U.S. patent application number 11/096457 was filed with the patent office on 2005-08-18 for pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures.
This patent application is currently assigned to The Procter & Gamble Company. Invention is credited to Amante, Joseph Michael, Cronk, Tony Ryan, Dittmar, Gregory Paul, Newby, Daniel Gary.
Application Number | 20050181053 11/096457 |
Document ID | / |
Family ID | 22954700 |
Filed Date | 2005-08-18 |
United States Patent
Application |
20050181053 |
Kind Code |
A1 |
Dittmar, Gregory Paul ; et
al. |
August 18, 2005 |
Pharmaceutical dosage form with multiple coatings for reduced
impact of coating fractures
Abstract
The present invention relates to a pharmaceutical composition in
a solid unit dosage form for oral administration in a human or
lower animal comprising: a. a safe and effective amount of a
therapeutically active agent; b. an inner coating layer selected
from the group consisting of poly(methacrylic acid, methyl
methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1,
and mixtures thereof; and c. an outer coating layer comprising an
enteric polymer or film coating material; wherein the inner coating
layer is not the same as the outer coating layer; wherein if the
inner coating layer is poly(methacrylic acid, methyl methacrylate)
1:1 then the outer coating layer is not poly(methacrylic acid,
methyl methacrylate) 1:2 or is not a mixture of poly(methacrylic
acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl
methacrylate) 1:2; and wherein the inner coating layer and the
outer coating layer do not contain any therapeutically active
agent. This invention further relates to a method of maintaining
the desired site of delivery of a therapeutic agent in the
gastrointestinal tract by administering the above compositions to a
human or lower animal.
Inventors: |
Dittmar, Gregory Paul;
(Norwich, NY) ; Amante, Joseph Michael; (Norwich,
NY) ; Cronk, Tony Ryan; (Mishawaka, IN) ;
Newby, Daniel Gary; (South New Berlin, NY) |
Correspondence
Address: |
Andrew A. Paul
8700 Mason Montgomery Rd.
Mason
OH
45040
US
|
Assignee: |
The Procter & Gamble
Company
Cincinnati
OH
|
Family ID: |
22954700 |
Appl. No.: |
11/096457 |
Filed: |
April 1, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11096457 |
Apr 1, 2005 |
|
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09996555 |
Nov 15, 2001 |
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6893662 |
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60252122 |
Nov 20, 2000 |
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Current U.S.
Class: |
424/472 |
Current CPC
Class: |
A61K 9/284 20130101;
A61K 9/2846 20130101; A61K 9/4891 20130101; A61K 9/2886 20130101;
A61K 31/196 20130101 |
Class at
Publication: |
424/472 |
International
Class: |
A61K 009/24 |
Claims
1-24. (canceled)
25. A pharmaceutical composition in a solid unit dosage form for
oral administration in a human or lower animal comprising: a. a
safe and effective amount of a therapeutically active agent; b. an
inner coating layer selected from the group consisting of
poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic
acid, methyl methacrylate) 1:1, and mixtures thereof; and c. an
outer coating layer having a minimum thickness from about 10 .mu.m
to about 200 .mu.m, applied to the inner coating layer, said outer
coating layer comprising a film coating material selected from the
group consisting of cellulose ethers, methyl cellulose,
ethylcellulose, carboxymethylcellulose,
carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, low viscosity
hydroxypropyl cellulose, low viscosity hydroxypropyl
methylcellulose, wax, carnauba wax, fatty alcohols, hydrogenated
vegetable oils, zein, shellac, sucrose, Arabic gum, polyethylene
glycol, polyvinylpyrolidone, gelatin, sodium alginate, dextrin,
psyllium husk powder, 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, and compatible mixtures thereof; wherein the
solid unit dosage form has a total weight from about 550 mg to
about 1500 mg; and wherein the inner coating layer and the outer
coating layer contain no therapeutically active agent.
26. The composition of claim 25 wherein the inner coating layer is
poly(methacrylic acid, methyl methacrylate) 1:2.
27. The composition of claim 25 wherein the film coating material
is selected from the group consisting of cellulose ethers, methyl
cellulose, ethylcellulose, carboxymethylcellulose,
carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, low viscosity
hydroxypropyl cellulose, low viscosity hydroxypropyl
methylcellulose, wax, carnauba wax, Arabic gum, polyethylene
glycol, polyvinylpyrolidone, 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, and compatible mixtures thereof.
28. The composition of claim 27 wherein the film coating material
is selected from the group consisting of cellulose ethers, methyl
cellulose, ethylcellulose, carboxymethylcellulose,
carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, and compatible mixtures
thereof.
29. The composition of claim 28 wherein the film coating material
is a mixture of hydroxypropyl cellulose and hydroxypropyl
methylcellulose.
