U.S. patent application number 13/399245 was filed with the patent office on 2012-06-14 for abuse resistant opioid drug-ion exchange resin complexes having hybrid coatings.
This patent application is currently assigned to Tris Pharma, Inc.. Invention is credited to Alivia Chaudhuri, KETAN MEHTA, Ashok Perumal, Yu-Hsing Tu.
Application Number | 20120148672 13/399245 |
Document ID | / |
Family ID | 46126842 |
Filed Date | 2012-06-14 |
United States Patent
Application |
20120148672 |
Kind Code |
A1 |
MEHTA; KETAN ; et
al. |
June 14, 2012 |
ABUSE RESISTANT OPIOID DRUG-ION EXCHANGE RESIN COMPLEXES HAVING
HYBRID COATINGS
Abstract
A sustained release formulation for opioid drugs is described.
The formulation contains an opioid-ion exchange resin complex
having a hybrid coating. The hybrid coating contains a cured
polyvinylacetate polymer and a pH-dependent enteric coating layer
mixed therein. Also provided are methods of making and using
same.
Inventors: |
MEHTA; KETAN; (Cranbury,
NJ) ; Tu; Yu-Hsing; (West Windsor, NJ) ;
Chaudhuri; Alivia; (Cranbury, NJ) ; Perumal;
Ashok; (Edison, NJ) |
Assignee: |
Tris Pharma, Inc.
Monmouth Junction
NJ
|
Family ID: |
46126842 |
Appl. No.: |
13/399245 |
Filed: |
February 17, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12154970 |
May 28, 2008 |
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13399245 |
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60941169 |
May 31, 2007 |
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Current U.S.
Class: |
424/465 ;
424/400; 424/482; 424/486; 424/78.1; 424/78.13 |
Current CPC
Class: |
A61K 9/10 20130101; A61K
47/61 20170801; A61P 25/04 20180101; A61K 9/5026 20130101; A61K
47/52 20170801; A61K 9/0095 20130101; A61K 9/2081 20130101 |
Class at
Publication: |
424/465 ;
424/400; 424/78.1; 424/78.13; 424/486; 424/482 |
International
Class: |
A61K 9/32 20060101
A61K009/32; A61K 47/48 20060101 A61K047/48; A61P 25/04 20060101
A61P025/04; A61K 9/00 20060101 A61K009/00 |
Claims
1. A coated modified release opioid-ion exchange resin complex
comprising: a pharmaceutically effective amount of an opioid bound
to a pharmaceutically acceptable ion exchange resin complex; a
hybrid modified release coating layer over the resin complex, said
hybrid coating comprising: a pH-independent, high tensile strength,
water permeable, water insoluble, diffusion barrier coating forming
component comprising polyinylacetate (PVA) and a plasticizer and an
enteric coating forming component having pH-dependent solubility in
an aqueous system which is non-reactive with barrier coating
component.
2. The opioid-ion exchange resin matrix according to claim 1,
wherein the opioid drug is selected from the group consisting of
opioid analgesics drugs selected from the group consisting of
hydrocodone, morphine, hydromorphone, oxycodone, codeine,
levorphanol, meperidine, methadone, oxymorphone, buprenorphine,
fentanyl and derivatives thereof, dipipanone, tramadol, etorphine,
dihydroetorphine, butorphanol, levorphanol, or salts thereof or
mixtures thereof.
3. The opioid-ion exchange resin matrix according to claim 1,
wherein the opioid is morphine or morphine sulfate.
4. The coated opioid-ion exchange resin complex according to claim
1, wherein the enteric polymer forming component comprises
polyvinyl acetate phthalate and at least one plasticizer.
5. The coated opioid-ion exchange resin complex according to claim
1, wherein the barrier coating forming component and enteric
polymer forming component are present in a ratio of about 20:1 to
about 3:1 wt/wt.
6. The coated opioid drug-ion exchange resin complex according to
claim 5, wherein the barrier coating forming component and enteric
polymer forming component are present in a ratio of about 6:1 to
4:1 wt/wt.
7. The coated opioid drug-ion exchange resin complex according to
claim 2, wherein the enteric coating forming component comprises a
polyinylacetate phthalate, at least one plasticizer, and one or
more selected from the group consisting of a detackifier, a
lubricant, an alkalizing agent, a viscosity modifier, and an
anti-caking agent.
8. The coated opioid drug-ion exchange resin complex according to
claim 7, wherein the enteric coating forming component comprises a
liquid plasticizer and a solid plasticizer.
9. The coated opioid drug-ion exchange resin complex according to
claim 9, wherein the liquid plasticizer is citroflex
triethylcitrate.
10. The coated opioid drug-ion exchange resin complex according to
claim 9, wherein the solid plasticizer is polyethylene glycol
3350.
11. The coated opioid drug-ion exchange resin complex according to
claim 7, wherein the enteric coating forming component comprises
titanized polyvinylacetate phthalate.
12. The coated opioid drug-ion exchange resin complex according to
claim 1, wherein the barrier coating forming component comprises
about 70% to about 95% w/w polyvinyl acetate.
13. The coated opioid drug-ion exchange resin complex according to
claim 12, wherein the barrier coating forming component comprises
PVA, a stabilizer, a surfactant and a plasticizer.
14. The coated opioid drug-ion exchange resin complex according to
claim 13, wherein the plasticizer comprises about 3 to about 10%
w/w of solids in the barrier coating forming component.
15. The coated opioid drug-ion exchange resin complex according to
claim 13, wherein the plasticizer in the barrier coating forming
component is selected from the group consisting of dibutyl
sebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol,
triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate,
tributyl citrate, triacetin, Soluphor P, and mixtures thereof.
16. The coated opioid drug-ion exchange resin complex according to
claim 15, wherein the plasticizer is triacetin.
17. The coated opioid drug-ion exchange resin complex according to
claim 13, wherein the stabilizer is a polyvinylpyrrolidone.
18. The coated opioid drug-ion exchange resin complex according to
claim 17, wherein the polyvinyl pyrrolidone comprises about 5 to
about 10% w/w of the barrier coating forming component.
19. The coated opioid drug-ion exchange resin complex according to
claim 13, wherein the surfactant is sodium lauryl sulfate.
20. The opioid-ion exchange resin complex according to claim 1,
wherein the hybrid coating comprises 25% to 50% by weight of the
coated complex.
21. The opioid-ion exchange resin complex according to claim 20,
wherein the hybrid coating comprises 30% to 45% by weight of the
coated complex.
22. A solid dose comprising the coated opioid drug-ion exchange
resin complex according to claim 1 and pharmaceutically acceptable
excipients, wherein the opioid-ion exchange resin complex is in a
matrix with at least one polymer to form an opioid-drug ion
exchange resin complex-matrix.
23. The solid dose according to claim 22, wherein the at least one
polymer is selected from the group consisting of a polyvinyl
acetate polymer, polyvinylpyrrolidone, ethyl cellulose, cellulose
acetate, acrylic based polymers or copolymers, cellulose phthalate,
and mixtures thereof.
24. A solid dose modified release morphine formulation comprising:
a pharmaceutically effective amount of morphine bound to a
pharmaceutically acceptable cationic exchange resin complex; a
cured hybrid modified release coating layer over the resin complex,
said hybrid coating comprising a single layer comprising a barrier
forming component comprising polyinylacetate (PVA) and a
plasticizer and an enteric coating component comprising
PVA-phthalate and at least one plasticizer.
25. The solid dose modified release morphine formulation according
to claim 24, wherein the barrier forming component further
comprises polyvinyl pyrrolidone and sodium laurel sulfate.
26. The solid dose modified release morphine formulation according
to claim 24, wherein the enteric coating component further
comprises a liquid plasticizer, a solid plasticizer, and at least
one or more of a detackifier, a lubricant, an alkalizing agent, a
viscosity modifier, and an anti-caking agent.
27. The solid dose modified morphine formulation according to claim
26, wherein the enteric coating component further comprises
citroflex triethylcitrate, talc, sodium bicarbonate, polyethylene
glycol 3350, stearic acid, sodium alginate, and silica.
28. The solid dose modified release morphine formulation according
to claim 24, wherein the cured hybrid coating comprises in about of
20:1 by weight to about 6:1 by weight barrier coating component to
enteric coating component.
29. The solid dose modified release morphine formulation according
to claim 24, wherein the hybrid coating comprises about 30% by
weight of the uncoated complex.
30. The solid dose modified release morphine formulation according
to claim 24, further comprising a solvating agent.
31. The solid dose modified release morphine formulation according
to claim 24, wherein said solid dose is a tablet.
32. The solid dose modified release morphine formulation according
to claim 24, further comprising a non-functional coating on the
cured hybrid coating layer.
33. The solid dose modified release morphine formulation according
to claim 32, wherein the non-functional coating comprises about 2%
by weight of the tablet.
34. The solid dose modified release morphine formulation according
to claim 24, wherein the tablet comprises a morphine-cation
exchange resin complex, at least one filler, at least one
lubricant, and at least one diluent.
35. The solid dose modified release morphine formulation according
to claim 34, wherein the filler comprises about 1 to 70% by weight
of the tablet.
36. The solid dose modified release morphine formulation according
to claim 34, wherein the filler is selected from the group
consisting of calcium silicate, microcrystalline cellulose, lactose
and combinations thereof.
37. The solid dose modified release morphine formulation according
to claim 34, wherein the lubricant comprises about 0.01% to about
5% w/w of the tablet.
38. The solid dose modified release morphine formulation according
to claim 34, wherein the lubricant is selected from the group
consisting of amorphous silica, talc, magnesium stearate, or
combinations thereof.
39. The solid dose modified release morphine formulation according
to claim 34, further comprising a disintegrant comprising about 1
to about 20% w/w of the tablet.
40. The solid dose modified morphine formulation according to claim
39, wherein the disintegrant is crospovidone.
41. A method of delivering a sustained release of morphine over a
period of at least 12 to 24 hours comprising orally administering
to a subject a solid dose modified release morphine formulation
according to claim 34.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 12/154,970, filed May 28, 2008, which is an
application that claims the benefit under 35 USC 119(e) of U.S.
Provisional Patent Application No. 60/941,169, filed May 31, 2007,
now expired.
BACKGROUND OF THE INVENTION
[0002] Opioids are commonly prescribed because of their effective
analgesic, or pain-relieving, properties. Medications that fall
within this class, referred to as prescription narcotics, include
morphine sulfate (e.g., Kadian.RTM., Avinza.TM.), codeine salts,
oxycodone HCl (e.g., OxyContin.TM., Percodan.TM., Percocet.TM.),
and related drugs. For example, OxyContin.TM. tablets are presently
commercially available in 10, 20, 40, 80, and 160 milligrams forms.
Morphine, for example, is often used before and after surgical
procedures to alleviate severe pain. Codeine, on the other hand, is
often prescribed for mild pain. In addition to their pain-relieving
properties, some of these drugs can be used to relieve coughs and
diarrhea. Codeine and diphenoxylate (Lomotil.TM.) are examples of
such drugs. However, opioid drugs are at times associated with side
effects including, e.g., stomach upset and other gastrointestinal
effects. Further, because of the sometimes addictive properties of
these drugs and the euphoria which can be associated with taking
them, including through routes other than those prescribed, these
opioid drugs are particular susceptible to abuse.
[0003] In order to reduce some of the gastrointestinal effects of
these drugs, sustained release dosage forms have been described.
For example, a sustained-release dosage form for morphine sulfate
has been described [WO 2006/124898], in which a morphine sulfate
core is coated with a matrix polymer insoluble at pH 1 to 7.5, an
enteric polymer soluble at pH 6 to 7.5, and an acid soluble polymer
which is soluble at pH 1 to 4, and having a ratio of acid soluble
polymer to enteric polymer of 1.45:1 to 2.5:1 on a weight basis.
Certain sustained release formulations are commercially available
under the trademark Kadian.RTM. and are currently available in 20,
30, 50, 60 and 100 mg capsules.
[0004] Attempts to reduce abuse of opioid by pharmacological
methods have been made. One such attempt involves including an
"opioid antagonist" along with the opioid "agonist". These
antagonists cannot be easily extracted from the agonist and will
cause an aversive effect in a physically dependent patient.
However, these antagonists may have other side effects which may be
disadvantageous.
