U.S. patent application number 10/067451 was filed with the patent office on 2002-08-01 for pharmaceuticals formulation.
Invention is credited to Knott, Trevor John, Leslie, Stewart Thomas, Malkowska, Sandra Theresc Antoinette, Miller, Ronald Brown, Mohammad, Hassan, Prater, Derek Allan.
Application Number | 20020102300 10/067451 |
Document ID | / |
Family ID | 10781098 |
Filed Date | 2002-08-01 |
United States Patent
Application |
20020102300 |
Kind Code |
A1 |
Miller, Ronald Brown ; et
al. |
August 1, 2002 |
Pharmaceuticals formulation
Abstract
A solid, oral, controlled release pharmaceutical dosage form
comprising a pharmaceutically active ingredient having a solubility
in water of greater than 1 gm in 250 ml water at 25.degree. C., the
active ingredient dispersed in a matrix wherein the dosage form
provides, as tested by the Ph. Eur. Basket method at 100 rpm 900 ml
aqueous buffer (pH 6.5) containing 0.05% w/w Polysorbate 80 at
37.degree. C., an essentially zero order rate of release of the
pharmaceutically active ingredient over a period of 8 hours, the
amount of pharmaceutically active ingredient released over eight
hours being in the range of 15% to 45%, and when tested in a group
of at least five healthy humans the median tmax, based on blood
sampling at half hourly intervals, is in the range of from about
2.5 to about 6 hours, and the ratio of mean Cmax to the mean plasma
level at 24 hours is in the range of about 1.5 to about 3.5.
Inventors: |
Miller, Ronald Brown;
(Basle, CH) ; Leslie, Stewart Thomas; (Cambridge,
GB) ; Malkowska, Sandra Theresc Antoinette; (Ely,
GB) ; Prater, Derek Allan; (Milton, GB) ;
Knott, Trevor John; (Bishops Stortford, GB) ;
Mohammad, Hassan; (Haslingfield, GB) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Family ID: |
10781098 |
Appl. No.: |
10/067451 |
Filed: |
February 5, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10067451 |
Feb 5, 2002 |
|
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|
09043321 |
Jul 27, 1998 |
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Current U.S.
Class: |
424/458 ;
424/469; 514/282 |
Current CPC
Class: |
A61K 9/1617 20130101;
A61K 9/2095 20130101; A61K 31/485 20130101; A61K 9/1641 20130101;
A61K 9/2013 20130101 |
Class at
Publication: |
424/458 ;
424/469; 514/282 |
International
Class: |
A61K 009/54; A61K
009/26; A61K 031/485 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 22, 1995 |
GB |
9519363.7 |
Claims
1. A solid, oral, controlled release pharmaceutical dosage form
which comprises a pharmaceutically active ingredient having a
solubility in water of greater than 1 gm in 250 ml water at
25.degree. C. dispersed in a matrix and wherein the dosage form
when tested by the Ph. Eur Basket method at 100 rpm 900 ml aqueous
buffer (pH 6.5) containing 0.05% w/w Polysorbate 80 at 37.degree.
C. has an essentially zero order rate of release of the
pharmaceutically active ingredient over a period of 8 hours, the
amount of pharmaceutically active ingredient released over eight
hours being in the range of 15% to 45%, and when tested in a group
of at least five healthy humans the median tmax, based on blood
sampling at half hourly intervals, is in the range of from 2.5 to 6
hours, and the ratio of mean Cmax to the mean plasma level at 24
hours is in the range of 1.5 to 3.5.
2 A pharmaceutical dosage form according to claim 1, wherein the
median tmax is in the range from 2.5 to 3.5 hours
3 A pharmaceutical dosage form, according to any one of the
preceding claims which has a W.sub.50 in the range from 15 to 35
hours, preferably from 20 to 30 hours, when tested in vivo as set
forth in claim 1.
4 A pharmaceutical dosage form according to claim 1, 2 or 3,
wherein the matrix comprises a mixture of an hydrophobic, fusible
material having a melting point of greater than 40.degree. c and a
hydrophilic, organic, polymeric fusible wicking agent
5 A pharmaceutical dosage form according to any one of claim 4
wherein the weight ratio of hydrophobic fusible material to
hydrophilic, organic polymeric wicking agent in the said mixture is
in the range from 8:1 to 16.1
6 A pharmaceutical dosage form according to any one of the
preceding claims, in which the pharmaceutically active ingredient
is a pharmaceutically acceptable salt of morphine, preferably
morphine sulphate or morphine hydrochloride.
