DESCRIPTION
TITLE OF THE INVENTION:
STABLE TABLET CONTAINING 4,5-EPOXYMORPHINAN DERIVATIVE
TECHNICAL FIELD
[0001]
The present invention relates to a stable tablet of a 4,5-epoxymorphinan
derivative or a pharmacologically acceptable acid addition salt thereof.
BACKGROUND ART
[0002]
A 4,5-epoxymorphinan derivative represented by the Formula (I) (described
later) or a pharmacologically acceptable acid addition salt thereof, which is the
effective ingredient of the present invention, has prominent antipruritic effect and has
been disclosed as a compound effective as a therapeutic drug for pruritus in a variety
of diseases accompanying pruritus (for example, see Patent Document 1). However,
the aforementioned 4,5-epoxymorphinan derivative has been known to be chemically
unstable to light, heat and oxygen, and with regard to the method of stabilizing such
4,5-epoxymorphinan derivative, it is described that a stable pharmaceutical
composition can be obtained by allowing the composition to contain a saccharide(s)
or sugar alcohol(s) and an antioxidant such as sodium thiosulfate (see Patent
Document 2). Yet, when the present inventors examined tableting of the 4,5-
epoxymorphinan derivative represented by the Formula (I) or a pharmacologically
acceptable acid addition salt thereof, it was revealed that, although a conventionally
known stabilization method in which an antioxidant such as sodium thiosulfate is
added is effective for stabilization of the effective ingredient in a liquid-form, in
cases where the method is employed for a tablet, it is difficult to obtain a tablet
whose decomposition is minimized over a long period of time in unpacked state or in
a normal package form and which maintains sufficient stability as a tablet.
[0003]
Conventionally, as a method of stabilizing various morphinan compounds
including morphine, a technique of adding a basic component to morphine (for
example, see Patent Document 3) and a method in which an antioxidant such as
sodium thiosulfate or tocopherol is combined with naloxone (for example, see Patent
Document 4), as well as a method in which a chelating agent and a citrate buffer are
added to methylnaltrexone (for example, see Patent Document 5) and a method in
which an organic acid and a chelate forming agent are blended with naltrexone
hydrochloride (for example, see Patent Document 6), have been disclosed.
However, none of these reports includes any description with regard to the type and
the content of disintegrating agent effective in stabilization, and the stabilization
effect imparted to a tablet by a specific disintegrating agent, crospovidone or sodium
carboxymethyl starch, has not been revealed.
[0004]
Meanwhile, as a tablet which comprises a saccharide such as lactose or a
sugar alcohol such as mannitol or erythritol and, as disintegrating agent,
crospovidone or sodium carboxymethyl starch, an intraorally disintegrating-type
tablet which is intended for improving the dose compliance and can be taken without
water has been disclosed (for example, see Patent Document 7). However, all of
such reports merely disclose a tablet which has superior intraoral quick disintegration
property along with formulation strength at a level which does not pose a problem in
handling, and the stabilization effect imparted by crospovidone or sodium
carboxymethyl starch has not been reported.
[0005]
In addition, as a method of stabilizing a drug by blending crospovidone or
sodium carboxymethyl starch, there are reports that fast release property is attained
and drug hydrolysis is suppressed by blending crospovidone with sarpogrelate
hydrochloride (see Patent Document 8); that a preparation which has both
disintegration property and tablet hardness, as well as excellent storage stability over
a long period of time, is attained by blending crospovidone or sodium carboxymethyl
starch with iguratimod (see Patent Document 9); and that the stability is improved by
blending crospovidone with vitamin or the like (for example, see Patent Document
10 and Non-patent Document 1). However, needless to say, since the mechanism
of drug destabilization is largely dependent on the chemical structure and
physiochemical properties of the drug, these reports offer no suggestion with regard
to the stability of the effective ingredient of the present invention, which is a 4,5-
epoxymorphinan derivative represented by the Formula (I) or a pharmacologically
acceptable acid addition salt thereof.
PRIOR ART DOCUMENTS
PATENT DOCUMENTS
[0006]
Patent Document 1: JP 3531170 B
Patent Document 2: WO 99/02158
Patent Document 3: JP 2-160719 A
Patent Document 4: WO 98/35679
Patent Document 5: WO 2004/091623
Patent Document 6: Japanese Translated PCT Patent Application Laid-open No.
2005-531515
Patent Document 7: WO 97/47287
Patent Document 8: JP 2007-56011 A
Patent Document 9: JP 2007-224021 A
Patent Document 10: JP 2002-302446 A
NON-PATENT DOCUMENT
[0007]
Non-patent Document 1: Volker Buehler, "Kolldon Polyvnylpyrrolidon for the
pharmaceutical industry", BASF brochure, pp. 186-187, August 1993 (2nd edition,
published in August 1993)
SUMMARY OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION
[0008]
An object of the present invention is to provide a stable tablet comprising a
4,5-epoxymorphinan derivative or a pharmacologically acceptable acid addition salt
thereof as an effective ingredient.
MEANS FOR SOLVING THE PROBLEMS
[0009]
In order to develop a stable tablet capable of enduring in unpacked state and
long-term storage, the present inventors intensively studied to discover that, among
those disintegrating agents commonly used for formulation, only crospovidone and
sodium carboxymethyl starch can, when made to co-exist with sodium thiosulfate
and a saccharide or sugar alcohol, allow a 4,5-epoxymorphinan derivative or a
pharmacologically acceptable acid addition salt thereof to more stably exist in a
tablet, thereby completing the present invention.
[0010]
That is, the present invention relates to the following inventions.