[0005] One attempt to reduce opioid abuse and avoid the use of an
agonist-antagonist combination has been described in US
2005/0163856A1, published Jul. 28, 2005. This patent application
describes an oxycodone formulation designed to provide a pH
independent release rate with a peak plasma level between 5-6 hours
after administration. The formulation provides an oxycodone mixed
with 40-65 wt % matrix forming polymer and 5 to 15 wt % of an ion
exchange resin.
[0006] Ion exchange resins coated with a diffusion barrier coating
have been described for the preparation of sustained release
systems for preparing sustained release formulations. See,
US-2006-0115529; WO 2006/101536; WO 2005/117843; US-2005-0265955
A1; WO 01/070194; U.S. Pat. Nos. 4,221,778, 4,996,047, 4,221,778
and 4,861,598. For example, U.S. Pat. No. 6,001,392 granted Dec.
14, 1999 describes certain acrylate based (e.g., EUDRAGIT polymer
system) and ethyl cellulose (e.g., SURELEASE, AQUACOAT) polymers
for coating a drug-ion exchange resin complex using either a
solvent or aqueous based coating to achieve sustained release of
the drug from the drug-ion exchange resin complex. There appears to
be no meaningful data regarding the integrity of the coating film.
Further, there is no data in the '392 patent of prolonged release
of the drug from the coated drug-ion exchange resin complex beyond
about 12 hours. There have been literature-reported drawbacks of
using ethyl cellulose based aqueous dispersions as coatings for
drug-ion exchange resin complexes.
[0007] Enteric coatings have been described as delayed release
polymers for providing an initial delay in drug release. See, e.g.,
U.S. Pat. No. 6,756,057 for amoxicillin and U.S. Pat. No. 6,555,127
for methylphenidate. Enteric coatings are also used for protecting
the body from drugs which cause gastric irritation (e.g., naproxen
which is commercially available as enteric coated tablet and
capsule formulations).
[0008] US-2006-0115529 and WO 2006/101536 describe the use of film
coatings for a fast melt tablet containing ion exchange resin
complex particles mixed with a dry binder and bulk diluent. One
suitable coating described is the KOLLICOAT SR30D polymer system.
Optional use of an enteric coat which is insoluble in acidic pH and
soluble in basic pH is described.
[0009] US-2004-0126428 describes a product which is described as
being abuse resistant. This product contains a core comprising a
resinate of an opioid formed from the drug (e.g., morphine sulfate)
and an ion exchange resin. A multi-component coating may also
applied to the core, which contains (a) from 1 to 85% by weight of
a matrix polymer which is insoluble at a pH of from 1 to 7.5 and
contributes to the control of the rate of release of the active
ingredient in the stomach and intestines; (b) from 1 to 30% of an
enteric polymer which is substantially insoluble at a pH of from 1
to 4, sufficient to delay the release of the active ingredient in
the stomach, but which is soluble at a pH of from 6 to 7.5 so as
not to substantially delay release in the intestines; (c) from 1 to
60% of a compound soluble at a pH of from 1 to 4.
[0010] US 2003-0099711 A1 describes using an ethyl cellulose
polymer in an aqueous based coating system as a barrier coating.
This publication further describes use of an optional enteric
coating over the barrier coating to delay the drug release.
[0011] Opioid drug formulations which provide a desired sustained
release profile without requiring an agonist-antagonist combination
to reduce abuse are desirable from a commercial drug
perspective.
SUMMARY OF THE INVENTION
[0012] The present invention provides a modified release tablet
formulation of an opioid drug bound to an ion exchange resin,
coated with a hybrid coating comprising a barrier coating
containing a polyvinyl acetate polymer and a plasticizer and an
enteric polymer mixed therewith.
[0013] Advantageously, the combination of sustained release
provided by the complexation of the opioid drug with the ion
exchange resin and the hybrid layer coating comprising the barrier
coating component and the enteric coating component, provide a
desired modified release profile while also providing favorable
abuse resistance properties.
[0014] In one embodiment, the drug-ion exchange resin complex
further comprises a solvating agent or a release retardant.
[0015] In a further embodiment, the invention provides a solid dose
modified release morphine formulation. This formulation may be a
tablet or a capsule containing granules of the invention and
contains a pharmaceutically effective amount of morphine bound to a
pharmaceutically acceptable cationic exchange resin complex. The
complex is provided with a cured hybrid modified release coating
directly thereon. The hybrid coating comprises a single cured layer
comprising a uniform mixture of a barrier forming component
containing at least a polyvinylacetate (PVA) polymer system and a
plasticizer and enteric coating forming component preferably
containing at least a PVA-phthalate and at least one
plasticizer.
[0016] The invention further provides a method of administering an
opioid drug (e.g., morphine) for a sustained period, the method
comprising administering a formulation of an opioid drug bound to
an ion exchange resin, coated with a hybrid coating as described
herein.
[0017] Other aspects and advantages of the invention will be
readily apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention provides an opioid drug-ion exchange
resin complex having a cured hybrid coating composed of a
water-insoluble, water-permeable based diffusion barrier coating
component and an enteric coating component. This cured, hybrid
coated opioid-drug ion exchange resin complex of the invention
provides desirable modified release properties while also providing
desired abuse resistance.
[0019] The "barrier coating component" is a polyvinylacetate-based
polymeric system, containing a plasticizer. Polyvinyl acetate, due
to its high tensile strength in the presence of a plasticizer(s),
provides a flexible coating film for use as the water-permeable
diffusion barrier coating that maintains its film integrity even
when subjected to severe physical force and stress such as during a
compression step in a tabletting machine or the grinding action of
a coffee beans grinder, mill, etc. As described herein, this
material remains substantially non-tacky and process-friendly with
the addition of a plasticizer during the coating operation in a
Wurster fluid bed or other coating operation and do not cause
agglomeration during the coating of very fine particles of drug-ion
exchange resins. Agglomeration (sometimes termed "caking" or "brick
formation") during a coating operation may otherwise impede the air
flow, destroy flow pattern, and/or clog the spray nozzle, thereby
increasing the possibility of an imperfect and uneven coating of
the drug-ion exchange resin particles.
[0020] As used herein, the term "enteric coat component" refers to
a polymer system having pH-dependent solubility. More particularly,
an enteric coat component used in the present invention is
insoluble in an aqueous system at acidic pH, e.g., in the range
typically found in the stomach, but soluble at higher pH such as
are found in the lower gastrointestinal tract. In one embodiment,
the enteric coat component is insoluble at pH 1 to about 5.5 and
soluble at a pH above about 5.5 in an aqueous system (e.g., gastric
juices). Further, the enteric polymer selected for use in the
invention is compatible with the barrier coating component of the
hybrid coat. More particularly, the enteric coating polymer(s) is
non-reactive with the barrier coating, i.e., does not form a gel or
gel-like substance, and allows uniform application of the hybrid
coating to the resin. For example, in one embodiment, the barrier
coating component is a polyvinylacetate-based polymeric system; the
inventors found that a mixture of this polymeric system with a
water insoluble methacrylic acid:acrylic acid ethylester 1:1
copolymer enteric coating polymers [commercially available as
Eudragit.TM. L30 D55] reacted to form a gel-like substance which
could not be satisfactorily applied as a coating material. In
another example, another methacrylic acid:ethylacrylic acid
copolymer [commercially available as a 30% dispersion under the
name Eudragit L100 55] when mixed with the barrier coating
component was found to cause undesirable "clumping" or clogging of
the coating apparatus when mixed with the barrier coating component
and prevented uniform application of the hybrid coating.
[0021] One particularly suitable enteric polymer is a
polyvinylacetate phthalate (PVAP) based system, which the inventors
found to combine and mix well with the polyinylacetate-based
barrier coating. One such enteric polymer system is available
commercially as SURETERIC.TM., which is described in U.S. Pat. No.
5,733,575 (see, particularly example 1), the disclosure of which is
incorporated by reference herein. The '575 patent describes an
enteric polymer system which, in one embodiment, is formed by the
mixture of PVAP with a liquid plasticizer, a solid plasticizer, a
detackifier and a lubricant. Suitably, the enteric polymer system
also contains an alkalizing agent, a viscosity modifier, an
anti-caking agent, and may include an anti-foam solution to prevent
foaming during preparation. The final enteric polymer solution is
passed through a 60 mesh screen. The '575 patent describes the use
of titanized PVAP or jet milled PVAP. In Example 1, titanized PVAP
is utilized, which is described earlier in the document as having
10% titanium dioxide mixed into the PVAP while it is being made.
The SURETERIC.TM. enteric dry powder composition is prepared as
described in Example 1 of the '575 patent, by mixing the liquid
plasticizer Citroflex triethylcitrate into titanized PVAP, the
alkalizing agent sodium bicarbonate, the solid plasticizer
polyethylene glycol 3350, the lubricant stearic acid, the viscosity
modifier sodium alginate, and Cabosil Eh5 silica (anti-caking), and
mixing in water with an antifoaming solution. Other suitable PVAP
systems useful in the invention may be designed taking into
consideration this information and the desirable enteric polymer
system properties described herein.
[0022] Advantageously, the hybrid coating material of the present
invention is sufficiently flexible that it can withstand the amount
of pressure applied during compression of the coated drug-ion
exchange resin particles into tablet or granular form. Further,
following oral delivery and after passing through the stomach and
into the higher pH level of the lower gastrointestinal tract, the
pH-dependent, water-soluble enteric polymer (e.g., PVAP based
system) begins to dissolve. Thus, the enteric polymer component of
the hybrid coating serves as a pH-dependent pore-former which
provides initial delayed release to the dosage unit, whereas the
water permeable barrier coating polymer system (polyvinyl
acetate-based system) continues to control release. These solid
oral dose units are believed to function in a manner similar to a
multiparticulate system; more particularly, the tablet or capsule
disintegrates in the stomach to release the particles (granules),
which release active drug evenly and reduce variability in the
release profile.
[0023] Thus, the drug release pattern from the compositions of the
present invention is controlled or modified by combining at least
one opioid drug (e.g., morphine sulfate) and an ion exchange resin
(e.g., a cationic resin) to form the drug-resin complex prior to
the application of the hybrid water-permeable diffusion barrier
coating-enteric coating layer.
[0024] Optionally, other water-insoluble polymers may be included
in the drug-ion exchange resin complex, including a single polymer
or mixtures thereof, such as may be selected from polymers of ethyl
cellulose, polyvinyl acetate, cellulose acetate, polymers such as
cellulose phthalate, acrylic based polymers and copolymers (such
as, for example, those available under EUDRAGIT brand name) or any
combination of such insoluble polymers or polymer systems herein
defined as a "release retardant". The drug-ion exchange resin
complex with or without a "release retardant" may be formulated to
achieve the desired length of time of drug release rate from such
drug-ion exchange resin complexes. Such coating systems could be
further customized by the incorporation of individual or a
combination of hydrophilic or lipophilic plasticizers with a
dispersion or suspension containing the barrier coating polymer.
Such plasticizers include, e.g., propylene glycol, polyethylene
glycol, triacetin, triethyl citrate, dibutyl sebacate, vegetable
oil, lipids, etc.
[0025] As used herein, the term "modified release" refers to
compositions of the invention which are characterized by having a
drug release from a drug-ion exchange complex of the invention over
a period of at least about 12 hours, and preferably up to about 24
hours. The release profile may be assessed using in vitro
dissolution assays known to those of skill in the art [e.g., USP
basket method or Paddle Method, or channel flow method]. The
release profile can be assessed in vivo (e.g., for bioequivalence
determinations), using plasma concentrations to assess maximum
concentration (Cmax) and area under the curve (AUC). Such assays
are well known to those of skill in the art.
[0026] For example, a modified release composition of the invention
can be tailored to at least essentially match the in vivo release
profile of a commercially available prescription opioid modified
release composition. In one embodiment, the composition of the
invention is tailored to meet the in vivo release profile of a 12
hour or 24 hour product, e.g., such as the sustained release
morphine sulfate KADIAN.RTM. morphine sulfate capsules, Avinza.RTM.
morphine sulfate, MS CONTIN.RTM. morphine sulfate or a
OxyCONTIN.RTM. oxycodone product [in vivo release profiles
published in product literature, also available from Kadian.RTM.
web cite and the Physician's Desk Reference]. See, also, U.S. Pat.
Nos. 5,508,042; 5,266,331; 5,549,912; 5,656,295, for a description
of the release profile of the Kadian.RTM. release profile. See,
also, U.S. Pat. No. 5,672,360.
