Time (h)
US006143328A
Ulllted States Patent [19]
[11] Patent Number:
Hea?eld et al.
[45]
[54]
6,143,328
Date of Patent:
SUSTAINEI) RELEASE COMPOSITIONS AND
A METHOD OF PREPARING
3,634,584
3,845,770
PHARMACEUTICAL COMPOSITIONS
3,870,790
3,916,889
Inventors: John
Joanne
Kn0tt>
Hea?eld,
Bishop’s
Fenstanton;
Stortford;
Trevor
*Nov. 7, 2000
1/1972 Poole ...................................... .. 424/21
11/1974 Theeuwes et al
. 128/260
3/1975 LoWey et al.
11/1975
..... .. 424/19
Russell ......... ..
.. 128/1458
(List continued
Theeuwes
on et
next
al. page.)
................. ..
Stewart Thomas Leslie, Cambridge;
Sandra Therese Antoinette
FOREIGN PATENT DOCUMENTS
Malkowska> Ely’ an of Unite?
9047732
7/1990 Australia .
Klngdom; Ronald Brown Mlller,
Basel, Switzerland; Derek Allan
9341654
2082573
2/1995
5/1993
Prater, Milton; Kevin John Smith,
_
Histon, both of United Kingdom
Australia .
Canada _
_
(L15t Connnued on next page)
[73] Assignee: Euro-Celtique, S.A., Petrusse,
OTHER PUBLICATIONS
Luxembourg
Abraham Sunshine, et al., “Analgesic or al ef?cacy of
tramadol hydrochlorine in postoperative pain”, Clin. Phar
mam] The“ Jun' 1992, pp 74()_746_
E. Beubler, “Medikamentose SchmerZtherapie: Kriterien,
[*]
Notice:
This patent is subject to a terminal dis-
Clalmer-
Moglichkeiten, Risken”, Therapiewoche Osterreich, 7, 2
[21] APPL NO-I 09/264,399
(1992), pp. 90—96 With English Translation.
[22] Filed,
N. YokokaWa, et'al., “Relationship DCIWG'GII plasma concen
Man 8’ 1999
tration of morphine and analgesic effectiveness”, Postgraa'
Med J» (1991) 67 (Suppl 2), PP- 550—554~
Related US. Application Data
[63]
Continuation of application No. 08/843,571, Apr. 18, 1997,
Pat. No. 5,879,705, which is a continuation of application
No. 08/269,208, Jun. 30, 1994, abandoned.
[30]
Jul. 27, 1993 [GB]
"mary
-
J
M S
x“m‘”e’_ @165
' ,Pear
_
LLC
United Kingdom ................. .. 9315467
Mal 1: 1994 [GB]
E
Attorney, Agent, or Fzrm—Davldson, Davidson & Kappel,
Foreign Application Priority Data
Nov. 23, 1993 [GB]
(Llst Connnued on next page)
P -
United Kingdom
9324045
United Kingdom
[57]
ABSTRACT
9403922
Sustained release pharmaceutical formulations containing
United Kingdom ................. .. 9404928
morphine, or a pharmaceutically acceptable Salt thereof, as
[51]
Int. cl.7 ............................. .. A61K 9/14; A61K 9/26;
A61K 9/52
active ingrediem> Suitable for administration on a Once daily
basis, are disclosed. In a ?rst aspect, an orally administrable
[52]
US. Cl. ........................ .. 424/489; 424/484; 424/469;
424/457; 424/486
Sustained release “nit dosage, for“? gives a Peak Plasma level
at 1.0 to hours after administration. In a second aspect, the
Mar. 14, 1994
[GB]
[58] Field of Search
424/464 451
424
469 489’ 452’
’
’
’
’
’ 465’ 457’
’
[56]
morphine of betWeen and 12 hours. AthlTd aspect concerns
the pharmaceutical unlt dosage form obtained by compress
ing multiparticulates comprising a pharmaceutically active
References Cited
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U S PATENT DOCUMENTS
2,738,303
formulation provides a W5O for the M-6-G metabolite for
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3/1956 Blythe ..................................... .. 167/82
13 Claims, 7 Drawing Sheets
g
160
- 16 '5
=5
14o
— 14 *9’
‘EC 120
M—6—-G
"12 “5,4
g 5 100
8 g 80
o v
60
“I:I
40
20
- 10 g g
-8 8 E
_
Morphlne
2
- 6
e v
_- 4
2
~
1
_
O
l
l
I
l
12
24
48
6O
Time (h)
O
O
72
2
6,143,328
Page 2
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514/356
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424/465
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377518
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4,935,246
4,967,486
6/1990 Ahreris ----- -11/1990 139911198 -
424/490
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2053681
2178313
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4,970,075
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424/451
9201446
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WIpO _________ __
A61K 9/5O
536/69
9202209
2/1992
WIpO _
A61K 9/22
Oshlack ....... ..
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. . . A618 31/485
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A618 9/22
A618 9/14
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4,990,341
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9206679
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A61K 9/16
5,007,790
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Shell ............ ..
424/451
9304675
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A61K 31/16
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5,024,842
6/1991 Sakamoto et al.
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424/502
424/473
9307859
W0 93 07861
4/1993
4/1993
WIpO _
WIpO _
A61K 9/16
__ A61K 9/5O
5,026,560
6/1991 M91999 9191
-- 424/494
9310765
6/1993
WIPO ............................ .. A618 9/22
Danielsen et al. .................... .. 264/101
Malkowska 9t a1~ ----------------- ~- 424/497
9318753
W0 94 03160
9/1993
2/1994
WIpO _
WIPO ............................ .. A618 9/32
5,122,384
5,126,145
6/1992 Paradissis et al.
..
