U.S. patent number RE39,239 [Application Number 10/246,183] was granted by the patent office on 2006-08-15 for methods for treating early morning pathologies.
This patent grant is currently assigned to Polichem SA. Invention is credited to Cesare Busetti, Tiziano Crimella.
United States Patent |
RE39,239 |
Busetti , et al. |
August 15, 2006 |
Methods for treating early morning pathologies
Abstract
The present invention provides methods of treating early morning
pathologies using a time-specific controlled release dosage
formulation which is administered prior to sleep, and which permits
or achieves delivery of a pharmaceutically active agent effective
for the treatment of the specific early morning pathology to be
treated, at about the time of awakening. The time-specific
controlled release dosage formulation comprises (1) a core
including the pharmaceutically active agent(s) effective for the
treatment of the early morning pathology, and (2) a swellable
polymeric coating layer substantially surrounding the core. The
swellable polymeric coating layer delays the release of the
pharmaceutically active agent from the core for a predetermined
period of time dependent upon the thickness of the swellable
polymeric coating layer, to effect delivery of the pharmaceutically
active agent at about the time of awakening.
Inventors: |
Busetti; Cesare (Milan,
IT), Crimella; Tiziano (Milan, IT) |
Assignee: |
Polichem SA (Lugano,
CH)
|
Family
ID: |
25150918 |
Appl.
No.: |
10/246,183 |
Filed: |
September 17, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
08790514 |
Jan 29, 1997 |
05788987 |
Aug 4, 1998 |
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|
Current U.S.
Class: |
424/480; 424/482;
424/458 |
Current CPC
Class: |
A61P
25/20 (20180101); A61K 9/4808 (20130101); A61P
11/06 (20180101); A61K 9/2866 (20130101); A61P
25/16 (20180101); A61P 11/08 (20180101); A61K
9/2886 (20130101); A61P 19/02 (20180101); A61P
9/10 (20180101); A61P 9/12 (20180101); A61P
13/00 (20180101); A61P 7/02 (20180101); A61K
9/0007 (20130101) |
Current International
Class: |
A61K
9/54 (20060101) |
Field of
Search: |
;424/400,458,480,482
;514/313,453,468,510 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 305 918 |
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305 918 |
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EP |
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366 621 |
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May 1990 |
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EP |
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0 366 621 |
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May 1990 |
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EP |
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453 001 |
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EP |
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EP |
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EP |
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EP |
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629 398 |
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Dec 1994 |
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EP |
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0 629 398 |
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Dec 1994 |
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EP |
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Other References
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by examiner .
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targeting. S.T.P. Pharma Sciences 5(1):83-88 (1985). cited by
examiner .
Persson et al., "Multivariate Parameter Evaluation of
Pharmaceutically Important Cellulose Ethers," J. Pharm. Sci.
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Interf. Sci. 213:152-159 (1999). cited by other .
Record of Interference No. 104,611, between U.S. Pat. No.
5,788,987, the parent of this reissue application, and U.S. Appl.
No. 09/023,574, assigned to ALZA Corporation. cited by other .
Andreotti et al., "Major Circadian Fluctuations in Fibrinolytic
Factors and Possible Relevance to Time of Onset of Myocardial
Infarction, Sudden Cardiac Death and Stroke," Am. J. Cardiol.
62:635-637 (Sep. 1988). cited by other .
Braunwold, "Heart Disease, Third Edition--A Textbook of
Cardiovascular Medicine," vol. 2:1234-1235 (1988). cited by other
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Gazzaniga et al., "Time-dependent oral delivery systems for colon
targeting," S.T.P. Pharma Sciences 5(1):83-88 (1995). cited by
other .
K. Nishimura et al., "Dosage Form Design for Improvement of
Bioavailability of Levodopa VI: Formulation of Effervescent
Enteric-Coated Tablets," J. Parm. Sci. 73(7):942-946 (1984). cited
by other .
Ridker et al., "Circadian Variation of Acute Myocardial Infarction
and the Effect of Low-Dose Aspirin in a Randomized Trial of
Physicians," Circulation 82:897-902 (1990). cited by other.
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Primary Examiner: Dodson; Shelley A.
Assistant Examiner: George; Konata M.
Attorney, Agent or Firm: Townsend and Townsend and Crew
LLP
Claims
That which is claimed:
1. A method for treating an early morning pathology, said method
comprising administering to a subject in need of treatment, a
time-specific controlled release dosage formulation
.[.comprising.]. .Iadd.consisting essentially of .Iaddend.(1) a
core including at least one pharmaceutically active agent effective
for the treatment of said morning pathology, and (2) .[.a.].
.Iadd.an outer .Iaddend.swellable .Iadd.and erodible
.Iaddend.polymeric coating layer substantially surrounding said
core; wherein said formulation is administered prior to sleep, and
wherein said swellable polymeric coating layer delays the release
of said pharmaceutically active agent from said core for a
predetermined period of time dependent upon the thickness of said
swellable polymeric coating layer, to permit delivery of said
pharmaceutically active agent at about the time of awakening and to
treat said early morning pathology.
2. The method according to claim 1, wherein said early morning
pathology is asthma and said pharmaceutically active agent is
selected from the group consisting of steroids, xanthines,
beta-2-agonist bronchodilators, and anti-asthmatic non-steroidal
antiinflammatory agents.
3. The method according to claim 2, wherein said pharmaceutically
active agent is selected from the group consisting of
betamethasone, dexamethasone, methylprednisolone, prednisolone,
prednisone, triamcinolone, theophylline, aminophylline,
doxophylline, salbutamol, fenoterol, clenbuterol, bambuterol, and
sodium cromoglycate.
4. The method according to claim 1, wherein said early morning
pathology is angina and said pharmaceutically active agent is
selected from the group consisting of antiangina agents.
5. The method according to claim 4, wherein said pharmaceutically
active agent is selected from the group consisting of isosorbide
mononitrate, and isosorbide dinitrate.
6. The method according to claim 1, wherein said early morning
pathology is arthritis and said pharmaceutically active agent is an
antiarthritis non-steroidal antiinflammatory agents.
7. The method according to claim 6, wherein said pharmaceutically
active agent is selected from the group consisting of sulfides,
mesalamine, salazopyrin, diclofenac, pharmaceutically acceptable
salts of diclofenac, nimesulide, ketoprofen, and piroxicam.
