U.S. patent application number 09/358828 was filed with the patent office on 2001-10-25 for melt-extrusion multiparticulates.
Invention is credited to CHASIN, MARK, HUANG, HUA-PIN, OSHLACK, BENJAMIN.
Application Number | 20010033865 09/358828 |
Document ID | / |
Family ID | 23306123 |
Filed Date | 2001-10-25 |
United States Patent
Application |
20010033865 |
Kind Code |
A1 |
OSHLACK, BENJAMIN ; et
al. |
October 25, 2001 |
MELT-EXTRUSION MULTIPARTICULATES
Abstract
A unit dose sustained-release oral dosage form containing a
plurality of melt-extruded particles, each consisting essentially
of a therapeutically active agent, one or more retardants, and an
optional water-insoluble binder is disclosed. The particles have a
length of from about 0.1 to about 12 mm and can be of varying
diameters and each unit dose provides a release of therapeutically
active agents over at least about 8 hours. Methods of preparing the
unit doses as well as extrusion processes and methods of treatment
are also disclosed.
Inventors: |
OSHLACK, BENJAMIN; (NEW
YORK, NY) ; HUANG, HUA-PIN; (ENGLEWOOD CLIFFS,
NJ) ; CHASIN, MARK; (MANALAPAN, NJ) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Family ID: |
23306123 |
Appl. No.: |
09/358828 |
Filed: |
July 22, 1999 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09358828 |
Jul 22, 1999 |
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08334209 |
Nov 4, 1994 |
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5965161 |
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Current U.S.
Class: |
424/457 |
Current CPC
Class: |
A61K 9/1617 20130101;
A61K 9/1652 20130101; A61K 9/145 20130101; A61P 25/04 20180101;
A61K 9/2077 20130101; A61K 9/2018 20130101; A61K 9/1635 20130101;
Y10S 514/951 20130101; Y10S 514/962 20130101; A61K 9/1694 20130101;
A61P 29/00 20180101; A61K 9/2027 20130101; B29B 9/06 20130101; A61K
9/2095 20130101; A61K 9/2081 20130101 |
Class at
Publication: |
424/457 |
International
Class: |
A61K 009/52 |
Claims
What is claimed is:
1. A unit dose sustained-release oral dosage form comprising a
plurality of melt extruded particles, each of said particles
comprising: (a) a therapeutically active agent; (b) one or more
retardants; and (c) an optional water insoluble binder; said
particles having a (length) size from about 0.1 mm to about 12 mm,
said unit dose providing a release of said therapeutically active
agent over at least about 6 hours.
2. The unit dose of claim 1, wherein said therapeutically active
agent is selected from the group consisting of systemically active
therapeutic agents, locally active therapeutic agents, disinfecting
agents, chemical impregnants, cleansing agents, deodorants,
fragrances, dyes, animal repellents, insect repellents, a
fertilizing agents, pesticides, herbicides, fungicides, and plant
growth stimulants.
3. The unit dose of claim 2, wherein said therapeutically active
agent is an opioid analgesic selected from the group consisting of
morphine, codeine, hydromorphone, hydrocodone, oxycodone,
oxymorphone, dihydrocodeine, dihydromorphine, and mixtures
thereof.
4. The dosage form of claim 3, wherein said opioid analgesic is
selected from the group consisting of 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, levophenacyl
morphan, 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 thereof and
mixtures thereof.
5. The dosage form of claim 3, wherein said opioid analgesic
consists of from about 2 mg to about 64 mg hydromorphone.
6. The dosage form of claim 3, wherein said opioid analgesic
consists of from about 5 mg to about 800 mg morphine.
7. The dosage form of claim 3, wherein said opioid analgesic
consists of from about 5 mg to about 400 mg oxycodone.
8. The dosage form of claim 1, wherein said retardant is selected
from the group consisting of acrylic polymers,
hydroxyalkylcelluloses and mixtures thereof.
9. The unit dose of claim 1, wherein said acrylic polymer is
comprised of monomers selected from the group consisting of an
ester of acrylic acid, an ester of methacrylic acid, an alkyl ester
of acrylic acid, an alkyl ester of methacrylic acid, and mixtures
of any of the foregoing.
10. The unit dose of claim 1, wherein said water insoluble binder
is selected from the group consisting of hydrogenated vegetable or
castor oil, paraffin, higher aliphatic alcohols, higher aliphatic
acids, long chain fatty acids, fatty acid esters, and mixtures
thereof.
11. The unit dose of claim 1, wherein said binder is selected from
the group consisting of higher aliphatic alcohols and
water-insoluble waxes.
12. The unit dose of claim 1, wherein said particles have a
diameter from about 0.1 to about 5 mm.
13. The unit dose of claim 1, wherein each of said particles
comprise from about 1% to about 99% of said retardant.
14. The unit dose of claim 1, wherein each of said particles
comprise from about 5% to about 95% of said retardant.
15. A method of preparing a multiparticulate sustained release oral
dosage form, comprising: (a) mixing together a therapeutically
active agent, a water-insoluble retardant, and an optional binder
to obtain a homogeneous mixture, the ratio of said water insoluble
retardant to said therapeutically active agent in said mixture
being sufficient to impart a release of said therapeutically active
agent from said particles over a time period of at least about 4
hours when said particle is exposed to an aqueous fluid; (b)
heating said homogenous mixture; (c) extruding said homogenous
mixture to thereby form strands; (d) cooling said strands
containing said homogeneous mixture; and (e) cutting said strands
into particles having a size from about 0.1 mm to about 12 mm; and
(f) dividing said particles into unit doses.
