is administered
three-times-per-day.
[0013] In one aspect, the invention provides a method for
administration of ibuprofen to a subject in need of ibuprofen
treatment. The method involves administering an oral dosage form
containing a therapeutically effective amount of ibuprofen and a
therapeutically effective amount of famotidine, where the oral
dosage form is administered three times per day (TID). In one
embodiment, the ibuprofen and the famotidine are in separate
compartments of the oral dosage form. In one embodiment, the
ibuprofen and the famotidine are in admixture in the oral dosage
form. In one embodiment, the famotidine and ibuprofen are released
from the dosage form rapidly, e.g., under in vitro assay
conditions.
[0014] In one embodiment, ibuprofen and famotidine are administered
in daily doses of about 2400 mg and about 80 mg respectively. In
some embodiments of this method, the oral dosage form contains
ibuprofen and famotidine in a ratio in the range of 29:1 to 32:1,
such as the range of 30:1 to 31:1. In one embodiment, the oral
dosage form contains 750 mg to 850 mg (e.g. about 800 mg) ibuprofen
and 24 mg to 28 mg (e.g., about 26.6 mg famotidine). In one
embodiment, the oral dosage form contains 775 mg to 825 mg (e.g.
about 800 mg) ibuprofen and 24 mg to 28 mg (e.g., about 26.6 mg
famotidine). In another embodiment, the oral dosage form contains
375 mg to 425 mg (e.g., about 400 mg) ibuprofen and 12 mg to 14 mg
(e.g., about 13 mg) famotidine.
[0015] In one embodiment, the TID administration of the dosage form
provides better gastric protection for the subject over a 24-hour
period than TID administration of the same daily quantity of
ibuprofen and two times a day (BID) administration of the same
daily quantity of famotidine. In one embodiment, the daily quantity
of ibuprofen is about 2400 mg and the daily quantity of famotidine
is about 80 mg. Thus, in certain aspects, the invention provides a
method in which TID administration of a dosage form containing
about 800 mg ibuprofen and about 26.6 mg famotidine provides better
gastric protection over a 24-hour period than TID administration of
the 800 mg ibuprofen and BID administration of 40 mg famotidine.
Equivalently, TID administration of two oral dosage forms
containing about 400 mg ibuprofen and about 13 mg (e.g., about 13.3
mg) famotidine provides better gastric protection over a 24-hour
period than TID administration 800 mg ibuprofen in a single or
split dose and BID administration of 40 mg famotidine in a single
or split dose.
[0016] Ibuprofen, in the form of a unit dose form of the invention,
may be administered to a subject is in need of ibuprofen treatment.
In various embodiments, the subject is in need of ibuprofen
treatment for a chronic condition (such as rheumatoid arthritis,
osteoarthritis or chronic pain) or a condition such as acute or
moderate pain, dysmenorrhea or acute inflammation.
[0017] In a different aspect the invention provides a solid oral
dosage form having a first portion containing a therapeutically
effective amount of ibuprofen and a second portion containing a
therapeutically effective amount of famotidine, where the first
portion completely surrounds the second portion or the second
portion completely surrounds the first portion; and having a
barrier layer disposed between the first and second portions, where
the ibuprofen and famotidine are released into solution rapidly. In
one embodiment an ibuprofen-containing core portion is surrounded
by a famotidine-containing layer and a barrier layer is interposed
between the core portion and famotidine-containing layer.
[0018] In another aspect, a solid oral dosage form is provided
which comprises particles of famotidine coated with a barrier layer
and situated in a matrix containing ibuprofen or compressed into a
tablet with ibuprofen and excipients. In one aspect, the ibuprofen
is ibuprofen DC-85 from BASF.
[0019] In one embodiment, the oral dosage form contains about 800
mg ibuprofen and about 26.6 mg (e.g., 26.67 mg) famotidine or about
400 mg ibuprofen and about 13 mg (e.g., 13.3 mg) famotidine. In
some embodiments, the oral dosage form contains ibuprofen and
famotidine in a ratio in the range of 29:1 to 32:1. In some
embodiments, the oral dosage form contains ibuprofen and famotidine
in a ratio in the range of 29:1 to 31:1.
[0020] In a specific embodiment, first portion comprises ibuprofen,
20-30% (w/w) lactose monohydrate; 0.1 to 2% colloidal silicon
dioxide; 3-7% crosscarmellose sodium; 1-3% hydroxy propyl methyl
cellulose; 2-6% silicified microcrystalline cellulose (Prosolv SMCC
90) and 0.1-2% magnesium stearate.
[0021] In one embodiment, at least 75% of the famotidine and at
least 75% of the ibuprofen in the dosage form are released within
15 minutes when measured in a Type II dissolution apparatus
(paddles) according to U.S. Pharmacopoeia XXIX at 37.degree. C. in
50 mM potassium phosphate buffer, pH 7.2 at 50 rotations per
minute.
[0022] In an aspect of the invention a method is provided for
treating a patient in need of ibuprofen treatment, where the
patient is at elevated risk for developing an NSAID-induced ulcer.
The method involves administering an oral dosage form comprising a
therapeutically effective amount of ibuprofen and a therapeutically
effective amount of famotidine, where the oral dosage form is
administered three times per day (TID), where the ibuprofen and the
famotidine are optionally in separate compartments of the oral
dosage form, and where the famotidine and ibuprofen are released
from the dosage form rapidly when agitated in 50 mM potassium
phosphate buffer, pH 7.2 at 37.degree. C. In one embodiment of this
method the oral dosage form may contain ibuprofen and famotidine in
a ratio in the range of 30:1 to 31:1.
[0023] In an aspect of the invention a method is provided for
reducing symptoms of dyspepsia in a subject in need of NSAID
treatment who has experienced symptoms of dyspepsia associated with
NSAID administration, comprising administering to the subject an
effective amount of a NSAID in combination with an effective amount
of famotidine, where the famotidine is administered three times per
day. In one embodiment of this method the NSAID is ibuprofen. In
one embodiment of this method from 25 mg to 27 mg famotidine is
administered three times per day. In one embodiment of this method
the famotidine and NSAID are administered as a single oral unit
dose form.
[0024] In an aspect of the invention a method is provided for
treating a person in need of famotidine treatment by administering
from 25 mg to 27 mg famotidine three times per day. In a related
aspect, the invention provides a solid oral dosage form comprising
famotidine or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable excipients, where the dosage
form comprises about 13 mg (e.g., 13.3 mg) or about 26.6 mg
famotidine. In one embodiment famotidine is the only
pharmaceutically active ingredient in the dosage form.
[0025] In an aspect of the invention a method is provided for
administration of ibuprofen to a subject by providing an oral
dosage form comprising 750 mg to 850 mg ibuprofen and 24 mg to 28
mg famotidine, where the ibuprofen and famotidine are present in a
ratio in the range of 29:1 to 32:1; or in the range of 29:1 to
31:1, administering a first dose of the oral dosage form;
administering a second dose of the oral dosage form; and
administering a third dose of the oral dosage form, where the first
dose, the second dose, and the third dose are administered within a
24 hour dosing cycle.
5.0 BRIEF DESCRIPTION OF THE FIGURES
[0026] FIG. 1 shows the predicted effect on intragastric pH of
administration of 26.6 mg famotidine TID. FIG. 1A (upper panel)
shows the predicted intragastric pH during TID dosing of famotidine
(80 mg/day). FIG. 1B (lower panel) shows the predicted plasma
famotidine concentration during TID dosing of famotidine (80
mg/day).
[0027] FIG. 2 shows the predicted effect on intragastric pH of
administration of 40 mg famotidine BID. FIG. 2A (upper panel) shows
the predicted intragastric pH during BID dosing of famotidine (80
mg/day). FIG. 2B (lower panel) shows the predicted plasma
famotidine concentration during BID dosing of famotidine (80
mg/day).
6.0-18.10 DETAILED DESCRIPTION
6.0 Definitions
[0028] "Famotidine" is
3-[2-(diaminomethyleneamino)thiazol-4-ylmethylthio]-N-sulfamoyl
propionamidine, including the polymorphic forms designated Form A
and Form B (see, e.g. U.S. Pat. Nos. 5,128,477 and 5,120,850) and
their mixtures, as well as pharmaceutically acceptable salts
thereof. Famotidine can be prepared using art-known methods, such
as the method described in U.S. Pat. No. 4,283,408. Famotidine's
properties have been described in the medical literature (see,
e.g., Echizen et al., 1991, Clin Pharmacokinet. 21:178-94).
[0029] "Ibuprofen" is 2-(p-isobutylphenyl) propionic acid
(C.sub.13H.sub.18O.sub.2), including various crystal forms and
pharmaceutically acceptable salts. Two enantiomers of ibuprofen
exist. As used herein in the context of solid formulations of the
invention, "ibuprofen" refers to a racemic mixture or either
enantiomer (including, for example, mixtures enriched in the
S-enantiomer, and compositions substantially free of the
R-enantiomer). Ibuprofen is available commercially and, for
example, ibuprofen preparations with mean particle sizes of 25, 38,
50, or 90 microns can be obtained from BASF Aktiengesellschaft
(Ludwigshafen, Germany). One useful ibuprofen product is directly
compressible formulation described in WO 2007/042445 (incorporated
herein by reference), a version of which is available from BASF
under the trade name Ibuprofen DC 85.TM.. Ibuprofen's properties
have been described in the medical literature (see, e.g., Davies,
1998, "Clinical pharmacokinetics of ibuprofen. The first 30 years"
Clin Pharmacokinet 34:101-54).
[0030] An "API" is an active pharmaceutical ingredient. As used
herein, "API" refers to ibuprofen and/or famotidine.
[0031] A "therapeutically effective amount" of ibuprofen is an
amount of ibuprofen or its pharmaceutically acceptable salt which
eliminates, alleviates, or provides relief of the symptoms for
which it is administered.
[0032] A "therapeutically effective amount" of famotidine is an
amount of famotidine or its pharmaceutically acceptable salt which
suppresses gastric acid secretion.
[0033] The terms "solid oral dosage form," "oral dosage form,"
"unit dose form," "dosage form for oral administration," and the
like are used interchangably, and refer to a pharmaceutical
composition in the form of a tablet, capsule, caplet, gelcap,
geltab, pill and the like.
[0034] An "excipient," as used herein, is any component of an oral
dosage form that is not an API. Excipients include binders,
lubricants, diluents, disintegrants, coatings, barrier layer
components, glidants, and other components. Excipients are known in
the art (see HANDBOOK OF PHARMACEUTICAL EXCIPIENTS, FIFTH EDITION,
2005, edited by Rowe et al., McGraw Hill). Some excipients serve
multiple functions or are so-called high functionality excipients.
For example, talc may act as a lubricant, and an anti-adherent, and
a glidant. See Pifferi et al., 2005, "Quality and functionality of
excipients" Farmaco. 54:1-14; and Zeleznik and Renak, Business
Briefing: Pharmagenerics 2004.
[0035] A "binder" is an excipient that imparts cohesive qualities
to components of a pharmaceutical composition. Commonly used
binders include, for example, starch; sugars, such as, sucrose,
glucose, dextrose, and lactose; cellulose derivatives such as
powdered cellulose, microcrystalline cellulose, silicified
microcrystalline cellulose (SMCC), hydroxypropylcellulose,
low-substituted hydroxypropylcellulose, hypromellose
(hydroxypropylmethylcellulose); and mixtures of these and similar
ingredients.
[0036] A "lubricant" is an excipient added to reduce sticking by a
solid formulation to the equipment used for production of a unit
does form, such as, for example, the punches of a tablet press.
Examples of lubricants include magnesium stearate and calcium
stearate. Other lubricants include, but are not limited to,
aluminum-stearate, talc, sodium benzoate, glyceryl mono fatty acid
(e.g. glyceryl monostearate from Danisco, UK), glyceryl dibehenate
(e.g. CompritolATO888.TM. Gattefosse France), glyceryl
palmito-stearic ester (e.g. Precirol.TM., Gattefosse France),
polyoxyethylene glycol (PEG, BASF) such as PEG 4000-8000,
hydrogenated cotton seed oil or castor seed oil (Cutina H R,
Henkel) and others.
[0037] A "diluent" is an excipient added to a pharmaceutical
composition to increase bulk weight of the material to be
formulated, e.g. tabletted, in order to achieve the desired
weight.
[0038] The term "disintegrant" refers to excipients included in a
pharmaceutical composition in order to ensure that the composition
has an acceptable disintegration rate in an environment of use.
Examples of disintegrants include starch derivatives (e.g., sodium
carboxymethyl starch and pregelatinized corn starch such as starch
1500 from Colorcon) and salts of carboxymethylcellulose (e.g.,
sodium carboxymethylcellulose), crospovidone (cross-linked PVP
polyvinylpyrrolidinone (PVP), e.g., Polyplasdone.TM. from ISP or
Kollidon.TM. from BASF).
[0039] The term "glidant" is used to refer to excipients included
in a pharmaceutical composition to keep the component powder
flowing as a tablet is being made, preventing formation of lumps.
Nonlimiting examples of glidants are colloidal silicon dioxides
such as CAB-O-SIL.TM. (Cabot Corp.), SYLOID.TM., (W.R. Grace &
Co.), AEROSIL.TM. (Degussa), talc, and corn starch.
[0040] The term "nonionic surfactant" refers to, for example and
not limitation, sucrose esters; partial fatty acid esters of
polyhydroxyethylenesorbitan, such as polyethylene glycol(20)
sorbitan monolaurate, monopalmitate, monostearate and monooleate;
polyethylene glycol(20) sorbitan tristearate and trioleate);
polyethylene glycol(4) sorbitan monolaurate and monostearate;
polyethylene glycol(5) sorbitan monooleate; polyhydroxyethylene
fatty alcohol ethers such as polyoxyethylene cetyl stearyl ether or
corresponding lauryl ethers; polyhydroxyethylene fatty acid esters;
ethylene oxide/propylene oxide block copolymers; sugar ethers and
sugar esters; phospholipids and their derivatives; and ethoxylated
triglycerides such as the derivatives of castor oil. Examples
include Cremophor.TM. RH 40; Cremophor.TM. RH 60, Tween.TM. 80.
[0041] The terms "over-coating," "over-coating layer," or
"over-coat" refer to an outer most coating or coatings of a unit
dose form such as a tablet or caplet, which may be added to improve
appearance, taste, swallowability, or other characteristics of the
tablet or caplet. The over-coating layer does not contain an API.
Suitable over-coatings are soluble in, or rapidly disintegrate in
water, and, for purposes of this invention, are not enteric
coatings. An exemplary over-coating material is Opadry II available
from Colorcon, Inc., Westpoint Pa.
[0042] "QD", "BID", "TID", "QID", and "HS" have their usual
meanings of, respectively, administration of medicine once per day,
twice per day, three times per day, four times per day or at
bedtime. Administration three times per day means that at least 6
hours, preferably at least 7 hours, and more preferably about 8
hours elapse between administrations. Administration three times
per day can mean administration about every 8 hours (e.g., 7 a.m.,
3 p.m. and 11 p.m.). In some cases in which quantitative
measurements are made, "TID administration" can mean administration
every 8.+-.0.25 hours.
[0043] As used herein, the term "daily quantity" refers to the
quantity of an API (ibuprofen or famotidine) administered over a
24-hour period under a specific dosing regimen.
[0044] The term "barrier layer" refers a layer in the unit dosage
form that is interposed between the ibuprofen-containing
compartment (e.g., an ibuprofen core or coated ibuprofen particles)
and the famotidine-containing compartment (e.g.,
famotidine-containing coating or coated famotidine particles).
Generally, the barrier layer does not contain an API. A barrier
layer of the invention may be a water-soluble, pH independent film
that promotes immediate disintegration for rapid release of the
coated drug (i.e., ibuprofen and/or famotidine). Usually a readily
soluble film is used. Materials that can be used for readily
soluble films are well known in the art and include cellulose
derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose phthalate, cellulose
acetate phthalate, and ethyl cellulose; methacrylic polymers,
amino-alkylmethacrylate copolymers (e.g. EudragitTME), polyvinyl
acetate phthalate and polyvinyl alcohol (PVA). A plasticizer (e.g.,
triacetin, diethyl phthalate, tributyl sebacate or polyethylene
glycol) may also be included. The barrier layer may include an
anti-adherent or glidant (e.g., talc, fumed silica or magnesium
stearate) and colorants such as titanium dioxide, iron oxide based
colorants or others. In one embodiment the barrier layer comprises
a non-toxic edible polymer, edible pigment particles, an edible
polymer plasticizer, and a surfactant. Materials include, for
example and not limitation, materials described in U.S. Pat. No.
4,543,370 (Colorcon), incorporated herein by reference. Exemplary
barrier layers include OPADRY.RTM., which is available from
Colorcon (West Point Pa. USA); OPADRY II.RTM. which is available
from Colorcon (West Point Pa. USA) and comprises HPMC, titanium
dioxide, plasticizer and other components; and polyvinyl
alcohol-polyethylene glycol copolymer marketed as Kollicoat.RTM. IR
(BASF). Suitable barrier layers, for illustration and not
limitation, include Kollicoat.RTM. IR (a polyvinyl
alcohol-polyethylene glycol graft copolymer) and Kollicoat IR
White.RTM. both manufactured by BASF Aktiengesellschaft
(Ludwigshafen, Germany). The thickness of the barrier layer can
vary over a wide range, but is generally in the range 20 to 3,000
microns, such as on the order of about 25 to 250 microns.
Preferably the barrier layer retards the release of API by less
than 5 minutes, preferably less than 4 minutes and more preferably
by less than 3 minutes.
[0045] A "subject in need of ibuprofen treatment" is an individual
who receives therapeutic benefit from administration of ibuprofen.
