U.S. patent application number 10/486898 was filed with the patent office on 2004-10-21 for sustained release micropellets and process for producing the same.
Invention is credited to Hamano, Fumiya, Hosono, Tetsuya, Kitano, Eisaku, Yoneda, Fumio.
Application Number | 20040208930 10/486898 |
Document ID | / |
Family ID | 19077585 |
Filed Date | 2004-10-21 |
United States Patent
Application |
20040208930 |
Kind Code |
A1 |
Yoneda, Fumio ; et
al. |
October 21, 2004 |
Sustained release micropellets and process for producing the
same
Abstract
Sustained release micropellets showing a stable
controlled-release of a drug without being affected by the changes
in pH value etc., characterized by being produced by coating core
particles with a layer containing a water-soluble drug and further
forming a film layer containing a water-insoluble polymer compound
and a plasticizer on the thus obtained particles, locating a
water-soluble filler layer between the water soluble
drug-containing layer and the film layer, and having an average
particle size of 300 .mu.m or less; medicinal compositions
containing these micropellets; and a process for producing the
same.
Inventors: |
Yoneda, Fumio; (Matsubara,
JP) ; Hamano, Fumiya; (Matsubara, JP) ;
Kitano, Eisaku; (Matsubara, JP) ; Hosono,
Tetsuya; (Matsubara, JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
19077585 |
Appl. No.: |
10/486898 |
Filed: |
February 17, 2004 |
PCT Filed: |
August 12, 2002 |
PCT NO: |
PCT/JP02/08245 |
Current U.S.
Class: |
424/470 |
Current CPC
Class: |
A61K 9/0095 20130101;
A61K 9/5078 20130101; A61K 9/5084 20130101; A61K 31/485
20130101 |
Class at
Publication: |
424/470 |
International
Class: |
A61K 009/26 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 17, 2001 |
JP |
2001-248426 |
Claims
1. Sustained release micropellets having an average particle size
of 300 .mu.m or less which comprise being produced by coating core
particles with a layer containing a water-soluble drug and further
forming a film layer containing a water-insoluble polymer compound
and a plasticizer on the particles and forming a water-soluble
filler layer between the water-soluble drug-containing layer and
the film layer.
2. The sustained release micropellets according to claim 1, wherein
the weight of the film layer is 20 to 50% of the total weight of
the particles and that of the water-soluble filler layer.
3. The sustained release micropellets according to claim 1, wherein
the film layer is composed of two or more layers comprising the
film layer not containing any water-soluble polymer compound and
the film layer containing a water-soluble polymer compound.
4. The sustained release micropellets according to claim 1, wherein
the water-soluble drug is a water-soluble analgesic and the
water-insoluble polymer compound is ethylcellulose.
5. The sustained release micropellets according to claim 4, wherein
the water-soluble analgesic is an opioid analgesic.
6. The sustained release micropellets according to claim 5, wherein
the opioid analgesic is morphine or a pharmaceutically acceptable
salt thereof.
7. The sustained release micropellets according to claim 1, wherein
the layer containing a water-soluble drug, the water-soluble filler
layer, and the film layer containing a water-insoluble polymer
compound and a plasticizer can be formed by layering or coating
using water or an aqueous solution as the solvent.
8. Medicinal compositions comprising the sustained release
micropellets described in claim 7.
9. The medicinal compositions according to claim 8, wherein two or
more types of sustained release micropellets with different
dissolution patterns are contained.
10. The medicinal compositions according to claim 8, wherein the
medicinal compositions are any of fine granules, powders and dry
syrups.
11. A process for producing sustained release micropellets having
an average particle size of 300 .mu.m or less which comprises
producing coated particles by coating core particles with a layer
containing a water-soluble drug and further forming a film layer
containing a water-insoluble polymer compound and a plasticizer on
the particles, and locating a water-soluble filler layer between
the water-soluble drug-containing layer and the film layer.
12. The process for producing sustained release micropellets
according to claim 11, wherein the weight of the film layer is 20
to 50% of the total weight of the coated particles and the
water-soluble filler layer.
13. The process for producing sustained release micropellets
according to claim 11, wherein the film layer is composed of two or
more layers including the film layer not containing any
water-soluble polymer compound and the film layer containing a
water-soluble polymer compound.