[ 1 ] A tablet comprising the following (1) to (4):
(1) as an effective ingredient, a 4,5-epoxymorphinan derivative represented by the
Formula (I) (described later) or a pharmacologically acceptable acid addition salt
thereof;
(2) sodium thiosulfate;
(3) at least one selected from the group consisting of saccharides and sugar alcohols;
and
(4) crospovidone, sodium carboxymethyl starch or a mixture thereof,
in which tablet the content of the aforementioned (4) is 1 to 20% by weight per unit
weight containing the aforementioned effective ingredient.
[2] The tablet according to [1], wherein the aforementioned (3) is at least one
selected from the group consisting of potato starch, saccharose, lactose, mannitol,
erythritol and maltitol.
[3] The tablet according to [1] or [2], wherein a part or the entirety of the
aforementioned (3) is granulated granules.
[4] The tablet according to [3], wherein the aforementioned granulated granules
are produced by extrusion granulation, stirring granulation, spray drying or fluidized
bed granulation.
[5] The tablet according to any one of [1] to [4], the tablet being produced by a
production method comprising the steps of dissolving or suspending the
aforementioned effective ingredient in water or a pharmacologically acceptable
solvent and adding the resulting liquid to the aforementioned saccharide or sugar
alcohol.
[6] The tablet according to any one of [1] to [5], wherein the tablet is in a coated
form.
EFFECTS OF THE INVENTION
[0011]
By allowing a tablet to comprise, as the effective ingredient, a 4,5-
epoxymorphinan derivative represented by the Formula (I) (described later) of the
present invention or a pharmacologically acceptable acid addition salt thereof and
blending thereto crospovidone or sodium carboxymethyl starch in a prescribed
amount, a fast-disintegrating tablet or an intraorally disintegrating tablet which has
superior storage stability and remains highly stable even after a long time since its
production can also be produced.
MODE FOR CARRYING OUT THE INVENTION
[0012]
The tablet according to the present invention will now be described. The
indispensable components of the tablet according to the present invention are:
(1) a 4,5-epoxymorphinan derivative represented by the Formula (I) (described later)
or a pharmacologically acceptable acid addition salt thereof (effective ingredient);
(2) sodium thiosulfate;
(3) at least one selected from the group consisting of saccharides and sugar alcohols;
and
(4) crospovidone, sodium carboxymethyl starch or a mixture thereof.
The component (4) is contained in an amount of 1 to 20% by weight per unit weight
containing the effective ingredient. The phrase "unit containing the effective
ingredient" used herein refers to a solid component unit directly in contact with the
effective ingredient in the preparation, and in the case of a film-coated tablet, it refers
to the core of the tablet, which is an essential part affecting the drug stability. The
phrase "% by weight per unit weight containing the effective ingredient" used herein
means a weight percentage with respect to the weight of the solid component unit
directly in contact with the effective ingredient in the preparation. A tablet
comprising the components (2) to (4) has a reduced decomposition of the effective
ingredient (1) and stably comprises the effective ingredient even after a long period
of time. The stability of the effective ingredient in a tablet can be evaluated by, for
example, leaving the tablet to stand in an open state under the condition of 40°C/75%
RH, which is the acceleration condition described in the Drug Approval and
Licensing Procedures in Japan (2006), and subsequently measuring the residual ratio
of the effective ingredient in the tablet by HPLC method or the like.
[0013]
The indispensable component (1) of the tablet according to the present
invention is a 4,5-epoxymorphinan derivative represented by the following Formula
(I) or a pharmacologically acceptable acid addition salt thereof.
[0014]
[Formula 1]

[0015]
Here, in the Formula (I), the double line composed of a dashed line and a
solid line represents a double bond or a single bond; R1 represents C1-C5 alkyl, C4-C7
cycloalkylalkyl, C5-C7 cycloalkenylalkyl, C6-C12 aryl, C7-C13 aralkyl, C4-C7 alkenyl,
allyl, C1-C5 furan-2-ylalkyl or C1-C5 thiophen-2-ylalkyl; R represents hydrogen,
hydroxy, nitro, C1-C5 alkanoyloxy, C1-C5 alkoxy, C1-C5 alkyl or -NR7R8; R7
represents hydrogen or C1-C5 alkyl; R8 represents hydrogen, C1-C5 alkyl or -
C(=O)R9; R9 represents hydrogen, phenyl or C1-C5 alkyl; R3 represents hydrogen,
hydroxy, C1-C5 alkanoyloxy or C1-C5 alkoxy; A represents -N(R4)C(=X)-, -
N(R4)C(=X)Y-, -N(R4)- or -N(R4)SO2- (wherein X and Y independently represent
NR4, S or O; R4 represents hydrogen, C1-C5 linear or branched alkyl or C6-C12 aryl;
and R4 in the formula may be the same or different); B represents a valence bond or
C1-C14 linear or branched alkylene (with the provisos that the alkylene is optionally
substituted by at least one substituent selected from the group consisting of C1-C5
alkoxy, C1-C5 alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro,
cyano, trifluoromethyl, trifluoromethoxy and phenoxy, and that 1 to 3 methylene
groups may be substituted by carbonyl group(s)), C2-C14 linear or branched acyclic
unsaturated hydrocarbon containing 1 to 3 double bonds and/or triple bonds (with the
provisos that the acyclic unsaturated hydrocarbon is optionally substituted by at least
one substituent selected from the group consisting of C1-C5 alkoxy, C1-C5
alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano,
trifluoromethyl, trifluoromethoxy and phenoxy, and that 1 to 3 methylene groups
may be substituted by carbonyl group(s)) or C1-C14 linear or branched saturated or
unsaturated hydrocarbon containing 1 to 5 thioether bonds, ether bonds and/or amino
bonds (with the provisos that a hetero atom does not directly binds to A, and that 1 to
3 methylene groups may be substituted by carbonyl group(s)); and R5 represents
hydrogen or an organic group having a basic skeleton shown below (with the proviso
that the organic group is optionally substituted by at least one substituent selected
from the group consisting of C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkanoyloxy, hydroxy,
fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato,
trifluoromethyl, trifluoromethoxy and methylenedioxy).
