U.S. patent application number 14/321125 was filed with the patent office on 2015-01-01 for tamper-resistant pharmaceutical compositions of opioids and other drugs.
The applicant listed for this patent is COLLEGIUM PHARMACEUTICAL, INC.. Invention is credited to Alison FLEMING, Jane C. HIRSH, Roman RARIY, Said SAIM, Ravi K. VARANASI.
Application Number | 20150005332 14/321125 |
Document ID | / |
Family ID | 44143221 |
Filed Date | 2015-01-01 |
United States Patent
Application |
20150005332 |
Kind Code |
A1 |
RARIY; Roman ; et
al. |
January 1, 2015 |
TAMPER-RESISTANT PHARMACEUTICAL COMPOSITIONS OF OPIOIDS AND OTHER
DRUGS
Abstract
Tamper-resistant pharmaceutical compositions have been developed
to reduce the likelihood of improper administration of drugs,
especially drugs such as opioids. The tamper-resistant compositions
retard the release of drug, even if the physical integrity of the
formulation is compromised (for example, by chopping with a blade
or crushing) and the resulting material is placed in water,
snorted, or swallowed. However, when administered as directed, the
drug is slowly released from the composition as the composition is
passes through the GI tract.
Inventors: |
RARIY; Roman; (Philadelphia,
PA) ; FLEMING; Alison; (Mansfield, MA) ;
HIRSH; Jane C.; (Wellesley, MA) ; SAIM; Said;
(New Milford, CT) ; VARANASI; Ravi K.;
(Cumberland, RI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
COLLEGIUM PHARMACEUTICAL, INC. |
Canton |
MA |
US |
|
|
Family ID: |
44143221 |
Appl. No.: |
14/321125 |
Filed: |
July 1, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12965572 |
Dec 10, 2010 |
8840928 |
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14321125 |
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12112937 |
Apr 30, 2008 |
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12965572 |
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10614866 |
Jul 7, 2003 |
7399488 |
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12112937 |
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12473073 |
May 27, 2009 |
8557291 |
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12965572 |
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12112993 |
Apr 30, 2008 |
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12473073 |
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10614866 |
Jul 7, 2003 |
7399488 |
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12112993 |
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61285231 |
Dec 10, 2009 |
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60393876 |
Jul 5, 2002 |
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60436523 |
Dec 23, 2002 |
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60443226 |
Jan 28, 2003 |
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60463514 |
Apr 15, 2003 |
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60463518 |
Apr 15, 2003 |
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60393876 |
Jul 5, 2002 |
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60436523 |
Dec 23, 2002 |
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60443226 |
Jan 28, 2003 |
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60463514 |
Apr 15, 2003 |
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60463518 |
Apr 15, 2003 |
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Current U.S.
Class: |
514/282 ;
264/13 |
Current CPC
Class: |
A61K 47/12 20130101;
A61K 31/485 20130101; B29C 70/60 20130101; A61K 9/4808 20130101;
A61K 9/1694 20130101; A61K 9/1641 20130101; A61K 47/44 20130101;
A61K 9/14 20130101; A61K 9/1635 20130101; A61K 9/1664 20130101;
A61P 29/00 20180101; A61K 9/5042 20130101; A61K 9/1617
20130101 |
Class at
Publication: |
514/282 ;
264/13 |
International
Class: |
A61K 9/14 20060101
A61K009/14; B29C 70/60 20060101 B29C070/60; A61K 47/44 20060101
A61K047/44; A61K 31/485 20060101 A61K031/485; A61K 47/12 20060101
A61K047/12 |
Claims
1. A tamper resistant pharmaceutical composition comprising a
plurality of multiparticulates each multiparticulate comprising:
(a) one or more drugs prone to abuse; and (b) one or more
excipients comprising fats, fatty substances, waxes, wax-like
substances or mixtures thereof; wherein the one or more drugs
interact ionically with one or more of the excipients and each
multiparticulate is in the form of a solid solution.
2-6. (canceled)
7. The tamper resistant composition of claim 1, wherein the one or
more excipients that interact ionically with said drug(s) are fatty
acids.
8-23. (canceled)
24. A tamper resistant pharmaceutical composition comprising a
plurality of multiparticulates each multiparticulate comprising:
(a) one or more drugs prone to abuse; and (b) one or more
excipients comprising fats, fatty substances, waxes, wax-like
substances or mixtures thereof comprising one or more ionic
components; wherein the ionic component of said one or more
excipients interacts with said one or more drugs.
25. A method of making a tamper resistant pharmaceutical
composition comprising: (a) dispersing or dissolving a drug prone
to abuse in one or more excipients comprising fats, fatty
substances, waxes, wax-like substances or mixtures thereof; (b)
forming multiparticulates via a spray congealing process from the
material obtained in step (a); and (c) coating the
multiparticulates obtained in step (b).
26-29. (canceled)
30. A tamper resistant pharmaceutical composition comprising a
plurality of multiparticulates made by a process comprising forming
multiparticulates via a spray congealing process from a dispersion
or solution comprising: (i) a drug prone to abuse; and (ii) one or
more excipients comprising fats, fatty substances, waxes, wax-like
substances or mixtures thereof; and (iii) optionally coating the
formed multiparticulates.
31. (canceled)
32. A tamper resistant pharmaceutical composition made by a process
comprising the steps of: (a) dissolving a drug prone to abuse in
one or more excipients comprising fats, fatty substances, waxes,
wax-like substances or mixtures thereof; and (b) forming
multiparticulates via a spray congealing process from the material
obtained in step (a); and (c) coating the multiparticulates
obtained in step (b).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Patent Appl.
Ser. No. 61/258,231, filed Dec. 10, 2009, which is a
continuation-in-part of U.S. patent application Ser. Nos.
12/112,937, filed Apr. 30, 2008 (a continuation-in-part of U.S.
patent application Ser. No. 10/614,866 filed Jul. 7, 2003, now U.S.
Pat. No. 7,399,488) and a continuation-in-part of U.S. patent
application Ser. No. 12/473,073, filed on May 27, 2009 (a
continuation-in-part of U.S. patent application Ser. No.
12/112,993, filed Apr. 30, 2008, which is a divisional of U.S.
patent application Ser. No. 10/614,866 filed Jul. 7, 2003), both of
which claim priority to U.S. Patent Appl. Ser. No. 60/393,876 filed
Jul. 5, 2002; U.S. Patent Appl. Ser. No. 60/436,523 filed Dec. 23,
2002; U.S. Patent Appl. Ser. No. 60/443,226 filed Jan. 28, 2003;
U.S. Patent Appl. Ser. No. 60/463,514 filed Apr. 15, 2003; and U.S.
Patent Appl. Ser. No. 60/463,518 filed Apr. 15, 2003, the
disclosures of all of which are incorporated by reference as if
fully set forth herein.
FIELD OF THE INVENTION
[0002] The present invention is generally in the filed of
pharmaceutical compositions, specifically compositions that are
designed to reduce the potential for improper administration of
drugs, such as those subject to abuse and methods of making
thereof.
BACKGROUND OF THE INVENTION
[0003] Oxycodone, morphine, and other opioid analgesics are
successful and therapeutically useful medications, e.g., as pain
killers, when administered orally. Unfortunately, they also pose a
severe threat for willful abuse due to their ability to alter mood
and/or cause a sense of euphoria. Traditional sustained released
formulations of such drugs, which contain a relatively large amount
of drug meant to be released from the formulation over an sustained
time period, are particularly attractive to abusers since the
sustained release action can be destroyed by crushing or grinding
the formulation. The resulting material (i.e., the crushed
formulation) can no longer control the release of drug. Depending
on the drug, abusers can then (1) snort the material, (2) swallow
the material or (3) dissolve the material in water and subsequently
inject it intravenously. The does of drug contained in the
formulation is absorbed immediately through the nasal or GI mucosa
(e.g., snorting or swallowing, respectively) or is administered in
a bolus to the systemic circulation (e.g., IV injection). These
abuse methods result in the rapid bioavailability of relatively
high doses of drug, giving the abuser a "high". Since relatively
simple methods (crushing, grinding, chewing and/or dissolution in
water) can be used to transform such formulations into an abusable
form, they provide virtually no deterrent to a potential
abuser.
[0004] For example, in recent years, there have been numerous
reports of diversion and abuse of sustained release formulations of
opioids such as oxycodone, oxymorphone and morphine. According to a
report from the Abuse and Mental Health Services Administration,
results from the 2007 National Survey on Drug Use and Health:
National findings (Rockville, Md.: US Dept. of Health and Human
Services), showed that in both 2006 and 2007, an estimated 5.2
million persons aged 12 or older (2.1 percent in each year) were
current nonmedical users of prescription pain relievers.
Additionally, from 2002 to 2007, there was an increase among
young-adults aged 18 to 25 in the rate of current use of
prescription pain relievers, from 4.1 to 4.6 percent. Data from
this survey also supports the notion that sustained-release
formulations susceptible to tampering methods such as chewing,
crushing and grinding likely contributes to the increasing rates of
prescription pain reliever abuse. For example, in 2007, there were
an estimated 554,000 new nonmedical users of OxyContin.RTM. (a
sustained release formulation of the active drug oxycodone).
[0005] Oxycodone is a controlled substance in Schedule II of the
Controlled Substances Act (CSA), which is administered by the Drug
Enforcement Administration (DEA). Despite the fact that Schedule II
provides the maximum amount of control possible under the CSA tor
approved drag products, in practice it is difficult for law
enforcement agencies to control the diversion or misuse of
legitimate prescriptions. Although abuse, misuse, and diversion are
potential problems for all opioids, including Oxycodone, opioids
are a very important pan of the medical armamentarium for the
management of pain when used appropriately under the careful
supervision of a physician.
[0006] U.S. Pat. No. 3,980,766 to Shaw et al. ("Shaw"), U.S. Pat.
No. 4,070,494 to Hoffmeister et al. ("Hoffmeister"), and U.S. Pat.
No. 6,309,668 to Bastin et al. ("Bastin") describe formulations
designed to prevent the injection of compositions meant for oral
administration.
[0007] Shaw describes the incorporation of an ingestible solid
which causes a rapid increase in viscosity upon concentration of an
aqueous solution thereof.
[0008] Hoffmeister describes the incorporation of a non-toxic,
water gelable material in an amount sufficient to render the drug
resistant to aqueous extraction.
[0009] Bastin describes a tablet for oral administration containing
two or more layers containing one or more drugs and one or more
gelling agents within separate layers of the tablet. The resulting
tablet forms a gel when combined with the volume of water necessary
to dissolve the drug allegedly reducing the extractability of the
drug from the tablet.
[0010] It should be noted that although these compositions
allegedly preclude abuse by injection, this approach fails to
prohibit rapid dissolution of the drug once the dosage form is
crushed into smaller particles or pieces. Thus, these formulations
are vulnerable to abuse by crushing and swallowing or snorting the
formulation, which are commonly reported methods of abuse.