[0027] In one embodiment, a tablet prepared from the hybrid coated
ion exchange resin complex of the invention provides an in vitro
dissolution rate of about 5 to about 20% in 1 hour, about 30% to
about 50% in 2 hours, about 70% to about 85% in 4 hours, and more
than 90% in 12 hours, e.g., as measured by the USP Paddle Method. A
capsule containing granules can be designed to provide a similar
release rate. The product is expected to provide an in vivo
therapeutic effect lasting for at least 12 up to about 24
hours.
[0028] The term "modified release" may include, e.g., compositions
which are extended release formulations (also termed "prolonged
release formulation"), sustained release formulations, certain
pulse delivery systems, or delay release formulations.
[0029] The hybrid coated opioid-ion exchange resin complexes of the
invention and formulations (Example 2) containing the complex
provide desirable abuse resistance properties. Certain commercial
opioid products, such as Kadian.RTM. morphine sulfate, report in
its product literature that the capsules are to be swallowed whole
or sprinkled in applesauce. The pellets in the Kadian.RTM. morphine
sulfate capsule are not to be chewed, crushed or dissolved, all of
which would lead to rapid release and absorption of morphine. The
OxyContin.RTM. oxycodone product literature contains a similar
warning for its oxycodone product. The hybrid coated opioid-ion
exchange resin complex of the invention is designed to provide an
advantage in delaying release of active over products which could
provide an almost immediate release of such active opioid
ingredient upon such abuse of such product.
[0030] Further properties of the hybrid coating system of the
present invention are discussed below.
[0031] As used herein in reference to numeric values provided
herein, the term "about" may indicate a variability of as much as
10%.
[0032] A detailed description of the components of the compositions
of the present invention follows.
Opioid Drugs
[0033] The formulations of the invention are particularly well
suited for oral dosage units containing opioid drugs having abuse
potential. In one embodiment, these oral dosage units are solid
dosage units. However, these formulations are adaptable to other
types of dosage units (e.g., suspension, etc) and other active
components.
[0034] In one embodiment, the opioid drugs are used in the
treatment of respiratory tract disorders such as, for example,
antitussive expectorants such as dihydrocodeine phosphate, codeine
phosphate, and noscapine hydrochloride. In another embodiment, the
opioid drugs are analgesics drugs such as hydrocodone, morphine,
hydromorphone, oxycodone, codeine, levorphanol, meperidine,
methadone, oxymorphone, buprenorphine, fentanyl and derivatives
thereof, dipipanone, tramadol, etorphine, dihydroetorphine,
butorphanol, levorphanol, or salts thereof or mixtures thereof. In
one embodiment, the opioid is morphine, oxycodone, hydrocodone, or
a salt thereof. In one embodiment, a morphine salt is morphine
sulfate; an oxycodone salt is oxycodone HCl; and a codeine salt is
codeine sulfate or phosphate.
[0035] The pharmaceutically acceptable salts include, but are not
limited to, inorganic acid salts such as hydrochloride,
hydrobromide, sulfate, phosphate and the like; organic acid salts
such as formate, acetate, trifluoroacetate, maleate, tartrate and
the like; sulfonates such as methanesulfonate, benzenesulfonate,
p-toluenesulfonate, and the like; amino acid salts such as
arginate, asparginate, glutamate and the like. Other suitable salts
will be readily apparent to one of skill in the art.
[0036] In certain embodiments, the amount of the opioid drug in the
composition may be about 1 mg to 250 mg. In another embodiment, the
amount of the opioid drug in the composition is about 5 mg to about
200 mg. In still another embodiment, the amount of the opioid drug
in the composition is about 10 mg to about 150 mg. The preceding
list is not intended to be exclusive. In some embodiments, the
composition of the invention is designed to provide a release
profile similar to a commercially available product. In such an
instance, the present invention provides an equivalent amount of
active opioid to the commercially available product based on
weight. In another embodiment, the present invention provides an
amount of active opioid bioequivalent to the commercially available
product, i.e., provides a finished formulation having an in vivo
release profile similar that of the commercial product. This can be
readily determined by taking into consideration the molecular
weight of the free base of the opioid drug bound to the resin, as
compared to the compound in the commercial product, and further
taking into consideration the percentage of active drug loaded on
the resin. These calculations are well within the skill of one in
the art.
Ion-Exchange Resin
[0037] Ion-exchange resins suitable for use in these preparations
are water-insoluble and comprise a preferably pharmacologically
inert organic and/or inorganic matrix containing functional groups
that are ionic or capable of being ionized under the appropriate
conditions of pH. Typically the size of the ion-exchange particles
is from about 10 microns to about 420 microns, preferably the
particle size is within the range of about 40 microns to about 250
microns for solid dosage forms, e.g., tablets and granules placed
in capsules. Particle sizes substantially below the lower limit are
generally difficult to handle in all steps of the processing.
Generally, uncoated drug-ion exchange resin particles of the
invention will tend to be at the lower end of this range, whereas
coated drug-ion exchange resin particles of the invention will tend
to be at the higher end of this range. However, both uncoated and
coated drug-ion exchange resin particles may be designed within
this size range. For additional discussion of ion exchange resins,
see, e.g., co-pending US Patent Publication No. US 2007-02155A1,
published Sep. 20, 2007, [application Ser. No. 11/724,966, filed
Mar. 15, 2007, entitled "Modified release formulations containing
drug-ion exchange resin complexes"] and its international
counterpart WO 2007/109104, published Sep. 27, 2007, which are
incorporated by reference.
[0038] A suitable ion exchange resin is selected depending upon the
charge of the active opioid or its salt. For example, cation
exchange resins are well suited for use with drugs and other
molecules having a cationic functionality, including, e.g.,
oxycodone, morphine, hydrocodone, oxymorphone, and hydromorphone,
as well as prodrugs, salts, isomers, polymorphs, and solvates
thereof. Cationic exchange resins have been described in the art
and also commercially available. Examples of commercially available
cationic resins include, without limitation, Dow XYS-40010.00 and
Dow XYS-40013.00 (The Dow Chemical Company), Amberlite IRP-69 (an
insoluble, strongly acidic, sodium polystyrene cation exchange
resin), Amberlite IRP-64 (weekly acidic), Amberlite IRP-120 (Rohm
and Haas), Amberlite IRP-88 (weakly acidic). Amberlite IRP-69 (Rohm
and Haas) is sulfonated polymers composed of polystyrene
crosslinked with 8% of divinylbenzene, with an ion exchange
capacity of about 4.5 to 5.5 meq/g of dry resin. It consists of
irregularly shaped particles with a size range of 47 to 149
microns. A series of cationic resins are also available from DOW
Chemical as the DOWEX.TM. 50WX series (Dow Chemical Company). There
are mainly four products with different particle size distribution:
cut-off mesh size is US Sieve No. 50 (300 microns) in the case of
Dowex.TM. 50WX2-50, 100 (150 microns) in Dowex.TM. 50WX2-100, 200
(75 microns) in Dowex.TM. 50WX2-200, and 400 (38 microns) in
Dowex.TM. 50WX2-400. Crosslinking is another important factor,
which can influence physical properties, equilibrium conditions,
drug loading, and drug release profiles. Resins of various degrees
of permeability are dependent on the divinylbenzene content, which
was described as the degree of resin crosslinkage and the number
after X is the percentage of divinylbenzene in the resin polymer.
For example, Dowex.TM. 50WX2-50 contains 2% divinylbenzene with
particle size is bigger than 50 mesh. Total exchange capacity of 2,
4 and 8% crosslinkage resins are 0.6, 1.1 and 1.7 meq/ml,
respectively. Still other ion exchange resins are available from
Sigma-Aldrich.
[0039] Both strongly acidic and weakly acidic resins (e.g.,
cationic resins) are commercially available and can be selected for
use. However, it will be understood that the strength of the bond
between the opioid drug and the resin will be affected by whether
the resin is strongly acidic or weakly acidic. More particularly, a
stronger bond will typically be formed by the strongly acidic resin
and thus, drugs loaded thereon will have a slower release profile
than those loaded on a weakly acidic resin. Thus, one of skill in
the art can select the desired type of resin to achieve a desired
release profile, further taking into consideration such factors as
the use of a release retardant, the thickness of the hybrid
coating, and the ratio of barrier coating component to enteric
coating component.
[0040] Other suitable resins can be selected by one of skill in the
art, taking into consideration the charge of the free base or salt
form of a desired opioid drug.
[0041] The selected ion-exchange resins may be further treated by
the manufacturer or the purchaser to maximize the safety for
pharmaceutical use or for improved performance of the compositions.
Impurities present in the resins may be removed or neutralized by
the use of common chelating agents, anti-oxidants, preservatives
such as disodium edetate, sodium bisulfate, and so on, by
incorporating them at any stage of preparation either before
complexation or during complexation or thereafter. These impurities
along with their chelating agent to which they have bound may be
removed before further treatment of the ion exchange resin with a
release retardant and diffusion barrier coating.
Opioid Drug-Ion Exchange Resin Complexes
[0042] Binding of the selected opioid drug or a combination of
drugs including at least one opioid drug to the ion exchange resin
can be accomplished using methods known in the art. See, e.g.,
co-pending US Patent Publication No. US 2007-02155A1, published
Sep. 20, 2007, [application Ser. No. 11/724,966, filed Mar. 15,
2007, entitled "Modified release formulations containing drug-ion
exchange resin complexes"] and its international counterpart WO
2007/109104, published Sep. 27, 2007, and the documents cited
therein, incorporated by reference.
[0043] The amount of drug that can be loaded onto a resin will
typically range from about 1% to about 75% by weight of the
drug-ion exchange resin particles. A skilled artisan with limited
experimentation can determine the optimum loading for any drug
resin complex, taking into such consideration as the desired amount
of active drug and the desired size of the final dose formulation.
For example, to reduce the size of a formulation or to increase the
amount of active drug, a higher loading percentage may be used.
Conversely, where a lesser amount of active drug is desired, a
loading percentage at the lower end of this range may be provided.
In one embodiment, loading of about 10% to about 40% by weight,
more desirably, about 15% to about 30% by weight, of the drug-ion
exchange resin particles can be employed. Typical loadings of about
25% by weight of the drug-ion exchange resin particles can be
advantageously employed.
[0044] Thus, in one aspect, the invention provides drug-ion
exchange resin complexes comprising an opioid drug loaded in an ion
exchange resin as described herein. The drugs and ion exchange
resins may be readily selected from amongst those drugs and resins
described herein. The invention further provides drug-ion exchange
resin matrixes defined as follows.
Release Retardants
[0045] The drug release rate from the compositions of the present
invention may be further prolonged or modified by treating the
drug-ion exchange resin complex prior to the application of the
hybrid coating described herein, with a release retardant which is
a water-insoluble polymer or a combination of a water-insoluble
polymers.
[0046] Advantageously, the release retardant does not form a
separate layer on the drug-ion exchange resin complex, but forms a
matrix therewith. Examples of suitable release retardants include,
for example, a polyvinyl acetate polymer or a mixture of polymers
containing same (e.g., KOLLICOAT SR 30D), cellulose acetates,
ethylcellulose polymers (e.g., AQUACOAT.TM. ECD-30 or
SURELEASE.TM.), acrylic based polymers or copolymers (e.g.,
represented by the EUDRAGIT family of acrylic resins), cellulose
phthalate, or any combination of such water-insoluble polymers or
polymer systems, all herein defined as "release retardants". These
retardants when used may further prolong or alter the release of
the drug from the coated drug-ion exchange resin complex and
maximize attaining the desired release profile. Further, use of a
release retardant permits in some cases lowering the amount of
coating thickness needed to attain a prolonged drug release of up
to 24 hours. These retardants can be used in either substantially
pure form or as a commercial preparation obtained from a vendor.
The preferred release retardant is a polyvinyl acetate polymer
system, e.g. the KOLLICOAT SR30D system, as described herein or an
acrylic polymer from the EUDRAGIT family. Examples of suitable
acrylic polymers from the EUDRAGIT family may include, e.g., a
copolymer comprising ethyl acrylate and methyl methacrylate (e.g.,
EUDRAGIT NE-30D), or EUDRAGIT RS, RL30D, RL100, or NE, which are
largely pH-independent polymers; less desirable, certain
pH-dependent members of the EUDRAGIT polymer family, e.g., the L,
S, and E, polymers may be selected].
