U.S. patent application number 13/683080 was filed with the patent office on 2014-05-22 for 5-aminosalicylic acid capsule formulation.
This patent application is currently assigned to WARNER CHILCOTT COMPANY, LLC. The applicant listed for this patent is WARNER CHILCOTT COMPANY, LLC. Invention is credited to Emma Boyd, Deborah Leigh Caldwell, Catherine Coulter, Ryan Loughlin, Stephen McCullagh.
Application Number | 20140141075 13/683080 |
Document ID | / |
Family ID | 50588745 |
Filed Date | 2014-05-22 |
United States Patent
Application |
20140141075 |
Kind Code |
A1 |
Boyd; Emma ; et al. |
May 22, 2014 |
5-AMINOSALICYLIC ACID CAPSULE FORMULATION
Abstract
A dosage form comprising a capsule containing one or more
tablets of 5-aminosalicylic acid or a salt thereof as an active
ingredient where each of the one or more tablets is enterically
coated is disclosed.
Inventors: |
Boyd; Emma; (Crumlin,
GB) ; Caldwell; Deborah Leigh; (Holywood, GB)
; Coulter; Catherine; (Ballymena, GB) ; Loughlin;
Ryan; (Crumlin, GB) ; McCullagh; Stephen;
(Belfast, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
WARNER CHILCOTT COMPANY, LLC |
|
|
|
|
|
Assignee: |
WARNER CHILCOTT COMPANY,
LLC
|
Family ID: |
50588745 |
Appl. No.: |
13/683080 |
Filed: |
November 21, 2012 |
Current U.S.
Class: |
424/452 ;
424/451; 424/456; 514/166 |
Current CPC
Class: |
A61K 9/2886 20130101;
A61P 1/00 20180101; A61K 9/4816 20130101; A61K 9/2846 20130101;
A61K 9/4808 20130101; A61P 29/00 20180101; A61K 31/606
20130101 |
Class at
Publication: |
424/452 ;
424/451; 514/166; 424/456 |
International
Class: |
A61K 9/48 20060101
A61K009/48; A61K 31/606 20060101 A61K031/606 |
Claims
1.-3. (canceled)
4. A dosage form comprising: (a) a capsule shell; and (b) at least
one tablet within the capsule shell, the at least one tablet
containing 5-aminosalicylic acid or a salt thereof as an active
ingredient and having an enteric coat that prevents release of the
5-aminosalicylic acid in the upper gastrointestinal tract, wherein
the capsule shell has less than about 10% by weight moisture
content at a relative humidity of 60% and a temperature of
25.degree. C.
5. The dosage form according to claim 4, wherein the dosage form is
stable.
6. The dosage form according to claim 5, wherein no more than 0.15%
w/w 5-[2-formyl-5-(hydroxymethyl-1H-pyrrol-1-yl]-2-hydroxybenzoic
acid accumulates upon storage of the dosage form at a relative
humidity of 60% and a temperature of 25.degree. C. for a period of
at least six months.
7. The dosage form according to claim 4, wherein the capsule shell
comprises gelatin, hydroxypropylmethyl cellulose, polyvinyl
alcohol, or a combination thereof.
8. The dosage form according to claim 4, wherein the capsule shell
comprises hydroxypropylmethyl cellulose.
9. The dosage form according to claim 4, wherein the at least one
tablet comprises a reducing sugar.
10. The dosage form according to claim 4, wherein the capsule shell
contains one, two, three, four or five tablets.
11. The dosage form according to claim 4, wherein the at least one
tablet contains from about 50 mg to about 1,800 mg of
5-aminosalicylic acid.
12. The dosage form according to claim 4, wherein the enteric coat
comprises a material capable of delivering the 5-aminosalicylic
acid to the colon of a human.
13. The dosage form according to claim 4, wherein the enteric coat
comprises a material selected from the group consisting of
poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic
acid, methyl methacrylate) 1:1, and mixtures thereof.
14. The dosage form according to claim 4, wherein the enteric coat
further comprises a plasticizer.
15. The dosage form according to claim 14, wherein the plasticizer
is selected from the group consisting of polyethylene glycols,
propylene glycols, 1,2-propylene glycol, dibutyl phthalate, dibutyl
sebacate, diethyl phthalate, tributyl citrate, triethyl citrate,
tributyrin, butyl phthalyl butyl glycolate, triacetin, castor oil,
citric acid esters, and combinations thereof.
16. The dosage form according to claim 4, wherein the enteric coat
further comprises inert solid particulates.
17. The dosage form according to claim 16, wherein the inert solid
particulates comprise a material selected from the group consisting
of talc, iron oxide, titanium dioxide, and combinations
thereof.
18. The dosage form according to claim 4, wherein the enteric coat
comprises a single enteric coating.
19. The dosage form according to claim 4, wherein the enteric coat
comprises a plurality of enteric coatings.
20. The dosage form according to claim 4, wherein the total
thickness of the enteric coat ranges from about 50 .mu.m to about
250 .mu.m.
21. The dosage form according to claim 4, wherein the enteric coat
comprises an inner layer of a first polyacrylic acid copolymer
enteric coating and an outer layer of a polyacrylic acid copolymer
enteric coating that is different than the inner layer.
22. The dosage form according to claim 21, wherein the inner layer
of enteric coating is poly(methacrylic acid, methyl methacrylate)
1:2 and the outer layer of enteric coating is poly(methacrylic
acid, methyl methacrylate) 1:1.
23. The dosage form according to claim 4, wherein the capsule does
not have an enteric coating.
24. The dosage form according to claim 4, wherein a drug-release
profile of the dosage form is pH dependent.
25. The dosage form according to claim 4, wherein the at least one
tablet is greater than 5 mm in diameter.
26. A kit comprising: a dosage form according to claim 4; and a
predetermined amount of desiccant.
27. A method of treating an inflammatory condition of the lower
gastrointestinal tract comprising administering a dosage form
according to claim 4 to a patient in need of treatment.
28.-30. (canceled)
31. The dosage form according to claim 10, wherein the capsule
shell contains one tablet.
32. The dosage form according to claim 8, wherein the at least one
tablet comprises a reducing sugar.
33. The dosage form according to claim 32, wherein the at least one
tablet is greater than 5mm in diameter.
34. The dosage form according to claim 33, wherein the capsule
shell contains one tablet.
35. A dosage form comprising: (a) a capsule shell; and (b) at least
one tablet within the capsule shell, the at least one tablet
containing 5-aminosalicylic acid or a salt thereof as an active
ingredient and having an enteric coat that prevents release of the
5-aminosalicylic acid in the upper gastrointestinal tract, wherein
the capsule shell has a moisture content such that no more than
0.15% w/w
5-[2-formyl-5-(hydroxymethyl-1H-pyrrol-1-yl]-2-hydroxybenzoic acid
accumulates upon storage of the dosage form at a relative humidity
of 60% and a temperature of 25.degree. C. for a period of at least
six months.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field
[0002] This invention relates to a dosage form that is a capsule
containing one or more tablets of 5-aminosalicylic acid or a salt
thereof as an active ingredient and each of the one or more tablets
being enterically coated. Simple encapsulation can be employed to
achieve benefits in handling. It has been unexpectedly discovered
that a capsule shell having a relatively low moisture content
provides a dosage form that inhibits the formation of degradants
within the enterically coated tablets contained within the capsule
shell during the storage of the dosage form.
[0003] 2. Related Background Art
[0004] The use of 5-aminosalicylic acid (mesalazine, mesalamine or
5-ASA) for the treatment of ulcerative colitis or Crohn's disease
of the colon is well known. U.S. Pat. Nos. 5,541,170 and 5,541,171
describe dosage forms of actives, such as 5-aminosalicylic acid,
that are enterically coated to facilitate delivery of the active
ingredient to the colon. More specifically, a capsule dosage form
containing 5-aminosalicylic acid with a gelatin capsule shell
having a coating of EUDRAGIT S100 applied to the capsule shell, is
exemplified. U.S. Pat. No. 6,893,662 describes dosage forms of
actives, such as 5-aminosalicylic acid, having inner and outer
polyacrylate coatings. None of these references discloses an
enterically coated tablet of 5-aminosalicylic acid in a
capsule.