30. The composition of claim 25 wherein the therapeutically active
agent is selected from the group consisting of laxatives,
anti-diarrheals, nonsteroidal anti-inflammatory agents,
glucocorticoids, antimicrobials, immunosuppressants,
chemotherapeutics or anti-cancer drugs, peptides, proteins,
cardiovascular drugs, psychotropic drugs, H2-blockers,
antiasthmatic agents, and antihistamines.
31. The composition of claim 30 wherein the therapeutically active
agent is a nonsteroidal anti-inflammatory agent.
32. The composition of claim 31 wherein the nonsteroidal
anti-inflammatory agent is 5-amino salicylic acid or a
pharmaceutically acceptable salt or ester thereof.
33. The composition of claim 32 wherein the 5-amino salicylic acid
or pharmaceutically acceptable salt or ester thereof is present in
an amount from about 700 mg to about 900 mg per solid unit dosage
form.
34. The composition of claim 25 wherein the outer coating layer has
a minimum thickness from about 30 .mu.m to about 150 .mu.m.
35. The composition of claim 25 wherein the total coating thickness
of the inner and outer coating layers combined is from about 5
mg/cm.sup.2 to about 40 mg/cm.sup.2.
36. The composition of claim 35 wherein the total coating thickness
is from about 10 mg/cm.sup.2 to about 15 mg/cm.sup.2.
37. The composition of claim 25 wherein the solid dosage form is
coated by continuous spray methods wherein the outer coating layer
is applied after the inner coating layer but before the inner
coating layer is dried or cured.
38. The composition of claim 25 wherein the solid unit dosage form
has a total weight from about 600 mg to about 1200 mg.
39. The composition of claim 38 wherein the solid unit dosage form
has a total weight from about 750 mg to about 1000 mg.
40. The composition of claim 25 wherein the solid dosage form is a
compressed tablet.
41. A method of consistent and reliable delivery and release of a
therapeutically active agent to the desired region of delivery by
orally administering the composition of claim 25.
42. A pharmaceutical composition in a solid unit dosage form for
oral administration in a human or lower animal comprising: a. a
safe and effective amount of 5-amino salicylic acid; b. an inner
coating layer comprising poly(methacrylic acid, methyl
methacrylate) 1:2; and c. an outer coating layer having a minimum
thickness from about 10 .mu.m to about 200 .mu.m, applied to the
inner coating layer, said outer coating layer comprising a mixture
of hydroxypropyl cellulose and hydroxypropyl methylcellulose.
43. A method of consistent and reliable delivery and release of
5-amino salicylic acid to the desired region of delivery by orally
administering the composition of claim 42.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/252,122, filed Nov. 20, 2000.
TECHNICAL FIELD
[0002] The present invention relates to novel unit dosage forms
comprising therapeutic agents with improved resistance to coating
fractures during processing, manufacturing or packaging.
BACKGROUND OF THE INVENTION
[0003] A number of prior art references teaches the advantages of
delivery of therapeutic agents to the lower part of the
gastrointestinal tract, especially the large intestine or the
colon. These reference illustrate the difficulty of formulating
dosage forms that will achieve this delivery benefit. For example,
U.S. Pat. Nos. 5,541,170 and 5,541,171, Rhodes et al., both issued
Jul. 30, 1996, discuss the delivery of pharmacologically active
agents, especially 5-aminosalicylic acid, to the large intestine
for the treatment of colonic or rectal disorders. U.S. Pat. No.
5,686,105, Kelm et al., issued Nov. 11, 1997, teaches colonic
delivery of therapeutic agents wherein the dosage form comprises a
coating system with at least one inner coating layer and one outer
coating layer. The inner coating layer is an enteric polymer that
begins to dissolve in an aqueous media at a pH between about 5 to
about 6.3, and the outer coating layer is an enteric polymer that
begins to dissolve in an aqueous media at a pH of between about 6.8
to 7.2. U.S. Pat. No. 5,171,580, Iamartino et al., issued Dec. 15,
1992, teaches pharmaceutical preparations containing an active
ingredient to be released in the lower part of the gastrointestinal
tract, the large intestine and especially the colon, consisting of
a core with the active, the core being coated with three protective
layers at different solubilities. This reference focuses on
providing more specific and reliable release of a therapeutic
active agent to the lower part of the gastrointestinal tract,
especially the colon, achieved with the three protection layers, as
well as the benefits of having a selective effect in the colon.
Other prior art references also focus on the benefits of delivering
therapeutic agents to the colon. These references include U.S. Pat.
No. 5,686,106, Kelm et al., issued Nov. 11, 1997; U.S. Pat. No.
5,914,132, Kelm et al, issued Jun. 22, 1999; U.S. Pat. No.
4,910,021. Davis et al, issued Mar. 20, 1990: U.S. Pat. No.
4,432,966, Zeitoun et al., issued Feb. 21, 1984; U.S. Pat. No.
5,654,004, Okayama et al., issued August 5, 1997; U.S. Pat. No.