[0016]
[Formula 2]
It is preferred that A be -N(R4)C(=O)-, -N(R4)C(=O)O-, -N(R4)- or -
N(R4)SO2- (wherein R4 represents hydrogen or C1-C5 linear or branched alkyl), and
preferred thereamong is -N(R4)C(=O)- or -N(R4)C(=O)O- (wherein R4 represents
hydrogen or C1-C5 linear or branched alkyl).
[0022]
It is preferred that B be C1-C3 linear alkylene, -CH=CH-, -C=C-, -CH2O- or -
CH2S-, and preferred thereamong is C1-C3 linear alkylene, -CH=CH- or -C=C-.
[0023]
It is preferred that R5 be hydrogen or an organic group having a basic
skeleton shown below (with the proviso that the organic group is optionally
substituted by at least one substituent selected from the group consisting of C1-C5
alkyl, C1-C5 alkoxy, C1-C5 alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine,
amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and
methylenedioxy).
[0024]
[Formula 3]

Organic groups represented by R5
[0025]
It is preferred that R6 be hydrogen.
[0026]
Examples of pharmacologically preferred acid addition salt include inorganic
acid salts such as hydrochloric acid salt, sulfuric acid salt, nitric acid salt,
hydrobromic acid salt, hydroiodic acid salt and phosphoric acid salt; organic
carboxylic acid salts such as acetic acid salt, lactic acid salt, citric acid salt, oxalic
acid salt, glutaric acid salt, malic acid salt, tartaric acid salt, fumaric acid salt,
mandelic acid salt, maleic acid salt, benzoic acid salt and phthalic acid salt; and
organic sulfonic acid salts such as methanesulfonic acid salt, ethanesulfonic acid salt,
benzenesulfonic acid salt, p-toluenesulfonic acid salt and camphorsulfonic acid salt,
and preferred thereamong are hydrochloric acid salt, hydrobromic acid salt,
phosphoric acid salt, tartaric acid salt, maleic acid salt, methanesulfonic acid salt and
the like; however, of course, the pharmacologically preferred acid addition salt is not
restricted thereto.
[0027]
In the present invention, particularly preferred as the 4,5-epoxymorphinan
derivative represented by the Formula (I) or a pharmacologically acceptable salt
thereof are 17-(cyclopropylmethyl)-3,14P-dihydroxy-4,5a-epoxy-6p-[N-methyl-
trans-3-(3-furyl)acrylamido]morphinan hydrochloric acid salt (hereinafter, referred to
as Compound 1) and 17-(cyclopropylmethyl)-3,14P-dihydroxy-4,5a-epoxy-6P-[N-
methyl-3-(4-trifluoromethylphenyl)propiolamido]morphinan hydrochloric acid salt
(hereinafter, referred to as Compound 2).
[0028]
[Formula 4]
(Compound 1)
[0029]
[0030]
The 4,5-epoxymorphinan derivative or a pharmacologically acceptable acid
addition salt thereof, which is the medicinal component in the tablet of the present
invention, can be produced, for example, in accordance with the method described in
Japanese Patent No. 2525552 or WO 93/15081.
[0031]
The content of the 4,5-epoxymorphinan derivative or a pharmacologically
acceptable acid addition salt thereof, which is the medicinal component in the tablet
of the present invention, is not particularly restricted as long as it is a therapeutically
effective amount. For example, it can be in the range of 0.01 to 10, 000
ug/preparation, and it is usually in the range of 0.1 to 1,000 ug/preparation.
[0032]
The indispensable component (2) of the tablet according to the present
invention is sodium thiosulfate. As sodium thiosulfate used in the present invention,
any of the generally commercially available ones may be employed. Sodium
thiosulfate may be an anhydride or a hydrate (pentahydrate); however, it is preferably
a hydrate. The content thereof may be any amount as long as it is not greater than
5% by weight per unit weight containing the effective ingredient; however, it is
preferably not greater than 0.5% by weight. The lower limit of the content is not
particularly restricted; however, it is usually not less than 0.00001% by weight per
unit weight containing the effective ingredient.
[0033]
The indispensable component (3) of the tablet according to the present
invention is at least one selected from the group consisting of saccharides and sugar
alcohols. As the saccharide and/or sugar alcohol used in the present invention, any
of the generally commercially available ones may be employed. Examples of the
saccharide and/or sugar alcohol include potato starch, saccharose, lactose, mannitol,
erythritol and maltitol, and preferred thereamong is mannitol. In the present
invention, as the indispensable component (3), the saccharide and sugar alcohol may
be used individually or two or more thereof may be used in combination. The
content thereof is not particularly restricted; however, with respect to the unit weight
of the preparation containing the effective ingredient, it is usually not less than 75%
by weight and may be any amount not less than 80% by weight, and it is preferably
not less than 85% by weight, more preferably not less than 90% by weight. Further,
the particle form of the saccharide and/or sugar alcohol used is not particularly
restricted and it may be granulated granules, powder, fine powder; however, from the
standpoint of the advantage in handling, it is preferred that the saccharide and/or
sugar alcohol be in the form of granulated granules in its partial or the entire amount.
In the present invention, the term, the saccharide and/or sugar alcohol which is/are
the indispensable component (3) "is/are partially or entirely in the form of granulated
granules", means either of the followings: to prepare the tablet of the present
invention by mixing a part of or the entirety of the saccharide and/or sugar alcohol in
the form of granulated granules with other raw material(s); and to, after mixing a part
of or the entirety of the saccharide and/or sugar alcohol in the form of powder with (a
partial or the entire amount of) other raw material(s), granulate the resulting mixture
into granules to subsequently prepare therefrom the tablet of the present invention.