[0005] It is known that 5-aminosalicylic acid dosage forms
formulated with a reducing sugar, such as lactose, are subject to
degradation, particularly when prepared using an aqueous wet
granulation technique or subjected to high humidity. This
degradation will produce a breakdown product
(5-[2-formyl-5-(hydroxymethyl-1H-pyrrol-1-yl]-2-hydroxybenzoic acid
(herein referred to as degradant B or deg B) that can limit shelf
life and reduce the performance of the product. It has been
surprisingly found that encapsulation of enterically coated tablets
can enhance stability. U.S. Patent Application Publication No.
2010/0210605 teaches that such degradation may be reduced by
providing a dosage form in a kit with a predetermined amount of
desiccant. While the use of low moisture hydroxypropylmethyl
cellulose (HPMC) capsules was known for use with capsule fills of
water-sensitive actives (see HPMC Capsules: New Generation Drug
Delivery Technology, Vol. 2, No. 2, March/April 2002), there was
little expectation that the moisture content of a capsule would
have a discernible effect on the stability of an enterically coated
tablet of 5-aminosalicylic acid contained therein.
BRIEF DESCRIPTION OF THE FIGURES
[0006] FIG. 1 is a plot of degradant B level over a 17 week storage
period at 40.degree. C./75% relative humidity, i.e., ICH
accelerated conditions, for dosage forms utilizing an HPMC capsule
shell, dosage forms utilizing a gelatin capsule shell, and for
enterically coated tablets which are not contained in a capsule
shell.
[0007] FIG. 2 is a plot of the continuous dissolution profile for
HPMC capsule dosage forms according to Example 1 under various
conditions.
[0008] FIG. 3 is a plot of the continuous dissolution profile for
HPMC capsule dosage forms according to Example 1 at 40.degree.
C./75% relative humidity.
SUMMARY OF THE INVENTION
[0009] The inventive dosage form comprises (a) a capsule shell; and
(b) at least one tablet within the capsule shell, the at least one
tablet containing 5-aminosalicylic acid or a salt thereof as an
active ingredient and having an enteric coat.
[0010] The inventive dosage form may also comprise (a) a capsule
shell having less than about 10% by weight moisture content in the
capsule shell at a relative humidity of 60% and a temperature of
25.degree. C.; and (b) at least one tablet within the capsule
shell, the at least one tablet containing 5-aminosalicylic acid or
a salt thereof as an active ingredient and having an enteric
coat.
[0011] According to the invention, the one or more tablets contain
a total of about 50 mg to about 1,800 mg of 5-aminosalicylic acid.
In a certain embodiment of the invention, the capsule shell
comprises HPMC. In certain embodiments, the enteric coat comprises
a single enteric coating or a plurality of enteric coatings. In
preferred embodiments, the enteric coat comprises an inner layer of
a first polyacrylic acid copolymer enteric coating and an outer
layer of a second polyacrylic acid copolymer enteric coating that
is different than the inner layer. Alternatively, in preferred
embodiments, the inner layer of enteric coating is poly(methacrylic
acid, methyl methacrylate) 1:2 and the outer layer of enteric
coating is poly(methacrylic acid, methyl methacrylate) 1:1. The
outer layer is applied on to the inner layer.
[0012] In certain embodiments, the enteric coat contains iron
oxide, the enteric coat provides delivery of the active ingredient
to the colon of a human, or the enteric coat comprises a material
selected from film coatings, cellulose derivatives, cellulose
ethers, methyl cellulose, ethylcellulose, carboxymethylcellulose,
carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, low viscosity
hydroxypropyl cellulose, low viscosity hydroxypropyl
methylcellulose, wax or wax like substance, such as carnauba wax,
fatty alcohols, hydrogenated vegetable oils, zein, shellac,
sucrose, Arabic gum, polyethylene glycol, polyvinylpyrolidone,
gelatin, sodium alginate, dextrin, psyllium husk powder,
polymethacrylates, anionic polymethacrylates, poly(methacrylic
acid, methyl methacrylate) 1:2 (Eudragit.RTM.S), poly(methacrylic
acid, methyl methacrylate) 1:1 (Eudragit.RTM.L), cellulose acetate
phthalate, cellulose acetate trimelliate, hydroxypropyl
methylcellulose phthalate (HPMCP), cellulose propionate phthalate,
cellulose acetate maleate, polyvinyl alcohol phthalate,
hydroxypropyl methylcellulose acetate succinate (HPMCAS),
hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate
phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and
combinations thereof.
[0013] The invention is also directed to a kit comprising a dosage
form of the present invention and a predetermined amount of
desiccant.
[0014] The invention is further directed to a method of treating an
inflammatory condition of the gastrointestinal tract comprising
administering a dosage form of the present invention to a patient
in need of treatment.
[0015] The invention is still further directed to a method of
improving the handling properties of a 5-aminosalicylic acid dosage
form comprising the step of: providing at least one tablet
containing 5-aminosalicylic acid or a salt thereof as an active
ingredient and having an enteric coat; and encapsulating the at
least one tablet in a capsule shell.
[0016] The invention is still further directed to a method of
improving the stability of a 5-aminosalicylic acid dosage form
comprising the steps of: providing at least one tablet containing
5-aminosalicylic acid or a salt thereof as an active ingredient and
having an enteric coat; and encapsulating the at least one tablet
in a capsule shell, wherein the capsule shell has less than about
10% by weight moisture content at a relative humidity of 60% and a
temperature of 25.degree. C.
[0017] Another embodiment of the invention is directed to a method
of modifying the dissolution profile of a dosage form upon storage
comprising the step of: providing the dosage form in a kit
comprising the dosage form and a predetermined amount of desiccant,
wherein the dosage form has (a) a capsule shell having less than
about 10% by weight moisture content in the capsule shell at a
relative humidity of 60% and a temperature of 25.degree. C. and (b)
at least one tablet within the capsule shell, the at least one
tablet containing 5-aminosalicylic acid or a salt thereof as an
active ingredient and having an enteric coat. In a preferred
embodiment, the dissolution profile of the dosage form upon storage
is substantially similar to the dissolution profile of the dosage
form upon manufacture.
DETAILED DESCRIPTION
[0018] A first embodiment of the present invention is directed to a
dosage form comprising (a) a capsule shell; and (b) at least one
tablet within the capsule shell, the at least one tablet containing
5-aminosalicylic acid or a salt thereof as an active ingredient and
having an enteric coat. The dosage form of the present invention
has improved handling properties. As used herein, "improved
handling properties" refers to a decreased need to employ soft
handling techniques when handling the dosage forms of the present
invention. It is known that handling enterically coated
5-aminosalicylic acid tablets using conventional means may cause
differences in product performance due to damage done to the
coating, i.e., coating fracture; dosage forms of the present
invention can be more readily handled, i.e., without the need for
soft handling techniques.
[0019] The capsule shell may comprise any material conventional in
the art for capsules. In certain preferred embodiments, the capsule
shell comprises, as a primary component, gelatin, HPMC, polyvinyl
alcohol (PVA), pullulan, carageenan or a combination thereof. The
capsule shell may include additives such as carageenan, pigments
such as titanium dioxide and iron oxides, potassium chloride or
combinations thereof. When present, one of ordinary skill in the
art can readily determine a suitable amount of such additives. It
is believed that capsule shells such as those disclosed in U.S.
Pat. No. 6,649,180 may be useful in the present invention.
[0020] The capsule shell may be purchased from commercially
available sources or made according to known methods. There is no
limitation on the size of the capsule shell, and it may be selected
from commercially available sizes such as 0, 00, 0e1, AAe1, 000 and
AAA. Preferably the capsule shell is size 0.