[0047] The quantity of polymer that is added as a release retardant
typically ranges from about 3% to about 30% or more by weight of
the uncoated drug-ion exchange resin particles. More preferably the
release retardant, if used, is in the range from about 5% to about
20% and most preferably in the range of about 10% to about 15% by
weight of the uncoated drug-ion exchange resin particles, depending
on the nature of the drug-ion exchange resin complex and the
desired release profile of the medicinal agent(s). In one
embodiment, the composition of the invention is designed to match
the in vivo release profile of a commercially available
drug(s).
[0048] These release retardants can be added during the formation
of the drug-ion exchange resin complex either in the beginning,
during the middle, or after substantial amount of complex formation
has taken place. In the more preferred embodiment, the retardant is
added after the formation of drug-ion exchange resin complex. Upon
mixing, the drug-ion exchange resin complex particles with the
release retardant, the mixture is dried and milled appropriately.
In some cases, the milling may be carried out before the complete
drying of the complex and then again further drying followed by
milling to obtain the desired complex characteristics.
[0049] The release rate of the present aqueous based hybrid coating
of the invention which are designed to provide finished dosage
orally ingestible pharmaceutical compositions such as tablets,
capsules, etc. are tailored to provide the desired drug release
profile over a period of about 8 to 24 hours, and preferably 12 to
24 hours.
[0050] This programmable release rate may be controlled by the
hybrid coating thickness and optionally, the use of "a release
retardant" component as described above, added to the drug-ion
exchange resin complex to form a fine particulate matrix prior to
the polymer film coating step. The release retardant is preferably
a water insoluble polymer as previously described such as a PVA
dispersion which has the same or similar composition of solids as
the preferred aqueous based film forming coating polymer dispersion
described herein used in the coating step or an acrylic based
polymer available commercially under the EUDRAGIT.TM. brand name,
manufactured by Degussa (previously manufactured by Rohm Pharma
Polymers). The properties of different EUDRAGIT.TM. compositions
commercially available are described in literature from Degussa or
Rohm Pharma and are also described in U.S. Pat. No. 6,419,960
(column 10-11), the disclosure of which is incorporated herein by
reference. Other water insoluble polymers include those listed in
column 10, lines 41-53 of U.S. Pat. No. 6,419,960 the disclosure of
which is incorporated herein by reference.
[0051] Another embodiment is the use of an impregnating (solvating)
agent as a release retardant incorporated into the pharmaceutically
acceptable drug ion-exchange resin complex prior to addition of the
aqueous based coating. This impregnating (solvating) agent is a
hydrophilic (water soluble) agent exemplified by those materials
described for example in U.S. Pat. No. 4,221,778 and published US
Patent application Publication No. US 2003/009971 A1, the
disclosures of which are incorporated herein by reference. Specific
examples of suitable impregnating agents include propylene glycol,
polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone
(e.g., KOLLIDON.TM. K30) mannitol, methyl cellulose, hydroxypropyl
methylcellulose, hydroxypropyl cellulose, and sorbitol.
[0052] In one embodiment, the coated drug-ion exchange resin
complex particles are mixed in the presence of a granulating agent,
to aid in providing particles with a relatively even particle size
range. The granulating agent can be one or more substances that do
not adversely react with the other components of the complex and/or
the active ingredient(s). Suitable granulating agents include the
release retardant, solvating agent, sweetener(s) and the like.
[0053] Suitably, the resulting drug-ion exchange resin complexes
are of a size in the range of about 20 microns to 420 microns,
which are predominantly in the range of about 40 microns to about
250 microns, with particles up to about 420 micron being used for
solid dosage forms, e.g., tablets and granules in capsules. It has
been found that particles above about 420 microns have a somewhat
undesirable mouth feel following administration.
Coating System
[0054] Suitably, the present invention provides a hybrid coating is
a cured coating composed of a water permeable, water insoluble
barrier coating component comprising at least a polyvinyl acetate
polymer and a plasticizer, and an enteric polymer component which
is insoluble in aqueous systems at the pH of the stomach and
soluble in aqueous systems at the higher pH of the gastrointestinal
tract. The water permeable, water insoluble barrier coating
comprises a blend of polymers comprising a polyvinyl acetate
polymer and polyvinylpyrrolidone. The plasticizer facilitates
uniform coating of the drug-ion exchange resin complex and enhances
the tensile strength of the barrier coating component and thus, the
hybrid coating.
[0055] The aqueous based dispersions that are used to provide a
diffusion barrier coating component of the hybrid coating are
characterized by having a relatively low tackiness in either the
absence or presence of plasticizer(s) and provide a high percent
elongation of the polymer film (elasticity) at break in the
presence or absence of plasticizer(s). More specifically, the
polymer film coating is characterized by exhibiting a tackiness as
measured by the Hossel method described by P. Hossel, Cosmetics and
Toiletries, 111 (8) 73 (1996) at 20.degree. C./80% RH and
30.degree. C./75% RH of about 2 or less in the presence or absence
of a plasticizer and preferably about 0.5 or less.
[0056] The relatively low tack barrier coating component of the
present invention provided by a polyvinyl acetate (PVA) polymer
facilitates more rapid and easier processing of the coating
composition and permits use of lower quantities of plasticizer.
This provides for enhanced elongation (elasticity) and flexibility
of the coating, a desirable property of the polymer without
significantly increasing tackiness to undesirable levels due to use
of a plasticizer.
[0057] Thus, the selection criteria for the plasticizer
incorporated into the aqueous based polymer dispersion composition
is to enhance high flexibility or elongation (elasticity) of the
coating at break measured by the texture analyzer TA-XT2 HiR
(Stable Microsystems) and by the method reported by the
manufacturer in its literature [i.e., Jan-Peter Mittwollen,
Evaluation of the Mechanical Behavior of Different Sustained
Release Polymers, Business Briefing: Pharmagenerics, 2003, pp. 1-3,
BASF], of at least about 100%, of at least about 125% and
preferably in a range between about 150% to about 400% while not
substantially increasing the tackiness of the polymer film greater
than about 2 (wherein the film is measured by the Hossel method
referenced above independent of any composition on which it has
been deposited). The higher elasticity ranges are usually achieved
with coatings of the present invention through the use of a
relatively small amount of plasticizer. By using relatively small
amount of plasticizer, the plasticizer does not achieve high enough
levels to negatively effect the properties of the coating. It has
been found that these objectives are achieved by using a relatively
lower percent by weight of the selected plasticizer(s) based on the
percent by weight of the solids in the aqueous based film forming
polymer composition.
[0058] Generally, a plasticizer is used in the percent range, or a
mixture of plasticizers combine to total, about 2 to about 30% by
weight (solids content) of the coating layer, more preferably about
2.5% to about 20% by weight of the coating layer on the coated
drug-ion exchange resin complex. Preferably a plasticizer in range
of about 3% to about 10% by weight of the coating layer based on
the coated complex provides desirable properties. However,
depending upon tabletting conditions, amounts of plasticizers in
the higher end of the general range provided may be desired (e.g.,
for high pressure compression).
[0059] Suitable plasticizers are either water soluble or water
insoluble. Examples of suitable plasticizers include, e.g., dibutyl
sebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol,
triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate,
tributyl citrate, triacetin [a triester of glycerol and acetic
acid, also known by the chemical name 1,3-diacetyloxypropane-2-yl
acetate], and Soluphor.RTM. P [2-pyrrolidone, BASF Corp], and
mixtures thereof. Other plasticizers are described in patent
application publication US 2003/0099711 A1, May 29, 2003, page 4
(0041) the disclosure of which is incorporated herein by
reference.
[0060] The barrier coating component is an aqueous bases polyvinyl
acetate (PVA) polymer based aqueous coating dispersion which is
mixed with a plasticizer as described herein. The PVA is insoluble
in water at room temperature. The PVA may be used in either
substantially pure form or as a blend. A commercial blend contains
primarily a polyvinyl acetate polymer, a stabilizer, and minor
amounts of a surfactant such as sodium lauryl sulfate. More
specifically, the preferred aqueous based coating solution is
KOLLICOAT SR 30 D (BASF Corporation) and whose composition is about
27% PVA polymer, about 2.7% polyvinylpyrrolidone (PVP), about 0.3%
sodium lauryl sulfate (solids content 30% w/w). See, also, U.S.
Pat. No. 6,066,334, which is incorporated by reference herein. The
PVP and surfactant help stabilize the aqueous dispersion of the
PVA. Generally, such stabilizing components are present in an
amount totaling less than about 10% w/w, and preferably less than
about 5% w/w. In one embodiment, if a substantially pure form of
PVA is used, it can be dissolved in a suitable non-aqueous solvent
with the enteric polymer component to form the hybrid coating
solution for the drug ion-exchange resin complex.
[0061] Where the hybrid coating comprises a PVA polymer in the
barrier coating component, the PVA polymer is present in an amount
of about 70% to about 90% w/w of the barrier coating component, at
least about 75%, at least about 80%, about 85% w/w of the barrier
coating component.
[0062] Where the barrier coating component also comprises PVP as a
stabilizer component (e.g., as is present in KOLLICOAT.TM. SR 30D),
the barrier coating component generally contains about 5 to about
10% w/w of polyvinyl pyrrolidone.
[0063] As described above, the enteric coating selected for use in
the present invention is a polymer which is insoluble at acidic pH
in an aqueous system, e.g., in gastric juices, but soluble at
higher pH such as are found in the lower gastrointestinal tract and
is non-reactive with the barrier coating. In one embodiment, where
the barrier coating comprises polyvinylacetate, the enteric coating
comprises a polyvinylacetate phthalate system.
[0064] According to the present invention, the components of the
hybrid coating, including, the barrier coating polymer component
and the enteric coating component are mixed in order to form a
homogenous mixture of the heterogeneous components. In one
embodiment, the barrier coating component and the enteric coating
component are dispersed in an aqueous based system, mixing at room
temperature for a sufficient period of time to ensure uniform
distribution of the component. Where a non-aqueous based system is
used, a suitable solvent for both the barrier coating component and
the enteric coating component is selected. One suitable solvent
system may include, e.g., methylene chloride.
[0065] In one embodiment, the hybrid coating contains about 20:1 to
about 3:1, based on solids content, of barrier coating component to
enteric coating component. In a further embodiment, the hybrid
coating contains 10:1 to 4:1, or about 6:1 to 4:1 barrier coating
to enteric coating, based on solids content.
[0066] Suitably, the hybrid coating is applied as an aqueous
dispersion using coating techniques such as are described herein,
e.g., the WURSTER process. Alternatively, other coating techniques
which result in uniform coating could be readily selected by one of
skill in the art.
[0067] In one embodiment, the hybrid barrier coating-enteric
coating is about 10% to about 60%, by weight, of the uncoated
drug-ion exchange resin complex. In another embodiment, the hybrid
barrier coating-enteric coating is about 25% to about 50% by weight
of the uncoated drug-ion exchange resin complex, about 30% to about
45% by weight of the uncoated complex, or about 35 to about 40% by
weight of the uncoated drug-ion exchange resin complex.
[0068] In one embodiment, the hybrid coating is cured and comprises
a polyvinyl acetate polymeric barrier coating system commercially
available as KOLLICOAT SR-30D, a plasticizer, and the enteric
coating component comprising polyvinyl acetate phthalate. The
coating can be cured for about 1 to about 24 hours. Alternatively,
the coating is cured for about 4 to about 16 hours, and in one
embodiment, at about 5 hours at high temperature, e.g., about
50.degree. C. to about 65.degree. C., and preferably about
60.degree. C.
[0069] The resulting coated particles are within the size range
described herein, i.e., they are preferably below about 420 microns
in size, with the majority falling within the range of about 40
micron to about 250 micron range.
[0070] Optionally, a non-functional film coating may be applied on
the exterior of the tablet, e.g., to permit application of a gloss
coat or a dye. Such a non-functional coating does not affect the
release profile of the dosage unit. Such a coating may be present
in an amount of about 1 to 10% w/w of the coated particle, and more
preferably, about 1 to about 5% w/w of the coated particle.
Examples of suitable coating compositions include those which are
commercially available, e.g., the OPADRY series from Colorcon. See,
U.S. Pat. No. 4,543,370, the disclosure of which is incorporated by
reference.
