U.S. patent application number 10/403146 was filed with the patent office on 2003-10-30 for sustained release oral formulations.
Invention is credited to Kalb, Oskar, Khanna, Satish Chandra, Ogorka, Jorg, Shah, Rajen.
Application Number | 20030203025 10/403146 |
Document ID | / |
Family ID | 27547321 |
Filed Date | 2003-10-30 |
United States Patent
Application |
20030203025 |
Kind Code |
A1 |
Ogorka, Jorg ; et
al. |
October 30, 2003 |
Sustained release oral formulations
Abstract
Pharmaceutical composition capable of releasing a
therapeutically effective dose of active agent, e.g.,
rivastigamine, in a time-controlled manner.
Inventors: |
Ogorka, Jorg; (Steinen,
DE) ; Kalb, Oskar; (Lorrach, DE) ; Shah,
Rajen; (Pune, IN) ; Khanna, Satish Chandra;
(Bottmingen, CH) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS, CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 430/2
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
27547321 |
Appl. No.: |
10/403146 |
Filed: |
March 31, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10403146 |
Mar 31, 2003 |
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10118183 |
Apr 8, 2002 |
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6565883 |
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10118183 |
Apr 8, 2002 |
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09818690 |
Mar 27, 2001 |
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09818690 |
Mar 27, 2001 |
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PCT/EP99/07298 |
Oct 1, 1999 |
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Current U.S.
Class: |
424/468 ;
514/490; 514/57 |
Current CPC
Class: |
A61K 9/2886 20130101;
A61K 9/2866 20130101; A61K 9/2077 20130101; A61K 9/5078 20130101;
A61K 9/5084 20130101; A61P 25/28 20180101; A61K 31/27 20130101 |
Class at
Publication: |
424/468 ; 514/57;
514/490 |
International
Class: |
A61K 031/325; A61K
031/717; A61K 009/22; A61K 031/27 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 1, 1998 |
GB |
9821298.8 |
Oct 1, 1998 |
GB |
9821299.6 |
Dec 3, 1998 |
GB |
9826654.7 |
Dec 16, 1998 |
GB |
9827624.9 |
Apr 6, 1999 |
GB |
9907822.2 |
Apr 6, 1999 |
GB |
9907823.0 |
Claims
1. A pharmaceutical composition comprising a first component
comprising a first active agent dose wherein on contact with water
70 to 95% of said dose is released within 3 to 4 hours, and a
second component comprising a second active agent dose, a water
soluble osmosis inducing agent and a water swellable excipient,
said second component having a water permeable coating which, in
use on contact with water, ruptures after a delay, and releases the
active agent.
2. A pharmaceutical composition according to claim 1, wherein the
coating in the second component is a semi-permeable membrane.
3. A pharmaceutical composition according to claim 1 or 2 wherein
the second component releases an effective dose of the active agent
6 to 12 hours after ingestion.
4. A pharmaceutical composition according to any one of claims 1 to
3 wherein the first component comprises a cellulose derivative
coating.
5. A pharmaceutical composition according to claim 4 wherein the
cellulose derivative coating comprises ethyl cellulose and
hydroxypropyl methylcellulose.
6. A pharmaceutical composition according to any one of claims 1 to
3 wherein the first component comprises the active agent in a
matrix.
7. A pharmaceutical composition according to claim 6 wherein in the
first component the active agent is in a hydrophilic gel forming
substance.
8. A pharmaceutical composition according to claim 7 wherein the
hydrophilic gel forming substance is present in a ratio of 10 to
50% by weight of the first component.
9. A pharmaceutical composition according to claim 7 or 8 wherein
the hydrophilic gel forming substance comprises
hydroxypropylmethylcellulose having a viscosity of 100,000
mPa-s.
10. A pharmaceutical composition according to any one of claims 1
to 9 wherein the second component has the following release
characteristics in water:
25 time (minutes) amount (percentage) 0 0-1 120 0-1 180 0-1 240
0-75 300 0-95 360 >99
11. A pharmaceutical composition according to any one of claims 1
to 10 wherein the active agent is rivastigmine.
12. A pharmaceutical composition according to any one of claims 1
to 11 comprising from 0.5 to 25% by weight of rivastigmine as
active agent of the total composition.
13. A pharmaceutical composition according to any one of claims 1
to 12 wherein the second component comprises a second coating.
14. A pharmaceutical composition comprising rivastigmine adapted so
that in use on oral administration a therapeutically effective dose
of rivastigmine is released only after 6 hours.
15. A pharmaceutical composition capable of releasing on
administration twice a therapeutically effective dose of
rivastigmine at different intervals upon oral administration.
16. A pharmaceutical oral controlled release tablet composition
comprising rivastigmine.
17. A pharmaceutical composition comprising Rivastigmine having the
following release characteristics in water:
26 time (minutes) amount (percentage) 30 1-40 60 10-60 120 40-80
180 60-90 240 65-95 300 70-99 360 75-99 420 >80
18. A controlled release, oral pharmaceutical composition
containing rivastigmine having the following release characteristic
in water or artificial stomach juices:
27 time (minutes) amount (percentage) 30 1-8 60 15-25 120 45-70 180
75-90 240 92-95 300 95-98 360 97-99 420 >99
19. A controlled release, oral pharmaceutical composition
containing rivastigmine having the following release characteristic
in water or artificial stomach juices:
28 time (minutes) amount (percentage) 30 5-25 60 25-45 120 50-70
180 65-80 240 70-90 300 75-95 360 80-90 420 85-95 480 85-95
20. A controlled release, oral pharmaceutical composition
containing rivastigmine having the following release characteristic
in water or artificial stomach juices:
29 time (minutes) amount (percentage) 30 25-40 60 45-65 120 65-85
180 75-95 240 75-96 300 85-97 360 87-98 420 90-98 480 90-99
21. A controlled release, oral pharmaceutical composition
containing rivastigmine wherein in use 50 to 80% of said
rivastigmine is released in artificial stomach juices within 3
hours.
22. A composition according to any one of claims 16 to 21
comprising coated particles.
23. A composition according to any one of claims 16 to 22
comprising coated pellets.
24. A composition according to Claim 22 or 23 wherein the coating
comprises a cellulose derivative.
25. A composition according to claim 24 wherein the cellulose
derivative comprises ethyl cellulose and hydroxypropyl
methylcellulose.
26. A pharmaceutical composition according to claim 16 or 17
wherein rivastigmine is in a hydrophilic swellable substance.
27. A pharmaceutical composition according to claim 26 wherein the
hydrophilic swellable substance comprises
hydroxypropylmethylcellulose 100,000 cps.
28. A pharmaceutical oral controlled release tablet composition
comprising rivastigmine having the following release characteristic
in water or artificial stomach juices:
30 time (minutes) amount (percentage) 30 28-35 60 40-55 120 58-75
180 70-90 240 80-95 300 88-98 360 >92
29. A pharmaceutical oral controlled release tablet composition
comprising rivastigmine wherein in use 60 to 90% of said
rivastigmine is released in artificial stomach juices within 3
hours.
30. Use of rivastigmine and excipients as defined in any one of
claims 1 to 29 in the manufacture of a medicament for the treatment
of patients with mild to moderately severe Dementia of the
Alzheimer's type by oral administration.
31. A pharmaceutical composition comprising a core coated with two
films, the first Inner film being a semi-permeable to water or body
fluids film applied directly on said core and comprising cellulose
acetate, the second outer film being a permeable to water or body
fluids film comprising ethylcellulose.
Description
[0001] This invention relates to a controlled release oral
pharmaceutical composition and more particularly to a unit dosage
that upon administration releases an active agent in a
time-controlled fashion.
[0002] Controlled release formulations may be formulated with
following aspects in mind:
[0003] a) the time until the release of active agent (lag time or
delay time)
[0004] b) the rate of release of active agent (fast or slow)
[0005] c) the duration of release of active agent (long or
short)
[0006] Such aspects may be observed in standard in vitro
dissolution tests, e.g., in-water or if desired in body fluids,
e.g., artificial gastric juices.
[0007] Little has been published on reliable time-controlled
release formulations allowing a release at a pre-determined time of
a single or repeated doses of active agents. There exists a need
for such formulations which are commercially acceptable.
[0008] After extensive testing, we have now found that it is
possible to produce a pharmaceutical composition capable of
releasing at a specific time, i.e., with a time delay or lag time,
a pharmaceutical active agent or active agent mixture, e.g.,
substantially independently of the concentration and type of ions
present in the gastrointestinal environment, e.g., hydrogen ions
and hydroxyl ions, i.e., independently of pH, phosphate ions, and
also independently of enzymes, present into the surrounding body
fluid.
[0009] The present invention provides in one aspect a
pharmaceutical composition comprising
[0010] a first component comprising a first active agent dose
wherein on contact with water (or body fluid) 70 to 95% of said
dose is released in water within 3 to 4 hours, and
[0011] a second component comprising a second active agent dose, a
water soluble osmosis inducing agent and a water swellable
excipient, said second component having a water (or body fluid)
permeable coating which, in use upon penetration by water, ruptures
after a certain delay time, e.g., due to the swelling of the
swellable excipient, and releases
[0012] (at a pre-determined time) the active agent
[0013] (hereafter referred to additionally as pharmaceutical
compositions of the present invention).
[0014] The present invention also provides a pharmaceutical
composition comprising
[0015] a first component comprising an active agent wherein 70 to
95% of said active agent in first component is released in water
within 3 to 4 hours, and
[0016] a second component comprising the active agent, a water
soluble osmosis inducing agent and a swellable excipient in water,
said second component having a coating which, upon penetration by
the aqueous fluids, breaks after a certain period due to the
swelling of the swellable excipient, and releases the active agent
at a pre-determined time.