14. The process for producing sustained release micropellets
according to claim 11, wherein the water-soluble drug is a
water-soluble analgesic and the water-insoluble polymer compound is
ethylcellulose.
15. The process for producing sustained release micropellets
according to claim 14, wherein the water-soluble analgesic is an
opioid analgesic.
16. The process for producing sustained release micropellets
according to claim 15, wherein the opioid analgesic is morphine or
pharmaceutically acceptable salt there of.
17. The process for producing sustained release micropellets
according to claim 11, wherein the layer containing a water-soluble
drug, the water-soluble filler layer, and the film layer containing
a water-insoluble polymer compound and a plasticizer can be formed
by layering or coating using water or an aqueous solution as the
solvent.
18. The process for producing a medicinal composition containing
the sustained release micropellets according to claim 17.
19. The process for producing a medicinal composition according to
claim 18, wherein the composition contains two or more types of
sustained release micropellets with different dissolution
patterns.
20. The process for producing the medicinal compositions according
to claim 18, wherein the medicinal compositions are any of fine
granules, powders and dry syrups.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to sustained release
micropellets with controlled release of a water-soluble drug,
medicinal compositions containing these micropellets, and a process
for producing the same.
BACKGROUND ART
[0002] A sustained release preparation with controlled release of a
drug can maintain the blood concentration of the drug within the
therapeutically effective range throughout a considerably long
period of time. That is, the sustained release preparation, as
compared with usual preparations, is more suitable for improvement
of the therapeutic effectiveness by maintaining the effective blood
concentration of the drug and also for improvement of patients' QOL
(quality of life) by suppression of adverse reactions caused by
unnecessary increase or drastic change of the blood concentration
and by maintenance of patients' compliance. Thus sustained release
preparations have long been studied from various viewpoints.
[0003] For example, sustained release oral preparations such as
spansules, spantalontabs, repetabs, etc. are known. However
preparations with a large diameter such as tablets and capsules may
be undesirable for oral administration in the aged, children, or
patients with difficulty in swallowing. For easier oral
administration of a sustained release preparation to these people,
the preparation should desirably be composed of as small as
possible units that are still capable of sustained release and be
able to be formulated as a suspension, paste, or syrup as needed.
Such a sustained release preparation composed of small units is
suitable also for easy adjustment of the dose when the necessary
dose varies according to the difference in sensitivity, tolerance,
progression of diseases, etc.
[0004] Microcapsule preparations are known among sustained release
preparations having an average particle size of 200 .mu.m or less.
For example, a preparation of microcapsules produced by the
drying-in-liquid method has been disclosed in Japanese Unexamined
Patent Publication No.109711/1986 etc. Production of microcapsules,
as compared with production of particles by layering or coating, is
industrially disadvantageous in respect of apparatus, equipments,
factors to be controlled, etc. In case of microcapsules containing
a water-soluble drug where water or an aqueous solvent is charged
in the capsule, problems such as softening of capsules due to
miscibility of the water with the coating film during capsulation
and/or water migration after capsulation and difficulty in
prevention of the influence of water on the content along
time-course, are apt to arise. In addition, when the organic
solvents are used in the production of the microcapsules, attention
should be paid to safety and environmental problems such as
residue, inflammability, exhaust gas of the organic solvents.
[0005] "Layering" means a technique for formation of granulation
product containing a drug, etc. by coating the surface of core
particles with the drug alone or in combination with a filler,
binder, etc. "Coating" is a technique for formation of a layer
consisting of fat or fatty oil, a polymer, etc. on the surface of
solid particles such as core particles or granulation product
whereby drug-release control, contribution to stability, or masking
of unpleasant odor, taste, etc. is attained. Layering methods
include granulation by spraying a solution, suspension, or
dispersion of the coating ingredients followed by drying, and
granulation by addition, adhesion, and binding of the coating
ingredients while spraying a binder-containing solution followed by
drying. Coating methods include spraying of a solution, suspension,
or dispersion of the film components followed by drying.
[0006] A persistent severe pain disturbs patients' daily activities
due to insomnia, loss of appetite, etc. may cause, in physical
conditions, loss of strength, general prostration, and even
aggravation of the underlying disease, and in mental conditions,
various adverse influences such as fear, anxiety, and apprehension
of occurrence of neurological symptoms such as depression.