6/1992 Evenstad et al. ..................... .. 424/465
W0 94 03161
W0 94 05262
2/1994
3/1994
WIpO _
WIpO _
5,132,142
7/1992
5,133,974
7/1992 Paradissis 9191
5,030,400
5,071,646
5,167,964
5,169,645
7/1991
12/1991
12/1992
12/1992
Jones et al. ........................... .. 427/196
9422431
10/1994
WIpO _
-- 424/480
9423700
10/1994
WIPO ............................ .. A618 9/16
Muhammed 9t a1~ ---------------- ~- 424/482
Shukla et al. ......................... .. 424/499
9600066
9601629
1/1996
1/1996
WIPO ........................ .. A618 31/485
WIpO _
_ A61K 31/485
9614058
3/1996
WIPO ............................ .. A618 9/14
5,178,863
1/1993 lvlalrnquiSt 9t 91-
5,196,203
3/1993
5,202,128
5,266,331
-- 424/490
Boehm .................................. .. 424/469
4/1993 Morella ................................. .. 424/469
11/1993 Oshlack et al.
. 424/468
5,273,760 12/1993 Oshlack et al-
424/480
5,283,065
5,286,493
"
OTHER PUBLICATIONS
Physicians Desk Reference 1994, 48th Edition, pp.
2/1994 Doyon etal. ......................... .. 424/467
2/1994 Oshlack et al.
.. 424/468
18214824
5,292,461
3/1994 Juch et al. .............................. .. 264/37
Abstracts.from the Twelfth Annual Congress of the Oncol'
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5,330,766
6/1994 Mayer et al. ........................... .. 514/25
7/1994 Morella et a1_
_ 424/490
Ogy Nursmg S°C1ety> May 1987
J. Lapin et al., “Cancer Pain Management With a Controlled
5,378,474
1/1995 Morella et al.
424/469
Release Oral Morphine Preparation”, Journ. of Pain and
5,403,593
5’411’745
4/1995 Royce ................................... .. 424/489
5/1995 Oshlack et a1‘
" 424/456
Sympton Manag., v 4 (3), pp. 146—151, 1989.
J. Lapin et al., “Guidelines for use of Controlled Release
5,453,283
9/1995
........................ ..
424/489
5,456,923 10/1995 Nakamichi et al. .................. ..
5,460,826 10/1995 Merrill et al.
..
5,472,712 12/1995 Oshlack et al. ....................... ..
5,500,227 3/1996 Oshlack et al. ....................... ..
5,508,042 4/1996 Oshlack et a1~
~~
Munch et al.
424/489
424/470
424/480
424/476
424/468
gerglsoiettall' """""""""""" "
,
,
5
ac
e
a.
....................... ..
575807578 12/1996 Oshlack et a1‘
" 424/468
5,601,842
2/1997
5,614,218
5,672,360
3/1997 Olsson .................................. .. 424/456
9/1997 Sackler .................................. .. 424/490
Bartholomaeus ..................... .. 424/464
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.
.
,,
Oral Morphme 1“ Cancer Pam Management ?ancer Nurs'
1ng> V 12 (4% W 202—8> 1989
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d—Release Morphine (MS Contin Tablets); A Review of the
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-
-
l1I2;iIi36I(1)OE11a;8C9;)ngr€SS, Symposium Services, No. 149, PP.
'
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2131350
0097523
3/1995
1/1984
Canada ...................... .. A618 31/135
European Pat. Off. ....... .. A61K 9/26
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6,143,328
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Pro?les of TWo Oral Controlled—Release Morphine Forrnu
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S. Bloorn?eld, et al., “Analgesic ef?cacy and potency of tWo
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Pharmacy, vol. 20, No. 7, pp. 1179—1197 (1994).
oral controlled—release rnorphine preparations”, Clin. Phar
rnacol. Ther.. vol. 53, No. 4, pp. 469—478, 1993.
Advertisement: MS Contin® ©1986, 1987 The Purdue
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U.S. Patent
Nov. 7,2000
Sheet 2 of7
(lw/?u)
uogoquaauoo augqdjow
@LOQ'NO
2:
("11/5")
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6,143,328
U.S. Patent
Nov. 7, 2000
Sheet 3 0f 7
6,143,328
("11/5")
uogonuaouoo augqdmw
72
3
(h)Time
UOQDJWGOUOO Q-Q-W
FIG.
U.S. Patent
Nov. 7, 2000
Sheet 4 0f 7
6,143,328
(lw/bu)
uogonueauoo GUllJdJOW
72
4
48
36
(h)Time
Morphilne
uogonuaauoo g-g-w
24
12
FIG.
U.S. Patent
Nov. 7,2000
Sheet 5 of7
(Wu/5")
uogonuaouoa 9U!L|dJOW
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(D
I
cm
2:
(Wu/5“)
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6,143,328
U.S. Patent
Nov. 7,2000
Sheet 6 of7
(Nu/5")
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NO
PPQCDQ'NO
o9
("u/5“)
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6,143,328
U.S. Patent
Nov. 7, 2000
Sheet 7 0f 7
6,143,328
(Wu/5“)
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6,143,328
1
2
SUSTAINED RELEASE COMPOSITIONS AND
A METHOD OF PREPARING
PHARMACEUTICAL COMPOSITIONS
The dosage unit form in accordance With the invention
should contain suf?cient morphine, or salt thereof, to give
therapeutic activity over a period of at least 24 hours. The
actual amount of morphine, or salt, in any particular dosage
This application is a continuation of US. Ser. No.
form Will of course depend upon a number of variables
08/843,571, ?led Apr. 18, 1997, issued as US. Pat. No.
5,879,705, Which is a continuation application of US. Ser.
No. 08/269,208 ?led Jun. 30, 1994 (abandoned).
including
the number of dosage forms intended to be
administered at any one time and (ii) the intended dosage for
any particular patient. Conveniently, hoWever, dosage unit
forms in accordance With the invention Will contain from 10
BACKGROUND OF THE INVENTION
This invention is concerned With improvements in and
relating to sustained release compositions and, more
particularly, is concerned With sustained release orally
administrable dosage unit forms containing morphine, or a
pharmaceutically acceptable salt thereof, as active ingredi
10
15
The present invention also relates generally to a method
of manufacturing an orally administrable dosage form, pref
erably sustained release granules/multiparticulates and com
metabolite of morphine and, itself,, has poWerful analgesic
properties, at least comparable With those of morphine.
ent.
pressed multiparticulates, such multiparticulates having
to 500 mg of morphine (calculated as morphine sulphate)
and thus, for example, typical dosage unit forms in accor
dance With the invention are those containing 20, 30, 60, 90,
120, 150 and 200 mg of morphine (calculated as above).