[0017] By "within 3 to 4 hours" is meant that at the end of a
period of 3 to 4 hours the specified dose of active agent, e.g.,
>80% or >85%, has been released.
[0018] The active agent may be a single active agent or may be a
mixture. The active agent may be the same in the first and second
doses or different in each dose. Preferably the active agent is the
same.
[0019] In one embodiment, the coating for the second component is a
film, e.g., semi-permeable membrane. The swellable excipient swells
in presence of water or body fluid which penetrates through the
coating and creates mechanical pressure within the second component
thereby causing the coating to rupture or break and the system to
open, e.g., like a lid of a box. Also, the swellable excipient may
act as an osmotic agent drawing the water into the second
component. The thickness of the coating is one of the parameters
that controls the time delay, with more coating resulting in a
longer time delay.
[0020] It will be appreciated that the term "rupture" preferably
refers to breaching but it may also refer to any film system which
rapidly (e.g. over 30 minutes or less) dissolves or disappears or
changes its properties to permit egress of the active agent
[0021] In another aspect there is provided a controlled release
formulation, e.g., the second component, for releasing an active
agent dose after a lag time wherein the active agent is released 6
to 12 hours, e.g., 8 hours, after ingestion.
[0022] The second component may be coated with two films. A first
film is directly in contact with the second component and is
preferably a semi-permeable membrane. The second film may be a
semi-permeable (e.g., allowing the passage of e.g. water or active
agent in one direction) or permeable. The films used in this
embodiment may be, e.g., 2 to 5 times, thinner than the one used in
a one-film embodiment. Such a composition may provide if desired
longer delay times for the second component with a good release of
the second dose of active agent. It further provides certain
advantages as, e.g., reducing the amount of coating used.
[0023] By "first component" is meant a component capable of
releasing immediately or in a controlled manner, e.g., sustained
release, a first therapeutically effective dose of active agent
when said first component is put in contact with water or body
fluids.
[0024] By "second component" is meant a component capable of
releasing immediately or in a controlled manner, e.g., sustained
release, a second therapeutically effective dose of active agent
when said second component is contacted to water or body
fluids.
[0025] By "semi-permeable membrane" is meant a membrane suitable
for the passage of the water (or body fluid) into an active agent
containing core which is coated with said membrane and hinders
egress of a dissolved active agent out of the core.
[0026] By "film", "film-coating" or "membrane" is meant, unless
stated otherwise, a coating which is applied onto a core component,
e.g., the first or second component.
[0027] By "delay time or lag time" is meant the duration of time
between administration of the composition and the release of an
effective dose of active agent from the first or second
component.
[0028] A person skilled in art will appreciate that various plasma
profiles may be obtained by varying, e.g.,:
[0029] the composition of the first and/or second components, e.g.,
the nature and amount of excipients and/or active agent(s)
[0030] the delay time
[0031] the type of semi-permeable and/or non semi permeable
membrane
[0032] the speed and nature of the active agent release onset (e.g.
fast, slow, exponential, logarithmic, linear), which may depend on
the rate of rupture of the membrane.
[0033] The composition according to the invention may be used for
administrating a wide variety of active agents.
[0034] The composition according to the invention is suitable for
example for water-soluble and also water-insoluble, solid,
pharmaceutical active ingredients, which may be inorganic-or in
particular organic active substances, and are to be used in
accordance with their indication as analgesics, antipyretics,
antirheumatics, sedatives, hypnotic agents, anti-epileptics,
depressants and stimulants, anaesthetics, neuroleptic analgesics,
antihistamines, antihypertensive agents, anticoagulants,
antithrombotic agents, psychopharmacological agents, psycholeptics,
chemotherapeutic agents, e.g. antibiotics, sulphonamides,
antituberculosis agents (tuberculostatic agents) or also
chemotherapeutic agents against tropical infections, diuretics,
spasmolytics, cardiovascular agents, e.g. sympathomimetics,
antihypertensive agents, cardiac stimulants, e.g. cardiac
glycosides and digitaloids, parenteral sugar therapeutics,
analeptics acting on the central nervous system, geriatric agents,
tonolytics (of striated muscles), anti-Parkinson agents, cytostatic
agents, immunosuppressants, tonics and vitamins, according to B.
Helwig (Moderne Arzneimittel), 1980.
[0035] As antibiotics, penicillin, tetracycline,
chlorotetracycline, bacitracin, nystatin, streptomycin, neomycin,
polymicin, gramicidin, oxytetracyclin, chloramphenicol,
erythromycin, rifampicin, cefazolin, cefoxitin, cefsulodin,
cefotiam and mefoxin may be used, and as chemo-therapeutic agents
sulfamethazine, sulfamerazine, sulfamethizole and sulfisoxazole may
be used, as solid active ingredients for the presentation according
to the invention. In addition, e.g. as sedatives and hypnotic
agents chloral hydrate, pentabarbital, phenobarnital, secobarbital,
codeine and carbromal may be used, and as cardiac glycosides and
digitaloids digitoxin and digoxin may be used, and as
sympathomimetics epinephrine may be used as the solid active
substance in water-soluble form or water-insoluble form.
[0036] In particular, antipyretics, analgesics and antirheumatics
may be used as the solid active ingredient in the presentation
according to the invention in suitable water-soluble form or
water-insoluble form, for example propyphenazone, aminophenazone,
aspirin (ASA), antipyrine, methyl nifenazine, melaminsulfone,
sulfenazone, phenacetin, pentazocine, lactophenin, paracetamol,
quinine, flufenamic acid, mefenamic acid, tolfenamic acid,
meclofenamic acid, niflumic acid, clonixin or clonixidin, flunixin,
ibuprofen, suprofen, ketoprofen, fenoprofen, pirprofen, diclotenac,
ibufenac, procticic acid, naproxen, cicloprofen, tolmetin,
clopirac, tiaprofenic acid, oxaprozin, fenclozic acid, fentiazac,
clidanac, fenclonac, fenoprofen, flurbiprofen, carprofen, sulindac,
cinmetacin, fenbuten, etodolac, butifufen.
[0037] Most advantageously, psychopharmacological agents may be
used as the solid active ingredient in the presentation according
to the invention, e.g. neuroleptics, antidepressants, thymoleptics,
thymerethical drugs and tranquilisers in water-soluble form or
water-insoluble form, such as thioridazine, imipramine,
desimipramine, clomipramine, ketimipramine, opipramol,
amitriptyline, nortriptyline, reserpine, aromazine, chlorpromazine,
fluopromazine, methopromazine, trimeprazine, diethazine,
promethazine, aminopromazine, mepazine, pipamazine and
maprotiline.
[0038] In addition, antihypertensive agents, such as oxprenolol and
metoprolol may be used as the solid active ingredient in the
presentation.
[0039] In a preferred embodiment a composition according to the
present invention is used for administering Rivastigmine
(Exelon.RTM.) which is useful in the treatment of patients with
mild to moderately severe dementia of the Alzheimer type, also
known as Alzheimer's Disease.
[0040] Rivastigmine may be administered as the hydrogen tartrate
(hta) in unit dosage form, e.g., an immediate release capsule, at a
dose of from 0.5 mg to 6 mg twice a day.
[0041] Little has been published in detail on Rivastigmine's
biopharmaceutical properties in humans. it is rapidly and
completely absorbed. We have found that it is metabolised mainly
through hydrolysis by esterases, e.g., acetyl and butyryl
cholinesterase and has a plasma half life of 1 hour. It is subject
to pre-systemic and systemic metabolism. We now have found that
sustained release formulations of Rivastigmine may be produced with
advantageous properties, e.g., better tolerability. Suitable test
may be effected in fasted beagle dogs.
[0042] According to the present invention, Rivastigmine may be used
in the form of the free base or a pharmaceutically acceptable salt
thereof. Preferably the hydrogen tartrate (hta) is used.
[0043] The composition of the invention allows, e.g., the
manufacture of once a day pharmaceutical oral forms for patients
who have to take more than one dose of an active agent per day,
e.g., at specific times, so that their treatment is simplified.
With such compositions tolerability may be improved, e.g., with
Rivastigmine, and this may allow a higher starting dose and a
reduced number of dose titration steps.
[0044] In a further aspect the invention relates to a
pharmaceutical composition comprising rivastigmine adapted so that
in use on oral administration a therapeutically effective dose of
rivastigmine is released only after 6 hours (hereafter referred to
additionally as pharmaceutical compositions of the present
invention).
[0045] In a further aspect the invention relates to a
pharmaceutical composition capable of releasing twice on
administration a therapeutically effective dose of rivastigmine at
different intervals upon oral administration (hereafter referred to
additionally as pharmaceutical compositions of the present
invention).
[0046] In preferred pharmaceutical composition of the invention, a
first therapeutically effective dose of rivastigmine is released
within 3 to 4 hours of ingestion and, subsequently, a second
therapeutically effective dose of rivastigmine is released 6 to 12,
preferably 8 to 10 hours, after ingestion.
[0047] The first component may be produced, e.g., by any
conventional methods to provide the desired controlled release
characteristics. It may be produced in solid form, e.g. a tablet,
(e.g., a matrix-tablet), coated particles (e.g., non-pareilles) or
pellets, e.g., coated pellets.
[0048] In one embodiment of said first component, the active agent
is incorporated in a hydrophilic substance forming a gel substance
on contact with water, e.g., which may be present in a ratio of
from 10 to 50%, e.g., 15 to 45%, by weight of the first component,
e.g., in the form of a controlled release tablet formulation, e.g.,
a matrix-tablet.