5,900,252, Calcanchi et al., issued May 4, 1999; U.S. Pat. No.
5,482,718, Shah et al, issued Jan. 9, 1996; U.S. Pat. No.
5,316,772, Jurgens et al., issued May 31, 1994; EP 225,189, Davies,
et al, published Jun. 10, 1987; and Khan et al., Drug Development
and Industrial Pharmacy, 26(5), 549-554 (2000).
[0004] None of the above prior art references, however, discusses
the problem or possibility of coating fractures that may occur
during processing, manufacturing, or packaging of the oral unit
dosage form. Coating fractures may cause unreliable or inconsistent
delivery or release of the therapeutic agent to the desired region
of the gastrointestinal tract. These fractures may be associated
with premature rupture or release of the unit dosage forms. Indeed,
coating fractures may especially be problematic for larger than
average size unit dosage forms or heavier unit dosage forms
resulting from using larger dosages/levels of the therapeutic
active.
[0005] The present invention, therefore, relates to solid unit
dosage forms for oral administration in humans or lower animals
which minimizes the impact or negative effects of coating
fractures, especially for larger or heavier unit dosage forms. By
reducing these negative effects, these compositions maintain the
desired site of delivery of the therapeutic agents in the
gastrointestinal tract.
SUMMARY OF THE INVENTION
[0006] The present invention relates to a pharmaceutical
composition in a solid unit dosage form for oral administration in
a human or lower animal comprising:
[0007] a. a safe and effective amount of a therapeutically active
agent;
[0008] b. an inner coating layer selected from the group consisting
of poly(methacrylic acid, methyl methacrylate) 1:2,
poly(methacrylic acid, methyl methacrylate) 1:1, and mixtures
thereof; and
[0009] c. an outer coating layer comprising an enteric polymer or
film coating material;
[0010] wherein the inner coating layer is not the same as the outer
coating layer; wherein if the inner coating layer is
poly(methacrylic acid, methyl methacrylate) 1:1 then the outer
coating layer is not poly(methacrylic acid, methyl methacrylate)
1:2 or is not a mixture of poly(methacrylic acid, methyl
methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate)
1:2; and wherein the inner coating layer and the outer coating
layer contain no therapeutically active agent.
[0011] In another embodiment the present invention relates to a
pharmaceutical composition in a solid unit dosage form for oral
administration in a human or lower animal comprising:
[0012] a. a safe and effective amount of a therapeutically active
agent;
[0013] b. an inner coating layer comprising poly(methacrylic acid,
methyl methacrylate) 1:2: and
[0014] c. an outer coating layer comprising an enteric polymer or
film coating material;
[0015] wherein the inner coating layer is not the same as the outer
layer coating. This invention further relates to a method of
maintaining the desired site of delivery of a therapeutic agent in
the gastrointestinal tract by reducing the impact of coating
fractures, through administering the above compositions to a human
or lower animal.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The phrase "safe and effective amount", as used herein,
means an amount of therapeutically active agent or other component
of the present compositions, high enough to provide a significant
positive modification of the condition to be treated, but low
enough to avoid serious side effects (at a reasonable benefit/risk
ratio), within the scope of sound medical judgment. A safe and
effective amount of therapeutically active agent or other component
of the present compositions, will vary with the particular
condition being treated, the age and physical condition of the
patient being treated, the severity of the condition, the duration
of the treatment, the nature of concurrent therapy, the agent
selected and like factors.
[0017] Therapeutically Active Agent
[0018] The methods and compositions of the present invention
comprise a safe and effective amount of the therapeutically active
agent. In one embodiment the therapeutic agents suitable for
incorporation into dosage forms of the present invention are those
for which treatment of the colon is therapeutically advantageous.
These include therapeutic agents useful for the treatment of
diseases of the colon such as constipation, diarrhea, irritable
bowel syndrome (IBS), Crohn's disease, colitis, ulcerative colitis,
carcinomas, idiopathic protitis, infection in which systemic
absorption of the therapeutic agent is neither required or desired,
and other diseases or disorders of the colon or rectum. These
include actives for constipation and laxatives such as picosulfate
and sennasides, anti-diarrheals such as loperamide, nonsteroidal
anti-inflammatory drugs such as salicylates, indomethacin,
ibuprofen, flurbiprofen, naproxen, piroxicam 5-amino salicylic acid
(or pharmaceutically acceptable salts or esters thereof),
balsalazide as well as agents disclosed in U.S. Pat. No. 4,412,992,
Chan, issued Nov. 1, 1983, as well as NSAIDS disclosed in U.S. Pat.