16. The method of claim 15, wherein said unit doses are placed into
gelatin capsules.
17. The method of claim 15, wherein said homogenous mixture is
heated to a temperature from about 30.degree. C. to about
200.degree. C. prior to extrusion.
18. The method of claim 15, wherein said therapeutically active
agent is selected from the group consisting of systemically active
therapeutic agents, locally active therapeutic agents, disinfecting
agents, chemical impregnants, cleansing agents, deodorants,
fragrances, dyes, animal repellents, insect repellents, a
fertilizing agents, pesticides, herbicides, fungicides, and plant
growth stimulants.
19. The method of claim 18, wherein said therapeutically active
agent is an opioid analgesic selected from the group consisting of
morphine, codeine, hydromorphone, hydrocodone, oxycodone,
oxymorphone, dihydrocodeine, dihydromorphine, and mixtures
thereof.
20. The method of claim 19, wherein said opioid analgesic is
selected from the group consisting of 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, levophenacyl
morphan, 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 thereof and
mixtures thereof.
21. The method of claim 18, wherein said opioid analgesic consists
of from about 2 mg to about 64 mg hydromorphone.
22. The method of claim 18, wherein said opioid analgesic consists
of from about 5 mg to about 800 mg morphine.
23. The method of claim 18, wherein said opioid analgesic consists
of from about 5 mg to about 400 mg oxycodone.
24. The method of claim 15, wherein said retardant is selected from
the group consisting of acrylic polymers, hydroxyalkylcelluloses
and mixtures thereof.
25. The method of claim 15, wherein said acrylic polymer is
comprised of monomers selected from the group consisting of an
ester of acrylic acid, an ester of methacrylic acid, an alkyl ester
of acrylic acid, an alkyl ester of methacrylic acid, and mixtures
of any of the foregoing.
26. The method of claim 15, wherein said water insoluble binder is
selected from the group consisting of hydrogenated vegetable or
castor oil, paraffin, higher aliphatic alcohols, higher aliphatic
acids, long chain fatty acids, fatty acid esters, and mixtures
thereof.
27. The method of claim 15, wherein said binder is selected from
the group consisting of higher aliphatic alcohols and
water-insoluble waxes.
28. The method of claim 15, further comprising adjusting the
aperture and aperture shape of the extruder to obtain a strand
having a diameter from about 0.1 mm to about 3 cm.
29. A sustained release unit dose formulation comprising the
particles prepared according to the method of claim 15.
30. A method of treating a patient with a sustained release
multiparticulate formulation of a therapeutically active agent,
comprising: (a) mixing together a therapeutically active agent, a
water-insoluble retardant, and an optional binder to obtain a
homogeneous mixture, the ratio of said water insoluble retardant to
said therapeutically active agent in said mixture being sufficient
to impart a release of said therapeutically active agent from said
particles over a time period of at least about 4 hours when said
particle is exposed to an aqueous fluid; (b) heating said
homogenous mixture; (c) extruding said homogenous mixture to
thereby form strands; (d) cooling said strands containing said
homogeneous mixture; and (e) cutting said strands into particles
having a size from about 0.1 mm to about 12 mm; (f) dividing said
particles into unit doses; and (g) administering said unit dose to
a patient.
31. A method of preparing a multiparticulate sustained release oral
dosage form, comprising: (a) directly metering into an extruder a
water-insoluble retardant, a therapeutically active agent, and an
optional binder; (b) heating said homogenous mixture; (c) extruding
said homogenous mixture to thereby form strands; (d) cooling said
strands containing said homogeneous mixture; and (e) cutting said
strands into particles having a size from about 0.1 mm to about 12
mm; and (f) dividing said particles into unit doses.
32. The unit dose of claim 1, wherein the diameter of said
particles is from about 0.1 mm to about 3 cm.
33. The dosage form of claim 1, wherein said therapeutically active
agent is an opioid and said retardant is an acrylic polymer.
34. The dosage form of claim 1, wherein said therapeutically active
agent is an opioid and said retardant is a
hydroxyalkylcellulose.
35. An opioid unit dose sustained-release oral dosage form having
substantially no feeding-fasting effect, comprising a plurality of
melt extruded particles, each of said particles comprising: (a) a
therapeutically active agent; (b) one or more retardants; and (c)
an optional water insoluble binder; said particles having a
(length) size from about 0.1 mm to about 12 mm, said unit dose
providing a release of said therapeutically active agent over at
least about 12-24 hours.
36. An opioid unit dose sustained-release oral dosage form having
substantially no feeding-fasting effect, comprising a plurality of
melt extruded particles, each of said particles comprising: (a) a
therapeutically active agent; (b) one or more retardants; and (c)
an optional water insoluble binder; said particles having a
(length) size from about 0.1 mm to about 12 mm, said unit dose
providing a release of said therapeutically active agent over at
least about 6 hours.
37. The dosage form of claim 35, wherein said therapeutically
active agent is an opioid and said retardant is an acrylic
polymer.