[0049] Hydrophilic gel forming substances commonly used in tablet
formulations may be used and reference is made to the extensive
literature on suitable substances, see in particular Fiedler's
"Lexicon der Hilfstoffe", 4th Edition, ECV Aulendorf 1996 and
"Handbook of Pharmaceutical Excipients" Wade and Weller Ed.(1994)
the contents of which are incorporated herein by reference.
[0050] Preferred hydrophilic gel forming substances which may be
used for the first component include one or more natural, partially
or totally synthetic, anionic or, preferably, non-ionic hydrophilic
gums, modified cellulose substances or protein aqueous substances
such as, for example, acacia, gum tragacanth, locust bean gum, guar
gum, karaya gum, agar, peptin, carrageen, soluble and insoluble
alginates, methylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose, sodium
carboxymethylcellulose, carboxypolymethylene, gelatin. Preferred
are cellulose which include methylcellulose, hydroxypropylcellulose
and especially hydroxypropylmethylcellulose and sodium
carboxymethylcellulose.
[0051] Especially preferred hydrophilic gel forming substances
which may be used for the first component comprises high-viscosity
hydrophilic swellable substances, e.g. substances having a
viscosity in the range of 10,000 to 200,000 mpa-s, e.g. 50,000 to
150,000 mpa-s, e.g., 100,000 mPa-s. A preferred swellable substance
which may be used is hydroxypropylmethylcellulose, e.g., Methocel,
e.g., K100M (100,000 mPa-s/2% solution in water at 20.degree. C.),
having a methoxyl content of, e.g., 15 to 30%, e.g., 19 to 24%, and
a hydroxypropoxyl content of, e.g., 5 to 15%, e.g., 7 to 12%.
Swellable substances with diverse viscosities may be prepared as
disclosed in "Handbook of Pharmaceutical Excipients" Wade and
Weller Ed.(1994).
[0052] The weight portion of hydrophilic gel forming substances in
the formulation may be from 10 to 50%, e.g., 25 to 50%, preferably
40%.
[0053] Said first component may comprise 3 to 20%, e.g. 5 to 15%,
e.g. 6 to 13% by weight of the active agent, e.g., rivastigmine
hydrogen tartrate (hta).
[0054] It may be also convenient to incorporate in the first
component at least one of other soluble or insoluble pharmaceutical
excipients as tablet diluents such as calcium sulphate, calcium
phosphate, lactose, mannitol, sucrose. For example,
microcristalline cellulose in granular powder and/or fine powder
may be incorporated e.g. from 10 to 50%. For example,
microcristalline cellulose fine powder may be present in a range of
20 to 50%, e.g, 30 to 40% by weight of the first component and
microcellulose granular powder in a range of 10 to 40%, e.g., 20 to
30% by weight of the first component.
[0055] At least one glidant, e.g., dispersed silicon dioxide, talc,
may be present in a range of 0.1 to 1% by weight of the first
component and at least one tablet lubricant, e.g., magnesium
stearate, stearic acid, hydrogenated castor oil, polyetheylene
glycol, may also be present in a range of 0.1 to 1% by weight of
the first component, preferably 0.5%.
[0056] For example, the first component in this specific embodiment
may have the following active agent, e.g., rivastigmine, release
characteristic in water or artificial stomach juices (e.g. 0.1 N
HCl):
1 time (minutes) amount (percentage) 30 28-35 60 40-55 120 58-75
180 70-90 240 80-95 300 88-98 360 >92
[0057] In a further embodiment of the first component, the active
agent is incorporated in coated particles comprising a diffusion
coating. The coating may be adapted to provide the controlled
release of the active agent. Coating aids, conveniently used in
coating formulation may be used. These coatings may include further
binders, lubricants, glidants, stabilising agents, fullers or
diluents, surfactants and the like. As disintegrants one can
particularly mention CMC-Ca CMC-Na, crosslinked PVP (Crospovidone,
Polyplasdone of Kollidon XL), Alginic acid, sodium alginate and
guar gum, most preferably crosslinked PVP, Crospovidone,
crosslinked CMC and Ac-Di-Sol.
[0058] As binders which may be used in these coatings one can
particularly mention polysaccharides, e.g. potato starch, wheat
starch, corn starch, hydroxypropylmethylcellulose, e.g., products
known under the registered trade marks Avicel .RTM., Filtrak.RTM.,
Heweten.RTM. Pharmacel.RTM..
[0059] Preferably cores which may be used for the first component
are inert and water soluble. Typically the diameter is about 0.5 to
1.5 millimetres.
[0060] The coatings which may be used for the first component may
comprise for example a cellulose derivative, e.g., which may be
applied as a film. Common cellulose coatings may be used and
reference is made to the extensive literature on suitable diffusion
controlling substances.
[0061] As a preferred cellulose coating for the first component,
one may use a coating comprising ethyl cellulose and hydroxypropyl
methylcellulose (hereafter HPMC).
[0062] The ethyl cellulose has preferably a molecular weight 10,000
to 15,000,000, e.g., 50,000 to 1,000,000, e.g., 75,000 to 80,000,
Daltons. It is preferably cellulose substituted by ca 2 to 3 ethoxy
groups per unit saccharide. Preferably it has an ethoxy content of
44-51%.
[0063] Ethyl cellulose as used in the examples preferably is ethyl
cellulose N10 Brand Aqualon.RTM. N10 (available from Dow Chemicals
Company).
[0064] Hydroxypropyl methyl cellulose has preferably a viscosity of
from 1 to 10 cps, e.g., 2 to 8 cps. Preferably it has a molecular
weight of from 10,000 to 1,500,000 Daltons, e.g., 100,000 to
1,000,000, e.g., 300,000 to 800,000. It is preferably cellulose
substituted by ethyl and hydroxypropyl groups.
[0065] Hydroxypropyl methyl cellulose preferably has a viscosity of
3 cps or 5 cps.
[0066] The particles may have a diffusion coating preferably
comprising ethyl cellulose and hydroxypropyl methylcellulose, e.g.,
in a ratio of from 15:1 to 1:1, e.g., from 9:1 to 1:1, e.g., from
8:1 to 2:1, e.g., from 7:1 to 3:1.
[0067] The particles may have a drug (active agent) coating
preferably comprising hydroxypropyl methylcellulose. The drug
coating may contain about 50 to 90% by weight of said active agent,
e.g., rivastigmine, for example from 50 to 80% by weight of
rivastigmine. The amount of drug may comprise, e.g., 3-15% of the
core.
[0068] Typically, the drug coating to diffusion coating ratio is
from 3:1 to 1:1.
[0069] If desired a protective coating may be present between the
diffusion coating and the drug coating. It may comprise
hydroxypropylmethylcellulose or ethyl cellulose. The protective
coating/diffusion coating ration may be, e.g., from 1:1 to 1:10,
e.g., from 1:2 to 1:8.
[0070] Silica may be present, e.g., in 10 to 70% by weight of the
film coating.
[0071] For example, the first component in this specific embodiment
may have one or more, e.g., all of the following active agent,
e.g., rivastigmine, release characteristic in water or artificial
stomach juices (e.g. 0.1 N HCl):
2 time (minutes) amount (percentage) 30 25-40 60 45-65 120 65-85
180 75-95 240 75-96 300 85-97 360 87-98 420 90-98 480 90-99
[0072] As a further example, the first component in this specific
embodiment may have the following active agent, e.g., rivastigmine,
release characteristic in water or artificial stomach juices (e.g.
0.1 N HCl):
3 time (minutes) amount (percentage) 30 5-25 60 25-45 120 50-70 180
65-80 240 70-90 300 75-95 360 80-90 420 85-95 480 85-95
[0073] In a further embodiment of the first component, the active
agent is incorporated into pellets, e.g. extruded pellets, which
may be coated with a diffusion coating as previously described. The
pellets may comprise the active agent, e.g., rivastigmine, in the
same form as for the particles. It may further comprise binders as
those mentioned above and diluents as calcium sulphate, calcium
phoshate, lactose, mannitol or sucrose.
[0074] For example, the first component in this specific embodiment
may have one or more, e.g., all of the following active agent,
e.g., rivastigmine, release characteristics in water or artificial
stomach juices (e.g. 0.1 N HCl):
4 time (minutes) amount (percentage) 30 1-40 60 10-60 120 40-80 180
60-90 240 65-95 300 70-99 360 75-99 420 >80
[0075] It may have preferable the following release
characteristics:
5 time (minutes) amount (percentage) 30 1-8 60 15-25 120 45-70 180
75-90 240 92-95 300 95-98 360 97-99 420 >99
[0076] The present invention further relates to a controlled
release oral pharmaceutical composition comprising a
therapeutically effective dose of Rivastigmine and pharmaceutically
acceptable excipients, e.g., the first component (hereafter
referred to additionally as pharmaceutical compositions of the
present invention).
[0077] The present invention further relates to a controlled
release oral pharmaceutical composition comprising a
therapeutically effective dose of Rivastigmine wherein in use 50 to
95%, e.g., 50 to 80%, 60 to 90%, 70 to 95%, of rivastigmine is
released in water or body fluids, e.g., artificial stomach juices
within 3 hours (hereafter referred to additionally as
pharmaceutical compositions of the present invention).
[0078] The delay time for the second component may be determined
precisely, e.g.,:
[0079] by the type and amount of water soluble excipients in the
core
[0080] by the water permeability and the number of film(s) coated
on the second component
[0081] by the mechanical strength, i.e., elasticity and tearing
strength, of the film,
[0082] by the type and amount of swellable excipient incorporated
in the core.