No. 4,552,899, Sunshine et al., issued Nov. 12, 1985, steriods such
as hydrocortisone, prednisone, prednisolone, prednisolone
phosphate, prednisolone metasulpho-benzoate sodium, prednisolone
sodium phosphate, beclomethasone dipropionate and beclomethasone
valerate, glucocorticoids such as dextramethazone, antimicrobials
or antiparasitic agents, (especially those effective against
anaerobic microbes such as methotrexate), 5-aminosalicylic
compounds, 4-aminosalicylic compounds, sulfasalazine, benzalazine,
erythromycin, chloroguine, iodochlorhydroxyquin, disodohydroxyquin,
neomycin and tetracyclines, immunosupressants such as cyclosporine
A, chemotherapeutics for treatment of carcinomas, gastointestinal
stimulants and prokinetic agents such as cisapride, peppermint oil
and other carminative essential oils, actives for the removal of
excess bile acids such as cholestyramine. The above references are
herein incorporated by reference in their entirety.
[0019] Certain therapeutic agents, particularly peptides and
proteins, are subject to lumenal degradation in the stomach and
small intestine. The colon may be a preferable site of absorption
for such compounds since lumenal enzymatic activity is less in the
colon (M. Mackay and E. Tomlinson, in Colonic Drug Absorption and
Metabolism, P. R. Bieck, ed., Marcel Dekker, Inc., New York, Basel,
Hong Kong, 137-158 (1993)). Peptides and proteins that may exhibit
improved systemic bioavailability benefit when released in the
colon include calcitonin, insulin, and human growth hormone. In
certain cases, the peptide or protein may be formulated with a
system than enhances the absorption of the macromolecule (M. Mackay
and E. Tomlinson, in Colonic Drug Absorption and Metabolism, P. R.
Bieck, ed., Marcel Dekker, Inc., New York, Basel, Hong Kong,
137-158 (1993)).
[0020] The therapeutically active agents are present in the solid
dosage forms in suitable unit dosage amounts. These amounts will be
known by those skilled in the art. In one embodiment the active
agent is 5-amino salicylic acid or pharmaceutically acceptable
salts or esters thereof at a dosage range of from about 400 mg to
about 1.5 grams per tablet, in another embodiment is from about 700
mg to about 900 mg per tablet.
[0021] The therapeutically active agent may be incorporated into
one of the several substrates described herein in a manner
consistent with the physical chemical properties of the drug and
its pharmacodynamics, using techniques known to those skilled in
the art.
[0022] The Inner and Outer Coating Layers
[0023] In one embodiment the coating layers of the present
invention do not contain any therapeutically active agent of the
present invention. In addition, the "coating layers" described
herein refer to completely encasing or coating all of the solid
unit dosage form (does not include coated microcrystal spheres,
coated pellets, coated beads, coated microparticles or particles,
or coated granules, of the therapeutically active agent).
[0024] Inner Coating Layer
[0025] The inner coating layer is selected from the group
consisting of poly(methacrylic acid, methyl methacrylate) 1:2,
poly(methacrylic acid, methyl methacrylate) 1:1, and mixtures
thereof. Generally the inner coating layer is selected based on the
preferred delivery site desired and is applied to the core of the
unit dosage form to achieve a minimum coating thickness from about
20 .mu.m to about 120 .mu.m. The coating thickness depends on the
actual size of the unit dosage form, but in one embodiment the
minimum coating thickness of the inner coating layer is from about
20 .mu.m to about 50 .mu.m.
[0026] In one embodiment the inner coating layer comprises poly
(methacrylic acid, methyl methacrylate) 1:2 (Eudragit.RTM. S), or
other enteric polymer material which has the same pH release
characteristics in aqueous media as Eudragit.RTM. S. Eudragit.RTM.
S, an anionic copolymer derived from methacrylic acid and methyl
methacrylate, with a ratio of free carboxyl groups to the ester
groups of approximately 1:2, and a mean molecular weight of
approximately 135,000, from Rohm Tech. In one embodiment the inner
coating layer is any other polymer with the same aqueous pH release
charcteristics as Eudragit.RTM. S.
[0027] Outer Coating Layer
[0028] The outer coating layer comprises an enteric polymer or film
coating material, wherein the inner coating layer is not the same
as the outer coating layer. Generally, if the inner coating layer
is poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit.RTM.
L) then the outer coating layer is not poly(methacrylic acid,
methyl methacrylate) 1:2 (Eudragit.RTM. S) or is not a mixture of
poly(methacrylic acid, methyl methacrylate) 1:1 and
poly(methacrylic acid, methyl methacrylate) 1:2. The outer coating
material can be any coating material that protects the inner
coating layer from fractures during handling and that dissolves or
is removed in the gastrointestinal tract prior to the inner coating
layer. The outer coating layer is either a single coating or
multiple coatings of either an enteric polymer material or film
coating material. In another embodiment the unit dosage form has a
single outer coating layer. In another embodiment the outer coating
layer is an anionic copolymer. In one embodiment the outer coating
cannot comprise an enteric polymer or mixtures thereof with the
same pH of release in aqueous media as Eudragit.RTM. S. If the
inner coating is poly(methacrylic acid, methyl methacrylate 1:2,
then the outer coating layer can only comprise poly(methacrylic
acid, methyl methacrylate 1:2 (Eudragit.RTM. S) if it is mixed with
another enteric polymer or film coating material such that the pH
of release, in aqueous media, for the mixture is less than the pH
of release (aqueous media) for poly(methacrylic acid, methyl
methacrylate 1:2 (Eudragit.RTM. S) alone.
