U.S. patent application number 11/441349 was filed with the patent office on 2007-01-04 for morphine sulfate microgranules, method for preparing same and compositions containing same.
This patent application is currently assigned to LABORATOIRES DES PRODUITS ETHIQUES ETHYPHARM. Invention is credited to Dominique Marechal, Pascal Oury, Pascal Suplie.
Application Number | 20070003620 11/441349 |
Document ID | / |
Family ID | 9546553 |
Filed Date | 2007-01-04 |
United States Patent
Application |
20070003620 |
Kind Code |
A1 |
Marechal; Dominique ; et
al. |
January 4, 2007 |
Morphine sulfate microgranules, method for preparing same and
compositions containing same
Abstract
The present invention relates to sustained-release morphine
sulfate microgranules each comprising a neutral support grain
coated with an active layer and with a sustained-release layer,
wherein the sustained-release layer contains a copolymer of
methacrylic acid, and a silica selected from hydrophobic fumed
silica, as well as pharmaceutical compositions containing them.
Inventors: |
Marechal; Dominique; (Dreux,
FR) ; Suplie; Pascal; (Montaure, FR) ; Oury;
Pascal; (Chesnay, FR) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
LABORATOIRES DES PRODUITS ETHIQUES
ETHYPHARM
|
Family ID: |
9546553 |
Appl. No.: |
11/441349 |
Filed: |
May 26, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10009341 |
Jun 19, 2002 |
7063864 |
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PCT/FR00/01573 |
Jun 8, 2000 |
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11441349 |
May 26, 2006 |
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Current U.S.
Class: |
424/469 |
Current CPC
Class: |
A61P 23/00 20180101;
A61K 9/501 20130101; A61P 25/00 20180101; A61K 31/485 20130101;
A61K 9/5026 20130101; A61K 9/5078 20130101; A61P 29/00 20180101;
A61P 25/02 20180101; A61P 25/04 20180101; A61K 9/5047 20130101 |
Class at
Publication: |
424/469 |
International
Class: |
A61K 9/26 20060101
A61K009/26 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 9, 1999 |
FR |
99/07259 |
Claims
1. Sustained-release morphine sulfate microgranules each comprising
a neutral support grain coated with an active layer and with a
sustained-release layer, wherein the sustained-release layer
contains a copolymer of methacrylic acid, and a silica selected
from hydrophobic fumed silica.
2. The microgranules according to claim 1, wherein the hydrophobic
fumed silica is a hydrophobic fumed silica after treated with
dimethyldichlorosilane based on a hydrophilic fumed silica with a
specific surface area of 130 m.sup.2/g.
3. The microgranules according to claim 1, wherein the hydrophobic
fumed silica represents from 0.2 to 1% by weight of the
microgranules.
4. The microgranules according to claim 1, wherein the copolymer of
methacrylic acid represents from 5 to 15% by weight of the total
weight of the microgranules.
5. The microgranules according to claim 1, wherein the copolymer of
methacrylic acid is selected from the group consisting of fully
polymerized copolymers of acrylic acid and methacrylic acid esters
with low content of quaterny ammonium groups, or mixtures
thereof.
6. The microgranules according to claim 1 wherein the copolymer of
methacrylic acid is selected from the group consisting of
poly(ethyl acrylate methyl methacrylate, trimethyamonioethyl
methacrylate chloride) with a (1:2:0.1) ratio or with a (1:2:0.2)
ratio, and mixtures thereof.
7. The microgranules according to claim 1, wherein the
sustained-release layer contains a mixture of two or more different
grades of said copolymer of methacrylic acid.
8. The microgranules according to claim 1, wherein the neutral
support grain coated with the active layer contains 40% to 50% of
morphine sulfate and 10 to 20% of at least one pharmaceutically
acceptable binder.
9. The microgranules according to claim 1, wherein the
sustained-release layer contains a plasticizer and a lubricant.
10. The microgranules according to claim 1 whose composition is as
follows: TABLE-US-00020 Morphine sulfate: 30 to 42% Neutral support
grain: 30 to 40% Binder: 10 to 20% Copolymer of methacrylic acid: 5
to 15% Plasticizer: 1 to 2.5% Lubricant: 1 to 4% Hydrophobic
silica: 0.2 to 1%
11. The microgranules according to claim 10 whose composition is as
follows: TABLE-US-00021 Morphine sulfate: 30 to 40% Neutral support
grain: 30 to 40% Binder: 10 to 20% Copolymer of methacrylic acid: 5
to 15% Plasticizer: 1 to 2.5% Lubricant: 2 to 4% Hydrophobic
silica: 0.2 to 1%
12. The microgranules according to claim 1, wherein the relative
mass proportion of the morphine sulfate to the neutral support
grain is between 40/60 and 60/40.
13. The microgranules according to claim 1, wherein the morphine
sulfate represents 30 to 40% by mass of the microgranules.
14. The microgranules according to claim 1, whose composition is as
follows: TABLE-US-00022 Morphine sulphate 37.56% Neutral support
grain (sugar sphere) 38.03% Binder (HPMC) 13.18% Methacrylic acid
copolymer 7.08% (Eudragit .RTM. RS 30D) Plasticizer
(Triethylcitrate) 1.42% Lubricant (Talc) 2.38% Hydrophobic fumed
silica 0.35% (Aerosil .RTM. R972)
15. A process for preparing the microgranules according to claim 1,
wherein the active layer and the sustained-release layer are
applied onto the neutral grains by spraying.