Therefore resolution or alleviation of pain has been the great
important problems as well as treatment of the underlying
disease.
[0007] A number of drugs are now available as analgesic agents,
among which morphine, an opioid analgesic agent, is representative.
The analgesic effect of morphine is remarkable. Morphine is
included in the list of basic drugs of The World Health
Organization (WHO) for patients suffering from cancer with
persistent severe pain, and WHO recommends oral administration
whenever possible, intrarectal administration when oral
administration is impossible, injection when intrarectal
administration is also impossible, dose adjusted for a patient,
regular administration at specified time intervals, efforts to
prevent adverse reactions due to the drug as far as possible,
consideration of patients' mental state, etc. Morphine, having a
short half-life, requires frequent administration; for instance,
every 4 hours even while sleeping at night is necessary for
persistent efficacy, and this has posed problems in patients'
compliance and QOL.
[0008] For solving these problems, sustained release preparations
of morphine have been developed, including MS CONTIN tablet (trade
name by Shionogi & Co. Ltd.) and capsules and sticks of KADIAN
(trade name by Faulding Co.) which are prepared by matrix formation
with a water-insoluble polymer compound or by film coating. MS
Contin tablets are film-coated tablets of about 7.1 mm in diameter
and about 4.4 mm in thickness, prepared by coating with a higher
alcohol film the granules where morphine sulfate is formed into
matrix with a gel-forming polymer compound such as
hydroxyethylcellulose. MS Contin tablets are sustained release
tablets as the basic unit designed so that morphine in the tablet
is released gradually by water that has penetrated through the
higher alcohol film into the tablet to maintain the analgesic
effect by twice-a-day administration. However, oral administration
is difficult in some cases and fine adjustment of the dose is
impossible because one tablet is the basic unit of the sustained
release. In addition, because the tablets, when broken, lose their
sustained releaseability, much morphine may be released at a time
when the patient has crunched the tablet in the mouth, so that the
blood concentration may be increased rapidly to cause serious
adverse reactions such as dyspnea and disturbance of consciousness.
KADIAN is a preparation of which units are sustained release
pellets (particles) of 1.0 to 1.7 mm in average particle size.
These sustained release pellets are filled in hard capsules to
prepare KADIAN capsules (No.2 or No.4 capsules), or divided and
packaged to prepare KADIAN sticks. The mechanism of sustained
release of KADIAN is pH-dependent control of release of morphine by
the coating of the hybrid type consisting of a water-insoluble
polymer compound, an acid-soluble polymer compound, and an enteric
polymer compound. However, in patients with decreased digestive
function, sustained release of the type that is dependent on the pH
in the digestive tract may not be effective enough. Furthermore,
there are some additional disadvantages in respect of easiness of
administration, such as bulkiness of preparations with high content
of morphine, and being unable to be prescribed in the form of a
suspension, paste, or syrup by addition of an adequate amount of
water, an aqueous solution etc. before administration.
[0009] In general, during layering or coating of core particles or
granulation products having an average particle size of 300 .mu.m
or less, cohesion or scattering of the particles or granulation
products is apt to occur, and the specific surface area becomes
large, so that it is difficult to obtain stable sustained release
preparations when the amount of the coating agent is 50% by weight
or less of the amount of the core particles or solid particles.
Japanese Unexamined Patent Publication No. 2001-106627 has
disclosed sustained release granules having an average particle
size of 50 to 250 .mu.m that can be prepared more easily than
microcapsules and without use of any organic solvents and can be
formulated into fine granules or dry syrup preparations where
weight ratio of the water-insoluble polymer compound is 40 to 150%
of that of the active ingredient, theophylline. However, as
theophylline is slightly soluble in water, the ability of granules
to sustain release hardly functions or is markedly decreased when
the drug is highly water-soluble. In WO98/10756, a method for
coating with a polymer that can sustain release when water is used
as the solvent, and a method for coating only with a heat-fused wax
were attempted: latex of ethylcellulose, copolymer of ethyl
acrylate and metacrylic acid, aminoalkyl methacrylate, etc. have
been developed as polymers that can sustain release with an aqueous
solvent, but even with these, it is difficult to control release of
a highly water-soluble drug over a long time period, and it has
been reported that the steady zero-order release of a drug is
impossible even with a very thick film for the release
controlling.