[0021] The dosage form of the present invention also comprises one
or more tablets within the capsule shell, the one or more tablets
containing 5-aminosalicylic acid or a salt thereof as an active
ingredient and having an enteric coat. As used herein, "or a salt
thereof" refers to any salt of 5-aminosalicylic acid formed with a
suitable counterion such as potassium, calcium, sodium or zinc. In
certain embodiments of the invention, the tablet comprises
mesalamine potassium or mesalimine sodium. The 5-aminosalicylic
acid or salt thereof may be purchased from known sources or made
according to known methods.
[0022] Preferably, the capsule shell contains one or four tablets,
but may contain two, three, five or more tablets. Importantly, each
of the tablets contains 5-aminosalicylic acid or a salt thereof and
has an enteric coat. In a preferred embodiment, the tablet(s) may
be mesalamine delayed-release tablets. The tablets may be placed
inside the capsule in any conventional manner without the need for
cushioning materials or additional excipients.
[0023] Tablet(s) suitable for use in the present invention are not
limited by size or shape, but are of such size and shape as to be
readily ingested and swallowed. Typically, the tablet(s) are
spherical, oblong, or elliptical. In a preferred embodiment of the
invention, the tablets are greater than about 5 mm in diameter and
no more than about 12 mm in diameter; in a preferred embodiment of
the invention, the tablets are greater than about 5 mm in length
and no more than about 30 mm in length. Tablets suitable for use in
the present invention are distinguished from "granulated"
formulations and "granulations" of 5-aminosalicylic acid with
regard to at least size; further "tablets" as used herein have
necessarily been compressed or subjected to compression techniques.
Tablet(s) suitable for use in the present invention are likewise
not limited by method of manufacture. They may be made by any
conventional compression or granulation (wet or dry) technique.
What is more, the tablet(s) may be purchased from commercially
available sources or made according to known methods.
[0024] Tablet(s) suitable for use in the present invention may have
any composition as long as they contain 5-aminosalicylic acid or a
salt thereof. Tablet(s) may comprise any ingredients useful in
pharmaceutical manufacture and suitable for 5-aminosalicylic acid
formulations. Suitable additional ingredients or excipients
include, without limitation, sugars, such as lactose and glucose;
starches, such as cornstarch, potato starch, and sodium starch
glycolate; cellulose and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose, cellulose acetate,
hypromellose, hydroxypropyl methyl cellulose, methyl cellulose,
microcrystalline cellulose; powdered tragacanth; malt; gelatin;
talc; solid lubricants, such as stearic acid, magnesium stearate,
or calcium sulfate; vegetable oils, such as peanut oil, cottonseed
oil, sesame oil, olive oil, corn oil, and oil of theobroma; polyols
such as propylene glycol, glycerin, sorbitol, mannitol, and
polyethylene glycol; alginic acid; emulsifiers/surfactants, such as
polysorbate detergents (Tweens.RTM.); wetting agents such as sodium
lauryl sulfate; coloring agents; flavoring agents; excipients;
tableting agents; stabilizers; antioxidants; preservatives;
fillers; binders; lubricants; disintegrants; pyrogen-free water;
isotonic saline; phosphate buffer solutions; and combinations
thereof. Excipients suitable for use in the present invention are
generally described in Remington's Pharmaceutical Sciences, Mack
Publishing Co. (19th edit. 1995); Modern Pharmaceutics, Vol. 7,
Chapters 9 & 10, Banker & Rhodes (1979); Lieberman, et al,
Pharmaceutical Dosage Forms: Tablets (1981); and Ansel,
Introduction to Pharmaceutical Dosage Forms, 2d (1976). An exact
tablet formulation can be readily selected according to criteria
well known to those skilled in the art.
[0025] The one or more tablets of the present invention preferably
contain a total of about 50 mg to about 1,800 mg of
5-aminosalicylic acid. When the dosage form of the present
invention contains more than one tablet, then the tablets may each
contain the same or a different amount of 5-aminosalicylic acid. In
a preferred embodiment of the present invention, the dosage form
contains one tablet having 400 mg, 600 mg or 800 mg
5-aminosalicylic acid. In another preferred embodiment, the dosage
form contains four tablets, each having 50 mg, 100 mg, or 150 mg
5-aminosalicylic acid.
[0026] According to the invention, the tablet(s) has an enteric
coat. As used herein, "coat" or "coating" refers to completely
encasing or covering the entire surface of a tablet. In certain
preferred embodiments, the coat or coating is a film coating, sugar
coating or a specialized coating such as compression coating,
electrostatic coating, dip coating or vacuum film coating. In
certain preferred embodiments, the tablet(s) has an enteric coat
according to U.S. Pat. Nos. 5,541,170 or 5,541,171 or 6,893,662,
the disclosure of each of which is incorporated by reference
herein. In a preferred embodiment of the present invention, the
capsule shell is not itself enterically coated, but rather only the
tablet(s) inside is enterically coated.
[0027] Generally, the enteric coat may comprise any material
capable of delivering the 5-aminosalicylic acid or a salt thereof
to the colon of a human, i.e., capable of preventing the release of
5-aminosalicylic acid prior to reaching the colon of a human or
capable of preventing release in the upper gastrointestinal tract.
More preferably, delivery of the 5-aminosalicylic acid is to the
right side of the colon. In another preferred embodiment of the
invention, the drug-release profile of the dosage form is pH
dependent.
[0028] In preferred embodiments, the enteric coat may comprise,
without limitation, poly(methacrylic acid, methyl methacrylate) 1:2
(Eudragit.RTM.S), poly(methacrylic acid, methyl methacrylate) 1:1
(Eudragit.RTM.L), and mixtures thereof. In other preferred
embodiments, the enteric coat may comprise, without limitation,
film coatings, cellulose derivatives, cellulose ethers, methyl
cellulose, ethylcellulose, carboxymethylcellulose,
carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, low viscosity
hydroxypropyl cellulose, low viscosity hydroxypropyl
methylcellulose, wax or wax like substance, such as carnauba wax,
fatty alcohols, hydrogenated vegetable oils, zein, shellac,
sucrose, Arabic gum, polyethylene glycol, polyvinylpyrolidone,
gelatin, sodium alginate, dextrin, psyllium husk powder,
polymethacrylates, anionic polymethacrylates, poly(methacrylic
acid, methyl methacrylate) 1:2 (Eudragit.RTM.S), poly(methacrylic
acid, methyl methacrylate) 1:1 (Eudragit.RTM.L), cellulose acetate
phthalate, cellulose acetate trimelliate, hydroxypropyl
methylcellulose phthalate (HPMCP), cellulose propionate phthalate,
cellulose acetate maleate, polyvinyl alcohol phthalate,
hydroxypropyl methylcellulose acetate succinate (HPMCAS),
hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate
phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and mixtures
thereof. One of ordinary skill in the art will readily appreciate
that the foregoing list comprises a number of enteric as well as
non-enteric materials; the present invention requires the presence
of an enteric coat. Therefore, at least one enteric material must
be present either in the presence or absence of other non-enteric
materials. In addition, other enteric polymer materials which have
the same pH release characteristics in aqueous media as, e.g.,
Eudragit.RTM.S, may also be suitable for use as the enteric coat of
the present invention. In other preferred embodiments, the enteric
coating is soluble at a pH of 6.4 or greater. In other preferred
embodiments, the enteric coating begins to dissolve in an aqueous
media, e.g., an aqueous buffer, at a pH of about 7.0. In still
other preferred embodiments, the enteric coating begins to dissolve
in an aqueous media, e.g., an aqueous buffer, at a pH of about
6.0.