Morphine-6-glucuronide (hereinafter M-6-G) is a knoWn
20
diameters ranging from 0.1 to 3.0 mm; the method of the
invention provides multiparticulates in an unexpectedly high
We have found, in accordance With another aspect of the
invention, that a pharmaceutical formulation, containing an
effective amount of morphine or pharmaceutically accept
able salt thereof, effective for at least 24 hourly dosing, is
characteriZed by a W5O for the M-6-G metabolite of betWeen
4 and 12 hours, and preferably has a Tmwc of M-6-G in the
range 1 to 6.5 hours, more preferably 3 to 6.5 hours, and
yield.
even more preferably 3.5 to 6 hours.
Morphine is an opioid analgesic Well established for use
in the treatment of pain, especially moderate to severe pain.
25
Morphine-containing compositions in sustained release
form are currently commercially available as so-called
“tWice-a-day” formulations, that is formulations having a
duration of activity of 12 hours or more and accordingly
requiring to be administered tWice a day.
30
time betWeen the ?rst (or only) upslope crossing and the last
(or only) doWnslope crossing in the plasma pro?le.
We have observed that, surprisingly, formulations in
OBJECTS AND SUMMARY OF THE
INVENTION
It is one object of the present invention to provide a
The W5O parameter de?nes the Width of the plasma pro?le
at 50% Cmwc, ie the duration over Which the plasma
concentrations are equal to or greater than 50% of the peak
concentration. The parameter is determined by linear inter
polation of the observed data and represents the difference in
35
accordance With the invention, Which are characteriZed by a
W5O for M-6-G in the range speci?ed, are usually also
characteriZed by a W5O for morphine Within a similar range.
morphine-containing sustained release orally administrable
Accordingly, in accordance With another, preferred, aspect
dosage unit form Which has an effective duration of activity
of the invention a pharmaceutical formulation, containing an
effective amount of morphine or pharmaceutically accept
able salt thereof, effective for at least 24 hour dosing, is
characteriZed by a W5O for morphine of betWeen 4 and 12
hours, and preferably has a Tmwc in the range of 1 to 6.5
hours, more preferably 1 to 4 hours eg. 1 to 3.5 hours after
administration.
Apreferred formulation in accordance With this aspect of
of 24 hours or more and, hence, is suitable for administration
on a once daily basis.
It has surprisingly been found, in accordance With the
present invention, that effective therapeutic activity over a
40
period of 24 hours or more may be obtained from a
morphine-containing sustained release formulation Which
gives an in vivo peak plasma level relatively early after
administration, that is from 1.0 to 6 hours after administra
tion preferably 1 to 4 hours eg 1 to 3.5 hours.
Accordingly, one embodiment of the composition of the
invention provides an orally administrable sustained release
dosage unit form containing morphine, or a pharmaceuti
cally acceptable salt thereof, as active ingredient Which
formulation gives a peak plasma level from 1 to 6 hours,
preferably 1 to 4 hours eg. 1 to 3.5 hours, after adminis
tration.
It has been found that in a group eg. n=5, of healthy
volunteers such dosage units, When administered in a single
dose in the fasted state, gave median Tmax values in the range
of 1 to 4.25 hours.
45
the range of about 5.5 to 12 or 5.5 to 11 or even 6 to 10
50
ment containing 60 mg morphine sulphate When adminis
55
60
When morphine base or a salt other than the sulphate is
molecular Weight of the base or salt.
in the range of from 65 ng/ml to 150 ng/ml. Another such
preferred embodiment is characteriZed by a Cmax for mor
phine in the range of from 7.5 to 20 ng/ml.
One preferred embodiment described herein, after single
(per ml of plasma) is preferably from 0.5><10_7 to 75x10“7
times the amount of morphine sulphate orally administered.
administered, the preferred ratio of drug administered to
peak plasma level should be adjusted according to the
hours.
The Cmwcs of formulations in accordance With the inven
tion are dose dependant. For instance, a preferred embodi
tered as a single dose is characteriZed by a Cmwc for M-6-G
When the morphine is administered as morphine sulphate
and the method of plasma analysis is high performance
liquid chromatography, the peak plasma level of morphine
the invention is characteriZed by the foregoing parameters
When dosed to patients in the fasted state.
Preferred values for W5O for M-6-G and morphine are in
65
dosing to 5 fasted volunteers Was found to have W50, for
morphine and M-6-G in the range 5.5 to 12 hours.
It has been found that in a group eg. n=5, of healthy
volunteers one embodiment of such dosage units, When
administered in a single dose in the fasted state, gave median
Tmwc values of M-6-G in the range of 3.5 to 6 hours, eg. 4
to 6.0 hours and for morphine in the range of 2.5 to 5 hours.
It has further been found, in accordance With the present
invention, that in order to achieve the desired time of peak
6,143,328
4
3
plasma level of morphine and M-6-G and to provide effec
We have found that the total amount of active ingredient
the modi?ed Ph. Eur. Basket method at 100 rpm in 900 ml
in the composition may vary Within Wide limits, for example
from 10 to 60% by Weight thereof.
The hydrophobic fusible component (b) should be a
aqueous buffer. (pH 6.5) containing 0.05% W/v Polysorbate
hydrophobic material such as a natural or synthetic Wax or
tive activity over a period of at least 24 hours, the in vitro
release characteristics of the formulation [When measured by
oil, for example hydrogenated vegetable oil or hydrogenated
80 at 37° C.] are preferably as set out beloW:
Hours After
% Morphine salt released
Start of Test
Suitable
Preferred
2
4
6
12
18
24
5-30
15-50
20-60
35-75
45-100
55-100
5-20
15-35
20-45
40-70
50-80
60-100
10
castor oil, and suitably has a melting point of from 35 to
100° C., preferably 45 to 90° C.