[0083] An appropriate coating for the second component may be a
semi-permeable membrane which is adapted to allow in use the
passage of water (in use gastrointestinal juices) into the core and
to hinders egress of the dissolved active agent out of the
core.
[0084] Water is drawn through the semi-permeable membrane at a rate
which may be controlled by the composition of the membrane. The
water which has penetrated the core dissolves at least part of the
active agent. Osmotic pressure is thereby produced. The greater the
pressure, the more molecules or ions go into solution, until under
normal circumstances a saturated solution is produced.
[0085] In one embodiment, upon penetration by water or body fluid,
the osmotic pressure, which as a consequence also induces swelling
of the swellable excipient, may be produced by the active agent,
e.g., rivastigmine, itself. However, a carrier which is soluble in
water may be added in order to produce the necessary osmotic
pressure. In this way, the osmotic pressure necessary for inducing
the operating principle of the second component can be attained in
such a way that the body fluid entering to balance the osmotic
gradient produces the desired swelling of the swellable excipient
(disintegrant) and after a certain delay time the rupturing or
breaking of the film coating allows the release of the active
agent. By optionally adding a water-soluble carrier in the core of
the tablet, the second component may be produced in almost
pH-independent form, i.e., independent of the concentration of
hydrogen ions and hydroxyl ions and/or independent of other ions,
such as phosphate ions, and also enzymes, for example in the
alimentary tract.
[0086] Appropriate semi-permeable membranes for the film layer
include the semi-permeable membranes described in literature, for
example in U.S. Pat. Nos. 3,916,899 and 3,977,404, which are
suitable for passage of the water (body fluid) and not the
dissolved active agent and are thus suitable for bringing about
osmosis. For example, artificially produced membranes may be used,
which consist of cellulose acetate, cellulose triacetate, agar
acetate, amylose acetate, cellulose acetate ethyl carbamate,
cellulose acetate phthalate, cellulose acetate methyl carbamate,
cellulose acetate succinate, cellulose acetate dimethylamino
acetate, cellulose acetate ethyl carbonate, cellulose acetate
chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate
methyl sulphonate, cellulose acetate butyl sulphonate, cellulose
ether, cellulose acetate propionate, cellulose acetate diethylamino
acetate, cellulose acetate octate, cellulose acetate laurate,
methyl cellulose, cellulose acetate-p-toluenesulphonate,
hydroxylated ethylene vinyl acetate, cellulose acetate butyrate and
of other cellulose acetate derivatives. Other appropriate
semi-permeable membranes are also hydroxypropylmethyl cellulose and
polymeric epoxides, copolymers of alkylene oxide and alkyl glycidyl
ether, polyglycols or polylactic acid derivatives and further
derivatives thereof. In addition, mixtures may also be used, e.g.
of water-insoluble acrylates, e.g., copolymer of ethyl acrylate and
methyl methacrylate.
[0087] Generally, all semi-permeable membranes which are known from
literature and have water-permeable properties are suitable for
producing the film for the second component.
[0088] Coating of, e.g., tablets, e.g., compressed tablets, core
particles or pellets, with a film comprising, e.g., a
semi-permeable membrane of required thickness, may be effected in
fluidised beds, coating pans or coating may be effected using,
e.g., tabletting machines (dry coated tablet).
[0089] The second component may for example also be contained in a
capsule, e.g., a gelatin capsule, which contains the active agent,
e.g., rivastigmine, a swellable excipient, optionally a
water-soluble carrier and other excipients, such as lubricants and
sustained release agents in powder form, and is coated with the
semi-permeable membrane as a film.
[0090] Appropriate films which may be used as a second coating for
the second component include membranes which may be permeable or
semi-permeable to water or body fluid, e.g., sustained release
membranes, as described in literature. This second film-coating may
be applied in the same manner as for the first film.
[0091] A preferred second film-coating for the second component
comprises ethylcellulose, e.g., Ethylcellulose Brand Aqualon.RTM.
N10 (available from Dow Chemicals Company). It may be applied,
e.g., by spraying a solution comprising Ethylcellulose and HPMC 5
cps in a weight ratio of from e.g., 15:1 to 1:1, e.g., 9:1 to 1:1,
e.g., from 8:1 to 2:1, e.g., from 7:1 to 3:1.
[0092] The ethyl cellulose has preferably a molecular weight 10,000
to 15,000,000, e.g., 50,000 to 1,000,000, e.g., 75,000 to 80,000,
Daltons. It is preferably cellulose substituted by ca 2 to 3 ethoxy
groups per unit saccharide. Preferably it has an ethoxy content of
44-51%.
[0093] Hydroxypropyl methyl cellulose has preferably a viscosity of
from 1 to 10 cps, e.g., 2 to 8 cps, preferably 3 cps or 5 cps.
Preferably it has a molecular weight of from 10,000 to 1,500,000
Daltons, e.g., 100,000 to 1,000,000, e.g., 300,000 to 800,000. It
is preferably cellulose substituted by ethyl and hydroxypropyl
groups.
[0094] In a preferred embodiment, the weight ratio between the
first and the second film applied on the second component is 20:1
to 1:5, e.g., 15:1 to 1:1, e.g., 10.1 to 2:1.
[0095] In a preferred embodiment of the invention, the film
thickness for the second component may be in a range of from 50 to
800 micrometers (.mu.m), e.g., 100 to 600 .mu.m. For a second
component having one film a preferred thickness is in the range of
from 300 to 500 .mu.m, e.g., 350 to 400 .mu.m. For a second
component having two films a preferred thickness is in the range of
from 100 to 300 .mu.m, e.g., 150 to 200 .mu.m.
[0096] The nature and the amount of the excipients and the active
agent of the second component (excluding film-coating(s) to be
ruptured) may the same or not as the first component.
[0097] Suitable swellable excipients or disintegrating agents for
the second component may be inert substances which swell rapidly
upon contact with aqueous liquids, e.g., alginic acid and
derivatives, agar-agar, cellulose such as microcrystalline or
microfine cellulose, methyl cellulose, crosslinked carboxymethyl
cellulose, carboxymethyl starch, modified starch, crosslinked
polyvinyl polypyrrolidone, Colloidal silicon dioxide, high
molecular weight polymers comprising ethylene oxide, bentonite,
Veegum, montmorillonite, dried citrus pulp, xylans and also
cationic and anionic exchangers such as cholestyramines.
[0098] Further excipients may be used to produce or induce the
osmosis in the swelling process in the second component are
water-soluble carriers (osmosis-inducing substances), e.g.,
substances that do not irritate the gastric or intestinal mucous
membranes, e.g. inorganic or organic salts such as sodium chloride,
sodium hydrogen phosphate, sodium nitrate and sodium acetate, or
also acids such as tartaric, citric or also succinic acid and also
sugars, especially e.g. mannitol, glucose, fructose, lactose and
dextran compounds with different molecular weights. The amount of
carrier may vary from a fragment to many times the quantity of
rivastigmine employed.
[0099] The lubricants which may be an optional further excipient
for the second component may be e.g., magnesium stearate, silicon
aerogel, talc, stearic acid, hydrogenated castor oil, polyethylene
glycol (PEG).
[0100] Optional additives for the second component may be, e.g.,
anti-oxidants, e.g, a-tocopherol or butylated hydroxytoluene
(BHT).
[0101] Optional additives in film coating for the second component
may be, e.g., pigments such as coloured iron oxides or titanium
dioxide and/or flavourings, e.g., sweeteners, e.g., saccharine, Na
cyclamate or sugar.
[0102] A preferred second component comprises, e.g., (weight
%):
6 Core Rivastigmine hta 0.5 to 25% Sodium Chloride 10 to 35% Avicel
PH 102 5 to 25% PVPP-XL 20 to 70% a-tocopherol 0.01 to 5% Aerosil
200 1 to 15% Magnesium Stearate 0.1 to 5% First Coating: Cellulose
Aceate 1 to 20% HPMC 0.1 to 1% Second Coating: Ethylcellulose 0.5
to 10% HPMC 0.1 to 2%
[0103] The invention further relates to a pharmaceutical
composition comprising a core coated with two films, the first
inner film being a semi-permeable to water or body fluids film
applied directly on said core and comprising cellulose acetate,
e.g., cellulose acetate E320 or 398-10, the second outer film being
a permeable to water or body fluids film comprising ethylcellulose,
e.g., Ethylcellulose N10.
[0104] The cores in question, comprising the active agent, e.g.,
rivastigmine, and excipients, e.g., may be the compressed tablets,
capsules and pellets that are usual in galenics and may be produced
by known processes. For example, the tablet mass may be produced by
mixing the active agents disintegrant and optional further
excipients, such as carriers, lubricants and if desired also
sustained release excipients as required. Production of the
compressed tablets and pellets may be effected, e.g., using the
tabletting machines which are known for the preparation of for
example round and rod-shaped compressed tablets and pellets, and
the capsules are filled using known capsule filling machines.
[0105] The sustained release excipients that are used may be
essentially water-insoluble excipients or mixtures thereof, e.g.,
lipids, inter alia fat alcohols, e.g. cetyl alcohol, stearyl
alcohol and cetostearyl alcohol; glycerides, e.g. glycerin
monostearate or mixtures of mono, di- and triglycerides of
vegetable oils; hydrogenated oils, such as hydrogenated castor oil
or hydrogenated cottonseed oil; waxes, e.g. beeswax or carnauba
wax; solid hydrocarbons, e.g. paraffin or mineral wax; fatty acids,
e.g. stearic acid; certain cellulose derivatives, e.g. ethyl
cellulose or acetyl cellulose; polymers or copolymers, such as
polyalkylenes, e.g. polyethylene, polyvinyl compounds, e.g.
polyvinyl chloride or polyvinyl acetate, as well as vinyl
chloride-vinyl acetate copolymers and copolymers with crotonic acid
or polymers and copolymers of acrylate and methacrylates, e.g.
copolymers of ethyl acrylate and methyl methacrylate.