Ibuprofen is indicated for treatment of mild to moderate pain,
dysmenorrhea, inflammation, and arthritis. In one embodiment, the
subject in need of ibuprofen treatment is under treatment for a
chronic condition. For example and without limitation, a subject in
need of ibuprofen treatment may be an individual with rheumatoid
arthritis, an individual with osteoarthritis, an individual
suffering from chronic pain (e.g., chronic low back pain, chronic
regional pain syndrome, chronic soft tissue pain), or an individual
suffering from a chronic inflammatory condition. In general, a
subject under treatment for a chronic condition requires ibuprofen
treatment for an extended period, such as at least one month, at
least four months, at least six months, or at least one year. In
another embodiment, the subject in need of ibuprofen treatment is
under treatment for a condition that is not chronic, such as acute
pain, dysmenorrhea or acute inflammation. Preferably the patient in
need of ibuprofen treatment does not suffer from a condition
characterized by hypersecretion of gastric acid (e.g.,
Zollinger-Ellison Syndrome). Preferably the patient does not suffer
from Barrett's ulceration or active severe oesophagitis. In certain
embodiments the subject does not have gastroesophageal reflux
disease (GERD). In certain embodiments the subject is not in need
of treatment for an ulcer. In certain embodiments the subject does
not suffer from dyspepsia. In certain embodiments the subject is at
elevated risk of developing an NSAID-induced ulcer. In some
embodiments the subject has a Body Mass Index in the normal
range.
[0046] An "ibuprofen responsive condition" is a condition for which
symptoms are reduced by administration of ibuprofen, such as mild
to moderate pain, dysmenorrhea, inflammation, arthritis (e.g.,
rheumatoid arthritis and osteoarthritis), chronic pain, chronic
inflammatory condition, chronic pain, acute pain and acute
inflammation.
[0047] A "subject in need of famotidine treatment" is an individual
who receives therapeutic benefit from administration of famotidine.
In one embodiment, the subject in need of famotidine treatment
requires treatment for non-ulcerative dyspepsia. In one embodiment,
the subject in need of famotidine treatment requires treatment for
gastroesophageal reflux disease (GERD) or for esophagitis due to
GERD or for ulcer (duodenal or gastric). In one embodiment, the
subject does not take ibuprofen for treatment of a chronic
condition. In one embodiment, the subject is not under NSAID
therapy (e.g., does not take ibuprofen and/or a different NSAID for
treatment of a chronic condition). In one embodiment, the subject
in need of famotidine treatment requires treatment for dyspepsia
but does not require treatment for ulcer, GERD or its
complications. As used herein, "subject in need of famotidine
treatment" specifically excludes any subject in need of treatment
for hypersecretion of gastric acid (e.g., Zollinger-Ellison
Syndrome). In certain embodiment, the patient does not suffer from
Barrett's ulceration or active severe oesophagitis. In certain
embodiments a "subject in need of famotidine treatment" does not
suffer from gastroesophageal reflux disease (GERD) or esophagitis
due to GERD. In certain embodiments a "subject in need of
famotidine treatment" does not have an ulcer. In certain
embodiments the subject does not suffer from dyspepsia.
[0048] A "famotidine responsive condition" is a condition for which
symptoms are reduced by administration of famotidine, such as
dyspepsia, GERD, esophagitis due to GERD, or ulcer.
[0049] A subject is "at elevated risk for developing an
NSAID-induced ulcer" if the subject in more susceptible than the
average individual to development of an ulcer when under treatment
with an NSAID. A high odds ratio for risk of development of
NSAID-associated ulcer complications is seen in individuals with a
past complicated ulcer (odds ratio 13.5), individuals taking
multiple NSAIDs or NSAIDs plus aspirin (odds ratio 9.0);
individuals taking high doses of NSAIDs (odds ratio 7.0),
individuals under anticoagulant therapy, such as low dose aspirin
(odds ration 6.4), individuals with a past uncomplicated ulcer
(odds ratio 6.1), and individuals older than 70 years (odds ratio
5.6) See, e.g., Gabriel et al., 1991, Ann Intern Med. 115:787;
Garcia Rodriguez et al. 1994, Lancet 343:769; Silverstein et al.
1995, Ann Intern Med. 123:241; and Sorensen et al., 2000, Am J
Gastroenterol. 95:2218. Subjects at increased risk for developing
an NSAID-induced ulcer may have one or more of these risk factors.
Subjects "at high risk for developing an NSAID-induced ulcer" are
individuals older than 80 years of age and subjects with a history
of NSAID-associated serious gastrointestinal complications (e.g.,
perforation of ulcers, gastric outlet obstruction due to ulcers,
gastrointestinal bleeding).
[0050] "Admixture" refers to a pharmaceutical composition made by
combining and mixing two or more drugs and one or more excipients
in the same compartment of a unit dosage form.
[0051] A "compartment" in the context of a unit dosage form is a
physical region of a tablet or other dosage form. Two components of
a unit dosage form are in "separate compartments" when they are
physically separated (e.g., by a barrier layer).
[0052] As used herein in the context of a unit dosage form, the
term "enteric" has its usual meaning and refers to a medicinal
preparation that passes through the stomach intact and
disintegrates in the intestine. An "enteric coating" remains
insoluble at gastric pH, then allows for release of the active
ingredient from a coated particle or coated dosage form at pH
greater than about 5.0, e.g., greater than pH 5.5, 6.0, 6.5, or
7.0
[0053] As used herein, "dyspepsia" refers to upper abdominal pain
or discomfort with or without symptoms of early satiety, nausea, or
vomiting with no definable organic cause, as diagnosed following
the Rome II criteria (Talley et al., 1999, Gut 45 (Suppl.
II):1137-42), or any subsequent modification thereof. According to
the Rome II criteria, a diagnosis of functional dyspepsia requires:
(1) persistent or recurrent abdominal pain or discomfort centered
in the upper abdomen; (2) symptom duration of at least 12 weeks,
which need not be consecutive, within the preceding 12 months; (3)
no evidence of organic disease (including at upper endoscopy) that
is likely to explain symptoms; (4) no evidence that dyspepsia is
exclusively relieved by defecation or association with the onset of
a change in the stool frequency or stool form (i.e., not irritable
bowel syndrome). In this context, "discomfort" is defined as an
unpleasant sensation, and may include fullness, bloating, early
satiety, and nausea. The definition includes, without limitation,
ulcer-like, dysmotility-like, and non-specific dyspepsia. Symptoms
of dyspepsia include nausea, regurgitation, vomiting, heartburn,
prolonged abdominal fullness or bloating after a meal, stomach
discomfort or pain, and early fullness.
[0054] A unit dose form is in an "aqueous environment" when it is
in a water-based solution in vivo (e.g., in the stomach) or in
vitro. One in vitro aqueous environment is 50 mM potassium
phosphate buffer, pH 7.2. Another in vitro aqueous environment is
50 mM potassium phosphate buffer, pH 4.5.
[0055] As used herein, a person with "normal body weight" has a
body mass index of 20-25 inclusive (calculated as weight
(kg)/[height (m)].sup.2).
[0056] As used herein, a "24-hour dosing cycle" or "24-hour dosing
period" refers to a 24-hour period of time during which a subject
is administered drug(s) and may correspond to a calender day (e.g.,
12:01 a.m. to midnight) or may span two calender days (noon day 1
to noon day 2).
[0057] All percentages are % w/w, unless specifically indicated
otherwise. Unless otherwise indicated, "% weight" is percent weight
of the specified component compared to the total weight of the unit
dosage (e.g., tablet). Optionally the % weight can be calculated as
if the total weight of the unit dosage form is the weight of the
ibuprofen portion, famotidine portion, and barrier layer, but not
including the over-coating (e.g., added to mask taste, improve ease
of swallowing, to improve appearance, and the like). Optionally the
% weight can be calculated based on the total weight of the unit
dosage form, including all coatings. "United States Pharmacopeia"
and "USP" mean the United States Pharmacopeia and National
Formulary 29th Revision (available from 12601 Twinbrook Parkway,
Rockville, Md. 20852-1790, USA). It will be appreciated that due to
rounding or practical limits on quantitive measurements, reference
to a quantity of API or excipient in a dosage form can include some
variation, such as .+-.10%, preferably .+-.5%, and more preferably
.+-.1%. It will be appreciated, for example, that a total quantity
of 80 mg famotidine can be administered in three doses of 26.6 mg
famotidine per dose.
7.0 TID Administration of Ibuprofen-Famotidine Oral Dosage Form
[0058] In one aspect the present invention relates to
administration of an oral dosage form comprising ibuprofen,
famotidine, and one or more pharmaceutically acceptable excipients,
to a patient in need of ibuprofen treatment. In part, the present
invention is directed to a method of reducing or preventing the
occurrence of gastrointestinal toxicity associated with the use of
ibuprofen, such as gastrointestinal ulceration and dyspepsia. In
one embodiment, the invention is directed to a method for
preventing toxicities associated with ibuprofen use in patients who
are specifically at risk for the development of such
toxicities.
[0059] When administered to avoid or mitigate the ulcerogenic
effects of long-term NSAID therapy, famotidine is administered at
40 mg BID (see Taha et al., 1996, supra). However, it has now been
determined using pharmacokinetic modeling (see Example 1) and in
clinical trials (see Example 2) that, surprisingly, TID
administration of famotidine provides a protective effect superior
to that achieved by BID dosing. For example, TID administration of
famotidine results in intragastric pH higher than 3.5 for a greater
proportion of the dosing cycle than conventional BID dosing.
[0060] Unexpectedly, treatment using the methods of the present
invention result in reduced interpatient variability with respect
to gastric pH in a population of patients receiving an
ibuprofen-famotidine combination treatment. This reduction
increases predictability of the treatment and reduces the
likelihood that any particular patient will experience detrimental
gastric pH in the course of ibuprofen-famotidine combination
treatment.
[0061] In addition, a human clinical study described in Example 3,
below, has shown that the pharmocokinetic parameters for concurrent
administration of immediate release forms of ibuprofen and
famotidine were not significantly different from pharmocokinetic
parameters for separate administration of the two APIs. When
administered concurrently, both ibuprofen and famotidine retain
immediate release characteristics of rapid absorption and rapid
attainment of the maximum plasma concentration (T.sub.max).
[0062] These data indicate that a treatment paradigm in which
ibuprofen and famotidine are administered as a unit dose form on a
TID (three times per day) schedule will deliver ibuprofen that is
bioequivalent to that of conventional TID dosing of ibuprofen,
while providing significant and superior protection from
ibuprofen-related side effects such as increased likelihood ulcer
development and dyspepsia. Administration of ibuprofen-famotidine
TID will provide superior protection, as measured by gastric pH,
compared to cotherapy with famotidine BID and ibuprofen TID.
[0063] Thus, in one aspect, the present invention provides a method
for administration of ibuprofen to a patient in need of ibuprofen
treatment by administering an oral dosage form comprising a
therapeutically effective amount of ibuprofen and a therapeutically
effective amount of famotidine, where the oral dosage form is
administered three times per day (TID). The invention also provides
oral unit dosage forms adapted for use in this method.
8.0 Incompatibility of Ibuprofen and Famotidine
[0064] It has been discovered that, under "forced degradation"
conditions, ibuprofen and famotidine in admixture are
pharmaceutically incompatible. Forced degradation conditions refer
to conditions of elevated temperature, or elevated temperature and
humidity, intended to accelerate the process of chemical
degradation. Forced degradation conditions for a period of time are
used to predict the effect of storage under more benign conditions
(e.g., room temperature) for a longer period of time. The present
invention overcomes this incompatibility by formulating the
ibuprofen and famotidine in separate compartments of the dosage
form.
[0065] Thus in one aspect, the present invention provides a method
for administration of ibuprofen to a patient in need of ibuprofen
treatment by administering an oral dosage form comprising a
therapeutically effective amount of ibuprofen and a therapeutically
effective amount of famotidine, wherein the oral dosage form is
administered three times per day (TID), and wherein the ibuprofen
and the famotidine are in separate compartments of the oral dosage
form. The invention also provides oral unit dosage forms adapted
for use in this method.
[0066] Surprisingly, however, in certain formulations ibuprofen and
famotidine are stable in admixture at room temperature. Thus,
alternatively, the invention overcomes the incompatibility of
ibuprofen and famotidine by selection of the formulation components
(see, e.g., Example 4 and exemplary unit dose form VII, below).
9.0 Ibuprofen-Famotidine Oral Dosage Forms
API Content, Dissolution Properties and Protective Properties
[0067] Exemplary formulations that may be used in the practice of
the invention are described below.
[0068] 9.1 API Content
[0069] The dosage forms of the invention comprise ibuprofen and
famotidine in amounts sufficient to provide therapeutic efficacy
when administered three times per day. At each administration time,
a single unit dosage form (e.g., tablet) may be administered, or
the appropriate amount of drug can be administered as a split dose
(e.g., the same amount of drug administered as two tablets taken
together). For example, TID administration of 800 mg ibuprofen and
26.6 mg famotidine can be in the form of a single unit dosage form
containing 800 mg ibuprofen and about 26.6 mg famotidine, two unit
dosage forms containing 400 mg ibuprofen and about 13.3 mg
famotidine, or even four unit dosage forms containing 200 mg
ibuprofen and about 7 mg famotidine. Preferably, a therapeutically
effective dose is administered as one or two tablets.
[0070] The therapeutically effective amount of ibuprofen so
administered is usually in the range 50 mg to 1000 mg. A
therapeutically effective dose for headache or mild pain may be 200
mg or 400 mg TID. A therapeutically effective dose for arthritis is
usually 800 mg TID.
[0071] In general, the unit dosage forms of the invention comprise
ibuprofen in an amount of about 50-1000 mg. In certain embodiments
the unit dosage form comprises ibuprofen in an amount of about
200-800 mg, about 300-500 mg, about 700-800 mg, about 400 mg or
about 800 mg ibuprofen.
[0072] For many applications the quantity of ibuprofen in the unit
dose form is about 800 mg (e.g., in the range 750 mg to 850 mg)
which allows administration of 2400 mg/day with TID administration
of one tablet, or the quantity of ibuprofen is about 400 mg (e.g.,
in the range 375 mg to 425 mg) which allows administration of 2400
mg/day with TID administration of two tablets.
[0073] The therapeutically effective amount of famotidine so
administered is usually in the range 7 mg to 30 mg. In general, the
unit dosage forms of the invention comprise famotidine in the range
of 12 mg to 28 mg. For many applications the quantity of famotidine
in the unit dose form is about 26.6 mg (e.g., in the range 24 mg to
28 mg) which allows administration of 80 mg/day with TID
administration of one tablet, or the quantity of famotidine is
about 13 mg (e.g., in the range 12 mg to 14 mg) which allows
administration of 80 mg/day with TID administration of two
tablets.
[0074] In one preferred embodiment, the oral unit dosage forms are
formulated to deliver a daily dose of about 2400 mg ibuprofen and
about 80 mg famotidine with three times per day administration. For
many applications the quantity of ibuprofen is about 800 mg (e.g.,
in the range 750 mg to 850 mg) and the quantity of famotidine is
about 26.6 mg (e.g., in the range 24 mg to 28 mg). This allows
administration of 2400 mg/day ibuprofen and 80 mg/day famotidine
with TID administration of one tablet. In a related embodiment, the
quantity of ibuprofen is about 400 mg (e.g., in the range 375 mg to
425 mg) and the quantity of famotidine is about 13 mg (e.g., in the
range 12 mg to 14 mg). This allows administration of 2400 mg/day
ibuprofen and 80 mg/day famotidine with TID administration of two
tablets. In a related embodiment, the quantity of ibuprofen is
about 200 mg (e.g., in the range 175 mg to 225 mg) and the quantity
of famotidine is about 6.6 mg (e.g., in the range 6 mg to 7
mg).
[0075] In one embodiment, the oral unit dosage forms are formulated
to deliver a daily dose of about 1800 mg ibuprofen and about 80 mg
famotidine with three times per day administration. For many
applications the quantity of ibuprofen is about 600 mg (e.g., in
the range 550 mg to 650 mg) and the quantity of famotidine is about
26.6 mg (e.g., in the range 24 mg to 28 mg). This allows
administration of 1800 mg/day ibuprofen and 80 mg/day famotidine
with TID administration of one tablet. In a related embodiment, the
quantity of ibuprofen is about 300 mg (e.g., in the range 275 mg to
325 mg) and the quantity of famotidine is about 13 mg (e.g., in the
range 12 mg to 14 mg). This allows administration of 1800 mg/day
ibuprofen and 80 mg/day famotidine with TID administration of two
tablets.
[0076] In other embodiments more or less API may be administered.
For example, in some cases the daily dose of ibuprofen is greater
than 2400 mg (e.g., 3200 mg). This amount can easily be
administered as, for example, three or six tablets per day,
particularly using an ibuprofen formulation that can be tabletted
with little excipient (e.g., BASF Ibuprofen DC 85.RTM.). If a
formulation that contains only the active S-enantiomer of ibuprofen
is used, a smaller quantity may sometimes be administered (e.g., an
amount that produces the same therapeutic effect as a therapeutic
dose of the racemic mixture).
[0077] In certain embodiments the ratio of ibuprofen to famotidine
in the dosage forms of the invention is in the range of 15:1 to
40:1, more often 20:1 to 40:1, and even more often 25:1 to 35:1. In
some embodiments the ratio of ibuprofen to famotidine in the dosage
forms of the invention is in the range of 29:1 to 32:1, such as
30:1 to 31:1. In one embodiment the ratio of ibuprofen to
famotidine is about 30:1. Exemplary amounts of ibuprofen and
famotidine include 800.+-.10% mg ibuprofen and 26.6.+-.10% mg
famotidine; 400.+-.10% mg ibuprofen and 13.3.+-.10% mg famotidine;
and 200.+-.10% mg ibuprofen and 6.65.+-.10% mg famotidine.
[0078] In certain embodiments the ratio of ibuprofen to famotidine
in the dosage forms of the invention is in the range of range of
20:1 to 25:1, such as 22:1 to 23:1. In one embodiment the ratio of
ibuprofen to famotidine is about 22.5:1. Exemplary amounts of
ibuprofen and famotidine include 600.+-.10% mg ibuprofen and
26.6.+-.10% mg famotidine.