DISCLOSURE OF THE INVENTION
[0010] A primary object of the present invention is to provide
sustained release micropellets and medicinal compositions
containing the micropellets that realize stable control of release
even when the drug is water-soluble, improve patients' compliance
and QOL, and make it easier or possible to administer orally to the
aged, children and even patients with decreased swallowing
function.
[0011] A second object is to provide sustained release micropellets
and medicinal compositions containing the micropellets that can be
prepared by layering or coating without use of organic solvents and
can be formulated in the form of suspension, paste, or syrup by
addition of a suitable amount of water, solution, etc. as needed
before administration.
[0012] The inventors have found, as the result of their researches
to accomplish the above-mentioned objects, that controlled release
micropellets showing stable sustained-release of a drug without
being affected by changes in pH value, etc. can be obtained when a
layer of a water-soluble filler, of which use for the
sustained-release of a water-soluble drug has been considered
generally unacceptable, is formed between the granulation product
and the film layer in the sustained-release micropellets produced
by coating core particles with a layer containing a water-soluble
drug and further forming a film layer containing a water-insoluble
polymer compound and a plasticizer on the particles. Thus the
inventors have completed the invention.
[0013] The sustained release micropellets of the invention usually
have an average particle size of 300 .mu.m or less, desirably of
150 to 300 .mu.m. These micropellets can be prepared by layering or
coating using the conventionally used rolling granulating
apparatus, fluidized bed coating apparatus, etc. The shape of
micropellets is not particularly limited but desirably granular or
globular shape.
[0014] The weight of the film layer containing a water-insoluble
polymer compound and a plasticizer is desirably 20 to 50%, more
desirably 25 to 40%, of the sum of the weight of the core particles
coated with a layer of a water-soluble drug and the weight of the
layer of a water-soluble filler. The film layer containing a
water-insoluble polymer compound and a plasticizer is desirably
composed of two or more layers including the film layer not
containing the water-soluble polymer compound and the film layer
containing the water-soluble polymer compound, and more desirably
the film layer containing the water-soluble polymer compound is
located outside the film layer not containing the water-soluble
polymer compound. In the sustained release micropellets of the
invention, the release control pattern appropriate for various
water-soluble drugs or patients can be selected readily by changing
the ratio of the film layer arbitrarily within the above-mentioned
range or by mixing micropellets with a different ratio of film
layers; even a pattern of controlling release of roughly zero order
can be obtained. In such a case, release of a drug is more
controlled by increasing the ratio of the film layer containing a
water-insoluble polymer compound and a plasticizer, particularly
the ratio of the film layer containing a water-insoluble polymer
compound and a plasticizer but not containing a water-soluble
polymer compound.
[0015] The water-soluble drugs of the present invention are not
particularly limited, and include, for example, analgesics,
anti-inflammatory agents, sympathomimetic agents, central nervous
system-acting agents, cardiotonics, anti-allergic agents,
anti-histamic agents, anti-hypertensive agents, antibiotics,
anti-neoplastic agents, antiarrhythmic agents, vitamins,
bronchodilating agents, etc.
[0016] Water-soluble drugs in this context mean those which require
less than 1000 ml, preferably less than 500 ml, of water for
dissolution of 1 g of the drug in the solubility test (degree of
dissolution within 30 minutes at 20.+-.5.degree. C. while
vigorously shaking for 30 seconds every 5 minutes) as described
under Description, General Notices, the pharmacopoeia of Japan
(JP), though the definition is not strict because it may vary
depending on the unit dose. Among the above-mentioned water-soluble
analgesics, especially desirable ones are opioid analgesics such as
morphine, codeine, hydromorphone, methadone, meperidine,
levorphanol, pethidine, tilidine, tramadol, fentanyl,
buprenorphine, piritramide, and derivatives thereof,
pharmaceutically acceptable salts thereof, and mixtures thereof.
The invention is particularly useful for water-soluble analgesics,
those that require 3 or more times administration per day when
given at an appropriate dose, those that require administration
during bed rest at night, and those with a short half-life in
blood, representative examples of which are morphine, its
derivatives, and its pharmaceutically acceptable salts.