In the former case, commercially available granulated granule may be used or
granulated granule prepared from powder-form saccharide and/or sugar alcohol may
also be used. Examples of powder mannitol include PEARLITOL (registered
trademark) 50C manufactured by Roquette Japan K.K.. Meanwhile, as the
granulated granule, those produced by any of the known techniques such as spray
drying, extrusion granulation, stirring granulation and fluidized bed granulation may
also be used. Spray-dried granules or extrusion-granulated granules are preferably
used since no tableting problem occurs and high tablet hardness can be attained.
Examples of known mannitol granulated granules include spray-dried granule
PEARLITOL (registered trademark) 200SD and extrusion-granulated granule
PEARLITOL (registered trademark) 300DC, both of which are manufactured by
Roquette Japan K.K.. In addition, when the particle diameter of the saccharide or
sugar alcohol is small, tableting problem easily occurs and when the particle
diameter is large, high tablet hardness is not likely to be attained; therefore, for
example, an average particle diameter may be, when measured in accordance with
the particle size measurement method described in the Japanese Pharmacopeia 15th
Edition, not less than 10 µm, and it is preferably not less than 30 µm, more
preferably not less than 50 µm. Further, the upper limit of the particle diameter is
usually not greater than 3,000 µm, particularly 1,000 µm; however, it is not restricted
thereto.
[0034]
The indispensable component (4) of the tablet according to the present
invention is crospovidone, sodium carboxymethyl starch or a mixture thereof. As
the crospovidone or sodium carboxymethyl starch used in the present invention, any
of the generally commercially available ones may be employed. Examples of
specific commercial products of crospovidone include Kollidon (registered
trademark) CL, CL-M, CL-F and CL-SF which are manufactured by BASF, as well
as Polyplasdone XL, XL-10 and INF-10 which are manufactured by IPS Ltd.
Examples of specific commercial products of sodium carboxymethyl starch include
Explotab (registered trademark) and VIVASTAR (registered trademark)
manufactured by JRS, Primojel (registered trademark) manufactured by DMV, and
Glycolys (registered trademark) manufactured by Roquette Japan K.K.. The
content of crospovidone or sodium carboxymethyl starch (the total amount when a
mixture thereof is used) may be 1 to 20% by weight per unit weight containing the
above-described effective ingredient. In order to ensure better quality and
performance of the tablet, the content may be preferably in the range of 2 to 15% by
weight, more preferably 5 to 10% by weight.
[0035]
In the tablet according to the present invention, in addition to the
indispensable components (1) to (4) described in the above, a pharmacologically
acceptable additive such as lubricant, flavoring agent or coloring agent may also be
added as required. Examples of the lubricant include magnesium stearate, calcium
stearate, talc, stearic acid, sucrose fatty acid ester and light anhydrous silicic acid.
[0036]
In the tablet according to the present invention, in addition to the
indispensable components (1) to (4) described in the above, a pharmacologically
acceptable vehicle, disintegrating agent or binding agent may also be added as
required. For example, xylitol, sorbitol, low-substituted hydroxypropyl cellulose,
crystalline cellulose, hydroxypropyl cellulose, partially-pregelatinized starch,
croscarmellose sodium, carboxymethyl cellulose or the like may also be added as
appropriate.
[0037]
The tablet according to the present invention can be produced in accordance
with a known method by using the above-described indispensable components and
arbitrary components (which include those having a role as a vehicle). The term
"tablet" used herein also encompasses, in addition to those conventional tablets taken
with water, fast-disintegrating tablets such as one described in WO 2006-038661
which have extremely quick disintegration property and can be normally
disintegrated intraorally within one minute only with an extremely small amount of
water content such as saliva, as well as intraorally-disintegrating tablets such as one
described in Patricia Van Arnum, "Advancing ODT Technology", Pharmaceutical
Technology, Vol. 3, No.10 pp. 66-76,2007 (published on October 2,2007), which
are normally disintegrated and dissolved intraorally without water within 60 seconds.
[0038]
The tablet according to the present invention cay be produced by a wet
granulation method comprising the steps of dissolving or suspending the above-
described effective ingredient (1) in water or a pharmacologically acceptable solvent
and adding the resulting liquid (solution or suspension) to the saccharide or sugar
alcohol. The addition of sodium thiosulfate or that of crospovidone or sodium
carboxymethyl starch can be carried out by an arbitrary step. For example, sodium
thiosulfate may be dissolved or suspended together with the effective ingredient in
water or a pharmacologically acceptable solvent and then added to the saccharide or
sugar alcohol. Crospovidone and/or sodium carboxymethyl starch may also be
dissolved or suspended together with the effective ingredient in water or
pharmacologically acceptable solvent and then added to the saccharide or sugar
alcohol. Alternatively, crospovidone and/or sodium carboxymethyl starch may be
added after adding sodium thiosulfate and the effective ingredient to the saccharide
or sugar alcohol and appropriately subjecting the resultant to granulation or size
selection. Further, the entire amount of the saccharide or sugar alcohol may be
added in the aforementioned step of adding the effective ingredient, or only a partial
amount of the saccharide or sugar alcohol may be used in the step, adding the
remaining amount in a later step.
[0039]
In the wet granulation, a commonly used apparatus is employed, and
examples thereof include fluidized bed granulators, tumbling fluidized bed
granulators, stirring granulators, cylindrical extrusion granulators and wet extrusion
granulators. In cases where water is used as the solvent for dissolving or
suspending the effective ingredient, a fluidized bed granulator and a tumbling
fluidized bed granulator capable of drying with spraying are suitable. Further, in
cases where a volatile solvent such as ethanol is used as the solvent for dissolving or
suspending the effective ingredient, a fluidized bed granulator, a tumbling fluidized
bed granulator and a stirring granulator are suitable.