[0079] In a preferred embodiment, the oral dosage form does not
contain a pharmaceutically active compound (i.e., drug compound)
other than ibuprofen and famotidine. In particular embodiments the
oral dosage form does not contain any NSAID other than ibuprofen
and/or does not contain any H2-receptor antagonist other than
famotidine. In certain embodiments the amount of famotidine is
other than 5 mg, other than 10 mg, other than 20 mg or other than
40 mg per dosage form.
[0080] 9.2 Rapid Release of Famotidine and Ibuprofen
[0081] In certain embodiments oral dosage forms of the invention
are formulated so that release of both APIs occurs (or begins to
occur) at about the same time. "At about the same time" means that
release of one API begins within 5 minutes of the beginning of
release of the second API, sometimes with 4 minutes, sometimes
within 3 minutes, sometimes within 2 minutes, and sometimes
essentially simultaneously. "At about the same time" can also mean
that release of one API begins before release of the second API is
completed. That is, the dosage form is not designed so that one of
the APIs is released significantly later than the other API. For
example, the barrier layer (described below), if present, is not
designed to significantly delay release of the API contained within
it. Combinations of excipients (which may include one or more of a
binder, a lubricant, a diluent, a disintegrant, a glidant and other
components) are selected which do substantially retard release of
an API. See e.g., HANDBOOK OF PHARMACEUTICAL MANUFACTURING
FORMULATIONS, 2004, Ed. Sarfaraz K Niazi, CRC Press; HANDBOOK OF
PHARMACEUTICAL ADDITIVES, SECOND EDITION, 2002, compiled by Michael
and Irene Ash, Synapse Books; and REMINGTON SCIENCE AND PRACTICE OF
PHARMACY, 2005, David B. Troy (Editor), Lippincott Williams &
Wilkins.
[0082] In some embodiments both the famotidine or ibuprofen are
formulated for immediate release, and not for release profiles
commonly referred to as delayed release, sustained release, or
controlled release. For example, in an embodiment the unit dosage
form is formulated so that famotidine and ibuprofen are released
rapidly under neutral pH conditions (e.g., an aqueous solution at
about pH 6.8 to about pH 7.4, e.g., pH 7.2). In this context
"rapidly" means that both APIs are significantly released into
solution within 20 minutes under in vitro assay conditions. In some
embodiments both APIs are significantly released into solution
within 15 minutes under in vitro assay conditions. In this context,
"significantly released" means that at least about 60% of the
weight of the API in the unit dosage form is dissolved, preferably
at least about 75%, more preferably at least about 80%, often at
least 90%, and sometimes at least about 95%. In one embodiment,
both famotidine and ibuprofen are at least 95% released in 30
minutes.
[0083] Dissolution rates may be determined using known methods.
Generally an in vitro dissolution assay is carried out by placing
the famotidine-ibuprofen unit dosage form(s) (e.g., tablet(s)) in a
known volume of dissolution medium in a container with a suitable
stirring device. Samples of the medium are withdrawn at various
times and analyzed for dissolved active substance to determine the
rate of dissolution. Dissolution may be measured as described for
ibuprofen in the USP or, alternatively, as described for famotidine
in the USP. One approach is illustrated in Example 6. Briefly, the
unit dose form (e.g., tablet) is placed in a vessel of a United
States Pharmacopeia dissolution apparatus II (Paddles) containing
900 ml dissolution medium at 37.degree. C. The paddle speed is 50
RPM. Independent measurements are made for at least three (3)
tablets. In one suitable in vitro assay, dissolution is measured
using a neutral dissolution medium such as 50 mM potassium
phosphate buffer, pH 7.2 ("neutral conditions") generally as
described in Example 6, below.
[0084] 9.3 Substantial Release of Famotidine and Ibuprofen Under
Low pH Conditions
[0085] In an embodiment the unit dosage form is formulated so that
famotidine and ibuprofen are both released rapidly under low pH
conditions. Release under low pH conditions is measured using the
assay described above and in Example 6, but using 50 mM potassium
phosphate buffer, pH 4.5 as a dissolution medium. As used in this
context, the APIs are released rapidly at low pH when a substantial
amount of both APIs is released into solution within 60 minutes
under low pH assay conditions. In some embodiments, a substantial
amount of both APIs is released into solution within 40 minutes
under low pH assay conditions. In some embodiments, a substantial
amount of both APIs is released into solution within 20 minutes
under low pH assay conditions. In some embodiments, a substantial
amount of both APIs is released into solution within 10 minutes
under low pH assay conditions. In this context, a "substantial
amount" means at least 15%, preferably at least 20%, and most
preferably at least 25% of ibuprofen is dissolved and at least 80%,
preferably at least 85%, and most preferably at least 90% of
famotidine is dissolved.
[0086] 9.4 Gastric Protection
[0087] As illustrated in Examples 1 and 2, TID administration to a
subject of famotidine results in an intragastric pH that is
elevated (in magnitude and/or duration), on average, relative to
the intragastric pH resulting from conventional BID administration
of famotidine, resulting in better gastric protection. As used
herein administration of a pharmaceutical composition or
compositions "provides better gastric protection" compared to
administration of a reference composition or compositions when
administration of the pharmaceutical composition maintains stomach
pH at a more basic level. It has now been discovered that TID
administration of famotidine provides better gastric protection
than conventional BID dosing of the same daily dose of drug.
[0088] Intragastric pH can be determined by art-known methods
using, for example, a nasogastric pH probe. One useful probe is the
Digitrapper.TM. pH 400 ambulatory pH recorder from Medtronic
Functional Diagnostics (Shoreview, Minn.). Typically pH is measured
several times minute (e.g., the Digitrapper.TM. pH 400 makes
measurements at a frequency of 1/4 Hz) and the median pH over a 24
hour period is calculated. Measurements can be calculated for
specific periods (e.g., upright, sleeping, postprandial, etc).
Measurements can be made after the subject has received the
appropriate dosage regimen for 1, 2 or 3 days or longer than 3
days, such as after several weeks of use.
[0089] An individual in need of ibuprofen treatment and receiving
ibuprofen-famotidine combination therapy will have greater gastric
protection when a unit dose containing famotidine (or containing a
famotidine plus ibuprofen combination) is administered TID.
Similarly, in a group of treated individuals in which responses are
somewhat variable, an individual may have a reduced likelihood of
gastric damage (e.g., exposure to low pH) when an
ibuprofen-famotidine unit dose form is administered TID. The
individual (or individuals in a group) may in some cases have
shared characteristics. In general the individual or individuals
(hereinafter, "individual") is an adult (over 18 years of age). In
one embodiment the individual is male. In one embodiment the
individual is female. In one embodiment the individual has an age
in the range 19-42 years. In various embodiments the individual may
have an age in years in the range of 20-30, 25-35, 30-40, 35-45,
40-50, 45-55, 50-60, 55-65, 60-70 or older than 70 years old. In
one embodiment the individual has a normal weight (i.e., a Body
Mass Index of 20-25). In one embodiment the individual does not
have a normal body weight (i.e., BMI <20 or BMI >25).
[0090] Gastric protection can be measured in a single individual or
in a group of individuals (a "patient population"). Measurements
can be made in a specified group of individuals to measure gastric
protection (e.g., to determine the median gastric pH) and the
median of the measure of gastric protection (e.g., time with
gastric pH >4; median pH over 24 hour period, etc.) determined.
In one embodiment the individuals in the group are male. In one
embodiment the individuals in the group are female. In one
embodiment the group includes both male and female individuals. In
one embodiment the group includes both individuals under treatment
for RA. In various embodiments the individuals in the group may
have an age in years in the range of 19-42, 20-30, 25-35, 30-40,
35-45, 40-50, 45-55, 50-60, 55-65, 60-70 or older than 70 years
old. In one embodiment the individuals in the group have a normal
weight (i.e., a Body Mass Index of 20-25). In another embodiment, a
patient population is a group of patients who are under the care of
the same doctor or healthcare provider or receive treatment at the
same health care facility or obtain therapeutics at the same
pharmacy.
[0091] 9.4.1 Fraction of 24-Hour Dosing Cycle with pH Above a
Specified Value
[0092] One measure of gastric protection is the fraction of a
24-hour dosing cycle during which amount of time pH is maintained
above a designated value (e.g., pH 2.5, pH 3.0, pH 3.5, pH 4.0, or
pH 4.5). For example, better gastric protection can be
characterized as pH above the designated value for more time in a
24 hour dosing cycle than administration of the reference
composition(s). TID administration of famotidine (or, alternatively
a unit dosage form of the invention containing famotidine and
ibuprofen) will maintain gastric pH of 2.5 or greater for at least
5, at least 6, at least 7, at least 8, at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, at
least 21, at least 22, or at least 23 hours of a 24 hour dosing
cycle. In one embodiment, TID administration of famotidine (or,
alternatively a unit dosage form of the invention containing
famotidine and ibuprofen) will maintain a gastric pH of 3.0 or
greater for at least 5, at least 6, at least 7, at least 8, at
least 9, at least 10, at least 11, at least 12, at least 13, at
least 14, at least 15, at least 16, at least 17, at least 18, at
least 19, at least 20, at least 21, at least 22, or at least 23
hours of a 24 hour dosing cycle. In one embodiment, TID
administration of famotidine (or, alternatively a unit dosage form
of the invention containing famotidine and ibuprofen) will maintain
a gastric pH of 3.5 or greater for at least 5, at least 6, at least
7, at least 8, at least 9, at least 10, at least 11, at least 12,
at least 13, at least 14, at least 15, at least 16, at least 17, at
least 18, at least 19, at least 20, at least 21, at least 22, or at
least 23 hours of a 24 hour dosing cycle. In one embodiment, TID
administration of famotidine (or, alternatively a unit dosage form
of the invention containing famotidine and ibuprofen) will maintain
a gastric pH of 4.0 or greater for at least 5, at least 6, at least
7, at least 8, at least 9, at least 10, at least 11, at least 12,
at least 13, at least 14, at least 15, at least 16, at least 17, at
least 18, at least 19, at least 20, at least 21, at least 22, or at
least 23 hours of a 24 hour dosing cycle. TID administration of
famotidine (or, alternatively a unit dosage form of the invention
containing famotidine and ibuprofen) will maintain gastric pH of
4.5 or greater for at least 5, at least 6, at least 7, at least 8,
at least 9, at least 10, at least 11, at least 12, at least 13, at
least 14, at least 15, at least 16, at least 17, at least 18, at
least 19, at least 20, at least 21, at least 22, or at least 23
hours of a 24 hour dosing cycle. In one embodiment of the present
invention, TID administration of famotidine (or, alternatively TID
administration a unit dosage form of the invention containing
famotidine and ibuprofen) results in a gastric pH above a specified
value (e.g., at least 2.5, at least 3.0, at least 3.5, at least 4.0
or at least 4.5) for more time in a 24-hour dosing cycle that than
BID administration of the same daily dose of famotidine (or,
alternatively a BID administration of the same daily dose of
famotidine and TID administration of the same daily dose of
ibuprofen) where the difference is (in minutes) at least 10, at
least 20, at least 30, at least 40, or at least 50, at least 60, at
least 120, at least 180, at least 240, at least 300 or more.
[0093] 9.4.2 Minimum Sustained Gastric pH
[0094] Another measure of gastric protection is the minimum
sustained gastric pH during a 24-hour dosing cycle. "Sustained pH"
refers to a gastric pH (or pH range) sustained for at least 10
minutes. Better gastric protection can be characterized as a higher
minimum sustained pH when measured over a 24-hour dosing period. In
one embodiment of the present invention, TID administration of
famotidine (or, alternatively a unit dosage form of the invention
containing famotidine and ibuprofen) results in a minimum sustained
pH of at least 2.0, preferably at least 2.3, more preferably at
least 2.5, and sometimes at least 3.0. In one embodiment of the
present invention, TID administration of famotidine (or,
alternatively TID administration a unit dosage form of the
invention containing famotidine and ibuprofen) results in a minimum
sustained pH that is higher than BID administration of the same
daily dose of famotidine (or, alternatively a BID administration of
the same daily dose of famotidine and TID administration of the
same daily dose of ibuprofen) where the difference in pH is at
least 0.2, at least 0.4, at least 0.5, at least 0.6, or at least
0.7 pH units.
[0095] 9.4.3 Median Gastric pH
[0096] Another measure of gastric protection is the median gastric
pH during a 24-hour dosing cycle. Better gastric protection can be
characterized as a higher median gastric pH over a 24-hour dosing
period. In one embodiment of the present invention, TID
administration of famotidine (or, alternatively a unit dosage form
of the invention containing famotidine and ibuprofen) results in a
median gastric pH of at least 2.5, at least 2.6, at least 2.7, at
least 2.8, at least 2.9, at least 3.0, at least 3.1, at least 3.2,
at least 3.3, at least 3.4, at least 3.5, at least 3.6, at least
3.7, at least 3.8, at least 3.9, at least 4.0, at least 4.1, at
least 4.2, at least 4.3, at least 4.4, at least 4.5, at least 4.6,
at least 4.7, at least 4.8, at least 4.9, at least 5.0, at least
5.1, at least 5.2, at least 5.3, at least 5.4, at least 5.5, at
least 5.6, at least 5.7, at least 5.8, at least 5.9, at least 6.0,
at least 6.1, at least 6.2, at least 6.3 or at least 6.4.
[0097] In one embodiment of the present invention, TID
administration of famotidine (or, alternatively TID administration
a unit dosage form of the invention containing famotidine and
ibuprofen) results in a median gastric pH that is higher than BID
administration of the same daily dose of famotidine (or,
alternatively a BID administration of the same daily dose of
famotidine and TID administration of the same daily dose of
ibuprofen) where the difference in pH is at least 0.2, at least
0.3, at least 0.4, at least 0.6, at least 0.7 or at least 0.8 pH
units.
[0098] For illustration, TID administration of a unit dosage form
containing 800 mg ibuprofen and 26.6 mg famotidine would provide
superior gastric protection than does TID administration of a unit
dosage form containing 800 mg ibuprofen and BID administration of a
unit dosage form containing 40 mg famotidine.
[0099] 9.5 Reduced Patient-to-Patient Variability
[0100] As shown in Example 2, interpatient variability in gastric
pH was significantly reduced when subjects received 80 mg/day
famotidine as three 26.7 mg doses (TID administration) compared to
two 40 mg doses (BID administration).
[0101] It is known that there may be considerable
patient-to-patient variability in the effects of drugs or drug
combination administered to a population of patients. This
interpatient variability complicates the treatment of many
disorders, and identifying methods to reduce side-effects
(toxicity) and maximize effectiveness in a diverse population is
challenging. In the case of subjects receiving ibuprofen and
famotidine treatment in combination, the interpatient variation
means that some patients have heightened susceptibility to
side-effects resulting from low gastric pH. Methods that reduce
interpatient variability should therefore reduce the incidence of
side-effects in the treated population. That is, reducing
inter-patient variability in a group reduces the risk that any
particular individual in the group will experience detrimental
gastric pH.
[0102] In one aspect, the present invention provides a method for
reducing interpatient variability with respect to gastric pH in a
population of patients receiving an ibuprofen-famotidine
combination treatment, by administering an oral dosage form
containing a therapeutically effective amount of ibuprofen and a
therapeutically effective amount of famotidine, where the oral
dosage form is administered three times per day (TID). In one
embodiment the population of patients in which interpatient
variability is reduced comprises all patients in need of or
receiving ibuprofen-famotidine combination therapy. In this
context, "ibuprofen-famotidine combination therapy" refers to
administration of ibuprofen and famotidine as part of the same
course of treatment which, as noted above, generally involves
administration of ibuprofen TID and administration of famotidine
BID. In other embodiments the population of patients in which
interpatient variability is reduced comprises a subpopulation of
patients in need of or receiving ibuprofen-famotidine combination
therapy such as individuals having a Body Mass Index in the range
of 20-25 and/or having an age in years in the range of 19-42,
20-30, 25-35, 30-40, 35-45, 40-50, 45-55, 50-60, 55-65, or
60-70.
[0103] The observed reductions in interpatient variability provides
important clinical benefits. These important clinical benefits
include fewer patients who experience a daily median pH below 2.5
It is believe patients experiencing a median pH below 2.5 are at
higher risk for gastric acid-induced ulceration when treated TID
compared to BID dosing. Notably, as discussed in Example 2, infra,
in a clinical study a 24-hour median gastric pH was below 2.5 for
three patients when receiving famotidine on a BID schedule, but no
patients when receiving famotidine on a TID schedule.
10.0 Exemplary Unit Dose Forms
[0104] Oral dosage forms of the invention may have a variety of
designs, provided the ibuprofen and the famotidine are in separate
compartments of the oral dosage form.
[0105] In some embodiments, the ibuprofen and the famotidine
compartments are separated by a barrier layer. In some embodiments,
the invention provides a solid oral dosage form with a first
portion comprising a therapeutically effective amount of ibuprofen
and a second portion comprising a therapeutically effective amount
of famotidine, where the ibuprofen portion completely surrounds the
famotidine portion or the famotidine portion completely surrounds
the ibuprofen portion; and a barrier layer disposed between the two
portions.
[0106] The API content of the unit dose forms is selected so that
TID administration delivers a therapeutically effective dose of
ibuprofen and a therapeutically effective dose of famotidine.
Preferably the oral dosage form comprises ibuprofen and famotidine
in the amounts and ratios described herein.
[0107] According to the invention, famotidine and ibuprofen are
released rapidly, as described above. It will be recognized,
therefore, that in this aspect of the invention neither the dosage
nor the APIs individually are enteric coated or formulated for
sustained or delayed release. The tablets are formulated so that
they disintegrate in the stomach after they are swallowed and do
not dissolve in the mouth or throat during the normal process of
oral administration. Other properties of the oral dosage forms of
the invention will be apparent to the reader.
[0108] With these properties in mind, exemplary oral dosage forms
are described below, for illustration and not for limitation. It
will be understood that many other forms may be made by one of
skill in the art guided by this disclosure, and that information
related to one dosage form below (e.g., a description of
excipients) may be used in connection with other forms.