8. The method according to claim 1, wherein said early morning
pathology is hypertension and said pharmaceutically active agent is
selected from the group consisting of calcium antagonists,
angiotensin-converting enzyme inhibitors, beta-blockers, centrally
active alpha-agonists, and alpha-1-antagonists.
9. The method according to claim 1, wherein said early morning
pathology is myocardial or cerebral infarction and said
pharmaceutically active agent is selected from the group consisting
of anticoagulant agents and antiplatelet agents.
10. The method according to claim 9, wherein said pharmaceutically
active agent is selected from the group consisting of warfarin,
acetylsalicylic acid, and ticlopidine.
11. The method according to claim 1, wherein said early morning
pathology is Parkinson's disease or Parkinsonism and said
pharmaceutically active agent is selected from the group consisting
of dopamine, L-Dopa/Carbidopa, selegiline, dihydroergocryptine, and
bromocriptine.
12. The method according to claim 1, wherein said early morning
pathology is sleep disorder, and said pharmaceutically active agent
is selected from the group consisting of sedatives and ansiolytic
agents.
13. The method according to claim 12, wherein said pharmaceutically
active agent is a benzodiazepine.
14. The method according to claim 1, wherein said early morning
pathology is incontinence, and said pharmaceutically active agent
is selected from the group consisting of
anticholinergic/antispasmodic agents and vasopressin analogues.
15. The method according to claim 14, wherein said pharmaceutically
active agent is selected from the group consisting of flavoxate,
oxybutynin, and desmopressine.
16. The method according to claim 1, wherein said formulation is
administered orally prior to sleep.
17. The method according to claim 1, wherein said swellable
polymeric coating layer comprises a hydrophilic swellable polymer
selected from the group consisting of methylcellulose,
carboxymethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose,
polyvinyolpyrrolidone, polyvinyl alcohol, acrylic acid polymer,
methacrylic acid copolymers, ethyl acrylate-methyl methacrylate
copolymers, natural rubbers, poloxamers, polysaccharides, and
mixtures thereof.
18. The method according to claim 1, wherein said swellable
polymeric coating layer is applied to said core by film
coating.
19. The method according to claim 1, wherein said swellable
polymeric coating layer is applied to said core by alternately (i)
wetting said core with a binder solution and (ii) coating said core
with powdered polymeric coating particles, a sufficient number of
times to produce the desired thickness of swellable polymeric
coating layer.
20. The method according to claim 19, wherein said binder solution
is selected from the group consisting of polyvinylpyrrolidone,
hydroxypropylmethylcellulose, polyvinyl alcohol,
hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose,
methacrylic acid copolymers, ethyacrylate-methylmethacrylate
copolymers, guar gum, arabic gum, xanthan gum, gelatine, pectin and
mixtures thereof; and said powdered polymeric coating particles
comprise a hydrophilic swellable polymer selected from the group
consisting of methylcellulose, carboxymethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, polyvinylolpyrrolidone, polyvinyl alcohol,
acrylic acid polymer, methacrylic acid copolymers, ethyl
acrylate-methyl methacrylate copolymers, natural rubbers,
poloxamers, polysaccharides, and mixtures thereof.
21. The method according to claim 1, wherein said swellable
polymeric coating layer comprises hydroxypropylmethylcellulose.
22. The method according to claim 1, wherein said swellable
polymeric coating layer comprises a mixture of 1)
hydroxypropylmethylcellose having a typical weight percent
substitution corresponding to 29% methoxyl and 8% hydroxypropoxyl
groups, and a nominal viscosity of 2% water solution at 20.degree.
C. ranging from 3 to 100 mPa.s; and 2) hydroxypropylmethylcellulose
having a typical weight percent substitution corresponding to 22.1%
methoxyl and 8.1% hydroxypropoxyl groups, and a nominal viscosity
of 2% water solution at 20.degree. C. ranging from 4,000 to 100,000
mPa.s.
23. The method according to claim 1, wherein said swellable
polymeric coating layer is sufficiently thick to achieve a
core:coating layer weight ratio of between about 20:1 and about
1:5.
24. The method according to claim 1, wherein said swellable
polymeric coating layer is sufficiently thick to achieve a
core:coating layer weight ratio of between about 5:1 and about
1:3.
25. The method according to claim 1, wherein said swellable
polymeric coating layer is not less than about 50 .mu.m thick.
26. The method according to claim 1, wherein said core further
comprises a disintegration enhancing agent.
27. The method according to claim 26, wherein said disintegration
enhancing agent is selected from the group consisting of citric
acid, tartaric acid, fumaric acid, maleic acid, succinic acid,
succinic anhydride, maleic anhydride, sodium dihydrogen phosphate,
disodium dihydrogen pyrophosphate, sodium dihydrogen citrate,
disodium hydrogen citrate, sodium bicarbonate, sodium carbonate,
potassium bicarbonate, potassium carbonate, sodium sesquicarbonate,
glycine sodium carbonate, calcium carbonate, L-lysine carbonate,
and arginine carbonate.
.Iadd.28. A method for treating an early morning pathology, said
method comprising administering to a subject in need of treatment a
time-specific controlled release dosage formulation comprising: (1)
a core including at least one pharmaceutically active agent
effective for the treatment of said morning pathology, and (2) an
outer swellable polymeric coating layer substantially surrounding
said core; wherein said formulation is administered prior to sleep,
and wherein swelling and erosion of said swellable polymeric
coating layer inhibits the release of said pharmaceutically active
agent from said core for a predetermined period of time dependent
solely upon the thickness of said swellable polymeric coating
layer, to permit delivery of said pharmaceutically active agent at
about the time of awakening and to treat said early morning
pathology..Iaddend.
.Iadd.29. A method for treating an early morning pathology, said
method comprising administering to a subject in need of treatment,
a time-specific controlled release dosage formulation comprising:
(1) a core including at least one pharmaceutically active agent
effective for the treatment of said morning pathology, and (2) an
outer, erodible, swellable polymeric coating layer consisting
essentially of at least one swellable polymer substantially
surrounding said core; wherein said formulation is administered
prior to sleep, and wherein the time delay before release of said
pharmaceutically active agent from said core is solely dependent on
the thickness of said swellable polymer, to permit delivery of said
pharmaceutically active agent at about the time of awakening and to
treat said early morning pathology..Iaddend.