The release modifying component (c), When a Water
soluble fusible material, is conveniently a polyethylene
glycol and, When a particulate material, is conveniently a
pharmaceutically acceptable material such as dicalcium
phosphate or lactose.
Incorporation of loWer levels of morphine, for example
15
betWeen 10 and 30% by Weight, necessitate inclusion of loW
levels of a release modifying component, for example 5 to
15% by Weight polyethylene glycol 6000, to achieve a
satisfactory in vitro release rate. At higher drug loadings, for
20
that only incorporation of very small amounts of polyeth
ylene glycol, for example 0.01 to 1% by Weight are required
example 40 to 60% by Weight it is particularly surprising
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 to 5 are plasma pro?les of morphine and M-6-G
in each of ?ve volunteers after dosing them With a formu
lation in accordance With the invention;
FIG. 6 shoWs the mean plasma pro?les of morphine and
to modify the in vitro release rate.
Alternatively the morphine (or salt thereof) may be for
25
mulated (eg by dry or Wet granulation or by blending) in a
controlled release mixture formed of components other than
M-6-G derived from the results illustrated in FIGS. 1 to 5;
fusible components. Suitable materials for inclusion in a
FIG. 7 shoWs the mean-plasma pro?les of morphine and
controlled release matrix include, for example
(a) Hydrophilic or hydrophobic polymers, such as gums,
M-6-G obtained using a knoWn controlled release morphine
preparation in nine volunteers.
cellulose ethers, protein derived materials, nylon, acrylic
30
DETAILED DESCRIPTION OF THE
PREFERRED EMBODIMENT
polyvinylpyrrolidones, cellulose acetate phthalate. Of these
polymers, cellulose ethers especially substituted cellulose
ethers such as alkylcelluloses (such as ethylcellulose),
The compositions of the invention may be provided in a
variety of forms, for example as tablet or capsules contain
ing granules, spheroids or pellets. Commonly, the compo
35
copolymers) are preferred. The controlled release matrix
thereof) together With a diluent Which may serve to modify
the release of the active ingredient. Apreferred form of unit
dose form in accordance With the invention comprises a
may conveniently contain betWeen 1% and 80% (by Weight)
of hydrophilic or hydrophobic polymer.
40
acids, hydrogenated vegetable oils such as Cutina (Trade
Mark), fatty alcohols (such as lauryl, myristyl, stearyl, cetyl
45
50
(c) Polyalkylene glycols. The matrix may contain up to
60% (by Weight) of at least one polyalkylene glycol.
the commercial production of dosage units containing mor
When using such a processing technique it has been found
that, in order to most readily achieve the desired release
characteristics (both in vivo and in vitro as discussed above)
the composition to be processed should comprise tWo essen
tial ingredients namely:
beesWax, glycoWax, castor Wax or carnauba Wax). Hydro
carbons having a melting point of betWeen 25° C. and 90°
C. are preferred. Of these long chain hydrocarbon materials,
fatty (aliphatic) alcohols are preferred. The matrix may
contain up to 60% (by Weight) of at least one digestible, long
chain hydrocarbon.
mm, preferably 0.25 to 2.0 mm. A preferred and novel
process of this kind is described beloW Which is suitable for
phine or other active substances.
or preferably cetostearyl alcohol), glyceryl esters of fatty
acids for example glyceryl esters of fatty acids for example
glyceryl monostearate mineral oils and Waxes (such as
a rate and energy input such that sufficient energy is supplied
to the fusible material to melt or soften it Whereby it forms
multiparticulates With the active ingredient. The resultant
multiparticulates are suitably sieved and cooled to give
multiparticulates having a particle siZe range from 0.1 to 3.0
(b) Digestible, long chain (Cs-C50, especially C8-C4O),
substituted or unsubstituted hydrocarbons, such as fatty
the active ingredient, a hydrophobic fusible carrier or diluent
and optionally a hydrophilic release modi?er. In particular,
the multiparticulates are preferably prepared by a process
essentially comprising forming a mixture of dry active
ingredient and fusible release control materials folloWed by
mechanically Working the mixture in a high speed mixer at
Cl-C6 hydroxyalkylcelluloses (such as hydroxypropylcel
lulose and especially hydroxyethyl cellulose) and acrylic
resins (for example methacrylates such as methacrylic acid
sition Will comprise the active ingredient (morphine or salt
capsule ?lled With multiparticulates essentially comprising
resins, polylactic acid, polyvinylchloride, starches,
55
A suitable matrix comprises one or more cellulose ethers
or acrylic resins, one or more C12-C36, preferably C14-C22,
aliphatic alcohols and/or one or more hydrogenated veg
etable oils.
A particular suitable matrix comprises one or more
60
alkylcelluloses, one or more C12C36, (preferably C14-C22)
aliphatic alcohols and optionally one or more polyalkylene
(a) active ingredient (morphine or salt thereof); and
(b) hydrophobic fusible carrier or diluent; optionally
together With
glycols.
Preferably the matrix contains betWeen 0.5% and 60%,
especially betWeen 1% and 50% (by Weight) of the cellulose
soluble fusible material or a particulate soluble or
ether.
The acrylic resin is preferably a methacrylate such as
insoluble organic or inorganic material.
methacrylic acid copolymer USNF Type A (Eudragit L,
(c) a release control component comprising a Water
65
6,143,328
5
6
Trade Mark), Type B (Eudragit S, Trade Mark), Type C
(Eudragit L 100-55, Trade Mark), Eudragit NE 30D,
Eudragit E, Eudragit RL and Eudragit RS. Preferably the
In step (c) the amount of additional fusible release control
material added is preferably betWeen 5% and 20% W/W of
the total amount of ingredients added, more preferably
betWeen 8 and 17% W/W.