[0011] U.S. Pat. Nos. 3,773,955 and 3,966,940 to Pachter et al.
describe formulations containing a combination of opioid agonists
and antagonists, in which the antagonist does not block the
therapeutic effect when the admixture is administered orally, but
which does not produce analgesia, euphoria or physical dependence
when administered parenterally by an abuser.
[0012] U.S. Pat. No. 4,457,933 to Gordon et al. describes a method
for decreasing both the oral and parenteral abuse potential of
strong analgetic agents by combining an analgesic dose of the
analgetic agent with an antagonist in specific, relatively narrow
ratios.
[0013] U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494 to Kaiko
et al. describe oral dosage forms including a combination of an
orally active opioid agonist and an orally active opioid antagonist
in a ratio that, when delivered orally, is analgesically effective
but that is aversive in a physically dependent subject. While such
a formulation may be successful in deterring abuse, it also has the
potential to produce adverse effects in legitimate patients.
[0014] The FDA recently approved two sustained release formulation
of opioid active ingredients with tamper resistant features. A
sustained release oxycodone tablet, designed to resist crushing and
to gel in the presence of water, is currently available. Also, a
multiparticulate-in-capsule product containing morphine and a
sequestered naltrexone is also commercially available; this product
is designed to release naltrexone (an opioid antagonist) to
counteract the euphoric effects of the opioid active ingredient
when the formulation is crushed, chewed or dissolved. While such
formulations off an improvement over previously available
formulations with respect to susceptibility to tampering, there are
disadvantages associated with the available products. For example,
tablet formulation that are difficult to crush, but not
crush-proof, can still be chopped or shredded into small particles
and do not address the needs of patients with difficulty
swallowing, and formulations containing antagonists have the
potential to cause harm to legitimate patients.
[0015] It is therefore an object of the present invention to
provide a pharmaceutical composition (e.g., a multiparticulate
composition) that reduces the potential for improper administration
of drugs without the addition of aversive agents or antagonists,
which have the potential to cause harm to legitimate patients. Such
a formulation significantly reduces the potential for improper
administration or use of drugs but, when administered as directed,
is capable of delivering a therapeutically effective does. Methods
of making and using such a formulation are also provided.
SUMMARY OF THE INVENTION
[0016] An abuse-deterrent pharmaceutical composition and methods of
making and using thereof have been developed. The compositions can
be used to reduce the likelihood of improper administration of
drugs, especially drugs prone to abuse such as oxycodone. The
technology is useful for a number of other drugs were sustained
release oral delivery is desired, and there is potential for abuse
if the drug does is made immediately available for nasal,
intravenous (IV) or oral administration. In a preferred embodiment,
the drug is formulated into multiparticulates containing lipophilic
or water-insoluble materials. In some embodiments, the drug is
modified to increase its lipophilicity prior to or during the
formulation of the multiparticulates. For example, the composition
is formulated with one or more excipients that interact ionically
with the drug to obtain a more lipophilic drug derivative. The
composition is then formulated as multiparticulates. In another
embodiment, the multiparticulates are produced using a spray
congealing process. In other embodiments, the formulation contains
lipophilic or water-insoluble materials or is made using a process
which increases the lipophilicity and/or water-insolubility of the
composition. In some embodiments, the composition additionally
contains one or more antioxidants, surfactants, or polymers.
[0017] The abuse-deterrent composition retards the release of drug
even if the physical integrity of the dosage form is compromised
(for example, by chopping with a blade or crushing) and the
resulting material is placed in water, snorted, or swallowed.
However, when administered as directed, the drug is released
slowly, typically over a period of 6-24 hours, from the composition
as the composition is broken down or dissolved gradually within the
GI tract by a combination of surfactant action of bile acids,
diffusion, mechanical erosion and, in some embodiments, enzymatic
degradation.
[0018] The multiparticulates or microparticulates described herein
can be made using a variety of techniques known in the art
including, but not limited to, spray congealing, spray chilling,
extrusion, spray drying, and bulk congealing with subsequent
milling. In one embodiment, beads or particles containing the
active agent (e.g., a fatty acid salt of the active agent) and
excipients are prepared using a spray congealing process.
[0019] In one embodiment, the multiparticulates have a D(0.1)
particle size from about 50 to 250 .mu.m, preferably from about 140
to about 190 .mu.m; a D(0.5) median particle size from about 150 to
about 750 .mu.m, preferably from about 200 to about 400 .mu.m; and
a D(0.9) particle size from about 200 to about 1200 .mu.m,
preferably from about 400 to about 700 .mu.m. The multiparticulates
are characterized by a span (i.e., [D(0.9)-D(0.1)]/D(0.5)) less
than 5, preferably less than 2, and more preferably less than 1.4.
In some embodiments, multiparticultes having a span of less than
1.4 are less prone to segregation during processing and/or achieve
the desired pharmacokinetic profile. D(0.1), D(0.5) and D(0.9) are
defined as the diameters where 10%, 50% or 90% w/w of the
multiparticulates have a smaller diameter, respectively, when
measured, e.g., using a laser diffraction technique. The terms
"D(0.5)" and "median particle size" are used interchangeably
herein. The multiparticulates can be geometrical shape. In some
embodiments, the multiparticulates may be irregular, oblong or
spherical in shape. In a preferred embodiment, the
multiparticulates are substantially round or spherical in shape
(e.g., beads).
[0020] In some embodiments, the individual drug-containing
multiparticulates are coated with one or more independent coating
layers. At least one of the coating materials is water-insoluble
and/or organic solvent-insoluble, so that in vitro dissolution of
the formulation will require more than one step. Thus, the drug is
not easily extractable from the formulations by conventional
chemical means. In contrast, when administered to the
gastrointestinal tract via swallowing, the drug will gradually be
released from the coated multiparticulates as a consequence of
diffusion, the gradual break down of the formulation via surfactant
action of bile acids, mechanical erosion and, in some embodiments,
enzymatic degradation. The particles can be coated using a variety
of techniques known in the art including, but not limited to, wet
granulation processes, spray coating processes, and/or coacervation
processes.
[0021] The pharmaceutical composition, when administered orally,
results in a desired drug release profile. The release profile
provides a therapeutic effect for an extended period of time,
typically form 6 to 24 hours, preferably from 12 to 24 hours.
Additional compositions may achieve a small immediate release dose
that precedes the extended release of drug. The compositions
disclosed herein may optionally contain a drug having no
appreciable abuse potential.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a picture of a portion of a spinning disc
atomizer.
[0023] FIG. 2 is a diagram of an exemplary pressure nozzle for the
preparation of multiparticulates.
[0024] FIG. 3 is a diagram of a large scale apparatus for the
production of multiparticulates, where the apparatus comprises a
large scale spinning disc atomizer.
[0025] FIG. 4 is a graph comparing a model predicted particule size
in microns with the actual median particle size in microns.
[0026] FIG. 5 is a graph showing the D(0.5) median particle size in
microns as a function of disc speed (rpm) and fan setting at high
feed temperature setting of 90.degree. C., and medium feed rate
(pump setting of 3.75 Hz).
[0027] FIG. 6 is a graph showing the effect of disc speed, and air
flow rate on the bead size distribution (span) at 90.degree. C.
DETAILED DESCRIPTION OF THE INVENTION
[0028] Disclosed herein are abuse-deterrent pharmaceutical
compositions and the method of making and using the
compositions.
I. Compositions
[0029] As used, herein, "composition" refers to the drug dosage
unit for administration to a patient. "Composition" may also be
used in reference solely to the active ingredient, or to a
formulation containing the active ingredient.
[0030] The currently available extended release dosage forms
containing narcotic analgesics and other drugs are subject to
misuse, in part, because mechanical destruction of the dosage form
exposes the encapsulated drug and allows for rapid dissolution of
the drug into aqueous media. Three properties of the dosage form
that contribute to this outcome are, (1) the high water solubility
of the drug salt form; (2) the lack of protection offered by the
hydrophilic and/or water soluble excipients in the formulation; and
(3) the ease with which the surface area of the formulation is
increased by simple chewing or crushing. Susceptibility to simple
methods such as chewing or crushing is particularly problematic for
monolithic controlled-release dosage forms. For monolithic dosage
forms, such as tablets, even splitting the unit into a few pieces
(without completely crushing it) can result in a dramatic increase
in the dissolution rate.
[0031] In the compositions disclosed herein, one or more of these
properties are altered in order to achieve an abuse-deterrent
composition. Specifically, in the one embodiment, the drug is
modified to increase its lipophilicity and reduce its water
solubility. The modified drug is homogeneously dispersed within one
or more excipients that are either slowly soluble or not soluble in
water. Dispersion within these materials further reduces the
accessibility of the drug when crushed and exposed to an aqueous
media. In some embodiments, the drug may be partially or fully
dispersed in the excipients on a molecular level. The intimate
mixture of modified drug and excipients is subsequently formulated
into multiparticulates, producing a formulation whose surface area
is minimally influenced by chewing or crushing.
[0032] The terms "tamper resistant composition," "abuse-detterent
composition" or "abuse-deterrent formulation" are used
interchangeably herein to refer to compositions that reduce the
potential for improper administration of drugs but that deliver a
therapeutically effective dose when administered as directed.
Improper administration includes tampering with the dosage form
and/or administering the drug by any route other than instructed.
For example, for a tablet or capsule, methods of tampering with the
dosage form may include, but are not limited to, breaking,
crushing, grinding, chewing and/or dissolving the tablet or the
contents of the capsule. For oral administration, improper
administration includes administering the drug by any route other
than via swallowing.
[0033] The abuse deterrent compositions preferably contain a drug
modified to increase its lipophilicity. In some embodiments, the
drug is homogenously dispersed within multiparticulates composed of
a material that is either slowly soluble in water or water
insoluble. The compositions maintain a slow release of drug if the
dosage form is chopped or crushed and the resulting material is
placed in water, snorted, or swallowed since most of the drug will
remain associated with or entrapped within portions of the core
material of the multiparticulates. In other embodiments, the drug
containing multiparticulates are coated with one or more coating
layers, where at least one coating is water insoluble and/or
organic solvent insoluble. The components of the resulting coated
multiparticulates are not mutually soluble m water or organic
solvents. Therefore, extraction of the drug from the formulation
cannot be carried out in one step. However, when administered as
directed, the drug is slowly released from the formulation via
diffusion and erosion within the environment of the
gastrointestinal tract.
[0034] A. Drugs to be Formulated
[0035] There are many drugs which can be delivered using the
compositions described herein. The Controlled Substances Act (CSA),
Title II of the Comprehensive Drug Abuse Prevention and Control Act
of 1970, places all substances that are regulated under existing
federal law into one of five schedules based upon the substance's
medicinal value, harmfulness, and potential for abuse or addiction.
Drugs that are preferred include those classified as Schedule II,
III, IV and V drugs. Drugs that are most preferable include those,
like oxycodone, that are currently formulated as extended or
controlled release compositions, where drug release is intended to
occur over a prolonged period of time through the gastrointestinal
tract, and immediate or burst release, for example, by inhalation
or injection, is undesirable. As used herein, drugs prone to abuse
refer to controlled substance specified as schedule II, III, IV and
V drugs. Other opioid analgesics that can be incorporated into the
compositions described herein include morphine and
hydromorphone.
