U.S. patent application number 11/056035 was filed with the patent office on 2005-09-01 for extrusion.
Invention is credited to Hayes, Geoffrey Gerard, Martinelli, Vincenzo, Mohammad, Hassan, Prater, Derek Allan, Tamber, Harjit, Walden, Malcolm, Whitelock, Steve.
Application Number | 20050191352 11/056035 |
Document ID | / |
Family ID | 32011772 |
Filed Date | 2005-09-01 |
United States Patent
Application |
20050191352 |
Kind Code |
A1 |
Hayes, Geoffrey Gerard ; et
al. |
September 1, 2005 |
Extrusion
Abstract
The invention relates to a process for preparing a controlled
release pharmaceutical extrudate using a melt extruder, wherein the
melt extruder comprises a die-head supporting a die-plate in which
orifices are located, and a cutter adjacent to the die-head, and
wherein the cutter cuts the extruded mix as it emerges under
pressure and still molten or softened from the orifices of the
die-plate.
Inventors: |
Hayes, Geoffrey Gerard;
(Saffron Walden, GB) ; Martinelli, Vincenzo;
(Cambridge, GB) ; Mohammad, Hassan; (Ely, GB)
; Prater, Derek Allan; (Milton, GB) ; Tamber,
Harjit; (Hitchin, GB) ; Walden, Malcolm;
(Hardwick, GB) ; Whitelock, Steve; (Milton,
GB) |
Correspondence
Address: |
JONES DAY
222 EAST 41ST ST
NEW YORK
NY
10017
US
|
Family ID: |
32011772 |
Appl. No.: |
11/056035 |
Filed: |
February 11, 2005 |
Current U.S.
Class: |
424/468 ;
264/109 |
Current CPC
Class: |
A61K 9/16 20130101; A61K
9/1635 20130101; Y10T 428/2982 20150115; A61K 9/1694 20130101 |
Class at
Publication: |
424/468 ;
264/109 |
International
Class: |
A61K 009/52; A61K
009/22 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 12, 2004 |
GB |
GB 0403098.7 |
Claims
1. A process for preparing a controlled release pharmaceutical
extrudate using a melt extruder, wherein the melt extruder
comprises a die-head supporting a die-plate in which orifices are
located, and a cutter adjacent to the die-head, and wherein the
cutter cuts the extruded mix as it emerges under pressure and still
molten or softened from the orifices of the die-plate
2. A process according to claim 1, wherein the cutter is a rotary
cutter with two diametrically opposed blades.
3. A process according to claim 1, wherein a stream of air of
reduced temperature is directed into the region of the surface of
the die-head during cutting.
4. A process for preparing a controlled release pharmaceutical
extrudate with rounded surfaces, which process comprises providing
a melt extruder comprising a die-head supporting a die-plate in
which orifices are located, and a cutter adjacent to the die-head,
feeding the mix through the extruder, cutting the extruded mix as
it emerges under pressure and still molten or softened from the
orifices of the die-plate, and adjusting the rate of extrusion and
the speed of the cutter blade to give generally cylindrical
multiparticulates, spherical or substantially spherical,
ellipsoidal or disc shaped multiparticulates.
5. A process according to claim 4, wherein the multiparticulates
are spherical or substantially spherical.
6. Melt extruded multiparticulates having rounded surfaces
obtainable by the process of claim 4.
7. Melt extruded multiparticulates according to claim 6, which are
generally cylindrical, spherical or substantially spherical,
ellipsoidal or disc shaped.
Description
[0001] The present invention relates to extrusion, and in
particular to melt extrusion of multiparticulates which provide
controlled release of an active ingredient.
BACKGROUND OF THE INVENTION
[0002] Multiparticulates of uniform dimensions with modified drug
release properties can readily be manufactured by melt extrusion
technology. Melt extrusion is a solvent-free single-step process
for manufacturing multiparticulates and is particularly useful for
drug release modification. By selection of suitable polymers and
additives, melt extrusion technology can be used both to enhance
the solubility, and subsequently the bioavailability, of poorly
water soluble drugs as well as to retard drug release of moderate
to highly water soluble drugs for controlled release products.
[0003] The backbone of melt extrusion technology is the application
of thermoplastic materials which act as binders for embedded drugs
in solution or dispersion form within the matrix. Thermoplastic
polymers with low glass transition temperatures (Tg) are preferred
for processing by melt extrusion. Lower processing temperatures are
also preferred with respect to the stability of heat sensitive
drugs and other necessary excipients. Polymer glass transition
temperatures can also be further reduced to facilitate processing
at lower temperature with optional addition of plasticisers.