Stage (a) of the process may be carried out in conven
tional high speed mixers With a standard stainless steel
matrix contains between 0.5% and 60% by Weight, prefer
ably betWeen 1% and 50% by Weight of the acrylic resin.
In the absence of polyalkylene glycol, the matrix prefer
ably contains betWeen 1% and 40%, especially betWeen 2%
and 36% (by Weight) of the aliphatic alcohol. When poly
alkylene glycol is present in the oral dosage form, then the
combined Weight of the aliphatic alcohol and the polyalky
lene glycol preferably constitutes betWeen 2% and 40%,
especially betWeen 2 and 36% (by Weight) of the matrix.
interior, eg a Collette Vactron 75 or equivalent mixer. The
mixture is processed until a bed temperature above 400 C. is
achieved and the resulting mixture acquires a cohesive
10
The polyalkylene glycol may be, for example, polypro
pylene glycol or, Which is preferred, polyethylene glycol.
The number average molecular Weight of the at least one
polyalkylene glycol is preferably betWeen 200 and 15000
especially betWeen 400 and 12000. The morphine
containing controlled release matrix can readily be prepared
by dispersing the active ingredient in the controlled release
system using conventional pharmaceutical techniques such
as melt granulation, Wet granulation, dry blending, dry
15
20
spheroids obtained by spheroniZing the morphine (or salt
cellulose.
The present invention also includes a process for the
manufacture of sustained release multiparticulates contain
ing morphine or a salt thereof Which comprises
(a) mechanically Working in a high-speed mixer, a mix
ture of morphine or salt thereof in particulate form and
mm to ?ne poWder in the case of non-aggregated original
material. Such material, in the case of the embodiments
described beloW, has the appearance of agglomerates Which
upon cooling beloW 40° C. have structural integrity and
resistance to crushing betWeen the ?ngers. At this stage the
agglomerates are of an irregular siZe, shape and appearance.
The agglomerates are preferably alloWed to cool. The
temperature to Which it cools is not critical and a tempera
ture in the range room temperature to 45° C. eg to 37° C.
granulation or coprecipitation.
Another form of sustained release formulation comprises
thereof) With a spheroniZing agent such as microcrystalline
granular texture, With particle siZes ranging from about 1—3
25
may be conveniently used.
The agglomerates are broken doWn by any suitable
means, Which Will comminute oversiZe agglomerates and
produce a mixture of poWder and small particles preferably
With a diameter under 2 mm. It is currently preferred to carry
out the classi?cation using a Jackson Crockett granulator
using a suitable siZed mesh, or a Comil With an appropriate
siZed screen. We have, found that if too small a mesh siZe is
used in the aforementioned apparatus the agglomerates
melting under the action of the beater or impeller Will clog
the mesh and prevent further throughput of mixture, thus
30
a particulate, hydrophobic fusible carrier or diluent
reducing yield. Amesh siZe of 12 or greater or a 94G Comill
screen have been found adequate.
The classi?ed material is returned to the high speed mixer
and processing continued. It is believed that this leads to
cementation of the ?ner particles into multiparticulates of
having a melting point from 35 to 150° C., e.g., to 100°
C. and optionally a release control component com
prising a Water soluble fusible material, or a particulate 35 uniform siZe range.
soluble or insoluble organic or inorganic material at a
In a preferred form of the method of the invention
speed and energy input Which alloWs the carrier or
diluent to melt or soften, Whereby it forms agglomer
ates;
(b) breaking doWn the larger agglomerates to give con
40
trolled release seeds; and
(c) continuing mechanically Working With a further addi
In order to ensure uniform energy input into the ingredi
tion of loW percentage of the carrier or diluent; and
ents in the high speed mixer it is preferred to supply at least
(d) optionally repeating step (c) and possible (b) one or
more eg up to ?ve times.
processing of the classi?ed materials is continued, until the
hydrophobic fusible materials used begin to soften/melt and
additional hydrophobic fusible material is then added. Mix
ing is continued until the mixture has been transformed into
multiparticulates of the desired predetermined siZe range.
45
The process is capable of giving a high yield (over 80%)
of multiparticulates in a desired siZe range, With a desired in
part of the energy by means of microWave energy.
Energy may also be delivered through other means such
as by a heating jacket or via the mixer impeller and chopper
blades.
vitro release rate, uniformity of release rate and in its
After the pellets have been formed they may then be
preferred form surprisingly an early peak plasma level for a
sieved to remove any over or undersiZed material and are
product With a 24 hour duration of activity.
The resulting multiparticulates may be sieved to eliminate
50 cooled or alloWed to cool.
The resulting pellets may be used to prepare dosage units
any over or undersiZed material then formed into the desired
such as tablets or capsules in manners knoWn per se.
dosage units by for example, encapsulation into hard gelatin
In this process of the invention the temperature of the
mixing boWl throughout the mechanical Working is chosen
capsules containing the required dose of the active sub
stance.
55 so as to avoid excessive adhesion of the material to the Walls
Preferably morphine sulphate is used in an amount Which
results in multiparticulates containing betWeen 10% and
60%, especially betWeen about 45% and about 60% W/W
active ingredient for a high dose product and 10 and 45% for
a loW dose product.
In this method of the invention all the drug is added in step
of the boWl. We have generally found that the temperature
should be neither too high nor too loW With respect to the
60
drug and particulate hydrophobic fusible carrier in a high
speed mixture ?rst mentioned above. For example in the
(a) together With a major portion of the hydrophobic fusible
release control material used. Preferably the amount of
fusible release control material added in step (a) is betWeen
25% and 45% W/W of the total amount of ingredients added
in the entire manufacturing operation, more preferably
betWeen 30% and 40%.
melting temperature of the material and it can be readily
optimiZed to avoid the problems mentioned above. The same
applies to the process of mechanically Working a mixture of
65
processes described beloW in the Examples a boWl tempera
ture of approximately 60° C. has been found to be satisfac
tory and avoid adhesion to the boWl.