[0036] The terms "drug", "active agent", and "pharmacologically
active agent" are used interchangeably herein to refer to a
chemical compound that induces a desired pharmacological,
physiological effect. The terms also encompass pharmaceutically
acceptable derivatives of those active agents specifically
mentioned herein, including, but not limited to, salts, solvates,
hydrates, complexes with one or more molecules, prodrugs, active
metabolites, and derivatives and analogs. When the terms "active
agent", "pharmalogically active agent" and "drug" are used, or when
a particular drug, such as oxycodone, is identified, it is to be
understood as including the active agent per se as well as
pharmaceutically acceptable salts, solvates, hydrates, complexes
with one or more molecules, prodrugs, active metabolites, and
analogs.
[0037] Examples of preferred drugs include 1-phenylcyclohexylamine,
1-piperidinocyclohexancarbonitrile, alfentanil, alphacetylmethadol,
alphaprodine, alprazolam, amobarbital, amphetamine, anileridine,
apomorphine, aprobarbital, barbital, barbituric acid derivative,
bemidone, benzoylecgonine, benzphetamine, betacetylmethadol,
betaprodine, bezitramide, bromazepam, burprenorphine,
butabartbital, butalbital, butorphanol, camazepam, cathine,
chloral, chlordiazepoxide, clobazam, clonazepam, clorazepate,
clotiazepam, cloxazolam, cocaine, codeine, chlorphentermine,
delorazepam, dexfenfluramine, dextromoramide, dextropropoxyphen,
dezocine, diazepam, diethylpropion, difenoxin, dihydrocodeine,
dihydromorphine, dioxaphentyl butyrate, dipanone, diphenoxylate,
diprenorphine, ecgonine, enadoline, eptazocine, estazolam,
ethoheptazine, ethyl loflazepate, ethylmorphine, etorphine,
femproponex, fencamfamin, fenfluramine, fentanyl, fludiazepam,
flunitrazepam, flurazepam, glutethimide, halazepam, haloxazolam,
hexalgon, hydrocodone, hydromorphone, isomethadone, hydryocodone,
ketamine, ketazolam, ketobemidone, levanone,
levoalphacetylmethadol, levomethadone, levomethadyl acetate,
levomethorphan, levorphanol, lofentanil, loperamide, loprazolam,
lorazepam, lormetazepam, lysergic acid, lysergic acid amide,
mazindol, medazepam, mefenorex, meperidine, meptazinol, metazocine,
methadone, methamphetmaine, methohexital, methotrimeprazine,
methyldihydromorphinone, methylphenidate, methylphenobarbital,
metopon, morphine, nabilone, nalbuphine, nalbupine, nalorphine,
narceine, nefopam, nicromorphine, nimetazepam, nitrazepam,
nordiazepam, normethadone, normorphine, ozazepam, oxazolam,
oxycodone, oxymorphone, pentazocine, pentobarbital, phenadoxone,
phenazocine, phencyclidine, phendiemtrazine, phenmetrazine,
pheneridine, piminodine, prodilidine, properidine, propoxyphene,
racemethorphan, racemorphan, racemoramide, remifentanil,
secobarbital, sufentanil, talbutal, thebaine, thiamylal,
thiopental, tramadol, trimeperidine, and vinbarbital.
[0038] In addition to the compounds above, the following scheduled
drugs may be incorporated into the composition: allobarbitone,
alprazolam, amylobarbitone, aprobarbital, barbital, barbitone,
benzphetamine, brallobarbital, bromazepam, brotizolam, busipirone,
butalbital, butobarbitone, butorphanol, camazepam, captodiame,
carbromal, carfentanil, carpipramine, cathine, chloral, chloral
betaine, chloral hydrate, chloralose, chlordiazepoxide,
chlorhexadol, chlormethizole edisylate, chlormezanone, cinolazepam,
clobazam, potassium clorazepate, clotiazepam, cloxazolam,
cyclobarbitone, delorazepam, dexfenfluramine, diazepam,
diethylpropion, difebarbamate, difenoxin, enciprazine, estazolam,
ethly loflazepate, etizolam, febarbamate, fencamfamin,
fenfluramine, fenproporex, fluanisone, fludiazepam, flunitraam,
flunitrazepam, flurazepam, flutoprazepam, gepirone, glutethimide,
halazepam, haloxazolam, hexobarbitone, ibomal, ipsapirone,
ketazolam, loprazolam mesylate, lorazepam, lormetazepam, mazindol,
mebutamate, medazepam, mefenorex, mephobarbital, meprobamate,
metaclazepam, methaqualone, methohexital, methylpentynol,
methylphenobarbital, midazolam, milazolam, morphine, nimetazepam,
nitrazepam, nordiazepam, oxazepam, oxazolam, paraldehyde, pemoline,
penabarbitone, pentazocine, pentobarbital, phencyclidine,
phenobarbital, phendimetrazine, phenmetrazine, phenprobamate,
phentermine, phenyacetone, pinazepam, pipradol, prazepam,
proxibarbal, quazepam, quinalbaritone, secobarbital,
secbutobarbitone, sibutramine, temazepam, tetrazepam, triazolam,
triclofos, zalepan, zaleplon, zolazepam, zolpidem, and
zopiclone.
[0039] Certain compounds described herein may exist in particular
geometric or stereoisomeric forms. The composition disclosed herein
contemplates all such compounds, including cis- and trans-isomers,
R- and S-enantiomers, diastereomers, (d)-isomers, (I)-isomers, the
racemic mixtures thereof, compounds of different spacial
conformations, and other mixtures thereof, as falling within the
scope of the invention. Additional asymmetric carbon atoms may be
present in a substituent such as an alkyl group. All such isomers,
as well as mixtures thereof, are intended to be included in this
invention.
[0040] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making salts thereof. Pharmaceutically acceptable
salts include salts of acidic (e.g., a carboxylic acid) or basic
groups (e.g., a primary, secondary or tertiary amine) present in
compounds disclosed herein. Examples of pharmaceutically acceptable
salts include, but are not limited to, mineral or organic acid
salts of basic residues such as amines: alkali or organic salts of
acidic residues such as carboxylic acids; and the like. The
pharmaceutically acceptable salts include conventional non-toxic
salts or the quarternary ammonium salts of the parent compound
formed, for example, from non-toxic inorganic or organic acids. For
example, such conventional non-toxic salts include those derived
from inorganic acids such as hydrochloric, hydrobromic, sulfuric,
sulfamic, phosphoric, nitric and the like; and the salts prepared
from organic acids such as acetic, propionic, succinic, glycolic,
lauric, capric, myristic, palmitic, stearic, oleic, linoleic,
lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic,
methanesulfonic, ethan disulfonic, oxalic, and isethionic.
[0041] The pharmaceutically acceptable salts of the compounds can
be synthesized from the parent compound (e.g., the unprotonated
base form of the compound, often referred to as the "free base" of
the compound), which contains a basic or acidic moiety, by
conventional chemical methods. Generally, such salts can be
prepared by reacting the free acid or base forms of these compounds
with the appropriate base or acid in water or in an organic
solvent, or in a mixture of the two; generally, non-aqueous media
like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
are preferred. Lists of suitable salts are found in Remington's
Pharmaceutical Sciences, 20th ed., Lippincott Williams &
Wilkins, Baltimore, Md., 2000, p. 704, the disclosure of which is
hereby incorporated by reference.
[0042] Pharmaceutically acceptable salts may also be prepared by
reacting the free acid or base forms of compounds with an
appropriate base or acid, respectively, in a melt process,
optionally in the presence of other pharmaceutically acceptable
excipients (e.g., waxes). As used herein, the term "melt process"
refers to a process where the free acid or base forms of the
compounds are dissolved in one or more excipients that are in
molten form (i.e., it is a solid at room temperature) to make a
solution wherein the base or acid interacts with the free acid or
base form of the compounds, respectively, to form the desired
pharmaceutically acceptable salt.
[0043] Optionally, the composition described herein can further
include a drug having no appreciable abuse potential.
[0044] B. Drug Modification
[0045] In some embodiments, the dissolution and/or solubility
characteristics of a drug are altered. Modification of the drug to
produce a more lipophilic and/or less soluble derivative serves to
reduce the dissolution rate and/or solubility of the drug in
aqueous media, such as water, and thus reduce the aqueous
extractability of the drug. Furthermore, if the drug is made more
lipophilic, it can be dissolved in a molten fatty substance and/or
wax like mixture; that is, the more lipophilic form of the drug is
substantially more soluble in the molten fatty substance and/or
wax-like mixture, as opposed to being mostly suspended or dispersed
as solid particles in the molten fatty substance and/or wax-like
mixture. Solubilization of the drug in lipophilic excipients can
enhance the abuse-deterrent properties of multiparticulates
formulated from the mixtures as it is more difficult to extract
drug from an intimately dispersed composition. Furthermore, such a
compositions is capable of controlling the release of drug, even
when formulated into relatively small multiparticulates.
Microparticulate compositions, in contrast to monolithic
compositions, are inherently less susceptible to tampering by
mechanisms such as chewing or crushing that are intended to
increase the surface area and, consequently, the release rate of
drug.
[0046] The terms "lipophilic derivative" and "liophililic drug
derivative", as used herein, refer to derivatives of the drug that
are less soluble or dissolve less rapidly in water than more
soluble salts of the drug; the more soluble salts being selected
from either base addition salts (for acidic drugs) or acid addition
salts (for basic drugs), such as by the addition of inorganic
acids. The examples of the latter include but are not limited to
hydrohalics, sulfates, and nitrates. In some embodiments, a
"liophilic derivative" or "lipophililic drug derivative", is formed
when the drug interacts ionically with one or more organic
excipients. Ionic interactions include, but are not limited to,
interactions between ionic moieties on a drug (e.g., cationic
moieties or anionic moieties) and one or more ionic components
(e.g., cationic moieties or anionic moieties) contained in the one
or more organic excipients. In some embodiments, ionic interactions
include, but are not limited to, the formation of salts. In other
embodiments, ionic interactions include hydrogen-bonding
interactions between basic drugs and acids (e.g., a nitrogen atom
on the drug and the hydrogen atom on the carboxylic acid of the
fatty acid) or acidic drugs and bases (e.g., a carboxylic acid
hydrogen atom and the nitrogen atom of the fatty amine). As used
herein, the term "fatty amine" includes, but is not limited to,
C.sub.5-C.sub.30 fatty amines including octyl amine, decylamine,
dodecylamine, tetradecylamine, hexadecylamine, octadecylamine, and
palmitylamine.
[0047] Exemplary methods that can be used to alter the drug's
lipophilicity and/or aqueous solubility are described below. It is
understood that two or more approaches can be combined to achieve a
desired dissolution and/or solubility profile.