[0029] In another embodiment the outer coating layer is an enteric
polymer material that begins to dissolve in an aqueous media at a
pH of less than about 7, in another embodiment at a pH of less than
about 6.8. Generally the outer coating layer is applied to the core
of the unit dosage form to achieve a minimum thickness of from
about 10 .mu.m to about 200 .mu.m, in another embodiment is from
about 30 .mu.m to about 150 .mu.m.
[0030] In one embodiment the outer coating layer is selected from
the group consisting of 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 camauba 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) 1:1, mixtures of poly(methacrylic acid,
methyl methacrylate) 1:2 and poly(methacrylic acid, methyl
methacrylate) 1:1, 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 compatible mixtures thereof.
[0031] In another embodiment the outer coating layer is selected
from the group consisting of cellulose derivatives, cellulose
ethers, methyl cellulose, ethylcellulose, carboxymethylcellulose,
carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, low viscosity
hydroxypropyl cellulose, low viscosity hydroxypropyl
methylcellulose, 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) 1:1, mixtures of
poly(methacrylic acid, methyl methacrylate) 1:2 and
poly(methacrylic acid, methyl methacrylate) 1:1, 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
compatible mixtures thereof.
[0032] In another embodiment the outer coating layer is selected
from the group consisting of anionic polymethacrylates,
poly(methacrylic acid, methyl methacrvlate) 1:1, mixtures of
poly(methacrylic acid, methyl methacrylate) 1:2 and
poly(methacrylic acid, methyl methacrylate) 1:1, 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
compatible mixtures thereof.
[0033] In another embodiment the outer coating layer is a single
layer of a mixture of poly(methacrylic acid, methyl methacrylate)
1:1 (Eudragit.RTM. L) and poly(methacrylic acid, methyl
methacrylate) 1:2 (Eudragit.RTM. S) in a ratio of about 1:10 to
about 1:10, preferably about 1:5 to about 1:3 more preferably about
2:3. The coating thickness depends on the actual size of the unit
dosage form, but in one embodiment the minimum coating thickness of
the outer coating layer is from about 10 .mu.m to about 50 .mu.m,
in another embodiment is from about 20 .mu.m to about 40 .mu.m.
[0034] In another embodiment the outer coating layer is a single
coating of an enteric polymer that begins to dissolve in aqueous
media at a pH between about 5 to about 6.3, in another embodiment
at a pH between about 5 to about 6, in even another embodiment at a
pH between about 5 to about 5.5.
[0035] In one embodiment, the function of the outer coating layer
is to prevent or minimize fractures of the inner coating layer
during formulation processing, manufacturing, and packaging, and
the function of the inner coating layer is to maintain the desired
point of release of the therapeutic active agent in the
gastrointestinal tract. For example if the inner coating is
poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit.RTM. S),
the present invention maintains the desired point of release, as
described, for example, in U.S. Pat. Nos. 5,541,170 and 5,541,171,
Rhodes et al., which are incorporated herein by reference in their
entirety.
[0036] In one embodiment the total coating thickness (both the
inner and outer coating layers together) is from about 5
mg/cm.sup.2 to about 40 mg/cm.sup.2, in another embodiment is from
about 10 mg/cm.sup.2 to about 15 mg/cm.sup.2.
[0037] Specific examples of the outer coating layer follow.
[0038] Eudragit.RTM. L, is an anionic copolymer derived from
methacrylic acid and methyl methacrylate, with a ratio of free
carboxyl groups to the ester groups of approximately 1:1, and a
mean molecular weight of approximately 135,000, from Rohm Tech;
[0039] Eudragit.RTM. L 30 D, is an aqueous acrylic resin
dispersion, an anionic copolymer derived from methacrylic acid and
ethyl acrylate with a ratio of free carboxyl groups to the ester
groups of approximately 1:1, and a mean molecular weight of
approximately 250,000; (it is supplied as an aqueous dispersion
containing 30% w/w of dry lacquer substance);
[0040] Eudragit.RTM. L 100-55, is an anionic copolymer derived from
methacrylic acid and ethyl acrylate, with a ratio of free carboxyl
groups to the ester groups of approximately 1:1, and a mean
molecular weight greater than about 100,000;
[0041] cellulose acetate phthalate or CAP.RTM., available from
Eastman Chemical;
[0042] cellulose acetate trimelliate, CAT.RTM. available from
Eastman Chemical;
[0043] hydroxypropyl methylcellulose phthalate (USP/NF type 220824)
HPMCP 50.RTM. and (USP/NF type 200731) HPMCP 55.RTM. available from
Shin Etsu Chemical;
[0044] polyvinyl acetate phthalate, PVAP.RTM., available from
Colorcon;
[0045] hydroxypropyl methylcellulose acetate succinate,
HPMCAS.RTM., available from Shin Etsu Chemical;
hydroxypropylcellulose, Klucel.RTM..