To produce tablets in accordance With the invention,
multiparticulates produced as described above may be
6,143,328
7
8
mixed or blended With the desired excipient(s), if any, using
conventional procedures eg using a Y-Cone or bin-blender
and the resulting mixture compressed according to conven
EXAMPLES 9 TO 12
tional tabletting procedure using a suitably siZed tabletting
Particles, having the formulations given in Table III
beloW, Were prepared by the steps of:
tooling. Tablets can be produced using conventional tablet
ting machines, and in the embodiments described beloW
kg) in the boWl of a 75 liter capacity Collette Vactron
i) Placing the ingredients (a) to (c) (total batch Weight 20
Mixer (or equivalent) equipped With variable speed
mixing and granulating blades;
Were produced on a standard single punch F3 Manesty
machine or Kilian RLE15 rotary tablet machine.
In order that the invention may be Well understood the
folloWing examples are given by Way of illustration only.
ii) Mixing the ingredients at about 150—350 rpm While
10
EXAMPLES 1 TO 8
applying heat until the contents of the boWl are agglom
erated.
iii) Classifying the agglomerated material by passage
Pellets, having the formulations given in Table I beloW,
Were prepared by the steps of:
(i) placing the ingredients, in a total amount by Weight of
iv) Warming and mixing the classi?ed material in the
10 kg, in the boWl of a 75 liter capacity Collette Vactron
boWl of a 75 liter Collette Vactron, With addition of
through a Comill and/or Jackson Crockett to obtain
controlled release seeds.
Mixer (or equivalent), equipped With variable speed
mixing and granulating blades;
(ii) mixing the ingredients While applying heat until the
contents of the boWl are pelletiZed;
ingredient (d), until uniform particles of the desired
pre-determined siZe range are formed in a yield of
greater than 80%. This takes approximately 15 minutes.
20
(iii) discharging the pellets from the mixer and sieving
v) Discharging the particles from the mixer and sieving
them to separate out the particles collected betWeen 0.5
them to separate out the pellets collected betWeen 0.5
and 2 mm aperture sieves.
and 2 mm aperture sieves.
TABLE III
25
TABLE I
EXAMPLE
EXAMPLE NO.
1
Morphine Sulfate
2
3
4
5
15
15
23
55
76
75
70
6
7
55
55
(Wt %)
Hydrogenated castor
30
Hydrogenated
42.8
44.95
0.2
0.05
42.0
vegetable oil
U.S.N.F. (Wt %)
8
9
10
7
6000 U.S.N.F.
35
(Wt %)
Dicalcium phosphate
anhydrous USP
The in vitro release rates of the products of Examples 1,
40
2. 3 and 5 Were assessed by the modi?ed Ph. Eur. Basket
method at 100 rpm in 900 ml aqueous buffer (pH 6.5) at 37°
C. For each of the products, six samples of the pellets, each
sample containing a total of 30 mg of morphine sulphate,
Were tested. The results set out in Table II beloW give the
mean values for each of the six samples tested.
a) Morphine Sulphate (Wt %)
55.0
52.19
53.48
b) Hydrogenated Vegetable
Oil USNF (Wt %)
c) Polyethylene Glycol 6000
34.95
33.17
33.98
0.05
0.047
0.049
d) Hydrogenated Vegetable
Oil USNF (Wt %)
10.0
14.60
12.49
Yield %
90.5
83.4
90.1
The in vitro release rates of Examples 9, 10 and 11 as Well
as Example 12 beloW Were assessed by modi?ed Ph. Eur.
the products, six samples of the particles, each sample
containing a total of 60 mg of morphine sulphate Were
tested. The results set out in Table IV beloW give the mean
values for each of the six samples tested.
TABLE IV
45
PRODUCT OF EXAMPLE
Hours After
Start of
TABLE II
1
Test
2
3
2
4
6
8
12
18
24
30
4
(% morphine released)
19
27
34
41
53
66
76
25
36
45
52
64
77
86
33
49
62
72
86
96
101
44
57
66
72
81
89
92
55
60
10
11
(% morphine released)
21
33
43
52
62
74
82
83
15
25
35
43
57
71
81
85
20
36
49
59
72
82
86
89
The procedure of Example 11 Was repeated but the
operation varied by adding the classi?ed particles to a cold
boWl of the Collette Vactron, folloWed by adding ingredient
(d) and mixing, heating by jacket heating and microWave
Pharmacokinetic studies in healthy human volunteers
have indicated peak plasma levels of from 2.2 to 21.6 ng/ml
of morphine at median times betWeen 1.0 and 3.5 hours
folloWing administration of a single capsule containing
9
Test
50
PRODUCT OF EXAMPLE
2
4
6
8
12
18
24
11
Basket method at 100 rpm in 900 ml aqueous buffer (pH 6.5)
containing 0.05% W/v polysorbate 80 at 37° C. For each of
(Wt %)
Hours After
Start of
10
USNF (Wt %)
oil U.S.N.F. (Wt %)
Polyethylene glycol
9
8
being applied during mixing. The in vivo release rate is
given in Table IVa and demonstrates that although the
65
composition of the products in Examples 11 and 12 are the
pellets of Examples 1, 2, 3 or 5 in an amount suf?cient to
same the different processing results in modi?ed release
provide a morphine sulphate dose of 30 mg.
rates.
6,143,328
9
10
knoWn bid morphine sulphate-containing preparation MST
CONTINUS® under a similar test conditions, and analyZing
TABLE IVa
the blood samples using a similar analytical procedure, as
PRODUCT OF EXAMPLE
Were used in the tests carried out With the formulations in
accordance With the invention and Which gave the results
Hours After
Start of Test
% of Morphine Released
2
4
6
8
12
18
24
30
15
24
30
36
46
57
65
71
illustrated in Table V and FIGS. 1 to 6. it can be seen MST
CONTINUS® resulted at 12 hours in mean plasma levels for
M-6-G and morphine of about 14 ng/ml and 2 ng/ml
respectively: the mean values for plasma levels at 24 hours
10
obtained using the preparation in accordance With the
present invention, and as illustrated in FIG. 6 Were M-6-G
17.5 ng/ml and morphine 2.5 ng/ml.