.Iadd.30. A method for treating an early morning pathology, said
method comprising administering to a subject in need of treatment a
time-specific controlled release dosage formulation comprising: (1)
a core including at least one pharmaceutically active agent
effective for the treatment of said morning pathology, and (2) an
outer, erodible swellable polymeric coating layer consisting
essentially of at least one swellable polymer substantially
surrounding said core; wherein said formulation is administered
prior to sleep, and wherein said swellable polymeric coating layer
controls the time delay before release of said pharmaceutically
active agent from said core for a predetermined period of time
dependent upon the thickness of said swellable polymeric coating
layer, to permit delivery of said pharmaceutically active agent at
about the time of awakening and to treat said early morning
pathology..Iaddend.
.Iadd.31. A method for treating an early morning pathology, said
method comprising administering to a subject in need of treatment a
time-specific controlled release dosage formulation consisting
essentially of: a first time-specific dosage unit consisting
essentially of: (1) a first core including a pharmaceutically
active agent effective for the treatment of said morning pathology
and a disintegration enhancing agent, and (2) a first, outer
swellable and erodible polymeric coating layer substantially
surrounding said core; wherein the thickness of said first
swellable polymeric coating layer controls the release of said
pharmaceutically active agent from said first core for a
predetermined period of time dependent upon the thickness of said
first swellable polymeric coating layer; and a second time-specific
dosage unit consisting essentially of: (1) a second core including
the pharmaceutically active agent effective for the treatment of
said morning pathology, and (2) a second swellable and erodible
polymeric coating layer substantially surrounding said core;
wherein the thickness of said second swellable polymeric coating
layer controls the release of said pharmaceutically active agent
from said second core for a predetermined period of time dependent
upon the thickness of said second swellable polymeric coating
layer, wherein said formulation is administered to the subject
prior to sleep, to permit delivery of said pharmaceutically active
agent at about the time of awakening, and to treat said early
morning pathology..Iaddend.
Description
FIELD OF THE INVENTION
The present invention relates to methods for medical treatment.
More particularly, the present invention relates to methods for
treating conditions or pathologies, the symptoms of which are more
pronounced in early morning.
BACKGROUND OF THE INVENTION
It is increasingly recognized that several chronic diseases display
rhythmic patterns in the manifestation of symptoms. In this field
there is particular interest in those conditions for which symptoms
are generally aggravated in the morning. These early morning
pathologies are typically treated by either night-time
administration of conventional medicines or relatively constant
administration of therapeutic agents with the goal of maintaining
constant levels of drug in the system of the afflicted subject. By
this protocol, the therapeutic benefit of the drag is assured at
the time of awakening when the symptoms are generally more
pronounced. Unfortunately, the low compliance of patients or the
continual exposure of the system to therapeutic agents may be
undesirable in some subjects or some situations. In an ideal
clinical situation, drug treatment would result in highest peak
plasma concentrations around the time of most frequent occurrence
of symptoms. In this instance the ideal drug delivery system should
allow administration at bed-time and delay the release of the drug
for as many hours as is required to reach therapeutic blood levels
at the more appropriate time.
Accordingly, it is an object of the present invention to provide
methods of treating early morning pathologies which provide
therapeutic benefits to the subject suffering therefrom while
avoiding unnecessary exposure of the body to the therapeutic agent.
It is a further object of the present invention to provide a
pharmaceutical formulation for the time-specific delivery of a
pharmaceutically active agent for the treatment of early morning
pathologies.
SUMMARY OF THE INVENTION
As a first aspect, the present invention provides a method for
treating an early morning pathology. As used herein, the phrase
"early morning pathology" relates to a pathologies, conditions,
disorders, diseases, or other illnesses the symptoms of which are
typically more pronounced, aggravated or acute during the last
hours of sleeping-time or after the afflicted subject awakens from
sleep. Most humans sleep at night, however, some humans have
alternate sleep schedules. Therefore, the term "early morning"
relates to the state of awakening from sleep as opposed to the time
of day. Individuals whose sleep schedule involves sleeping during
the daytime and working at night may exhibit some of these
pathologies in the evening or night when they awaken from
sleep.
The methods of the present invention comprise administering to a
subject in need of treatment, a time-specific controlled release
dosage formulation which is administered prior to sleep, and which
permits or achieves delivery of a pharmaceutically active agent
effective for the treatment of the specific morning pathology to be
treated, at about the time of awakening or a few hours in advance
of awakening. The time-specific controlled release dosage
formulation comprises (1) a core including the pharmaceutically
active agent(s) effective for the treatment of the early morning
pathology, and (2) a swellable polymeric coating layer
substantially surrounding the core. The swellable polymeric coating
layer delays the release of the pharmaceutically active agent from
the core for a predetermined period of time dependent upon the
thickness of the swellable polymeric coating layer, to effect
delivery of the pharmaceutically active agent at the more
appropriate time (e.g., at about the time of awakening).
As a second aspect, the present invention provides a pharmaceutical
formulation for the time-specific delivery of a pharmaceutically
active agent to a subject in need of the therapeutic effects
thereof. The formulation comprises: (1) a core comprising the
pharmaceutically active agent and a disintegration enhancing agent;
and (2) a swellable polymeric coating layer substantially
surrounding the core. The swellable polymeric coating layer delays
the release of said pharmaceutically active agent from the core for
a predetermined period of time dependent upon the thickness of said
swellable polymeric coating layer. The disintegration enhancing
agent accelerates the disintegration of the core upon
disintegration of the swellable polymeric coating layer to improve
the rate of release of the pharmaceutically active agent from the
core when the desired time for release is reached.
As a third aspect, the present invention provides a pharmaceutical
formulation for the time-specific delivery of a pharmaceutically
active agent to a subject in need thereof. The formulation
comprises: (1) a first time-specific dosage unit comprising (a) a
core containing the pharmaceutically active agent and a
disintegration enhancing agent; and (b) a swellable polymeric
coating layer substantially surrounding the core; and (2) a second
time-specific dosage unit comprising (a) a core containing the
pharmaceutically active agent; and (b) a swellable polymeric
coating layer substantially surrounding the core. The swellable
polymeric coating layer delays the release of the pharmaceutically
active agent from the core for a predetermined period of time
dependent upon the thickness of the swellable polymeric coating
layer. The disintegration enhancing agent accelerates the
disintegration of the core upon dissolution of the swellable
polymeric coating layer to improve the rate of release of the
pharmaceutically active agent from the core. In this embodiment,
the core containing the active ingredient may be differently
formulated so as to allow the prompt release of the active
component or a further controlled or sustained release, after the
desired lag-time. For this purpose, either conventional core
excipients or excipients which are capable of forming a matrix
system may be used.