[0029] Preferably the enteric coat of the present invention also
comprises a plasticizer. Appropriate plasticizers include
polyethylene glycols, propylene glycols, 1,2-propylene glycol,
dibutyl phthalate, dibutyl sebacate, diethyl phthalate, tributyl
citrate, triethyl citrate, tributyrin, butyl phthalyl butyl
glycolate, triacetin, castor oil, citric acid esters, and
combinations thereof. Plasticizer(s) are present in an amount to
facilitate the coating process and to obtain an even coating film
with enhanced physical stability. One of ordinary skill in the art
would readily determine a suitable amount of plasticizer(s) for
inclusion.
[0030] In addition, to facilitate the coating process, the coating
material may also comprise inert solid particulates. Preferred
inert solid particulates include talc, iron oxide and titanium
dioxide. When present, one of ordinary skill in the art can readily
determine a suitable amount for inclusion.
[0031] Generally, the enteric coat suitable for use in the present
invention comprises a single enteric coating or a plurality of
enteric coatings. When a plurality of enteric coatings is employed,
then each of the plurality of enteric coatings may be the same or
different in thickness and/or composition. In one embodiment of the
invention, the total thickness of the coating ranges preferably
from about 50 .mu.m to about 250 .mu.m, more preferably from about
75 .mu.m to about 175 .mu.m, and most preferably from about 100
.mu.m to about 150 .mu.m; in a more preferred embodiment, at least
two coatings comprise the noted total thickness. In another
preferred embodiment, the total thickness of a single enteric
coating ranges preferably from about 40 .mu.m to about 110 .mu.m,
more preferably from about 55 .mu.m to about 95 .mu.m, and most
preferably from about 70 .mu.m to about 80 .mu.m. In yet another
preferred embodiment, the total thickness of a combination of at
least two enteric coatings ranges preferably from about 60 .mu.m to
about 125 .mu.m, more preferably from about 75 .mu.m to about 110
.mu.m, and most preferably from about 90 .mu.m to about 95 .mu.m;
in a more preferred embodiment, the thickness of an inner coating
is approximately double that of an outer coating.
[0032] A suitable amount of coating can also be specified by
referring to weight gain per surface area for a given tablet. In
one embodiment of the invention, the weight gain per surface area
ranges preferably from about 1 mg/cm.sup.2 to about 22 mg/cm.sup.2,
more preferably from about 6 mg/cm.sup.2 to about 17 mg/cm.sup.2,
and most preferably from about 11 mg/cm.sup.2 to about 12
mg/cm.sup.2; in a more preferred embodiment, at least two coatings
comprise the noted total weight gain. In another preferred
embodiment, the weight gain per surface area of a single enteric
coating ranges preferably from about 3 mg/cm.sup.2 to about 16
mg/cm.sup.2, more preferably from about 6 mg/cm.sup.2 to about 13
mg/cm.sup.2, and most preferably from about 9 mg/cm.sup.2 to about
10 mg/cm.sup.2. In yet another preferred embodiment, the weight
gain per surface area of a combination of at least two enteric
coatings ranges preferably from about 6 mg/cm.sup.2 to about 19
mg/cm.sup.2, more preferably from about 9 mg/cm.sup.2 to about 16
mg/cm.sup.2, and most preferably from about 12 mg/cm.sup.2 to about
13 mg/cm.sup.2; in a more preferred embodiment, the weight gain
attributable to an inner coating is approximately double that of an
outer coating.
[0033] The enteric coat of the present invention may be applied to
the tablet(s) of the present invention in any manner known in the
art, typically through the application of enteric polymers onto the
tablet(s) as solutions in organic solvents or as
solutions/suspensions in aqueous media, followed by drying and
curing. Solvents commonly employed as vehicles are water, methylene
chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl
acetate and combinations thereof. The choice of the solvent is
based primarily on the solubility of the polymer, ease of
evaporation, and viscosity of the solution. Some polymers are also
available as aqueous systems. These include Eudragit.RTM.L30D
(methacrylic acid-ethyl acrylate ester copolymer marketed by
Rohm-Haas GmBH, West Germany); Aquateric.RTM. (cellulose acetate
phthalate-containing product marketed by FMC Corporation,
Philadelphia, Pa.); and Coateric.RTM. (a polyvinyl acetate
phthalate based product marketed by Colorcon, Inc., West Point,
Pa.). Coating can be achieved by methods known to one skilled in
the art such as by using fluidized bed equipment, perforated pans,
a regular pharmaceutical pan, compression coating, continuous or
short spray methods, or by drenching. Likewise drying or curing of
the enteric coat (either single or multiple coats) may be
accomplished by any known means. When more than one enteric coat is
present, an outer coating layer is applied after an inner coating
layer, but may be applied before, during or after the inner coating
layer is dried and/or cured.
[0034] In a certain preferred embodiment of the invention, a single
enteric coating or at least one of a plurality of enteric coatings
is a polyacrylic acid copolymer. In a certain preferred embodiment,
the enteric coat of the one or more tablets comprises a single
enteric coating comprised of a polyacrylic acid copolymer. In a
certain preferred embodiment, the enteric coat comprises an inner
layer of a first polyacrylic acid copolymer enteric coating and an
outer layer of a polyacrylic acid copolymer enteric coating that is
different than the inner layer, and more preferably the inner layer
of enteric coating is poly(methacrylic acid, methyl methacrylate)
1:2 and the outer layer of enteric coating is poly(methacrylic
acid, methyl methacrylate) 1:1. In certain embodiments, the single
enteric coating will be Eudragit.RTM.S. In other embodiments, the
inner enteric coating will comprise Eudragit.RTM.S, and the outer
enteric coating will comprise Eudragit.RTM.L.
[0035] When more than one tablet is present in the capsule, then
the tablets may have the same or different composition, size and/or
shape and the same or different enteric coat.
[0036] A second embodiment of the present invention is directed to
a dosage form comprising (a) a capsule shell having less than about
10% by weight moisture content in the capsule shell at a relative
humidity of 60% and a temperature of 25.degree. C.; and (b) at
least one tablet within the capsule shell, the at least one tablet
containing 5-aminosalicylic acid or a salt thereof as an active
ingredient and having an enteric coat. The dosage forms of this
embodiment have improved stability, i.e., decreased presence of
5-[2-formyl-5-(hydroxymethyl-1H-pyrrol-1-yl]-2-hydroxybenzoic acid
(degradant B) upon storage, etc., as compared to enterically coated
tablets and, in a preferred embodiment, as compared to similar
dosage forms employing capsule shells with too high a moisture
content. Degradant B is a typical degradant upon storage of
5-aminosalicylic acid formulations produced using a reducing sugar
such as lactose. In one embodiment, "stable" or "stability" refers
to a dosage form which accumulates no more than about 0.15% w/w
degradant B upon storage at a relative humidity of 60% and a
temperature of 25.degree. C., when measured according to a
recognized stability testing method under International Conference
on Harmonization (ICH) storage conditions. As used herein,
"improved stability" or "improving stability" refers to a dosage
form of the present invention which achieves stability as defined
above, i.e., which accumulates less degradant B upon storage as
compared to a control such as enterically coated tablets and dosage
forms employing capsule shells with too high a moisture content.
Preferably the dosage forms of the present invention are stable for
a period of at least 6 months, more preferably at least 12 months,
and most preferably at least 18 months when stored without
desiccant; preferably the dosage forms of the present invention are
stable for a period of at least 12 months, more preferably at least
24 months, and most preferably at least 36 months when stored with
a suitable amount of desiccant.
[0037] The capsule shell suitable for use in this embodiment of the
invention is a capsule shell having less than about 10% by weight
moisture content at a relative humidity of 60% and a temperature of
25.degree. C. More preferably, the weight moisture content of the
capsule shell is less than about 7.5% at a relative humidity of 60%
and a temperature of 25.degree. C. Preferred weight moisture
content of the capsule will depend upon the storage conditions. For
example, further preferred embodiments of the invention are those
in which the weight moisture content of the capsule shell is less
than about 6% at a relative humidity of 50% and a temperature of
25.degree. C. or in which the weight moisture content of the
capsule shell is less than about 11.5% at a relative humidity of
75% and a temperature of 40.degree. C. Moisture content is
expressed as the equilibrium moisture content and was determined
using a conventional Dynamic Vapor Sorption (DVS) technique.