EXAMPLE 13
Particles Were produced analogously to Examples 9 to 12
Particles produced according to Examples 9 to 12 Were
each blended With puri?ed talc and magnesium stearate and
15
but having the folloWing ingredients:
used to ?ll hard gelatin capsules such that each capsule
contains 60 mg of morphine sulphate. The capsules pro
Wt %
duced Were used in open, randomized crossover pharmaco
kinetic studies. As part of these studies patients received
after overnight fasting either one capsule according to the
20
invention or one MST CONTINUS® tablet 30 mg (a tWice
a day preparation). Fluid intake Was unrestricted from 4
hours after dosing. AloW-fat lunch Was provided four hours
Morphine sulphate
55.0
Hydrogenated vegetable oil
Polyethylene glycol 6000
44.7
0.3
Samples of the particles Were then blended With magne
after dosing, a dinner at 10 hours post dose and a snack at 25 sium stearate and puri?ed talc in tWo lots (1 and 2) using a
13.5 hours post-dose. No other food Was alloWed until a 24
Y-Cone or bin-blender-machine. The blended mixtures Were
hour post-dose blood sample had been Withdrawn. Blood
samples Were taken at the folloWing times 1, 1.5, 2, 2.5, 3,
3.5, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours post-dose.
The pharmacokinetic studies using these capsules gave
then each compressed on a 7.1 mm diameter normal concave
30
tooling on a single punch F3 Manestr tabletting machine.
The ingredients per dosage unit amounted to the folloWing:
peak plasma levels of from 3.2 to 29.2 ng/ml of morphine at
median times between 2 and 6 hours folloWing administra
tion and blood sampling according to the above protocol.
TABLE VI
Mg! lablet
The capsules containing particles produced according to
Examples 10 and 12 in particular gave a mean Cmax of 11.9
ng/ml at median Tmwc 4 hours and mean Cmwc of 9.2 ng/ml
at median Tmwc 2.5 hours respectively (these values repre
sent the mean of the individual Cmax and Tmax values). In
contrast the Cmax and Tmwc for the patients Who received
MST CONTINUS® tablets Were 10.6—11.4 ng/ml and
2.0—2.5 hours respectively. It Was found, however, that the
35
Morphine Sulphate
Hydrogenated Vegetable Oil
Polyethylene Glycol
Sub Total
40
plasma concentrations of morphine in the blood of patients
given capsules according to the invention at 24 hours Were
greater than the concentrations at 12 hours in those patients
given MST CONTINUS® tablets.
The pharmacokinetic studies based on the particles pro
duced in Example 9, and directed to morphine and
morphine-6-glucuronide folloWing administration of a cap
Tablet Ingredient
45
Volunteer
W50 (h)
Morphine
1
2
3
4
5
147.7
83.8
73.4
72.8
82.5
5.0
3.5
6.0
5.0
3.5
7.54
5.69
11.97
7.02
6.75
8.18
4.24
8.45
5.99
6.67
Mean
92.0
—
31.5
—
7.79
2.43
6.71
sd
Median
—
5.0
—
—
Minimum
Maximum
72.8
147.7
3.5
6.0
5.69
11.97
4.24
8.45
1.72
60.00
48.77
0.33
109.1
109.1
1.42
2.0
Puri?ed Talc
2.18
3.0
ticles (each sample containing 60 mg of morphine sulphate)
Was assessed by the modi?ed Ph. Eur Basket method
described above. For the dissolution of the tablets the Ph.
Eur. Basket Was replaced by the Ph. Eur. Paddle Method.
The results are shoWn in Table VII beloW:
TABLE VII
Hours After
Start of
TABLE V
W50 (h)
M-6-G
60.00
48.77
0.33
Magnesium Stearate
teers in the fasted state gave the results shoWn in Table V and
50
FIGS. 1 to 6.
M-6-G
Tmax (h)
2
The dissolution of the samples of non-compressed par
sule containing 60 mg of morphine sulphate in ?ve volun
M-6-G
Cmax (ng/ml)
1
Test
55
60
1
2
4
8
12
16
24
30
36
Particles
Tablet 1
Tablet 2
% morphine sulphate released
27
43
63
82
88
91
93
94
95
13
20
29
42
50
57
65
70
74
11
17
26
37
44
NR"
NR"
NR"
NR"
"NR = Not recorded
The above results shoW that the tabletting procedure
FIG. 7, by contrast shoWs the mean plasma pro?les
obtained after dosing nine healthy volunteers With the
results in a considerable reduction in the release rate of the
active ingredient.
6,143,328
11
12
EXAMPLE 14
for 24 hourly dosing, characteriZed by a Width of the plasma
pro?le at 50% CmaX (W50) for the morphine-6-glucoronide
metabolite of morphine of betWeen 4 and 12 hours, said
The procedure of Example 13 Was repeated but With the
following variations.
multparticulates being prepared by miXing together said
The particles Were made With the following ingredients.
5
morphine or salt thereof and said natural or synthetic Wax or
oil at a rate and energy input suf?cient to cause said natural
or synthetic Wax or oil to melt or soften Whereby it forms
said multiparticulates containing said morphine or salt
Wt %
Morphine Sulphate
55.0
Hydrogenated Vegetable Oil
Polyethylene Glycol 6000
44.4
0.6
10
thereof.