[0048] In one embodiment, the drug's liophilicity/solubility is
modified by forming an ionic interaction (e.g., forming a salt)
between a drug molecule and a charged lipophilic compound. In this
case the lipophilicity of the resulting salt can be manipulated by
varying the lipophilicity of the counter-ion. In general,
lipophilic acids or amines with chain lengths between
C.sub.5-C.sub.30 are lipophilic counter-ion candidates. Some
specific examples include, but are not limited to, linoleic acid,
octanoic acid, capric acid, lauric acid, myristic acid, palmitic
acid, stearic acid, oleic acid, octyl amine, lauryl amine, stearyl
amine, palmityl amine, linoleyl amine, and oleyl amine.
[0049] The formation of an ionic interaction (e.g., forming a salt)
between a pharmaceutically active agent and an excipient such as a
fatty acid or amine can be accomplished by a melt process, with or
without the use of a solvent. In some embodiments, one or more
fatty acids or amines are heated above their melting point and the
pharmaceutically active agent, in free base or acid form, is added
to the molten fatty acid or amine either directly or after
dissolution of the active agent in an appropriate solvent, such as
ethanol or methylene chloride. When the active agent interacts
ionically with the fatty acid or fatty amine the interaction can be
such that, e.g., the fatty acid protonates a protonatable moiety on
the active agent (e.g., a primary, secondary or tertiary amine)
thereby placing a charge on the moiety and generating an ionized
moiety (e.g., a protonated amine or ammonium moiety) on the active
agent. The ionized moiety, in turn, interacts with the carboxylate
ion of the fatty acid, which is itself ionized. In some
embodiments, the interaction between the ionized moiety of the
active agent and the carboxylate ion of the fatty acid can be
intimate (e.g., an intimate ion pair), it can be separated by
solvent or it can be separated by one or more excipient molecules.
The fatty acids or amines are present, preferably, in an amount one
to fifteen dates the molar amount of the pharmaceutically active
agent, more preferably, two to ten times the molar amount of the
pharmaceutically active agent. The mass of fatty acid or amine
required to dissolve the active agent is a function of the chain
length of the fatty acid or amine. Some factors determining the
amount of fatty acid or amine required to dissolve a given amount
of active agent include but are not limited to base strength, acid
strength, steric hindrance, and the ability of the active agent to
form non-covalent interactions with the fatty acid or fatty amine
(e.g., hydrogen bonding).
[0050] Other salts of the pharmaceutically active agent, which are
contemplated by the present invention in order to alter the
solubility and/or dissolution rate relative to the parent drug
compound (e.g., the free acid or free base form of the compound)
include, but are not limited to, pectinate,
[0051] In some embodiments, salts of the pharmaceutically active
agent, which are contemplated by the present invention, include
those salts where the counter-ion is polymeric in nature. For
example, anionic copolymers based on methacrylic acid and methyl
methacrylate sold under the trade name Eudragit (e.g., Eudragit
L100 and Eudragit S100), acrylic acid polymers, and crosslinked
acrylic acid polymers may be used to form a salt with drug
molecules. Naturally occurring polymers and their derivatives, for
example, carboxymethylcellulose, may also be used to form a salt
with the drug molecules. In the case of polymeric counter-ions, the
number of drug molecules reacted with the polymer to form a salt
may or may not be equimolar with respect to the number of
salt-forming sites on the polymer chain.
[0052] In another embodiment, a drug is covalently modified to
increase its lipophilicity. For example, a lipophilic compound can
be covalently attached to a drug molecule via an ester or amide
linkage. Such drug derivatives are cleaved in vivo, thus releasing
the parent compound.
[0053] In one embodiment, the drug is made more lipophilic by
eliminating or reducing the overall charge of the drug molecule.
For example, for a basic drug, a water soluble salt (such as
hydrochloride, sulfate, or maleate) can be converted to a free base
using techniques known in the art. In the case of an acidic drug, a
water soluble salt (such as sodium, potassium, or the like) can be
converted to a free acid.
[0054] C. Drug Containing Multiparticulates
[0055] In some embodiments, the drug is formulated with one or more
excipients to form multiparticulates. As used herein, the terms
"multiparticulate," "particle", "microparticle," and "bead," which
are used interchangeably, refer to a composition containing a drug
dispersed within one or more excipients. The terms "coated
multiparticulate" and "coated microparticle," which are used
interchangeably, refer to a composition containing a drug
containing multiparticulate coated with one or more coating layers
of material. Multiparticulates and coated multiparticulates have a
size of from about 1 to about 3000 microns in diameter, for
example, from about 10 to about 3000 microns, form about 100 to
about 1000 microns, from about 500 to about 2000 microns, from
about 1000 to about 3000 microns, from about 500 to about 1500
microns or from about 1 to about 1000 m microns.
[0056] In one embodiment, the multiparticulates have a D(0.1)
particle size form about 50 to about 250 .mu.m, preferably from
about 140 to about 190 .mu.m; a D(0.5) median particle size from
about 150 to about 750 .mu.m, preferably from about 200 to about
400 .mu.m; and a D(0.9) particle size from about 200 to about 1200
.mu.m, preferably from about 400 to about 700 .mu.m. The
multiparticulates are characterized by a span (i.e.,
[D(0.9)-D(0.1)]/D(0.5)) less than 5, preferably less than 2, and
more preferably less than 1.4. In some embodiments,
multiparticulates having a span of less than 1.4 are less prone to
segregation during processing and/or are more likely to achieve the
desired pharmacokinetic profile. D(0.1), D(0.5) and D(0.9) are
defined as the diameters where 10%, 50% or 90% w/w of the
microparticles have a smaller diameter, respectively, when
measured, e.g., using a laser diffraction technique. The
multiparticulates can be any geometrical shape. In some
embodiments, the multiparticulates may be irregular, oblong or
spherical in shape. In a preferred embodiments, the
multiparticulates are substantially round or spherical in shape
(e.g., beads).
[0057] The term "solid dispersion" is defined as a system having
small particles of drug, typically of less than 400 .mu.m in size,
more typically less than 100 .mu.m in size, and most typically less
than 10 .mu.m in size, of one phase dispersed in another phase (the
carrier phase). The term "solid solution" is defined as a system in
a solid state wherein the drug is molecularly dispersed throughout
a matrix such that the system is chemically and physically uniform
or homogenous throughout.
[0058] In one embodiment, the multiparticulates contain a solid
dispersion of drug in one or more excipients. In some embodiments,
the one or more excipients have a low peroxide content in order to
reduce oxidation of the drug or excipients.
[0059] The solid dispersion can be created by homogenously
dispersing the drug, in the form of fine particles, within the one
or more excipients. More preferably, the solid dispersion is formed
by partially dissolving the drug in molten excipient(s) or
partially dissolving the drug with the excipient(s) in a mutual
solvent (e.g., methylene choloride) during the formulation of the
multiparticulates. In another embodiment, the multiparticulates
contain a solid solution of drug and one or more excipients. In
some embodiments, to create a solid solution, the drug is
completely solubilized in the molten excipient(s) or completely
dissolved with the excipient(s) in a co-solvent (e.g., methylene
chloride) during the formulation of the multiparticulates. This is
accomplished through the selection of materials and the manner in
which they are processed.
[0060] Preferred excipients appropriate for the preparation of drug
containing multiparticulates, or that are found in the final
formulation, either dissolve slowly in water or are insoluble in
water. As used herein, the term "dissolves slowly in water" refers
to materials that are not completely dissolved in water within a
period of 30 minutes. Suitable materials include fats, fatty
substances, waxes, wax-like substances and mixtures thereof.
Suitable fats and fatty substance include fatty alcohols (such as
lauryl, myristyl stearyl, cetyl or cetostearyl alcohol), fatty
acids and derivatives, including but not limited, to the conjugate
bases of the fatty acid (i.e., the carboxylate ion), fatty acid
esters, fatty acid glycerides (mono-, di- and tri-glycerides),
fatty amines, and hydrogenated fats. Specific examples include, but
are not limited to stearic acid, palmitic acid, myristic acid,
lauric acid, capric acid, hydrogenated vegetable oil, hydrogenated
cottonseed oil, hydrogenated castor oil, hydrogenated oils
available under the trade name Sterotex.RTM., cocoa butter,
glyceryl behenate (available under the trade name COMPRITOL
888.RTM.), glyceryl dipalmitostearate (available under the trade
name PRECIROL.RTM.), and stearyl alcohol. Suitable waxes and
wax-like materials include natural or synthetic waxes,
hydrocarbons, and normal waxes. Specific examples of waxes include
beeswax, glycowax, castor wax, carnauba wax, paraffins,
microcrystalline wax and candelilla wax. As used herein, a wax-like
material is defined as any material which is normally solid at room
temperature and has a melting point of from about 30 to 300.degree.
C. Certain polymers may also be used as excipients in the
formulation of drug containing multiparticulates. Suitable polymers
include ethylcellulose and other natural or synthetic cellulose
derivatives. Polymers which are slowly soluble and form a gel in an
aqueous environment, such as hydroxypropyl methylcellulose or
polyethylene oxide (e.g., PEO-PPO block copolymers) may also be
suitable as excipients for drug containing multiparticulates.
[0061] In some cases, it may be desirable to incorporate one or
more substances into the formulations contemplated herein to change
the dissolution behavior or the physical and/or chemical stability
of the formulation. In some embodiments, these substances alter the
rate of water penetration into the hydrophobic drug containing
multiparticulates, thereby changing the dissolution behavior of the
formulation. Non-limiting examples of such substances include
rare-controlling (wicking) agents. Such agents may be formulated
along with the fats or waxes listed above. Examples of
rate-controlling materials include certain starch derivatives
(e.g., waxy maltodextrin and drum dried corn starch), cellulose
derivatives (e.g., hydroxypropylmethylcellulose,
hydroxypropylcellulose, methylcellulose, and
carboxymethylcellulose), polyvinyl pyrrolidone, alginic acid, and
lactose or mixtures thereof.
[0062] Additionally, a pharmaceutically acceptable surfactant, for
example, lecithin, sodium dodecyl sulfate, poloxamer, Cremophor
(polyethoxylated castor oil), Polyoxylglycerides (e.g.,
polyethylene glycol fatty acid esters), sorbitan stearates, or
polysorbates, or mixtures of two or more surfactants, may be added
to alter the dissolution behavior of the multiparticulates. Other
acceptable surfactants include inorganic salts of fatty acids
(e.g., potassium and sodium salts of fatty acids). Mixtures of
mono-, di- and tri-glycerides and mono- and di-fatty acid esters of
polyethylene glycol, available under the trade name such as
GELUCIRE.RTM. or Myrj.RTM. are also suitable. In some embodiments,
the surfactants are present in the multiparticulates or a
combination thereof. Other inactive ingredients, such as
hydroxypropylmethylcellulose, poloxamer or polyvinyl pyrrolidone
may also be added as needed to impart a desirable attribute such as
inhibiting crystallization of one or more components of the
multiparticulates.