[0109] 10.1 Exemplary Oral Dosage Form I
[0110] In one version, the oral dosage form comprises an ibuprofen
core ("core"), a surrounding layer containing famotidine
("famotidine layer") and a barrier layer interposed between the
core and famotidine layer. In one embodiment famotidine coat
entirely surrounds the ibuprofen core. Optionally the tablet is
coated by one or more over-coating layers, for example, to improve
appearance, taste, swallowability, or for other reasons. Methods
for formulation and manufacture of pharmaceutical unit dose forms
are known in the art, see, e.g., HANDBOOK OF PHARMACEUTICAL
MANUFACTURING FORMULATIONS, 2004, Ed. Sarfaraz K Niazi, CRC Press;
HANDBOOK OF PHARMACEUTICAL ADDITIVES, SECOND EDITION, 2002,
compiled by Michael and Irene Ash, Synapse Books; and REMINGTON
SCIENCE AND PRACTICE OF PHARMACY, 2005, David B. Troy (Editor),
Lippincott Williams & Wilkins. One of ordinary skill in the art
guided by this disclosure will be able to make a variety of
suitable oral unit dose forms.
[0111] 10.1.1 The Ibuprofen Core of Exemplary Oral Dosage Form
I
[0112] The ibuprofen core may vary in shape and may be, for
example, round, ovoid, oblong, cylindrical (e.g., disk shaped) or
any other suitable geometric shape, for example rectilinear.
Preferably the tablet has a disk or ovoid shape is shaped like a
flattened disk, ovoid or torpedo. The edges of the tablets may be
beveled or rounded. The tablet may also be shaped as a caplet
(capsule form tablet). The tablets may be scored, embossed or
engraved. In one embodiment, the core does not have an internal
hole extending all or part-way through the pill. For example, in
one embodiment the core is not shaped like a cup or donut.
[0113] The tablet of the invention comprises a therapeutically
effective amount of ibuprofen API. This is usually in the range 50
mg to 1000 mg. For many applications the quantity of ibuprofen is
about 800 mg (e.g., in the range 750 mg to 850 mg, or in the range
775-825 mg) which allows administration of 2400 mg/day with TID
administration of one tablet, or the quantity of ibuprofen is about
400 mg (e.g., in the range 375 mg to 425 mg) which allows
administration of 2400 mg/day with TID administration of two
tablets. In addition to ibuprofen the core may contain excipients
such as one or more disintegrants, binders, glidants, or
lubricants. For example, the core may contain lactose (e.g.,
lactose monohydrate); colloidal silicon dioxide; sodium
croscarmellose; hydroxy propyl methyl cellulose; silicified
microcrystalline cellulose and/or magnesium stearate. In one
embodiment ibuprofen core comprises ibuprofen, 20-30% (w/w) lactose
monohydrate; 0.1 to 2% colloidal silicon dioxide; 3-7%
crosscarmellose sodium; 1-3% hydroxy propyl methyl cellulose; 2-6%
silicified microcrystalline cellulose (e.g., Prosolv SMCC 90) and
0.1-2% magnesium stearate. In some embodiments, the core does not
contain a lubricant.
[0114] In one embodiment, the core comprises Ibuprofen DC 85 (BASF)
which comprises 85% API, or a similar directly compressible
ibuprofen formulation described in WO 2007/042445 (i.e., an
ibuprofen formulation comprising 50 to 99% by weight crystalline
ibuprofen, 1 to 15% of a highly dispersible adjuvant having a
minimum surface of 100 m.sup.2/g, wherein at least 50% of the
surface of the ibuprofen crystals is coated with the highly
dispersible adjuvant, and 0 to 40% other adjuvants. Exemplary
formulations using Ibuprofen DC 85, for illustration and not
limitation, include: [0115] 1) Ibuprofen DC 85 (88.24% w/w);
microcrystalline cellulose (7.76%); crosslinked sodium
carboxymethylcellulose (3.00%); silica (0.05%); and magnesium
stearate (0.50%); [0116] 2) Ibuprofen DC 85 (88.24% w/w); corn
starch (7.76%); crosslinked sodium carboxymethylcellulose (3.00%);
silica (0.05%) and magnesium stearate (0.50%); [0117] 3) Ibuprofen
DC 85 (88.24% w/w); lactose (7.76%); crosslinked sodium
carboxymethylcellulose (3.00%); silica (0.05%) and magnesium
stearate (0.50%).
[0118] The core may be formed using art-known techniques including
wet granulation, dry granulation, direct compression or any other
pharmaceutically acceptable process. The appropriate amount of the
ibuprofen formulation (i.e., the amount containing the unit dose of
API) may be compression pressed into individual cores.
Alternatively, the core may be formed by molding.
[0119] In one embodiment, the core portion is at least 50%
ibuprofen by weight, preferably at least 60%, and more preferably
at least 70%, and even more preferably at least 80% ibuprofen.
[0120] 10.1.2 The Barrier Layer of Exemplary Oral Dosage Form I
[0121] The barrier layer may be composed of any of a variety of
materials that (1) separate the core and famotidine layer and (2)
rapidly disintegrate in an aqueous (e.g., gastric) environment so
that the ibuprofen is rapidly released.
[0122] The barrier layer may comprise fillers, binders,
disintegrants, lubricants, glidants, and the like, as known in the
art. Suitable fillers for use in making the barrier layer, or a
portion thereof, by compression include water-soluble compressible
carbohydrates such as sugars, which include dextrose, sucrose,
maltose, and lactose, sugar-alcohols, which include mannitol,
sorbitol, maltitol, xylitol, starch hydrolysates, which include
dextrins, and maltodextrins,
[0123] In one embodiment, the ibuprofen cores are coated with
Opadry II.TM. white (Colorcon Y-22-7719) according to
manufacturer's instructions to a weight gain of 1.5-2.0% w/w. Other
known barrier layer materials include hydroxypropyl methylcellulose
phthalate, polyvinyl acetate phthalate, and cellulose acetate
phthalate. In one embodiment, the barrier layer formulation will
contain at least one coating layer polymer and a coating solvent
(preferably water) used for processing and removed by drying. The
coating layer polymer may be hydroxypropyl methylcellulose,
polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers or
hydroxypropyl cellulose. A plasticizer (e.g., triacetin, diethyl
phthalate, tributyl sebacate or polyethylene glycol) may also be
included. The coating layer may include an anti-adherent or glidant
(e.g., talc, fumed silica or magnesium stearate) and colorants such
as titanium dioxide, iron oxide based colorants or others.
[0124] The thickness of the barrier layer can vary over a wide
range, but is generally in the range 20 to 3,000 microns, such as
on the order of about 25 to 250 microns. Preferably the barrier
layer retards the release of API by less than 5 minutes, preferably
less than 4 minutes and more preferably by less than 3 minutes.
[0125] The barrier layer may be formed by any method, including
compression, molding, dipping, or spray coating.
[0126] 10.1.3 The Famotidine Layer of Exemplary Oral Dosage Form
I
[0127] The famotidine layer is applied over the barrier coat. The
famotidine layer can be applied by compression, spray coating, or
other methods. In a preferred embodiment, the famotidine layer is
applied by spray coating a formulation containing famotidine and
excipients such as polymers, plasticizers, and the like. In one
example, famotidine is combined with Opadry II (Colorcon) and spray
coated over the ibuprofen core or barrier layer.
[0128] The dosage form of the invention comprises a therapeutically
effective amount of famotidine API. For many applications the
quantity of famotidine is about 26.6 mg (e.g., in the range 24 mg
to 28 mg) which allows administration of 80 mg/day with TID
administration of one tablet, or the quantity of famotidine is
about 13 mg (e.g., in the range 12 mg to 14 mg) which allows
administration of 80 mg/day with TID administration of two
tablets.
[0129] 10.1.4 Over Coating Layers of Exemplary Oral Dosage Form
I
[0130] In some embodiments, the tablets are coated for oral
administration, to make the tablet easier to swallow, to mask
taste, for cosmetic reasons, or for other reasons. Coating of
tablets and caplets is well known in the art. Coating systems are
typically mixtures of polymers, plasticizers, coloring agents and
other excipients, which can be stirred into water or an organic
solvent to produce a dispersion for the film coating of solid oral
dosage forms such as tablets.
[0131] Usually a readily soluble film is used. Materials that can
be used for readily soluble films include cellulose derivatives
(such as hydroxypropylmethyl cellulose) or amino-alkylmethacrylate
copolymers (e.g. EudragitTME). Suitable coat layers, for
illustration and not limitation, include Kollicoat.RTM. IR (a
polyvinyl alcohol-polyethylene glycol graft copolymer) and
Kollicoat IR White.RTM. both manufactured by BASF
Aktiengesellschaft (Ludwigshafen, Germany).
[0132] 10.2 Exemplary Oral Dosage Form II
[0133] In one version, the oral dosage form comprises many small
particles of ibuprofen, each coated with a barrier layer, with the
particles situated in a matrix or medium containing famotidine. The
barrier layers may be made as described above (e.g., using
Kollicoat.TM., Opadry.TM. or similar materials). In this version
the particles may have a variety of sizes, ranging from a mean or
average size of 200 microns to 2000 microns or more. For example,
and not for limitation, the mean size can be in the range 200-1500,
600-700, 700-800, 800-900, 900-1000, 1100-1200, 1200-1300,
1300-1400, 1400-1500, 1500-1600, 1600-1700, 1700-1800, 1800-1900,
1900-2000 microns or more. In one embodiment at least 80%, and more
often at least 90% of the particles are in the size range of
350-800 microns. In some embodiments a mixture of particle sizes is
used. The ibuprofen particles may be contained in or distributed in
a matrix containing famotidine. The matrix can include binders,
lubricants, diluents, disintegrants, and other components known in
the art. As used in this context, the term "matrix" does not
connotate any particular structure.
[0134] In one version, the ibuprofen particles can be contained in
a capsule that also contains famotidine and suitable excipients or
carriers.
[0135] 10.3 Exemplary Oral Dosage Form III
[0136] In one version, the oral dosage form comprises many small
particles of famotidine coated with a barrier layer and situated in
a matrix containing ibuprofen. The barrier layers may be made as
described above (e.g., using Opadry or similar materials). In
certain versions, the particles may have a variety of sizes,
ranging from a mean or average size of 100 microns to 2000 microns
or more. For example, and not for limitation, the particles can be
in the range 200-800, 200-600, 200-400, 350-800, or 350-600. In
some embodiments a mixture of particle sizes is used. The matrix or
tablet can include binders, lubricants, diluents, disintegrants,
and other components known in the art. In one embodiment the matrix
consists primarily of ibuprofen. In one embodiment the ibuprofen is
Ibuprofen DC 85.TM. (BASF). In one version, the famotidine
particles can be contained in a capsule that also contains
ibuprofen and suitable excipients or carriers.
[0137] In one version, the unit dose form comprises coated
famotidine particles mixed with ibuprofen (which may be Ibuprofen
DC 85.TM.) and compressed into tablets. In one approach the coated
famotidine particles are prepared by spray granulating famotidine
onto a carrier particles, coating the resulting granule with a
barrier layer, and optionally a further protective layer.
[0138] In certain embodiments, the carrier particles may be an
inert material such as microcrystalline cellulose (fine grade;
e.g., Avicel PH101 [FMC Corp.]), or the like. The famotidine may be
spray granulated onto the carrier particles in any suitable manner,
e.g., in a fluid bed processor, using a solution of famotidine, an
optional film former, an optional anti-static agent, and other
optional excipients and diluents. For instance, Opadry II.RTM. or
similar materials, e.g., such as those described in U.S. Pat. No.
4,802,924, incorporated herein by reference, may be used as a film
former, and talc or similar inert material may be used as an
anti-static agent. By way of non-limiting example, the famotidine
spray mixture may comprise about 75% active, about 20% film former,
and about 5% anti-static agent, by weight.
[0139] The famotidine spray mixture is coated onto the inert
material until the desired amount of famotidine is added, such as a
weight gain per particle or on a batch basis of 20% to 200%. For
example, the 1.25 parts famotidine mixture can be sprayed on 1 part
microcrystalline cellulose to a weight gain of about 90% to 110%
(i.e., about 100%).
[0140] A barrier layer may be applied over the famotidine coated
granules. Again, the barrier layer of the famotidine particles may
be made as described above (e.g., using Opadry.RTM.,
Kollicoat.RTM., or similar materials). In certain embodiments, the
barrier layer may be applied to about a 5-50% weight gain per
particle or on a batch basis, e.g., a 20% weight gain.
[0141] In certain embodiments, the optional polymeric protective
coating may be applied to about a 5%, 10%, 20%, or more than 20%
weight gain per particle on a batch basis, depending on the degree
of protective elastic/compressibility properties desired.
[0142] The resulting famotidine granules are preferably large
enough for convenient handling and to maximize content uniformity
of the resulting unit dose forms. In some embodiments the
famotidine granules are in the size range of 100 microns to 1000
microns, such as in the range of 350-800 microns. Particle size is
usually determined based on the ability of particles to pass
through an opening (e.g., using a US sieve series, or Tyler
equivalent mesh). In one embodiment at least about 80%, and usually
at least 90%, of the famotidine particles are in the size range of
less than 800 microns, e.g., 350-800 microns.
[0143] Particle size can be determined by microscopy, laser
diffraction, dynamic light scanning (DLS), sieve analysis, or other
methods. In a preferred embodiment particle size is determined by
sieve analysis. Sieve analysis methods are routine in the art. For
example, sieve analysis can be preformed using an ATM sonic sifter.
The equipment may be set to run for 10 minutes with sift and pulse
at amplitude #6. Sieves may be nested in the following order: #20
mesh (850 microns), #20 mesh (420 microns), #60 mesh (250 microns),
#120 mesh (125 microns), #325 mesh (45 microns), and fines pan
(<45 microns). Samples are run in duplicate and the generated
percent retained reflect the average of the two measurements
[0144] The famotidine particles may then be blended with ibuprofen
granules and compressed into tablets in any suitable method known
in the art. Optionally a lubricant, such as magnesium stearate, may
be added to the ibuprofen-famotidine mixture prior to the
compression step.
[0145] In one version the ibuprofen is in the form of granules with
a mean particle size under 100 microns (e.g., 25, 38, 50, or 90
microns). Suitable ibuprofen preparations are available from BASF
Aktiengesellschaft, Ludwigshafen, Germany. In one version the
ibuprofen is in the form of an ibuprofen containing active agent
preparation as described in patent publication US 20030045580
(assigned to BASF A.G.). In one version the ibuprofen is in the
form of an ibuprofen preparation as described in patent publication
US 20050003000 (assigned to BASF A.G.). In one version, the unit
dose form contains coated famotidine granules, ibuprofen and
excipients. Excipients may include binders (e.g., SMCC), lubricants
(e.g., magnesium stearate), diluents, disintegrants (e.g.,
croscarmellose), coatings, barrier layer components, glidants
(e.g., colloidal silicon dioxide). In one version a nonionic
surfactant having an hydrophiliclipophilic balance (HLB) of at
least 9 is included in the product (see, e.g., U.S. Pat. No.
6,251,945).
[0146] In one version the ibuprofen is in the form of the product
DC 85 (BASF Aktiengesellschaft, Ludwigshafen, Germany). DC 85
comprises ibuprofen (>80%), silica, croscarmellose sodium and
cellulose and is supplied in the form of granules with a median
size of about 700 microns (>90% in the range 300-1400 microns).
Optionally DC 85 are used which have a size distribution similar to
that of the famotidine granules (e.g., at least at least about 80%,
sometimes at least 90%, and sometimes at least 95% of the DC 85
particles are in the size range of 350-800 microns in an embodiment
in which the majority of famotidine particles lie in that size
range). DC-85 ibuprofen particles of desired size can be obtained
by milling.
[0147] In one version, the unit dose form contains coated
famotidine granules, DC 85 ibuprofen and a lubricant such as
magnesium stearate.
[0148] A final coating (e.g., Opadry.RTM., Opadry II.RTM.,
Kollicoat.RTM. or similar materials) may be applied using, e.g., a
48'' Accella coata according to manufacturer's instructions, as
generally recognized by those skilled in the art.
[0149] 10.4 Exemplary Oral Dosage Form IV
[0150] In one version, the oral dosage form comprises many small
particles of ibuprofen, each coated with a barrier layer, and many
small particles of famotidine each coated with a barrier layer and
situated in a matrix containing ibuprofen. The barrier layers may
be the same or different. The two types of particles can be
contained in a matrix or medium to give form to the unit dosage
(e.g., tablet).
[0151] In one version, the ibuprofen particles and famotidine
particles are contained in a capsule, optionally with excipients or
carriers.
[0152] 10.5 Exemplary Oral Dosage Form V
[0153] In one version, the oral dosage form comprises famotidine
and Ibuprofen DC 85.TM. (BASF) or famotidine and a coated ibuprofen
product made according to the method of U.S. Pat. No. 6,251,945. In
this embodiment, a nonionic surfactant coating of the ibuprofen
separates the ibuprofen portion from the famotidine portion of the
dosage form. In one embodiment, the unit dosage consists
essentially of famotidine, Ibuprofen DC 85.TM., and optionally an
over-coating coat. In other embodiments, the oral dosage form
comprises additional excipients.
[0154] 10.6 Exemplary Oral Dosage Form VI
[0155] In one version, the oral dosage form comprises famotidine
and ibuprofen in a bilayer tablet, with famotidine plus excipient
in one layer and ibuprofen plus excipient in the second layer.
Usually the two layers are separated by a barrier layer. Usually an
over-coating is also present.
[0156] 10.7 Exemplary Oral Dosage Form VII (Admixture Forms)
[0157] Exemplary unit dose forms I-VI, above, which are provided
for illustration and not limitation, are characterized by having
the ibuprofen and famotidine APIs in different compartments of the
tablet. In an other aspect, unit dose forms of the invention
comprise ibuprofen (or other NSAID) in admixture with famotidine
and at least one excipient. The unit dose form may be a tablet,
caplet, gelcap, or other form. In some embodiments the dosage form
includes a core comprising the ibuprofen and famotidine, which core
is surrounded by an over coating which may be added to improve
appearance, taste, swallowability, or other characteristics of the
dosage form. It is preferred that the solid formulation of the
present invention is durable to usual external manipulation yet
able dissolve at the acceptable rate.