[0040]
As the apparatus for mixing the preparation, a commonly used apparatus is
employed, and examples thereof include V-shaped mixers, ribbon mixers and air
blenders.
[0041]
For compression molding, a commonly used apparatus is employed, and
examples thereof include single-punch tableting machines and rotary tableting
machines. The molding pressure in tableting is not particularly restricted and may
be any pressure as long as the resulting tablet has such a tablet hardness that would
not be an issue in handling. For example, the tableting pressure may be set at 200
to 10,000 kgf/cm2, preferably 500 to 5,000 kgf/cm2.
[0042]
The amount of the lubricant to be added is not particularly restricted; however,
for example, in the case of magnesium stearate, the amount is preferably about 0.1 to
5.0% by weight, more preferably 0.5 to 3.0% by weight per unit weight containing
the effective ingredient.
[0043]
The thus obtained tablet according to the present invention comprising a
morphinan derivative represented by the Formula (I) or a pharmacologically
acceptable acid addition salt thereof as the effective ingredient can be made into a
coated preparation by adding a coating agent as required. As the coating agent, a
functional base may be selected in accordance with the purpose and, for example,
any of the generally commercially available ones, such as hydroxypropylmethyl
cellulose, ethyl cellulose, carboxymethylethyl cellulose and premixed products
thereof, may be used.
[0044]
For film coating operation, a commonly used apparatus is employed, and a
pan coating machine is suitable for producing film-coated tablets.
EXAMPLES
[0045]
In order to clarify the superior effects of the present invention, the present
invention will now be explained by way of examples thereof; however, the present
invention is not restricted thereto. It is noted here that, in the following examples,
PEARLITOL (registered trademark) 200SD which is a spray-dried granule of
mannitol, PEARLITOL (registered trademark) 300DC which is a extrusion-
granulated granule of mannitol and PEARLITOL (registered trademark) 50C which
is a powder-form mannitol are abbreviated as "mannitol SD", "mannitol DC" and
"mannitol C", respectively (all of these products are manufactured by Roquette Japan
K.K.). Further, the "Compound 1" is, as stated in the above, 17-
(cyclopropylmethyl)-3,14P-dihydroxy-4,5a-epoxy-6p-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan hydrochloric acid salt
Example 1
[0017]
R6 represents hydrogen, C1-C5 alkyl or C1-C5 alkanoyl.
[0018]
The double line composed of a dashed line and a solid line in the Formula (I)
represents, as described in the above, a double bond or a single bond; however, it is
preferably a single bond.
[0019]
Further, in the Formula (I), R1 is preferably methyl, ethyl, propyl, butyl,
isobutyl, cyclopropylmethyl, allyl, benzyl or phenethyl, more preferably
cyclopropylmethyl or allyl.
[0020]
It is preferred that R and R independently be hydrogen, hydroxy, acetoxy or
methoxy.
[0021]
Mannitol SD was weighed in an amount of 126.645 parts by weight
(hereinafter, abbreviated as "parts" and the same applies in the followings unless
otherwise specified). It was then sieved through a mesh having 1 mm openings and
placed into a mortar. The thus obtained granules were mixed for 5 minutes in the
mortar while spraying thereto a spray solution in which 0.005 parts of the Compound
1 and 0.1 parts of sodium thiosulfate hydrate (Kokusan Chemical Co., Ltd.) were
dissolved in distilled water. The resultant was dried at 45 °C for 2 hours using a
hot-air dryer (PS-212, Espec Corporation) to produce granulated granules. The
granulated granules were subjected to size selection using a comil (197S, Powrex
Corporation) and added with 2.6 parts of crospovidone (Kollidon (registered
trademark) CL, BASF), and the resultant was mixed for 15 minutes using a V-shaped
mixer (Tsutsui Scientific Instruments Co., Ltd.). To the thus obtained mixture, 0.65
parts of magnesium stearate (Taihei Chemical Industrial Co., Ltd.) was further added,
and the resultant was mixed for 5 minutes. The thus obtained granules were made
into a tablet of 130 mg using a tableting machine (Correct 19, Kikusui Seisakusho
Ltd.).
Example 2
Mannitol SD was weighed in an amount of 38.475 parts, sieved through a
mesh having 1 mm openings and loaded into a fluidized bed granulator(FLO-5,
Freund Corporation). A spray solution in which 0.005 parts of the Compound 1 and
0.1 parts of sodium thiosulfate hydrate were dissolved in distilled water was sprayed
to the thus obtained granules to produce granulated granules. The granulated
granules were processed using the comil to obtain size-selected granules. To 38.58
parts of the thus obtained size-selected granules, 84.27 parts of mannitol SD and 6.5
parts of crospovidone were added, and the resultant was mixed for 15 minutes using
the V-shaped mixer. To the thus obtained mixture, 0.65 parts of magnesium
stearate (Taihei Chemical Industrial Co., Ltd.) was further added, and the resultant
was mixed for 5 minutes. The thus obtained granules were made into a tablet of
130 mg using a tableting machine (Correct 19, Kikusui Seisakusho Ltd.).
Example 3
A tablet was produced in the same manner as in Example 2, except that
mannitol SD and crospovidone were added in an amount of 77.77 parts and 13 parts,
respectively, to 38.58 parts of the size-selected granules of Example 2.
Example 4
A tablet was produced in the same manner as in Example 2, except that
mannitol SD and crospovidone were added in an amount of 71.27 parts and 19.5
parts, respectively, to 38.58 parts of the size-selected granules of Example 2.
Example 5
A tablet was produced in the same manner as in Example 1, except that the
content of mannitol SD of Example 1 was 103.245 parts and that of crospovidone
was 26 parts.