7 A pharmaceutical dosage form according to claim 5, which is
suitable for once a day dosing.
8 A pharmaceutical dosage form according to any one of the
preceding claims, in the form of a tablet or a capsule containing
multiparticulates.
9 A process for preparing a dosage form according to any one of the
preceeding claims comprising: (a) mechanically working in a high
shear mixer a mixture of hydrophobic fusible binder and a minor
amount of an organic, fusible, polymeric material which in the
finished dosage form is capable of functioning as a wicking agent
at a speed and temperature at which the binder melts or softens and
the mixture forms agglomerates; (b) extruding the agglomerates
whereby the extrudate is obtained as extruded pieces or an elongate
extrudate is formed into pieces; (c) continuing mechanically
working the pieces in a high shear mixer; and (d) continuing
mechanically working with additional binder material at a
temperature and speed at which the additional binder melts or
softens.
10 A process according to claim 8, wherein in stage (d) the
additional binder melts or softens and binds with the particles
11 A solid, oral, controlled release pharmaceutical dosage form
which comprises a pharmaceutically active ingredient having a
solubility in water of greater than 1 gm in 250 ml water at
25.degree. C. dispersed in a matrix, the dosage form being
obtainable by a process as defined in claim 9 or claim 10.
Description
[0001] This invention relates to a solid, oral, controlled release
pharmaceutical dosage form.
[0002] The literature is replete with examples of controlled
release pharmaceutical preparations for oral usage.
[0003] PCT/SE93/00642 describes an oral morphine preparation having
essentially complete bioavailability and, for the major part of the
dissolution, an essentially zero order and essentially pH
independent release of morphine for a period of at least 8 hours,
in the form of a tablet having a core containing morphine sulphate
and a buffering agent, the tablet core being coated with a
diffusion membrane comprising a terpolymer of vinyl chloride,
vinylacetate and vinylalcohol.
[0004] EP 0377518 describes a sustained release pellet composition
containing a core element including at least one active ingredient
of high solubility, and a core coating for the core element which
is partly soluble at a highly acidic pH to provide a slow rate of
release of active ingredient and wherein the active ingredient is
available for absorption at a relatively constant faster rate in
the intestines over an extended period of time such that blood
levels are maintained within the therapeutic range over an extended
period of time. A typical embodiment in this patent publication is
a morphine sulphate containing preparation suitable for twice a day
dosing obtained by a process which comprises coating core seeds
with the active ingredient and then coating the resulting core
seeds with a controlled release coating material containing ethyl
cellulose, an acrylic co-polymer, a plasticiser and a detackifying
agent using a solution of the aforesaid substances in an organic
solvent.
[0005] PCT/SE94/00264 describes controlled release preparations
containing a salt of morphine, comprising a number of core seeds
coated with a barrier membrane. In the Example a conventional
granulation is carried out with morphine hydrochloride, lactose and
microcrystalline cellulose. The resulting morphine hydrochloride
cores are then coated with a controlled release membrane containing
hydroxypropyl methyl cellulose, ethyl cellulose and plasticisers
using a solution of these substances in a mixed solvent of ethanol
and methyl isobutyl ketone.
[0006] PCT/SE93/0025 describes a process for manufacturing
sustained release pellets comprising pelletizing a mixture of a
drug in finely divided form and a binder consisting of one or more
water-insoluble wax-like binder substances with a melting point
above 40.degree. C., the pelletization being performed by
mechanically working the mixture in a high shear mixer under the
input of a sufficient amount of energy for the binder to melt and
pelletization to take place. In a typical example in this patent
publication paracetamol is pelletized using glycerol monostearate
and optionally a lipophilic binder substance such as stearyl
alcohol, triglyceride DS, Beeswax or microcrystalline wax, together
with calcium hydrogen phosphate as a filler.
[0007] EP 0636370 describes a sustained release pharmaceutical
formulation containing morphine which is suitable for
administration on a once daily basis. The dosage form is typically
in the form of multiparticulates obtained by mechanically working
in a high shear mixer a pharmaceutically acceptable morphine salt
and a hydrophobic fusible carrier or diluent having a melting point
from 35.degree. C. to 150.degree. C. and optionally a release
control component comprising a water-soluble fusible material or a
particulate, soluble or insoluble organic or inorganic material, at
a speed and energy input which allows the carrier or diluent to
melt or soften whereby it forms agglomerates, breaking down the
agglomerates to give controlled release particles and optionally
continuing mechanically working optionally with the addition of a
low percentage of the carrier or diluent.