[0071] Suitably, the coated drug-ion exchange resin complexes of
the invention are still within the size range identified above. The
coated drug-ion exchange resin composition may be stored for future
use, packaged, or promptly formulated with conventional
pharmaceutically acceptable carriers to prepare finished ingestible
compositions for delivery orally, nasogastric tube, or via other
means. The compositions according to this invention may, for
example, take the form of solid preparations such as capsules
(which may include liquigels or the granular hybrid coated ion
exchange resin complexes), powders, tablets, caplets, etc.
Finished Formulations
[0072] The hybrid coated drug-ion exchange resin complexes of the
present invention, can readily be formulated with pharmaceutically
acceptable excipients according to methods well known to those of
skill in the art. In one embodiment, these formulations contain a
coated opioid drug-ion exchange resin complex of the invention,
optionally with a release retardant. In another embodiment, such
formulations may also contain a selected amount of uncoated
drug-ion exchange resin complex, optionally with a release
retardant as described herein.
[0073] In yet another embodiment, the formulations of the invention
may contain more than one active component. For example, the
formulation may contain more than one drug loaded into an ion
exchange resin to form a complex of the invention.
[0074] The coated drug-ion exchange resin complex of the invention
may be formulated for delivery by any suitable route. However, the
complex is particularly well suited for oral delivery and is so
formulated.
[0075] In one particularly desirable embodiment, the coated
drug-ion exchange resin complex of the invention is formulated into
a solid oral dose form such as a modified release tablet or
granules in a capsule. In one embodiment, the solid dosage form
contains at least one hybrid coated opioid-ion exchange resin
complex of the invention in admixture with components such as
fillers, lubricants, and disintegrants. In one embodiment, one or
more fillers is present in an amount of about 1 to 70% w/w of the
dosage unit. For example, a dosage unit may contain about 5 to 15%
w/w calcium silicate, about 10 to 50% w/w microcrystalline
cellulose, about 10 to about 50% w/w lactose, or combinations of
these fillers/diluents. In another embodiment, one or more
lubricants may be present in an amount of about 0.01% to about 5%
w/w of the dosage unit. For example, a dosage unit may contain
about 0.2 to about 2% w/w amorphous silica, about 0.5 to about 5%
w/w talc, about 0.05 to about 1.5% magnesium stearate, or
combinations of these lubricants. In one embodiment, the solid
dosage unit contains about 1 to about 20% w/w of a disintegrant.
For example, about 4 to about 8% w/w crospovidone may be present in
the solid dosage unit alone or in combination with another
disintegrant.
[0076] The drug-ion exchange resin coated compositions may be
formulated using conventional pharmaceutically acceptable carriers
or excipients and well established techniques. Without being
limited thereto, such conventional carriers or excipients include
diluents (e.g., microcrystalline cellulose, lactose), fillers
(e.g., calcium silicate), binders and adhesives (i.e., cellulose
derivatives and acrylic derivatives), lubricants (i.e., magnesium
or calcium stearate, or vegetable oils, polyethylene glycols, talc,
sodium lauryl sulfate, amorphous silica, polyoxy ethylene
monostearate), thickeners, solubilizers, humectants, disintegrants
(e.g., crospovidone), colorants, flavorings, stabilizing agents,
sweeteners, and miscellaneous materials such as buffers and
adsorbents in order to prepare a particular pharmaceutical
composition. The stabilizing agents may include preservatives and
anti-oxidants, amongst other components which will be readily
apparent to one of ordinary skill in the art.
[0077] When formulated into a liquid suspension, a variety of these
or additional excipients may be included. For example, a suspension
may contain thickeners or humectants. Suitable thickeners include,
e.g., tragacanth; xanthan gum; bentonite; starch; acacia and lower
alkyl ethers of cellulose (including the hydroxy and carboxy
derivatives of the cellulose ethers). Examples of cellulose
include, e.g., hydroxypropyl cellulose, hydroxypropyl methyl
cellulose, sodium carboxy methylcellulose, microcrystalline
cellulose (MCC), and MCC with sodium carboxylmethyl cellulose. In
one embodiment, tragacanth is used and incorporated in an amount of
from about 0.1 to about 1.0% weight per volume (w/v) of the
composition, and more preferably about 0.5% w/v of the composition.
Xanthan gum is used in the amount of from about 0.025 to about 0.5%
w/v and preferably about 0.25% w/v. A humectant may be included to
give the suspension greater viscosity and stability. Suitable
humectants useful in the finished formulations include glycerin,
polyethylene glycol, propylene glycol and mixtures thereof.
[0078] Oral liquid suspensions of the present invention may also
comprise one or more surfactants in amounts of up to about 5.0% w/v
and preferably from about 0.02 to about 3.0% w/v of the total
formulation. The surfactants useful in the preparation of the
finished compositions of the present invention are generally
organic materials which aid in the stabilization and dispersion of
the ingredients in aqueous systems for a suitable homogenous
composition. Preferably, the surfactants of choice are non-ionic
surfactants such as poly(oxyethylene) (20) sorbitan monooleate and
sorbitan monooleate. These are commercially known as TWEENS and
SPANS and are produced in a wide variety of structures and
molecular weights.
[0079] Whereas any one of a number of surfactants may be used,
preferably a compound from the group comprising polysorbate
copolymers (sorbitan-mono-9-octadecenoate-poly(oxy-1,2-ethanediyl))
is employed. This compound is also added functions to keep any
flavors and sweeteners homogeneously dissolved and dispersed in
solution.
[0080] Suitable polysorbates include polysorbate 20, polysorbate
40, polysorbate 80 and mixtures thereof. Most preferably,
polysorbate 80 is employed. The surfactant component will comprise
from about 0.01 to about 2.0% w/v of the total composition and
preferably will comprise about 0.1% w/v of the total weight of the
composition.
[0081] A second emulsifer/surfactant useful in combination with
polysorbates may be employed and is preferably a poloxamer such as
Poloxamer 407. Poloxamer 407 has an HLB (hydrophilic/lipophilic
balance) of about 22 and is sold under the tradename Pluoronic-127
(BASF-NJ). The two surfactants can be employed in substantially
equivalent amounts. For example, the Poloxamer 407 and polysorbate
80 may each be employed together at levels of approximately from
about 0.02 to about 4.0% w/v of the total weight of the
formulation.
[0082] Aqueous suspensions may be obtained by dispersing the
drug-ion exchange resin compositions in a suitable aqueous vehicle,
optionally with the addition of suitable viscosity enhancing
agent(s) (e.g., cellulose derivatives, xanthan gum, etc).
Non-aqueous suspensions may be obtained by dispersing the foregoing
compositions in a suitable non-aqueous based vehicle, optionally
with the addition of suitable viscosity enhancing agent(s) (e.g.,
hydrogenated edible fats, aluminum state, etc.). Suitable
non-aqueous vehicles include, for example, almond oil, arachis oil,
soybean oil or soybean oil or fractionated vegetable oils such as
fractionated coconut oil.
[0083] Useful preservatives include, but are not limited to, sodium
benzoate, benzoic acid, potassium sorbate, salts of edetate (also
known as salts of ethylenediaminetetraacetic acid, or EDTA, such as
disodium EDTA), parabens (e.g., methyl, ethyl, propyl or
butyl-hydroxybenzoates, etc.), and sorbic acid. Amongst useful
preservatives include chelating agents some of which are listed
above and other chelating agents, e.g., nitrilotriacetic acid
(NTA); ethylenediaminetetracetic acid (EDTA),
hydroxyethylethylenediaminetriacetic acid (HEDTA),
diethylenetriaminepentaacetic acid (DPTA),
1,2-Diaminopropanetetraacetic acid (1,2-PDTA);
1,3-Diaminopropanetetraacetic acid (1,3-PDTA);
2,2-ethylenedioxybis[ethyliminodi(acetic acid)] (EGTA);
1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane (BPTETA);
ethylenediamine (EDAMINE);
Trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA);
ethylenediamine-N,N'-diacetate (EDDA); phenazine methosulphate
(PMS); 2,6-Dichloro-indophenol (DCPIP);
Bis(carboxymethyl)diaza-18-crown-6 (CROWN); porphine; chlorophyll;
dimercaprol (2,3-Dimercapto-1-propanol); citric acid; tartaric
acid; fumaric acid; malic acid; and salts thereof. The
preservatives listed above are exemplary, but each preservative
must be evaluated in each formulation, to assure the compatibility
and efficacy of the preservative. Methods for evaluating the
efficacy of preservatives in pharmaceutical formulations are known
to those skilled in the art. Preferred preservatives are the
paraben preservatives including, methyl, ethyl, propyl, and butyl
paraben. Methyl and propyl paraben are most preferable. Preferably,
both methyl and propyl paraben are present in the formulation in a
ratio of methyl paraben to propyl paraben of from about 2.5:1 to
about 16:1, preferably 9:1.
[0084] In the instance where auxiliary sweeteners are utilized, the
present invention contemplates the inclusion of those sweeteners
well known in the art, including both natural and artificial
sweeteners. Thus, additional sweeteners may be chosen from the
following non-limiting list: Water-soluble sweetening agents such
as monosaccharides, disaccharides and polysaccharides such as
xylose, ribose, glucose, mannose, galactose, fructose, high
fructose corn syrup, dextrose, sucrose, sugar, maltose, partially
hydrolyzed starch, or corn syrup solids and sugar alcohols such as
sorbitol, xylitol, mannitol and mixtures thereof.
[0085] In general, the amount of sweetener will vary with the
desired amount of sweeteners selected for a particular liquid
suspension. This amount will normally be 0.001 to about 90% by
weight, per volume of the final liquid suspension composition, when
using an easily extractable sweetener. The water-soluble sweeteners
described above, are preferably used in amounts of about 5 to about
70% by weight per volume, and most preferably from about 10 to
about 50% by weight per volume of the final liquid suspension
composition. In contrast, the artificial sweeteners [e.g.,
sucralose, acesulfame K, and dipeptide based sweeteners] are used
in amounts of about 0.005 to about 5.0% and most preferably about
0.01 to about 2.5% by weight per volume of the final liquid
suspension composition. These amounts are ordinarily necessary to
achieve a desired level of sweetness independent from the flavor
level achieved from flavor oils.
[0086] Suitable flavorings include both natural and artificial
flavors, and mints such as peppermint, menthol, artificial vanilla,
cinnamon, various fruit flavors, both individual and mixed,
essential oils (i.e., thymol, eucolyptol, menthol and methyl
salicylate) and the like are contemplated. The amount of flavoring
employed is normally a matter of preference subject to such factors
as flavor type, individual flavor, and strength desired. Thus, the
amount may be varied in order to obtain the result desired in the
final product. Such variations are within the capabilities of those
skilled in the art without the need for undue experimentation. The
flavorings are generally utilized in amounts that will vary
depending upon the individual flavor, and may, for example, range
in amounts of about 0.01 to about 3% by weight per volume of the
final composition weight.
[0087] The colorants useful in the present invention include the
pigments such as titanium dioxide that may be incorporated in
amounts of up to about 1% by weight per volume, and preferably up
to about 0.6% by weight per volume. Also, the colorants may include
dyes suitable for food, drug and cosmetic applications, and known
as D&C and F.D. & C. dyes and the like. The materials
acceptable for the foregoing spectrum of use are preferably
water-soluble. Illustrative examples include indigoid dye, known as
F.D. & C. Blue No. 2, which is the disodium salt of
5,5-indigotindisulfonic acid. Similarly, the dye known as F.D.
& C. Green No. 1 comprises a triphenylmethane dye and is the
monosodium salt of 4-[4-N-ethyl
p-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulfoniumbenzyl)-2,-
5-cyclohexadienimine]. A full recitation of all F.D. & C. and
D. & C. and their corresponding chemical structures may be
found in the Kirk-Othmer Encyclopedia of Chemical Technology, in
Volume 5, at Pages 857-884, which text is accordingly incorporated
herein by reference. Optionally, these or similar components may
also be included in a non-functional coating for a tablet.
[0088] Suitable oils and fats that are usable would include
partially hydrogenated vegetable or animal fats, such as coconut
oil, palm kernel oil, beef tallow, lard, and the like. These
ingredients are generally utilized in amounts with respect to the
ingestible product of up to about 7.0% by weight, and preferably up
to about 3.5% by weight of the final product.