Example 6
Mannitol SD was weighed in an amount of 96.745 parts, sieved through a
mesh having 1 mm openings and loaded into a fluidized bed granulator (FLO-5,
Freund Corporation). A spray solution in which 0.005 parts of the Compound 1 and
0.1 parts of sodium thiosulfate hydrate were dissolved in distilled water was sprayed
to the thus obtained granules to produce granulated granules. Next, mannitol C was
weighed in an amount of 26 parts, sieved through a mesh having 1 mm openings and,
along with 6.5 parts of crospovidone, loaded into a stirring granulator (NMG-3L,
Nara Machinery Co., Ltd.). Subsequently, the thus loaded mixture was granulated
while adding thereto distilled water to produce granules. The granulated granules
produced by the fluidized bed granulator and those produced by the stirring
granulator were respectively processed using the comil to obtain size-selected
granules. To 129.35 parts of the thus size-selected granules, 0.65 parts of
magnesium stearate (Taihei Chemical Industrial Co., Ltd.) was added, and the
resultant was mixed for 5 minutes. The thus obtained granules were made into a
tablet of 130 mg using a tableting machine (Correct 19, Kikusui Seisakusho Ltd.).
Example 7
A tablet was produced in the same manner as in Example 1, except that
mannitol SD of Example 1 was replaced with different grade mannitols, mannitol DC
and mannitol C, in an amount of 96.745 parts and 26 parts, respectively, and that the
content of crospovidone was 6.5 parts.
Example 8
A tablet was produced in the same manner as in Example 1, except that
mannitol SD of Example 1 was replaced with lactose (Pharmatose (registered
trademark) 200M, DMV) in an amount of 122.095 parts and that the contents of
crospovidone and magnesium stearate were 6.5 parts and 1.3 parts, respectively.
Example 9
A tablet was produced in the same manner as in Example 1, except that
mannitol SD of Example 1 was partially replaced with erythritol (Nikken Chemical
Laboratory Co., Ltd.) in such a manner that the contents of mannitol SD and
erythritol were 83.095 parts and 39 parts, respectively, and that the contents of
crospovidone and magnesium stearate were 6.5 parts and 1.3 parts, respectively.
Example 10
A tablet was produced in the same manner as in Example 1, except that
mannitol SD of Example 1 was partially replaced with potato starch (ST-P, Nippon
Starch Chemical Co., Ltd.) in such a manner that the contents of mannitol SD and
potato starch were 83.095 parts and 39 parts, respectively, and that the contents of
crospovidone and magnesium stearate were 6.5 parts and 1.3 parts, respectively.
Example 11
A tablet was produced in the same manner as in Example 1, except that
mannitol SD of Example 1 was replaced with maltitol (powder maltitol G-3, Towa-
Kasei Co., Ltd.) in an amount of 122.095 parts and that the contents of crospovidone
and magnesium stearate were 6.5 parts and 1.3 parts, respectively.
Example 12
A tablet was produced in the same manner as in Example 1, except that
mannitol SD of Example 1 was replaced with saccharose (Suzu Funmatsu Yakuhin
K.K.) in an amount of 122.095 parts and that the contents of crospovidone and
magnesium stearate were 6.5 parts and 1.3 parts, respectively.
Example 13
A tablet was produced in the same manner as in Example 2, except that
mannitol SD and sodium carboxymethyl starch (EXPLOTAB (registered trademark),
JRS Pharma) were added in an amount of 88.17 parts and 2.6 parts, respectively, to
38.58 parts of the size-selected granules of Example 2.
Example 14
A tablet was produced in the same manner as in Example 1, except that the
content of mannitol SD of Example 1 was 116.245 parts and that crospovidone was
replaced with sodium carboxymethyl starch in an amount of 13 parts.
Example 15
A tablet was produced in the same manner as in Example 1, except that the
content of mannitol SD of Example 1 was 116.245 parts and that crospovidone was
partially replaced with sodium carboxymethyl starch in such a manner that the
contents of crospovidone and sodium carboxymethyl starch were both 6.5 parts each.
Comparative Example 1
Weighed in a standard bottle were 10 parts by weight of the Compound 1 and
100 parts of crystalline cellulose (Avicel (registered trademark) PH-101, Asahi Kasei
Corporation). Distilled water in an amount of 30 parts was added thereto and the
resultant was mixed with a glass rod. After drying the thus obtained granules, the
dried granules were made into a tablet of 100 mg using a single-punch tableting
machine (RIKEN POWER, Riken Seiki Co., Ltd.).
Comparative Example 2
A tablet was produced in the same manner as in Comparative Example 1,
except that crystalline cellulose of Comparative Example 1 was replaced with
polyvinyl alcohol (PVA EG-5, Nippon Synthetic Chemical Industry Co., Ltd.).
Comparative Example 3
A tablet was produced in the same manner as in Comparative Example 1,
except that crystalline cellulose of Comparative Example 1 was replaced with
hydroxypropyl cellulose (HPC-L (registered trademark), Nippon Soda Co., Ltd.).
Comparative Example 4
A tablet was produced in the same manner as in Comparative Example 1,
except that crystalline cellulose of Comparative Example 1 was replaced with
croscarmellose sodium (Ac-di-sol (registered trademark), FMC Bio Polymer)
(hereinafter, abbreviated as Ac-di-sol).
Comparative Example 5
A tablet was produced in the same manner as in Comparative Example 1,
except that crystalline cellulose of Comparative Example 1 was replaced with
carmellose calcium(CMC-Ca ECG-505, Gotoku Chemical Co., Ltd.) (hereinafter,
abbreviated as CMC-Ca).