[0008] Embodiments are described in EP 0636370 in which the mean
Cmax obtained in a group of five health volunteers when dosed at 60
mg of morphine sulphate is approximately 8 ng/ml and the W.sub.50
value for morphine is approximately 8 6 hours.
[0009] The mean plasma curve includes a relatively high peak of
about 10 ng/ml at about 3 hours after dosing which tails off
rapidly to reach a fairly stable, but declining level about 12
hours after dosing, with the ratio of mean Cmax to the mean plasma
level at 24 hours of about 4 5.
[0010] According to the present invention there is provided a
solid, oral, controlled release pharmaceutical dosage form which
comprises a pharmaceutically active ingredient having a solubility
in water of greater than 1 gm in 250 ml water at 25.degree. C.
dispersed in a controlled release matrix, wherein the dosage form
when tested by the Ph. Eur. Basket method at 100 rpm 900 ml aqueous
buffer (pH 6.5) containing 0 05% w/w Polysorbate 80 at 37.degree.
C. has an essentially zero order rate of release of the
pharmaceutically active ingredient over a period of 8 hours, the
amount of pharmaceutically active ingredient released over eight
hours being in the range of 15% to 45% by weight, and when tested
in a group of at least five healthy humans the median tmax, based
on blood sampling at half hourly intervals, is in the range of from
2.5 to 6 hours, and the ratio of mean Cmax to the mean plasma level
at 24 hours is in the range of 1 5 to 3.5.
[0011] Polysorbate 80 is described in entry 7559 at page 1207 in
Merck Index. Eleventh Edition 1989 published by Merck & Co.
Inc. It is an oleate ester of sorbitol and its anhydrides
copolymerised with approximately 200 moles of ethylene oxide for
each mole of sorbitol and sorbitol anhydrides.
[0012] A preferred dosage form in accordance with the invention has
a median tmax in the range from 2.5 to 3.5 hours.
[0013] In a preferred embodiment the dosage form according to the
present invention has a mean W.sub.50 in the range from 15 to 35
hours, more preferably 20 to 30 hours when tested in vivo as set
forth above.
[0014] In preferred embodiments the matrix comprises an
hydrophobic, fusible material having a melting point of greater
than 40.degree. C. and may also include a wicking agent which may
be a hydrophilic, organic, polymeric, fusible substance or a
particulate soluble or insoluble inorganic material.
[0015] In embodiments of the process of the invention described
below it is believed the resulting matrix comprises an inner region
which is a mixture comprising an hydrophobic, fusible material and
active ingredient and preferably wicking agent surrounded by a
contiguous, outer, mantle region comprising an hydrophobic, fusible
material have a reduced concentration of, or being substantially
free from, said pharmaceutically active ingredient and wicking
agent, though the invention is not limited to this theory.
[0016] The pharmaceutically active ingredient is preferably present
in an amount suitable for twice or once a day dosing. The preferred
active ingredient is morphine or a pharmaceutically acceptable salt
of morphine, preferably morphine sulphate or morphine hydrochloride
and is preferably present in an amount suitable for once a day
dosing. The dosage forms may preferably contain 30 to 400 mg of
morphine as pharmaceutically acceptable salt.
[0017] The dosage form of the invention is conveniently in the form
of a tablet or a capsule containing multiparticulates.
[0018] Although morphine and pharmaceutically acceptable morphine
salts have been mentioned above as preferred active ingredients,
other suitable water soluble active ingredients include
hydromorphone hydrochloride, diamorphine hydrochloride tramadol
hydrochloride and dihydrocodeine tartrate.
[0019] Preferably the weight ratio of hydrophobic, fusible material
to wicking agent in the matrix or inner region thereof is in the
range from 8 1 to 16.1 preferably 8 1 to 12.1.
[0020] Suitably the weight ratio of hydrophobic, fusible material
in the said mixture to hydrophobic, fusible material in the mantle
region is in the range of from 3 1 to 12.1.
[0021] Suitable hydrophobic, fusible materials are natural or
synthetic waxes, oils, fatty acid glycerides or other esters for
example hydrogenated vegetable oil or castor oil and suitable
hydrophilic, organic, fusible wicking agents include polyethylene
glycols (PEGs) of various molecular weights e.g. 1,000 to 20,000
preferably 4,000 to 10,000 and suitable particulate inorganic
wicking agents include dicalcium phosphate and lactose. It is
preferred to use an hydrophilic fusible, organic polymeric as
wicking agent.