38. The dosage form of claim 36, wherein said therapeutically
active agent is an opioid and said retardant is a
hydroxyalkylcellulose.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to a process of making
granulates or multiparticulates which are useful, for example, in
pharmaceutical dosage forms. In particular, the invention relates
to a process for melt-extruding pharmaceutical agents with
excipients to form multiparticulates suitable for inclusion in
solid dosage forms such as capsules, tablets and the like.
[0002] It is known in the pharmaceutical art to prepare
compositions which provide for controlled (slow) release of
pharmacologically active substances contained in the compositions
after oral administration to humans and animals. Such slow release
compositions are used to delay absorption of a medicament until it
has reached certain portions of the alimentary tract. Such
sustained-release of a medicament in the alimentary tract further
maintains a desired concentration of said medicament in the blood
stream for a longer duration than would occur if conventional rapid
release dosage forms are administered.
[0003] Over the years, several different methods of preparing
controlled release pharmaceutical dosage forms have been suggested.
For example, direct compression techniques, wet granulation
techniques, encapsulation techniques and the like have been
proposed to deliver pharmaceutically active ingredients to the
alimentary tract over extended periods.
[0004] Melt granulation techniques have also been suggested to
provide controlled release formulations. Melt granulation usually
involves mechanically working an active ingredient in particulate
form with one or more suitable binders and/or pharmaceutically
acceptable excipients in a mixer until one or more of the binders
melts and adheres to the surface of the particulate, eventually
building up granules.
[0005] PCT International Publication No. WO 92/06679 discloses melt
granulating methods for producing pellets containing
therapeutically active substances. The method includes mechanically
working a mixture containing the active substance in cohesive form
with a binder having a melting point of 40-100.degree. C., while
supplying sufficient energy to melt the binder and form "overmoist"
spherical pellets and thereafter adding an additional cohesive
substance while maintaining the mechanical working to finally
produce dry pellets.
[0006] PCT International Publication No. WO 93/18753 also discloses
another melt extrusion process for preparing sustained-release
pellets. This method includes pelletizing a mixture containing drug
in finely divided form and a binder which includes one or more
water-insoluble-wax-like binder substances with a melting point
above 40.degree. C. using a high shear mixer.
[0007] In the spite of the foregoing advances, a need for further
alternatives in the field of controlled release formulations has
been sought. The present invention addresses this need.
OBJECTS AND SUMMARY OF THE INVENTION
[0008] It is therefore an object of the present invention to
provide improved methods for producing multiparticulates containing
pharmaceutically active ingredients and excipients.
[0009] It is a further object of the present invention to provide
multiparticulates containing pharmaceutically active ingredients
which display improved controlled-release characteristics.
[0010] These objects and others have been accomplished by the
present invention, which relates in part to a unit dose
sustained-release oral dosage form containing a plurality of
melt-extruded particles, each of said particles comprising:
[0011] a) a therapeutically active agent;
[0012] b) one or more retardants; and
[0013] c) an optional water-insoluble binder.
[0014] The particles have an average length of from about 0.1 to
about 12 mm and the unit dose provides a release of the
therapeutically active agent over at least about 8 hours.
[0015] Another aspect of the invention provides a method of
preparing a multiparticulate sustained-release oral dosage form.
This method includes mixing together a therapeutically effective
agent, a water-insoluble retardant and an optional binder to form a
homogeneous mixture, heating the mixture and thereafter extruding
the mixture into strands. The strands are then cooled, and reduced
to particles having a size of from about 0.1 to about 12 mm. This
aspect further includes dividing the particles into unit doses. The
ratio of water-insolube retardant material to therapeutically
active agent is sufficient to impart a release of the active agent
from the multiparticulate system over an extended time period. In
this regard, the retardant will comprise about 5-95% of
melt-extruded multiparticulate. The multiparticulate
sustained-release system can be included within a hard gelatin
capsule or other oral dosage forms such as a compressed tablet.
Methods of preparing such dosage forms are also provided
herein.
[0016] In yet a further aspect of the invention, there is provided
a method of treating a patient with sustained-release
multi-particulate formulations prepared as described above. This
method includes administering a unit dose sustained release oral
dosage form containing the novel melt-extruded particles to a
patient in need of the active ingredient contained therein. For
purposes of the present invention, a unit dose is understood to
contain an effective amount of the therapeutically active
agent.
[0017] A still further aspect of the invention provides an
alternative method of preparing a multiparticulate sustained oral
dosage form. This aspect includes directly metering into an
extruder a homogeneous mixture of a water-insoluble retardant, a
therapeutically active agent, and an optional binder, heating the
homogeneous mixture, extruding said mixture to form strands,
cooling the strands and cutting the strands into particles having a
size of from about 0.1 to 12 mm and dividing the particles into
unit doses. The ratio of hydrophobic material, namely
water-insoluble retardant (and optional binder) to the
therapeutically active agent is sufficient to impart a controlled
release of the therapeutically active agent from the melt-extruded
particles and unit doses over a time period of at least 8
hours.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The following drawings are illustrative of embodiments of
the invention and are not meant to limit the scope of the invention
as encompassed by the claims.