[0158] In one embodiment, the solid tablet carrier contains at
least one, and preferably at least two, of the following
components: microcrystalline cellulose, croscarmellose sodium,
lactose, magnesium stearate, hydroxypropyl cellulose, starch and
talc. For example, the unit dose form may contain one or more of
the following excipients: 5-15% microcrystalline cellulose, 0.5-5%
croscarmellose sodium, 10-85% lactose, 0.5-5% magnesium stearate,
2-6% hydroxypropyl cellulose, 3-15% pregelatinized starch (e.g.
starch 1500), and/or 1-10% talc. In one embodiment the unit dose
form comprises all of the all of the above excipients. It is most
preferred, in this embodiment, that the tablet formulation
comprises a therapeutically effective amount of ibuprofen or its
pharmaceutically acceptable salts, in combination with famotidine
with pharmaceutically acceptable excipients in a
pharmacokinetically effective ratio. In one embodiment the
excipients include microcrystalline cellulose 5-15% by weight,
croscarmellose sodium 0.5-5% by weight, lactose 10-85% by weight,
magnesium stearate 0.5-5% by weight, hydroxypropyl cellulose 2-6%
by weight, pregelatinized starch 3-15% by weight and talc 1-10% by
weight.
[0159] In the formulations of the invention, the excipients are
present in an amount sufficient to allow for release of the
ibuprofen and famotidine from the tablet after administration to a
subject in need of this therapeutic combination in a fashion
allowing for absorption into the blood at a time and concentration
such that the therapeutic effects match that of ibuprofen
administered alone and that of famotidine administered alone. As
described in Example 3, it was demonstrated in human clinical
studies that there are no significant differences between the
pharmacokinetic parameters for either ibuprofen or famotidine when
administered alone compared to administration in combination. It
was concluded that both ibuprofen and famotidine can be considered
bioequivalent when administered in combination compared to separate
administration.
[0160] In a different embodiment, the pharmaceutical composition
comprises microcrystalline cellulose 5-10% by weight,
croscarmellose sodium 1-4% by weight, lactose 20-75% by weight,
magnesium stearate 1-3% by weight, hydroxypropyl cellulose 3-5% by
weight, pregelatinized starch 5-10% by weight and talc 2-6% by
weight.
[0161] In another embodiment, the dosage for comprises 60-80%
ibuprofen; 1.5-3.0% famotidine; 9-11% microcrystalline cellulose;
2-4% silicified microcrystalline cellulose; and 0.5-2.5%
croscarmellose sodium.
[0162] Preferably the formulation comprises 60-80% ibuprofen;
1.5-3.0% famotidine; 9-11% microcrystalline cellulose; 2-4%
silicified microcrystalline cellulose; 1-3% low substituted
hydroxylpropylcellulose; and 0.5-2.5% croscarmellose sodium.
[0163] In one embodiment the formulation comprises ibuprofen,
famotidine, microcrystalline cellulose, pregelatinized starch,
hydroxypropyl cellulose, low substituted hydroxypropyl cellulose,
silicon dioxide, silicified microcrystalline cellulose,
croscarmellose sodium and magnesium stearate.
[0164] In one embodiment the formulation comprises 60-80%
ibuprofen; 1.5-3.0% famotidine; 9-11% microcrystalline cellulose;
0.5-1.5% pregelatinized starch, 0.2-1% hydroxypropyl cellulose,
1-3% low substituted hydroxypropyl cellulose, 0.2-1% silicon
dioxide, 2-4% silicified microcrystalline cellulose; 0.5-2.5%
croscarmellose sodium, and 0.5-2.9% magnesium stearate.
[0165] In one embodiment the formulation comprises 76-78%
ibuprofen; 1.5-2.5% famotidine; 9-11% microcrystalline cellulose;
0.5-1.5% pregelatinized starch, 0.2-1% hydroxypropyl cellulose,
1-3% low substituted hydroxypropyl cellulose, 0.2-1% silicon
dioxide, 2-4% silicified microcrystalline cellulose; 0.5-2.5%
croscarmellose sodium, and 0.5-2.9% magnesium stearate.
[0166] In certain embodiments the microcrystalline cellulose is
comprised of a first population of particles having a median
particle size of about 50 microns (e.g., EMOCEL 50M) and a second
population of particles having a median particle size of
approximately 90 microns (e.g., EMOCEL 90M). In some embodiments,
50-micron particles are present in at least 10-fold excess, and
sometimes at least a 20-fold excess, over 90-micron particles.
[0167] In certain embodiments the silicified microcrystalline
cellulose (SMCC) is comprised of a first population of particles
having a median particle size of about 50 microns (e.g., PROSOLV 50
from Penwest) and a second population of particles having a median
particle size of approximately 90 microns (e.g., PROSOLV 90 from
Penwest). In one embodiment, the two populations are present in
approximately equal quantities. In experiments inclusion of SMCC
and low substituted hydroxypropylcellulose in the formulation
resulted in tablets with better compressibility.
[0168] In one embodiment the unit dose form has the following
composition:
TABLE-US-00001 Famotidine 1.5-2.5% Microcrystalline cellulose
(median 9-10% particle size 50 microns) Starch (pregelatinzed)
0.8-10% Hydroxypropyl cellulose 0.4-0.8% Ibuprofen 70-80% Colloidal
silicon dioxide 0.05-0.10% Microcrystalline cellulose (median
0.2-0.6% particle size 90 microns) Silicified microcystalline
cellulose 1-2% (median particle size 50 microns) Silicified
microcrystalline cellulose 1-2% (median particle size 90 microns)
Low substituted HPC 1-2% Croscarmellose sodium 1-3% Magnesium
stearate 2-2.9%
[0169] In one embodiment the unit dose form has the following
composition:
TABLE-US-00002 Famotidine 1.9% Microcrystalline cellulose (median
9.6% particle size 50 microns) Starch (pregelatinzed) 0.96%
Hydroxypropyl cellulose 0.58% Ibuprofen 76.9% Colloidal silicon
dioxide 0.08% Microcrystalline cellulose (median 0.42% particle
size 90 microns) Silicified microcystalline cellulose 1.73% (median
particle size 50 microns) Silicified microcrystalline cellulose
1.73% (median particle size 90 microns) Low substituted HPC 1.54%
Croscarmellose sodium 2.0% Magnesium stearate 2.5%
[0170] In one embodiment the unit dose form has the following
composition:
TABLE-US-00003 Famotidine 13.3 mg Microcrystalline cellulose
(median 50.7 mg particle size 50 microns) Pregelatinzed starch 5 mg
Hydroxypropyl cellulose 3 mg Ibuprofen 400.0 mg Colloidal silicon
dioxide 0.4 mg Microcrystalline cellulose (median 2.2 mg particle
size 90 microns) Silicified microcystalline cellulose 9.0 mg
(median particle size 50 microns) Silicified microcrystalline
cellulose 9.0 mg (median particle size 90 microns) Low substituted
HPC 8.0 mg Croscarmellose sodium 10.4 mg Magnesium stearate 13.0 mg
total 524.0 mg
[0171] In one embodiment the unit dose form has the following
composition:
TABLE-US-00004 Famotidine 2.5% Microcrystalline cellulose (e.g.,
Emcocel .RTM. 50 M) 9.7% Pregelatinzed starch (e.g., Starch 1500)
0.95% Hydroxypropyl cellulose (e.g., Klucel EXF) 0.57% Ibuprofen 90
76.3% Colloidal silicon dioxide 0.08% Microcrystalline cellulose
(e.g., Emcocel .RTM. 90M) 0.42% Silicified microcystalline
cellulose (e.g., ProSolv 1.72% SMCC .RTM. 50) Silicified
microcrystalline cellulose (e.g., ProSolv 1.72% SMCC .RTM. 90) Low
substituted HPC (e.g., LH-11) 1.53% Croscarmellose sodium 2.0%
Magnesium stearate 2.5%
[0172] It has been discovered that, under "forced degradation"
conditions, ibuprofen and famotidine in admixture are
pharmaceutically incompatible. This incompatibility has commercial
disadvantages in that tablet content may change over time. As shown
in Example 4, below, famotidine alone is stable when stored for 2
weeks at 60.degree. C., but is degraded when stored as a mixture
with ibuprofen for 2 weeks at 60.degree. C. or for 1 month at
40.degree. C. and 75% relative humidity. Similarly, famotidine
degradation is seen when a famotidine-ibuprofen admixture in the
form of a tablet is stored 1 month at 60.degree. C. Surprisingly,
however, the tablet form is stable at room temperature for at least
4 months. This suggests that contrary to the conclusion that would
be drawn from conventional stress testing, ibuprofen-famotidine
tablets according to the invention are stable for a prolonged
period under normal storage conditions.
[0173] 10.8 Exemplary Method of Manufacture of an Embodiment of
Oral Dosage Form I
[0174] It is within the ability of one of ordinary skill in the
art, guided by the present disclosure and with reference to the
pharmaceutical literature, to prepare and manufacture unit dosage
forms of the invention.
[0175] For example, for illustration and not for limitation, in one
approach an oral dosage form of Form 1 (above) uses wet
granulation. A dry mix containing ibuprofen, a binder or binders
(e.g., lactose monohydrate, hydroxy propyl methyl cellulose),
disintegrant (e.g., crosscarmellose sodium) and glidant (e.g.,
colloidal silicon dioxide) is prepared. An aqueous solution
containing a binder (e.g., hydroxy propyl methyl cellulose) is
blended with the dry mix. The resulting wet material is milled and
dried to form granules. The granules are blended with binder (e.g.,
silicified microcrystalline cellulose), disintegrant (e.g.,
crosscarmellose sodium), glidant (e.g., colloidal silicon dioxide)
and lubricant (e.g., magnesium stearate). The final blend is
compressed (e.g., using a DC 16 compression machine) to form the
cores.
[0176] A barrier coat of Opadry II (Colorcon) is applied by spray
coating according to the manufacturer's instructions. For example,
one part Opadry II concentrate is added to four parts (by weight)
distilled water with stirring to form a dispersion. The ibuprofen
core tablets are placed in a rotating pan in a chamber where the
temperature is maintained at 60-70.degree. C. in order to control
product temperature at 40-45.degree. C. The famotidine-containing
coating material is sprayed using a spray gun above the pan. (It
can be expected that approximately 75% of the famotidine will coat
the core, with about 25% lost during the coating process.) For
example, and not for limitation, an Accela-Cota 60 inch pan
equipped with four mixing baffles rotating at 5 rpm may be used.
The spray apparatus may be the Five Spraying Systems 1/4 JAU air
gun using 2850 fluid nozzles, 134255-45 aircaps and 60 psi
atomizing air. The delivery system may be a pressure pot. The
delivery rate may be 110 g/min/gun.
[0177] A famotidine layer can then be applied. A polymer containing
famotidine can be applied to the coated core by, for example, spray
coating or compression methods known in the art. In one approach,
famotidine is mixed with Opadry II (Colorcon) in an about 1:1 ratio
and applied generally as described above.
[0178] An overcoating layer can then be applied. In one embodiment,
after the famotidine layer is applied, the unit dose forms are
coated with Opadry II (Colorcon, Inc. West Point Pa.).
[0179] 10.9 Exemplary Method of Manufacture of an Embodiment of
Admixture Oral Dosage
[0180] A famotidine-ibuprofen tablet having suitable properties can
be made using a wet granulation process and includes as components
ibuprofen, famotidine, microcrystalline cellulose, silicified
microcrystalline cellulose, and croscarmellose sodium.
[0181] In a related aspect, the invention provides methods for
making ibuprofen/famotidine tablets with the above-described
content and properties. In general it is desirable that tablets for
oral administration have a high degree of uniformity as to weight
and content, have dissolution properties appropriate for the API(s)
being administered, and are chemically stable.
[0182] Methods for preparing tablets from a solid formulation are
well known in the art. Briefly, tablets are usually formed by
pressure applied to the material to be tabletted on a tablet press.
A tablet press includes a lower punch which fits into a die from
the bottom and an upper punch having a corresponding shape and
dimension, which enters the die cavity from the top after the
tabletting material fills the die cavity. The tablet is formed by
pressure applied on the lower and upper punches. To prepare a
tablet containing one or more active ingredients, the mixture to be
compressed into the dosage forms should have certain physical
characteristics for processing. Among other things, the mixture to
be compressed must be free-flowing, must be lubricated, and must
possess sufficient cohesiveness to ensure that the solid dosage
form remains intact after compression. The ability of the material
to flow freely into the die is important in order to provide for
uniform filling of the die and continuous movement of the material
from the source of the material, e.g. a feed hopper. The lubricity
of the material is important in the preparation of the solid dosage
forms in which the compressed material must be readily ejected from
the punch faces.
[0183] Thus, compressibility and uniformity are important
properties of a solid dosage formulation to be tabletted.
[0184] There are three general methods of preparation of materials
to be included in a solid dosage form prior to compression: (1)
direct compression; (2) dry granulation; and (3) wet granulation
(including high shear mixer granulation and fluidized bed
granulation).
[0185] In direct compression procedures, the materials to be
included in the solid dosage form are compressed directly, without
modifying the physical nature of the material itself. For solid
dosage forms wherein the drug itself constitutes a substantial
portion of the total weight of the solid dosage form, the use of
direct compression is limited to those situations where the drug
itself must exhibit physical characteristics, such as cohesiveness,
that make it a good candidate for direct compression with the rest
of the ingredients. Tablets containing famotidine as the sole
active ingredient can be manufactured by direct compression.
However, this approach is not ideal for manufacturing tablets
comprising ibuprofen and famotidine, primarily due to the poor
solubility and low cohesiveness of ibuprofen.
[0186] In dry granulation (also called "direct dry mixing")
procedures, the tablet components are mixed, followed by slugging,
dry screening, lubricating, and compression into tablets. Dry
granulation may be used where one of the constituents, either the
drug or the diluent, has sufficient cohesive properties to be
tabletted. Tablets made by this process exhibited poor content
uniformity for famotidine (84-87%) and a poor dissolution rate for
famotidine (92-95% famotidine released after 30 minutes in a
dissolution test).
[0187] Wet granulation procedures includes mixing the powders to be
incorporated into a solid dosage form in an appropriate blender
(such as a twin shell blender or double-code blender), and then
adding solutions of a binding agent to the mixed powders to
obtained a granulation. Thereafter, the damp mass is screened (e.g.
in a 6-, 8-, 15-, 25-mesh screen), and dried (e.g. by tray drying,
using a fluid-bed dryer, a spray dryer, microwave, vacuum, or
infra-red dryer). A wet granulation approach to preparing
ibuprofen/famotidine tablets is described in Examples 3-5 and was
shown to be superior. Wet granulation provided a pre-compression
material with better wetting properties, easing disintegration and
dissolution. In addition, the content uniformity of the tablets
prepared was improved.
[0188] In one aspect, the invention provides a method of making a
tablet comprising ibuprofen and famotidine by: [0189] a) preparing
famotidine granules by wet granulation of 10 parts famotidine, 50
parts microcrystalline cellulose, 5 parts pregelatinized starch and
3 parts hydroxylpropyl cellulose, using water as the liquid,
milling and screening the product; [0190] b) mixing 400 parts
ibuprofen and 0.4 parts colloidal silicon dioxide to produce
intermediate mixture I; [0191] c) mixing 2.2 parts microcrystalline
cellulose, 9 parts SMCC 50, 9 parts SMCC90, 8 parts low substituted
HPC, and 10.4 parts croscarmellose sodium to produce intermediate
mixture II; [0192] d) combining the intermediate mixture I and the
famotidine granules incrementally by combining a first portion of
intermediate mixture I with the famotidine granules and mixing,
adding a second portion of intermediate mixture I and mixing,
adding a third portion of intermediate mixture I and mixing, and
optionally combining additional portions, thereby producing
intermediate mixture III; [0193] e) combining intermediate mixture
II and intermediate mixture III to produce intermediate mixture IV;
[0194] f) adding 13 parts magnesium stearate to intermediate IV,
thereby producing a ibuprofen/famotidine solid formulation; and,
[0195] g) compressing the ibuprofen/famotidine solid formulation to
form tablets.
[0196] Using the methods described herein the solid pharmaceutical
compositions of the invention can be formed into tablets with at
least about 90%, at least about 95% or at least about 97% content
uniformity.
[0197] In one aspect, the invention provides a method of making a
tablet comprising ibuprofen and famotidine by: [0198] a) preparing
famotidine granules by wet granulating famotidine in the presence
of a binder and disintegrant and milling and screening the product;
[0199] b) mixing ibuprofen and a glident to produce an
ibuprofen/glident mixture (intermediate mixture I); [0200] c)
mixing microcrystalline cellulose, silicified microcrystalline
cellulose, low substituted HPC, and croscarmellose sodium
(intermediate mixture II); [0201] d) combining the famotidine
granules with intermediate mixture II to produce intermediate
mixture III; [0202] e) combining intermediate mixture I and
intermediate mixture III to produce intermediate mixture IV; [0203]
f) combining magnesium stearate to intermediate IV, thereby
producing a ibuprofen/famotidine solid formulation; and, [0204] g)
compressing the ibuprofen/famotidine solid formulation to form
tablets.
[0205] In one embodiment, the famotidine granules in (a) are
prepared by combining and blending famotidine, microcrystalline
cellulose, pregelatinized starch and hydroxypropyl cellulose,
adding water as the granulating liquid, drying the famotidine, and
milling and screening the product.
[0206] In one embodiment, the glident in step (b) is colloidal
silicon dioxide.