[0017] Core particles used in the invention are those used for
usual layering such as powder or crystalline cellulose, starch,
sugar, etc. and not particularly limited as far as those by which
sustained release micropellets of the invention having an average
particle size of 300 .mu.m or less can be obtained after specified
layering and coating, the average particle size being desirably 100
to 250 .mu.m and more desirably 150 to 200 .mu.m. The shape of the
particles is not particularly limited but desirably granular or
globular.
[0018] Water-insoluble polymer compounds include cellulose esters
such as ethylcellulose and butylcellulose, copolymers of acrylic
acid/methyl methacrylate, etc., copolymers of ethyl
methacrylate/aminoalkyl methacrylate, etc., analogues thereof, and
mixtures thereof, and desirably cellulose esters, and more
desirably ethylcellulose. Water-insoluble polymer compounds in this
context are those that require not less than 10000 ml of water for
dissolution of 1 g of the compound in the solubility test described
above.
[0019] Plasticizers include triethyl citrate, tributyl citrate,
triacetin, diethyl acetate, phthalate esters, and castor oil. The
ratio of a plasticizer to a water-insoluble polymer compound is 10
to 50% by weight, desirably 15 to 35% by weight.
[0020] Water-soluble polymer compounds include
hydroxypropylmethylcellulos- e, hydroxypropylcellulose,
methylcellulose, sodium carboxymethylcellulose, polyethyleneglycol
and water-soluble polysaccharides, among which
hydroxypropylmethylcellulose is the most desirable. Water-soluble
polymer compounds in this context are those 1 g of which is soluble
in less than 10000 ml of water in the solubility test described
above.
[0021] Fillers include oligosaccharides such as lactose, sucrose,
D-mannitol, sorbitol, and glucose, polysaccharides such as dextrin,
dextran and pullulan, starches such as corn starch, .alpha.-starch,
and carboxymethyl starch, celluloses such as crystalline cellulose,
crystalline cellulose carmellose sodium, and low substituted
hydroxypropylmethylcellulose, silicic acids such as synthetic
aluminum silicate and magnesium aluminometasilicate, inorganic acid
salts such as calcium phosphate, calcium carbonate, and calcium
sulfate, xanthan gum, acacia, etc. Fillers used in the layer of
water-soluble filler are water-soluble fillers including
oligosaccharides such as lactose, sucrose, mannitol, sorbitol, and
glucose, water-soluble polysaccharides such as dextrin, acacia, and
mixtures thereof, among which oligosaccharides are particularly
desirable and lactose is further desirable. Water-soluble fillers
in this context are those 1 g of which is soluble in less than 100
ml of water in the solubility test described above.
[0022] For formation of the layer of a water-soluble filler by
layering or coating, the filler is desirably used as an almost
saturated solution, a solution of a higher concentration, a
dispersion, or a suspension in water or an aqueous solution to be
used, and may contain an additive such as a binder described below
as needed within the range of the conventional method.
[0023] Binders include polyvinylpyrrolidone,
hydroxypropylmethylcellulose, hydroxypropylcellulose,
methylcellulose, hydroxyethylcellulose, mixtures thereof, etc.;
stabilizers include citric acid, tartaric acid, succinic acid,
fumaric acid, maleic acid, sodium hydrogen sulfite, etc.;
lubricants include light anhydrous silicic acid, talc, magnesium
stearate, magnesium oxide, titanium oxide, etc. These compounds may
be added and used as needed according to the conventional
method.
[0024] The sustained release micropellets of the invention can be
produced by layering and coating using water or an aqueous solution
as the solvent without using any organic solvent, and can be
formulated into medicinal compositions in the form of fine
granules, powders, and dry syrups, according to the conventional
method by addition of acceptable additives in the field of
formulation, such as a filler, sweetening agent, flavoring agent,
binder, disintegrator, suspending agent, perfume, artificial color,
stabilizer, lubricant, etc. In addition, sustained release
micropellets and medicinal compositions thereof of the invention
can be filled in hard capsules or supplied as sub-packaging powder,
etc.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1: Pattern of dissolution of morphine in Example 6.
[0026] ".smallcircle.": Dissolution pattern from sustained release
micropellets of Example 2.
[0027] ".circle-solid.": Dissolution pattern from sustained release
micropellets of Example 3.
[0028] FIG. 2: Pattern of dissolution of morphine in Example 7.
[0029] ".DELTA.": Paddle rate of 50 rotations per minute.