These and other objects and aspects of the present invention are
set forth in further detail in the detailed description and
examples hereinbelow.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides methods of treating morning
pathologies. Examples of specific late night-time or early morning
pathologies include but are not limited to, asthma, angina,
hypertension, myocardial or cerebral infarction, arthritis,
incontinence, Parkinson's disease or Parkinsonism and sleep
disorders (e.g. those related to anticipated wakening). In each of
these conditions, the symptoms of the condition are typically
aggravated, more acute, or worse during the night, or just after
the subject awakens. The term "sleep" as used herein refers to a
prolonged period of rest during which the individual exhibits
decreased activity. Typically sleep is a period of rest lasting for
3 or more hours, more typically about 6-8 hours for most adult
humans. The term "sleep" as used herein relates to periods of
resting wherein all the clinical stages of sleep are not achieved
as well as periods of rest wherein all the clinical stages of sleep
are achieved. The term "awaken" or "awakening" relates to the
physical condition of arousal from sleeping or resting, and is
characterized by an increase in the level of physical activity. The
period of awakening is generally understood to occur from about 4
or more hours after the commencement of sleep.
The methods and pharmaceutical formulations of the present
invention are useful for the treatment of the foregoing late
night-time or early morning pathologies is that the methods and
formulations of the present invention are useful for effecting the
delivery of a pharmaceutically active agent at about late
night-time or early morning, at which time the symptoms of early
morning pathologies are typically aggravated or more acute. The
specific pharmaceutically active agents employed in the methods and
formulations of the present invention will of course, depend upon
the specific morning pathology which is desireously treated. The
pharmaceutically active agent delivered according the methods of
the present invention or using the formulations of the present
invention is a pharmaceutically active agent which is
therapeutically effective against the condition or pathology being
treated.
Examples of specific pharmaceutically active agents which may be
included in the pharmaceutical formulations of the present
invention include but are not limited to antiasthmatics, antiangina
agents, antiarthritis agents, antiarrhythmic and antihypertensive
agents, anticoagulant and antiplatelet agents, anti-Parkinson
agents, sedatives, ansiolytic agents, anticholinergic and
antispasmodic agents, vasopressin analogues, and peptide and
biopolymeric agents.
In the embodiment wherein the early morning pathology which is
desireously treated is asthma, the pharmaceutically active agent of
the formulation is an antiasthmatic agent. Specific examples of
antiasthmatic agents include but are not limited to steroids, such
as betamethasone, dexamethasone, methylprednisolone, prednisolone,
prednisone, triamcinolone and the like; xanthines such as
theophylline, aminophylline, doxophylline, and the like;
beta-2-broncodilators, such as salbutamol, fenoterol, clenbuterol,
bambuterol, salmeterol, formoterol and the like; and antiasthmatic
antiinflammatory agents such as sodium cromoglycate, and the
like.
In the embodiment wherein the early morning pathology which is
desireously treated is angina, the pharmaceutically active agent of
the formulation is an antiangina agent. Specific examples of
antiangina agents include but are not limited to isosorbide
mononitrate, isosorbide dinitrate, and the like.
In the embodiment wherein the early morning pathology which is
desireously treated is arthritis, the pharmaceutically active agent
of the formulation is an antiarthritis agent. Specific examples of
antiarthritis agents include but are not limited to antiarthritis
non-steroidal antiinflammatory agents such as sulfides, mesalamine,
salazopyrin, diclofenac, pharmaceutically acceptable salts of
diclofenac, nimesulide, ketoprofen, piroxicam, naproxene, ibuprofen
and the like.
In the embodiment wherein the early morning pathology which is
desireously treated is arrythmia or hypertension, the
pharmaceutically active agent of the formulation is an
antiarrhythmic or antihypertension agent. Specific examples of
antiarrhythmic or antihypertension agents include but are not
limited to calcium antagonists, angiotensin-converting enzyme
inhibitors, beta-blockers, centrally active alpha-agonists,
alpha-1-antagonists, and the like.
In the embodiment wherein the early morning pathology which is
desireously treated is myocardial or cerebral infarction, the
pharmaceutically active agent of the formulation is an
anticoagulant or antiplatelet agent. Specific examples of
anticoagulant or antiplatelet agents include but are not limited to
warfarin, acetylsalicylic acid, ticlopidine, and the like.
In the embodiment wherein the early morning pathology which is
desireously treated is Parkinson's disease or Parkinsonism, the
pharmaceutically active agent of the formulation is an
antiParkinsons's agent. Specific examples of antiParkinson's agents
include but are not limited to dopamine, L-Dopa/Carbidopa,
selegiline, dihydroergocryptine, bromocriptine, pergolide,
lisuride, apomorphine and the like.
In the embodiment wherein the early morning pathology which is
desireously treated is sleep disorder such as those associated with
anticipated wakening, the pharmaceutically active agent of the
formulation is a sedative or ansiolytic agent. Specific examples of
sedative or ansiolytic agents include but are not limited to
benzodiazepines and the like.
In the embodiment wherein the early morning pathology which is
desireously treated is incontinence, the pharmaceutically active
agent of the formulation is a anticholinergic or antispasmodic
agent or a vasopressin analogue. Specific examples of
anticholinergic or antispasmodic agents and vasopressin analogues
include but are not limited to flavoxate, oxybutynin, desmopressin,
and the like.
Specific examples of suitable peptide or biopolymeric agents
include but are not limited to calcitonin, leuprolide and other
LHRH agonists, hirudin, cyclosporin, insulin, somatostatin,
protirelin, interferon, desmopressin, thymopentin, pidotimod,
ematopoietin, melatonin, granulokyne, and heparin.
The core of the time-specific formulation of the present invention
may also include one or more pharmaceutically acceptable excipients
in addition to the pharmaceutically active agent. Pharmaceutically
acceptable excipients which may be employed are well known to those
skilled in the art and include any conventional pharmaceutically
acceptable tabletting excipients. Examples of suitable excipients
include but are not limited to microcrystalline cellulose, dibasic
calcium phosphate dihydrate, starch, sodium starch glycolate,
crospovidone, croscarmellose sodium, magnesium stearate, lactose,
maleic acid, colloidal silicon dioxide, talc, and glyceryl
behenate.