16. A pharmaceutical composition containing microgranules according
to claim 1.
17. The pharmaceutical composition according to claim 16, having
substantially no food effect on the bioavailability of morphine
sulfate.
18. The pharmaceutical composition according to claim 16, in the
form of capsules or tablets.
Description
[0001] The present invention concerns a novel sustained-release
morphine sulphate formulation for oral administration.
[0002] The present invention also applies to the process for
manufacturing this formulation and to the pharmaceutical
preparations containing it.
[0003] In the present application, "morphine sulphate" is intended
to mean the sulphate salt, optionally hydrated, of (5 alpha, 6
alpha)-7,8-didehydro-4,5-epoxy-17-methylmorphinane-3,6-diol.
[0004] The oral administration of morphine sulphate is the best
suited treatment for relieving chronic pain. Many oral formulations
of morphine sulphate have been described in the prior art.
[0005] EP 205 282 (EUROCELTIQUE) relates to granules comprising
morphine sulphate, an aliphatic alcohol and a water-soluble
hydroxyalkylcellulose.
[0006] These granules are coated with a derivative of mucoadhesive
cellulose, such as hydroxypropylmethyl-cellulose, and present a
release profile over 12 hours, with a plasmatic peak situated
between 1 and 3 hours.
[0007] EP 377 518 (FAULDING) discloses sustained-release granules
containing a very water-soluble active principle such as morphine.
The granules make it possible to maintain plasmatic levels higher
than 75% of the maximum for at least 3 hours.
[0008] These granules comprise an active core coated with a
polymeric layer which allows a slow release of the active principle
at a very acid pH and a constant faster release of the active
principle at a pH which is less acid to basic, over an extended
period of time.
[0009] This polymeric layer contains three compounds: a polymeric
matrix which is insoluble whatever the pH, an enteric polymer, the
solubility of which is pH-dependent, and a polymer which is soluble
in acid medium.
[0010] The preparations described in EP 377 518 have a
bioavailability requiring an administration which should be at
least twice daily.
[0011] A subject of EP 553 392 (EUROCELTIQUE) is a process for
preparing a stable sustained-release formulation consisting of
granules obtained in a fluidized air bed by spraying an aqueous
solution of active principle over neutral grains, followed by a
coating with HPMC, by a coating with an acrylic polymer and by a
protective film required for reducing the agglomeration of the
granules.
[0012] EP 636 366 (EUROCELTIQUE) discloses sustained-release
morphine sulphate microgranules comprising a neutral core coated
with an active layer consisting of an active principle/HPMC
mixture, of a sustained-release layer consisting of Eudragit.RTM.
RS D and/or of Eudragit.RTM. RL D, and of an HPMC film, which
represents 5% of gain in mass.
[0013] In documents EP 533 392 and EP 636 366, the granules undergo
a heat treatment above the glass transition temperature of the
polymeric coating, in order to stabilize its structure. This heat
treatment is carried out at 45.degree. C. approximately for at
least 24 hours, which considerably lengthens the duration of the
process.
[0014] EP 647 448 (EUROCELTIQUE) discloses morphine sulphate
granules, the in vitro dissolution profile of which stretches over
24 hours. The granules consist of Neutral grains coated with active
principle and with lactose. The active layer is covered with a film
of Opadry.RTM., and then coated with Aquacoat ECD 30.RTM., Eudragit
RS 30 D.RTM. or a Eudragit RS.RTM./Eudragit RL.RTM. mixture:
97.5/2.5. The titre of the granules described in this document is
quite low, of the order of 15%.
[0015] U.S. Pat. No. 5,445,829 (KV Pharmaceutical) relates to a
formulation which is capable of releasing the active principle
exclusively between 12 and 24 hours after the administration.
[0016] This formulation contains 0 to 50% of immediate particles
and the complement of controlled-release particles consisting of
immediate particles coated with a cellulose derivative as delaying
polymer.
[0017] WO 94/22431 (KAPIPHARMACIA) discloses a controlled-release
formulation of a morphine salt.
[0018] This formulation can be administered in a single daily
dosage intake. At 32 hours, the plasma concentration is higher than
Cmax/2 and the fluctuations in the release profile are very small
over this period, and so the plasmatic concentration is virtually
constant over 24 hours.
[0019] The formulation disclosed in WO 94/22431 consists, for
example, of granules containing a core of morphine salt, of lactose
and of a binder, coated with a film of HPMC/EC and of triethyl
citrate.
[0020] This formulation uses a mixture of two polymers, one being
soluble and the other being insoluble in water.
[0021] WO 95/31972 (EUROCELTIQUE) discloses sustained-release
morphine sulphate granules consisting of a neutral core coated with
active principle and with hydrated lactose, the bulk density of
which is between 0.4 and 0.9 g/ml. The delayed-release layer
coating the active principle contains for example an acrylic
polymer, an alkylcellulose, a hydrogenated vegetable oil or a
mixture thereof.
[0022] This document teaches that the binding of the morphine
sulphate to the neutral cores requires the addition of the lactose
as a diluent.