[0022] The dosage forms of the present invention have a
significantly lower Cmax and greater W.sub.50 than dosage forms
made according to the method described in EP 636370 whilst
surprisingly retaining an advantageously short median tmax of 2.5
to 6 hours
[0023] Dosage forms of the present invention can be prepared by a
process comprising:
[0024] (a) mechanically working in a high shear mixer a mixture of
hydrophobic, fusible binder and a minor amount of an organic,
fusible, polymeric material which in the finished dosage form is
capable of functioning as a wicking agent at a speed and
temperature at which the binder melts or softens and the mixture
forms agglomerates,
[0025] (b) extruding the agglomerates whereby the extrudate is
obtained as extruded pieces or an elongate extrudate is formed into
pieces,
[0026] (c) continuing mechanically working the pieces in a high
shear mixer suitably until particles of reproducible in vitro
release rate when tested according to the in vitro method set forth
above have been achieved; and
[0027] (d) continuing mechanically working with additional binder
material at a temperature and speed at which the additional binder
melts or softens and binds with the particles
[0028] A preferred process uses identical hydrophobic, fusible
material in stage (d) as in stage (a)
[0029] Preferably in stage (a) the weight ratio of hydrophobic,
fusible material to wicking agent, preferably hydrophobic, organic,
polymeric wicking agent, used is in the range from 8:1 to 16:1
preferably 8 1 to 12.1.
[0030] Preferably the weight ratio of hydrophobic, fusible material
used in stage (a) to hydrophobic, fusible material use in stage (d)
is in the range from 3 1 to 12.1 preferably 3 1 to 7:1.
[0031] The resulting multiparticulates may be sieved or otherwise
size selected and filled into capsules e.g. hard gelatine capsules,
or may be compressed into tablets. Usually the particles are of a
size 0.5 mm to 3.0 mm and a spherical or spheroidal.
[0032] The higher shear mixer may be one conventionally used in the
pharmaceutical formulation art and we have found satisfactory
results can be achieved using a Collette Gral 75 or equivalent
mixer.
[0033] Generally in stage (a) the mixture is processed until a bed
temperature above 40.degree. C. is achieved and the mixture softens
but does not melt and the resulting mixture acquires a cohesive
granular texture, with particles ranges from 0.5 to 3.0 mm to fine
powder in case of non-aggregated material. The mixture may be
processed until it has the appearance of agglomerates which, upon
cooling below 40.degree. C. have structural integrity and
resistance to crushing between the fingers. At this stage the
agglomerates are of an irregular size, shape and appearance. The
resulting mass is then extruded.
[0034] Extrusion may be carried out by passing the agglomerates
through a conventional extruder e.g. a Caleva extruder. An extruder
may be used fitted with gears with suitably sized holes to provide
pieces of desired size.
[0035] Usually the extrusion is though orifices having a diameter
of about 0.25 mm to 1.5 mm eg 0 5 mm or 1.0 mm The length of the
extrudate pieces may be eg 0 5 to 1.5 cm eg 1 0 cm
[0036] The preparation avoids the complicated forms of prior art
preparations in that it does not require the use of controlled
release coatings or buffers, whilst at the same time enabling
dosing at only twice preferably once a day and without large
fluctuations in blood plasma levels during the dosing
intervals.
EXAMPLE 1
[0037] The bowl of a Collette Gral 10 was preheated to a jacket
temperature of 61.degree. C. and allowed to stabilise 540.5 g of
morphine sulphate, 36 g of polyethylene glycol 6000 and 343 2 g of
hydrogenated vegetable oil were placed in the pre-heated jacketed
bowl and left to warm with no mixing for about 4 minutes.
[0038] The machine was then run for about 20 to 25 minutes with
mixer and chopper blades running at 425 rpm and setting 1
respectively
[0039] The resulting granules/agglomerates were then immediately
removed and passed through a Caleva extruder fitted with 1 mm hole
gears.
[0040] The extruded pieces were placed in the bowl of the Collette
Gral 10 which had been preheated to a jacket temperature of
61.degree. C. and left with no mixing for 4 minutes. Processing was
then carried out as follows:
[0041] (a) for 4 minutes at mixer speed 100 rpm and chopper speed
setting 1;
[0042] (b) for 4 minutes at mixer speed 200 rpm, chopper setting 1
and jacket temperature 58.degree. C.; and
[0043] (c) for 9 minutes at mixer speed 400 rpm, chopper setting 1
and jacket temperature 55.degree. C.