[0089] Wetting agents also may be employed in the inventive
compositions to facilitate the dispersion of any hydrophobic
ingredients. The concentration of wetting agents in the composition
should be selected to achieve optimum dispersion of the ingredient
within the composition with the lowest feasible concentration of
wetting agent. It should be appreciated that an excess
concentration of wetting agent may cause the composition, as a
suspension, to flocculate. Those skilled in the art are well versed
in suitable empirical methods to determine the appropriate wetting
agents and concentrations to achieve optimum dispersion and avoid
flocculation. Suitable wetting agents are listed in the US
Pharmacoepia 29.
[0090] Where desired, the hybrid coated drug-ion exchange granules
or particles of the invention are loaded into a capsule. Typically,
a capsule is a shell which readily dissolves in the stomach and can
be made from a variety of orally ingestible products (e.g.,
gelatin, hydroxypropylmethylcellulose (vegetarian)). Thus, the
capsule does not affect the release profile of the composition of
the invention. Suitable capsule shells are readily obtained from a
variety of commercial sources including, e.g., Capsuline,
CapsuleGel, Shinogi, and United Capsules). Typically, the capsule
shell selected is of size 0 or 1. The amount of granules loaded
into the capsule depends upon the size of the capsule and the
amount of active desired. For example, where the drug is designed
to provide the equivalent of 100 mg of morphine sulfate, 450 mg of
hybrid coated morphine-cation exchange resin may be loaded into a
size 0 capsule. However, other suitable shell sizes can be readily
determined.
[0091] Optionally, where needed to facilitate flow while filling a
capsule, a coated drug-ion exchange resin complex may be mixed with
a lubricant. Suitable lubricants can be readily selected from among
those known in the art, e.g., magnesium stearate, talc, etc.
[0092] The following examples are provided to more specifically
illustrate the modified release compositions of the present
invention and not intended to be limiting. They are for
illustrative purposes only and it is realized that changes and
variations can be made without departing from the spirit and scope
of the invention.
Example 1
Preparation of Hybrid Coated Morphine Resin Complex
[0093] The following example describes the preparation of a hybrid
coated morphine-ion exchange resin complex, in which the cation
exchange resin utilized is the Amberlite IRP-69 brand cross-linked
polysytrene resin. The formed morphine-ion exchange resin complex
may be referred to as morphine polistyrex for convenience.
TABLE-US-00001 Ingredient Quantity Morphine Resin Complex Morphine
Sulfate 810 g Purified Water 13600 g AMBERLITE IRP-69 RESIN 1358 g
KOLLIDON K-30 polyvinylpyrrolidone 180 g Purified water 421 g
Coated Morphine Resin Complex KOLLICOAT SR-30D polymer system
693.38 g (30% dispersion) (208.0164 g solids) Triacetin 10.37 g
SURETERIC 90G18507 White 41.6 g polyvinylacetate phthalate polymer
system Purified Water 554.65 g Morphine Resin Complex 600 g
[0094] The following was performed at room temperature unless
otherwise specified. The morphine resin complex was prepared by
first dissolving 810 g of morphine sulfate in 13.6 liters of
purified water, and then slowly adding 1358 g of AMBERLITE.TM.
IRP-69 resin with continuous mixing using a propeller mixer
(ARROW.TM.). The dispersion was mixed for 1 hour and upon
completion, the dispersion was filtered through a Buchner funnel
with the aid of vacuum. The dispersion/filtration process was
repeated twice with 4800 g of purified water. The wet resin complex
was then dried in a VECTOR.TM. FLM-1 fluid bed processor at
50.degree. C. until the moisture content was about 15-25%. In a
separate container 180 g of KOLLIDON K-30.TM. polyvinylpyrrolidone
(PVP) was added into 421 g of purified water and mixed using a
propeller mixer (ARROW.TM.) until dissolved. The aqueous KOLLIDON
K-30.TM. PVP solution was then slowly added to the wet resin
complex in a Hobart type mixer (Kitchen Aid) to form a uniform
mass. The wet mass was again dried at 50.degree. C. in a VECTOR.TM.
FLM-1 fluid bed processor to a moisture content of about 15-25%,
thereby forming granules. The semi-dried granules were then milled
through a 40 mesh screen using CO-MIL.TM. brand mill and drying
continued under 50.degree. C. until the moisture content was
between 3-7%. The dried granules were then milled through a 40 mesh
screen using CO-MIL.TM. brand mill [QUADRO]. The 40 mesh screen
allows particles of less than 420 microns to pass through.
[0095] In a separate container, 10.37 g of triacetin and 693.38 g
of KOLLICOAT.TM. SR-30D (which is a 30% dispersion of a polyinyl
acetate polymer system as described above) were mixed for 1 hour
(solution-A). 41.6 g of SURETERIC.TM. 90G18507 White
polyinylacetate phthalate (PVAP) was dispersed in 554.65 g of
purified water and mixed for 30 minutes (solution-B) using a
propeller mixer (ARROW.TM.). Solution-B was added into Solution-A
and mixed for 1 hour using a propeller mixer (ARROW.TM.). The final
coating solution was passed through a 40 mesh screen. The coating
process was performed in a VECTOR.TM. FLM-1 fluid bed processor by
applying 1,200 g of coating solution to 600 g of Morphine Resin
Complex using the WURSTER process that resulted in 40% weight gain.
The coating conditions were controlled at a product temperature of
25-35.degree. C., air flow of 10-25 cfm, nozzle pressure of 2-3
kg/cm.sup.2, accelerator air pressure of 1 kg/cm.sup.2, and spray
rate of 2.5-10 g/min so that uniform coating was achieved. The
coated Morphine Resin Complex was then placed at 60.degree. C. in a
VWR.TM. convection oven for 5 hours.
[0096] The resulting hybrid coated morphine resin complex still
passes through a 40 mesh screen.
[0097] The dried hybrid coated morphine resin complex is ready for
tabletting (Example 2), formulation into a suspension (Example 3)
or assembly into a capsule (Example 4).
Example 2
Tabletting of Hybrid Coated Morphine-Resin Complex
TABLE-US-00002 [0098] Ingredient Quantity Hybrid coated Morphine
Ion Resin Complex 266.84 g (from example 1) Calcium silicate,
(RXCIPIENT .TM. FM1000) 40.5 g Silicon dioxide, (RXCIPIENT .TM.
GL100) 4.5 g Microcrystalline cellulose, (AVICEL .RTM. PH 101)
127.74 g Crospovidone, (KOLLIDON .TM. CL-SF) 18 g Lactose
monohydrate, (FLOWLAC .TM. 100) 96.6 g Talc (IMPERIAL .TM. 500) 9 g
Magnesium Stearate 2.1 g TOTAL 565.28 g Hybrid Coated Morphine
Modified Release tablets OPADRY .RTM. WHITE YS-1-18202-A-PVAP 20 g
Purified water 80 g Hybrid Coated Morphine ER tablets 200 g
[0099] Hybrid coated Morphine Ion Resin Complex (266.84 g, from
example 1), calcium silicate (RXCIPIENT.TM. FM1000) (40.5 g),
silicon dioxide (RXCIPIENT.TM. GL100) (4.5 g), microcrystalline
cellulose (AVICEL.RTM. PH 101) (127.74 g), crospovidone
(KOLLIDON.TM. CL-SF) (18 g), lactose monohydrate (FLOWLAC.TM. 100)
(96.6 g), and talc (IMPERIAL.TM. 500) (9 g) were passed through 40
mesh screen and mixed for 10 minutes using a cube blender
(ERWEKA.TM. AR-402). Magnesium stearate (2.1 g) was passed through
40 mesh screen and added into the blender and further mixed for 5
minutes. The blend was compressed into tablets using a rotary
tablet press (MINI PRESS.TM.) fitted with a 0.3440''.times.0.7500''
capsule shape tooling. Tablets were compressed with weight of
942.14 mg (equivalent to 100 mg morphine sulfate), hardness of 7-11
kp, at machine speed of 5-30 rpm, resulting in tablets of
approximately 1 gram each in size.
[0100] In order to provide a desired, non-functional coating on the
tablets, OPADRY.RTM.WHITE YS-1-18202-A (20 g) was dispersed into 80
g purified water and mixed for 45 minutes using a propeller mixer
(ARROW.TM.). The coating process was performed in a perforated
coating pan (VECTOR.TM. LDCS-5) by applying 20 g of coating
solution to 200 of the approximately 1 g Morphine-Ion Exchange
Modified Release tablets to provide about a 2% wt gain to each
tablet. The coating conditions were controlled using an exhaust
temperature of 30.degree. C. and a spray rate of 5 g/min.
[0101] This tabletted form of the hybrid coated morphine-cation
exchange resin complex exemplified in Example 2 was designed to
have desired abuse resistance and an in vivo release profile
essentially the same as the currently commercially available
Kadian.RTM. 100 mg morphine sulfate capsule which has a 12-24 hours
extended release formulation.
[0102] In vitro dissolution was assessed in the USP Standard paddle
test (apparatus 2), at a speed of 50 rpm, a bath temperature of
37.+-.0.5.degree. C., in a dissolution medium of 500 mL 0.1 N
hydrochloric acid for 1 hour, followed by addition of 500 mL of
phosphate buffer to a pH 7.5. The tabletted form of the hybrid
coated morphine-cation exchange resin complex has an in vitro
dissolution release rate of morphine of 11.4% in 1 hour, 49.4% in 2
hours, 67.4% in 3 hours, 77.0% in 4 hours, and 95.1% in 12 hours.
It will be understood by one of skill in the art that two
compositions can have different in vitro dissolution rates, yet
provide bioequivalent in vivo release rates.
Example 3
Preparation of Hybrid Coated Morphine Modified Release
Suspension
TABLE-US-00003 [0103] Ingredient Quantity Placebo Suspension Base
Citric acid, anhydrous 8 g High Fructose Corn Syrup 42 1,200 g
Sucrose 600 g Starch 92 g Xanthan gum 7.6 g Glycerin 400 g
Methylparaben 7.2 g Propylparaben 0.8 g Strawberry Banana Flavor
44.88 g Purified Water QS 3484.91 g Hybrid Coated Morphine - Ion
Exchange Resin Complex Modified Release Suspension Purified Water
200 g Sodium Metabisulfite 1 g Polysorbate 80 1 g Hybrid Coated
Morphine Ion Exchange Resin 18.59 g (From Example 1) Placebo
Suspension Base 871.2 g Purified Water QS 1,000 mL
[0104] A placebo suspension base was prepared by first dissolving 8
g of citric acid in an appropriate amount of purified water,
followed by adding 600 g of sucrose and 1200 g of high fructose
corn syrup to achieve complete solution. 92 g of starch was then
slowly introduced to the main container under high shear mixing
condition to achieve uniform dispersion. In another container, 400
g glycerin was added and heated to 45-50.degree. C. followed by
addition of 7.2 g of methylparaben and 0.8 g propylparaben. After
both of the parabens were completely dissolved, the solution was
cooled to room temperature and 7.6 g Xanthan gum was slowly
introduced to the solution to form a uniform dispersion. The gum
dispersion was then transferred to the main container under high
speed/shear mixing condition to achieve uniform suspension. 44.88 g
of Strawberry/Banana flavor was added and the Placebo suspension
base was achieved by addition of the remaining purified water and
mixed until uniform.
[0105] To prepare the suspension, 200 g water was weighed to the
main container followed by the addition of 1 g of Sodium
Metabisulfite and Polysorbate 80. These components were mixed until
completely dissolved. 871.2 g of Placebo Suspension Base was then
added. The hybrid coated morphine ion exchange complex of example 1
was then added slowly under conditions of gentle mixing. The final
suspension was obtained by adding an appropriate amount of purified
water to make up the volume to 1000 mL followed by gentle mixing
until a uniform suspension is obtained.
Example 4
Hybrid Coated Morphine Modified Release Granules in Capsule
TABLE-US-00004 [0106] Ingredient Quantity Coated Morphine Ion
Exchange Resin Complex 450 g (From Example 1) Magnesium Stearate
4.5 g
[0107] A hybrid coated morphine-ion exchange resin complex that may
be prepared according to example 1 is taken and blended with 1%
Magnesium Stearate in a cube blender for 3 minutes at batch
scale.
[0108] Approximately 454 mg of the blend is then filled into a Size
0 hard gelatin capsule to provide an amount of active equivalent to
100 mg morphine sulfate.
Example 5
Preparation of Hybrid Coated Morphine-Resin Complex
[0109] This example illustrates the preparation of a hybrid coated
opioid-ion exchange resin complex with a different hybrid coating
than that illustrated in Example 1. This hybrid coating contains a
higher percentage of the barrier coating polymer as compared to the
enteric polymer.