[0023] The release profiles of the microgranules given by way of
example show that these granules are suitable for one dosage intake
per day.
[0024] WO 96/14059 (EUROCELTIQUE) discloses a process for extruding
spherical particles containing morphine sulphate, a support the
melting point of which is between 35 and 150.degree. C. and a
sustained-release agent.
[0025] The support is a hydrogenated vegetable oil or a PEG (Mw
1000 to 20,000). The in vitro dissolution profile of these
particles is 67% at 24 hours. No in vitro result is provided.
[0026] WO/960066 (ALZA) describes a composition containing morphine
sulphate, polyvinylpyrrolidone and a polyalkylene oxide.
[0027] This document claims that the formulation provides a
sustained release over time, but gives no example either in vitro
or in vivo, and so it is difficult, upon reading the document, to
estimate whether the administration should be one or more dosage
intakes per day.
[0028] The subject of the present invention concerns
sustained-release morphine sulphate microgranules each comprising a
neutral support grain coated with an active layer and with a
sustained-release layer, characterized in that the
sustained-release layer contains a copolymer of methacrylic acid,
and a hydrophobic fumed silica.
[0029] According to the present invention, the preferred copolymers
of methacrylic acid are chosen among ammonio-methacrylate
copolymers, i.e. fully polymerized copolymers of acrylic acid and
methacrylic acid esters with low content of quaterny ammonium
groups.
[0030] Such polymers are, for example, those sold under the trade
names: [0031] Eudragit.RTM. RS (Rohm): (poly(ethyl acrylate methyl
methacrylate, trimethylamonioethyl methacrylate chloride) 1:2:0.1,
and [0032] Eudragit.RTM. RL (Rohm): (poly(ethyl acrylate methyl
methacrylate, trimethylamonioethyl methacrylate chloride)
1:2:0.2
[0033] Eudragit.RTM. RS are poorly permeable to water whereas
Eudragit.RTM. RL are highly permeable water. Both polymers are
water-insoluble.
[0034] Among the grade Eudragit.RTM. RS (low permeability to
water), methacrylic acid copolymers that can be used are, for
example, those sold under the trade names Eudragit.RTM. RS 12.5,
Eudragit.RTM. RS 100 and Eudragit.RTM. RS PO.
[0035] According to the present invention, the methacrylic acid
copolymer is preferably conditionned as an aqueous solution, like
the one sold under the trade name Eudragit.RTM. RS 30 D (30%
aqueous dispersion) as it does not need to be used with organic
solvents.
[0036] Among the grade Eudragit.RTM. RL (high permeability to
water), methacrylic acid copolymers that can be used are, for
example, those sold under the trade name Eudragit.RTM. RL 12.5,
Eudragit.RTM. RL 100 and Eudragit.RTM. RL PO.
[0037] According to the present invention, the methacrylic acid
copolymer is preferably conditionned as an aqueous solution, like
the one sold under the trade name Eudragit.RTM. RL 30 D (30%
aqueous dispersion) as it does not need to be used with organic
solvents.
[0038] According to a particular embodiment of the invention, the
sustained release layer contains a mixture of two or more different
grades of methacrylic acid copolymers.
[0039] In particular, the sustained release layer is composed of a
mixture of methacrylic acid of low (Eudragit.RTM. RS) and high
(Eudragit.RTM. RL) permeability. Such a mixture is advantageously
used to adapt the permeability of the sustained release layer in
order to obtain the desired dissolution profile.
[0040] Preferably, when the sustained release layer is composed of
a mixture of methacrylic acid copolymers of low and high
permeability, the ratio between low permeability copolymer and high
permeability copolymer is comprised between 95:5 and 60:40.
[0041] More preferably, when the sustained release layer is
composed of a mixture of such copolymers, the low permeability
copolymer is Eudragit.RTM. RS 30 D and the high permeability
copolymer is Eudragit.RTM. RL 30 D.
[0042] According to the present invention, the hydrophobic fumed
silica represents advantageously 0.2 to 1% by weight of the
microgranules.
[0043] Said hydrophobic fumed silica (or also called hydrophobic
colloidal silica) have the same chemical formula (S.sub.iO.sub.2)
than non hydrophobic silica but do present an important hydrophobic
character vis a vis water. Hydrophobic silica to be used in the
present invention are preferably chosen among the silica called
"fumed silica" i.e silica which have undergone a heating treatment
(at 400.degree. C.) modifying their surface state, rendering them
very hydrophobic. Such silica are practically insoluble in water.
Aerosil.RTM. R 972 (Degussa) is preferred as hydrophobic fumed
silica.
[0044] Hydrophobic fumed silicas are produced by chemical treatment
of hydrophilic fumed silica (SiO.sub.2) with silanes or siloxanes.
In the finished product, the treatment agent is chemically bonded
to the previously hydrophilic oxide. This can convert the natural
hydrophilic fumed into a hydrophobic material.
[0045] One production method of fumed silica involves a continuous
flame hydrolysis technique. It involves the conversion of silicon
tetra chloride (SiCl.sub.4) to the gas phase using an oxy hydrogen
flame. It then reacts with water to yield silica (SiO.sub.2) and
hydrochloric acid thus:
SiCl.sub.4+H.sub.2O.fwdarw.SiO.sub.2+HCl
[0046] The HCl is easily separated as it remains in the gas phase,
while the fumed silica is solid.