[0038] The capsule shell may comprise any material which allows for
attainment of the noted weight moisture content. In certain
preferred embodiments, the capsule shell comprises HPMC, polyvinyl
alcohol (PVA) or a combination thereof. The capsule shell may
include additives such as carageenan, pigments such as titanium
dioxide and iron oxides, potassium chloride or combinations
thereof. When present, one of ordinary skill in the art can readily
determine a suitable amount of such additives. It is believed that
capsule shells such as those disclosed in U.S. Pat. No. 6,649,180
may be useful in the present invention.
[0039] The capsule shell may be purchased from commercially
available sources or made according to known methods. There is no
limitation on the size of the capsule shell, and it may be selected
from commercially available sizes such as 0, 00, 0e1, AAe1, 000 and
AAA. Preferably the capsule shell is size 0.
[0040] The dosage form of the present invention also comprises one
or more tablets within the capsule shell, the one or more tablets
containing 5-aminosalicylic acid or a salt thereof as an active
ingredient and having an enteric coat. As used herein, "or a salt
thereof" refers to any salt of 5-aminosalicylic acid formed with a
suitable counterion such as potassium, calcium, sodium or zinc. In
certain embodiments of the invention, the tablet comprises
mesalamine potassium or mesalimine sodium. The 5-aminosalicylic
acid or salt thereof may be purchased from known sources or made
according to known methods.
[0041] Preferably, the capsule shell contains one or four tablets,
but may contain two, three, five or more tablets. Importantly, each
of the tablets contains 5-aminosalicylic acid or a salt thereof and
has an enteric coat. In a preferred embodiment, the tablet(s) may
be mesalamine delayed-release tablets. The tablets may be placed
inside the capsule in any conventional manner without the need for
cushioning materials or additional excipients.
[0042] Tablet(s) suitable for use in the present invention are not
limited by size or shape, but are of such size and shape as to be
readily ingested and swallowed. Typically, the tablet(s) are
spherical, oblong, or elliptical. In a preferred embodiment of the
invention, the tablets are greater than about 5 mm in diameter and
no more than about 12 mm in diameter; in a preferred embodiment of
the invention, the tablets are greater than about 5 mm in length
and no more than about 30 mm in length. Tablets suitable for use in
the present invention are distinguished from "granulated"
formulations and "granulations" of 5-aminosalicylic acid with
regard to at least size; further "tablets" as used herein have
necessarily been compressed or subjected to compression
techniques.
[0043] Tablet(s) suitable for use in the present invention are
likewise not limited by method of manufacture. They may be made by
any conventional compression or granulation (wet or dry) technique.
What is more, the tablet(s) may be purchased from commercially
available sources or made according to known methods. The invention
is particularly suited to 5-aminosalicylic acid tablets, which are
formulated with a reducing sugar, such as lactose, and which are
subject to degradation, particularly when prepared using an aqueous
wet granulation technique or subjected to high humidity.
[0044] Tablet(s) suitable for use in the present invention may have
any composition as long as they contain 5-aminosalicylic acid or a
salt thereof. Preferably tablet(s) suitable for use in the present
invention also contain a reducing sugar such as lactose. Tablet(s)
may comprise any ingredients useful in pharmaceutical manufacture
and suitable for 5-aminosalicylic acid formulations. Suitable
additional ingredients or excipients include, without limitation,
sugars, such as lactose and glucose; starches, such as cornstarch,
potato starch, and sodium starch glycolate; cellulose and its
derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose, cellulose acetate, hypromellose, hydroxypropyl methyl
cellulose, methyl cellulose, microcrystalline cellulose; powdered
tragacanth; malt; gelatin; talc; solid lubricants, such as stearic
acid, magnesium stearate, or calcium sulfate; vegetable oils, such
as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and
oil of theobroma; polyols such as propylene glycol, glycerin,
sorbitol, mannitol, and polyethylene glycol; alginic acid;
emulsifiers/surfactants such as polysorbate detergents
(Tweens.RTM.); wetting agents such as sodium lauryl sulfate;
coloring agents; flavoring agents; excipients; tableting agents;
stabilizers; antioxidants; preservatives; fillers; binders;
lubricants; disintegrants; pyrogen-free water; isotonic saline;
phosphate buffer solutions; and combinations thereof. Excipients
suitable for use in the present invention are generally described
in Remington's Pharmaceutical Sciences, Mack Publishing Co. (19th
edit. 1995); Modern Pharmaceutics, Vol. 7, Chapters 9 & 10,
Banker & Rhodes (1979); Lieberman, et al, Pharmaceutical Dosage
Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical
Dosage Forms, 2d (1976). An exact tablet formulation can be readily
selected according to criteria well known to those skilled in the
art.
[0045] The one or more tablets of the present invention preferably
contain a total of about 50 mg to about 1,800 mg of
5-aminosalicylic acid. When the dosage form of the present
invention contains more than one tablet, then the tablets may each
contain the same or a different amount of 5-aminosalicylic acid. In
a preferred embodiment of the present invention, the dosage form
contains one tablet having 400 mg, 600 mg or 800 mg
5-aminosalicylic acid. In another preferred embodiment, the dosage
form contains four tablets, each having 50 mg, 100 mg, or 150 mg
5-aminosalicylic acid.
[0046] According to the invention, the tablet(s) has an enteric
coat. As used herein, "coat" or "coating" refers to completely
encasing or covering the entire surface of a tablet. In certain
preferred embodiments, the coat or coating is a film coating, sugar
coating or a specialized coating such as compression coating,
electrostatic coating, dip coating or vacuum film coating. In
certain preferred embodiments, the tablet(s) has an enteric coat
according to U.S. Pat. Nos. 5,541,170 or 5,541,171 or 6,893,662,
the disclosure of each of which is incorporated by reference
herein. In a preferred embodiment of the present invention, the
capsule shell is not itself enterically coated, but rather only the
tablet(s) inside is enterically coated.
[0047] Generally, the enteric coat may comprise any material
capable of delivering the 5-aminosalicylic acid to the colon of a
human, i.e., capable of preventing the release of 5-aminosalicylic
acid prior to reaching the colon of a human or capable of
preventing release in the upper gastrointestinal tract. More
preferably, delivery of the 5-aminosalicylic acid is to the right
side of the colon. In another preferred embodiment of the
invention, the drug-release profile of the dosage form is pH
dependent.
[0048] In preferred embodiments, the enteric coat may comprise,
without limitation, poly(methacrylic acid, methyl methacrylate) 1:2
(Eudragit.RTM.S), poly(methacrylic acid, methyl methacrylate) 1:1
(Eudragit.RTM.L), and mixtures thereof. In other preferred
embodiments, the enteric coat may comprise, without limitation,
film coatings, cellulose derivatives, cellulose ethers, methyl
cellulose, ethylcellulose, carboxymethylcellulose,
carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, low viscosity
hydroxypropyl cellulose, low viscosity hydroxypropyl
methylcellulose, wax or wax like substance, such as carnauba wax,
fatty alcohols, hydrogenated vegetable oils, zein, shellac,
sucrose, Arabic gum, polyethylene glycol, polyvinylpyrolidone,
gelatin, sodium alginate, dextrin, psyllium husk powder,
polymethacrylates, anionic polymethacrylates, poly(methacrylic
acid, methyl methacrylate) 1:2 (Eudragit.RTM.S), poly(methacrylic
acid, methyl methacrylate) 1:1 (Eudragit.RTM.L), cellulose acetate
phthalate, cellulose acetate trimelliate, hydroxypropyl
methylcellulose phthalate (HPMCP), cellulose propionate phthalate,
cellulose acetate maleate, polyvinyl alcohol phthalate,
hydroxypropyl methylcellulose acetate succinate (HPMCAS),
hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate
phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and mixtures
thereof. One of ordinary skill in the art will readily appreciate
that the foregoing list comprises a number of enteric as well as
non-enteric materials; the present invention requires the presence
of an enteric coat. Therefore, at least one enteric material must
be present either in the presence or absence of other non-enteric
materials. In addition, other enteric polymer materials which have
the same pH release characteristics in aqueous media as, e.g.,
Eudragit.RTM.S, may also be suitable for use as the enteric coat of
the present invention. In other preferred embodiments, the enteric
coating is soluble at a pH of 6.4 or greater. In other preferred
embodiments, the enteric coating begins to dissolve in an aqueous
media, e.g., an aqueous buffer, at a pH of about 7.0. In still
other preferred embodiments, the enteric coating begins to dissolve
in an aqueous media, e.g., an aqueous buffer, at a pH of about
6.0.