[0004] WO 9614058 provides a sustained-release pharmaceutical
formulation, comprising a melt-extruded blend of a therapeutically
active agent, one or more materials selected from the group
consisting of alkylcelluloses, acrylic and methacrylic acid
polymers and copolymers, shellac, zein, hydrogenated castor oil,
hydrogenated vegetable oil, and mixtures thereof; and one or more
hydrophobic fusible carriers which provide a further retardant
effect and are selected from the group consisting of natural or
synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof,
the fusible carrier having a melting point from 30 to 200.degree.
C. The melt-extruded blend is divided into a unit dose containing
an effective amount of said therapeutically active agent to render
a desired therapeutic effect and providing a sustained-release of
said therapeutically active agent for a time period of from about 8
to about 24 hours.
[0005] Furthermore, WO 9614058 describes a method of preparing a
sustained-release pharmaceutical extrudate suitable for oral
administration. The method comprises:
[0006] blending a therapeutically active agent together with (1) a
material selected from the group consisting of alkylcelluloses,
acrylic and methacrylic acid polymers and copolymers, shellac,
zein, hydrogenated castor oil, hydrogenated vegetable oil, and
mixtures thereof and (2) a fusible carrier selected from the group
consisting of natural or synthetic waxes, fatty acids, fatty
alcohols, and mixtures thereof; said retardant material having a
melting point between 30-200.degree. C. and being included in an
amount sufficient to further slow the release of the
therapeutically active agent;
[0007] heating said blend to a temperature sufficient to soften the
mixture sufficiently to extrude the same;
[0008] extruding said heated mixture as a strand having a diameter
of from 0.1-3 mm;
[0009] cooling said strand; and
[0010] dividing said strand to form non-spheroidal
multi-particulates of said extrudate having a length from 0.1-5 mm;
and
[0011] dividing said non-spheroidal multi-particulates into unit
doses containing an effective amount of said therapeutically active
agent, said unit dose providing a sustained-release of said
therapeutically active agent for a time period of from about 8 to
about 24 hours.
[0012] Thus, in practice, the stranded extrudate is congealed on a
conveyor belt and cut into pellets. Such pellets typically have a
cylindrical shape.
SUMMARY OF THE INVENTION
[0013] According to the present invention, we provide a process for
preparing a controlled release pharmaceutical extrudate, wherein a
cutter cuts the extruded mix as it emerges under pressure and still
molten from the orifices of the die-plate.
[0014] The cutter is suitably a rotary cutter with one or more
blades which sweep over the surface of the die-head to pass the
orifices. Two diametrically opposed blades are preferred. Ideally,
the outer surface of the die-head is coated with a non-stick
material, e.g. polytetrafluoroethylene (PTFE). As the cut extrudate
multiparticulates expand and cool, they tend to form rounded
surfaces. By appropriate adjustment of the rate of extrusion and
the speed of the cutter blade, as well as generally cylindrical
multiparticulates, it is possible for example to arrange for
spherical or substantially spherical, ellipsoidal or disc shaped
multiparticulates to be obtained. In one embodiment a stream of air
is directed into the region of the surface of the die-head, the air
being at a reduced temperature to cool the extrudate and to speed
solidification.
[0015] Spherical multiparticulates produced by this method offer a
number of advantages:
[0016] Better batch to batch reproducibility.
[0017] Easier coating and lower coating weight required.
[0018] Better capsule filling and higher yield.
[0019] More stable at elevated temperature.
[0020] More tamper resistant.
[0021] Reduce or eliminate some problems that arise during
conveying and pelletising the strands such as strands fracturing to
different length pellets and possible static charge.
[0022] Our preferred compositions include a water insoluble
ammonium methacrylate copolymer. The insoluble ammonium
methacrylate copolymer is suitably Eudragit RS PO, which is an
ammonio methacrylate copolymer. In particular, Eudragit RS PO is a
sparingly water permeable thermoplastic polymer which can
significantly retard release of embedded oxycodone in its matrix.
The insoluble ammonium methacrylate copolymer can form all or part
of the release controlling material employed in the extrusion
method.