In one particularly preferred embodiment, the core of the
time-specific formulation includes, in addition to the
pharmaceutically acceptable agent, a disintegration enhancing
agent. The disintegration enhancing agent accelerates the
disintegration of the core once the swellable polymeric coating
layer is removed by dissolution or erosion. The disintegration
enhancing agent provides the advantage that the pharmaceutically
active agent is more readily delivered to the system by virtue of
the faster disintegration of the core. The faster delivery of the
pharmaceutically active agent to the system which results from the
presence of the disintegration enhancing agent within the core
advantageously produces a "spike" in the level of pharmaceutically
active agent in the system. Thus, in the embodiment wherein the
disintegration enhancing agent is present in the core, the
pharmaceutically active agent is delivered substantially faster
which causes the level of pharmaceutically active agent in the
system to rapidly reach the maximum level, rather than more slowly
as a stream which gradually reaches the maximum level of delivered
drug. Suitable disintegration enhancing agents for use in the
methods of the present invention include pharmaceutically
acceptable excipients capable of generating effervescence. Specific
examples of suitable disintegration enhancing agents include but
are not limited to food acids, such as citric acid, tartaric acid,
fumaric acid, maleic acid, succinic acid, and the like; acid
anhydrides, such as succinic anhydride, fumaric anhydride, and the
like; acid salts such as sodium dihydrogen phosphate, disodium
dihydrogen pyrophosphate, sodium dihydrogen citrate, disodium
hydrogen citrate, and the like; and carbonates such as sodium
bicarbonate, sodium carbonate, potassium bicarbonate, potassium
carbonate, sodium sesquicarbonate, calcium carbonate, glycine
sodium carbonate, L-lysine carbonate, arginine carbonate, and the
like.
The core can be prepared by any suitable tabletting technique known
to those skilled in the art. For example, the pharmaceutically
active ingredient may be admixed with the excipient(s) and, if
present, the disintegration enhancing agent, and advantageously
formed into a tablet using a conventional tabletting press, or
dosed into a capsule.
According to the methods and formulations of the present invention,
the preformed core, is substantially surrounded by a swellable
polymeric coating layer. The swellable polymeric coating layer
typically comprises a hydrophilic gelling polymer or "swellable
polymer" which swells on contact with gastro-intestinal juices to
form a continuous film surrounding the core. The coating layer must
sufficiently protect the integrity of the core for the desired
period of time, without regard to the pH of the medium to which it
is subjected. Once the desired, pre-delivery time period has
elapsed, the core should be capable of relatively quick
disintegration so that the pharmaceutically active agent is
released as quickly as possible at the predetermined delivery time.
Thus, it is desirable that the formulation be capable of the fast,
time-specific release of the pharmaceutically active agent. The
polymeric coating layer may be comprised of any suitable
hydrophilic gelling polymer known to those skilled in the art. For
example, suitable hydrophilic gelling polymers include but are not
limited to cellulosic polymers, such as methylcellulose,
carboxymethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose, and the like;
vinyl polymers, such as polyvinylpyrrolidone, polyvinyl alcohol,
and the like; acrylic polymers and copolymers, such as acrylic acid
polymer, methacrylic acid copolymers, ethyl acrylate-methyl
methacrylate copolymers, and the like; and mixtures thereof.
Currently, the preferred swellable polymeric coating layer
comprises hydroxypropylmethylcellulose.
Alternatively, the swellable polymeric coating layer may be
comprised of other substances which are capable of becoming freely
permeable with exactly defined kinetics following hydration in
aqueous fluids. Such substances include polysaccharides, such as
gelatin, saccharose, sorbitol, mannaese, and jaluronic acid;
polyaminoacids; polyalcohols; polyglycols; and the like
In addition to the foregoing, the swellable polymeric coating layer
may also include additional excipients such as lubricants, flow
promoting agents, plasticizers, antisticking agents, natural and
synthetic flavorings and natural and synthetic colorants. Specific
examples of additional excipients include polyethylene glycol,
polyvinylpyrrolidone, talc, magnesium stearate, glyceryl behenate,
stearic acid, and titanium dioxide.
The swellable polymeric coating layer may be applied to the core
using conventional film (or spray) coating techniques, double press
coating or by the inventors' new method involving the alternate
application of binder and powdered polymeric coating particles. In
one preferred embodiment, the swellable polymeric coating layer is
applied using film coating techniques whereby the hydrophilic
gelling polymer is solubilized in an aqueous solution. Typically,
the polymer used for film coating exhibits a viscosity ranging from
about 3 to 100 mPa.s. at 25.degree. C. in a 2% aqueous
solution.
Although some organic solvents may be employed in the film coating
application of the swellable polymeric coating layer, the inclusion
of organic solvents in the film coating solution utilized in the
methods of the present invention is not required.
The solution of hydrophilic gelling polymer can be applied to the
core by any means of film coating including but not limited to
fluid bed, or pan coating. Preferably, the solution of polymer is
sprayed on the core to form the swellable polymeric coating
layer.
The polymer is applied on the core (preferably by film-coating) in
order to build the desired thickness of the swellable polymeric
coating layer. For example, in the embodiment wherein film coating
is employed, the core is sprayed with the solution of polymer until
the desired thickness of swellable polymeric coating layer is
achieved.
In another preferred embodiment, the swellable polymeric coating
layer is applied to the core by an alternating two-step application
of a binder solution and powdered polymeric coating particles. In
the first step, the core is wet with the binder solution which
serves to adhere the powdered polymeric coating particles to the
core. Suitable binder solutions may include conventional
pharmaceutically acceptable binder agents solubilized in a suitable
solvent. Specific examples of binder agents include but are not
limited to vinyl polymers, such as polyvinylpyrrolidone, polyvinyl
alcohol, and the like; cellulosic polymers, such as
hydroxypropylmethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, and the like; acrylic polymers and
copolymers such as methacrylic acid copolymers, ethyl
acrylate-methylmethacrylate copolymers, and the like; natural or
synthetic gums, such as guar gum, arabic gum, xanthan gum, and the
like; proteins or carbohydrates, such as gelatin, pectin, and the
like; and mixtures thereof. Currently, polyvinylpyrrolidone is the
preferred binder agent.
Suitable solvents for solubilizing the binder agents include
solvents which are capable of substantially completely solubilizing
the specific binder agent(s) selected and which are
pharmaceutically and biologically acceptable for ingestion.
Suitable solvents will be readily determinable by those skilled in
the art. Water is currently the preferred solvent for solubilizing
the binder agent, as it is pharmacologically and biologically well
suited for ingestion. However, other examples of suitable solvents
will be appreciated by those skilled in the art and are
contemplated by the methods of the present invention.