[0106] A person skilled in the are may use other excipients than
those disclosed above to obtain the desire effect. Reference is
made to the extensive literature on suitable excipients provided in
the art in particular Fiedler's "Lexicon der Hilfstoffe", 4th
Edition, ECV Aulendorf 1996 and "Handbook of Pharmaceutical
Excipients" Wade and Weller Ed.(1994) the contents of which are
incorporated herein by reference.
[0107] As already stated initially, the release which is to be
effected at different time intervals may be controlled precisely by
the composition and the layer thickness of the coating (film) used
for the second component, mechanical strength and elasticity and
optionally through the quantity and swelling property of the
swelling or disintegrating agent.
[0108] The second component, e.g., with one film, according to the
invention may have one or more, e.g., all of the following release
characteristics in water:
7 time (minutes) amount (percentage) 0 0-1 120 0-1 180 0-1 240 0-85
300 0-97 360 >99.5
[0109] The second component, e.g., with two films, according to the
invention may have one or more, e.g., all of the following release
characteristics in water:
8 time (minutes) amount (percentage) 0 0-1 120 0-1 180 0-1 240 0-85
300 0-97 360 0-99.5 420 0-100 480 70-100 540 75-100 600 85-100 660
90-100 720 >50
[0110] The rupture time may lead to 85% or more, e.g., 90%, of the
active agent in the second component released within 30
minutes.
[0111] The pharmaceutical composition according to the invention
preferably comprises from 0.5 to 25%, e.g., 1 to 10%, e.g., 2 to
5%, by weight of rivastigmine of the total composition.
[0112] The pharmaceutical compositions or the present invention are
useful in the known indications of the particular active agent
incorporated therein.
[0113] The exact amounts of active agent doses and of the
formulation to be administered depend on a number of factors, e.g.,
the condition to be treated, the desired duration of treatment and
the rate of release of active agent.
[0114] For example, the amount of the active agent required and the
release rate thereof may be determined on the basis of known in
vitro or in vivo techniques, determining how long a particular
active agent concentration in the blood plasma remains at an
acceptable level for a therapeutic effect.
[0115] For example, for rivastigmine, dosages in the range of 1 mg
to 12 mg of active agent per day for a 70 or 75 kilogram mammal,
e.g., humans, and in standard animal models, may be use. A
surprisingly increased tolerability of rivastigmine provided by the
compositions may be observed in animal tests and in clinical
trials.
[0116] The pharmaceutical compositions of the invention are, e.g.,
administered, e.g., orally once-a-day, if two active agent doses
are present and twice-a-day if a second active agent dose is
present.
[0117] In a further aspect, the present invention provides the use
of an active agent, e.g., rivastigmine, and excipients as defined
above in the manufacture of a medicament for a once-a-day treatment
of patients with, e.g., mild to moderately severe Dementia of the
Alzheimer's type by oral administration.
[0118] In the following non-limitative examples, the invention is
more fully clarified. If not otherwise stated, the parts are parts
by weight. Temperatures are given in degrees Celsius.
[0119] Preparation of the First Component
[0120] The first component may be produced in conventional manner
by mixing the components. Below are examples of specific forms of
first component allowing various release profile of the active
agent contained therein.
EXAMPLE 1
First Component in the Form of a Matrix Tablet
[0121] The resultant mixture may be in powder form which may be
pressed to form a tablet in conventional tabletting machines at
compression pressures of, e.g., 2000 to 16000 lbs/sq.in.
[0122] A. Preparation of a Granulate:
[0123] Ingredients
[0124] rivastigmine, e.g., hta
[0125] microcrystalline-cellulose, e.g., fine powder
[0126] purified water for dissolving the drug substance
[0127] Rivastigmine hta is dissolved in 10 to 20%, e.g., 16.3% by
weight of purified water of the total granulate and the solution
stirred until clear. A crossbar stirrer may be used at .sub.1 e.g.,
150-200 rpm, e.g., 180 rpm for 10-20 minutes, e.g., 15 minutes.
[0128] Microcrystalline-cellulose fine powder is sieved, e.g.,
through a manual or vibration sieve fitted with a screen and having
a mesh width of, e.g., 1600 micrometers, and a wire diameter of,
e.g., 500 micrometers, into a vessel of, e.g., a Collette Gral.RTM.
10 high shear mixer.
[0129] At mixer setting I and chopper setting I, the powder is wet
granulated in the high shear mixer with the aqueous drug substance
solution (granulation liquid) which is added at a rate of 0.5 to 1
l/min, e.g. 0.75 l/min.
[0130] The dissolving vessel (used for the preparation of the
granulation liquid) is rinsed with the purified water and the
rinsing liquid added at mixer setting I and chopper setting I at a
rate of 0.5 to 1 l/min, e.g. 0.75 l/min.
[0131] The chopper setting is then increased to 11 and
approximately 1 minute mixing is applied. The granulation stopped
and the wall of the Collette Gral.RTM. vessel cleaned. The wet
granulate is mixed for an additional minute at mixer setting I and
chopper setting II.
[0132] The wet granulate is then dried by e.g. transferring it from
the high shear mixer to a fluidized bed dryer bowl and applying an
inlet air temperature from 40 to 60.degree. C., e.g. 50.degree. C.,
until a LOD (loss of density) of 2.5-5.0% is reached (corresponding
to a product temperature of approx. 31.degree. C.).
[0133] The dried granulate is then broken by e.g., passing it
through an oscillator with a screen (e.g. mesh width 800
micrometers and wire diameter 320 micrometers) into the container
of a free fall mixer (e.g. Turbula.RTM. T10A).
[0134] B. Preparation of the Tablet Mixture:
[0135] Ingredients
[0136] hydroxypropylmethyl-cellulose K100M
[0137] microcrystalline cellulose, e.g., granular powder
[0138] highly dispersed silicon dioxide
[0139] Microcrystalline-cellulose (MCC) granular powder,
hydroxypropylmethyl-cellulose and silicon dioxide highly dispersed
may be premixed manually in a plastic bag or in a free fall mixer
for approximately two minutes. The silicon dioxide may be dispersed
into the HPMC and MCC in order to reduce any dedusting during the
subsequent sieving step.
[0140] The pre-mixture may be sieved by passing it through a sieve
(or vibration sieve). The mesh width used may be, e.g., 800
micrometers and wire diameter 320 micrometers.
[0141] The dry pre-mixture may be transferred into the container of
the free fall mixer (e.g. Turbula.RTM. T10A) and mixed with the
granulate until 100 rotations are reached, e.g., 20 rpm for 5
minutes.
[0142] Magnesium stearate may be manually premixed with about 10
parts of the dry pre-mixture in plastic bag or in a free fall mixer
for about two minutes. The magnesium stearate may be dispersed in
order to prevent any re-agglomeration after the subsequent sieving
step.
[0143] The premixture may be sieved by, e.g., passing it manually
through a sieve (or vibration sieve). The mesh width used may be
for example 800 micrometers and the wire diameter 320
micrometers.
[0144] The magnesium stearate pre-mixture is transferred into,
e.g., the container of a free fall mixer (e.g. Turbula.RTM. T10A)
containing the rest of pre-mixture and the whole tablet mixture is
mixed until 100 rotations are reached, e.g., at 20 rpm for 5
minutes.
[0145] C. Tabletting
[0146] Tablets are formed by compression on, e.g., an excentic
single punch tabletting machine (e.g. Comprex.RTM.) or a rotary
tablet press (e.g., Betapress.RTM., Korsch.RTM. PH250) using, e.g.,
6 mm punches (round, convex, bevelled edges).
[0147] Non-limitative examples of the first component which may be
prepared by the process disclosed above are provided in the
following table:
9 Composition No. 1 2 3 rivastigmine hta (mg) 7.2 7.2 7.2
micocristalline cellulose fine powder (mg) 25.95 25.95 25.95
hydroxypropylmethylcellulose K100M (mg) 18.75 22.50 30.05
microcristalline cellulose granular powder 22.35 18.60 11.05 (mg)
magnesium stearate (mg) 0.375 0.375 0.375 silicon dioxide highly
dispersed (mg) 0.375 0.375 0.375 Total weight 75 mg 75 mg 75 mg
[0148] The compositions No. 1, 2 and 3 provide the following
release profile when dissolved into water:
10 Composition 1: Time (min.) 30 60 120 180 240 300 360 420 480
Drug release (%) 29.3 42.6 60.5 73.3 82.6 89.4 93.5 96.4 97.8
Composition 2: Time (min.) 30 60 120 180 240 300 360 420 480 Drug
release (%) 33 51.9 72.6 84.5 92.3 96.8 98.9 99.9 100 Composition
3: Time (min.) 30 60 120 180 240 300 360 420 480 Drug release (%)
32.1 46 64.3 77.6 85.5 91.7 95.1 97.2 97.8
EXAMPLE 2
First Component in the Form of Coated Particles
[0149] The preparation protocol of the film solutions is given
hereafter. A non-limitative Example of a composition obtained
according to this protocol will illustrate the invention.