[0030] ".circle-solid.": Paddle rate of 100 rotations per
minute.
[0031] ".quadrature.": Paddle rate of 200 rotations per minute.
[0032] FIG. 3: Pattern of dissolution of morphine in Example 8.
[0033] ".diamond-solid.": pH 1.2, ".DELTA.": pH4.0,
".quadrature.":pH6.8, ".circle-solid.": water.
BEST MODE FOR CARRYING OUT THE INVENTION
[0034] The invention will be explained in detail in the following
Examples, though the scope of the claimed invention is not limited
only to these Examples.
EXAMPLE 1
[0035] In a Teflon-coated rolling fluidized bed granulating-coating
apparatus, with electrostatic protection as needed, 660 g of
crystalline cellulose particles having an average particle size of
not more than 200 .mu.m was sprayed with an aqueous solution in
which 330 g of morphine sulfate, 60 g of hydroxypropylcellulose,
8.3 g of citric acid, and 0.7 g of sodium hydrogen sulfite had been
dissolved under the conditions of air supply of 20 to 40
m.sup.3/hr, inlet air temperature of 77 to 83.degree. C., outlet
air temperature of 34 to 37.degree. C., rotor rotation of 240 to
280 rpm, spray rate of 4 to 8 g/min, spray air pressure of 1.8 to
2.0 kg/cm.sup.2, spray air volume of 25 to 30 L/min, side-air
quantity of 60 to 70 L/min, followed by drying under the conditions
of the air temperature of 45.degree. C. at the outlet, to give a
granulation product coated with a layer containing morphine
sulfate. Then the granulation product was sprayed with an aqueous
dispersion or suspension of 84 g of lactose and 7 g of
hydroxypropylcellulose followed by drying, so that the granulation
product was coated with a lactose layer.
EXAMPLE 2
[0036] A portion of the granulation product coated with a lactose
layer obtained in Example 1 was subjected to spray-coating in a
rolling fluidized bed granulating-coating apparatus under the
conditions of air supply of 35 to 55 m.sup.3/hr, inlet air
temperature of 77 to 83.degree. C., outlet air temperature of 36 to
38.degree. C., rotor rotation of 250 to 300 rpm, spray rate of 5 to
11 g/min, spray air pressure of 1.8 to 2.0 kg/cm.sup.2, spray air
volume of 25 to 30 L/min, side-air quantity of 60 to 70 L/min, and
drying temperature of 54 to 56.degree. C., with an aqueous
dispersion/suspension of 120 g of ethylcellulose and 40 g of
triethyl citrate so that the weight of solid ingredients became to
be 10% of the weight of the granulation product coated with a
lactose layer, and the coated product was dried. The product was
further subjected to spray-coating with an aqueous
dispersion/suspension of 115 g of ethylcellulose, 28 g of triethyl
citrate, and 7 g of hydroxypropylmethylcellulose so that the weight
of solid ingredients became to be 15% of the weight of the
granulation product coated with a lactose layer, and the coated
product was dried, to give sustained release micropellets having an
average particle size of 300 .mu.m or less.
EXAMPLE 3
[0037] Another portion of the granulation product coated with a
lactose layer obtained in Example 1 was subjected to spray-coating
in the rolling fluidized bed granulating-coating apparatus under
the same conditions as in Example 2 with an aqueous
dispersion/suspension of 120 g of ethylcellulose and 30 g of
triethyl citrate so that the weight of solid ingredients became to
be 25% of the weight of the granulation product coated with a
lactose layer, and the product was dried. The product was further
subjected to spray-coating with an aqueous dispersion/suspension of
115 g of ethylcellulose, 28 g of triethyl citrate, and 7 g of
hydroxypropylmethylcellulose so that the weight of solid
ingredients became to be 10% of the weight of the granulation
product coated with a lactose layer, and the product was dried, to
give sustained release micropellets having an average particle size
of 300 .mu.m or less.