[0047] Hydrophobic fumed silica of different grades may be provided
by Degussa (Aerosil.RTM. R972, Aerosil.RTM. R974, Aerosil.RTM.
R104, Aerosil.RTM. R106, Aerosil.RTM. R202, Aerosil.RTM. R805,
Aerosil.RTM. R812, Aerosil.RTM. R812 S, Aerosil.RTM. R816,
Aerosil.RTM. R7200, Aerosil.RTM. R8200, Aerosil.RTM. R9200) or by
Thornley Company (Dumasil.RTM.100-FG, Dumasil.RTM.100-Z-FG,
Dumasil.RTM.300-FG).
[0048] According to the present invention, the preferred fumed
silica is Aerosil.RTM. R972.
[0049] Aerosil.RTM.R972 is a hydrophobic fumed silica after treated
with DDS (Dimethyldichlorosilane) based on a hydrophilic fumed
silica with a specific surface area of 130 m.sup.2/g.
[0050] Hydrophobic fumed silica are generally used in
pharmaceutical formulations as lubricants or anti-tacking agents.
As such, they are commonly used in quantity varying from 2 to 10%
by weight of the total weight of the composition.
[0051] In the present invention, the hydrophobic fumed silica is
used in a much smaller amount (0.1 to 2% by weight of the
microgranules). Furthermore, it is not used as an anti-tacking
agent but as a hydrophobising agent.
[0052] In the present invention, the applicant has discovered that
introducing small quantities (0.1 to 2% by weight of the
microgranules) of such a hydrophobic fumed silica in the sustained
release layer, allow to obtain sustained release microgranules
which are less sensitive to pH conditions than other formulations
of the prior art. Indeed, dissolution profile of microgranules
according to the invention is less subject to change when pH
conditions are varying as shown in the example 3 and FIG. 2).
[0053] Surprisingly, the microgranules of the invention exhibit the
advantage of lacking a protective film coating the
sustained-release layer. In addition, it is not necessary to
subject the microgranules to a very lengthy heat treatment (longer
than 24 hours) as in the prior art to improve the structure of the
sustained-release layer.
[0054] This surprising effect may be due to the fact that
hydrophobic fumed silica has a high specific surface area (BET)
thereby providing an excellent protection against water, even with
low quantites.
[0055] The acrylic copolymer represents advantageously 5 to 15% by
weight of the microgranules.
[0056] The relative mass proportion of the morphine sulphate and of
the neutral support grain is preferably between 40/60 and
60/40.
[0057] The morphine sulphate represents advantageously 30 to 40% by
mass of the microgranules.
[0058] The neutral support grain coated with the active layer
contains preferably 40% to 50% of morphine sulphate and 10 to 20%
of at least one pharmaceutically acceptable binder. Preferably, the
active layer further contains a conventional lubricant.
[0059] The sustained-release layer contains preferably a
plasticizer and a lubricant. The plasticizer and the lubricant are
used in conventional amounts and chosen from the pharmaceutically
acceptable plasticizers and lubricants which are well known to
persons skilled in the art. The plasticizer is for example
triethylcitrate. The lubricant is for example talc.
[0060] Advantageously, the lubricant is used both in the active
layer and in the sustained-release layer.
[0061] The composition of the microgranules according to the
invention is advantageously as follows: TABLE-US-00001 Morphine
sulphate 30-42% Neutral support grain 30-40% Binder 10-20%
Methacrylic acid copolymer 5-15% Plasticizer 1-2.5% Lubricant 1-4%
Hydrophobic fumed silica 0.2-1%
[0062] More preferably, The composition of the microgranules
according to the invention is as follows: TABLE-US-00002 Morphine
sulphate 30-40% Neutral support grain 30-40% Binder 10-20%
Methacrylic acid copolymer 5-15% Plasticizer 1-2.5% Lubricant 2-4%
Hydrophobic fumed silica 0.2-1%
[0063] The most preferred composition of the microgranules
according to the present invention is: TABLE-US-00003 Morphine
sulphate 37.56% Neutral support grain (sugar 38.03% sphere) Binder
(HPMC) 13.18% Methacrylic acid copolymer 7.08% (Eudragit .RTM. RS
30D) Plasticizer (Triethylcitrate) 1.42% Lubricant (Talc) 2.38%
Hydrophobic fumed silica 0.35% (Aerosil .RTM. R972)
[0064] The neutral support grains have a particle size of between
200 and 1000 .mu.m, preferably of between 400 and 600 .mu.m.
[0065] The present invention also concerns a process for preparing
the microgranules described above. This process is carried out
entirely in aqueous medium. It comprises a step of spraying the
active principle in aqueous solution and/or suspension
(drug-layering solution and/or suspension) on neutral support
grains and a step of coating the resulting product with one or more
methacrylic copolymer, still in aqueous solution and/or
suspension.
[0066] The granules are advantageously prepared in a perforated
rotary turbomixer or a fluidized air bed. The spraying of the
drug-layering solution and/or suspension and the coating of the
coating solutions and/or suspensions is preferably continuous and
followed by a drying step at a temperature of between 30 and
65.degree. C.