[0063] In some cases, suitable antioxidants may be added to the
composition. Anti-oxidants include, but are not limited to,
butylated hydroxytoluene (BHT); ascorbic acid, its salts and
esters; Vitamin E, tocopherol and its salts; sulfites such as
sodium metabisulphite; cysteine and its derivatives; citric acid;
propyl gallate, and butylated hydroxyanisole (BHA). Chelating
agents may also be needed. Suitable chelating agents include, but
are not limited to, EDTA, a salt of EDTA, desferrioxamine B,
deferoxamine, dithiocarb sodium, pencillamine, pentetate calcium, a
sodium salt of pentetic acid, succimer, trientine, nitrilotriacetic
acid, trans-diaminocyclohexanetetraacetic acid (DCTA),
diethylenetriamine-pentaacetic acid,
bis(aminoethyl)glycolether-N,N,N',N'-tetraacetic acid,
iminodiacetic acid, citric acid, tartaric acid, fumaric acid, or a
salt thereof.
[0064] Encapsultaion or incorporation of drug into excipient(s) to
produce drug containing multiparticulates can be achieved through
known pharmaceutical formulation techniques. To create a
composition that protects drug from exposure upon mechanical
disruption (e.g., grinding, chewing, or chopping), the drug is
intimately dispersed within the one or more excipients. In the case
of formulation in fats, waxes or wax-like materials, the one or
more excipients are heated above their melting temperature and the
drug is added to form a mixture where drug particles are suspended
in the one or more excipients, where the drug is dissolved in the
one or more excipients, or a mixture where a portion of the drug
particles are suspended in the one or more excipients and another
portion of the drug is dissolved in the one or more excipients.
Multiparticulates can be subsequently formulated through several
methods including, but not limited to, spray congealing, spray
chilling, spray drying, extrusion, bulk congealing into capsules
and bulk congealing with subsequent milling. In a preferred
process, one or more excipients are heated above its melting
temperature, the drug is added, and the molten excipient-drug
mixture is congealed to form solid, spherical particles via a
spraying process using one or more nozzles, a spinning cylinder or
a spinning disc. Alternatively, the molten excipient-drug mixture
can be extruded and pelletized to form pellets or beads.
Descriptions of these processed can be found in "Remington--The
science and practice of pharmacy", 20th Edition, Jennaro et. al.,
(Phila, Lippencott, Williams, and Wilkens, 2000.
[0065] In a preferred process, spherical or substantially spherical
particles are produced. Spherical particles may introduce an
additional barrier to deter tampering with the compositions.
Smaller, round or substantially round particles act as "ball
bearings" that are more difficult to crush or grind, and if
crushed, do not allow for significant enough decrease in particle
size or surface areas of the particles in order to have a
significant and adverse effect on release rate.
[0066] In a preferred embodiment, multiparticulates include a solid
solution of drug and one or more excipients. One approach to
achieving a solid solution is to formulate a salt composed of a
pharmaceutically active agent and one or more fatty acids or amines
along with other waxy and/or fatty excipients. In this embodiment,
the salt may be formed during the formulation process itself. To
accomplish this, the one or more fatty acids or amines are melted
and mixed with the free base or acid form of the active agent at a
temperature above the melting point(s) of the fatty acid(s) or
amine(s). One or more additional excipients including but not
limited to fat, Fatty substance(s), wax, wax-like substance(s),
polymeric substances, or antioxidants can be included in the molten
mixture. The molten solution is then formulated into
multiparticulates via, e.g., spray congealing, spray chilling,
spray drying, extrusion, bulk congealing into capsules and bulk
congealing with subsequent milling.
[0067] In some embodiments, the molar concentration of fatty acid
or amine may need to be higher than that of the drug in order to
achieve a homogenous single phase during the melt process. For
example, it has been found that, for oxycodone, a molar ration in
excess of about 7:1 fatty acid (e.g., myristic acid) to drug
results in a homogenous melt using this technique. The molar ratio
needed to obtain a homogeneous melt may depend on the type and
quantity of additional excipients added. For example, some fat or
wax excipients, such as natural waxes (eg, beeswax and carnauba
wax) may contain free fatty acids or other components that can
interact ionically with the drug. Such fat or wax excipients may
reduce the amount of fatty acid excipient required to obtain a
homogeneous melt as compared to fat or wax excipients that do not
interact with the drug. In one embodiment, the molar ratio of fatty
acid or fatty amine to drug is from about 1:1 to about 15:1,
preferably from about 6:1 to about 15:1. However, molar ratios
greater than 15:1, for example 15:1 to 25:1, preferably 15:1-20:1,
may be required depending on the fatty acid or fatty amine, the
drug to be formulated, and/or the additional excipient(s).
[0068] For some excipients it may be desirable to use a solvent
evaporation technique to produce drug containing multiparticulates.
In this case drug and one or more excipients are co-dissolved in a
mutual solvent and multiparticulates can subsequently be produced
by several techniques including, but not limited to, forming an
emulsion in water or other appropriate media, spray drying or by
evaporating the solvent from the bulk solution and milling the
resulting material.
[0069] In addition to modification of the drug itself, processing
conditions can be used to influence the dispersion of the drug
within water-insoluble or slowly water soluble materials. For
example, in the case where the water insoluble or slowly soluble
material is melted and the drug is fully or partially dissolved
under stirring conditions, the temperature, agitation rate and time
of processing will influence the degree of dissolution achieved.
More specifically, a more homogenous dispersion may be achieved
with a higher temperature, faster stirring rate and/or longer
processing time. Ultrasound can also be applied to the molten
mixture to increase the degree of dispersion and/or the rate of
dissolution of the drug.
[0070] In some embodiments, the drug in a particulate form is
homogeneously dispersed in a water-insoluble or slowly water
soluble material. To minimize the size of the drug particles within
the composition, the drug powder itself may be milled to generate
fine particles prior to formulation. The process of jet milling,
known in the pharmaceutical art, can be used for this purpose. In
some embodiments drug in a particulate form is homogeneously
dispersed in a wax or wax like substance by heating the wax or wax
like substance above its melting point and adding the drug
particles while stirring the mixture. In this case a
pharmaceutically acceptable surfactant may be added to the mixture
to facilitate the dispersion of the drug particles.
D. Coasted Drug Containing Multiparticulates
[0071] In some embodiments, drug containing multiparticulates or
drug particles are encapsulated. Drug containing multiparticulates
can be encapsulated in water insoluble materials, slowly water
soluble materials, organic insoluble materials and/or materials
with pH dependent solubilities.
[0072] In general, any coating procedure which provides a
contiguous coating on each multiparticulate can be used. Coating
procedures known in the arts include, but are not limited to, fluid
bed coating processes and microencapsulation. Detailed descriptions
of these processes can be found in "Remington--The science and
practice of pharmacy", 20th Edition, Jennaro et al., (Phila.
Lippencott, Williams, and Wilkens, 2000.
[0073] The water-insoluble coating materials may be selected from
natural or synthetic film-formers used alone, in admixture with
each other, or in admixture with plasticizers, pigments and other
substances to alter the characteristics of the coating. A
water-insoluble but water-permeable diffusion barrier may contain
ethyl cellulose, methyl cellulose and mixtures thereof. The
water-permeable diffusion barrier may also include ammonio
methacrylate copolymers sold under the trade name EUDRAGIT.RTM.
(Rohm Pharma), such as EUDRAGIT RS, EUDRAGIT RL, EUDRAGIT NE and
mixtures thereof. Other synthetic polymers, for example, polyvinyl
acetate (available under the trade name KOLLICOAT.RTM.), can also
be used to form water-insoluble but permeable coatings.
[0074] The coating may also include a water-insoluble but
enzygmatically degradable material. In some instances the
substrates of digestive enzymes are naturally water-insoluble and
can be utilized in the formulation without further processing.
Solid esters of fatty acids, which are hydrolyzed by lipases, can
be spray coated onto multiparticulates or drug particles. Mixtures
of waxes (beeswax, carnauba wax, etc.) with glyceryl monostearate,
stearic acid, palmitic acid, glyceryl monopalmitate and cetyl
alcohol will also form films that are dissolved slowly or broken
down in the GI tract. Zein is an example of a naturally
water-insoluble protein. It can be coated onto drug containing
multiparticulates or drug particles by spray coating or by wet
granulation techniques. In addition to naturally water-insoluble
materials, some substrates of digestive enzymes can be treated with
cross-linking procedures, resulting in the formation of non-soluble
networks. Many methods of cross-linking proteins, initiated by both
chemical and physical means, have been reported. In some
embodiments, chemical cross-linking agents are used. Examples of
chemical cross-linking agents include, but are not limited to,
aldehydes (e.g., gluteraldehyde and formaldehyde), epoxy compounds,
carbodimides, and genipin. In addition to these cross-linking
agents, oxidized and native sugars have been used to cross-link
gelatin. Cross-linking can also be accomplished using enzymatic
means; for example, transglutaminase has been approved as a GRAS
substance for cross-linking seafood products. Finally,
cross-linking can be initiated by physical means, for example
application of a stimulus, such as heat, UV irradiation and gamma
irradiation.
[0075] To produce a coating layer of cross-linked protein
surrounding drug containing multiparticulates or drug particles, a
water soluble protein can be spray coated onto the
multiparticulates and subsequently cross-linked by one of the
methods described above. Alternatively, drug containing
multiparticulates can be microencapsulated within protein by
coacervation-phase separation, for example, by addition of salts
and subsequently cross-linked. Some suitable proteins for this
purpose include gelatin, alburnin, casein, and gluten.
[0076] Polysaccharides can also be cross-linked to form a
water-insoluble network. For many polysaccharides, this can be
accomplished by reaction with calcium salts or multivalent cations
which cross-link the main polymer chains. Pectin, alginate,
dextran, amylose and guar gum are subject to cross-linking in the
presence of multivalent cations. Complexes between oppositely
charged polysaccharides can also be formed; pectin and chitosan,
for example, can be complexed via electrostatic interactions.
Insoluble coatings can be formed on particles in this fashion. It
should be noted that in many cases polysaccharides are broken down
specifically by enzymes produced by bacteria within the colon.
[0077] In some cases a water-insoluble but enzygmatically
degradable coating including both a protein and a polysaccharide
can be produced if the components are oppositely charged
polyelectrolytes. Under the proper temperature, pH, and
concentrations, the two polymers can interact through their
opposite electrical charges and form a water-insoluble complex. If
a core particle is present at the time the complex phase separates,
it will be coated. For example, gelatin and gum arabic can be
coated onto a core particle utilizing this process. Optionally, the
complex can be made irreversibly insoluble by subsequent
cross-linking induced by chemical or physical means.
[0078] Coating materials may also include a pH sensitive polymer
which is insoluble in the acid environment of the stomach, and
soluble in the snore basic environment of the GI tract. These
coatings, referred to as enteric coatings, create a dosage form
designed to prevent drug release in the stomach. Preventing drag
release in the stomach has the advantage of reducing side effects
associated with irritation of the gastric mucosa and/or of
minimizing exposure of drug to very low pH. Avoiding release within
the stomach can be achieved using enteric coatings known in the
art. The enteric coated formulation remains intact or substantially
intact in the stomach, however, once the formulation reaches the
small intestines, the enteric coating dissolves and exposes either
drug-containing carrier particles or drug-containing carrier
particles coated with extended release coating.