[0019] FIG. 1 is a graph displaying the dissolution results of
Examples 1 and 2;
[0020] FIG. 2 is a graph displaying the dissolution rates of
Examples 3-6;
[0021] FIGS. 3a and 3b are graphs displaying the pH dependency of
the dissolution results of Examples 3 and 5 respectively;
[0022] FIG. 4 is a graph displaying the dissolution results of
Examples 7 and 8;
[0023] FIG. 5 is a graph displaying the dissolution results of
Examples 9 and 10;
[0024] FIG. 6 is a graph displaying the dissolution results of
Examples 11 and 12;
[0025] FIG. 7 is a graph displaying the dissolution results of
Examples 13 and 14;
[0026] FIG. 8 is a schematic representation of a system for
carrying out the present invention; and
[0027] FIG. 9 is a graph displaying the results of Example 5.
DETAILED DESCRIPTION
[0028] In accordance with the present invention, there are provided
methods for preparing multiparticulates using melt-extrusion
techniques and sustained release oral unit dosage forms containing
a plurality of the melt extruded particulates. In accordance
therewith, a therapeutically active agent is combined with one or
more suitable controlled-release retardants, and optionally, a
water-insoluble binder, extruded and thereafter rendered into a
plurality of melt-extruded particles or multiparticulates, such as
spheres, beads or the like.
[0029] Pharmaceutical Agents
[0030] The active pharmaceutical agent(s) included in the
controlled release multiparticulates of the present invention
include systemically active therapeutic agents, locally active
therapeutic agents, disinfecting agents, chemical impregnants,
cleansing agents, deodorants, fragrances, dyes, animal repellents,
insect repellents, a fertilizing agents, pesticides, herbicides,
fungicides, and plant growth stimulants, and the like. The only
limitation on the ingredient is that the pharmaceutical agent is
capable of undergoing the inventive extrusion process without
substantially losing its sought-after effect.
[0031] A wide variety of therapeutically active agents can be used
in conjunction with the present invention. The therapeutically
active agents (e.g. pharmaceutical agents) which may be used in the
compositions of the present invention include both water soluble
and water insoluble drugs. Examples of such therapeutically active
agents include anti-histamines (e.g., dimenhydrinate,
diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate),
analgesics (e.g., aspirin, codeine, morphine, dihydromorphone,
oxycodone, etc.), non-steroidal anti-inflammatory agents (e.g.,
naproxyn, diclofenac, indomethacin, ibuprofen, sulindac),
anti-emetics (e.g., metoclopramide), anti-epileptics (e.g.,
phenytoin, meprobamate and nitrezepam), vasodilators (e.g.,
nifedipine, papaverine, diltiazem and nicardirine), 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, bendrofluazide), 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. The above list is not meant to be exclusive.
[0032] In certain preferred embodiments, the multiparticulate
systems of the present invention include one or more compounds
known as opioid analgesics. Opioid analgesic compounds which may be
used in 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 thereof, mixtures of any of the foregoing, mixed
mu-agonists/antagonists, mu-antagonist combinations, and the
like.
[0033] In certain particularly preferred embodiments, the opioid
analgesic is selected from morphine, codeine, hydromorphone,
hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,
oxymorphone, hydrates and solvates of any of the foregoing,
mixtures of any of the foregoing, and the like.
[0034] Controlled Release Retardants and Binders
[0035] According to the present invention, in order to obtain a
controlled release of the active agent, the therapeutically active
agent is homogeneously combined with a sufficient amount of a
release-retardant material and, optionally, a water-insoluble
binder prior to undergoing extrusion. The retardant can be a
hydrophobic material such as a water-insoluble acrylic polymer or
alkylcellulose, or a water soluble material such as
hydroxyalkylcelluloses and related materials. If unit doses of the
multiparticulate are to have about a 12 hour or shorter release
pattern, hydroxyalkylcelluloses, for example will be extruded with
the therapeutic agent. If release rates of greater than about 12
hours are desired, water-insoluble materials are selected. It is,
of course, within the scope of the invention to have particles
containing mixtures of the water soluble and insoluble
polymers.
[0036] In certain preferred embodiments of the present invention,
the hydrophobic polymer is a pharmaceutically acceptable acrylic
polymer, including but not limited to acrylic acid and methacrylic
acid copolymers, methyl methacrylate copolymers, ethoxyethyl
methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate
copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic
acid alkylamide copolymer, poly(methyl methacrylate),
poly(methacrylic acid) (anhydride), methyl methacrylate,
polymethacrylate, poly(methyl methacrylate), poly(methyl
methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate
copolymer, poly(methacrylic acid anhydride), and glycidyl
methacrylate copolymers.
[0037] The melt-extruded particle will comprise from about 1 to
about 99% by weight of the retardant and preferably from about 5 to
95% by weight. Other retardant polymers which may be used for the
extrusion process of the present invention, as those skilled in the
art will appreciate, include other cellulosic polymers, including
other alkyl cellulosic polymers, may be substituted for part or all
of water-insoluble portion of the retardant in the
multiparticulate.
[0038] The terms "sustained release" and "extended duration" are
defined for purposes of the present invention as the release of the
drug (i.e., opioid analgesic) at such a rate that blood (e.g.,
plasma) levels are maintained within the therapeutic range but
below toxic levels over a period of time greater than 6 hours, more
preferably for periods of up to about 24 hours, or longer.