[0207] In one embodiment the invention provides a method of making
a tablet comprising ibuprofen and famotidine by: [0208] a)
preparing famotidine granules by wet granulation of 10 parts
famotidine, 50 parts microcrystalline cellulose, 5 parts
pregelatinized starch and 3 parts hydroxylpropyl cellulose, using
water as the liquid, milling and screening the product; [0209] b)
mixing 400 parts ibuprofen and 0.4 parts colloidal silicon dioxide
to produce intermediate mixture I; [0210] c) mixing 2.2 parts
microcrystalline cellulose, 9 parts SMCC 50, 9 parts SMCC90, 8
parts low substituted HPC, and 10.4 parts croscarmellose sodium to
produce intermediate mixture II; [0211] d) combining the
intermediate mixture I and the famotidine granules incrementally by
combining a first portion of intermediate mixture I with the
famotidine granules and mixing, adding a second portion of
intermediate mixture I and mixing, adding a third portion of
intermediate mixture I and mixing, and optionally combining
additional portions, thereby producing intermediate mixture III;
[0212] e) combining intermediate mixture II and intermediate
mixture III to produce intermediate mixture IV; [0213] f) adding 13
parts magnesium stearate to intermediate IV, thereby producing a
ibuprofen/famotidine solid formulation; and, [0214] g) compressing
the ibuprofen/famotidine solid formulation to form tablets.
[0215] Using the methods described herein the solid pharmaceutical
compositions of the invention can be formed into tablets with
content uniformity (n=10) as shown below.
TABLE-US-00005 Mean (% Claim) RSD Ibuprofen 102.3 2.6% Famotidine
101.4 1.9%
[0216] Dissolution results indicated at least 95% of ibuprofen or
famotidine released after 10 minutes (measured under neutral
dissolution conditions).
11.0 Packaging
[0217] In one aspect the invention provides a container, such as a
vial, containing ibuprofen/famotidine unit dose forms of the
invention, instructions to take the medication 3.times. daily are
affixed to the container, or packaged with the container. In one
embodiment the container contains a one-month supply of tablets (or
other oral dosage form). In one embodiment, for example, the number
of tablets in the container is from 89-94 tablets (e.g., 89, 90,
91, 92, 93 or 94 tablets). In one embodiment the number of tablets
in the container is about 100 (e.g. 100.+-.10). In a related aspect
the invention provides a container containing a two-month supply of
ibuprofen/famotidine tablets of the invention. The number of
tablets in the container may be about 200 (e.g., 200.+-.10) or may
be in the range 178-188 tablets.
[0218] In a related aspect, the invention provides a container as
described above, including instructions to take the medication
3.times. daily, except containing unit dose forms comprising
famotidine and a non-ibuprofen NSAID as described herein (with a
number of tablets as described above). In a related aspect, the
invention provides a container as described above, including
instructions to take the medication 3.times. daily, except
containing unit dose forms comprising famotidine without any NSAID
as described herein (with a number of tablets as described
above).
12.0 TID Administration of Famotidine
[0219] Famotidine may be used for treatment (short term and
maintenance) of duodenal ulcer, short term treatment of active
benign gastric ulcer, gastroesophageal reflux disease (GERD), short
term treatment of esophagitis due to GERD and has been administered
to treat dyspepsia. At present famotidine is usually administered
to BID or QD at a daily dose of 10, 20 or 40 mg. However, as
demonstrated in Example 1, TID administration of famotidine
provides better gastric protection than BID administration.
[0220] Thus, in an aspect, the invention provides a method for
treatment of a famotidine-responsive condition by administering
famotidine three times per day.
[0221] In one aspect, the invention provides a method for
administering famotidine three times per day to treat or prevent
NSAID-induced dyspepsia. While generally regarded as safe, a common
side effect of NSAID administration is the development of upper
gastrointestinal (GI) symptoms, such as dyspepsia. Among patients
taking NSAIDs regularly dyspepsia is reported weekly in up to about
30% of patients and up to about 15% daily (see, e.g., Larkai et
al., 1989, J. Clin. Gastroenterol. 11:158-62; Singh et al., 1996,
Arch. Intern. Med. 156:1530-6). Thus, in one aspect, the invention
provides a method of reducing symptoms of dyspepsia in a subject in
need of NSAID treatment who has experienced symptoms of dyspepsia
associated with NSAID administration, comprising administering to
the subject an effective amount of a NSAID in combination with an
effective amount of famotidine, wherein the famotidine is
administered three times per day. The two drugs can be administered
concurrently as separate formulations or combined as a single
dosage form. In one embodiment the NSAID is ibuprofen. In various
embodiments the subject requires treatment with the NSAID for at
least one week, at least two weeks, at least one month, or at least
three months.
13.0 Famotidine Unit Dose Forms Suitable for TID Administration
[0222] In an aspect of the invention, a unit dose form comprising
famotidine and excipients is provided, where famotidine is the sole
pharmaceutically active agent and the unit dose form contains
famotidine sufficient to deliver a total daily dose of about 80 mg
when administered on a TID schedule. In one version, for example,
the quantity of famotidine is about 26.6 mg (e.g., in the range 24
mg to 28 mg) which allows administration of about 80 mg/day with
TID administration of one tablet, or the quantity of famotidine is
about 13 mg (e.g., in the range 12 mg to 14 mg, e.g., 13.3 mg)
which allows administration of 80 mg/day with TID administration of
two tablets. Other ranges and amounts are those described
hereinabove for ibuprofen-famotidine unit dose forms.
[0223] In one embodiment famotidine is the only pharmaceutically
active agent in the unit dose forms. In one embodiment the unit
dose form does not contain an NSAID.
14.0 Famotidine-NSAID Dose Forms
[0224] In an aspect of the invention a unit dose form comprising
famotidine, excipients and an NSAID is provided, where the
famotidine content is sufficient to deliver a total daily dose of
70-85 mg, preferably 75-80 mg famotidine when administered
three-times per day. Suitable NSAIDs include, without limitation,
aspirin, diclofenac, meclofenamate, mefenamic acid, meloxicam,
nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam,
sulindac, tenoxicam, diflunisail, tiaprofenic acid, tolmetin,
etodolac, fenoprofen, floctafenine, flurbiprofen, indomethacin, and
ketoprofen, as well as ibuprofen. In one embodiment, the NSAID and
famotidine are in separate compartments of the unit dose, rather
than admixed. In one embodiment, the NSAID is formulated for
modified- or sustained release (e.g., so that the NSAID is released
over a period of about 8 hours).
15.0 Method of Treatment
[0225] In another aspect, the invention provides a method of
treating a patient in need of ibuprofen treatment, comprising
prescribing or administering the ibuprofen/famotidine unit dose
forms (e.g., tablets) of the invention. In one embodiment the
patient is instructed to ingest the drug tablets three times daily.
In one embodiment the patient is instructed to ensure there is at
least a 6-hr interval between administrations of consecutive
doses.
[0226] In one aspect the invention provides a method of treating a
patient in need of ibuprofen treatment, where the patient is at
elevated risk for developing an NSAID-induced ulcer. In one aspect
the invention provides a method of treating a patient in need of
ibuprofen treatment, where the patient is at high risk for
developing an NSAID-induced ulcer.
[0227] In one aspect the invention provides a method of reducing,
in a subject in need of ibuprofen treatment, the risk of developing
an ibuprofen-induced symptom or condition such as ulcer or GERD.
This method involves administering to the subject an effective
amount of a ibuprofen in combination with an effective amount of
famotidine, wherein the famotidine is administered three times per
day. In an embodiment, the ibuprofen and famotidine are
administered as a single unit dosage form.
[0228] In one aspect the invention provides a method of reducing
symptoms of a famotidine-responsive condition, such as dyspepsia,
in a subject in need of NSAID treatment who has experienced
symptoms of a famotidine-responsive condition, such as dyspepsia,
associated with NSAID administration, by administering to the
subject an effective amount of a NSAID in combination with an
effective amount of famotidine, wherein the famotidine is
administered three times per day. In an embodiment, the ibuprofen
and famotidine are administered as a single unit dosage form.
[0229] In one aspect the invention provides a method of reducing
symptoms of dyspepsia in a subject not taking an NSAID, by
administering to the subject an effective amount of famotidine,
wherein the famotidine is administered three times per day.
[0230] In a related aspect, the invention provides the use of
famotidine in combination with ibuprofen for the manufacture of a
medicament for treatment of an ibuprofen responsive condition,
wherein said medicament is adapted for oral administration in a
unit dosage form for administration three times per day. In a
preferred embodiment, the unit dosage form has an amount of
famotidine such that TID administration delivers about 80 mg
famotidine per day (e.g., about 13 mg or about 26.6 mg per unit
dose form). In a related aspect, the medicament has the form as
described herein.
17.0 Business Methods
[0231] Also provided is a business method comprising manufacturing,
marketing, using, distributing, selling, or licensing, the
ibuprofen-famotidine oral dosage forms of the invention. For
example, the invention provides a method of doing business
comprising (i) manufacturing ibuprofen/famotidine tablets of the
invention, or having said tablets manufactured, and (ii) selling
the ibuprofen/famotidine tablets to pharmacies or hospitals.
[0232] Also provided is a business method comprising manufacturing,
marketing, using, distributing, selling, or licensing, the
famotidine-only oral dosage forms of the invention. For example,
the invention provides a method of doing business comprising (i)
manufacturing famotidine tablets of the invention, or having said
tablets manufactured, and (ii) selling the famotidine tablets to
pharmacies or hospitals.
[0233] The invention also provides a method of doing business by
advertising or selling a solid oral unit dosage form of the
invention with instructions to take the dosage form on a TID
schedule. In one embodiment the oral dosage form contains
famotidine. In one embodiment the oral dosage form contains
famotidine and ibuprofen.
[0234] The invention also provides a method of doing business by
advertising or selling a solid oral unit dosage form of the
invention with instructions to take the dosage form on a TID
schedule.
18.0 Examples
18.1 Example 1
Administration of Famotidine TID Provides Superior Gastric
Protection Compared to Administration of Famotidine BID
[0235] Pharmocokinetic modeling shows that TID administration of
famotidine and ibuprofen according to the method of the present
invention provides protection superior to that achieved by
conventional cotherapy. FIG. 1A shows the predicted effect on
intragastric pH of administration of 26.6 mg famotidine TID. FIG.
1B shows the predicted effect on intragastric pH of administration
of 40 mg famotidine BID. Modeling shows that over a twenty-four
hour interval, intragastric pH is greater than 3.5 during for
several more hours per day than achieved using TID administration
of famotidine compared to conventional BID dosing. In FIG. 1,
administration of 80 mg/day famotidine using TID dosing is shown to
maintain pH greater than 3.5 for about 21 hours per twenty-four
hour interval, while the same daily dose administered BID dosing
maintains pH greater than 3.5 for about 17 hours per twenty-four
hour interval. The precise duration of pH elevation can be
confirmed in clinical trials and may deviate somewhat from the
predicted values (with the TID dosing remaining more effective than
the BID dosing).
[0236] Methodology: Mean plasma concentration versus time data from
a single dose bio equivalence study (world wide web at
fda.gov/cder/foi/and a/2001/75-311_Famotidine_Bioeqr.pdf, n=30)
comparing 40 mg Pepcid and generic famotidine (Teva Pharm) were
best fitted to a one compartment oral absorption model with a lag
time using a nonlinear least-squares regression program, WinNonlin
(Pharsight.RTM.). The following pharmacokinetic parameters for
Pepcid were obtained:
TABLE-US-00006 Parameter Units Estimate V/F L 241.8 k.sub.a
h.sup.-1 0.8133 k.sub.el h.sup.-1 0.2643 T.sub.lag h 0.3677
where V/F is the apparent volume of distribution, k.sub.a is the
absorption rate constant, k.sub.el is the elimination rate constant
and T.sub.lag is the absorption lag time.
[0237] The relationship between plasma concentrations of Pepcid and
intragastric pH in one patient were digitized from FIG. 4 of
Echizen and Ishizaki, supra, page 189. The digitized plasma
concentration vs. intragastric pH were fitted using a nonlinear
least-squares regression program, WinNonlin to a sigmoid Emax model
using the following equation:
E = E 0 + E max * C .gamma. E C 50 .gamma. * C .gamma.
##EQU00001##
where E is the intragastric pH at C, E.sub.o is the intragastric pH
at time zero, E.sub.max is the maximum intragastric pH, EC.sub.50
is the Pepcid concentration at one-half of Emax, C is the plasma
concentration of Pepcid and .gamma. is the shape factor. The
estimated pharmacodynamic parameters are listed below:
TABLE-US-00007 Parameter Units Estimate E.sub.max -- 7.80 EC.sub.50
ng/mL 32.6 E.sub.0 -- 1.88 .gamma. -- 4.80
[0238] Using the pharmacokinetic parameters obtained above together
with the pharmacodynamic parameters above, plasma concentrations as
well as intragastric pH as a function of time were simulated for
various dose regimens.
18.2 Example 2
Administration of Famotidine TID Provides Superior Gastric
Protection Compared to Administration of Famotidine BID
[0239] A randomized, open-label, two-period, crossover study was
carried out to compare the effects on gastric pH of administration
of 80 mg per day of famotidine when administered for five
consecutive days in two versus three divided doses each day.
A. Study Subjects
[0240] Thirteen healthy subjects participated in the study. The
subjects' demographic parameters are provided in Tables 1 and
2.
TABLE-US-00008 TABLE 1 Baseline Demographic Information 9 Male 4
Female Mean Age: 27.2 years Range 19-42 Mean Body Mass Index*: 22.8
Range 19-27 *Body mass index (BMI) is calculated as weight
(kg)/[height (m)].sup.2
[0241] The normal range for BMI varies, however, 20-25 can be
considered the normal range. Nine subjects had a BMI in the normal
range ("Normal Weight group"), and four subjects (ID#107, 111, 112
and 113) had a BMI outside of the normal range (Table 2).
TABLE-US-00009 TABLE 2 Baseline Demographic Information Subject #
Age Gender Body Mass Index 102 22 Female 21 103 39 Male 22 104 27
Female 23 105 22 Female 22 106 23 Male 25 107 26 Male 19 108 42
Male 24 109 26 Male 23 110 29 Male 27 111 28 Female 19 112 19 Male
26 113 24 Male 22 201 27 Male 24
B. Study Protocol
[0242] Subjects were assigned randomly, in approximately a 1:1
ratio, to one of two, two-period treatment sequences as follows:
[0243] Treatment Sequence 1: 40 mg famotidine BID.times.5 days,
followed by 26.6 mg famotidine TID.times.5 days. [0244] Treatment
Sequence 2: 26.6 mg famotidine TID.times.5 days, followed by 40 mg
famotidine BID.times.5 days.
[0245] There was a washout of at least one week between
administration of the last dose of Treatment Period 1 and
administration of the first dose of Treatment Period 2.
[0246] PEPCID.RTM. (famotidine) for Oral Suspension (Merck &
Co., Inc., 40 mg/5 mL) was administered with water. During
treatment periods in which famotidine was administered TID,
medication was administered at approximately 0800, 1600, and 2400
on each day of dosing. During treatment periods in which famotidine
is to be administered BID, medication is administered at
approximately 0800 and 2000 on each day of dosing.
[0247] All doses of study medication were administered orally, on
an open-label basis. Subjects were prohibited from taking any
medications or interventions that decrease gastric acid secretion
or neutralize gastric acid, and any medications that are known or
suspected to cause dyspepsia or gastrointestinal ulcers, throughout
the study period.
[0248] Subjects were screened within 20 days prior to study entry
and remained at the study center beginning at approximately 1500 h
on Study Day 0 and continuing until approximately 1000 h on Study
Day 6 of both treatment periods. (The first day of dosing for each
treatment period is designated Study Day 1, and the last day of
dosing is designated Study Day 2). Subjects were followed for 14
days after administration of their last dose of study
medication.
[0249] Gastric pH was measured continuously, using a nasogastric pH
probe, during the 24 hours following administration of the first
dose of study medication on Study Day 1, and during the 24 hours
following administration of the first dose of study medication on
Study Day 5, during both treatment periods. Blood samples were
collected prior to initiation of dosing, and prior to
administration of the second dose of study medication on Study Day
1 and Study Day 5 during both treatment periods for determination
of trough plasma famotidine concentrations. For each patient the
median pH during a 24 hour period (or subperiod thereof) was
calculated. To measure the effect of treatments for a group of
individuals, the average or mean of the measured medians for
several individuals was determined (i.e., average={[M.sub.1+M.sub.2
. . . M.sub.x]/X} where "x" is the number of individuals in the
group and each "M" is the median for an individual in the
group).
C. Results
[0250] Based on pH measurements made during the 24 hours following
administration of the first dose of study medication on Study Day 1
during both treatment periods, TID dosing resulted in a higher
gastric pH and less time of exposure to acidic conditions than BID
dosing (measured as an average of measurements for all subjects or
for subjects of normal weight). This result is consistent with the
modeling in Example 1 showing that TID dosing provides better
gastric protection. In addition, it was discovered that,
surprisingly, there was significantly less patient-to-patient
variation in response to treatment under the TID dosing regimen
compared to the BID regimen.
[0251] i) Median Gastric pH
[0252] The median gastric pH over 24 hours (starting with the first
administration of study drug) was measured. Table 3 shows the mean
of 24 hour pH values for all subjects and compares the BID dosing
regimen to the TID dosing regimen. The mean of the 24 hour value
(medians) for all subjects for the BID dosing was 3.3 pH units
compared to 3.6 units for the TID dosing. The 0.3 pH unit
difference represents a 300% difference in activity of hydrogen
ions.
TABLE-US-00010 TABLE 3 24 Hour pH Values BID TID Number 13 13 Mean
3.3 3.6 SD 1.1 0.7 Avr. Dev. 0.9 0.6 Range 1.8-5.1 2.5-4.4 Max-Min
3.3 1.9
[0253] For the subset of subjects with a BMI in the normal range
("normal weight subjects") the difference between BID and TID was
more pronounced, with a mean pH of 3.1 during the BID period and
3.6 during the TID period (Table 4). The 0.5 pH unit difference
represents a 500% difference in activity of hydrogen ions.
TABLE-US-00011 TABLE 4 24 Hour pH Values for Normal Weight Subjects
BID TID Number 9 9 Mean 3.1 3.6 SD 1.1 0.7 Avr. Dev 0.9 0.5 Range
1.8-4.0 2.5-4.4 Max-Min 2.2 1.9
[0254] During the 24 hour pH measurement periods, pH values were
recorded during a variety of conditions such as sitting upright,
lying asleep, during meals and just after a meal. Each of these
conditions affects the gastric pH in different manner.