[0067] It is not necessary for the granules according to the
invention to undergo a heat treatment for the structure of the film
to be satisfactory.
[0068] The present invention finally concerns the pharmaceutical
compositions containing the microgranules of the invention
optionally obtained according to the process described above.
[0069] Said pharmaceutical composition may be in the form of
capsules containing said microgranules or in the form of tablets
prepared from said microgranules.
[0070] Said pharmaceutical composition has substantially no food
effect on the bioavailability of morphine sulfate.
[0071] The following examples illustrate the invention without
limiting the scope thereof.
[0072] The percentages are expressed by weight.
[0073] FIG. 1 represents the mean of the in vitro dissolution
profile of four formulations according to the invention (curves 1,
2, 3 and 4). The percentage of dissolution is on the x-axis and the
time (hours) on the y-axis.
[0074] FIG. 2 represents the influence of pH condition on the in
vitro dissolution profile of microgranules according to the present
invention (curve (.smallcircle.) is water+NaCl 0.1M; curve
(.DELTA.) is pH 6.8+NaCl 0.1M ; curve (X) is pH 4.5+NaCl 0.1M;
curve (*) is pH 1.2+NaCl 0.1M).
[0075] FIG. 3 represents plasma concentrations of morphine
following a single dose of ZOMORPH 60 mg in fasting (.box-solid.)
or fed (.tangle-solidup.) conditions and of SKENAN LP 60 mg in
fasting condition (.circle-solid.)
[0076] FIG. 4 represents plasma concentrations of
morphine-6-glucuronide following a single dose of ZOMORPH 60 mg in
fasting (.box-solid.) or fed (.tangle-solidup.) conditions and of
SKENAN LP 60 mg in fasting condition (.circle-solid.)
EXAMPLE 1 (Batch A)
Preparation of the Granules
[0077] A drug-layering solution containing 74.7% of purified water,
6.6% of Pharmacoat 603.RTM. (hydroxy-propylmethylcellulose) and
18.7% of morphine sulphate is prepared. Stirring is maintained
until the solution is homogeneous, and then throughout the
emplacing.
[0078] Neutral support grains (400 to 600 .mu.m) are placed in a
rotating perforated turbomixer. The emplacing of the active
principle on the neutral grains is carried out by continuous
spraying of the emplacing solution described above, with a support
of hot air at a temperature of between 35 and 60.degree. C.
[0079] The mass of the active microgranules obtained is sieved
through a screen of mesh size ranging from 0.71 to 0.85 mm.
[0080] A coating solution is prepared by successively adding
Eudragit.RTM. RS 30 D (an aqueous dispersion containing 30% of
poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl
methacrylate chloride) 1:2:0.1), triethyl citrate, talc and
Aerosil.RTM. R 972 (hydrophobic fumed silica) to the purified
water. Stirring of the suspension is maintained until the mixture
is homogeneous, and then throughout the coating.
[0081] The active microgranules are placed in a rotating perforated
turbomixer and continuously sprayed with the coating suspension
described above, at a temperature of 30.degree. C. The mass of
microgranules obtained is sieved through a screen of mesh size
ranging from 0.8 to 1 mm.
[0082] This step can be repeated one or more times. The granules
are then lubricated with an amount of talc which is equivalent to
0.5% of the coated mass obtained.
[0083] The microgranules obtained have the following composition:
TABLE-US-00004 Batch A Amount % mg by mass Morphine sulphate 12.5
37.3 Neutral grains 12.5 37.3 Pharmacoat 603 .RTM. 4.4 13.0
Eudragit RS 30 D .RTM. 2.7 8.2 Triethylcitrate 0.5 1.6 Talc 0.7 2.1
Aerosil R972 .RTM. 0.1 0.4 Content (mg/g) 371
In vitro Dissolution Tests
[0084] The previously obtained microgranules are dissolved in 500
ml of water at 37.degree. C. in a machine with paddles revolving at
100 revolutions/min. The U.V. absorbance reading is measured at two
wavelengths, 285 nm and 310 nm. TABLE-US-00005 Batch A Time (hours)
1 2 3 4 5 6 7 8 9 10 15 20 Percentage 6.6 20.8 38.8 55.8 69.9 79.9
86.3 90.7 93.2 94.8 97.8 98.3 of dissolution
[0085] The in vitro dissolution profile of Batch A is represented
by Curve 3 of the figure.
Tests for Stability of the Gelatin Capsules of Microgranules (Batch
A1)
[0086] The stability properties of the microgranules which have
been previously obtained and packaged in size 3 gelatin capsules
each containing 60 mg of morphine sulphate are measured under
storage conditions of at 25.degree. C. and 60% relative humidity,
for 24 months.
[0087] It is observed that the water content of the microgranules
is stable at 6% on average, that the appearance of the gelatin
capsules is satisfactory and that the active principle titre is in
compliance and homogeneous.
[0088] The dissolution profiles are fairly stable over time.
[0089] After 24 months, the content of pseudomorphine and
ampomorphine impurities is in compliance with standards (i.e. less
than 0.5%).
[0090] The stability of the same gelatin capsules is also studied
for 6 months at 40.degree. C. and 75% relative humidity.