[0079] Enteric coated particles can be prepared as described in
"Pharmaceutical dosage form tablets", eds. Liberman et. al. (New
York, Marcel Dekker, Inc., 1989), "Remington--The science and
practice of pharmacy", 20th ed., Lippincott Williams & Wilkins,
Baltimore, Md. 2000, and "Pharmaceutical dosage forms and drug
delivery systems", 6th Edition, Ansel et. al., (Media, Pa.:
Williams and Wilkins, 1995). Examples of suitable coating materials
include, but are not limited to, cellulose polymers, such as
cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl
methylcellulose phthalate and hydroxypropyl methylcellulose acetate
succinate; polyvinyl acetate phthalate, acrylic acid polymers and
copolymers, and certain methacrylic resins that are commercially
available under the trade name EUDRAGIT.RTM. (Rohm Pharma).
Additionally the coating material may contain conventional carriers
such as plasticizers, pigments, colorants, glidants, stabilization
agents, and surfactants.
[0080] In some cases it may be desirable to coat the particles with
a coating which is soluble in aqueous solutions but insoluble in
hydroalcoholic solutions. In this case the coating material may or
may not have pH sensitive solubility in aqueous solutions.
[0081] In other cases it may be desirable to combine coating
materials to produce a tailored release of drug. For example,
combinations of insoluble polymers and pH dependent polymers can
produce a pH dependent sustained release profile. Combinations of
insoluble polymers (e.g., ethylcellulose), water-soluble polymers
(e.g., HPMC or PEG) and pH dependent swellable polymers (e.g.,
carboxyvinylpolymer) have also been reported to produce pH
dependent sustained release profiles.
[0082] In one embodiment, the particles are coated with cellulose
acetate phthalate. Cellulose acetate phthalate is typically used as
an enteric coating.
E. Control of Oxidative Degradation
[0083] In some cases it may be necessary to prevent oxidative
degradation of th active pharmaceutical ingredient and/or the one
or more inactive excipients in the composition. Oxidation of one or
more components may occur during the formulation process itself or
during the shelf-life of the composition. Oxidation may result from
exposure to the oxygen content of air or, alternatively, may be
related to impurities in the excipients. For example, highly
reactive species such as peroxides, hydro-peroxides, superoxides,
hypochlorites and/or formic acid may be present in excipients as
manufacturing or raw-material-related impurities. Also, trace metal
impurities in excipients, such as iron and copper, can catalyze
oxidation reactions. Several approaches may be taken to reduce or
eliminate reactions involving oxygen in the composition. In one
embodiment, an antioxidant may be included in the composition to
mitigate the degradation of the drug in such cases. If the source
of oxidation is a reactive manufacturing-related impurity in one or
more of the excipients, the anti-oxidant can be co-melted with the
excipient(s) in order to protect the drug from these reactive
species.
[0084] Chelating agents may also be employed to scavenge trace
metals. Controls over the exposure to environmental oxygen may also
be employed. For example, in embodiments where a melt process is
employed, a closed tank can be used. An inert gas, such as nitrogen
or argon, can be sparged through the melt and/or introduced into
the head space of the tank. The inert can also be introduced
following vacuum removal of environmental oxygen.
[0085] Suitable antioxidants include, but are not limned to,
butylated hydroxytoluene (BHT); ascorbic acid, its salts and
esters; Vitamin E, tocopherol and its salts; sulfites such as
sodium metabisulphite; cysteine and its derivatives; citric acid;
propyl gallate; and butylated hydroxyanisole (BHA). Suitable
chelating agents include, but are not limited to, EDTA, a salt of
EDTA, desferrioxamine B, deferoxamine, dithiocarb sodium,
penicillamine, pentetate calcium, a sodium salt of pentetic acid,
succimer, trientine, nitrilotriacetic acid,
trans-diaminocyclohexanetetraacetic acid (DCTA),
diethylenetriamine-pentaacetic acid,
bis(aminoethyl)glycolether-N,N,N',N',-tetraacetic acid,
iminodiacetic acid, citric acid, tartaric acid, fumaric acid, or a
salt thereof.
[0086] The concentration of the antioxidant is generally from about
0.001% to about 1% w/w, preferably from about 0.01% to about 0.5%
w/w. However, concentrations of less than 0.001% or greater than
0.5% may be used, provided the concentration is sufficient to
stabilize the formulation and is non-toxic.
[0087] In some instances it may be advantageous to reduce or
eliminate the presence of reactive species within the excipients.
This is particularly true for embodiments in which a hot melt
process is used to create a solid dispersion or solid solution. It
has been demonstrated that controlling the peroxide value in
carnauba wax, for example, can reduce the formation of oxidation
by-products. Depending on the specific ratio used in the
formulation, waxy materials, such as carnauba wax, with a peroxide
value less than 25 ppm, more preferably less than 5 ppm, and most
preferably less than 3 ppm are preferred in some embodiments.
F. Dosage Forms
[0088] In one embodiment a drug is partially dissolved within a
water-insoluble or slowly water soluble material during the
manufacturing process, for example, by mixing at a temperature
above the melting point of the excipients, and the mixture is
formulated into multiparticulates. In a preferred embodiment a drug
is fully dissolved within a water-insoluble or slowly water soluble
material during the manufacturing process, for example, by mixing
at a temperature above the melting point of the excipients, and the
mixture is formulated into multiparticulates. In still a further
embodiment, the drug containing multiparticulates, where the drug
is homogeneously dispersed in a particulate form, or has been
partially or fully dissolved within one or more excipients during
the manufacturing process, are coated with one or more coatings to
form coated multiparticulates.
[0089] The multiparticulates, coated multiparticulates, or a
mixture thereof are formed into a solid dosage form suitable for
oral administration. For example, multiparticulates or coated
multiparticulates can be incorporated into hard shell capsules,
dispersed within a soft gelatin capsule, or tableted by
compression. Appropriate excipients, such as magnesium stearate as
a lubricant, colloidal silicon dioxide as a glidant, sodium starch
glycolide, sodium croscarmellose or crospovidone as a disintegrant,
and lactose or microcrystalline cellulose as fillers may be
included.
[0090] Examples of suitable hard shell capsules include capsules
formed from gelatin, hydroxypropylmethylcellulose, polysaccharide,
and other pharmaceutically acceptable polymer materials. In some
embodiments hydroxypropylmethylcellulose capsules, marketed under
the trade name Vcaps.RTM., can be employed.
[0091] In some embodiments, drug containing multiparticulates are
blended with extragranular material and filled into hard shell
capsules. The extragranular material can serve several functions.
One or more extragranular materials, such as lubricants or
glidants, can be used to keep the multiparticulates from sticking
together. Examples of suitable materials for this purpose include,
but are not limited to, magnesium stearate, zinc stearate,
colloidal silicone dioxide, talc, starch, calcium stearate,
hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate,
sodium benzoate, sodium acetate, leucine, sodium oleate, sodium
lauryl sulfate, magnesium lauryl sulfate and polyethylene glycol.
In other embodiments, the extragranular material is a natural or
synthetic gel forming excipient, added to form a gel or viscous
environment around the particles when exposed to an aqueous
environment. Extragranular material of this type can be used to
modulate the release of drug from the dosage form. Examples of
suitable materials include, but are not limited to,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose,
polyvinyl pyrrolidone and sodium alginate.
[0092] In some embodiments, the compositions are coated with an
enteric coating. Enteric coatings known in the art are applied
directly to the abuse-deterrent multiparticulate or coated
multiparticulate compositions or are applied to the surface of a
capsule or tablet containing the abuse deterrent multiparticulate
and/or coated multiparticulate compositions. Enteric coatings known
in the art include, for example, acrylic polymers that are
commercially available under the trade name EUDRAGIT.RTM.,
cellulose acetate phthalate, hydroxypropylmethyl-cellulose
phthalate, polyvinylacetate phthalate, shellac,
hydroxypropyl-methylcellulose succinate, cellulose acetate
trimelliate or mixtures thereof. In one embodiment, the particles
are coated with cellulose acetate phthalate.
[0093] Dosage forms can include one or more drugs. When the dosage
form includes two or more drugs they can be Scheduled drugs or can
be a combination of Scheduled and non-Scheduled drugs. The drugs
can be incorporated into the same multiparticulates. Alternatively,
the drugs can be incorporated into separate multiparticulate
compositions where the Scheduled drugs are incorporated into abuse
deterrent multiparticulate compositions and the non-Scheduled drugs
are incorporated into abuse deterrent multiparticulate
compositions, sustained release compositions known in the art or
immediate release compositions known in the art. The compositions
containing the different drugs can be formulated into a single
solid dosage form suitable for oral administration; for example,
they can be incorporated into a hard capsule shell, or combined
with appropriate excipients and compressed into a tablet form.
[0094] Examples of non-scheduled drugs that may be included in
dosage forms described herein include, but are not limited to,
aspirin, acetaminophen, non-steroidal anti-inflammatory drugs,
cyclooxygenase II inhibitors, N-methyl-D-aspartate receptor
antagonists, glycine receptor antagonists, triptans,
dextromethorphan, promethazine, fiorinal, guaifensin, butalbital,
and caffeine.
[0095] An immediate release dose can be incorporated into the
formulation in several ways. Immediate release multiparticulates
can be made utilizing standard methodologies and formulated along
with abuse-deterrent multiparticulate and/or coated
multiparticulate compositions in a suitable oral dosage form.
Alternatively, a coating containing drug which is available for
immediate release can be placed on a tablet containing
abuse-deterrent multiparticulate and/or coated multiparticulate
compositions plus appropriate excipients. Additionally, an
immediate dose of drug can be granulated or blended with rapidly
dissolving excipients and subsequently compressed (1) as one layer
of bi-layer tablets in which the abuse-deterrent multiparticulate
and/or coated multiparticulate compositions are compressed as the
other layer, or (2) as the outer layer of compression-coated
tablets in which the abuse-deterrent multiparticulate and/or coated
multiparticulate compositions are compressed as the inner core, or
(3) into tablets in which abuse-deterrent multiparticulate and/or
coated multiparticulate compositions are embedded.
[0096] In some embodiments, the immediate release portion of the
dosage form contains a lipophilic drug derivative. For example,
salt derivatives or complexes that are insoluble at a neutral pH
but dissociate, thereby releasing the parent compound, at an acidic
pH are ideal for immediate release within the stomach. Exemplary
salts, such as salts of oxycodone, that may exhibit this property
include, but are not limited to, the tannate, phthalate,
salicylate, gallate, pectinate, phytate, saccharinate, asesulfamate
and terephthalate salts. Use of salts or complexes in the immediate
release portion or the dosage form reduces the abase potential of
the immediate release dose if the formulation is crushed and (1)
snorted or (2) dissolved in water since these salts will be poorly
soluble under these conditions. It is understood by the one of
ordinary skill in the art that such salts or complexes may also be
used to formulate an immediate release dosage form without a
sustained release portion.