[0049] Preferably the enteric coat of the present invention also
comprises a plasticizer. Appropriate plasticizers include
polyethylene glycols, propylene glycols, 1,2-propylene glycol,
dibutyl phthalate, dibutyl sebacate, diethyl phthalate, tributyl
citrate, triethyl citrate, tributyrin, butyl phthalyl butyl
glycolate, triacetin, castor oil, citric acid esters, and
combinations thereof. Plasticizer(s) are present in an amount to
facilitate the coating process and to obtain an even coating film
with enhanced physical stability. One of ordinary skill in the art
would readily determine a suitable amount of plasticizer(s) for
inclusion.
[0050] In addition, to facilitate the coating process, the coating
material may also comprise inert solid particulates. Preferred
inert solid particulates include talc, iron oxide and titanium
dioxide. When present, one of ordinary skill in the art can readily
determine a suitable amount for inclusion.
[0051] Generally, the enteric coat suitable for use in the present
invention comprises a single enteric coating or a plurality of
enteric coatings. When a plurality of enteric coatings is employed,
then each of the plurality of enteric coatings may be the same or
different in thickness and/or composition. In one embodiment of the
invention, the total thickness of the coating ranges preferably
from about 50 .mu.m to about 250 .mu.m, more preferably from about
75 .mu.m to about 175 .mu.m, and most preferably from about 100
.mu.m to about 150 .mu.m; in a more preferred embodiment, at least
two coatings comprise the noted total thickness. In another
preferred embodiment, the total thickness of a single enteric
coating ranges preferably from about 40 .mu.m to about 110 .mu.m,
more preferably from about 55 .mu.m to about 95 .mu.m, and most
preferably from about 70 .mu.m to about 80 .mu.m. In yet another
preferred embodiment, the total thickness of a combination of at
least two enteric coatings ranges preferably from about 60 .mu.m to
about 125 .mu.m, more preferably from about 75 .mu.m to about 110
.mu.m, and most preferably from about 90 .mu.m to about 95 .mu.m;
in a more preferred embodiment, the thickness of an inner coating
is approximately double that of an outer coating.
[0052] A suitable amount of coating can also be specified by
referring to weight gain per surface area for a given tablet. In
one embodiment of the invention, the weight gain per surface area
ranges preferably from about 1 mg/cm.sup.2 to about 22 mg/cm.sup.2,
more preferably from about 6 mg/cm.sup.2 to about 17 mg/cm.sup.2,
and most preferably from about 11 mg/cm.sup.2 to about 12
mg/cm.sup.2; in a more preferred embodiment, at least two coatings
comprise the noted total weight gain. In another preferred
embodiment, the weight gain per surface area of a single enteric
coating ranges preferably from about 3 mg/cm.sup.2 to about 16
mg/cm.sup.2, more preferably from about 6 mg/cm.sup.2 to about 13
mg/cm.sup.2, and most preferably from about 9 mg/cm.sup.2 to about
10 mg/cm.sup.2. In yet another preferred embodiment, the weight
gain per surface area of a combination of at least two enteric
coatings ranges preferably from about 6 mg/cm.sup.2 to about 19
mg/cm.sup.2, more preferably from about 9 mg/cm.sup.2 to about 16
mg/cm.sup.2, and most preferably from about 12 mg/cm.sup.2 to about
13 mg/cm.sup.2; in a more preferred embodiment, the weight gain
attributable to an inner coating is approximately double that of an
outer coating.
[0053] The enteric coat of the present invention may be applied to
the tablet(s) of the present invention in any manner known in the
art, typically through the application of enteric polymers onto the
tablet(s) as solutions in organic solvents or as
solutions/suspensions in aqueous media, followed by drying and
curing. Solvents commonly employed as vehicles are water, methylene
chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl
acetate and combinations thereof. The choice of the solvent is
based primarily on the solubility of the polymer, ease of
evaporation, and viscosity of the solution. Some polymers are also
available as aqueous systems. These include Eudragit.RTM.L30D
(methacrylic acid-ethyl acrylate ester copolymer marketed by
Rohm-Haas GmBH, West Germany); Aquateric.RTM. (cellulose acetate
phthalate-containing product marketed by FMC Corporation,
Philadelphia, Pa.); and Coateric.RTM. (a polyvinyl acetate
phthalate based product marketed by Colorcon, Inc., West Point,
Pa.). Coating can be achieved by methods known to one skilled in
the art such as by using fluidized bed equipment, perforated pans,
a regular pharmaceutical pan, compression coating, continuous or
short spray methods, or by drenching. Likewise drying or curing of
the enteric coat (either single or multiple coats) may be
accomplished by any known means. When more than one enteric coat is
present, an outer coating layer is applied after an inner coating
layer, but may be applied before, during or after the inner coating
layer is dried and/or cured.
[0054] In a certain preferred embodiment of the invention, a single
enteric coating or at least one of a plurality of enteric coatings
is a polyacrylic acid copolymer. In a certain preferred embodiment,
the enteric coat of the one or more tablets comprises a single
enteric coating comprised of a polyacrylic acid copolymer. In a
certain preferred embodiment, the enteric coat comprises an inner
layer of a first polyacrylic acid copolymer enteric coating and an
outer layer of a polyacrylic acid copolymer enteric coating that is
different than the inner layer, and more preferably the inner layer
of enteric coating is poly(methacrylic acid, methyl methacrylate)
1:2 and the outer layer of enteric coating is poly(methacrylic
acid, methyl methacrylate) 1:1. In certain embodiments, the single
enteric coating will be Eudragit.RTM.S. In other embodiments, the
inner enteric coating will comprise Eudragit.RTM.S, and the outer
enteric coating will comprise Eudragit.RTM.L.
[0055] When more than one tablet is present in the capsule, then
the tablets may have the same or different composition, size and/or
shape and the same or different enteric coat.
[0056] The dosage forms of the first and second embodiments of the
present invention are preferably packaged as part of a kit which
comprises at least one of the present dosage forms and a
predetermined amount of desiccant. Therefore, a third embodiment of
the invention is directed to such a kit.
[0057] As used herein, a "desiccant" is a material that will absorb
moisture by physical and/or chemical means. Activated desiccants
are desiccants that have been treated by heating and ventilating,
or by other means, to develop an internal surface on which moisture
and certain vapors or gases may collect. Common desiccants include,
but are not limited to, silica gel, indicating silica gel,
molecular sieves, clay or montmorillonite, activated carbon,
alumina, and combinations thereof. Suitable desiccants are
commercially available, either in bulk or predetermined amounts, or
may be made according to known methods.
[0058] Desiccant quantities may be adjusted depending on the need
of the application. For example, a bulk product may be stored in a
drum with a suitable amount of a desiccant, or it may first be
divided into smaller batches and stored appropriately with a
smaller quantity of a desiccant. The moisture initially in a
package from the drug substance, excipients, and fillers, as well
as moisture permeation into the package over its shelf life, will
determine the amount of desiccant required in a given package. The
quantity of desiccant in an ideal case should be at least
sufficient to absorb this moisture and maintain a desiccated
environment within the package for the product's shelf life.