EXAMPLE 4
[0038] Sustained release micropellets obtained in Example 2 and
those in Example 3 were mixed at the ratio of 1:1, and 135 g of the
resultant mixture (containing about 30 g of morphine sulfate), 832
g of lactose, 240 g of D-mannitol, 120 g of sucrose, 120 g of
crystalline cellulose-carmellose sodium, 8 g of xanthan gum, and 8
g of sodium lauryl sulfate were charged in a rolling fluidized bed
granulating-coating apparatus for spray-granulation with an aqueous
solution containing 5 g of aspartame, 2 g of sodium chloride, and 3
g of citric acid and an aqueous solution containing 24 g of
polyvinylpyrrolidone (K30) under the conditions of air supply of 40
to 50 m.sup.3/hr, inlet air temperature of 80.degree. C., outlet
temperature of 34 to 37.degree. C., rotor rotation of 240 to 280
rpm, spray rate of 4 to 8 g/min, spray air pressure of 1.8 to 2.0
kg/cm.sup.2, spray air volume of 20 to 30 L/min, and air
temperature of 45.degree. C. at the outlet during drying, and the
product was dried, followed by sizing the particles with a sieve
after addition of 3 g of light anhydrous silicic acid, to give fine
granules (dry syrup) containing 2% of morphine sulfate.
EXAMPLE 5
[0039] Sustained release micropellets obtained in Example 2 and
those in Example 3 were mixed at the ratio of 1:1, and 405 g of the
resultant mixture (containing about 90 g of morphine sulfate), 640
g of lactose, 200 g of D-mannitol, 100 g of sucrose, 100 g of
crystalline cellulose-carmellose sodium, 10 g of xanthan gum, and 6
g of sodium lauryl sulfate were charged in a rolling fluidized bed
granulating-coating apparatus for spray-granulation with an aqueous
solution containing 2 g of sodium chloride and 4 g of citric acid
and an aqueous solution containing 30 g of polyvinylpyrrolidone
(K30) under the same conditions as in Example 4, and the product
was dried, followed by sizing the particles with a sieve after
addition of 3 g of light anhydrous silicic acid, to give fine
granules containing 6% of morphine sulfate (dry syrup), which was
divided by 0.5 g per pouch by a powder-dividing and packaging
machine. (0.5 g of the powder in a pouch contains 30 mg of morphine
sulfate.)
EXAMPLE 6
[0040] Sustained release micropellets obtained in Example 2 and
those in Example 3 were separately subjected to determination of
the dissolution rate of morphine by using water as the test
solution at the paddle rate of 100 rpm as directed in the Method
(2) under the Dissolution Test, General Tests of the Japanese
Pharmacopoeia (JP) The dissolution patterns are illustrated in FIG.
1.
EXAMPLE 7
[0041] Fine granules (dry syrup) obtained in Example 4 were
subjected to determination of the dissolution rate of morphine by
using water as the test solution at the paddle rate of 50, 100 or
200 rpm as directed in the Method (2) under the Dissolution Test,
General Tests, JP. The dissolution patterns are illustrated in FIG.
2.
EXAMPLE 8
[0042] Fine granules (dry syrup) obtained in Example 5 were
subjected to determination of the dissolution rate of morphine by
using a solution of pH.12, pH4.0, pH6.8 or water as the test
solution at the paddle rate of 50 rpm as directed in the Method (2)
under the Dissolution Test, General Tests of JP. The dissolution
patterns are illustrated in FIG. 3
INDUSTRIAL APPLICABILITY
[0043] Sustained release micropellets of the present invention
having an average particle size of 300 .mu.m or less and medicinal
compositions containing these sustained release micropellets have a
stable release-controlling action without being affected by pH,
etc., and make oral administration or nasogastric
tube-administration easy or possible in children, the aged, and
even in patients with decreased swallowing function, when
administered as they are or after formulation into suspension,
paste, or syrup by addition of an appropriate amount of water, an
aqueous solution, etc. before administration as needed. The basic
unit that shows sustained release is a small particle and it is
possible to change arbitrarily the ratio of the film layer within
the specified range or to mix the preparations with different
ratios of the film layer, so that the micropellets are suitable for
improvement of patient's compliance and QOL because the dose of a
drug and the control pattern can be adjusted even when the
necessary amount varies depending on the difference in sensitivity,
tolerance, or progress of the disease, etc. In addition, the
sustained release micropellets, being able to be produced by
layering and coating using water or an aqueous solution as the
solvent, have no adverse effect on the environment due to residue,
flammability, waste gas, etc. of an organic solvent. Thus the
present micropellets have many advantages also in the process for
production.
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