[0023] A further preferred polymer which can form part of the
release controlling material is a neutral poly(ethyl acrylate,
methyl methacrylate) copolymer. Neutral poly(ethyl acrylate, methyl
methacrylate) copolymer is commercially available in the form of an
aqueous dispersion. Two products, Eudragit NE 30 D and Eudragit NE
40 D, comprise respectively 30% and 40% of the polymer. These
products are used conventionally in the preparation of controlled
release coats.
[0024] We now find that by utilising a neutral poly(ethyl acrylate,
methyl methacrylate) copolymer in the preparation of controlled
release pharmaceutical extrudates, we can obtain melt extruded
multiparticulates which exhibit rubber-like characteristics. Such
rubbery extrudates can exhibit enhanced resistance to tamper. In
particular, it appears that the rubbery characteristics are
imparted by the step of melt extrusion. Tamper resistance is of
special importance for products containing opioid analgesics or
other active ingredients which are subject to abuse.
[0025] The neutral poly(ethyl acrylate, methyl methacrylate)
copolymer is suitably employed in an amount by weight of up to 66%
in the mix for extrusion, say 20 to 66% of the extrusion mix, more
typically from 20 to 50%, such as 30 to 40% of the extrusion
mix.
[0026] The neutral poly(ethyl acrylate, methyl methacrylate) can be
employed with other ingredients including a drug or other active
ingredient.
[0027] A plasticiser and/or a lubricant is preferred when using an
extruder with a relatively low torque capability such as a
Leistritz Micro 18 machine. With a larger extruder, such as a
Leistritz Micro 27, similar formulations, without or with
relatively low levels of plasticiser and/or lubricant, may be
processed.
[0028] The plasticiser is normally chosen from water insoluble
solids such as cetyl alcohol, stearyl alcohol and cetostearyl
alcohol; water soluble solids such as sorbitol and sucrose and high
molecular weight polyethylene glycol, water insoluble liquids such
as dibutyl sebacate and tributyl citrate and water soluble liquids
such as triethyl citrate, propylene glycol and low molecular weight
polyethylene glycol. Stearyl alcohol is a preferred plasticiser.
Another preferred plasticiser is a high molecular weight
polyethylene glycol of MW 1000 to 20000, such as PEG 6000.
[0029] A lubricant can be included. The lubricant is normally a
solid at room temperature, and is suitably chosen from stearic
acid, glycerol dibehenate, magnesium stearate, calcium stearate,
talc and silicone dioxide (fused silica). The presence of lubricant
in the melt extrusion formulation improves blending, kneading and
conveying and reduces cohesion and adhesion forces. Smooth
extrusion at low to moderate temperatures improves batch to batch
reproducibility and reduces the strain on both the product and
equipment. Stearic acid, possibly in the form of a salt, is a
preferred lubricant. Another preferred lubricant is glycerol
dibehenate.
[0030] A drug is usually present as active agent in the
multiparticulates. The reader is referred to WO 9614058 for
examples which is incorporated herein in full by specific
reference. Oxycodone is a typical drug for use in the products and
processes of this invention.
[0031] Therapeutically active agents which may be used in
accordance with the present invention include both water soluble
and water insoluble drugs. Examples of such therapeutically active
agents include antihistamines (e.g. dimenhydrinate,
diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate),
analgesics (e.g., aspirin, codeine, morphine, dihydromorphone,
oxycodone, etc) non-steroidal anti-inflammatory agents (e.g.
naproxen, diclofenac, indomethacin, ibruprofen, sulindac),
anti-emetics (e.g. metoclopramide, methylnaltrexone),
anti-epileptics (e.g., phenyloin, meprobamate and nitrazepam),
vasodilators (e.g. nifedipine, papaverine, diltiazem and
nicardipine), anti-tussive agents and expectorants (e.g., codeine
phosphate), anti-asthmatics (e.g. theophylline), antacids,
anti-spasmodics (e.g. atropine, scopolamine), antidiabetics (e.g.
insulin), diuretics (e.g. ethacrynic acid, bendrofluthiazide),
anti-hypotensives (e.g., propranolol, clonidine), antihypertensives
(e.g. clonidine, methyldopa), bronchodilators (e.g. albuterol),
steroids (e.g., hydrocortisone, triamcinolone, prednisone),
antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics,
psychotropics, antidiarrheals, mucolytics, sedatives,
decongestants, laxatives, vitamins, stimulants (including appetite
suppressants such as phenylpropanolamine), as well as salts,
hydrates, and solvates of the same.