Desiccant Quantity Calculation
[0059] Total moisture to be absorbed by desiccant (g)-product
moisture (g)+permeation of moisture over projected shelf life in
the package (g)+moisture from package fillers (g)
[0060] Once the total moisture (g) to be absorbed is calculated,
one calculates the desiccant quantity needed as follows:
Quantity of desiccant ( g ) required = total moisture to be
absorbed by deisiccant ( g ) desiccant capacity at projected
storage conditions ( g water / g desiccant ) ##EQU00001##
[0061] The amount of desiccant required may depend upon the number
of unit dosage forms to be packaged per container and the water
absorptive capacity of the desiccant. This calculation governs the
predetermined quantity of desiccant to be provided. Typically, the
predetermined desiccant quantity is in excess of the desiccant
required. One of ordinary skill in the art will readily appreciate
how to use these calculations and determine an appropriate amount
of desiccation.
[0062] According to a preferred embodiment of the present
invention, an appropriate amount of desiccant is employed to absorb
moisture from the dosage form. Such a level of desiccation can be
achieved using a capsule shell suitable for use in the second
embodiment of the present invention, i.e., an HPMC capsule, while
such desiccation may not possible for higher moisture content
capsules such as gelatin capsules. It is important to note,
however, that even in the absence of desiccation, HPMC capsule
formulations of the present invention have benefits over similar
formulations employing gelatin capsules and over formulations
employing no capsules, as demonstrated in FIG. 1 described
herein.
[0063] A fourth embodiment of the invention is directed to a method
of treating an inflammatory condition of the gastrointestinal tract
by administering the dosage form of either the first or second
embodiment to a patient in need of treatment. Inflammatory
conditions of the gastrointestinal tract include, without
limitation, ulcerative colitis, irritable bowl syndrome,
diverticulitis, and Crohn's disease; the treatment of ulcerative
colitis and irritable bowel syndrome by 5-aminosalicylic acid is
well known. Dosage forms according to the first or second
embodiment of the invention comprise from about 50 mg to about
1,800 mg of 5-aminosalicylic acid. One of ordinary skill in the art
could readily employ one or more dosage forms of the present
invention to provide a patient in need of treatment with a
therapeutically effective dosage of 5-aminosalicylic acid.
[0064] A fifth embodiment of the invention is directed to a method
of improving the handling properties of a 5-aminosalicylic acid
dosage form comprising the steps of: providing at least one tablet
containing 5-aminosalicylic acid or a salt thereof as an active
ingredient and having an enteric coat; and encapsulating the at
least one tablet in a capsule shell. All details with regard to the
capsule shell composition, tablet composition, enteric coating
composition, etc. are the same as set forth for the first
embodiment of the invention.
[0065] A sixth embodiment of the invention is directed to a method
of improving the stability of a 5-aminosalicylic acid dosage form
comprising the steps of: providing at least one tablet containing
5-aminosalicylic acid or a salt thereof as an active ingredient and
having an enteric coat; and encapsulating the at least one tablet
in a capsule shell having less than about 10% by weight moisture
content at a relative humidity of 60% and a temperature of
25.degree. C. All details with regard to the capsule shell
composition, tablet composition, enteric coating composition, etc.
are the same as set forth for the second embodiment of the
invention.
[0066] A seventh embodiment of the invention is directed to a
method of modifying the dissolution profile of a dosage form upon
storage comprising the step of: providing the dosage form in a kit
comprising the dosage form and a predetermined amount of desiccant,
wherein the dosage form has (a) a capsule shell having less than
about 10% by weight moisture content in the capsule shell at a
relative humidity of 60% and a temperature of 25.degree. C. and (b)
at least one tablet within the capsule shell, the at least one
tablet containing 5-aminosalicylic acid or a salt thereof as an
active ingredient and having an enteric coat. All details with
regard to the capsule shell composition, tablet composition,
enteric coating composition, desiccant amount, etc. are the same as
set forth for the second and third embodiments of the
invention.
[0067] As set forth herein, "dissolution profile" refers to the
percentage of 5-aminosalicylic acid dissolved at each of specified
sampling intervals, e.g., every 15 minutes, when a dosage form is
tested according to the standard protocol for mesalamine
delayed-release tablets set forth at pages 3819-3820 of USP 35
Official Monographs. It has been shown that the dissolution profile
for certain dosage forms of the present invention exhibits an
undesirable delay in the release of active ingredient. Such an
effect is shown as a "shift to the right" in the dissolution
profile upon storage of the dosage form. As used herein, "modifying
the dissolution profile" refers to the prevention or lessening of
the right shift in dissolution profile during storage. While
5-aminosalicylic acid formulations are typically stored in the
presence of desiccant in order to preserve the stability of those
formulations, i.e., in order to prevent the formation of certain
known degradants, the present inventors have discovered that the
use of a predetermined amount of desiccant (determined as indicated
above) has the added benefit of preventing or lessening the right
shift of the dissolution profile upon storage. In a preferred
embodiment, the dissolution profile of the dosage form upon storage
is substantially similar to the dissolution profile of the dosage
form upon manufacture. As used herein, "substantially similar"
refers to dissolution profiles which have a similarity factor (f2)
score of 50-100. One of ordinary skill in the art can readily
determine a similarity factor (f2) using the guidance provided in,
e.g., Guidance for Industry--Dissolution Testing of Immediate
Release Solid Oral Dosage Forms, U.S. Department of Health and
Human Services, Food and Drug Administration, Center for Drug
Evaluation and Research (CDER), August 1997, BP1. "Storage" is as
defined above with regard to the second embodiment of the
invention.
[0068] The following examples will illustrate the practice of the
present invention in some of the preferred embodiments. Other
embodiments within the scope of the claims will be apparent to one
skilled in the art.
EXAMPLES
Example 1
HPMC Capsule Compared to Gelatin Capsule and Tablet
[0069] Tablets were manufactured via wet granulation and
compression on a rotary tablet press using the components noted in
Table 1 below. The resulting round, concave tablets (approximately
5.5 mm wide and 4.87 mm thick) were then coated with a functional
coat (i.e., a first enteric coat) using the components noted in
Table 2 according to known methods. Then the tablets were coated
with an outer coat (i.e., a second enteric coat) using the
components noted in Table 2 below using a conventional coating pan,
i.e., solution/suspension is sprayed over a moving bed of tablets
and dried in situ.
TABLE-US-00001 TABLE 1 Core tablet formulation. Quantity per tablet
Ingredient Concentration (% w/w) (mg) Mesalamine, USP 76.54 100.00
Lactose D 20 14.62 19.10 Povidone 1.67 2.18 Sodium Starch Glycolate
3.50 4.57 Magnesium Stearate 1.19 1.55 Talc USP 1.99 2.60 Colloidal
Silicon Dioxide 0.49 0.65 Subtotal 100.00 130.65
TABLE-US-00002 TABLE 2 Enteric coat formulation. Quantity
Concentration per tablet Coat Ingredient (% w/w) (mg) Functional
Eudragit .RTM.S 62.90 7.34 Talc 16.88 1.97 Iron oxide red 8.23 0.96
Iron oxide yellow 1.46 0.17 Dibutyl sebacate 10.54 1.23 Subtotal
100.00 11.67 Outer Eudragit .RTM.L 63.22 0.55 Talc 17.24 0.15 Iron
oxide red 8.05 0.07 Iron oxide yellow 1.15 0.01 Dibutyl sebacate
10.34 0.09 Subtotal 100.00 0.87 Polish coating polyethylene glycol
100.00 0.2 6000 Subtotal 100.00 0.2
[0070] Next four identical tablets were manually loaded into either
a gelatin or HPMC capsule. Details of capsules used are shown in
Table 3.