TABLE-US-00005 Ingredient Quantity Morphine Resin Complex Morphine
Sulfate 810 g Purified Water 13600 g AMBERLITE IRP-69 RESIN 1358 g
KOLLIDON K-30 .TM. (PVP) 180 g Purified water 421 g Hybrid coated
Morphine Resin Complex KOLLICOAT SR-30D .TM. polymer system 770.42
g (30% dispersion) (231.126 g solids) Triacetin 11.53 g SURETERIC
.TM. 90G18507 White brand 17.34 g (PVAP) Purified Water 500.71 g
Morphine Resin Complex 600 g
[0110] The morphine ion exchange resin complex was prepared by
first dissolving 810 g of morphine sulfate in 13.6 liters of
purified water, and then slowly adding 1358 g of AMBERLITE.TM.
IRP-69 resin with continuous mixing using a propeller mixer
(ARROW.TM.). The dispersion was mixed for 1 hour and upon
completion, the dispersion was filtered through a Buchner funnel
with the aid of vacuum. The dispersion/filtration process was
repeated twice with 4800 g of purified water. The wet resin complex
was then dried in a VECTOR.TM. FLM-1 fluid bed processor at
50.degree. C. until moisture content was about 15-25%. In separate
container 180 g of KOLLIDON.TM. K-30 PVP was added into 421 g of
purified water and mixed using propeller mixer (ARROW.TM.) until
dissolved. The aqueous KOLLIDON.TM. K-30 solution was then slowly
added to the wet resin complex in a Hobart type mixer (Kitchen Aid)
to form a uniform mass. The wet mass was again dried at 50.degree.
C. in a VECTOR.TM. FLM-1 fluid bed processor to the moisture
content about 15-25%. The semi-dried granules were then milled
through a 40 mesh screen using CO-MIL.TM. brand mill and continued
drying under 50.degree. C. until the moisture content was between
3-7%. The dried granules were then milled through a 40 mesh screen
using CO-MIL.TM. brand mill [QUADRO].
[0111] In separate container, 11.53 g of triacetin and 770.42 g of
KOLLICOAT.TM. SR-30D polymer system were mixed for 1 hour
(solution-A). 17.34 g of SURETERIC.TM. 90G18507 white PVAP was
dispersed in 500.71 g of purified water and mixed for 30 minutes
(solution-B) using propeller mixer (ARROW.TM.). Solution-B was
added into Solution-A and mixed for 1 hour using propeller mixer
(ARROW.TM.). The final coating solution was passed through 40 mesh
screen. The coating process was performed in a VECTOR.TM. FLM-1
fluid bed processor by applying 1,200 g of hybrid coating solution
to 600 g of Morphine Ion Resin Complex of this example using the
WURSTER process that resulted in 40% weight gain. The coating
conditions were controlled at a product temperature of
25-35.degree. C., air flow of 10-25 cfm, nozzle pressure of 2-3
kg/cm2, accelerator air pressure of 1 kg/cm2, and spray rate of
2.5-10 g/min so that uniform coating was achieved. The coated
Morphine Resin Complex was then placed at 60.degree. C. in a
VWR.TM. convection oven for 5 hours.
Example 6
Preparation of Hybrid Coated Morphine Resin Complex
[0112] This example illustrates the preparation of a coated
opioid-ion exchange resin complex with a different hybrid coating
than that illustrated in Example 1 (or Example 5). This hybrid
coating contains a higher percentage by weight of the enteric
coating polymer as compared to the percentage of this component in
Example 1 (and Example 5).
TABLE-US-00006 Ingredient Quantity Morphine Ion Exchange Resin
Complex Morphine Sulfate 810 g Purified Water 13600 g AMBERLITE
IRP-69 Resin 1358 g KOLLIDON K-30 PVP 180 g Purified water 421 g
Coated Morphine Ion Resin Complex KOLLICOAT SR-30D polymer system
641.979 g (192.5937 g solids) (30% dispersion) Triacetin 9.633 g
SURETERIC 90G18507 White 57.785 g PVAP system Purified Water
590.603 g Morphine Resin Complex 600 g
[0113] The morphine resin complex was prepared by first dissolving
810 g of morphine sulfate in 13.6 liters of purified water, and
then slowly adding 1358 g of AMBERLITE.TM. IRP-69 resin with
continuous mixing using propeller mixer (ARROW.TM.). The dispersion
was mixed for 1 hour and upon completion, the dispersion was
filtered through a filtration apparatus (Buchner funnel) with the
aid of vacuum. The dispersion/filtration process was repeated twice
with 4800 g of purified water. The wet resin complex was then dried
in a VECTOR.TM. FLM-1 fluid bed processor at 50.degree. C. until
moisture content was about 15-25%. In separate container 180 g of
KOLLIDON.TM. K-30 PVP was added into 421 g of purified water and
mixed using propeller mixer (ARROW.TM.) until dissolved. The
KOLLIDON.TM. K-30 PVP solution was then slowly added to the wet
resin complex in a Hobart type mixer (Kitchen Aid) to form uniform
mass. The wet mass was again dried at 50.degree. C. in a VECTOR.TM.
FLM-1 fluid bed processor to the moisture content around 15-25%.
The semi-dried granules were then milled through a 40 mesh screen
using CO-MIL.TM. brand mill and continued drying under 50.degree.
C. until the moisture content was between 3-7%. The dried granules
were then milled through a 40 mesh screen using CO-MIL.TM. brand
mill [QUADRO].
[0114] In a separate container, 9.633 g of triacetin and 641.979 g
of KOLLICOAT.TM. SR-30D polyvinylacetate polymer system were mixed
for 1 hour (solution-A). 57.785 g of SURETERIC.TM. 90G18507 white
PVAP was dispersed in 590.603 g of purified water and mixed for 30
minutes (solution-B) using a propeller stirrer (ARROW.TM.)
Solution-B was added into Solution-A and mixed for 1 hour using a
propeller stirrer (ARROW.TM.). The final coating solution was
passed through 40 mesh screen. The coating process was performed in
a VECTOR.TM. FLM-1 fluid bed processor by applying 1,200 g of
coating solution to 600 g of Morphine Resin Complex using WURSTER
process that resulted in 40% weight gain. The coating conditions
were controlled at an product temperature of 25-35.degree. C., air
flow of 10-25 cfm, nozzle pressure of 2-3 kg/cm.sup.2, accelerator
air pressure of 1 kg/cm.sup.2, and spray rate of 2.5-10 g/min so
that uniform coating was achieved. The coated Morphine Resin
Complex was then placed at 60.degree. C. in VWR.TM. convection oven
for 5 hours.
Example 7
Preparation of Hybrid Coated Morphine Resin Complex
TABLE-US-00007 [0115] Ingredient Quantity Morphine Resin Complex
Morphine Sulfate 450 g Purified Water 5 L AMBERLITE IRP-69 Resin
807 g KOLLICOAT SR-30D polymer 501 g system Coated Morphine Resin
Complex KOLLICOAT SR-30D polymer 693.38 g system (30% dispersion)
Triacetin 10.37 g SURETERIC 90G 18507 White 41.6 g PVAP system
Purified Water 554.65 g Morphine Resin Complex 600 g
[0116] The morphine resin complex is prepared by first dissolving
450 g of morphine sulfate in 5 liters of purified water, and then
slowly adding 807 g of AMBERLITE.TM. IRP-69 resin with continuous
mixing. The dispersion is mixed for 1 hour and upon completion, the
dispersion is filtered through a filtration apparatus such as a
Buchner funnel with the aid of vacuum. The dispersion/filtration
process is repeated twice with 4800 g of purified water. The wet
resin complex is then dried in a VECTOR.TM. FLM-1 fluid bed
processor at 50.degree. C. until moisture content is about 15-25%.
KOLLICOAT.TM. SR-30D of 501 g is then slowly added to the wet resin
complex in a Hobart type mixer (Kitchen Aid) to form a uniform
mass. The wet mass is again dried at 50.degree. C. in a VECTOR.TM.
FLM-1 fluid bed processor to the moisture content around 20%. The
semi dried granules are then milled through a 40 mesh screen using
CO-MIL.TM. brand mill and drying continued at 50.degree. C. until
the moisture content is about 3-7%. The dried granules are then
milled through a 40 mesh screen using CO-MIL.TM. brand mill
[QUADRO].
[0117] In a separate container, 10.37 g of triacetin and 693.38 g
of KOLLICOAT.TM. SR-30D PVA polymer system are mixed for 1 hour
(solution-A). SURETERIC.TM. 90G 18507 White PVAP is dispersed in
554.65 g of purified water and mixed for 30 minutes (solution-B)
using propeller mixer (ARROW.TM.). Solution B is added into
Solution A and mixed for 1 hour using propeller mixer (ARROW.TM.).
The final coating is passed through 40 mesh screen. The coating
process is performed in a VECTOR.TM. FLM-1 fluid bed processor by
applying 1,200 g of coating solution to 600 g of Morphine Resin
Complex using the WURSTER process that resulted in 40% weight gain.
The coating conditions are controlled at an inlet temperature of
25-35.degree. C., air flow of 10-25 cfm, nozzle pressure of 2-3
kg/cm.sup.2, accelerator air pressure of 1 kg/cm.sup.2, and spray
rate of 2.5-10 g/min so that uniform coating is achieved. The
coated Morphine Resin complex is then placed at 60.degree. C. in
VWR.TM. convection oven for 5 hours.
[0118] The dried coated morphine resin complex is ready for
formulation, e.g., as described in Example 8.
Example 8
Preparation of Morphine Modified Release Tablets
TABLE-US-00008 [0119] Ingredient Quantity Hybrid coated Morphine
Resin Complex (from example 7) 266.84 g Calcium silicate (RXCIPIENT
.TM. FM 1000) 40.5 g Silicon dioxide (RXCIPIENT .TM. GL 100) 4.5 g
Microcrystalline cellulose (AVICEL .RTM. PH 101) 127.74 g
Crospovidone (KOLLIDON .TM. CL-SF) 18 g Lactose monohydrate
(FLOWLAC .TM. 100) 96.6 g Talc (IMPERIAL .TM. 500) 9 g Magnesium
Stearate 2.1 g TOTAL (uncoated tablet) 565.28 g Hybrid Coated
Morphine Modified Release Tablets OPADRY .RTM. WHITE YS-1-18202-A
20 g Purified water 80 g Morphine Modified Release Tablets
(containing coated 200 g morphine resin complex)
[0120] Hybrid coated Morphine Resin Complex (from example 7)
(266.84 g), calcium silicate (RXCIPIENT.TM. FM 1000) (40.5 g),
silicon dioxide (RXCIPIENT.TM. GL 100) (4.5 g), microcrystalline
cellulose (AVICEL.RTM. PH 101) (127.74 g), crospovidone
(KOLLIDON.TM. CL-SF) (18 g), lactose monohydrate (FLOWLAC.TM. 100)
(96.6 g), and talc (IMPERIAL.TM. 500) (9 g) are passed through 40
mesh screen and mixed for 10 minutes using a cube blender
(ERWEKA.TM. AR-402). Magnesium stearate (2.1 g) is passed through
40 mesh screen and added into blender and further mixed for 5
minutes. The blend is compressed into tablets using a rotary tablet
press (MINIPRESS.TM.) fitted with a 0.3440.times.0.7500 capsule
shape tooling. Tablets are compressed with weight of 942.14 mg
(equivalent to 100 mg morphine sulfate), hardness of 7-11 kp, at
machine speed of 5-30 rpm.
[0121] A non-functional coating may be prepared and applied as
follows. OPADRY.RTM. WHITE YS-1-18202-A brand (20 g) is dispersed
into 80 g purified water and mixed for 45 minutes using propeller
mixer (ARROW.TM.). The coating process is performed in a perforated
coating pan (VECTOR.TM. LDCS-5) by applying 20 g of coating
solution to 200-1 g Morphine ER tablets. The coating conditions are
controlled by exhaust temperature of 30.degree. C. and spray rate
of 5 g/min.