[0039] In certain preferred embodiments, the acrylic polymer is
comprised of one or more ammonio methacrylate copolymers. Ammonio
methacrylate copolymers are well known in the art, and are
described in NF XVII as fully polymerized copolymers of acrylic and
methacrylic acid esters with a low content of quaternary ammonium
groups.
[0040] In one preferred embodiment, the acrylic polymer is an
acrylic resin lacquer such as that which is commercially available
from Rohm Pharma under the Tradename Eudragit.RTM.. In further
preferred embodiments, the acrylic polymer comprises a mixture of
two acrylic resin lacquers commercially available from Rohm Pharma
under the Tradenames Eudragit.RTM. RL30D and Eudragit.RTM. RS30D,
respectively. Eudragit.RTM. RL30D and Eudragit.RTM. RS30D are
copolymers of acrylic and methacrylic esters with a low content of
quaternary ammonium groups, the molar ratio of ammonium groups to
the remaining neutral (meth)acrylic esters being 1:20 in
Eudragit.RTM. RL30D and 1:40 in Eudragit.RTM. RS30D. The mean
molecular weight is about 150,000. Edragit.RTM. and
Eudragit.RTM.L-100 are also preferred. The code designations RL
(high permeability) and RS (low permeability) refer to the
permeability properties of these agents. Eudragit.RTM. RL/RS
mixtures are insoluble in water and in digestive fluids. However,
multiparticulate systems formed to include the same are swellable
and permeable in aqueous solutions and digestive fluids.
[0041] The polymers described above such as Eudragit.RTM. RL/RS may
be mixed together in any desired ratio in order to ultimately
obtain a sustained-release formulation having a desirable
dissolution profile. Desirable sustained-release multiparticulate
systems may be obtained, for instance, from 100% Eudragit.RTM. RL,
50% Eudragit.RTM. RL and 50% Eudragit.RTM. RS, and 10%
Eudragit.RTM. RL:Eudragit.RTM. 90% RS. Of course, one skilled in
the art will recognize that other acrylic polymers may also be
used, such as, for example, Eudragit.RTM. L.
[0042] In other preferred embodiments, the hydrophobic polymer
which may be used is a hydrophobic cellulosic material such as
ethylcellulose. Those skilled in the art will appreciate that other
cellulosic polymers, including other alkyl cellulosic polymers, may
be substituted for part or all of the ethylcellulose included in
the hydrophobic polymer portion of the multiparticulates of the
present invention.
[0043] In certain preferred embodiments, the release-modifying
agent or retardant is selected from materials such as
hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and
mixtures of the foregoing.
[0044] The retardants may also include a plasticizer. Examples of
suitable plasticizers for ethylcellulose include water insoluble
plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl
citrate, tributyl citrate, and triacetin, although it is possible
that other water-insoluble plasticizers (such as acetylated
monoglycerides, phthalate esters, castor oil, etc.) may be used.
Triethyl citrate is especially preferred.
[0045] Examples of suitable plasticizers for the acrylic polymers
of the present invention include citric acid esters such as
triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and
possibly 1,2-propylene glycol, polyethylene glycols, propylene
glycol, diethyl phthalate, castor oil, and triacetin, although it
is possible that other water-insoluble plasticizers (such as
acetylated monoglycerides, phthalate esters, castor oil, etc.) may
be used. Triethyl citrate is especially preferred.
[0046] The binder portion of the melt-extruded particles is
optionally included. It has been fouond that the binder can be
reduced or even eliminated from the extrusion if the physical
properties and relationships between the therapeutically active
ingredient and retardant(s) allow a sufficiently cohesive extruded
strand to exit the apparatus. A non-limiting list of suitable
binders includes hydrogenated vegetable or castor oil, paraffin,
higher aliphatic alcohols, higher aliphatic acids, long chain fatty
acids, fatty acid esters, and mixtures thereof.
[0047] The binder material may consist of one or more
water-insoluble wax-like thermoplastic substances possibly mixed
with one or more wax-like thermoplastic substances being less
hydrophobic than said one or more water-insoluble wax-like
substances. In order to achieve constant release, the individual
wax-like substances in the binder material should be substantially
non-degradable and insoluble in gastrointestinal fluids during the
initial release phases.
[0048] Useful water-insoluble wax-like substances may be those with
a water-solubility that is lower than about 1:5,000 (w/w).
[0049] Binder materials are preferably water-insoluble with more or
less pronounced hydrophilic and/or hydrophobic trends.
Specifically, the wax-like substance may comprise fatty alcohols,
fatty acid esters, fatty acid glycerides (mono-, di-, and
tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes,
stearic aid, stearyl alcohol and hydrophobic and hydrophilic
polymers having hydrocarbon backbones.
[0050] In addition to the foregoing, the melt-extruded particles
can be prepared to include pharmaceutically acceptable carriers and
excipients. It is to be understood that these materials can be
mixed with the particles after extrusion as well. Specific examples
of pharmaceutically acceptable carriers and excipients that may be
used to formulate oral dosage forms are described in the Handbook
of Pharmaceutical Excipients, American Pharmaceutical Association
(1986), incorporated by reference herein. Techniques and
compositions for making solid oral dosage forms are described in
Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and
Schwartz, editors) Second Edition, published by Marcel Dekker,
Inc., incorporated by reference herein. Techniques and compositions
for making tablets (compressed and molded), capsules (hard and soft
gelatin) and pills are also described in Remington's Pharmaceutical
Sciences, (Arthur Osol, editor), 1553-1593 (1980), incorporated by
reference herein.