[0097] Additional mechanisms to reduce the potential for abuse can
also be incorporated during the process of formulating tablets or
capsules. For example, ingredients can be added to deter chewing or
snorting of the final formulation. For example, an intensely bitter
substance may deter chewing, while an intensely spicy ingredient,
such as capsaicin, may deter snorting. The addition of a colored
dye, which would stain the skin and mucosal surface of the nose
following snorting may also serve to reduce this practice.
[0098] In some embodiments, the contemplated compositions
comprising a plurality of multiparticulates comprise one or more
additional excipients that are combined with the multiparticulates.
The one or more additional excipients comprise diluents,
lubricants, gel forming excipients, and combinations thereof. In
other embodiments, each multiparticulate or coated multiparticulate
comprises optional excipients including, but are not limited to
diluents, binders, lubricants, disintigrants, colorants,
plasticizers and the like. Diluents, also termed "fillers," are
typically necessary to increase the bulk of a solid dosage form so
that a practical size is provided for compression of tablets.
Examples of diluents include cellulose, dry starch,
microcrystalline cellulose, dicalcium phosphate, calcium sulfate,
sodium chloride confectioner's sugar, compressible sugar,
dextrates, dextrin, dextrose, sucrose, mannitol, powdered
cellulose, sorbitol, and lactose.
[0099] Binders are used to impart cohesive qualities powdered
materials and can include materials such as starch, gelatin,
sugars, natural and synthetic gums, polyethylene glycol,
ethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,
carboxymethylcellulose, waxes and polyvinyl pyrrolidone.
[0100] Lubricants are used to facilitate tablet and capsule
manufacture. Examples of lubricants include talc, magnesium
stearate, zinc starate, calcium stearate, hydrogenated vegetable
oils stearic acid, sodium stearyl fumarate, sodium benzoate, sodium
acetate, leucine, sodium oleate, sodium lauryl sulfate, magnesium
lauryl sulfate and polyethylene glycol.
[0101] Disintegrants can be added to pharmaceutical formulations in
order to facilitate "breakup" or disintegration after
administration. Materials used for this purpose include starches,
clays, celluloses, aligns, gums, and cross-linked polymers.
[0102] A plasticizer may be included in coating materials to alter
their mechanical properties. Examples of plasticizers include
benzyl benzoate, chlorobutanol, dibutyl sebacate, diethyl
phthalate, glycerin, mineral oil, polyethylene glycol, sorbitol,
triacetin, triethyl citrate, glycerol, etc.
[0103] One or more surfactants may also be added to the final
dosage form to modulate the release of drug from the
multiparticulate composition. Examples include, but are not limited
to, lecithin, sodium dodecyl sulfate, poloxamer, Cremophor,
polysorbates, and polyoxyglycerides.
[0104] In addition to the additives above, coloring and flavoring
agents may also be incorporated into the composition.
II. Methods of Making
[0105] The compositions described herein can be made using a
variety of techniques known in the art including, but not limited
to, spray congealing, spray chilling, spray drying, extrusion, bulk
congealing into capsules and bulk congealing with subsequent
milling. In one embodiment, beads containing the active agent or a
fatty acid salt thereof and excipients are prepared via spray
congealing utilizing a spinning disc atomization process. In this
process, a molten mixture or solution of the active agent and
excipients is pumped onto a heated, rotating disc. The disc
generates centrifugal force which distributes the melt as a uniform
sheet and accelerates it toward the edge of the disc where it forms
ligaments that break into droplets that rapidly congeal into beads
having diameters in microns. The disc can alternatively incorporate
vanes that channel the melt at the periphery of the disc. A general
description of apparatuses that employ such a rotating disc may be
found, e.g., in U.S. Pat. Nos. 7,261,529 and 3,015,128, both of
which are incorporated by reference as if fully set forth
herein.
[0106] Process parameters such as disc speed, melt feed rate, melt
feed temperature, and/or air flow can affect bead size and/or bead
size distribution. Under some circumstances, feed rate has little
effect on the median bead size or distribution (span). In some
instances, bead size can be decreased with increased disc speed and
low air flow rates. In still other instances, the span can be
decreased with increased disc speed and high feed temperatures.
[0107] In some embodiments, the temperature at which the melt is
manufactured is controlled in order to avoid significant
degradation of drug and/or carrier material. In some embodiments,
the melt preparation and processing temperature is higher than the
melting point of the bead formulation, i.e. the temperature at
which the melt is completely liquid, by 1-30.degree. C., preferably
1-5.degree. C. higher, to minimize potential product degradation
and/or adverse side reactions.
[0108] Melt feed temperature, the temperature at which the melt is
fed onto, e.g., a spray congealing device, should also be
1-30.degree. C. higher than the melting point, preferably be
3-10.degree. C. higher than the melting point to minimize the
amount of heat that needs to dissipate from the beads before they
congeal.
[0109] In one embodiment, the multiparticulates have a D(0.1)
particle size front about 50 to about 250 .mu.m, preferably from
about 140 to about 190 .mu.m; a D(0.5) median particle size from
about 150 to about 750 .mu.m, preferably from about 200 to about
400 .mu.m; and a D(0.9) particle size from about 200 to about 2500
.mu.m preferably from about 400 to about 700 .mu.m. The
multiparticulates are characterized by a span (i.e.,
[D(0.9)-D(0.1)]/D(0.5)) less than 5, preferably less than 2, and
more preferably less than 1.4. In some embodiments,
multiparticulates having a span of less than 1.4 are less prone to
segregation during processing and/or are more likely to achieve the
desired pharmacokinetic profile D(0.1), D(0.5) and D(0.9) are
defined as the diameters where 10%, 50% or 90% w/w of the
microparticles have a smaller diameter, respectively, when
measured, e.g., using a laser diffraction technique. The terms
"D(0.5)" and "median panicle size" are used interchangeably herein.
The multiparticulates can be any geometrical shape. In some
embodiments, the multiparticulates may be irregular, oblong or
spherical in shape. In a preferred embodiment, the
multiparticulates are substantially round or spherical in shape
(e.g., beads).
[0110] Disc speed, feed rate and air flow rate depend on the melt
formulation and desired size and span. Bead with spans less than 5
may be produced. Conditions that yield a narrow span are preferred
to avoid significant particle segregation during downstream
processing. A span of less than about 2, and more preferably less
than about 1.4 is preferred.
II. Methods of Administration
[0111] In addition to providing a deterrent to common, methods of
abuse/diversion, the formulation can provide a sustained release of
drug over an extended time period. This is a natural consequence of
the fact that, in the formulations described herein, drug is slowly
released from a predominantly water-insoluble, hydrophobic matrix
as it passes through the GI tract. The barrier components may be
degraded as the matrix passes through the GI tract, for example, by
enzymes, the surfactant action of bile acids, and/or mechanical
erosion.
[0112] In some embodiments, an immediate release of drug is
achieved within the stomach in order to provide rapid therapeutic
onset.
[0113] The pharmaceutical, drug composition is generally
administered orally. The appropriate dosage formulations can be
obtained by calculation of the pharmacokinetics of the formulation,
then adjusting using routine techniques to yield the appropriate
drug levels based on the approved dosage forms. Any suitable amount
of drug containing multiparticulates or coated multiparticulates
can be included in the final formulation. The selection of a
suitable amount of drug containing multiparticulates depends on the
dosage desired and is readily determined by those skilled in the
art.
[0114] In addition to oral administration, some embodiments may
also be administered by other routes, including, but not limited
to, rectal and nasal administration. Some embodiments may also be
suitable for formulation as oral liquids.
[0115] The present composition and method of making and using the
composition will be further understood by reference to the
following non-limiting examples.
Example 1
Preparation of Drug Containing Multiparticulates
TABLE-US-00001 [0116] TABLE 1 Compositions Composition Composition
Composition Composition of of of of Formulation Formulation
Formulation Formulation Ingredient A B C D Oxycodone 5 g 5 g 10 g 5
g Base Myristic Acid -- -- 50 g 30 g Stearic Acid 34 g 34 g -- --
Yellow 10 g -- 10 g 10 g Beeswax Carnauba wax 5 g 10 g 20 g 10
g
Procedure:
[0117] 1. Fatty acid (myristic or stearic acid) was melted in an
erlenmeyer flask in a silicone oil bath at 100.degree. C. The
mixture was stirred and kept under an argon blanket for this and
all subsequent steps.
[0118] 2. Oxycodone base was introduced into the molten fatty acid
and the melt was stirred until the oxycodone base was completely
dissolved and a clear liquid was formed.
[0119] 3. Yellow beeswax was added and dissolved under constant
stirring.
[0120] 4. Carnauba wax was added and dissolved under constant
stirring.
[0121] 5. The resulting homogenous molten solution was poured onto
aluminum foil and allowed to solidify at room temperature.
[0122] 6. The bulk material obtained was combined with small
quantities of dry ice and subjected to size reduction in a mortar
and pestle.
[0123] 7. The dry ice was allowed to dissipate and the particles
were sieved to obtain various size ranges. Particles 20-40 mesh in
size (400-841 micron) were subjected to testing.
Example 2
Release of Drug from Crushed Multiparticulates
[0124] In vitro testing was conducted in order to assess the
influence of crushing of the multiparticulates produced in Example
1 on the release in simulated stomach conditions. A currently
marketed sustained release formulation of oxycodone,
OxyContin.RTM., was also subjected to crushing and dissolution for
comparison purposes.
[0125] Multiparticulates (Formulations A, B, C or D, all 20-40 mesh
in starting particle size) and OxyContin.RTM. tablets were crushed
using a glass mortar and pestle. The resulting crushed material was
placed in a dissolution vessel equipped with paddles (USP Apparatus
II). 900 mL of 0.1N HCl pre-warmed to 37.degree. C. was added to
the vessels and stirred for 15 minutes. After 15 minutes the amount
of oxycodone released was determined. The results are shown in
Table 2.
TABLE-US-00002 TABLE 2 Drug Release from Crushed Compositions %
Relaeased in 15 minutes in 0.1N Sample HCl (n = 3) Oxycontin .RTM.
95.6 +/- 2.7 (40 mg Tablet) Formulation A 31.6 +/- 2.6
(multiparticulates containing 40 mg oxycodone HCl equivalent)
Formulation B 19.7 +/- 1.4 (multiparticulates containing 40 mg
oxycodone HCl equivalent) Formulation C 14.8 +/- 1.1
(multiparticulates containing 20 mg oxycodone HCl equivalent)
Formulation D 18.2 +/- 1.6 (multiparticulates containing 20 mg
oxycodone HCl equivalent)
[0126] As illustrated in the table above, the multiparticulate
compositions of Example 1 release only a fraction of the total drug
load in simulated stomach conditions when crushed. In contrast, a
currently marketed sustained release composition, OxyContin.RTM.,
released approximately 96% of the drug load when crushed and
exposed to identical conditions.