A/Ingredients:
[0150] The ingredients for the preparation of the film solutions
are provided in the following table:
11 Component Comment Supplier Rivastigmine hta rivastigmine
hydrogen tartrate Novartis Non-pareilles sugar spheres 0.85-1.0 mm
H. G. Werner (USP) HPM-cellulose 3 Hydroxypropyl methylcellulose
Shin-Etsu 3 cps Chemicals Co. Ltd. Ethylcellulose Ethylcellulose
N10 Dow Chemicals N10 Company HPM-cellulose 5 Hydroxypropyl
methylcellulose Dow Chemicals 5 cps Company Aerosil 200 silicon
dioxide highly dispersed Degussa AG Magnesium -- FACI SRL stearate
Hardgelatine size 3, Cap + Body: rich yellow Capsulgel N.V.
capsules opaque, CONISNAP 6 dimple
[0151] B/Preparation of Film Solutions
[0152] The % are expressed by weight of the solution prepared (qsp.
purified water for 1, 2 and 3).
[0153] 1. Preparation of the Aqueous HPMC-solution (5%)
[0154] HPMC 3 cps is dispersed in purified water in a stainless
steel vessel while stirring approximately 2 min at 500 rpm in a
crossbar stirrer. The solution is stirred until clear (30 min) at a
speed of 250 rpm. The obtained solution is allowed to stand still
for 12 h in a stainless steel vessel.
[0155] 2. Preparation of the Aqueous Rivastigmine/HPMC Film
Solution
[0156] Rivastigmine hta (15-25%) is dissolved in the HPMC-solution
(3-5%) while stirring (Rivastigmine/HPMC solution). The solution
obtained is stirred until clear (approx. 15 min) in a stainless
steel vessel (crossbar stirrer speed: 250 rpm). Then, silicon
dioxide (1-3%) is dispersed in the Rivastigmine/HPMC-solution while
stirring in a stainless steel vessel (crossbar stirrer speed: 250
rpm). The solution obtained is stirred for approximately 10
minutes. If needed the silicon dioxide may be dispersed in 2 parts
of the Rivastigmine/HPMC-solution using a mortar and pestle before
adding the rest of the solution.
[0157] 3. Preparation of the Aqueous HPMC Film Solution
[0158] Silicon dioxide (1.5-3%) is dispersed in the HPMC-solution 3
cps (3-7%) while stirring in a stainless steel vessel (crossbar
stirred speed: 250 rpm). The solution is stirred for approximately
10 minutes. If needed, the silicon dioxide is dispersed in 2 parts
of the Rivastigmine/HPMC-solution using a mortar and pestle before
adding the rest of the solution.
[0159] 4. Preparation of the Organic Solvent
[0160] Ethanol 94% (w/w) and acetone are mixed (see proportions in
paragraph 5) during approximately 2 minutes in a stainless steel
vessel acetone (crossbar stirrer speed: 250 rpm).
[0161] 5. Preparation of the Organic Polymer Film Solution
[0162] Ethylcellulose N10 (5-10%) and the HPMC 5 cps (0.5-2%) are
dispersed in a stainless steel vessel in the organic solvent
(acetone (45-65%) and ethanol 94%(35-45%)) while stirring
approximately 1 minute in a crossbar stirrer speed: 500 rpm stir
the solution until clear approximately 30 minutes (speed: 250 rpm)
in stainless steel vessel. The solution is let stand still for 12
h.
[0163] C/Coating
[0164] 1. Aqueous Coating
[0165] A fluidized bed dryer Glatt WST 5 (batch size: approximately
1.5 kg) is adjusted to the required inlet air temperature
(60.degree. C.) and the spray rate to 15 g/min (pressure: 2.5 bar)
by means of the variation of the peristaltic pump with a silicon
tube (internal diameter 4.0 mm). The Wurster column (6 inch) with a
binary spray nozzle (1.0-1.2 mm diameter) in the center of the base
plate that sprays in line with the air stream, is pre-warmed to
45.degree. C. The non-pareilles are added and the air flap is
adjusted to the airflow required for gentle fluidization of the
non-pareilles inlet air quantity approximately 325 m.sup.3/h.). The
Rivastigmine/HPMC-solution from step A is then sprayed immediately
in order to minimise abrasion of the no stainless steel vessel
non-pareilles. The product temperature is approximately 45.degree.
C.
[0166] Then, the stainless steel vessel and the silicon tubing are
rinsed with the HPMC-solution 3 cps (approximately 25 g). For the
protective coating, the aqueous HPMC-solution is sprayed (rinsing
liquid--first; the rest of the HPMC-solution--second). The
stainless steel vessel and the silicon tubing are then rinsed with
purified water (approximately 25 g) and then the rinsing water
sprayed.
[0167] 2. Organic Coating
[0168] A fluidized bed dryer Glatt WST 5 (batch size: approximately
1.5 kg) is adjusted at the inlet air temperature (50.degree. C.)
and the spray rate to 25 g/min (pressure: 2.5 bar) by means of the
variation of the peristaltic pump with silicone tube (internal
diameter 4.0 mm). The Wurster column (6 inch) with a binary spray
nozzle (1.0-1.2 mm diameter) in the center of the base plate that
sprays in line with the air stream is used. The organic solvent is
sprayed to remove the rest of the purified water from the tubing
system and the nozzles (to prevent crystallisation of
ethylcellulose (organic polymer film solution) in the tubes). The
product temperature is approximately 40.degree. C.
[0169] Then, the organic polymer film solution is sprayed. The
stainless steel vessel and the silicon tubing are rinsed with
approximately 50 g of the organic solvent ethanol/acetone and the
rinsing liquid is sprayed. The coated non-pareilles are dried at an
inlet air temperature of 50.degree. C. until the product
temperature increases by 2.degree. C.
[0170] The coated non-pareilles are dried manually in a Waldner
tray dryer (inlet air temperature: 30.degree. C.) for 6 hours to
remove any residue of the organic solvent from the coating and
passed through a sieve (sieve size 1250 mm and wire diameter 400
mm) to remove agglomerates.
[0171] 3. Preparation of the Capsule Filing Mixture:
[0172] Magnesium stearate is manually passed through a sieve having
a mesh width of 800 mm and a wire diameter of 320 mm. The sieved
magnesium stearate is then mixed with the coated pellets in a free
fall mixer (Turbula 101) at 20 rpm for 5 minutes, i.e., 100
rotations.
[0173] 4. Capsule Filing
[0174] The capsule filling mixture is filled on a automatic capsule
filling machine (Zanasi LZ 5) into empty hardgelatine capsule
shells (CONI-SNAP 6 dimple, size 3). The nominal fill weight is as
mentioned above.
[0175] The process parameters are as follows:
[0176] speed: 3000 HK/h
[0177] dosator/piston:
[0178] size: # 4
[0179] height: 12-14 mm
[0180] vacuum: 0.7 bar
[0181] feed hopper: none
[0182] D/Preparation of a Composition of Exelon MR Bid 4.5 MG
HKP
[0183] The composition is prepared according to the process
described above. The ingredients are given in the table below:
12 weight weight Phase Components (mg) (mg) aqueous rivastigmine
hta 7.20 7.20 drug substance/ hydroxypropyl methylcellulose 1.50
1.50 polymer 3 cps solution.sup.1,3 silicon dioxide highly
dispersed 0.75 0.75 (drug loading) purified water 28.50 28.50
aqueous polymer hydroxypropyl methylcellulose 1.50 1.50
solution.sup.1,3 3 cps (protective silicon dioxide highly dispersed
0.75 0.75 coating) purified water 28.50 28.50 organic polymer
ethylcellulose N10 4.05 7.35 solution.sup.2,3 hydroxypropyl
methylcelluloses 0.45 3.15 (diffusion 5 cps coating) ethanol 94%
(w/w) 16.20 37.80 acetone 24.30 56.70 .sup.15% HPMC-solution
.sup.210% polymer-solution/organic solvent (60% acetone, 40%
ethanol 94% (w/w)) .sup.35% excess (loss on spraying)
[0184] Composition of a Capsule of Exelon MR BID 4.5 mg HKP
13 Total film quantity (% of the theoretical capsule 3.0 content
(=150 mg)) Diffusion coating (ethylcellulose:hydroxyp- ropyl 90:10
70:30 methylcellulose) Phase Component i) ii) Core non-pareilles
(placebo) 134.40 129.15 Coating 1 rivastigmine hta 7.20 7.20 (drug
loading) hydroxypropyl methylcellulose 1.50 1.50 3 cps silicon
dioxide highly 0.75 0.75 dispersed Coating 2 hydroxypropyl
methylcellulose 1.50 1.50 (protective coating) 3 cps silicon
dioxide highly dispersed 0.75 0.75 Coating 3 ethylcellulose N10
4.05 7.35 (diffusion coating) hydroxypropyl methylcellulose 0.45
3.15 5 cps lubricant magnesium stearate 0.15 0.15 Total fill weight
150.75 151.50 capsules CONISNAP size 3 49.00 49.00 TOTAL (mg) 199.5
200.50 The following release profile is obtained Time 30 60 120 180
240 300 360 420 480 (min.) Drug 32.5 55.1 76.4 84.1 88.0 90.6 92.4
93.8 94.9 release i) (% in 15.5 36.3 61.2 72.9 79.7 83.4 86.5 89.1
90.6 0.1 HCl) ii)
[0185] E/Dosage Strengths:
[0186] For all dosage strengths the same coated non-pareilles (with
the same drug load) are used. Different dosage strengths (1.5 mg-9
mg) are obtained by varying the capsule fill weight, as outlined in
the table below.