The binder solution should be of sufficient viscosity to enable the
wetting of the cores by any suitable wetting technique known to
those skilled in the art. For example, the cores may be wetted with
the binder solution by rotating the cores in a bath containing the
binder solution. The cores may be suitably wetted by manual
application of the binder solution by ladling the binder solution
over the cores as the cores are rotating in a conventional coating
pan. Alternatively, the cores may be wetted by spraying the binder
solution on the cores. In one embodiment, the wetting step is
advantageously carried out using conventional automated pan coating
equipment wherein the cores are sprayed with the binder solution
while rotating in the pan.
To provide the coating layer, the wetted cores are coated with dry,
powdered polymeric coating particles which adhere to the
binder-wetted core due to the presence of the binder on the surface
of the core. The polymeric coating particles typically comprise a
hydrophilic gelling polymer or "swellable" polymer which swells on
contact with gastro-intestinal juices to form a continuous film
surrounding the core, as described herein above. Currently, the
preferred powdered polymeric particles comprise
hydroxypropylmethylcellulose.
Hydroxypropylmethylcellulose is a polymer which is available in
many forms, including forms of different molecular weight,
extremely different viscosity and different substitution grade. The
inventors have also discovered that it is advantageous in certain
applications to utilize mixtures or blends of two or more different
forms of hydroxypropylmethylcellulose as the polymeric coating
particles. In one preferred embodiment, the polymeric coating
particles of the coating layer comprise a mixture of polymeric
coating particles having differing molecular weights and solubility
characteristics. For example, the coating layer may be comprised of
polymeric coating particles comprising a mixture of a)
hydroxypropylmethylcellulose having i) a typical weight percent
substitution corresponding to 29% methoxyl and 8% hydroxypropoxyl
groups, and ii) a nominal viscosity of a 2% watery solution at
20.degree. C. ranging from 3 to 100 mPa.s; and b)
hydroxypropylmethylcellulose having i) a typical weight percent
substitution corresponding to 22.1% methyoxyl and 8.1%
hydroxypropoxyl groups, and ii) a nominal viscosity of a 2% watery
solution at 20.degree. C. ranging from 4,000 to 100,000 mPa.s. An
example of the first type of hydroxypropylmethylcellulose is
METHOCEL E5.RTM., and an example of the second type is METHOCEL
K15M.RTM., both of which are commercially available from
Colorcon.
The polymer(s) of the swellable polymeric coating layer partially
hydrates on the outer surface thereof after ingestion to form a
gel-like layer that acts as a skin, controlling the rate of erosion
of the coating layer. As a consequence, the release of delivery of
the pharmaceutically active agent contained within the core is
inhibited for the predetermined period of time.
Grades of hydroxypropylmethylcellulose having different degrees of
substitution also possess different rates of hydration. The
inventors have discovered that by utilizing mixtures or blends of
two or more polymers with different rates of hydration, it is
possible to obtain a layer with improved characteristics in terms
of the rate-controlled hydration of the same.
Because the formulations and methods of the present invention may
include either a single hydroxypropylmethylcellulose or a blend of
two or more different forms of hydroxypropylmethylcellulose as the
powdered polymeric coating particles, for simplicity, the term
"hydroxypropylmethylcellulose" as used herein, including the
claims, refers to either a single hydroxypropylmethylcellulose or a
blend of two or more forms of the polymer.
After the powdered polymeric coating particles are applied to the
wetted core, the steps of first, wetting the core with binder and
second, coating with the powdered polymeric coating particles are
repeated sequentially one or more additional times in order to
build the desired thickness of the swellable polymeric coating
layer around the core. In other words, the alternating steps of
wetting the core and coating with the powdered polymeric coating
particles are repeated in alternate fashion so that prior to each
application of the powdered coating particles, the core is first
wetted with the binder solution. In this manner, the repeated
applications of binder solution and powdered polymeric coating
particles build or increase the thickness of the swellable
polymeric coating layer to the desired measure. The number of
repeated wetting and coating cycles is dependent upon the desired
delivery time of the pharmaceutically active agent. The thicker the
swellable polymeric coating layer around the core, the longer the
latency or lag time prior to delivery of the pharmaceutically
active agent.
The swellable layer may also be applied by double-press coating,
also known as compression-coating. The main advantage in comparison
with the film-coating or the sugar-coating procedure is the
elimination of water or other solvents during manufacturing. The
manufacturing scheme normally starts with the loading of the bottom
layer into the die from the hopper, then the core is centered on
the bed of coating, this operation is followed by the deposition of
the top layer of the coating. Finally, the whole is compressed by
passing the punches between the compression rolls.
Irrespective of the method of application, the swellable polymeric
coating layer is typically applied to the core to achieve the
desired predetermined thickness of swellable polymeric coating. The
desired predetermined thickness of the swellable polymeric coating
layer is dependent upon the desired lag time or delay prior to
delivery of the pharmaceutically active agent. The thicker the
swellable polymeric coating layer around the core, the longer the
latency, or lag time prior to delivery of the agent. Typically, the
swellable polymeric coating layer is applied to a thickness
sufficient to achieve a weight gain of between about 5 and about
500 percent, preferably between about 10 and about 200 percent as
determined by solid substance. The swellable polymeric coating
layer is sufficiently thick to provide a core:coating layer weight
ratio of between about 20:1 and about 1:5 inclusive, or a thickness
in excess of about 10 .mu.m up to about 3 mm, inclusive.
Preferably, the swellable polymeric coating layer is sufficiently
thick to achieve a core:coating layer weight ratio of between about
5:1 and about 1:3 inclusive, or a thickness of between about 50
.mu.m and about 1500 .mu.m.
The methods of the present invention for the treatment of early
morning pathologies are particularly advantageous because the
time-specific formulation of the present invention permits the
delivery of a pharmaceutically active agent at the time that the
therapeutic effects of the agent are needed and beneficial while
avoiding the constant exposure of the body to drug. Conventionally,
early morning pathologies are treated by maintaining constant
levels of the drug in the body so that the therapeutic effects of
the drug are continually present. However, the therapeutic effects
of the drug are generally not continuously required throughout the
night-time, and thus the maintenance of constant drug levels in the
subject causes unnecessary exposure to drug at times when the
therapeutic effects of the drug are not required. The methods of
the present invention avoid the unnecessary exposure of the body to
drug during those times when the therapeutic effects of the drug
are not needed (i.e., early during night-time just after the
subject falls asleep) while still providing the therapeutic effects
of the drug when needed, i.e., during late night-time and at the
period of awakening. This advantage is achieved by administering a
pharmaceutical formulation according to the present invention prior
to sleeping. The pharmaceutical formulation of the present
invention delays the release of the pharmaceutically active agent
so that the agent is delivered at about the last few hours of night
or sleep or at the time of awakening to treat the early morning
pathology. Although the formulation has been ingested prior to
sleeping, the pharmaceutically active agent is not delivered until
about the last few hours or night-time or sleeping or the time of
awakening so that the subject is not exposed to the
pharmaceutically active agent throughout the entire night.