Example 3
Preparation of Oxycodone Containing Multiparticulates Using a
Spinning Disc Atomization Process
[0127] Batch size: 1000 g
TABLE-US-00003 TABLE 3 Composition Component Quantity(g)/Batch
Oxycodone base 91 Myristic acid 545 Beeswax 182 Carnauba Wax 182
Total 1000.0
Procedure:
[0128] 1. Myrisitc acid was melted at 85.degree. C. in a silicone
oil bath while constantly flowing argon above the surface of the
solution.
[0129] 2. Beeswax was added to the molten fatty acid and mixed
until a clear, homogenous solution was obtained.
[0130] 3. Carnauba wax was added to the molten solution and mixed
until a clear, homogenous solution was obtained.
[0131] 4. Oxycodone base was added to the molten solution and mixed
until a clear, homogenous solution was obtained.
[0132] The resulting molten solution was transferred to a feed
kettle and continuously metered onto a spinning disc atomizer (see
FIG. 1) in order to form solid, spherical multiparticulates. These
multiparticulates can be optionally spay coated with, for example,
cellulose acetate phthalate.
Example 4
Preparation of Coated Drug Containing Multiparticulates
[0133] The drug-containing particles from Example 3 can be spray
coated with cellulose acetate phthalate.
Example 5
Preparation of Oxymorphone Containing Multiparticulates
[0134] Batch size: 630.6 g
TABLE-US-00004 TABLE 4 Composition Component Quantity(g)/Batch
Oxymorphone base 60 Stearic acid 420 Beeswax 30 Carnauba Wax NF 120
Butylated Hydroxyanisole 0.6 Total 630.6
Procedure:
[0135] 1. Stearic acid was melted in an erlenmeyer flask in a
silicone oil bath at 100.degree. C. Note the composition was
subjected to stirring and was kept under an argon blanket for this
and all subsequent steps.
[0136] 2. Butylated hydroxyanisole was added to the molten stearic
acid while mixing.
[0137] 3. Oxymorphone base was introduced into the molten fatty
acid and the melt was stirred until all oxymorphone base dissolved
and a clear liquid was formed.
[0138] 4. Beeswax was added and dissolved under constant
stirring.
[0139] 5. Carnuaba wax was added and dissolved under constant
stirring.
[0140] 6. The resulting homogenous molten solution was poured onto
aluminum foil and allowed to solidify at room temperature.
[0141] 7. The bulk wax obtained was combined with dry ice and
subjected to size reduction in a mortar and pestle.
[0142] 8. The dry ice was allowed to dissipate and the particles
were sieved to obtain particles in the 40-80 mesh size range.
Example 6
Preparation of Capsules for Oral Administration
[0143] The drug containing multiparticulates from Examples 1, 3, 4,
and 5 can be blended with one or more suitable lubricants and,
optionally, one or more glidants, and incorporated into an
appropriately sized hard shell capsules.
Example 7
Use of Spray Nozzles to Prepare Oxymorphone Formulation Beads
Containing Additives
[0144] The formulations in Table 5 were prepared using
laboratory-scale melt and spray congealing process using a spray
nozzle to form beads. Base formulation components [stearic acid
(SA), beeswax (BW) and carnauba wax (CW)] were successively added
to a stainless steel beaker equipped with a heating water jacket
and allowed to melt with stirring at a controlled temperature of
approximately 85.degree. C. Additives such as polymers (PVP K29/32,
Polyvinyl Pyrrolidone), surfactants such as Gelucire 50/13
(Gattefosse, mono- and di-C.sub.16 and C.sub.18 fatty acid esters
of polyethylene glycol, a blend of mono-, di-, and tri-glycerides
of C.sub.16 and C.sub.18 and some free PEG and fatty acids),
Poloxamer 407 (BASF, triblock copolymer consisting of a central
hydrophobic block of polypropylene glycol flanked by two
hydrophilic blocks of polyethylene glycol), and/or Span 60
(Sorbitan Monostearate) were added in the amount set forth in Table
5, below, and allowed to dissolve in the melt. Oxymorphone free
base, the active pharmaceutical ingredient (API), was then added
and mixed until complete dissolution occurred, resulting in a clear
melt. The formulation was kept blanketed with inert gas throughout
the melt manufacture.
[0145] Beads were produced by spraying the melt into an enclosure
lined with a plastic sheeting. The melt was sprayed into the
enclosure using a syringe equipped with a plastic pressure nozzle
at its end. See FIG. 2. the syringe plunger was pressed through the
barrel using a pneumatic piston. The piston activated with an air
pressure sufficient to press the melt through the barrel at a speed
high enough to atomize the melt and produce beads. Spraying was
oriented at approximately 45.degree. angle to provide maximum
contact time with room air and threreby allow the beads to cool and
congeal before they collect at the bottom of the enclosure.
Microscopic examination showed that the resulting product is
composed of regular, spherical particles. Particle size can be
decreased by increasing air pressure.
TABLE-US-00005 TABLE 5 Oxymorphone Formulations prepared using a
spray nozzle Parts w/w of each Base Formulation formulation % of
each additive Formulation component Poloxamer Gelucire Span PVP
D(0.5) # API SA BW CW 407 50/13 60 K29/32 (.mu.m) I 1 8 1 2 0 0 0 0
540 II 1 8 1 2 0 0 0 0 450 III 1 8 3 3 0 0 0 0 435 IV 1 9 1 2 0 0 0
0 388 V 1 8 1 2 0 0 .sup. 5% 0 416 VI 1 9 1 2 0 0 0 .sup. 5% 511
VIII 1 8 1 2 2.5% 0 0 0 499 IX 1 8 1 2 0 2.5% 0 0 381 X 1 8 1 2 0
1.5% .sup. 3% 366
Example 8
Use of Spray Nozzles to Prepare Oxycodone Formulation Beads
Containing Additives
[0146] The same procedure as in Example 6 was used to produce beads
of Oxycodone formulation. The basic formulation includes the drug,
a fatty acid [lauric acid (LA), myristic acid (MA) or stearic acid
(SA)], beeswax (BW), carnauba wax (CW) and/or microcyrstalline wax
(MW, multi-wax). Table 6 lists the formulations and their median
particle size.
TABLE-US-00006 TABLE 6 Oxycodone Formulations Prepared using a
Spray Nozzle Parts w/w of each Base Formulation % of each additive
Formulation Component Gelucire PEG D(0.5) # API LA MA SA BW CW MW
50/13 LA 1450 (.mu.m) I 1 0 6 0 0.5 3.5 0 0 0 0 197 II 1 0 6 0 0.5
3.5 0 0 0 0 206 III 1 0 0 8 2 2 0 3 0 0 237 IV 1 0 0 9 0 0 3 3 0 0
250 V 1 0 0 8 1 2 0 2 0 0 447 VI 1 0 0 8 1 2 0 2 5 0 345 VIII 1 0 0
8 1 2 0 1.5 0 1.5 292 IX 1 5 0 0 3 3 0 0 0 0 296
Example 9
Use of a Spinning Disc to Prepare Oxycodone Formulations: Effects
of Process Parameters on Bead Size, Size Distribution, and
Segregation. Batch Size: 160 kg
[0147] In this example, the melt was manufactured in a jacketed
1300 L stainless steel vessel. Manufacture started by hearing the
jacket to 85.degree. C. and adding MA to the vessel from the open
top of the vessel. The vessel lid was then closed and the MA was
melted completely with mixing. The remaining excipients (BW and CW)
and the API were vacuum-transferred individually into the melt from
the bottom of the vessel. The melt was pumped at a controlled flow
rate and temperature onto the center of a 12'' diameter spinning
disc. The beads were collected at the bottom of a large bead
collection chamber. A fan at the top of the chamber was used to
pump air with controlled temperature through the collection
chamber. See FIG. 3. A 4-factor (feed temperature, disc speed, melt
feed rate and fan speed), 2 level, 1/2 factorial design of
experiments (DOE) with 4 center-points was conducted to identify
critical process parameters and determine their effects on particle
size and bead temperature. Eight (8) additional runs were also
conducted to extend the range of disc speed and feed rate.
Experimental runs were started when process parameters reached
their set points. A representative sample from each run was tested
for particle size using a Malvern MasterSizer S laser diffraction
instrument. Experimental data were analyzed using the Slat-Ease
Design Expert Software, Version 7.
[0148] FIG. 4 shows a good correlation between the predicted median
particle size and the actual median particle size for particles
made using the process described above. FIG. 5 shows that the size
of the beads made by this process decreases with increasing disc
speed. FIG. 6 shows that, at low fan speed (29 Hz), the span
([D(0/9)-D(0.1)]/D(0.5)) decreases with increasing disc speed. At
high fan speed (32 Hz), the span increases. The large span is an
indication of less control over the atomization process at the
higher fan speed. High air flow rates associated with high fan
speed are thought to interfere with the normal melt spray travel
path off the edge of the disc. A similar effect was observed for
melts at lower temperature.
[0149] A low span (<5) is desirable to minimize segregation of
the beads by size during downstream processing such as blending and
encapsulation. A span <1.4 is preferred to minimize segregation.
A low span may also provide a more desirable pharmacokinetic
profile,
[0150] Bead segregation during encapsulation can also result in
capsules with varying dissolution or release profile. Blending the
heads with small levels of additives such as colloidal silicon
dioxide serves to reduce the severity of bead segregation.
Example 10
Formation of Ionic Complex between Oxycodone and Myristic Acid
[0151] Samples of oxycodone base; a physical mix (i.e., a
non-melted mix) of oxycodone base and a model fatty acid (myristic
acid); and a congealed melt of oxycodone base and myristic acid
were prepared. The samples were tested by Fourier Transform
Infrared (FTIR) spectroscopy. Solid State Carbon-13 (C.sup.13)
nuclear magnetic resonance (NMR), and Solution C-13 and Proton
(H.sup.1) NMR.
[0152] The FTIR study showed the presence of an IR band at or near
1571 cm.sup.-1 in the Oxycodone/myristic acid congealed melt not
seen in either the free base or Oxycodone/myristic acid physical
blend. The band was assigned to a salt of myristic acid and
oxycodone formed by interaction of the carboxylic group of myristic
acid with the nitrogen in the tertiary amine group of oxycodone.
Solid state C.sup.13 NMR snowed significant changes to the
oxycodone signals in the congealed melt. For example, significant
shifts were observed in the chemical shifts for the bridge carbon
atoms adjacent the oxycodone tertiary amine. These results suggest
the presence of a long-lived and stable complex or salt of
oxycodone and myristic acid.
[0153] Although the invention has been described in some detail by
way of illustration and example for purposes of clarity of
understanding, it will be obvious that certain changes and
modifications may be practiced within the scope of the appended
claims. Modifications of the above-described modes for carrying out
the invention that are within the skill in medicine, pharmacology,
microbiology, and/or related fields are intended to be within the
scope of the following claims.
[0154] All publications (e.g., non-patent literature), patent
application publications, and patent applications mentioned in this
specification are indicative of the level of skill of those skilled
in the art to which this invention pertains. All such publications
(e.g., non-patent literature), patent application publications, and
patent applications are herein incorporated by reference to the
same extent as if each individual publication, patent, patent
application, publication, or patent application was specifically
and individually set forth herein in its entirety.
* * * * *