Specifically, measurements taken while upright tend to be more
consistent due to the position of the pH probe while values taken
during meals are altered due to the acidity of the food.
[0255] Table 5 presents the pH values taken while the subjects were
in the upright position, the most reliable measure of gastric pH.
As shown, the gastric pH during this period was 0.5 units higher
for the TID dosing period compared to the BID dosing period. For
the subset of normal weight subjects, the difference in pH during
the upright period was 0.8 units (Table 6) with the TID dosing
period having a higher mean pH than the BID dosing period.
TABLE-US-00012 TABLE 5 pH Values Taken in the Upright Position BID
TID Number 13 13 Mean 3.2 3.7 SD 1.2 0.8 Avr. Dev. 1.0 0.7 Range
1.8-5.1 2.3-4.7 Max-Min 3.3 2.4
TABLE-US-00013 TABLE 6 Upright pH Values for the Normal Weight
Subjects BID TID Mean 3.0 3.8 SD 1.0 0.9 Avr. Dev. 0.8 0.6 Range
1.8-4.6 2.3-4.7 Max-Min 2.8 2.4
Summary
[0256] Mean gastric pH was higher during the first 24 hours of drug
dosing during the TID arm than during the BID arm of the study.
TABLE-US-00014 TABLE 7 Amount By Which TID Dosing Provided Superior
Gastric Protection Compared To BID Dosing (Mean of Group; Expressed
as pH Units) Parameter measured All Subjects Normal Weight Group
Gastric pH (24 h) 0.3 0.5 Upright Gastric pH 0.5 0.8
TABLE-US-00015 TABLE 8 Famotidine Effect on Gastric pH by Subject
and Period Subject Drug type Median pH Median pH No. Period given
(24 hour) (Upright) 102 1 TID 26.6 mg 3.8 3.8 2 BID 40 mg 4.0 4.0
103 1 BID 40 mg 2.6 2.6 2 TID 26.6 mg 2.9 2.9 104 1 TID 26.6 mg 3.6
3.6 2 BID 40 mg 4.8 4.8 105 1 TID 26.6 mg 2.5 2.5 2 BID 40 mg 2.0
2.0 106 1 TID 26.6 mg 3.9 3.9 2 BID 40 mg 1.8 1.8 107 1 BID 40 mg
4.4 4.4 2 TID 26.6 mg 3.1 3.1 108 1 BID 40 mg 3.8 3.8 2 TID 26.6 mg
4.4 4.4 109 1 TID 26.6 mg 4.0 4.0 2 BID 40 mg 3.6 3.6 110 1 TID
26.6 mg 2.5 3.0 2 BID 40 mg 2.1 2.1 111 1 BID 40 mg 5.1 5.1 2 TID
26.6 mg 4.5 4.5 112 1 BID 40 mg 4.2 4.2 2 TID 26.6 mg 3.1 3.1 113 1
TID 26.6 mg 4.4 4.4 2 BID 40 mg 3.8 3.8 201 1 BID 40 mg 3.6 3.6 2
TID 26.6 mg 4.5 4.5
[0257] ii) Exposure to Gastric pH Below 3.5
[0258] Another important measure of benefit is the duration of time
a subject spends during the 24 hour period with a gastric pH below
certain critical values. The time spent below these values
represents time during which the subject is at risk for
complications such as gastric ulcers caused by gastric acid. The pH
values that have been examined for this analysis are pH <3.5
(this section) and pH <4.0 (Section iii, below).
[0259] Tables 9-11 show the effect of dosing on the time gastric pH
is below 3.5. Gastric pH was below 3.5 for 19.5 minutes less (on
average) during the TID period compared to the BID dosing period
(Table 9). For normal weight subjects gastric pH was below 3.5 for
89.3 minutes less during the TID period compared to the BID dosing
period (Table 10).
TABLE-US-00016 TABLE 9 Time Below pH 3.5 BID TID Number 13 13
Average 713.0 693.5 SD 211.7 152.2 Avr. Dev. 169.1 124.7 Range
459-1165 514-950 Max-Min 706 436
TABLE-US-00017 TABLE 10 Time Below pH 3.5 (Normal Weight Subjects)
BID TID Average 752.0 662.7 SD 217.8 155.6 Avr. Dev. 175.1 116.7
Range 486-1165 514-950 Max-Min 679 436
TABLE-US-00018 TABLE 11 Total and Fraction Time pH < 3.5, by
Subject and Period Subject Drug type Time pH < 3.5 Fraction time
No. Period given (min) pH < 3.5 (%) 102 1 TID 26.6 mg 681 47.3 2
BID 40 mg 654 45.4 103 1 BID 40 mg 914 63.5 2 TID 26.6 mg 845 58.7
104 1 TID 26.6 mg 700 48.7 2 BID 40 mg 486 33.8 105 1 TID 26.6 mg
950 66 2 BID 40 mg 1165 80.9 106 1 TID 26.6 mg 654 45.4 2 BID 40 mg
965 67 107 1 BID 40 mg 560 38.9 2 TID 26.6 mg 789 54.8 108 1 BID 40
mg 565 39.2 2 TID 26.6 mg 463 32.1 109 1 TID 26.6 mg 578 40.1 2 BID
40 mg 687 47.7 110 1 TID 26.6 mg 904 62.9 2 BID 40 mg 907 63 111 1
BID 40 mg 459 31.9 2 TID 26.6 mg 575 40 112 1 BID 40 mg 575 39.9 2
TID 26.6 mg 784 54.4 113 1 TID 26.6 mg 514 35.7 2 BID 40 mg 628
43.6 201 1 BID 40 mg 704 49.3 2 TID 26.6 mg 579 40.2
[0260] iii) Exposure to Gastric pH Below 4.0
[0261] Tables 12-14 show the effect of dosing on the time gastric
pH is below 4.0. Gastric pH was below 4.0 for 23.1 minutes less (on
average) during the TID period compared to the BID dosing period
(Table 12). For subjects in the normal weight group gastric pH was
below 4.0 for 89.9 minutes less during the TID period compared to
the BID dosing period (Table 13).
TABLE-US-00019 TABLE 12 Time Below pH 4.0 TIME (Minutes) pH < 4
BID TID Number 13 13 Average 806.5 783.4 SD 204.0 138.4 Avr. Dev.
158.8 111.9 Range 514-1224 589-1048 Max-Min 710 459
TABLE-US-00020 TABLE 13 Time Below pH 4.0 (Normal Weight Subjects)
TIME (Minutes) pH < 4 BID TID Average 854.1 764.2 SD 202.1 145.2
Avr. Dev. 155.7 105.4 Range 714-1224 589-1048 Max-Min 510 459
TABLE-US-00021 TABLE 14 Total and Fraction Time pH < 4.0, by
Subject and Period Time pH < 4 Fraction time Subject No. Period
Famotidine (min) pH < 4 (%) 102 1 TID 26.6 mg 767 53.2 2 BID 40
mg 714 49.6 103 1 BID 40 mg 1034 71.8 2 TID 26.6 mg 934 64.9 104 1
TID 26.6 mg 782 54.3 2 BID 40 mg 547 38.0 105 1 TID 26.6 mg 1048
72.8 2 BID 40 mg 1224 85.0 106 1 TID 26.6 mg 737 51.2 2 BID 40 mg
1005 69.8 107 1 BID 40 mg 640 44.4 2 TID 26.6 mg 855 59.4 108 1 BID
40 mg 841 58.4 2 TID 26.6 mg 589 40.9 109 1 TID 26.6 mg 718 50.0 2
BID 40 mg 803 55.8 110 1 TID 26.6 mg 962 66.0 2 BID 40 mg 961 66.7
111 1 BID 40 mg 514 35.7 2 TID 26.6 mg 644 44.7 112 1 BID 40 mg 683
47.4 2 TID 26.6 mg 857 59.5 113 1 TID 26.6 mg 658 45.7 2 BID 40 mg
763 53.0 201 1 BID 40 mg 756 52.5 2 TID 26.6 mg 645 44.8
TABLE-US-00022 TABLE 15 Summary Mean reduction in time with gastric
pH below critical value in subjects receiving drug TID compared to
subjects receivng drug BID Parameter measured All Subjects Normal
Weight Group time < pH 3.5 19.5 min 89.3 min time < pH 4.0
23.1 min 89.9 min
[0262] iv) Less Patient-to-Patient Variability
[0263] The data provided above demonstrate that when famotidine was
administered TID, less subject-to-subject variation in gastric pH
was observed than when famotidine was administered BID. As shown in
Table 16 (compiled from Tables 3-15) the subject-to-subject
variability is considerably less for TID dosing compared to BID
dosing, as measured by standard deviation, average absolute
deviation and range. For example, the range of 24 hour pH values
for BID dosing was 1.8 to 5.1, or 3.3 pH units, between the minimum
value and the maximum value. By comparison, the range was 2.5 to
4.4, or a 1.9 pH units, for TID dosing.
[0264] Decreased variability has important clinical implications.
By extrapolation from these data, when famotidine (or famotidine
and ibuprofen) is administered to a large population of patients,
fewer patients will experience gastric pH levels markedly different
from the group average. Thus, any individual patient treated with
ibuprofen/famotidine according to the present invention is less
likely to experience the detrimental effects of low gastric pH that
would be the case with BID dosing of famotidine. That is, the
incidence of side effects in a population treated according to the
present invention can be expected to be lower than in an equivalent
population receiving BID dosing.
TABLE-US-00023 TABLE 16 Reduced Subject-to-Subject Variability BID
TID pH Range (max-min) 3.3 pH units 1.9 pH units Average Absolute
Deviation 0.9 0.5 Standard Deviation 1.1 0.7 pH Range (max-min),
normal weight subjects 2.2 pH units 1.9 pH units Average Absolute
Deviation 0.9 0.5 Standard Deviation 1.1 0.7 pH Range (max-min) in
upright position 3.3 pH units 2.4 pH units Average Absolute
Deviation 1.0 0.7 Standard Deviation 1.2 0.8 pH Range (max-min) in
Upright position, normal weight subjects 2.8 pH units 2.4 pH units
Average Absolute Deviation 1.0 0.9 Standard Deviation 0.8 0.6 Time
below pH 3.5 range (min-max) 706 min 436 min Average Absolute
Deviation 169.1 124.7 Standard Deviation 211.7 152.2 Time below pH
3.5 range (min-max), normal weight subjects 679 min 436 min Average
Absolute Deviation 175.1 116.7 Standard Deviation 217.8 155.6 Time
below pH 4.0 range (min-max) 710 min 459 min Average Absolute
Deviation 158.8 111.9 Standard Deviation 204.0 138.4 Time below pH
4.0 range (min-max), normal weight subjects 510 min 459 min Average
Absolute Deviation 155.7 105.4 Standard Deviation 202.1 145.2
[0265] v) Patient 106
[0266] As discussed above, for most of the subjects studied, TID
dosing provided an increase in gastric protection, and this
protection was accompanied by less patient-to-patient variability
in response. Notably, the 24-hour median gastric pH was below 2.5
for three patients in the BID period, but for no patients in the
TID period.
[0267] Response in individual patients varied, as is expected for
administration of any drug regimen. The data in Table 17 illustrate
that very significant differences in gastric protection may be seen
in some patients.
TABLE-US-00024 TABLE 17 Subject 106 Summary Parameter BID period
TID period Difference Median pH 1.8 3.9 2.1 pH Units Median pH
(Upright) 1.8 4.0 2.2 pH Units Time pH < 4 1005 min 737 min 268
min (% of 24-hour period) (69.8%) (51.2%)
[0268] vi) Summary
[0269] It will be appreciated from this disclosure (see Examples
1-3) that administration of famotadine and ibuprofen according to
the present invention results in one or more advantages over
conventional administration:
[0270] 1. Superior gastric protection when administered to a
population of individuals (i.e., patients in need of ibuprofen
treatment or famotidine treatment) especially populations of normal
weight individuals.
[0271] 2. Reduced interpatient variability when administered to a
population of individuals resulting in a reduction in side-effects
and improved safety.
[0272] 3. High magnitude individual benefit in a subset of patients
for whom gastric pH is substantially elevated using the methods of
the invention when compared to BID dosing.
18.3 Example 3
Pharmacokinetic Drug-Drug Interaction Study of Ibuprofen and
Famotidine in Healthy Male Subjects
[0273] This example demonstrates that pharmocokinetic parameters of
concurrent administration of ibuprofen and famotidine (as in the
unit dose forms of the invention) are bioequivalent to separate
administration of the two APIs. An open-label, randomized,
single-dose, oral administration, two-period crossover study was
conducted. Six male subjects were assigned randomly to Sequence 1
or Sequence 2:
[0274] Sequence 1 [0275] Period 1: 800 mg ibuprofen [Motrin.RTM.],
followed 24 hr later by 40 mg famotidine [Pepcid.RTM.]. [0276]
Period 2: Concurrent administration of 800 mg ibuprofen and 40 mg
famotidine.
[0277] Sequence 2 [0278] Period 1: Concurrent administration of 800
mg ibuprofen and 40 mg famotidine. [0279] Period 2: 800 mg of
ibuprofen, followed 24 hr later by 40 mg famotidine.
[0280] Following administration of ibuprofen and famotidine plasma
ibuprofen and/or famotidine concentrations were determined in
samples collected predose and at 0.25, 0.5, 1.0, 1.5, 2, 4, 6, 8,
10, 12, 14, 18, and 24 hr after administration of ibuprofen and/or
famotidine. Ibuprofen and famotidine plasma concentrations, and
computed pharmacokinetic parameters, were listed and summarized by
dose (mean, standard deviation, 95% confidence interval, minimum,
maximum). Individual and mean (by time) concentration-versus-time
curves for each treatment, plotted on a semi-log scale, were
examined. Intra-subject comparisons were made between Period 1 and
Period 2.
[0281] WinNonLin version 2.1 was used to analyze the
pharmacokinetic parameters from the concentration-versus-time data
based a non-compartmental model. The pharmacokinetic values then
were transferred to MS Excel or Graphpad Prism for calculation of
means, SDs, confidence intervals, etc., for preparation of tables
and figures, and for performance of statistical testing.
[0282] Analyses of variance appropriate for a two-period crossover
design were performed on the computed parameters including terms
for sequence, subject within sequence, formulation, and period.
Analyses were performed on the observed data and on natural
logarithm-transformed data for area under the
concentration-versus-time curve (AUC) and maximum observed plasma
concentration (C.sub.max). Ninety-five (95) % confidence intervals
were computed for the differences in treatment means.
[0283] After confirming the absence of a period effect for the
pharmacokinetic parameters, individual AUC and C.sub.max data were
pooled for each treatment (i.e., for both ibuprofen and famotidine
administered alone and in combination) for bioequivalence testing.
The individual data then were log-transformed (natural log) and the
differences for each drug between administration alone versus in
combination were determined for each subject. The means and 95%
confidence intervals of these log-transformed differences were
calculated, and the upper and lower bound of the log-transformed
range were normalized and then tested for bioequivalence. These
intervals were evaluated in relation to the criterion equivalence
interval of 80% to 125% for log-transformed data. Tables 18-20 show
the results of the analyses:
TABLE-US-00025 TABLE 18 Pharmacokinetic Parameters (mean .+-. SD,
95% CI) for Ibuprofen and Famotidine When Administered Alone and In
Combination Ibuprofen Famotidine Parameter Alone With Famotidine
Alone With Ibuprofen t.sub.max (hr) (95% CI) 1.58 .+-. 0.49 2.25
.+-. 1.89 1.67 .+-. 0.52 2.17 .+-. 0.93 (1.07-2.10) (0.27-4.23)
(1.13-2.21) (1.19-3.14) C.sub.max (ng/mL) 56,279 .+-. 8,486 55,666
.+-. 12,106 143 .+-. 31 159 .+-. 50 (95% CI) (47,374-65,184)
(42,961-68,370) (111-175) (107-211) t.sub.1/2 (hr) (95% CI) 2.50
.+-. 0.55 2.56 .+-. 0.59 3.66 .+-. 0.19 3.49 .+-. 0.35 (1.92-3.07)
(1.95-3.18) (3.46-3.86) (3.12-3.85) K.sub.el (95% CI) 0.29 .+-.
0.06 0.28 .+-. 0.06 0.19 .+-. 0.01 0.20 .+-. 0.02 (0.23-0.35)
(0.22-0.34) (0.18-0.20) (0.18-0.22) AUC.sub.(last) 236,992 .+-.
62,862 234,851 .+-. 67,655 883 .+-. 173 934 .+-. 275 (ng/mL hr)
(95% CI) (171,023-302,961) (163,851-305,850) (701-1064) (646-1222)
AUC 245,124 .+-. 63,697 235,156 .+-. 67,749 893 .+-. 175 944 .+-.
279 (ng/mL hr) (95% CI) (178,279-311,970) (164,058-306,254)
(710-1077) (651-1236)
TABLE-US-00026 TABLE 19 Bioequivalence Test Results for AUC
(log-transformed values) for Ibuprofen and Famotidine When
Administered Alone Versus In Combination AUC(.sub.last)
AUC.sub.(last) In Drug Alone Combination Difference 95% CI
Ibuprofen 12.35 12.33 0.02 0.94-1.11 Famotidine 6.765 6.799 -0.034
0.79-1.19 .sup.1 Test criterion: CI within 0.8-1.25
TABLE-US-00027 TABLE 20 Bioequivalence Test Results for C.sub.max
(log-transformed values) for Ibuprofen and Famotidine When
Administered Alone Versus In Combination C.sub.max C.sub.max In
Drug Alone Combination Difference 95% CI Ibuprofen 10.93 10.91 0.02
0.85-1.23 Famotidine 4.94 5.02 -0.08 0.76-1.12 .sup.1Test
criterion: CI within 0.8-1.25
[0284] There were no significant differences between the treatment
means for the pharmacokinetic parameters for either ibuprofen or
famotidine when administered alone versus in combination. It was
concluded that both ibuprofen and famotidine can be considered
bioequivalent when administered in combination compared to separate
administration.