In one embodiment, the time-specific formulation for use in the
methods of the present invention includes multiple time-specific
dosage units. The first time-specific dosage unit includes (1) a
core comprising the pharmaceutically active agent and a
disintegration enhancing agent, and (2) a swellable polymeric
coating layer substantially surrounding the core. The second
time-specific dosage unit includes (1) a core comprising the
pharmaceutically active agent without the disintegration enhancing
agent, and (2) a swellable polymeric coating layer substantially
surrounding the core. This multi-unit formulation is advantageous
in that the presence of the disintegration enhancing agent in the
first dosage unit causes the core of that unit of the formulation
to more quickly disintegrate and release the pharmaceutically
active agent more rapidly, compared to the second unit which does
not include the disintegration enhancing unit. The core of the
second unit disintegrates and releases the pharmaceutically active
agent more slowly and gradually, as compared to the first unit. The
disintegration of the first unit provides a quick delivery of the
pharmaceutically active agent while the slower disintegration of
the second unit provides a continuing delivery stream of
pharmaceutically active agent. The result is a single
pharmaceutical formulation which provides quick onset of the
therapeutic benefits of the pharmaceutically active agent with
prolonged effects of those benefits.
Suitable patient populations for which the methods and formulations
of the present invention are directed include mammals in general,
and in particular, humans.
This invention may be embodied in many different forms and should
not be construed as limited to the embodiments set forth herein;
rather, these embodiments are provided so that this disclosure will
be thorough and complete, and will fully convey the scope of the
invention to those skilled in the art. Many modifications and other
embodiments of the invention will come to mind in one skilled in
the art to which this invention pertains having the benefit of the
teachings presented in the foregoing descriptions and the
associated drawings. Therefore, it is to be understood that the
invention is not to be limited to the specific embodiments
disclosed. Although specific terms are employed, they are used in a
generic and descriptive sense only and not for purposes of
limitation, and that modifications and embodiments are intended to
be included within the scope of the appended claims.
The following examples are provided to further illustrate specific
embodiments of the present invention, and should not be construed
as limiting thereof. In these examples, "mg" means milligrams, "g"
means grams, "mm" means millimeters, ".mu.m" means micrometer, "kp"
means 9.807 Newton, "mPa.s" means milliPascal per second, "min."
means minute(s), and ".degree.C." means degrees Centigrade. All
percentages are in percent by weight of the tablet unless otherwise
indicated. Disintegration tests are carried out according to the
standard procedures set forth in the United States Pharmacopoeia
for testing the disintegration of tablets.
EXAMPLE 1
Diclofenac sodium (25 mg), 94.5 mg of dibasic calcium phosphate
dihydrate, 113 mg of microcrystalline cellulose, 25 mg of tartaric
acid, 25 mg of sodium bicarbonate and 1.5 mg of colloidal silicon
dioxide, are mixed thoroughly. Magnesium stearate (1 mg) is added
and thoroughly mixed for another 5 min. The granular mixture is
formed into tablet cores of 8.7 mm diameter, weighing 285 mg each,
using a rotary tablet press. The cores show a disintegration time
lower than 1 min. in water, a Schleuninger hardness higher than 10
kp, and a friability lower than 0.1%.
The swellable polymeric coating layer is applied on to the tablets
in an automatic coating pan using the following solution:
TABLE-US-00001 Hydroxypropylmethylcellulose 7.5% w/w (METHOCEL E50
.RTM.) PEG 6000 1.5% w/w Purified water 91.0% w/w
The solution is applied until a weight gain corresponding to 50% of
core weight is achieved. The coated tablets show a dissolution time
lag in excess of 300 min., followed by a quick disintegration of
the tablet.
EXAMPLE 2
Cores (20,000) containing 25 mg diclofenac sodium are prepared
according to Example 1.
The cores are heated to 40.degree. C. and the coating layer is
applied onto the cores in a two-step procedure, using an automatic
coating pan. In the first step, the cores are wetted with a binder
solution including 5% METHOCEL E5.RTM.. 10% polyvinylpyrrolidone,
and 85% purified water. In the second step, the wetted cores are
treated with a dry mixture including 90% METHOCEL K15M.RTM., 9%
talc and 1% colloidal silicon dioxide. Steps 1 and 2 are repeated
until a weight gain corresponding to 30% of total tablet weight is
achieved.
The coated tablets showed a dissolution time lag in excess of 300
min., followed by a quick disintegration of the tablet.
EXAMPLE 3
Verapamil HCl (40 mg), 79 mg of dibasic calcium phosphate
dehydrate, 18 mg of microcrystalline cellulose, 25 mg of citric
acid, 35 mg of sodium bicarbonate, and 2 mg of colloidal silicon
dioxide, are mixed thoroughly. Magnesium stearate (1 mg) is added
and thoroughly mixed for another 5 min. The granular mixture is
formed into tablet cores of 6.8 mm diameter, weighing 200 mg each
using a rotary tablet press. The cores show a disintegration time
lower than 1 min. in water, a Schleuninger hardness higher than 10
kp and a friability lower than 0.1%.
The cores are heated to 40.degree. C. and the coating layer is
applied onto the cores in a two-step procedure, using an automatic
coating pan. In the first step, the cores are wetted with a binder
solution including 5% METHOCEL E5.RTM., 10% polyvinylpyrrolidone,
and 85% purified water. In the second step, the wetted cores are
treated with a dry mixture including 90% METHOCEL K15M.RTM., 9%
talc and 1% colloidal silicon dioxide. Steps 1 and 2 are repeated
until a weight gain corresponding to 50% of total tablet weight is
achieved.
The coated tablets showed a dissolution time lag in excess of 300
min., followed by a quick disintegration of the tablet.