[0091] It is observed that the active principle titre is in
compliance and homogeneous. The dissolution is stable at 6 months.
Moreover, the water content is stable.
[0092] The stability results are presented in the following tables.
TABLE-US-00006 Percentage of dissolution in vitro (Batch A1)
Storage conditions 25.degree. C., 60% RH Hours T0 1M 3M 6M 9M 12M
18M 24M 1 7.8 7.4 7.7 7.1 6.1 6.5 6.4 5.5 2 21.6 21.9 23.2 22.4
18.9 19.7 20.1 17.0 4 55.2 57.3 60.2 58.1 52.7 53.1 52.9 50.6 6
78.9 81.7 83.7 81.0 77.8 76.1 73.4 76.1 8 89.9 93.4 93.8 90.8 90.1
86.7 81.9 88.5 12 96.0 100.2 98.8 95.9 97.5 93.0 86.2 95.4 16 96.4
100.6 99.8 96.9 98.7 94.6 86.9 95.4
[0093] TABLE-US-00007 Percentage of dissolution in vitro (Batch A1)
Storage conditions 40.degree. C., 75% RH Hours T0 1M 2M 3M 6M 1 7.8
6.0 5.9 6.1 6.3 2 21.6 19.8 19.7 19.7 21.0 4 55.2 57.1 57.3 57.0
58.7 6 78.9 83.1 81.8 81.9 83.2 8 89.9 94.3 92.1 92.9 94.0 12 96.0
100.1 97.5 98.7 100.3 16 96.4 101.5 98.0 99.6 102.4
[0094] TABLE-US-00008 Active principle content (Batch A1) T0 1M 2M
3M 6M 9M 12M 18M 24M 25.degree. C., mg/gelatin 59.0 58.4 -- 56.7
59.3 58.1 58.0 57.6 57.0 60% RH capsule Variation -- -1.0 -- -3.9
0.5 -1.5 -1.7 -2.4 -3.4 in % 40.degree. C., mg/gelatin 59.0 57.4
58.7 57.5 58.4 -- -- -- -- 75% RH capsule Variation 0 2.7 -0.5 -2.5
-1.0 -- -- -- -- in %
[0095] TABLE-US-00009 Water content (Karl Fisher) (Batch A1) T0 1M
2M 3M 6M 9M 12M 18M 24M 25.degree. C., 6.1% 5.9% -- 5.9% 6.1% 4.8%
6.1% 6.1% 5.9% 60% RH 40.degree. C., 6.1% 6.6% 6.0% 5.3% 6.8% -- --
-- -- 75% RH
Pharmacokinetic Study No. 1.
[0096] The bioavailability of gelatin capsules of Batch A1 is
compared to that of a reference morphine formulation (containing a
dose of 30 mg), after 7-day repeated dose administration in 24
healthy volunteers. TABLE-US-00010 Plasmatic concentration of
Morphine 6(glucuronide) morphine Gelatine Gelatin capsules of
Reference capsules of Reference microgranules (Batch microgranules
(Batch S (Batch A1) S 1079) (Batch A1) 1079) 60 mg 30 mg 60 mg 30
mg C.sub.max (ng/ml)* 18.3 12.8 77.6 59.2 C.sub.min (ng/ml)** 7.9
6.8 31.0 30.4 T.sub.max (h)* 5 5 6 3 *means **medians
[0097] It is noticed that at Day 7, the plasmatic concentrations of
morphine from the gelatin capsules of the invention at 24 hours are
higher than the plasmatic concentrations from the reference at 12
hours (+1.1 ng/ml), which is a sign of good cover over 24
hours.
Pharmacokinetic Study No. 2
[0098] The bioavailability of gelatin capsules of Batch A2 is
compared to that of a reference morphine formulation, after
administration of a single dose of 60 mg in healthy volunteers.
[0099] The gelatin capsules of Batch A2 are of size 3 and contain a
dose of 60 mg of morphine sulphate per gelatin capsule.
TABLE-US-00011 Plasmatic concentration of morphine 6(glucuronide)
morphine Gelatine Gelatin capsules of Reference capsules of
Reference microgranules of the microgranules of the of the prior
art of the prior art invention (Batch invention (Batch (Batch A2) S
1055) (Batch A2) S 1055) C.sub.max (ng/ml)* 6.97 13.16 64.0 114.8
C.sub.min (ng/ml)** 6.0 2.0 5.0 3.0 T.sub.max (h)* 218.9 186.9
1471.49 1536.5 *means **medians
[0100] The formulation of the invention and the reference are
bioequivalent over the area under the curve parameters, which
demonstrates an equivalent absorption of both products. Conversely,
the release profile of the formulation of the invention appears
more delayed than the reference, with a later T.sub.max and a lower
C.sub.max.