[0032] In embodiments of the invention directed to opioid
analgesics, the opioid analgesics used in accordance with the
present invention include alfentanil, allylprodine, alphaprodine,
anileridine, benzylmorphine, bezitramide, buprenorphine,
butorphanol, clonitazene, codeine, cyclazocine, desomorphine,
dextromoramide, dezocine, diampromide, dihydrocodeine,
dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
ketobemidone, levallorphan, levorphanol, levophenacylmorphan,
lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,
morphine, myrophine, nalbuphine, narceine, nicomorphine,
norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,
opium, oxycodone, oxymorphone, papaveretum, pentazocine,
phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,
piritramide, propheptazine, promedol, properidine, propiram,
propoxyphene, sufentanil, tramadol, tilidine, salts therof,
mixtures of any of the foregoing, mixed mu-agonists/antagonists,
mu-antagonist combinations, and the like. The opioid analgesic may
be in the form of the free base, or in the form of a
pharmaceutically acceptable salt, or in the form of a
pharmaceutically acceptable complex.
[0033] In certain preferred embodiments, the opioid analgesic is
selected from morphine, codeine, hydromorphone, hydrocodone,
oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, tramadol
or mixtures thereof.
[0034] In one preferred embodiment the sustained-release opioid
oral dosage form of the present invention includes hydromorphone as
the therapeutically active ingredient in an amount from about 4 to
about 64 mg hydromorphone hydrochloride. Alternatively, the dosage
form may contain molar equivalent amounts of other hydromorphone
salts or of the hydromorphone base. In other preferred embodiments
where the opioid analgesic is other than hydromorphone, the dosage
form contains an appropriate amount to provide a substantially
equivalent therapeutic effect. For example, when the opioid
analgesic comprises morphine, the sustained-release oral dosage
forms of the present invention include from about 5 mg to about 800
mg morphine, by weight (based on morphine sulfate). When the opioid
analgesic comprises oxycodone, the sustained-release oral dosage
forms of the present invention include from about 5 mg to about 400
mg oxycodone. When the opioid analgesic is tramadol, the
sustained-release oral dosage forms of the invention include from
about 50 mg to about 800 mg tramadol by weight, based on the
hydrochloride salt.
[0035] The sustained-release dosage forms of the present invention
generally achieve and maintain therapeutic levels substantially
without significant increases in the intensity and/or degree of
concurrent side effects, such as nausea, vomiting or drowsiness,
which are often associated with high blood levels of opioid
analgesics. There is also evidence to suggest that the use of the
present dosage forms leads to a reduced risk of drug addiction.
[0036] In the present invention, the oral opioid analgesics have
been formulated to provide for an increased duration of analgesic.
Surprisingly, these formulations, at comparable daily dosages of
conventional immediate-release drug, are associated with a lower
incidence in severity of adverse drug reactions and can also be
administered at a lower daily dose than conventional oral
medication while maintaining pain control.
[0037] When the therapeutically active agent included in the dosage
forms of the present invention is an opioid analgesic, the dosage
form may further include one or more additional which may or may
not act synergistically with the opioid analgesics of the present
invention. Examples of such additional therapeutically active
agents include non-steroidial anti-inflammatory agents, including
ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen,
fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen,
carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen,
suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid,
indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin,
acemetacin, fentiazac, clidanac, oxpinac, mefenamidic acid,
meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid,
diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the
like. Other suitable additional drugs which may be included in the
dosage forms of the present invention include acetaminophen,
aspirin, salicylate-derived analgesics and antipyretics or salts
thereof, and other non-opioid analgesics.
[0038] The additional (non-opioid) therapeutically active agent may
be included in controlled release form or in immediate release
form. The additional drug may be incorporated into the controlled
release matrix along with the opioid; incorporated as a separated
controlled release layer or immediate release layer; or may be
incorporated as a powder, granulation, etc, in a gelatin capsule
with the extrudates of the present invention.
[0039] Suitable percentage amounts for the preferred ingredients
are given in the following table, based on the total weight of the
specified ingredients:
1 more most typical preferred preferred preferred range range range
range water insoluble 5 to 66 15 to 50 20 to 45 25 to 45 neutral
poly(ethyl acrylate, methyl methacrylate) copolymer active agent*
up to 60 5 to 55 5 to 50 10 to 45 water insoluble 0 to 85 5 to 75 5
to 60 5 to 45 ammonium methacrylate copolymer plasticiser 0 to 30 0
to 25 3 to 25 3 to 20 lubricant 0 to 25 0 to 25 0 to 20 0 to 15
*the amount of active agent can be 0% in placebo formulations for
trials or development work
[0040] Other additives may also be employed to produce
multiparticulates within a set of predetermined specifications.