2. An oral sustained release pharmaceutical formulation
comprising multiparticulates including morphine or a phar
maceutically acceptable salt thereof dispersed in a matriX of
a natural or synthetic Wax or oil With a melting point of from
TWo lots of tablets (3 and 4) Were produced from the
particles using a 7.1 mm diameter concave tooling. The
ingredients per dosage unit Were as folloWs;
15
about 35 degrees C. to about 100 degrees C., said multpar
ticulates having in vitro release characteristics such that the
multiparticulates, When assessed by the modi?ed European
Pharmacopeia Basket Method at 100 rpm in 900 ml aqueous
buffer at pH 6.5 containing 0.5% polysorbate at 37 degrees
TABLE VIII
MgZTablet
Tablet Ingredient
Morphine Sulphate
Hydrogenated Vegetable Oil
Polyethylene Glycol 6000
Sub Total
20
3
4
60.00
48.44
0.655
60.00
48.44
0.655
109.1
109.1
PoloXamer 188
—
5.0
Magnesium Stearate
2.0
2.0
Puri?ed Talc
3.0
3.0
C., releases from 5 to 30% of morphine tWo hours after start
of test, 15 to 50% at 4 hours after start of test; 20% to 60%
at 6 hours after start of test; 35 to 75% at 12 hours after start
of test, from 45 to 100% at 18 hours after start of test and
55 and 100% at 24 hours after start of test such that the
multiparticulates provide a time to peak plasma level of
25
morphine in about 1.0 to about 6.0 hours after
administration, and When administered in an effective
amount, provide morphine plasma levels effective for 24
hourly dosing, characteriZed by a Width of the plasma pro?le
at 50% CmaX (W50) for the morphine-6-glucoronide
compressed particles (each sample containing 60 mg of
metabolite of morphine of betWeen 4 and 12 hours, Wherein
said multiparticulates are prepared by a process comprising
the steps of
a) miXing together a particulate form of said morphine or
morphine sulphate) Were assessed by the methods described
pharmaceutically acceptable salt thereof, a particulate
30
The dissolution of the tablets and samples of non
above. The results are shoWn in Table IX beloW:
35
soften Whereby it forms agglomerates; and
(b) breaking doWn the agglomerates to give said multi
TABLE IX
Hours After
Start of
Test
Particles
Tablet 3
particulates.
Tablet 4
3. An oral sustained release pharmaceutical formulation
% morphine sulphate released
40
1
2
4
8
12
16
24
56
75
90
95
97
NR*
NR*
form of said natural or synthetic Wax or oil, at a speed
and energy input Which alloWs the carrier to melt or
16
24
34
46
54
NR"
NR"
19
28
38
52
60
67
77
maceutically acceptable salt thereof and a natural or syn
thetic Wax or oil, said multiparticulates characteriZed by a
Width of the plasma pro?le at 50% CmaX (W50) for said
morphine of betWeen 4 and 12 hours after administration
45
and When administered in an effective amount, provide
suf?cient analgesia for about 24 hours after administration.
4. The oral sustained release pharmaceutical formulation
of claim 3, Wherein said multiparticulates are prepared by a
process comprising the steps of miXing together said mor
50
phine or salt thereof and said natural or synthetic Wax or oil
at a rate and energy input suf?cient to cause said natural or
synthetic Wax or oil to melt or soften Whereby it forms said
*NR = Not recorded
These results demonstrate again a dramatic reduction in
the release rate of the morphine sulphate resulting from
compression tabletting of the particles; comparison of the
release rates for Tablets 3 and 4 also shoW that the release
rate can be adjusted by use of a surface active agent (in this
case PoloXamer 188) as a tabletting eXcipient, the release
rate for tablet 4 Which contains the surface active agents
multparticulates containing said morphine and thereafter
separating said multiparticulates having a siZe range from
55 about 0.1 mm to about 3 mm.
5. The oral sustained release pharmaceutical formulation
as claimed in claim 1, Wherein said multiparticulates provide
a time to peak plasma level of morphine in about 1.0 to about
being greater than that for tablet 3 Without the surface active
agent.
We claim:
1. An oral sustained release pharmaceutical formulation
comprising multiparticulates including morphine or a phar
comprising multiparticulates including morphine or a phar
60
maceutically acceptable salt thereof dispersed in a matriX of
3.5 hours after administration.
6. The oral sustained release pharmaceutical formulation
a natural or synthetic Wax or oil With a melting point of from
as claimed in claim 2, Wherein said multiparticulates provide
a time to peak plasma level of morphine in about 1.0 to about
about 35 degrees C. to about 100 degrees C., such that the
multiparticulates provide a time to peak plasma level of
3.5 hours after administration.
7. The oral sustained release pharmaceutical formulation
morphine in about 1.0 to about 6.0 hours after
administration, and When administered in an effective
amount, provide morphine plasma levels Which are effective
65
as claimed in claim 3, Wherein said multiparticulates provide
a time to peak plasma level of morphine in about 1.0 to about
3.5 hours after administration.
6,143,328
13
8. The oral sustained release pharmaceutical formulation
as claimed in claim 1, Wherein said multiparticulates further
comprise a release modi?er.
14
12. The oral sustained release pharmaceutical formulation
as claimed in claim 9, Wherein said release modi?er com
prises a material selected from the group consisting of a
9. The oral sustained release pharmaceutical formulation
Water soluble fusible material, a particulate soluble organic
as claimed in claim 2, Wherein said multiparticulates further 5 material, a particulate insoluble organic material, a particu
comprise a release modi?er.
late inorganic soluble material, a particulate inorganic
insoluble material and miXtures thereof.
10. The oral sustained release pharmaceutical formulation
13. The oral sustained release pharmaceutical formulation
as claimed in claim 3, Wherein said multiparticulates further
comprise a release modi?er.
as claimed in claim 10, Wherein said release modi?er
11. The oral sustained release pharmaceutical formulation 10 comprises a material selected from the group consisting of
as claimed in claim 8, Wherein said release modi?er com
a Water soluble fusible material, a particulate soluble organic
prises a material selected from the group consisting of a
material, a particulate insoluble organic material, a particu
Water soluble fusible material, a particulate soluble organic
late inorganic soluble material, a particulate inorganic
insoluble material and miXtures thereof.
material, a particulate insoluble organic material, a particu
late inorganic soluble material, a particulate inorganic 15
insoluble material and miXtures thereof.
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