EXAMPLE 2 (Batches B, C and D)
Preparation of the Granules
[0101] Granules of the following composition are prepared according
to the protocol of Example 1. TABLE-US-00012 Batch B Batch C Batch
D Amount % by Amount % by Amount % by (kg) mass (kg) mass (g) mass
Morphine sulphate 13.7 35.1 31.0 40.9 728.8 41.9 Neutral grains
15.4 39.7 26.0 34.3 573.7 33.0 Pharmacoat 603 .RTM. 4.8 12.3 10.8
14.3 204.1 11.7 PEG 4000 -- -- -- -- 51.0 2.9 Eudragit RS 30 D
.RTM. 3.2 8.2 5.1 6.7 126.5 7.3 Triethylcitrate 0.6 1.6 1.0 1.3
24.9 1.4 Talc 1.0 2.6 1.7 2.2 24.9 1.4 Aerosil .RTM. R972 0.1 0.40
0.2 0.3 6.2 0.4 Content (mg/g) 371.3 368.5 397.9
[0102] Batch B is prepared as in Example 1 in a Glatt perforated
turbomixer, whereas Batches C and D are respectively prepared in an
O'Hara perforated turbomixer or in a Laf Huttlin.
[0103] Tests for in vitro Dissolution of the Microgranules
TABLE-US-00013 Time (h) 1 2 3 4 5 6 7 8 9 10 15 20 24 % of Batch B
11.0 29.0 46.2 60.4 71.5 79.9 86.0 90.3 93.4 95.5 98.7 -- --
dissolution Batch C 5.3 22.2 42.1 58.5 71.6 81.6 88.5 93.0 95.9
97.8 100.4 -- -- Batch D 7.1 20.2 34.8 47.9 58.7 67.4 74.5 80.2
85.0 88.7 97 99.6 100.5
[0104] The in vitro dissolution profiles of Batches B, C and D are
represented by curves 2, 1 and 4, respectively, of the figure.
Tests for Dissolution of the Gelatin Capsules of Microgranules
[0105] The gelatin capsules of Batches B2, B1, D1 and C1 contain a
dose of 60 mg of morphine sulphate. TABLE-US-00014 Time (h) 1 2 3 4
5 6 8 10 12 14 % dissolution Batch B1 15.2 34.1 51.1 64.8 75.3 83.2
93.3 -- 100.4 -- Batch C1 6.5 24.1 -- 60.3 -- 81.9 92.2 96.3 97.4
98.5
[0106] Tests for Stability at 25.degree. C., 60% RH of Gelatin
Capsule Batch B2 (Microgranules of Batch B) TABLE-US-00015 T0 15 D
1M 2M 3M 6M Water -- 5.50% 6.00% 6.16% 6.00% 6.02% content (%)
Dissolution (hours) 1 21.2 19.2 14.7 6.9 15.6 16.6 2 45.1 43.1 29.5
22.1 35.7 37.9 3 63.5 62.0 42.9 36.7 53.3 55.8 4 76.1 75.7 54.4
49.4 67.1 69.3 5 85.2 85.2 64.0 60.1 77.3 79.3 6 91.3 91.6 71.9
68.8 84.8 86.5 7 95.5 95.7 78.2 76.0 90.3 91.5 8 98.2 98.4 83.6
81.5 94.1 95.0 12 102.2 102.9 96.3 93.1 101.2 101.0
[0107] Tests for Stability at 40.degree. C., 75% RH of Gelatin
Capsules Batch D1 (Microgranules of Batch D) TABLE-US-00016 T0 15 D
1M 2M 3M 6M Water 6.19% 6.40% 6.29% 6.20% 6.30% 6.38% content (%)
Dissolution (hours) 1 11.8 11.9 12.2 12.6 11.6 12.5 2 28.7 28.7
31.0 33.1 31.6 34.3 3 45.8 45.2 48.1 50.6 49.1 51.8 4 59.3 58.4
61.2 63.9 62.5 64.9 5 69.8 68.8 71.5 74.1 72.8 75.2 6 77.9 77.1
79.6 82.1 80.7 83.0 8 88.5 88.8 90.3 91.9 90.8 88.7 10 94.2 95.5
95.4 96.0 95.0 95.7 12 97 98.7 97.6 97.5 96.7 97.1
EXAMPLE 3
pH Independency
[0108] The aim of this example was to analyse the dissolution
behavior of microgranules according to the present invention in
dissolution media exhibiting different pH.
[0109] Four different pH conditions were tested (Water; pH 6.8; pH
4.5 and pH 1.2). The dissolution results are presented on the
following FIG. 2.
[0110] In order not to be influenced by the nature of the different
ions used in the buffer solution (chloride, acetate, phosphate,
citrate . . . ), all the media were saturated with NaCl, used at a
concentration of 0.1 M.
[0111] Sustained release microgranules of morphine sulfate were
manufactured according to the method described in example 1.
[0112] Dissolution measurements were performed using the Paddle
method at 100 rpm, at 37.degree. C. in a 500 mL media. Each
measurement was repeated 6 times.
[0113] These microgranules have the following composition:
TABLE-US-00017 Amount Material (kg) % by mass Morphine Sulfate
51.87 38.08 Neutral cores #30 52.00 38.17 HPMC 603 18.20 13.36
Eudragit .RTM. RS30D (v.s) 8.84 6.49 Triethyl citrate 1.76 1.29
Aerosil .RTM. R972 0.43 0.32 Talc 3.13 2.30 Purified water 238.49
N/A Total dry mass 136.23 100.0
FIG. 2 shows that microgranules according to the invention present
a dissolution profile independent from the pH conditions of the
dissolution medium.