Bulking agents for example lactose, microcrystalline cellulose and
calcium phosphate, are widely used pharmaceutical excipients and
can be used in the present invention to modify the release rates
and/or total release. Other release modifying agents may also be
considered to modulate the release rate and/or enhance total
release.
[0041] The ingredients are blended, and melt extruded. Details of
such procedures are given in WO 9614058 incorporated herein in full
by specific reference.
[0042] For the present invention, we prefer to employ a twin screw
extruder. In some embodiments the raw material is fed, as a powder
blend, by a feeder, into the first segment of an extruder barrel
preferably at relatively low temperature (for example 10-20.degree.
C.) to ensure a constant flow of material to the high temperature
barrels. The feeder provides a uniform current of the material to
the extruder. Consistency is desirable as irregular and variable
feeding rates can produce multiparticulates with various physical
properties, such as density and porosity.
[0043] In other embodiments, for example when using an aqueous
dispersion of a polymer, e.g. Eudragit NE 30 D or Eudragit NE 40 D,
the raw material may first be wet granulated and dried, and then
fed as dried granules or powder to the extruder.
[0044] The preferred extruder is designed with twin screws, which
may have co-rotating or counter-rotating screws, for the tasks of
conveying, blending and compressing the blend as well as providing
mechanical energy. The extruder will be equipped with heating means
and cooling means as required. The screws which perform a
significant part of this melt extrusion process are built of
different smaller elements. The mixing and kneading process can be
significantly altered by changing the type, length and
configuration of the screws elements. Short residence times and
moderate to low shear forces contribute to safe processing and
stable product even with heat sensitive drugs.
[0045] Screw rotating speeds may play a part in the quality of the
multiparticulates produced. High rotation speeds without
appropriate compensation of the feed rate may produce high porosity
multiparticulates with a variable drug release rate. On the other
hand slow screw rotation would induce unnecessary long residence
times. A vacuum connected to the extruder barrel is desirable to
remove trapped air and residual moisture from within the plastified
material and thus produce dense multiparticulates ideally of low
porosity.
[0046] The extrusion head is typically designed to produce multiple
strands of fixed diameter, for example 1.0 mm. The number, shape
and diameter of the orifices can be changed to suit a predetermined
specification.
[0047] In addition to the screw speed, the other main influential
parameters are the screw torque, individual barrel temperature, and
extrusion head pressure and temperature.
[0048] As it emerges under pressure as a fluid mix from the
orifices of the die-head of the extruder, the mix is cut. By
appropriate optimisation of the conditions, as well as generally
cylindrical multiparticulates, it is readily possible to obtain
spherical or substantially spherical, ellipsoidal or disc shaped
multiparticulates.
[0049] The multiparticulates may be divided into unit doses such
that each individual unit dose includes a dose of drug for
adminstration to a mammal, preferably a human patient.
[0050] For the preferred drug, oxycodone or salt thereof,
preferably the hydrochloride, a suitable dose of the active agent
is 5 to 400 mg, especially 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 60 mg,
80 mg, 120 mg or 160 mg unit dosages. In this respect, a unit dose
contains an effective amount of the therapeutically active agent to
produce pain relief and/or analgesia to the patient. The dose of
oxycodone administered to a patient will vary due to numerous
factors, including the weight of the patient, tolerance, the
severity of the pain, the metabolic status and the nature of any
other therapeutic agents being administered.
[0051] The resultant multiparticulates can be employed as a fill in
a capsule. Thus, the present invention provides a capsule suited
for once or twice a day dosing. Other dosage forms of the
controlled release formulation can be provided.
[0052] In one preferred embodiment, the multiparticulates are
filled into gelatin capsules each containing a unit dose. The fill
weight in the capsule is preferably in the range 80 to 500 mg, more
preferably 120 to 500 mg. In a variation of this invention, the
unit doses of multiparticulates may be incorporated into other
solid pharmaceutical dosage formulations, for example using
compression or shaping or forming into tablets, or by forming the
extruded product into the form of a suppository.
[0053] The preferred capsules or other unit dose forms of this
invention preferably are designed for administration at intervals
of about 12 or 24 hours.