[0044] (d) 73 g of hydrogenated vegetable oil were then added and
processing was continued under the same conditions for a further
minute.
[0045] The resulting multiparticulates were immediately passed
through a sieve (0 5 to 2.0 mm) and the 0.5-2.0 mm fraction
retained.
[0046] The retained multiparticulates were mixed with minor amounts
of talc and magnesium stearate and encapsulated in hard gelatine
capsules so that each capsule contained the following
constituents.
1 mg Morphine Sulphate BP 60.00 Hydrogenated vegetable oil NF 46.10
Polyethylene glycol 6000 Ph Eur 4.00 Talc Ph Eur 0.55 Magnesium
Stearate Ph Eur 0 33
EXAMPLE 2
[0047] Example 1 was repeated but using 526 g of morphine sulphate,
35 g of polyethylene glycol 6000, and 334 g hydrogenated vegetable
oil in the initial processing and subsequently adding 88 g of
hydrogenated vegetable oil in stage (d) Capsules were obtained
containing multiparticulates having the following constituents:
2 mg/capsule Morphine sulphate BP 60.00 Hydrogenated vegetable oil
NF 48.10 Polyethylene glycol 600 Ph. Eur. 4 0 Talc Ph. Eur. 0 56
Magnesium stearate Ph Eur 0.33
REFERENCE EXAMPLE 1
[0048] The multiparticulates obtained in Examples 1 and 2 were
tested using the Ph. Eur Basket method at 100 rpm in 900 ml aqueous
buffer (pH 6.5) containing 0.05% w/v Polysorbate 80 at 37.degree.
C. and the release rates of morphine are shown in Table 1.
3 % Morphine released (mean) Hour Example 1 Example 2 1 4.7 2 7 2
8.6 5 4 3 12.6 8 1 4 16.3 11.0 5 20.4 13.8 6 24.3 16.8 8 32.2 22.9
10 39.7 29.3 14 53.4 41.1 24 76.6 62.7
REFERENCE EXAMPLE 2
[0049] The capsules obtained in Examples 1 and 2 and, by way of
comparison, capsules obtained according to EP-A-636370 were tested
in a single dose study in five healthy volunteers and blood samples
were taken every half hour.
[0050] The results are as shown in the following tables 2, 3 and
4.
4TABLE 2 CAPSULE ACCORDING TO EP-A 636370 CONTAINING 60 MG MORPHINE
SULPHATE Vol Cmax (ng/ml) tmax (h) W50 (h) C24 (ng/ml) Cmax/C24 1
9.42 5 7.25 2.63 3.58 2 1.50 4 5.47 1.59 7.23 3 -- -- -- -- -- 4
11.72 3 5.19 2.45 4.78 5 7.12 3 15.68 2.77 2.57 6 11.33 3 4.01 2.38
4.76 Mean 10.22 7.52 2.36 4.58 sd 1.96 4.71 0.46 1.74 Median 3
Range 3-5
[0051]
5TABLE 3 CAPSULE ACCORDING TO EXAMPLE 1 Vol Cmax (ng/ml) tmax (H)
W50 (h) C24 (ng/ml) Cmax/C24 1 5.32 3 43.30 3.12 1.71 2 4.55 5
34.88 2.33 1.95 3 3.87 3 52.38 1.84 2.10 4 8.37 3 19.23 3.58 2.34 5
8.24 3 5.37 2.89 2.85 6 5.90 3 12.98 2.90 2.03 Mean 6.04 28.02 2.78
2.16 sd 1.88 18.39 0.61 0.39 Median 3 Range 3-5
[0052]
6TABLE 4 CAPSULE ACCORDING TO EXAMPLE 2 Vol Cmax (ng/ml) tmax (H)
W50 (h) C24 (ng/ml) Cmax/C24 1 4.72 13 33.45 2.98 1.58 2 3.93 3
36.84 2.50 1.57 3 -- -- -- -- -- 4 6.91 3 20.63 3.41 2.03 5 5.90 3
24.93 3.08 1.92 6 6.31 3 13.15 2.60 2.43 Mean 5.55 25.80 2.91 1.91
sd 1.21 9.59 0.37 0.36 Median 3 Range 3-13
* * * * *