[0046] To enhance the elasticity of the coating materials,
preferably the coating material of the present invention also
comprises a plasticizer. Appropriate plasticizers include
polyethylene glycols, propylene glycols, 1,2-propylene glycol,
dibutyl phthalate, diethyl phthalate, tributyl citrate, tributyrin,
butyl phthalyl butyl glycolate (Santicizer.RTM. B-16, from
Monsanto, St. Louis, Mo.), triacetin, castor oil and citric acid
esters; in another embodiment the plasitcizer is dibutyl phthalate,
tributyl citrate, or triethyl citrate. These plasticizers are
present in an amount to facilitate the coating process and to
obtain an even coating film with enhanced physical stability.
Generally the coating material comprises from about 0% to about 50%
of a plasticizer, preferably from about 2% to about 25% by weight,
more preferably from about 10% to about 20% by weight of the
enteric polymer.
[0047] In addition, to facilitate the coating process, the coating
material may also comprise inert solid particulates. Preferred
inert solid particulates include talc and titanium dioxide.
[0048] The selections of optional plasticizer, optional inert solid
particulate, and levels thereof, coating formulation type (solvent,
ammoniated aqueous solution, or aqueous dispersion), and process
are based upon the specific enteric polymer or film coatings used
and the type of dosage form used according to criteria known to
those skilled in the art. The solvent for the coating layers may be
organic or aqueous. In one embodiment the coating layer is obtained
via the use of an aqueous dispersion of the coating material.
[0049] The Dosage Form and Method of Making the Dosage Form
[0050] A safe and effective amount of therapeutically active agent
is incorporated into a solid unit dosage form. The term "solid unit
dosage form" means any dosage form, preferably non-liquid, intended
to be swallowed and having a sufficiently defined form to be
coated. Solid unit dosage forms may be selected from the group
consisting of a hard or soft capsule or a compressed tablet. In one
embodiment the solid dosage forms of the present invention are
selected from the group consisting of soft gelatin capsules; hard
gelatin capsules; and compressed tablets of any size or shape. In
one embodiment the unit dosage form of the present invention
comprises a unit dosage form from about 550 mg to about 1.5 gram
total weight, in another embodiment from about 600 mg to about 1.2
grams total weight, and in even another embodiment from about 750
mg to about 1 gram total weight.
[0051] In one embodiment the unit dosage form is a spherical or
elliptical soft elastic gelatin capsule. The soft elastic gelatin
capsule is filled with therapeutically active agent suspended in a
suitable vehicle compatible with the soft gelatin capsule.
[0052] In still another embodiment the unit dosage form is a hard
capsule (i.e. starch or gelatin hard. capsule), for example a
starch capsule such as Capill.RTM. from Capsulgel (Greenwood, S.C.)
in which the length of the long axis of the capsule is less than
about 10 mm and not more than about 1.5 times greater than the
short axis diameter of the capsule. The capsule may be filled with
a solid form of therapeutically active agent as described above, or
alternatively with therapeutically active agent dissolved or
suspended in a suitable vehicle compatible with the capsule
wall.
[0053] In another embodiment the unit dosage form is a compressed
spherical or elliptical tablet. The tablet is comprised of a solid
form of therapeutically active agent and is compressed using
conventional equipment and processes.
[0054] In addition to the therapeutically active agent the
compositions of this invention also generally comprise
pharmaceutiacally acceptable excipients. As used herein,
"excipient" means one or more compatible solid or liquid filler
diluents or encapsulating substances which are suitable for
administration to a subject. The term "compatible", as used herein,
means that the components of the composition are capable of being
commingled with the active agent, and with each other, in a manner
such that there is no interaction which would substantially reduce
the pharmaceutical efficacy of the composition under ordinary use
situations. Pharmaceutically-accepted excipents must, of course, be
of sufficiently high purity and sufficiently low toxicity to render
them suitable for administration to the subject being treated.
Excipients may act to facilitate incorporation of the
therapeutically active agent into the dosage form, modify the
release of the therapeutically active agent from the dosage form,
stabilize the therapeutically active agent. or enhance absorption
of the therapeutically active agent. Excipients should be safe for
their intended use at the levels employed in the formulation. The
formulation of therapeutically active agent and excipients is
selected according to criteria well known to those skilled in the
art to achieve the desired release rate, stability, absorption, and
to facilitate the dosage form manufacture.