[0054] A preferred drug for inclusion in the multiparticulates is
oxycodone or a salt thereof, preferably the hydrochloride. A unit
dose form suitable for 12-hourly dosing then suitably has an
oxycodone dissolution rate in vitro, when measured by the USP
Paddle Method (see the U.S. Pharmacopoeia XXII 1990) at 100 rpm in
900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. of
between 12.5 and 42.5% (by wt) oxycodone released after 1 hour,
between 25 and 56% (by wt) oxycodone released after 2 hours,
between 45 and 75% (by wt) oxycodone released after 4 hours and
between 55 and 85% (by wt) oxycodone released after 6 hours.
Furthermore, we prefer that the peak plasma level of oxycodone
obtained in vivo occurs between 2 and 4.5 hours after
administration of the dosage form.
[0055] More information on desirable characteristics for such
oxycodone formulations is given in WO 9310765 which is incorporated
herein in full by specific reference.
[0056] As an alternative, the capsules or other unit dose forms of
this invention are designed for administration at intervals of
about 24 hours. To this end, the unit dose form suitably has an
oxycodone dissolution rate in vitro, when measured by the USP
Basket Method at 100 rpm in 900 ml aqueous buffer at a pH between
1.6 and 7.2 at 37.degree. C. of from 0% to about 40% at 1 hour,
from about 8% to about 70% at 4 hours, from about 20% to about 80%
at 8 hours, from about 30% to about 95% at 12 hours, from about 35%
to about 95% at 18 hours, and greater than about 50% at 24 hours.
Furthermore, we prefer that the peak plasma level of oxycodone
obtained in vivo is reached at about 2 hours to about 17 hours
after administration at steady state of the dosage form.
[0057] More information on desirable characteristics for such
oxycodone formulations is given in WO 02087512 which is
incorporated herein in full by specific reference.
[0058] In a variation, the present invention provides unit doses
which contain an opioid and an opioid antagonist effective to
prevent tampering. In this respect, reference is made to WO 0313433
which is incorporated herein in full by specific reference. In
particular, the unit dose can contain oxycodone and naltrexone.
[0059] To this end, the present invention provides melt extruded
multiparticulates of an opioid such as oxycodone, and melt extruded
multiparticulates of an opioid antagonist such as naltrexone. In a
preferred formulation antagonist multiparticulates do not release
the antagonist on conventional administration, and for example have
a non-release coating. Both populations of opioid and opioid
antagonist are preferably visually and physically identical.
[0060] An important aspect of this invention is a capsule with a
unit dose fill of less than 500 mg, comprising up to about 350 mg
of oxycodone multiparticulates, and up to about 200 mg of
tamper-proof oxycodone antagonist multiparticulates. For example,
there can be 120 to 300 mg of oxycodone multiparticulates, and 125
to 175 mg of tamper-proof oxycodone antagonist
multiparticulates.
SUMMARY OF THE DRAWINGS
[0061] Reference is made in the following experimental section to
the accompanying drawings, in which:
[0062] FIG. 1 shows the die-head of a melt extruder.
[0063] FIG. 2 shows a rotary cutter for use with the die-head of
FIG. 1.
[0064] FIGS. 3 to 5 show the products of Example 1, Example 2 and
Example 3, respectively.
EXAMPLES OF THE INVENTION
[0065] In accordance with the novel cutting procedure of the
present invention, extrudate emerges from the twelve orifices of
the die-head shown in FIG. 1 of a Leistritz Micro 18 extruder. A
rotary cutter with two blades, as shown in FIG. 2, is used to cut
the extruded mix as it emerges under pressure and still molten from
the orifices of the die-plate. The blades sweep over the surface of
the die-head to pass the orifices. As the cut extrudate
multiparticulates expand and cool, they tend to form rounded
surfaces.
[0066] The following formulations were employed.
2 Examples (% w/w) Material Example 1 Example 2 Example 3 Lactose
25.0 8.23 10.0 anhydrous Eudragit RS PO 56.25 74.90 37.0 Stearyl
alcohol 6.25 10.0 Stearic Acid 12.5 6.0 Eudragit NE 40 D 37.0
Triethyl citrate 8.23 PEG 6000 4.94 Magnesium 3.70 Stearate Total
100 100 100 Comment Surface Surface cutting Surface cutting cutting
Successful very Successful very Successful good good good
[0067] By appropriate adjustment of the conditions, there was no
problem to obtain near-spherical multiparticulates (see FIGS. 3 to
5).
* * * * *