14 Dosage strengths capsule fill weight (approx.) capsule size 1.5
mg 50 mg 4 3.0 mg 100 mg 3 4.5 mg 150 mg 3 6.0 mg 200 mg 2 9.0 mg
300 mg 2
[0187] For the dosage strengths 6.0 mg, 3.0 mg and 1.5 mg, placebo
non-pareilles could be added to optimise the filling degree of the
capsules if needed.
EXAMPLE 3
First Component in the Form of Coated Pellets
[0188] A/Ingredients:
[0189] Rivastigmine hydrogen tartrate
[0190] Microcristalline cellulose Avicel.RTM. PH-101 (FMC
Corporation, Philadelphia, USA)
[0191] Lactose 200 mesh (DMV, Vehgel, Netherlands)
[0192] Ethylcellulose N10 (Dow Chemicals Company, USA)
[0193] Hydroxypropyl methylcellulose 5 cps (Dow Chemicals Company,
USA)
[0194] Magnesium stearate
[0195] Hardgelatine capsules: size 3, Cap+Body: rich yellow opaque,
CONISNAP.RTM. 6 dimple (Capsulgel N.V.).
[0196] The amounts of the ingredients to be used are provided in
the protocol description or in paragraph G/below.
[0197] B/Preparation of the Drug and Film Solutions
[0198] The % mentioned below in 1, 2 and 3 are expressed by weight
of the solution prepared:
[0199] 1. Preparation of the Aqueous Rivastigmine Solution
[0200] Rivastigmine is dissolved in water, e.g., in a stainless
steel vessel, while stirring and the solution is stirred until
clear approximately 15 min at 250 rpm in, e.g., a crossbar stirrer.
The amount of water is about 39% of the dry core weight which are
prepared as described below.
[0201] 2. Preparation of the Organic Solvent
[0202] Ethanol 94% (w/w) and acetone are mixed (acetone
(60%)/ethanol 94%(40%)) during approximately 2 minutes in a
stainless steel vessel (crossbar stirrer speed: 250 rpm).
[0203] 3. Preparation of the Organic Polymer Film Solution
[0204] Ethylcellulose N10(8%) and the HPMC 5 cps (2%) are dispersed
in a stainless steel vessel in the organic solvent (90%) while
stirring approximately 1 minute in a crossbar stirrer (speed: 500
rpm). The solution is stirred until clear approximately 30 minutes
(speed: 250 rpm) in, e.g., stainless steel vessel. The solution is
allowed to stand for 12 h.
[0205] C/Preparation of the Pellets
[0206] The lactose and Avicel.RTM. are loaded in a Collette
Gral.RTM. (10 or 25 L) and mixed for 2 minutes (plow-slow,
Chopper-slow). The rivastigmine solution is added into the mix of
Avicel.RTM. and lactose in the Collette Gral.RTM. with the plow at
slow speed (Chopper-off).
[0207] After the drug solution is pumped into the Collette
Gral.RTM., additional water is added to the same container for
rinsing. The quantity of the additional water is 18.5% of the dry
weight of the core. This additional water is pumped into the mix
from above with plow at slow speed(Chopper-of).
[0208] The mix from above is granulated in the Collette Gral.RTM.
for about 15 minutes (Plow slow, Chopper-off). The machine is
stopped at 5 minute intervals and the walls of the vessel scraped
The chopper is turned on at slow speed for the last two to three
minutes.
[0209] The wet mass from above is extruded into thin strands
(Parameters: Twin screw extruder from Gabler.RTM., screen size: 1
mm, screw speed: 50 rpm, dosage machine position: 1.8, pressure of
the mass: 10 bar).
[0210] The extruded mass is spheronized, i.e., formed into pellets,
using a 3 kg charge at a time (Parameters: Spheronizer from Wyss
Pharmex.RTM., charge in the spheronizer: 3 kg, rotational speed:
870 rpm, spheronization time: 6 minutes).
[0211] The wet pellets are dried (Parameters: Aeromatic.RTM. fluid
bed drier, inlet air temperature: 60.degree. C., exhaust
temperature: 47 to 49.degree. C., dry to LOD (loss of drying) of
2.5 to 3.0%).
[0212] The dried pellets are manually sieved to exclude the
agglomerates. All that passes through the sieve is collected for
coating (sieve size:1600 micrometers).
[0213] D/Coating
[0214] 1. Organic Coating
[0215] A fluidized bed dryer Glatt.RTM. WST 5 (batch size:
approximately 1.5 kg) is adjusted at the inlet air temperature
(50.degree. C.-325 m.sup.3/h) and the spray rate to 25 g/min
(pressure: 2.5 bar) by means of the variation of the peristaltic
pump with silicone tube (internal diameter 4.0 mm). The Wurster
column (6 inch) with a binary spray nozzle (1.0-1.2 mm diameter) in
the center of the base plate that sprays in line with the air
stream is used. The organic solvent is sprayed to remove the rest
of the purified water from the tubing system and the nozzles (to
prevent crystallisation of ethylcellulose (organic polymer film
solution) in the tubes). The product temperature is approximately
40.degree. C.
[0216] Then, the organic polymer film solution is sprayed. The
stainless steel vessel and the silicon tubing are rinsed with
approximately 50 g. of the organic solvent ethanol/acetone and the
rinsing liquid is sprayed. The coated pellets are post-dried at an
inlet air temperature of 50.degree. C. until the product
temperature increases by 2.degree. C.
[0217] The coated pellets are dried manually in a Waldner.RTM. tray
dryer of type HW 15/2N (inlet air temperature: 30.degree. C.) for 6
hours to remove any residue of the organic solvent from the coating
and then passed through a sieve (sieve size 1600 micrometers and
wire diameter 400 micrometers) to remove agglomerates.
[0218] E/Preparation of the Capsule Filing Mixture:
[0219] Magnesium stearate is passed through a sieve having a mesh
width of 800 micrometers and a wire diameter of 320 micrometers.
The sieved magnesium stearate is then mixed with the coated pellets
in a free fall mixer (Turbula.RTM. 101) at 20 rpm for 5 minutes,
i.e., 100 rotations.
[0220] F/Capsule Filing
[0221] The capsule filling mixture is filled on a automatic capsule
filling machine (Zanasi.RTM. LZ 5) into empty hardgelatine capsule
shells (CONI-SNAP.RTM. 6 dimple, size 3). The nominal fill weight
is as mentioned above (Process parameters: speed: 3000 HK/h,
dosator piston: size # 4 and height: 12-14 mm, vacuum:0.7 bar, feed
hopper: none).
[0222] G/Composition of Exelon MR BID 4.5 mg HKP
[0223] The composition is prepared according to the process
described above.
15 Total film quantity (% of the theoretical capsule content 3.0
(=150 mg)) Diffusion coating (ethylcellulose:hydroxypropyl 80:20
methylcellulose) Phase Component weight (mg) Core rivastigmine hta
7.20 lactose 200 mesh 60.30 microcristalline cellulose (Avicel
.RTM.) 67.5 Diffusion coating ethylcellulose N10 3.24 hydroxypropyl
methylcellulose 5 cps 0.81 lubricant magnesium stearate 0.15 Total
fill weight 139.20 capsules CONISNAP .RTM. size 3 49.00 TOTAL
188.20 The following release profile is obtained: Time (min.) 30 60
120 180 240 300 360 420 Drug release 4.2 21.9 57.8 84.8 94.5 97.9
99.4 99.9 (% in 0.1 N HCl)
[0224] H/Dosage Strengths:
[0225] For all dosage strengths the same pellets (with the same
drug load) are used. Different dosage strengths (1.5 mg-9 mg) are
obtained by varying the capsule fill weight, as outlined in the
table below.
16 Dosage strengths capsule fill weight (approx.) capsule size 1.5
mg 46.4 mg 4 3.0 mg 92.8 mg 3 4.5 mg 139.2 mg 3 6.0 mg 185.6 mg 2
9.0 mg 278.4 mg 2
[0226] For the dosage strengths 6.0 mg, 3.0 mg and 1.5 mg, placebo
pellets could be added to optimise the degree of filling of the
capsules if needed.
[0227] Preparation of the Second Component
[0228] The second component may be produced in conventional manner
by mixing the components, e.g., in order to obtain coated particles
or pellets as for the first component and then by applying one or
more film coatings as above described.
EXAMPLE 4
Second Component in the Form of a Matrix Tablet Coated with One
Film
[0229] A second component which contains 4.8 mg rivastigmine hta as
the rivastigmine in the pressed core, e.g. compressed tablet, is
coated with an appropriate film. This system, that releases the
rivastigmine after a pre-determined time when placed in an aqueous
fluid, may be produced as follows:
[0230] A. Preparation of the Core:
[0231] The mass for 5000 cores is prepared as follows. 24 g of
rivastigmine hta are dissolved in 1000 g of purified water. 400 g
of Polyplasdone (polyvinylpolypyrrolidone crosslinked) and 221 g of
sodium chloride are placed in a mixer cum granulation machine,
e.g., Diosana.RTM.D. This mixture is mixed for 5 minutes and the
solution of rivastigmine hta added to this slowly and
wet-granulated. The wet mass is then passed through a 2 millimetres
sieve and dried using a fluidised-bed drier at 60.degree. C. After
drying, the granules are passed through a sieve of 1 millimetre.
The granules are weighed and mixed with the appropriate amounts of
silica gel, e.g., Aerosil.RTM., and microcrystalline cellulose for
20 minutes in a tumbling mixer (Turbula.RTM. mixer) and pressed as
indicated above into cores each of 178 mg total weight. A 8 mm
concave punch (R=12) in a tablet press having only one punch, e.g.,
Kilian EKO.RTM., may be used.