EXAMPLE 4
Reduced "Food-Effect"
[0114] a) Aim of the Study
[0115] This example presents pharmacokinetic studies realized on
the microgranules according to the present invention in order to
determine the influence of food on the bioavailability of morphine
sulfate.
[0116] b) Preparation of the Formulations
[0117] Five capsules of different strengths, each filled with
morphine sulfate sustained release microgranules prepared according
to the process described in example 1 (20 mg, 40 mg, 60 mg, 120 mg
and 200 mg) were prepared. The percentage composition of each
strength is the same.
[0118] The relative proportion of each constituents is indicated in
the following table: TABLE-US-00018 Name of Capsule ingredients
Amount (mg) % Strengh 20 40 60 120 200 formula Function Morphine 20
40 60 120 200 37.55 Active sulfate ingredient Sucrose 15.59 31.185
46.78 93.555 155.925 29.28 Ingredient of core granules Maize starch
4.66 9.315 13.97 27.945 46.575 8.75 Ingredient of core granules
Hypromellose 7.00 14.00 21.05 42.10 70.20 13.18 Binder Eudragit
.RTM. RS 3.80 7.55 11.30 22.70 37.70 7.08 Coating 30D* agent
Triethyl 0.75 1.50 2.30 4.55 7.60 1.42 Plasticiser citrate Talc
1.25 2.50 3.80 7.55 12.70 2.38 Lubricant Hydrophobic 0.20 0.40 0.60
1.20 1.90 0.35 Hydrophobic fumed silica agent Purified water** NQ
NQ NQ NQ NQ NQ Solvent Total mass 53.25 106.45 159.80 319.60 532.60
100.00 (*Quantities expressed as dry material; **This solvent is
eliminated during manufacture; NQ: not quantified)
[0119] c) Pharmacokinetic Study
[0120] This study was conducted in two different conditions: when
microgranules are taken with food ("fed state") and without food
("fast state") in order to determine the influence of food intake
on pharmacokinetic properties of the microgranules according to the
present invention ("food effect").
[0121] This study was conducted with a single dose of
sustained-release morphine sulphate. Morphine and its metabolite,
morphine-6-glucuronide, were assayed by Algorithme Pharma
(Montreal, Canada) using HPLC with a Limit of Quantification of 1
and 2.5 ng/mL for morphine and morphine-6-glucuronide
respectively.
[0122] The pharmacokinetic parameters were compared by ANOVA except
median of Tmax, which were compared by Friedman's test. The 90%
confidence interval of the ratio of log transformed geometric means
of test/reference were calculated for AUCT, AUC.infin. (single
administrations) and Cmax.
[0123] The statistical analysis of each pharmacokinetic parameter
was conducted using the Kinetic program (version 1.02). This
software consists in an in-house application developed, tested and
verified by the CRO Algoritme Pharma.
[0124] Pharmacokinetics data obtained for this study in fasting
state versus fed state are shown in the following table:
TABLE-US-00019 Fast/fed ratio of log- Fast transformed mean Fed
mean geometric Parameter (CV %) (CV %) p*** mean (90% CI) Morphine
Cmax (ng/mL) 10.76 11.88 NS 90 (32.41) (30.90) (80-100) Tmax (hour)
5.50* 5.50* NS** -- (4-8) (5-9) AUCT (ng h/mL) 177.78 169.54 NS 104
(24.33) (21.17) (98-111) AUC.infin. (ng h/mL) 229.45 218.98 NS 105
(21.17) (20.40) (98-112) Kel (hour.sup.-1) 0.0377 0.0412 NS --
(23.86) (43.15) t1/2el (hour) 19.62 19.79 NS -- (29.25) (42.55)
Morphine-6-glucuronide Cmax (ng/mL) 65.01 80.68 <0.01 81 (24.70)
(30.07) (73-90) Tmax (hour) 6.00* 6.00* NS** (4-9) (5.50-9) AUCT
(ng h/mL) 1081.44 1098.09 NS 98 (19.51) (13.10) (93-103) AUC.infin.
(ng h/mL) 1245.34 1343.39 NS 93 (18.63) (24.01) (87-100) Kel
(hour.sup.-1) 0.0467 0.0442 NS (27.24) (49.75) t1/2el (hour) 16.05
22.84 NS (30.99) (97.39)
[0125] The pharmacokinetics profiles obtained in fed state and fast
state for morphine sulphate and morphine-6-glucuronide for the
microgranules according to the invention (Zomorph.RTM. 60 mg) are
represented with the pharmacokinetic profile of one sustained
release formulation of the prior art (Skenan.RTM. LP 60 mg) on
FIGS. 3 and 4 respectively.
[0126] These data show that the concomitant administration of a
high fat content meal ("fed state") does not modify the
pharmacokinetic profile of morphine, the 90% confidence limit of
the fast versus fed ratio of mean AUCT, AUC.infin. and C.sub.max
values being in the 0.80-1.25 bioequivalence interval.
[0127] Regarding the metabolite, fast and fed administrations
provide equivalent AUC and median T.sub.max are similar.
[0128] In spite of the moderately higher mean Cmax value induced by
concomitant food absorption, one can conclude that overall,
microgranules according to the invention have a pharmacokinetic
profile that is not clinically significantly affected by food and
that this microgranules may be equally administered with or without
food.
* * * * *