Comparative Example 6
A solid preparation was produced in accordance with the technique described
in WO 99/02158 (Patent Document 2). Lactose and crystalline cellulose were
weighed in an amount of 49.91 parts and 26.4 parts, respectively, and loaded into the
fluidized bed granulator. A spray solution in which 0.01 parts of the Compound 1,
0.08 parts of sodium thiosulfate hydrate and 3.2 parts of hydroxypropyl cellulose
(HPC-SL (registered trademark), Nippon Soda Co., Ltd.) were dissolved in distilled
water was sprayed to the thus obtained formulation powder to produce granulated
granules. The granulated granules were processed using the comil to obtain size-
selected granules. To 79.6 parts of the thus obtained size-selected granules, 0.4
parts of magnesium stearate was added, and the resultant was mixed for 5 minutes.
The thus obtained granules were made into a tablet of 80 mg using the tableting
machine.
Comparative Example 7
Mannitol SD was weighed in an amount of 78.895 parts, sieved through a
mesh having 1 mm openings and loaded into a fluidized bed granulator (FLO-5,
Freund Corporation). A spray solution in which 0.005 parts of the Compound 1 and
0.1 parts of sodium thiosulfate hydrate were dissolved in distilled water was sprayed
to the thus obtained granules to produce drug-carrying granules. To 79 parts of the
thus obtained drug-carrying granules, 15 parts of mannitol SD and 5 parts of Ac-di-
sol were added, and the resultant was mixed for 15 minutes using a V-shaped mixer
(permeation-mode S-5, Tsutsui Scientific Instruments Co., Ltd.). To the thus
obtained mixture, 1 part of magnesium stearate was further added, and the resultant
was mixed for 5 minutes. The thus obtained granules were made into a tablet of
100 mg using the tableting machine.
Comparative Example 8
Drug-carrying granules were prepared in the same manner as in Comparative
Example 7, and the subsequent mixing and tableting were carried out in the same
manner as in Comparative Example 7, except that 10 parts of mannitol SD and 10
parts of CMC-Ca in place of Ac-di-sol were added to 79 parts of the drug-carrying
granules.
Comparative Example 9
A tablet was produced in the same manner as in Example 1, except that the
content of mannitol SD was 90.245 parts and that of crospovidone was 39 parts.
Comparative Example 10
A tablet was produced in the same manner as in Example 1, except that the
content of mannitol SD was 77.245 parts and that of crospovidone was 52 parts.
Comparative Example 11
A tablet was produced in the same manner as in Example 2, except that the
content of mannitol SD was 122.845 parts and that sodium thiosulfate hydrate was
not added.
Example 16
The tablets obtained in each of Examples 1 to 15 and Comparative Examples
1 to 11 were left to stand in an open state under the condition of 40°C/75% RH,
which is the acceleration condition described in the Drug Approval and Licensing
Procedures in Japan (2006), and the residual ratio (%) of the drug was subsequently
measured by HPLC method to evaluate the stability thereof (Tables 1 and 2).
[0046]
As shown in Tables 1 and 2, for Comparative Example 6 in which saccharide
and sodium thiosulfate were blended without crospovidone and for Comparative
Example 11 in which sugar alcohol and crospovidone were blended without sodium
thiosulfate, the drug residual ratio was measured to be low at 94.4% and 83.3%,
respectively. In addition, Comparative Examples 1 to 5, 7 and 8 in which
crospovidone or sodium carboxymethyl starch was not blended and Comparative
Examples 9 and 10 in which the content of crospovidone was not less than 30% also
exhibited low residual ratios. In contrast, those tablets described in Examples 1 to
15, which comprise sodium thiosulfate, saccharide or sugar alcohol, and 1 to 20% by
weight of crospovidone, sodium carboxymethyl starch or a mixture thereof per unit
weight containing the effective ingredient, all exhibited a residual ratio of not less
than 96% even when they were stored unpacked for one month under the condition
of 40°C and 75% RH, and showed a prominent stabilization effect as compared to
the formulations of Comparative Examples; therefore, it was demonstrated that those
tablets of Examples 1 to 15 can ensure sufficient stability also when handled as a
pharmaceutical.
[0049]
Example 17
Mannitol SD was weighed in an amount of 38.475 parts, sieved through a
mesh having 1 mm openings and loaded into the fluidized bed granulator. Then, a
spray solution in which 0.005 parts of the Compound 1 and 0.1 parts of sodium
thiosulfate hydrate were dissolved in distilled water was sprayed to the thus obtained
granules to produce granulated granules. The granulated granules were processed
using the comil to obtain size-selected granules. To 38.58 parts of the thus obtained
size-selected granules, 84.27 parts of mannitol SD and 6.5 parts of crospovidone
were added, and the resultant was mixed for 15 minutes using the V-shaped mixer.
To the thus obtained mixture, 0.65 parts of magnesium stearate (Taihei Chemical
Industrial Co., Ltd.) was further added, and the resultant was mixed for 5 minutes.
The thus obtained granules were made into a tablet of 130 mg using a tableting
machine (Correct 19, Kikusui Seisakusho Ltd.). Next, this tablet was loaded into a
film coating machine (Hicoater Mini, Freund Corporation) and a solution in which
OPADRY-OY7300 (Japan Colorcon) was dissolved or dispersed was sprayed to the
tablet to produce a coated tablet of 137 mg in which 7 mg of coating agent was added
to 130 mg of the tablet.
Example 18
Mannitol DC was weighed in an amount of 96.745 parts, sieved through a
mesh having 1 mm openings and loaded into the fluidized bed granulator. Then, a
spray solution in which 0.005 parts of the Compound 1 and 0.1 parts of sodium
thiosulfate hydrate were dissolved in distilled water was sprayed to the thus obtained
granules to produce granulated granules. Then, mannitol C was weighed in an
amount of 25.9675 parts, sieved through a mesh having 1 mm openings and, along
with 6.5 parts of crospovidone, loaded into the stirring granulator. Subsequently,
the thus loaded mixture was granulated while adding thereto distilled water into
which 0.0325 parts of iron sesquioxide was dispersed, thereby producing granulated
granules. The granulated granules produced by the fluidized bed granulator and
those produced by the stirring granulator were respectively processed using the comil
to obtain size-selected granules. To 129.35 parts of the thus size-selected granules,
0.65 parts of magnesium stearate was added, and the resultant was mixed for 5
minutes. The thus obtained granules were made into a WR tablet of 130 mg using
the tableting machine.