[0051] An optional process for preparing the multiparticulates and
unit doses of the present invention includes directly metering into
an extruder a water-insoluble retardant, a therapeutically active
agent, and an optional binder; heating said homogenous mixture;
extruding said homogenous mixture to thereby form strands; cooling
said strands containing said homogeneous mixture; and cutting said
strands into particles having a size from about 0.1 mm to about 12
mm; and dividing said particles into unit doses. In this aspect of
the invention, a relatively continuous manufacturing procedure is
realized.
[0052] Multiparticulates and Multiparticulate Systems
[0053] The multiparticulate system can be, for example, in the form
of granules, spheroids or pellets depending upon the extruder exit
orifice. For purposes of the present invention, the terms
"multiparticulate(s)" and "multiparticulate system(s)" and
"melt-extruded paricles" shall refer to a plurality of units,
preferably within a range of similar size and/or shape and
containing one or more active agents and one or more excipients,
preferably including a retardant as described herein. In this
regard, the multiparticulates will be of a range of from about 0.1
to about 12 mm in length and have a diameter of from about 0.1 to
about 5 mm. In addition, it is to be understood that the
multiparticulates can be any geometrical shape within this size
range such as beads, microspheres, seeds, pellets, etc.
[0054] The multiparticulate can thereafter be included in a capsule
or in any other suitable solid form.
[0055] The term "unit dose" is defined for purposes of the present
invention as the total amount of substrates needed to administer a
desired dose of drug (e.g., opioid analgesic) to a patient.
[0056] In one especially preferred embodiment, oral dosage forms
are prepared to include an effective amount of multiparticulates
within a capsule. For example, a plurality of the melt extruded
particles may be placed in a gelatin capsule in an amount
sufficient to provide an effective controlled-release dose when
ingested and contacted by gastric fluid. In certain preferred
embodiments of the present invention, the sustained-release
multiparticulate systems are coated with a sustained-release
coating. The coating formulations of the present invention should
be capable of producing a strong, continuous film that is smooth
and elegant, capable of supporting pigments and other coating
additives, non-toxic, inert, and tack-free.
[0057] In order to obtain a sustained-release of opioid, for
example, sufficient to provide an analgesic effect for the extended
durations set forth in the present invention, the melt extruded
particles comprising the therapeutically active agent may be coated
with a sufficient amount of hydrophobic material to obtain a weight
gain level from about 2 to about 30 percent, although the overcoat
may be greater depending upon the physical properties of the
particular opioid analgesic compound utilized and the desired
release rate, among other things. In certain preferred embodiments
of the present invention, the hydrophobic polymer comprising the
sustained-release coating is a pharmaceutically acceptable acrylic
polymer, such as those described hereinabove.
[0058] The solvent which is used for the hydrophobic material may
be any pharmaceutically acceptable solvent, including water,
methanol, ethanol, methylene chloride and mixtures thereof. It is
preferable however, that the coatings be based upon aqueous
dispersions of the hydrophobic material.
[0059] In one preferred embodiment the multiparticulate is used in
a sustained-release opioid oral dosage form and 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 form about 5 mg
to about 800 mg morphine, by weight. 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. In these aspects of the invention, the multiparticulate
can be encapsulated or compressed into solid oral dosage forms
using standard techniques.
[0060] The unit dosage forms of the present invention may further
include combinations of multiparticulates containing one or more of
the active agents disclosed above before being encapsulated.
Furthermore, the unit dosage forms can also include an amount of an
immediate release active agent for prompt therapeutic effect.
[0061] The controlled-release formulations of the present invention
slowly release the therapeutically active agent, e.g., when
ingested and exposed to gastric fluids, and then to intestinal
fluids. The controlled-release profile of the formulations of the
invention can be altered, for example, by varying the amount of
retardant, i.e., hydrophobic polymer, by varying the amount of
plasticizer relative to hydrophobic polymer, by the inclusion of
additional ingredients or excipients, by altering the method of
manufacture, etc.
[0062] For example, hydromorphone-containing multiparticulate may
also be overcoated with an aqueous dispersion of the hydrophobic
polymer. The aqueous dispersion of hydrophobic polymer preferably
further includes an effective amount of plasticizer, e.g. triethyl
citrate. Pre-formulated aqueous dispersions of ethylcellulose, such
as Aquacoat.RTM. or Surelease.RTM., may be used. If Surelease.RTM.
is used, it is not necessary to separately add a plasticizer.
Alternatively, pre-formulated aqueous dispersions of acrylic
polymers such as Eudragit.RTM. can be used. These coating solutions
may also contain film-formers, plasticizers, a solvent system
(i.e., water), a colorant to provide elegance and product
distinction. Color may also be added to or during the extrusion of
the therapeutically active agent and retardant.