18.4 Example 4
Trough Concentrations of Famotidine
[0285] Trough concentrations of famotidine were determined in blood
samples from the subjects of the study described in Example 2.
Samples were collected prior to initiation of dosing, and prior to
administration of the second dose of study medication on Study Day
1 and Study Day 5 during both treatment periods. The results are
presented in Table 21 below.
TABLE-US-00028 TABLE 21 Trough Plasma Concentration of Famotidine
Plasma Concentration of Famotidine (ng/mL) 40 mg BID 26.6 mg TID
Day 1 Day 5 Day 1 Day 5 Mean 10.5 15.7 9.7 15.7 SD 2.8 4.6 4.9
8.9
[0286] If more frequent dosing of famotidine led to plasma
accumulation, the day 5 trough data for TID dosing would be
significantly higher than the trough values for day 5 with BID
dosing. As can be seen, the trough plasma values for the two dosing
regimen were the same (15.7 ng/mL). It can be concluded from this
that TID dosing does not lead to plasma accumulation of
famotidine.
18.5 Example 5
Ibuprofen-Famotidine Compatibility Studies
[0287] As shown in Table 22, substantial degradation of famotidine
was observed in the famotidine-ibuprofen mixture (1:29 ratio) under
stress conditions in the presence of ibuprofen. In the absence of
ibuprofen, famotidine is stable.
TABLE-US-00029 TABLE 22 Famotidine/Ibuprofen Stability Under Stress
Conditions Famotidine API Storage condition Content* Famotidine 2
weeks at 60.degree. C. 98% Famotidine + Ibuprofen 2 weeks at
60.degree. C. 81% Famotidine + Ibuprofen 1 mo at 40.degree. C./75%
RH 54% *Famotidine content was determined by analytical HPLC and
expressed as percent of target content.
[0288] Similarly, as shown in Table 23 substantial degradation of
famotidine was observed in the tablet dosage form containing
ibuprofen in a tablet formulation under stress conditions. The
tablets contained 10 mg famotidine, 800 mg ibuprofen and the
following excipients: pregelatinized starch (Starch 1500);
hydroxypropyl cellulose; colloidal silicon dioxide;
microcrystalline cellulose (Emcocel.RTM. 50M and 90M); SMCC
(ProSolv.RTM. 50); SMCC (ProSolv.RTM. 90); low substituted HPC
(LH-11); croscarmellose; sodium; and magnesium stearate. The
tablets were prepared as described in Example 8-5 of U.S. Patent
App. Pub. No. 2007-0043096 A1, which is incorporated by
reference.
TABLE-US-00030 TABLE 23 Stability of Famotidine in Tablet Under
Stress Conditions Storage Famotidine Drugs in Tablet Formulation
Condition Content* Famotidine (13.3 mg) + Ibuprofen (400 mg)
Initial 100% Famotidine (13.3 mg) + Ibuprofen (400 mg) 1 week at
60.degree. C. 39% Famotidine (13.3 mg) + Ibuprofen (400 mg) 1 month
at 83% 40.degree. C./75% RH Famotidine (13.3 mg) + Ibuprofen (400
mg) 2 months at 55% 40.degree. C./75% RH Famotidine (13.3 mg) +
Ibuprofen (400 mg) 3 months at 32% 40.degree. C./75% RH *Famotidine
content was determined by analytical HPLC and expressed as percent
of target content.
TABLE-US-00031 TABLE 24A Stability of Famotidine in Tablet (400 mg
Ibuprofen, 10 mg Famotidine) Under Stress Conditions Amt. of Stage
Conditions Ibuprofen Amt. of famotidine 1 month at 25.degree.
C./60% RH 100.3 98.8 8 months at ambient temp. 101.4 97.3 1 week at
60.degree. C. 93.0 60.2 1 month at 60.degree. C. 99.1 4.1 "Amt. of
ibuprofen/famotidine" refers to the amount of drug remaining at the
end of the storage period (as % of original content). Drug content
was determined by analytical HPLC.
[0289] In other studies, approximately 0.5 g famotidine API was
mixed with 14.5 g ibuprofen. After grinding, API mixture was stored
in glass vials under the conditions indicated. As shown in Table
24B, substantial degradation of famotidine was observed.
TABLE-US-00032 TABLE 24B Famotidine/Ibuprofen Stability Under
Stress Conditions API Ibuprofen (% control) Famotidine (% control)
Mixture 1 wk 40.degree. C. 1 wk 60.degree. C. 2 wks 60.degree. C. 1
wk 40.degree. C. 1 wk 60.degree. C. 2 wks 60.degree. C. Famotidine
96.1 121.0 100.1 Famotidine-Ibuprofen 104.7 99.9 96.4 94.4 85.7
46.0
18.6 Example 6
Determination of Dissolution
[0290] One method for determination of the rate and extent of
dissolution can be carried out using the methods described in the
United States Pharmacopeia and National Formulary 29th Revision,
under the following conditions: [0291] Dissolution Apparatus:
Apparatus II (Paddles) [0292] Dissolution Medium: 50.0 mM Potassium
Phosphate Buffer, pH 7.2 [0293] Dissolution Medium Volume: 900 mL
[0294] Temperature in Vessel: 37.0.degree. C..+-.0.5.degree. C.
[0295] Speed: 50 RPM [0296] Sampling Time: 10 min 20 min., 30 min.,
45 min 60 min and infinity @ 250 rpm for 15 min [0297] Sampling
Volume: 1 mL [0298] Sinker: None
[0299] When desired, the dissolution medium or other parameters may
be varied. Typically a unit dose form is added to the vessel and
dissolution is started. At specified times a portion (e.g., 2 ml)
of medium is withdrawn and the amount of API in solution is
determined using routine analytical methods (e.g., HPLC).
[0300] The assay above was used to determine the dissolution
characteristics of a unit dose form prepared as described in
Example 9 (following storage for 1 month 25.degree. C./60% RH) with
the result shown in Table 25.
TABLE-US-00033 TABLE 25 % Released Time (min) Ibuprofen Famotidine
5 43.7 28.9 10 94.9 77.7 15 97.6 90.0 30 98.4 99.8 45 98.5 102.2 60
98.6 103.1 75 99.2 104.1
18.7 Example 7
Manufacture of Ibuprofen/Famotidine Unit Dose Forms
[0301] This example describes how to make a particular
ibuprofen/famotidine unit dose form.
A. Producing the Ibuprofen Core
TABLE-US-00034 [0302] TABLE 26 % mg/ Item Material w/w tablet
Function/Supplier 1. Ibuprofen USP 64.00 800 API/BASF 2. Lactose
Monohydrate NF 24.00 300 Binder/Kerry (80M) Biosci. 3. Colloidal
Silicon Dioxide NF 0.48 6 Glidant/Cabot (Cab-O-Sil M5P) 4.
Croscarmellose Sodium NF 2.40 30 Disintegrant/FMC Ac-di-Sol 5A.
Hypromellose USP, Methocel 1.44 18 Binder/Dow E-5 LV Premium
(Intragranular in dry mix) 5B Hypromellose USP, Methocel 0.48 6
Binder/Dow E-5 LV Premium (Intragranular as solution) 6. Purified
Water USP -- q.s. 7. Prosolv SMCC 90 (silicified 3.76 47 Binder/JRS
microcrystalline cellulose) 8. Croscarmellose Sodium NF 2.40 30
Disintegrant/FMC (Ac-di-Sol) 9. Colloidal Silicon Dioxide NF 0.32
4.0 Glidant/Cabot (Cab-O-Sil M5P) 10. Magnesium Stearate NF 0.72
9.0 Lubricant/Peter Greven Core tablet weight 100.0 1250
[0303] Items 1-5A are sifted through Quadro Comil 16-mesh and mixed
(Blend 1). Item 5B is dissolved in water and slowly added to Blend
1 using a mixer. Additional water is added and mixed. The wet
material is dried at 50.degree. C. for 12 h, milled using a 16-mesh
screen with appropriate spacer, and dried until the LOD at
50.degree. C. is below 0.5% w/w. Dried granules and extra granular
material is transferred to a 3 cu. ft. V blender and mix for 3
minutes.
[0304] Items 7-9 are sifted through Quadro Comil using 16-mesh
screen with appropriate spacer.
[0305] Item 10 (lubricant) is sifted through 30 mesh hand screen
and transferred to the above blender and mixed for 3 minutes. The
final blend is compressed into tablets using a DC 16 compression
machine set with 0.3750.times.0.8125 caplet shaped punches. The
target tablet weight is 1250 mg with range of 3.0% and hardness of
10-20 Kp.
B. Barrier Layer
[0306] The compressed tablets are coated with Opadry II white
(Y-22-7719) according to manufacturer's instructions to a weight
gain of 1.5-2.0% w/w.
C. Famotidine layer
[0307] Famotidine and Opadry II (Colorcon) are mixed at a 1:1 ratio
and the unit dose form amount of famotidine is applied by spray
coating.
D. Over Coating Layer
[0308] Opadry II white is applied over the famotidine layer by
spray coating.
18.8 Example 8
Manufacture of Ibuprofen/Famotidine Unit Dose Forms
[0309] In one version, the oral dosage form comprises many small
particles of famotidine coated with a barrier layer and situated in
a matrix containing ibuprofen.
[0310] A famotidine suspension (75% famotidine, 20% Opadry, 5%
talc) is sprayed onto microcrystalline cellulose (Avicel PH 101) to
100% buildup. The particles are coated with a barrier coating
comprised of Opadry II White (cat. #Y-22-7719) and then coated with
a protective coating comprised of a PEG 6000 and microcrystalline
cellulose (1:1).
[0311] The famotidine granules are mixed with ibuprofen granules
(prepared as described in Table 27, infra) in a proportion that
results in an ibuprofen:famotidine (800:26.6) mixture. Colliodal
silicon dioxide, croscarmellose, silicified microcrystalline
cellulose, and magnesium stearate are added to the
ibuprofen-famotidine mixture, and the resulting mixture is
compressed into tablets containing 800 mg ibuprofen and 26.6 mg
famotidine (calculated weight).
[0312] Optionally the tablets can be coated with a protective
coating (overcoating layer).
[0313] If ibuprofen DC85 (BASF Aktiengesellschaft, Ludwigshafen,
Germany) is used colliodal silicon dioxide, croscarmellose,
silicified microcrystalline cellulose may be omitted.
18.9 Example 9
Manufacture of Ibuprofen/Famotidine Unit Dose Forms
[0314] This example describes manufacture of a tablet containing
ibuprofen granules and coated famotidine granules.
[0315] A. Ibuprofen Granule
TABLE-US-00035 TABLE 27 Item Material % w/w mg/tablet
Function/Supplier 1. Ibuprofen 25 USP 68.96 800 API/BASF 2. Lactose
Monohydrate NF (80M) 25.86 300 Binder/Kerry Biosci 3. Colloidal
Silicon Dioxide NF 0.52 6 Glidant/Cabot (Cab-O-Sil M5P) 4.
Croscarmellose Sodium NF Ac-di-Sol 2.59 30 Disintegrant/FMC 5A.
Hypromellose USP, Methocel E-5 LV 1.55 18 Binder/Dow Premium
(Intragranular in dry mix) 5B Hypromellose USP, Methocel E-5 LV
0.52 6 Binder/Dow Premium (Intragranular as solution) 6. Purified
Water USP -- q.s. Process aid Total weight 100.0 1160
[0316] Items 1-5A are sifted through Quadro Comil 16-mesh and mixed
(Blend 1). Item 5B is dissolved in water and slowly added to Blend
1 using a mixer. Additional water is added and mixed. The wet
material is dried at 50.degree. C. for 12 h, milled using a 16-mesh
screen with appropriate spacer, and dried until the LOD at
50.degree. C. is below 0.5% w/w. Dried granules and extra granular
material is transferred to a V-blender and mixed for 3 minutes.
[0317] B. Famotidine Granule
TABLE-US-00036 TABLE 28 % mg/ Item Material w/w tablet
Function/Supplier STEP-I (Spray Granulation-Top Spray) 1
Microcrystalline Cellulose 45.47 35.5 Inert material/FMC NF (Avicel
PH 101) 2 Famotidine USP 34.05 26.6 Active/DRL 3 Opadry II white
(Y-22-7719) 9.09 7.1 Coating/Colorcon 4 Talc NF 2.30 1.8
Glidant/Imperial 5 Purified water USP N/A q.s. Process aid STEP-II
(Barrier Coating-Bottom Spray) 1 Opadry White (YS-1-7003) 9.09 7.1
Coating/Colorcon 2 Purified water USP N/A q.s. Process aid Total
weight 100.0 78.1
[0318] Set up the Glatt fluid bed processor and add
microcrystalline cellulose to Glatt. Disperse famotidine in
purified water under mechanical stirring for 5 minutes. Add Opadry
followed by talc and let it run for 30 minutes. Homogenize the
above suspension for 20-30 minutes. Keep mixing at slow speed to
avoid air entrapment
[0319] Set up the peristaltic pump and spray the drug suspension
completely. Dry the product to a product temperature of around
40-44.degree.. Sift the spray granulated famotidine through Quadro
comil #20 mesh.
[0320] Spray Opadry suspension equivalent to 10% weight gain in the
Glatt fluid bed processor. Dry the final product to a product
temperature of around 40-44.degree. C. Discharge and sift it
through ASTM #30 mesh to remove any agglomerate.
[0321] C. Final Blending
TABLE-US-00037 TABLE 29 Item Material % w/w mg/tablet
Function/Supplier 1 Ibuprofen Granules 87.34 1160.0 Process Granule
2 Famotidine Coated 5.88 78.10 Process Granule Granules 3 Prosolv
SMCC 90 3.54 47.00 Diluent/JRS 4 Croscarmellose 2.26 30.00
Disintegrant/FMC Sodium NF 5 Colloidal Silicon 0.30 4.00
Glidant/Cabot Dioxide NF 6 Magnesium 0.68 9.00 Lubricant/Peter
Greven Stearate NF Total weight 100.0 1328.1
[0322] Weigh appropriate amount of ibuprofen granules, famotidine
granules and the extra-granular materials. Blend geometrically
famotidine and ibuprofen granules in appropriate blenders.
[0323] Add the sifted extra-granular materials (Prosolv SMCC 90,
croscarmellose sodium and colloidal silicon dioxide sifted through
16-mesh screen) to above granules and mix for 3 minutes.
[0324] Sift magnesium stearate through 30 mesh screen and transfer
to the above blender and lubricate for 3 minutes.
[0325] D. Tabletting
[0326] Set DC-16 compression machine with bisect punches and
compress the blend to tablets with target weight of 1.328 g,
hardness of 10-20 Kp, disintegration time less than 15 minutes.
[0327] E. Film Coating
TABLE-US-00038 TABLE 30 % mg/ Item Material w/w tablet
Function/Supplier 1 Ibuprofen/famotidine Granules 1328.1 Process
Granule/PII 2 Opadry II White (85F18422) ~3.0 39.90
Coating/Colorcon 3 Purified water USP q.s. Process aid/PII Total
weight 100.0 1368.0
[0328] Disperse Opadry II white (85 F18422) in water under
mechanical stirring. Continue mixing for 45 minutes at slow speed.
Load approximately 80-90 kg of compressed tablets in Acella Cota
with a 48'' coating pan. Coat the tablets to a weight gain of
2.5-3.5% w/w following optimum coating parameters.
[0329] In other related embodiments tablets are made as above
except that the amount of any non-API component can vary from the
amounts above by up to plus or minus 10%. For example, the lactose
monohydrate component in Table 27 could vary in the range from
about 23.3 to about 28.4. APIs can vary in amounts as described
elsewhere herein.
18.10 Example 10
Stability of Ibuprofen/Famotidine Tablet (800/26.6 mg) with Opadry
Coatings
[0330] As described above, a barrier layer separating ibuprofen and
famotidine can be comprised of a wide variety of compounds. Many
suitable coating material are commercially available as "Opadry"
including, for example Opadry II White (Colorcon Code Y-22-7719)
which contains HPMC, Glycerol, Polydextrose, Titanium Dioxide,
Triacetate, and Macrogol; Opadry white (Colorcon Code YS-1-7003)
HPMC 2910, PEG 400, Polysorbate 80, and Titanium Dioxide; and
Opadry II White (Colorcon Code 85F18422) which contains PVA-partial
hydrolyzed, Titanium Dioxide (E171), Macrogol 3350, and Talc.
[0331] Tablets were prepared essentially as described in Example 9
("Opadry White YS-1-7003") or essentially as described in Example 8
(i.e., as in Example 9 except that Opadry II [Y-22-7719] was used
instead of Opadry White in the barrier layer and an additional
protective layer was applied by coating with a suspension of PEG
6000 and microcrystalline cellulose [1:1] in water). As shown in
Table 31, use of Opadry White in the barrier layer gave superior
results compared to Opadry II White.
TABLE-US-00039 TABLE 31 EFFECT OF BARRIER COAT ON FAMOTIDINE
STABILITY (TOTAL FAMOTIDINE IMPURITIES) Opadry II (Y-22-7719)
Opadry White (YS-1-7003) Time Impurities % Impurities % Initial 0.5
0.5 1 wk 50.degree. C. 51.0 2.0 2 wk 40.degree. C./75% RH 3.6 0.4 1
mo 40.degree. C./75% RH 6.5 0.5 ***
[0332] All publications and patent documents (patents, published
patent applications, and unpublished patent applications) cited
herein are incorporated herein by reference as if each such
publication or document was specifically and individually indicated
to be incorporated herein by reference. Citation of publications
and patent documents is not intended as an admission that any such
document is pertinent prior art, nor does it constitute any
admission as to the contents or date of the same. The invention
having now been described by way of written description and
example, those of skill in the art will recognize that the
invention can be practiced in a variety of embodiments and that the
foregoing description and examples are for purposes of illustration
and not limitation of the following claims.
* * * * *