Example 19
For the tablet obtained in Example 18, the intraoral disintegration time in
three subjects consisting of a healthy adult male and female was measured. The
time required for the tablet to be completely disintegrated by saliva without taking
water into the mouth and chewing the tablet (the time required for the subject to no
longer have a feel of foreign matter in the mouth) was measured, and the average of
the measurements for the three subjects was used as the intraoral disintegration time.
As the result, the intraoral disintegration time was approximately 9 seconds;
therefore, it was confirmed that the tablet has excellent disintegration property.
We claim:
[Claim 1]
A tablet comprising the following (1) to (4):
(1) as an effective ingredient, a 4,5-epoxymorphinan derivative represented by
the Formula (I):
[Formula 1]
[wherein,
the double line composed of a dashed line and a solid line represents a double
bond or a single bond;
R1 represents C1-C5 alkyl, C4-C7 cycloalkylalkyl, C5-C7 cycloalkenylalkyl,
C6-C12 aryl, C7-C13 aralkyl, C4-C7 alkenyl, allyl, C1-C5 furan-2-ylalkyl or C1-C5
thiophen-2-ylalkyl;
R2 represents hydrogen, hydroxy, nitro, C1-C5 alkanoyloxy, C1-C5 alkoxy, Ci-
C5 alkyl or -NR7R8;
R7 represents hydrogen or C1-C5 alkyl;
R8 represents hydrogen, C1-C5 alkyl or -C(=O)R9;
R9 represents hydrogen, phenyl or C1-C5 alkyl;
R represents hydrogen, hydroxy, C1-C5 alkanoyloxy or C1-C5 alkoxy;
A represents -N(R4)C(=X)-, -N(R4)C(=X)Y-, -N(R4)- or -N(R4)SO2- (wherein
X and Y independently represent NR4, S or O; R4 represents hydrogen, C1-C5 linear
or branched alkyl or C6-C12 aryl; and R in the formula may be the same or
different);
B represents a valence bond, C1-C14 linear or branched alkylene (with the
provisos that said alkylene is optionally substituted by at least one substituent
selected from the group consisting of C1-C5 alkoxy, C1-C5 alkanoyloxy, hydroxy,
fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl,
trifluoromethoxy and phenoxy, and that 1 to 3 methylene groups may be substituted
by carbonyl group(s)), C2-C14 linear or branched acyclic unsaturated hydrocarbon
containing 1 to 3 double bonds and/or triple bonds (with the provisos that said
acyclic unsaturated hydrocarbon is optionally substituted by at least one substituent
selected from the group consisting of C1-C5 alkoxy, C1-C5 alkanoyloxy, hydroxy,
fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl,
trifluoromethoxy and phenoxy, and that 1 to 3 methylene groups may be substituted
by carbonyl group(s)) or C1-C14 linear or branched saturated or unsaturated
hydrocarbon containing 1 to 5 thioether bonds, ether bonds and/or amino bonds (with
the provisos that a hetero atom does not directly binds to A, and that 1 to 3
methylene groups may be substituted by carbonyl group(s));
R5 represents hydrogen or organic group having a basic skeleton shown
below (with the proviso that said organic group is optionally substituted by at least
one substituent selected from the group consisting of C1-C5 alkyl, C1-C5 alkoxy, Ci-
C5 alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano,
isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy);
[Formula 2]
Organic groups represented by R
and R6 represents hydrogen, C1-C5 alkyl or C1-C5 alkanoyl.J
or a pharmacologically acceptable acid addition salt thereof;
(2) sodium thiosulfate;
(3) at least one selected from the group consisting of saccharides and sugar
alcohols; and
(4) crospovidone, sodium carboxymethyl starch or a mixture thereof,
wherein the content of said (4) is 1 to 20% by weight per unit weight containing said
effective ingredient.
[Claim 2]
The tablet according to claim 1, wherein said (3) is at least one selected from
the group consisting of potato starch, saccharose, lactose, mannitol, erythritol and
maltitol.
[Claim 3]
The tablet according to claim 1 or 2, wherein a part or the entirety of said (3)
is granulated granules.
[Claim 4]
The tablet according to claim 3, wherein said granulated granules are
produced by extrusion granulation, stirring granulation, spray drying or fluidized bed
granulation.
[Claim 5]
The tablet according to any one of claims 1 to 4, said tablet being produced
by a production method comprising the steps of dissolving or suspending said
effective ingredient in water or a pharmacologically acceptable solvent and adding
the resulting liquid to said saccharide or sugar alcohol.
[Claim 6]
The tablet according to any one of claims 1 to 5, wherein said tablet is in a
coated form.

The present invention relates to a stable tablet comprising a 4,5-
epoxymorphinan derivative or a pharmacologically acceptable acid addition salt
thereof as an effective ingredient. That is, the tablet according to the present
invention comprises: (1) as the effective ingredient, a specific 4,5-epoxymorphinan
derivative or a pharmacologically acceptable acid addition salt; (2) sodium
thiosulfate; (3) at least one selected from the group consisting of saccharides and
sugar alcohols; and (4) crospovidone, sodium carboxymethyl starch or a mixture
thereof, in which tablet the content of the aforementioned (4) is 1 to 20% by weight
per unit weight containing the aforementioned effective ingredient.