EXAMPLE 4
Isosorbide-5-mononitrate (20 mg), 135 mg of Lactose S.D., 34 mg of
microcrystalline cellulose, 30 mg of glycine sodium carbonate, 10
mg of fumaric acid, and 5 mg of colloidal silicon dioxide are mixed
thoroughly. Magnesium stearate (1 mg) is added and thoroughly mixed
for another 5 min. The granular mixture is formed into tablet cores
of 8.7 mm diameter, weighing 280 mg each using a rotary tablet
press. The cores show a disintegration time lower than 1 min. in
water, a Schleuninger hardness higher than 10 kp and a friability
lower than 0.1%.
The swellable polymeric coating layer is applied onto the tablets
in an automatic coating pan using the following solution:
TABLE-US-00002 Hydroxypropylmethylcellulose 8.0% w/w (METHOCEL E50
.RTM.) PEG 6000 2.0% w/w Purified water 90.0% w/w
The solution is applied until a weight gain corresponding to 50% of
core weight is achieved. The coated tablets show a dissolution time
lag in excess of 300 min., followed by a quick disintegration of
the tablet.
EXAMPLE 5
Tablet cores containing 1 mg of lorazepam as the active ingredient,
25 mg of tartaric acid, and 25 mg of sodium bicarbonate as an
effervescent disintegration enhancing agent are heated to
40.degree. C. and coated in a two-step procedure, using an
automatic coating pan. In the first step, the cores are wetted with
a binder solution including 15% polyvinylpyrrolidone and 85%
purified water. In the second step, the wetted cores are treated
with a dry mixture including 45% METHOCEL E5.RTM., 45% NATROSOL
HHR.RTM., 9% talc and 1% colloidal silicon dioxide. Steps 1 and 2
are repeated until a weight gain corresponding to 35% of total
tablet weight is achieved. The coating layer is determined to be
approximately 0.7-0.8 mm in thickness. The coating time was 6
hours. The coated tablets showed a disintegration time lag in
excess of 300 min.
EXAMPLE 6
Comparative Example--Fluid Bed Coating
Tablets containing 1 mg of lorazepam are coated with a coating
layer using a fluid bed apparatus. The cores are heated to
40.degree. C. and the coating layer is applied by continuously
spraying a solution including 7.5% METHOCEL E50.RTM., 0.5% PEG
6000.RTM., 1% colloidal silicon dioxide, and 91% purified water,
until a layer corresponding to 50% weight gain is applied. The
coated tablets showed a disintegration time lag in excess of 300
min.
EXAMPLE 7
Bromocryptine mesylate (2.87 mg), 30 mg of microcrystalline
cellulose, and 20 mg of maleic acid are mixed thoroughly. Lacose
S.D. (125.78 mg), 20 mg of sodium carbonate, 0.35 mg colloidal
silicon dioxide, and 1 mg magnesium stearate are added and
thoroughly mixed for another 10 min. The granular mixture is formed
into tablet cores of 6.8 mm diameter, weighing 200 mg using a
rotary tablet press. The cores show a disintegration time lower
than 1 min. in water, a Schleuninger hardness higher than 10 kp and
a friability lower than 0.1%.
The cores are heated to 40.degree. C. and the coating layer is
applied onto the cores in a two-step procedure, using an automatic
coating pan. In the first step, the cores are wetted with a binder
solution including 7% METHOCEL E50.RTM., 3% PEG 400.RTM., and 90%
purified water. In the second step, the wetted cores are treated
with a dry mixture including 90% METHOCEL K15M.RTM., 9% talc and 1%
colloidal silicon dioxide. Steps 1 and 2 are repeated until a
weight gain corresponding to 30% of total tablet weight is
achieved. The coated tablets showed a disintegration time lag in
excess of 5 hours followed by a rapid dissolution profile.
EXAMPLE 8
A capsule (I) containing a total amount of 75 mg of diclofenac
sodium is composed of: (II) a tablet containing 25 mg of diclofenac
sodium able to promptly release the active after about 5 hours from
the ingestion; and (III) two tablets containing each 25 mg of
diclofenac sodium able to start a sustained release of the active
ingredient after about 5 hours from the ingestion. The system is
manufactured as follows:
Tablets (II):
Diclofenac sodium (25 mg), 65 mg of dibasic calcium phosphate
dihydrate, 38 mg of microcrystalline cellulose, 25 mg of tartaric
acid, 25 mg of sodium bicarbonate and 1 mg of colloidal silicon
dioxide, are mixed thoroughly. Magnesium stearate (1 mg) is added
and thoroughly mixed for another 5 min. The granular mixture is
formed into tablet cores of 6 mm diameter, and about 5.8 mm high,
weighing 180 mg each, using a rotary tablet press. The cores show a
disintegration time lower than 1 min. in water, a Schleuninger
hardness higher than 10 kp and a friability lower than 0.1%. A
swellable polymeric coating layer is applied onto the tablets in an
automatic coating pan using the following solution:
TABLE-US-00003 Hydroxypropylmethylcellulose 7.5% w/w (METHOCEL E50
.RTM.) PEG 6000 1.5% w/w Purified water 91.0% w/w
The solution is applied until a weight gain corresponding to 50% of
core weight is achieved. The coated tablets show a dissolution time
lag in excess of 240 min., followed by a quick disintegration of
the tablet.
Tablets (III):
Diclofenac sodium (25 mg), 85 mg of dibasic calcium phosphate
dihydrate, 49 mg of microcrystalline cellulose, 20 mg of
hydroxypropylmethylcellulose (METHOCEL K15M.RTM.), are mixed
thoroughly. Magnesium stearate (1 mg) is added and thoroughly mixed
for another 5 min. The granular mixture is formed into tablet cores
of 6 mm diameter, and about 5.8 mm high, weighing 180 mg each,
using a rotary tablet press. The cores show a dissolution profile
of zero order until the 80% of the active is dissolved in more than
8 hours, a Schleuninger hardness higher than 10 kp and a friability
lower than 0.1%.
A swellable polymeric coating layer is applied onto the tablets in
an automatic coating pan using the same technological approach
described for Tablets (II).
The coated tablets show absence of dissolution for at least 240
min., followed by a sustained release of the active for more than 8
hours.
Capsules (I)
One tablet (II), and two tablets (III) are dosed into a capsule
size 00, corresponding to a total amount of 75 mg of diclofenac
sodium. The capsules show absence of dissolution for about 4 hours,
followed by a prompt dissolution of a fraction of 25 mg of the
active ingredient and the sustained release of the remaining 50 mg
of diclofenac sodium for at least 8 hours.
The foregoing is illustrative of the present invention and is not
to be construed as limiting thereof. The invention is defined by
the following claims, with equivalents of the claims to be included
therein.
* * * * *