[0055] Some examples of pharmaceutically-acceptable excipients or
components thereof are sugars, such as lactose, glucose, and
sucrose; starches, such as cornstarch, potato starch, and sodium
starch glycolate at a level of about 1% to about 8% by weight, in
another embodiment from about 2% to about 4% by weight; cellulose
and its derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose, cellulose acetate; 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, such as the
Tweens.RTM.; wetting agents such as sodium lauryl sulfate; coloring
agents; flavoring agents; excipients; tableting agents;
stabilizers; antioxidants; preservatives; pyrogen-free water;
isotonic saline; and phosphate buffer solutions. Excipients are
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). Their
selection will depend on secondary considerations like taste, cost,
and shelf stability, etc. which are not critical for the purposes
of the subject invention, and can be made without difficulty by
those skilled in the art.
[0056] In one embodiment all of the dosage forms of the present
invention are uniform in size prior to coating with the coating
layers. The uniform size allows for uniform coating thickness and
more uniform dissolution of the coating layers.
[0057] Enteric polymers are generally applied onto the unit dosage
forms as solutions in organic or aqueous solvents. The 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.
[0058] 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.). Unlike organic solutions, these aqueous-based systems
can be prepared at high concentration without encountering high
viscosity. Also, these aqueous systems do not have the problems
associated with the organic systems such as flammability, toxicity
of the residual solvent in the dosage form, etc.
[0059] 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. For example, a plasticized
dispersion of coating polymer may be applied onto the tablet core
comprising the therapeutic active agent by spraying using any
suitable spray equipment known in the art. In one embodiment the
solid unit dosage forms are coated by continuous spray methods. In
one embodiment the outer coating layer is applied after the inner
coating layer but before the inner coating layer is dried and/or
cured. In yet another embodiment the outer coating layer is applied
immediately, e.g. within seconds, after the inner coating layer is
applied. If a shiny finish coat is desired on the solid dosage
forms of the present invention, a small quantity of polyethylene
glycol can be applied to the finished dosage form.
[0060] The following non-limiting examples provide typical
formulations for compositions of the present invention.
EXAMPLE 1
[0061] A wet granulation of 5-ASA (active ingredient), lactose, and
povidone is blended with talc, magnesium stearate, sodium starch
glycolate, and colloidal silicon dioxide. The blend is compressed
into approximately 1034 mg tablets containing 800 mg of the active
ingredient on a standard pharmaceutical rotary tablet press.
[0062] An inner layer of an EUDRAGIT.RTM. S coating of 9.2
mg/cm.sup.2 dried coating (i.e. about 62 microns) is applied to the
core tablets first by pouring a portion of the coating formula
without pigments and then by spraying coating onto the tablets. The
coating suspension sprayed onto the tablets contains approximately
62% by weight on a dry basis of Eudragit.RTM.0 S and is based in
isopropyl alcohol and acetone with dibutylphthalate as the acting
plasticizer.
[0063] An outer coating is either applied immediately following the
application of the inner coating or once the inner coating has
cured. The outer coating layer is sprayed onto the tablets to
achieve of 4.1 mg/cm.sup.2 dried coating (i.e. about 28 microns).
This coating suspension contains approximately 61% by weight on a
dry basis of EUDRAGIT.RTM. S and L in a ratio of 3:2. It is based
in isopropyl alcohol and acetone with dibutylphthalate as the
acting plasticizer.
EXAMPLE 2
[0064] A wet granulation of 5-ASA (active ingredient), lactose, and
povidone is blended with talc, magnesium stearate, sodium starch
glycolate, and colloidal silicon dioxide. The blend is compressed
into approximately 1570 mg tablets containing 1200 mg of the active
ingredient on a standard pharmaceutical rotary tablet press.
[0065] An inner layer of an EUDRAGIT.RTM. S and L mixture of 8.8
mg/cm.sup.2 dried coating (i.e. about 60 microns) is applied to the
core tablets first by pouring a portion of the coating formula
without pigments and then by spraying coating onto the tablets. The
coating suspension sprayed onto the tablets contains approximately
61% by weight on a dry basis of Eudragit.RTM. S and L in a ratio of
3:2 and is based in isopropyl alcohol and acetone with
dibutylphthalate as the acting plasticizer.
[0066] An outer coating is applied immediately following the
application of the inner coating or once the inner coating has
cured. The outer coating layer is sprayed onto the tablets to
achieve of 11.9 mg/cm.sup.2 dried coating (i.e. about 80 microns).
This coating suspension contains approximately 38% by weight on a
dry basis of EUDRAGIT.RTM. L and is based in isopropyl alcohol and
acetone with triethyl citrate as the acting plasticizer.
EXAMPLE 3
[0067] A wet granulation of 5-ASA (active ingredient), lactose, and
povidone is blended with talc, magnesium stearate, sodium starch
glycolate, and colloidal silicon dioxide. The blend is compressed
into approximately 690 mg tablets containing 500 mg of the active
ingredient on a standard pharmaceutical rotary tablet press.