TABLE-US-00003 TABLE 3 Details of capsules. Ingredient Color
Manufacturer Capsule Size Gelatin Clear Capsugel Bornem, Rijksweg
11, 0el Belgium. HPMC (V cap Clear Capsugel Bornem, Rijksweg 11,
0el plus) Belgium.
[0071] Accelerated stability testing was conducted for tablets made
and coated according to Example 1 but not placed in a capsule shell
(Batch 1 below). These tablets, as well as dosage forms, with an
outer coat and with gelatin or HPMC capsule shell (Batches 2 and 3,
respectively), were placed in a 30 ml HDPE bottle sealed with a
foil innerseal and child-resistant cap (CRC) (15 tablets or
capsules per bottle). Three batches were stored at accelerated
stability conditions. Batch 1 consisted of 100mg tablets (60
tablets in total per bottle--equivalent to 15.times.400 mg
capsules). Batch 2 consisted of 15 gelatin capsules, each loaded
with 4.times.100 mg tablets. Batch 3 consisted of 15 HPMC capsules,
each loaded with 4.times.100 mg tablets.
[0072] Each batch was stored in stability cabinets at accelerated
storage conditions--40.degree. C./75% relative humidity--for 17
weeks. At each time point, batches were assayed for the amount of
degradant B present according to known methods. Results are shown
in Table 4 below and in accompanying FIG. 1.
TABLE-US-00004 TABLE 4 Levels of Deg B in each of the batches over
time (% w/w). Time Batch (weeks) 1 2 3 0 0 0 0 4 0.188 0.306 0.116
8 0.373 0.464 0.239 17 0.704 0.717 0.394
[0073] As can be seen from FIG. 1, dosage forms comprising
enterically coated tablets in an HPMC capsule exhibit improved
stability as compared to enterically coated tablets and as compared
to dosage forms comprising enterically coated tablets contained
within a gelatin capsule under accelerated storage conditions.
Example 2
HPMC Capsule
[0074] Tablets were manufactured via wet granulation and
compression on a rotary tablet press using the components noted in
Table 5 below. The resulting capsule-shaped tablets (approximately
14.7 mm.times.5.9 mm) were then coated with a functional coat
(i.e., a first enteric coat) using the components noted in Table 6
below according to known methods using a conventional coating pan,
i.e., solution/suspension is sprayed over a moving bed of tablets
and dried in situ. Finally coated tablets were manually loaded into
a capsule having the composition shown in Table 6.
TABLE-US-00005 TABLE 5 Core tablet formulation. Ingredient Quantity
per tablet (mg) Mesalamine, USP 400.0 Lactose monohydrate 76.4
Povidone 8.7 Sodium Starch Glycolate 18.3 Magnesium Stearate 6.2
Talc USP 10.4 Colloidal Silicon Dioxide 2.6 Purified water.sup.1 --
Subtotal 522.6
TABLE-US-00006 TABLE 6 Enteric coat formulation. Coat Ingredient %
w/w Mg/tablet Functional Methacrylic acid 2.7 17.79 copolymer, type
B (Eudragit .RTM.S 12.5.sup.2) Talc 0.7 4.74 Iron oxide red 0.4
2.30 Iron oxide yellow 0.1 0.42 Dibutyl sebacate 0.5 3.02
Acetone.sup.1 -- -- Water.sup.1 -- -- Subtotal 4.4 28.27 Polish
coating polyethylene glycol 0.1 0.57 6000 Purified water.sup.1 --
-- Subtotal 0.1 0.57 Capsule Hydroxypropyl 14.8 96 methylcellulose
(size 0, Vcaps .RTM. Plus) Subtotal 14.8 96 Total 100.0 647.44
.sup.1processing aid, not present in final product, except in trace
amounts .sup.2Eudragit .RTM. S 12.5 is an isopropyl alcohol
solution containing 12.5% methacrylic acid copolymer, NF Type B
[0075] ICH stability studies were conducted on a number of batches.
The packaging configuration consisted of 12 capsules in a 90 cc
bottle with a foil innerseal and child-resistant cap, packed with
7'' cotton and with and without desiccant (the amount of desiccant
ranged between 0 and 2 g). Samples were stored at accelerated
(40.degree. C./75% RH) and long term (25.degree. C./60% RH) storage
conditions. Two batches were stored at accelerated and long term
storage conditions. Batch A contained 12 HPMC capsules in a 90 cc
HDPE bottle with 0 g of desiccant. Batch B contained 12 HPMC
capsules in a 90 cc HDPE bottle with 2 g of desiccant. A summary of
assay and degradant B levels following storage of samples at
25.degree. C./60% RH conditions is shown in Table 7.
TABLE-US-00007 TABLE 7 Summary of Assay and Deg B Levels Following
Storage at 25.degree. C. 60% RH. Assay (%) Deg B (% w/w) Batch T =
0 T = 6 months T = 0 T = 6 months A 99.9 101.9 0 0.006 (<LOD) B
99.9 101.1 0 0.006 (<LOD) LOD = limit of detection
Testing
Dissolution Profile
[0076] The dissolution profile of the HPMC capsule dosage form of
Example 1 was determined at various times, both at 25.degree.
C./60% relative humidity and 40.degree. C./75% relative humidity,
when stored with 4 g desiccant (2.times.2 g StripPax.RTM. Multisorb
desiccant packets), and the results are shown in FIG. 2 when 180
HPMC capsule dosage forms of Example 1 were placed in a 325 ml
bottle packed with 3-4 inches of cotton and sealed with an
induction seal. A shift to the right resulting in slower
dissolution was seen in the presence of this level of desiccation.
Dissolution testing followed the standard protocol for mesalamine
delayed-release tablets set forth at pages 3819-3820 of USP 35
Official Monographs.
[0077] However, when stored with 15 g desiccant (3.times.5 g
Minipax.degree. dessicant) at 40.degree. C./75% relative humidity
in the otherwise same packaging configuration, the dissolution
profile of the dosage form after both one and two months of storage
is remarkably similar to the dissolution profile of the dosage form
at time 0 as shown in FIG. 3. In other words, the shift to the
right of the dissolution profile seen upon storage with 4 g
desiccant is markedly reduced when the dosage form is stored with
15 g desiccant.
Handling
[0078] The handling properties of the HPMC capsule dosage form of
Example 2 were tested. Specifically, a batch of HPMC capsule dosage
forms of Example 2 were friabilated for 15 minutes using a
Pharmaceutical Development Copley FR1000 tablet friability tester.
The tablets within the capsule dosage forms were then removed and
quick tested, i.e., immersed in 0.1N HCl for 120 minutes followed
by pH 6.0 buffer for 120 minutes. The same steps, i.e.,
friabilation and quick test, were performed for tablets having the
same composition as those in the capsule dosage form of Example 2.
In other words, tablets without the inventive encapsulation were
friabilated and then quick tested. Fourteen (14) "early openers"
were observed for these tablets which were not contained in a
capsule during friabilation. In contrast, only three (3) "early
openers" were observed for the tablets contained in the HPMC
capsule dosage forms of Example 2. "Early openers" refer to tablets
which show signs of compromise of the integrity of the enteric
coating, i.e., visible signs of damage to the enteric coating upon
observation while submerged in the test medium. These results
indicate that encapsulation exerts a positive influence on the
handling properties of the tablets.
[0079] Numerous alterations, modifications, and variations of the
preferred embodiments disclosed herein will be apparent to those
skilled in the art, and they are all anticipated and contemplated
to be within the spirit and scope of the claimed invention. For
example, although specific embodiments have been described in
detail, those with skill in the art will understand that the
preceding embodiments and variations can be modified to incorporate
various types of substitute, additional or alternative materials.
Accordingly, even though only few variations of the present
invention are described herein, it is to be understood that the
practice of such additional modifications and variations and the
equivalents thereof, are within the spirit and scope of the
invention as defined in the following claims. All patent
applications, patents, and other publications cited herein are
incorporated by reference in their entirety.
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