[0063] The plasticized aqueous dispersion of hydrophobic polymer
may be applied onto the multiparticulate comprising the
therapeutically active agent by spraying using any suitable spray
equipment known in the art. In a preferred method, a Wurster
fluidized-bed system is used in which an air jet, injected from
underneath, fluidizes the multiparticulate material and effects
drying while the acrylic polymer coating is sprayed on. A
sufficient amount of the aqueous dispersion of hydrophobic polymer
to obtain a predetermined controlled-release of said
therapeutically active agent when the coated particulate is exposed
to aqueous solutions, e.g. gastric fluid, is preferably applied,
taking into account the physical characteristics of the
therapeutically active agent, the manner of incorporation of the
plasticizer, etc.
[0064] In addition to the above ingredients, a controlled-release
matrix may also contain suitable quantities of other materials,
e.g. diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art in amounts up to about 50% by weight of the particulate if
desired.
[0065] In a further aspect of the present invention, a process for
the preparation of a multiparticulate controlled release, oral
dosage form is provided, This aspect includes homogeneously mixing
a therapeutically effective agent with a water-insoluble retardant
and, optionally, a binder; extruding the mixture, cooling the
exiting extruded strands, rendering the strands into particles
having a size of from about 0.1 to about 12 mm in length and
optionally, encapsulating or compressing and shaping the granules
into tablets. The diameter of the extruder aperture or exit port
can also be adjusted to vary the thickness of the extruded strands.
Furthermore, the exit part of the extruder need not be round; it
can be oblong, rectangular, etc. The exiting strands can be reduced
to particles using a hot wire cutter, guillotine, etc.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0066] As shown in FIG. 8, a typical melt extrusion systems capable
of carrying-out the present invention include a suitable extruder
drive motor having variable speed and constant torque control,
start-stop controls, and ammeter. In addition, the system will
include a temperature control console which includes temperature
sensors, cooling means and temperature indicators throughout the
length of the extruder. In addition, the system will include an
extruder such as twin-screw extruder which consists of two
counter-rotating intermeshing screws enclosed within a cyclinder or
barrel having an aperture or die at the exit thereof. The feed
materials enter through a feed hopper and is moved through the
barrel by the screws and is forced through the die into strands
which are thereafter conveyed such as by a continuous movable belt
to allow for cooling and being directed to a pelletizer or other
suitable device to render the extruded ropes into the
multiparticulate system. The pelletizer can consist of rollers,
fixed knife, rotating cutter and the like. Suitable instruments and
systems are available from distributors such as C. W. Brabender
Instruments, Inc. of South Hackensack, N.J. Other suitable
apparatus will be apparent to those of ordinary skill in the
art.
[0067] General Pellet Manufacturing Procedure
[0068] Premix the required amount of drug, polymers, and optional
binder (wax).
[0069] Charge a powder feeder with proper amount of drug/excipient
blend.
[0070] Set temperatures of extruder to the required temperature,
depending on the formulation. Wait until the corresponding heating
zones reach steady temperatures. Start the feeder and the extruder.
The drug/excipient powder blend is melted and intimately mixed in
the extruder. The diameter of the extruder aperture can be adjusted
to vary the thickness of the resulting strand.
[0071] Set the conveyor belt speed to an appropriate speed (e.g.,
3-100 ft/min). Allow the extruded semisolid strand(s) to be
congealed and transported to the pelletizer. Additional cooling
devices may be needed to ensure proper congealing. (The conveyor
belt may not be needed to cool the strand, if the material congeals
rapidly enough.)
[0072] Set the roller speed and cutter speed (e.g., to 3-100 ft/min
and 100-800 rpm). Cut the congealed strands to desired size (e.g.,
3-5 mm in diameter, 0.3-5 mm in length).
[0073] Collect the pellet product.
[0074] Fill a desired weight of pellets into hard gelatin capsules
to obtain an appropriate does of the drug.
Dissolution Method
USP II Paddle at 100 rpm
[0075] 1st hour in 700 ml simulated gastric fluid or SGF
[0076] thereafter, 900 ml simulated intestinal fluid SIF
Using HPLC procedures for Assay
[0077] The following examples illustrate various aspects of the
present invention. They are not meant to be construed to limit the
claims in any manner whatsoever.
EXAMPLES 1-2
[0078] In these examples, chlorpheniramine maleate controlled
release pellets were prepared according to the above manufacturing
procedure using ethylcellulose and an acrylic polymer (Eudragit
RSPO), respectively as the retardant. The formulations are set
forth in Tables 1 and 2 below. The dissolution of these
formulations is set forth in FIG. 1. Drug release rate from
ethylcellulose pellets (prepared at 105.degree. C.) is
significantly slower than that from Eudragit RS pellets (prepared
at 85.degree. C.).
1TABLE 1 EX. 1 Composition Amt. (mg) per Capsule Chlorpheniramine
Maleate 60 Ethyl Cellulose 84 Stearic Acid 36 Total 180
[0079]
2TABLE 2 EX. 2 Composition Amt. (mg) per Capsule Chlorpheniramine
Maleate 60 Eudragit RSPO 84 Stearic Acid 36 Total 180
EXAMPLES 3-6
Ex. 3
[0080] The excipients used in Ex. 2 were employed to make morphine
sulfate controlled release pellets. The drug release rate was
slower than expected especially during later hours of the
dissolution.
Ex. 4-6
[0081] To increase the drug dissolution rate during later hours,
varying amounts of Eudragit L-100 were incorporated in the
formulation. The drug dissolution rate increases with increasing
amount of Eudragit L-100 in the formulation.