[0068] An inner layer of an EUDRAGIT.RTM. S coating of 15.6
mg/cm.sup.2 dried coating (i.e. about 105 microns) is applied to
the core tablets first by pouring a portion of the coating formula
without pigments and then by spraying coating onto the tablets. The
coating suspension sprayed onto the tablets contains approximately
62% by weight on a dry basis of Eudragit.RTM. S and is based in
isopropyl alcohol and acetone with dibutylphthalate as the acting
plasticizer.
[0069] An outer coating is applied immediately following the
application of the inner coating or once the inner coating has
cured. The outer coating layer is a hydroxpropyl methylcellulose
coating applied to a thickness of about 100 microns of dried
coating according to the following formula:
1 Component Weight per Tablet Dri-Klear.sup.1 3.7 g White
Chroma-Tone.sup.2 1 g Water 48 g .sup.1Dri-Klear is a mixture of
hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropyl
cellulose, and silicon dioxide, manufactured by CHR Hansen.
.sup.2White Chroma-Tone is a mixture of titanium dioxide and
hydroxypropyl methylcellulose, manufactured by CHR Hansen.
EXAMPLE 4
[0070] Core tablets are manufactured to the following formula:
2 Component Weight per Tablet Ketoprofen 2 mg Lactose 4.96 mg
Starch 0.80 mg polyvinylpyrrolidone (PVP) 0.16 mg Magnesium
stearate 0.8 mg
[0071] An inner layer of an EUDRAGIT.RTM. S coating about 20
microns is applied to the core tablets by spraying coating of the
following formula:
3 Component EUDRAGIT .RTM. S100 3 g Diethyl phthalate 0.75 ml
Silicone fluid 200/20CS 0.75 ml Methanol 25 parts 100 ml
Dichloromehtane 75 parts
[0072] An outer coating layer is applied to the core tablet and
inner coating layer. The outer coating layer is a hydroxpropyl
methylcellulose coating applied to a thickness of about 150 microns
of dried coating according to the following formula:
4 Component Dri-Klear.sup.3 3.7 g White Chroma-Tone.sup.4 1 g Water
48 g .sup.3Dri-Klear is a mixture of hydroxypropyl methylcellulose,
polyethylene glycol, hydroxypropyl cellulose, and silicon dioxide,
manufactured by CHR Hansen. .sup.4White Chroma-Tone is a mixture of
titanium dioxide and hydroxypropyl methylcellulose, manufactured by
CHR Hansen.
EXAMPLE 5
[0073] Applied to the core tablets described in Example 4 is an
inner layer of an aqueous EUDRAGIT.RTM. L 30 D-55 coating of about
70 microns dried coating of the following formula:
5 Component EUDRAGIT .RTM. L 30 D-55 260 g Talc 39 g Polyethylene
glycol 6000 16 g Water 345 g
[0074] An outer coating layer is then applied as a hydroxpropyl
methylcellulose coating to a thickness of about 50 microns of dried
coating according to the following formula:
6 Component Dri-Klear.sup.5 3.7 g White Chroma-Tone.sup.6 1 g Water
48 g .sup.5Dri-Klear is a mixture of hydroxypropyl methylcellulose.
polyethylene glycol, hydroxypropyl cellulose, and silicon dioxide,
manufactured by CHR Hansen. .sup.6White Chroma-Tone is a mixture of
titanium dioxide and hydroxypropyl methylcellulose, manufactured by
CHR Hansen.
EXAMPLE 6
[0075] The following formulation is encapsulated within soft or
hard gelatin capsules:
7 Component Weight per Tablet Insulin 20 i.u. (c.a. 1 mg) Sodium
5-methoxy salicyclate 150.0 mg PEG 4000 3.5 mg PEG 600 187.5 mg
Capsule fill wt 342 mg
[0076] Thereafter, the capsule is coated. An inner layer of an
EUDRAGIT.RTM. S coating is applied to the capsules by spraying
coating of the following formula to a thickness of about 100
microns dried coating:
8 Component EUDRAGIT .RTM. S100 70 g Triethyl citrate 14 g Acetone
283 g Isopropyl Alcohol 483 g
[0077] Following the application of the inner coating, an outer
coating layer of an EUDRAGIT.RTM. S and L mixture at a ratio of 2:3
of about 20 microns is applied to the tablets by spraying a coating
of the following formula:
9 Component Weight per Tablet EUDRAGIT .RTM. L100 42 g EUDRAGIT
.RTM. S100 28 g Triethyl citrate 14 g Acetone 283 g Isopropyl
Alcohol 483 g
[0078] While particular embodiments of the present invention have
been described, it will be obvious to those skilled in the art that
various changes and modifications of the present invention can be
made without departing from the spirit and scope of the invention.
It is intended to cover, in the appended claims, all such
modifications that are within the scope of this invention.
* * * * *