[0232] B. Preparation of Film Lacquer:
[0233] 4000 compressed cores are coated with a semi-permeable film
(or membrane) of the composition below using the fluidised bed
process in a current of air, e.g., Glatt-wurster
17 cellulose acetate containing 32% acetyl 139.5 g cellulose
acetate containing 39.8% acetyl 145.5 g hydroxypropylmethyl
cellulose (HPMC) 15.0 g methylene chloride 6750 g methanol 750
g
[0234] The film-coating (semi-permeable membrane coating) is
effected with the above mentioned organic lacquer which contains 4%
solid film constituent in a solvent mixture of methylene chloride
methanol. However, other solvent mixture such acetone/alcohol/water
instead of methylene chloride/methanol may also be used.
[0235] The cores are coated with layers of film of differing
thicknesses, i.e., different weights, for example with
approximately 55 mg, 70 mg, 80 mg/core, or more for obtaining
lag-times of, e.g., 3-4, 5-6 or 7-8 hours, and dried in the current
of air in a fluidised bed drier for 48 hours at 40.degree..
18 C. Compositions Quantity/tablet (mg) 1/Ingredients
Polyplasdone-XL or Crosspovidone 80.0 Colloidal Silicone Dioxide
5.0 Sodium Chloride 44.2 Rivastigmine hta 4.8 Polyplasdone-XL or
Crosspovidone 20.0 Avicel PH 102 23.0 Magnesium Stearate 1.0 Core
Weight 178.0 Cellulose Acetate E320 25.52 Cellulose Aceate 398-10
26.74 HPMC 603 2.74 Total Weight 233.0 2/Ingredients
Polyplasdone-XL or Crosspovidone 80.0 Colloidal Silicone Dioxide
5.0 Sodium Chloride 44.2 Rivastigmine hta 4.8 Polyplasdone-XL or
Crosspovidone 20.0 Avicel PH 102 23.0 Magnesium Stearate 1.0 Core
Weight 178.0 Cellulose Acetate E320 32.48 Cellulose Aceate 398-10
34.03 HPMC 603 3.49 Total Weight 248.0
[0236] D. Determination of the Release of Rivastigmine:
[0237] Film-coated tablets as described above having two different
film thicknesses (coated with a film of different weight) are
placed in a beaker containing 200 ml of deionised (desalted) water
of 37.degree. C., and the time taken for the breaking of the film
(semi-permeable membrane) of the two tablets is determined. The
details are given in Tables 1 and 2:
19TABLE 1 drug release DR (%) in water, 50 rpm, film thickness: 55
mg minutes cell 1 cell 2 cell 3 cell 4 cell 5 cell 6 0 0.0 0.0 0.0
0.0 0.0 0.0 120 0.8 0.7 0.9 0.9 0.7 0.7 150 0.7 0.8 0.7 0.7 0.6 0.7
180 0.7 0.8 0.7 0.7 0.6 0.7 210 53.4 1.4 0.9 0.7 46.9 0.6 240 64.0
64.4 67.0 0.7 57.5 0.7 300 76.6 81.7 89.5 69.8 69.7 82.1 360 83.1
92.2 94.5 77.7 78.4 86.8
[0238]
20TABLE 2 drug release DR (%) in water, 50 rpm, film thickness: 70
mg min cell 1 cell 2 cell 3 cell 4 cell 5 cell 6 0 0.0 0.0 0.0 0.0
0.0 0.0 240 0.6 0.4 0.3 0.3 0.3 0.2 270 0.5 1.0 1.3 0.8 0.5 0.6 300
45.6 0.3 42.9 46.8 0.5 2.2 330 63.7 59.1 61.8 61.0 33.0 45.1 360
72.7 71.2 69.8 70.1 51.2 56.0 420 84.7 84.0 81.6 81.8 65.7 69.5
EXAMPLE 5
Second Component in the Form of a Matrix Tablet Coated with Two
Films
[0239] A. Preparation of the Core:
[0240] The mass for 70,000 cores is prepared as follows. 336 g of
rivastigmine hta is dissolved in about 6400 g of purified water and
12 g of alpha-tocopherol is dissolved in about 388 g ethanol (in
case of BHT a similar solution would also be prepared). 6938 g of
Polylasdone-XL, 1660 g of Microcrystalline Cellulose, 3094 g of
Sodium Chloride (previously milled), and 350 g of colloidal silicon
dioxide (Aerosil 200) are sieved through a 1600 .mu.m sieve and are
transferred into a 75 L Collette Gral High Shear Mixer. In the
Collette Gral the dry powders are mixed for one minute with Plow at
slow speed and Chopper off. After that the alpha-tocopherol
solution and the rivastigmine solutions are added slowly with the
Plow and Chopper both operating at a slow speed. Additional
purified water is added to form granules. After that the Collette
Gral is operated for 2 minutes with the Plow at slow and Chopper at
fast speeds. Then the granules are dried in the fluidized bed dryer
with inlet air temperature of about 70.degree. C., till a Loss on
Drying of less then 4% is achieved. After that the dried granules
are sieved through an 800 .mu.m sieve and mixed with the magnesium
stearate (previously sieved) for 5 minutes in a free fall blender.
This mixture is then compressed into tablets of 178 mg using oblong
tooling of size 10.times.5.2 mm using a suitable tablet press.
[0241] B. Film Coating:
[0242] First the two solutions for the two films are prepared. 499
g of Cellulose Acetate 398-10, 499 g of Cellulose Acetate 320S and
53 g of 3 cps HPMC are dissolved in a solvent mixture of 70%
Acetone, 20% Ethanol and 10% Purified Water to form a 7.5% solution
by weight of solid components. 441 g of Ethyl Cellulose N10 and 49
g of 5 cps HPMC are dissolved in a solvent mixture of 60% Acetone
and 40% Ethanol to form a 5% solution by weight of the solid
components. Up to 5% extra solution may be prepared to account for
the loss from spray drying during the coating process. The tablets
prepared above are coated in a suitable Perforated Coating Pan by
spraying first the Cellulose Acetate solution and then the Ethyl
Cellulose solution, to target film weights. Other solvent systems
such as methylene chloride/methanol may also be used.
21 C. Compositions Ingredients Quantity/tablet (mg) Rivastigmine
hta 4.8 4.8 Sodium Chloride 44.2 44.2 Avicel PH 102 23.712 23.712
PVPP-XL 99.11 99.11 a-tocopherol 0.178 0.178 Aerosil 200 5.0 5.0
Magnesium Stearate 1.0 1.0 Core Weight 178.0 178.0 Cellulose Aceate
398-10 7.125 7.125 Cellulose Acetate E320 7.125 7.125 HPMC 603
0.750 0.750 Ethylcellulose N10 4.5 6.3 HPMC 5 cps 0.5 0.7 Total
Weight 198 200
[0243] In a further composition a-tocopherol may be replaced by BHT
(butylated hydroxytoluene):
22 Ingredients Quantity/tablet (mg) Rivastigmine hta 4.8 Sodium
Chloride 44.2 Avicel PH 102 23.0 PVPP-XL 99.11 BHT 0.890 Aerosil
200 5.0 Magnesium Stearate 1.0 Core Weight 178.0 Cellulose Aceate
398-10 9.5 Cellulose Acetate E320 9.5 HPMC 603 1.0 Ethylcellulose
N10 2.7 HPMC 5 cps 0.3 Total Weight (mg) 201
[0244] D. Determination of the Release of Rivastigmine:
23TABLE 1 drug release DR (%) in water, 50 rpm, oblong tablet
(approximate size 10.25 mm (millimeters) .times. 5.5 mm .times.
4.80-4.85 mm) minutes cell 1 cell 2 cell 3 cell 4 cell 5 cell 6 240
0.0 0.0 0.0 0.0 0.0 0.0 300 0.0 0.0 0.0 0.0 0.0 0.0 360 58.1 0.0
0.0 59.8 0.0 0.0 420 89.6 62.4 58.9 83.4 0.0 60.6 480 92.0 96.0
85.4 97.2 97.1 85.5 540 99.0 97.9 95.2 100.9 95.8 97.6 600 99.4
100.2 102.7 101.0 100.2 99.9 660 100.4 100.9 103.0 102.3 102.1
102.5 720 102.1 101.8 103.2 99.4 104.2 101.6
[0245]
24TABLE 2 drug release DR (%) in water, 50 rpm, round tablet
(approximate size: 8.57 .times. 5.58 millimeters) minutes cell 1
cell 2 cell 3 cell 4 cell 5 cell 6 240 0.0 0.0 0.0 0.0 0.0 0.0 300
0.0 0.0 0.0 0.0 96.5 0.0 360 92.5 0.0 0.0 0.0 99.4 0.0 420 100.9
0.0 0.0 0.0 99.8 0.0 480 101.6 89.5 0.0 0.0 100.3 0.0 540 101.5
98.0 0.0 0.0 100.2 88.7 600 100.9 100.1 94.4 0.0 99.4 97.0 660
101.7 101.7 100.1 0.0 98.8 101.0 720 102.1 100.7 101.8 76.2 99.2
102.1
EXAMPLE 5
Capsule Filing
[0246] The capsule filling mixture comprising first and second
component together (or alone if desired) is filled on a automatic
capsule filling machine (Zanasi.RTM. LZ 5) into empty hardgelatine
capsule shells (CONISNAP.RTM. 6 dimple, size 3). The nominal fill
weight is as mentioned above. The process parameters are as
follows:
[0247] speed: 3000 HK/h
[0248] dosator piston:
[0249] size:# 4
[0250] height: 12-14 mm
[0251] vacuum: 0.7 bar
[0252] feed hopper: none
* * * * *