Example 9
Preparation of Hybrid Coated Oxycodone Ion Exchange Resin
Complex
TABLE-US-00009 [0122] Ingredient Quantity Oxycodone Resin Complex
Oxycodone HCl 450 g Purified Water 5 L AMBERLITE IRP-69 Resin 1,427
g KOLLICOAT SR-30D polymer 500 g system (30% dispersion) Coated
Oxycodone Resin Complex KOLLICOAT SR-30D polymer 693.38 g system
(30% dispersion) Triacetin 10.37 g SURETERIC 90G 18507 White 41.6 g
PVAP system Purified Water 554.65 g Oxycodone Ion Exchange Resin
600 g Complex
[0123] An Oxycodone ion exchange resin complex may be prepared in
accordance with the present invention as follows. 450 g of
oxycodone HCl is dissolved in 5 liters of purified water, and then
slowly adding 807 g of AMBERLITE.TM. IRP-69 resin with continuous
mixing. The dispersion is mixed for 1 hour and upon completion,
filter the dispersion through a filtration apparatus (Buchner
funnel) with the aid of vacuum. The dispersion/filtration process
is repeated twice with 4800 g of purified water. The wet resin
complex is then dried in a VECTOR.TM. FLM-1 fluid bed processor at
50.degree. C. until moisture content is about 15-25%. KOLLICOAT.TM.
SR-30D of 501 g is then slowly added to the wet resin complex in a
Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet
mass is again dried at 50.degree. C. in a VECTOR.TM. FLM-1 fluid
bed processor to the moisture content around 20%. The semi dried
granules are then milled through a 40 mesh screen using CO-MIL.TM.
brand mill and continued drying at 50.degree. C. until moisture
content is about 3-7%. The dried granules are then milled through a
40 mesh screen using CO-MIL.TM. brand mill [QUADRO].
[0124] In a separate container, 10.37 g of triacetin and 693.38 g
of KOLLICOAT.TM. SR-30D are mixed for 1 hour (solution-A).
SURETERIC.TM. 90G 18507 White is dispersed in 554.65 g of purified
water and mixed for 30 minutes (solution-B) using propeller mixer
(ARROW.TM.). Solution B is added into Solution A and mixed for 1
hour using propeller mixer (ARROW.TM.). The final coating is passed
through 40 mesh screen. The coating process is performed in a
VECTOR.TM. FLM-1 fluid bed processor by applying 1,200 g of coating
solution to 600 g of Oxycodone Resin Complex using WURSTER process
that results in 40% weight gain. The coating conditions are
controlled at an inlet temperature of 25-35.degree. C., air flow of
10-25 cfm, nozzle pressure of 2-3 kg/cm.sup.2, accelerator air
pressure of 1 kg/cm.sup.2, and spray rate of 2.5-10 g/min so that
uniform coating is achieved. The coated oxycodone complex is then
placed at 60.degree. C. in VWR.TM. convection oven for 5 hours.
Example 10
Preparation of Hybrid Coated Oxycodone Modified Release Tablets
TABLE-US-00010 [0125] Ingredient Quantity Hybrid Coated Oxycodone
Resin Complex 266.84 g (from example 9) Calcium silicate (RXCIPIENT
.TM. FM 1000) 40.5 g Silicon dioxide (RXCIPIENT .TM. GL 100) 4.5 g
Microcrystalline cellulose (AVICEL .RTM. PH 101) 127.74 g
Crospovidone (KOLLIDON .TM. CL-SF) 18 g Lactose monohydrate
(FLOWLAC .TM. 100) 96.6 g Talc (IMPERIAL .TM. 500) 9 g Magnesium
Stearate 2.1 g TOTAL 565.28 g Coated Oxycodone Modified Release
Tablets OPADRY .RTM. WHITE YS-1-18202-A 20 g Purified water 80 g
Uncoated Oxycodone ER Tablets 200 g
[0126] Using a coated Oxycodone Resin Complex (that may be prepared
as in Example 9) (266.84 g), calcium silicate (RXCIPIENT.TM. FM
1000) (40.5 g), silicon dioxide (RXCIPIENT.TM. GL 100) (4.5 g),
microcrystalline cellulose (AVICEL.RTM. PH 101) (127.74 g),
crospovidone (KOLLIDON.TM. CL-SF) (18 g), lactose monohydrate
(FLOWLAC.TM. 100) (96.6 g), and talc (IMPERIAL.TM. 500) (9 g) are
passed through 40 mesh screen and mixed for 10 minutes using cube
blender (ERWEKA.TM. AR-402). Magnesium stearate (2.1 g) is passed
through a 40 mesh screen, added into the blender and further mixed
for 5 minutes. The blend is compressed into tablets using rotary
tablet press (MINIPRESS.TM.) fitted with a 0.3440.times.0.7500
capsule shape tooling. Tablets are compressed with weight of 942.14
mg (equivalent to 100 mg morphine sulfate), hardness of 7-11 kp, at
machine speed of 5-30 rpm.
[0127] A non-functional coating may be prepared and applied as
follows. OPADRY.RTM.WHITE YS-1-18202-A-20 g is dispersed into
purified water (80 g) and mixed for 45 minutes using propeller
mixer (ARROW.TM.). The coating process is performed in a perforated
coating pan (VECTOR.TM. LDCS-5) by applying 20 g of coating
solution to 200-1 g Oxycodone modified release tablets. The coating
conditions are controlled by exhaust temperature of 30.degree. C.
and spray rate of 5 g/min.
Example 11
Preparation of Hybrid Coated Opioid Resin Complex Using Dowex
Resin
[0128] A coated morphine ion exchange resin complex may be prepared
as described in Example 1, using a strongly acidic Dow.TM. resin in
place of the Amberlite.TM. resin described in Example 1.
TABLE-US-00011 Ingredient Quantity Morphine Ion Resin Complex
Morphine Sulfate 450 g Purified Water 5 L DOW XYS-40010.00 807 g
KOLLICOAT SR-30D polymer 501 g system (30% dispersion) Hybrid
Coated Morphine Ion Resin Complex KOLLICOAT SR-30D polymer 693.38 g
system (30% dispersion) Triacetin 10.37 g SURETERIC 90G 18507 White
41.6 g PVAP system Purified Water 554.65 g Morphine Ion Resin
Complex 600 g
[0129] A morphine sulfate complex may be prepared by first
dissolving 450 g of morphine sulfate in 5 liters of purified water,
and then slowly adding 807 g of DOWEX.TM. resin with continuous
mixing. The dispersion is mixed for 1 hour and upon completion, the
dispersion is filtered through a filtration apparatus (Buchner
funnel) with the aid of vacuum. The dispersion/filtration process
is repeated twice with 4800 g of purified water. The wet resin
complex is then dried in a VECTOR.TM. FLM-1 fluid bed processor at
50.degree. C. until moisture content is about 15-25%. KOLLICOAT.TM.
SR-30D of 501 g is then slowly added to the wet resin complex in a
Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet
mass is again dried at 50.degree. C. in a VECTOR.TM. FLM-1 fluid
bed processor to the moisture content around 20%. The semi dried
granules are then milled through a 40 mesh screen using CO-MIL.TM.
brand mill and continued drying at 50.degree. C. until moisture
content is about 3-7%. The dried granules are then milled through a
40 mesh screen using CO-MIL.TM. brand mill [QUADRO].
[0130] In a separate container, 10.37 g of triacetin and 693.38 g
of KOLLICOAT.TM. SR-30D are mixed for 1 hour (solution-A).
SURETERIC.TM. 90G 18507 White is dispersed in 554.65 g of purified
water and mixed for 30 minutes (solution-B) using propeller mixer
(ARROW.TM.). Solution B is added into Solution A and mixed for 1
hour using propeller mixer (ARROW.TM.). The final coating is passed
through 40 mesh screen. The coating process is performed in a
VECTOR.TM. FLM-1 fluid bed processor by applying 1,200 g of coating
solution to 600 g of Morphine sulfate Complex using WURSTER process
that results in 40% weight gain. The coating conditions are
controlled at an inlet temperature of 25-35.degree. C., air flow of
10-25 cfm, nozzle pressure of 2-3 kg/cm.sup.2, accelerator air
pressure of 1 kg/cm.sup.2, and spray rate of 2.5-10 g/min so that
uniform coating is achieved. The coated morphine resin complex is
then placed at 60.degree. C. in VWR.TM. convection oven for 5
hours.
Example 12
[0131] It is desirable to reduce the ability of an abuser to
"release" the active drug in a form which is readily injected or
otherwise administered to achieve a "high". Thus, the ability to
deter immediate release of the drug from the composition of the
invention by abuse is desired.
[0132] Hybrid Coated Morphine Ion Exchange resin tablets of the
invention prepared in Example 2 were assessed for abuse potential.
Each of eight beakers contained an amount of hybrid coated morphine
ion exchange resin equivalent to 200 mg morphine sulfate, i.e.,
each contained two tablets prepared as described in Example 2 or
ground tablets.
[0133] The contents of each beaker were either assessed either "as
is" (2 soaked tablets per beaker) or "ground" (prior to the
placement in the beaker, tablets were ground and the equivalent of
200 mg morphine sulfate placed in each beaker). For the "ground
samples", the tablets were ground in a coffee grinder which is
commercially available for home use for one minute [MR. COFFEE.RTM.
grinder, Model IDS57], resulting in a mixture ranging from powder
to granular size.
[0134] For each of the "as is" and "ground" tablet samples, the
testing involved soaking (i) in water with stirring at room
temperature, (ii) in water without stirring at room temperature,
(iii) in 40% ethanol solution with stirring at room temperature,
(iv) in 40% ethanol solution without stirring at room temperature.
For each sample subjected to stirring, the solution was stirred in
a VWR 5-position standard multiposition stirrer at a setting of
3.
[0135] Release from "as is" or "ground" tablets under each of these
conditions was assessed at designated times (10 minutes, 30
minutes, 1 hr, 3 hr, and 6 hr). More particularly, each sample was
analyzed for the percentage (%) of morphine in solution using high
performance liquid chromatography (HPLC) against a standard of
morphine sulfate. The standard consisted of a commercially
purchased morphine sulfate, API version. For HPLC, a C18 column was
set with the flow rate of 1 mL/min with detector set at 280 nm was
used. The mobile phase consists of 20% (v/v) methanol, 0.1%
triethylamine (v/v), 0.005M octanesulfonic acid sodium salt, 0.177
M sodium acetate, and pH adjusted to 6.5 with glacial acetic
acid.
[0136] In the samples subjected to water treatment, the amount of
morphine released ranged from 2.0% at 10 minutes to 2.5% at 6 hours
(ground, unstirred) and ranged from 2.2% at 10 minutes to 7.3% at 6
hours (ground, stirred). The amount of morphine release in the "as
is" samples subjected to water treatment was lower, ranging from
2.9% (10 min) to 5.2% (6 hours) for stirred and ranging from 1.6%
(10 minutes) to 0.8% (6 hours) for unstirred.
[0137] The sample subjected to grinding and ethanol with stirring
showed the highest release of active, ranging from 7.2% of morphine
being released at 10 minutes to 14.8% of morphine being released at
6 hours. The sample subjected to grinding and ethanol without
stirring showed release ranging from 2.4% morphine release (at 10
minutes) to 5.3% morphine release (6 hours).
[0138] The "as is" sample subjected to ethanol solution with
stirring showed a release of active ranging from 0.4% (10 minutes)
to 5.7% (6 hours); whereas the "as is" sample subjected to ethanol
solution without stirring showed a release of active ranging from
0.2% (10 minutes) to 2.3% (6 hours).
[0139] As anticipated, these results showed that when soaked intact
(i.e., "as is"), the release of morphine is relatively low.
However, when subjected to abuse, e.g., by grinding, a higher
percentage of morphine release is observed for the tablet of
Example 2.
[0140] The abuse potential of granules taken from a 100 mg
Kadian.RTM. extended release capsule was also assessed using the
conditions described above. The results of this assessment showed
that when the granules from the Kadian.RTM. extended release
capsule were soaked intact ("as is"), a relatively low release of
morphine sulfate was observed, with the exception of soaking in 40%
ethanol at 6 hours where a significant release was observed.
[0141] The ground granules from the Kadian.RTM. capsule showed a
significantly greater percentage of morphine sulfate released as
compared to amount of active released from the ground tablet of
Example 2 (results described above) under the same conditions.
[0142] All patents, patent publications, and other publications
listed in this specification are incorporated herein by reference.
While the invention has been described with reference to a
particularly preferred embodiment, it will be appreciated that
modifications can be made without departing from the spirit of the
invention. Such modifications are intended to fall within the scope
of the appended claims.
* * * * *