3TABLE 3 EX. 3 Composition Amt. (mg) per Capsule Morphine Sulfate
60 Eudragit RSPO 42 Stearic Acid 18 Total 120
[0082]
4TABLE 4 EX. 4 Composition Amt. (mg) per Capsule Morphine Sulfate
60 Eudragit RSPO 38.4 Eudragit L-100 3.6 Stearic Acid 18 Total
120
[0083]
5TABLE 5 EX. 5 Composition Amt. (mg) per Capsule Morphine Sulfate
60 Eudragit RSPO 36 Eudragit L-100 6 Stearic Acid 18 Total 120
[0084]
6TABLE 6 EX. 6 Composition Amt. (mg) per Capsule Morphine Sulfate
60 Eudragit RSPO 33.6 Eudragit L-100 8.4 Stearic Acid (SA) 18 Total
120
[0085] As seen in FIG. 3a, the drug dissolution rate obtained from
the product of Ex. 3 showed a significant pH dependency. The
release rate was slower in SIF (simulated intestinal fluid) than in
SGF (simulated gastric fluid).
[0086] In FIG. 3b, it can be seen that due to the addition of
Eudragit L-100, the drug dissolution rate obtained from Ex. 5 was
less pH dependent. The drug release rate was faster in SIF during
later hours of dissolution which is desirable for complete
bioavailability.
EXAMPLES 7-8
[0087] As demonstrated in FIG. 4, with proper choice of
plasticizers, the drug release rate from the formula containing
Eudragit L-100 can be reduced. This may be necessary to achieve
desirable plasma drug concentration profiles after oral
administration of the pellets.
7TABLE 7 EX. 7 Composition Amt. (mg) per Capsule Morphine Sulfate
60 Eudragit RSPO 33.6 Eudragit L-100 8.4 Stearic Acid (SA) 9
Diethyl Phthalate (DEP) 9 Total 120
[0088]
8TABLE 8 EX. 8 Composition Amt. (mg) per Capsule Morphine Sulfate
60 Eudragit RSPO 33.6 Eudragit L-100 8.4 Stearic Acid (SA) 9
Tributyl Citrate (TBC) 9 Total 120
EXAMPLES 9-10
[0089] A different polymer/wax combination was used as an
alternative formulation. As seen in FIG. 5, the drug dissolution
rate from ethylcellulose/polyvinyl acetate phthalate was somewhat
faster.
9TABLE 9 EX. 9 Composition Amt. (mg) per Capsule Morphine Sulfate
60 Ethyl Cellulose 38.4 Polyvinyl Acetate Phthalate 3.6 Stearic
Acid 18 Total 120
[0090]
10TABLE 10 EX. 10 Composition Amt. (mg) per Capsule Morphine
Sulfate 60 Ethyl Cellulose 34.8 Polyvinyl Acetate Phthalate 7.2
Stearic Acid 18 Total 120
EXAMPLES 11-12
[0091] The formula used in Ex. 5 was applied to oxycodone
hydrochloride. Due to the higher potency of oxycodone, only 20 mg
of drug was used. The missing 40 mg was replaced by 40 mg of talc
(Ex. 12). No replacement was used in Ex. 11. When tested in only
SGF or SIF, the use of Eudragit L causes the formulation to become
less pH dependent. The results are shown in FIG. 6.
11TABLE 11 EX. 11 Composition Amt. (mg) per Capsule Oxycodone
Hydrochloride 20 Eudragit RSPO 36 Eudragit L-100 6 Stearic Acid 18
Total 120
[0092]
12TABLE 12 EX. 12 Composition Amt. (mg) per Capsule Oxycodone
Hydrochloride 20 Eudragit RSPO 36 Eudragit L-100 6 Stearic Acid 18
Talc 40 Total 120
EXAMPLES 13-14
Hydromorphone
[0093] The formula used in Ex. 5 was applied to hydromorphone
hydrochloride. Due to the higher potency of hydromorphone, only 8
mg of drug was used. The missing 52 mg was replaced by 52 mg of
talc (Ex. 14) or 52 mg of excipients (Ex. 13). The results are
shown in FIG. 7.
13TABLE 13 EX. 13 Composition Amt. (mg) per Capsule Hydromorphone 8
Hydrochloride Eudragit RSPO 67.2 Eudragit L-100 11.2 Stearic Acid
33.6 Total 120
[0094]
14TABLE 14 EX. 14 Composition Amt. (mg) per Capsule Hydromorphone 8
Hydrochloride Eudragit RSPO 36 Eudragit L-100 6 Stearic Acid 18
Talc 52 Total 120
EXAMPLE 15
[0095] In this Example, a bioavailability study was undertaken.
Fourteen subjects were given the morphine sulphate formulations of
Example 3. The results are provided in Table 15 below and in FIG.
9.
15 TABLE 15 Group AUC C.sub.max T.sub.max Example 3 Fasted 230 15.7
2.1 Example 3 Fed 213 14.0 3.2
[0096] From the above data, it can be seen that the formulation is
an ideal candidate for an extended release or once-a-day product
without a food effect.
[0097] The examples provided above are not meant to be exclusive.
Many other variations of the present invention would be obvious to
those skilled in the art, and are contemplated to be within the
scope of the appended claims.
* * * * *