U.S. patent application number 14/918112 was filed with the patent office on 2016-04-21 for extended release abuse deterrent liquid fill dosage form.
This patent application is currently assigned to Pharmaceutical Manufacturing Research Services, Inc.. The applicant listed for this patent is Pharmaceutical Manufacturing Research Services, Inc.. Invention is credited to Matthew N. Hart, Steven F. Kemeny, Nicholas R. Myslinski, Edwin R. Thompson, Eric R. Thompson.
Application Number | 20160106737 14/918112 |
Document ID | / |
Family ID | 55748149 |
Filed Date | 2016-04-21 |
United States Patent
Application |
20160106737 |
Kind Code |
A1 |
Thompson; Edwin R. ; et
al. |
April 21, 2016 |
Extended Release Abuse Deterrent Liquid Fill Dosage Form
Abstract
The present disclosure relates to an oral, extended release,
abuse deterrent dosage form containing a controlled release agent,
a second agent and/or polyethylene glycol, and at least one active
pharmaceutical ingredient susceptible to abuse. The dosage form is
stable at high temperatures and abuse deterrent to oral and
parenteral administration via dose dumping, extraction, and
purification. The present disclosure also relates to processes of
preparing the dosage form.
Inventors: |
Thompson; Edwin R.;
(Horsham, PA) ; Thompson; Eric R.; (Chalfont,
PA) ; Myslinski; Nicholas R.; (Bensalem, PA) ;
Kemeny; Steven F.; (Philadelphia, PA) ; Hart; Matthew
N.; (Palmyra, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pharmaceutical Manufacturing Research Services, Inc. |
Horsham |
PA |
US |
|
|
Assignee: |
Pharmaceutical Manufacturing
Research Services, Inc.
Horsham
PA
|
Family ID: |
55748149 |
Appl. No.: |
14/918112 |
Filed: |
October 20, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62066298 |
Oct 20, 2014 |
|
|
|
Current U.S.
Class: |
424/10.3 ;
424/452; 514/282 |
Current CPC
Class: |
A61P 25/04 20180101;
A61K 31/485 20130101; A61K 9/4858 20130101; A61K 9/4866
20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/48 20060101 A61K009/48 |
Claims
1. An extended release, abuse deterrent capsule comprising: (a) an
active substance susceptible to abuse; (b) a controlled release
agent that has a melting temperature less than or equal to about
70.degree. C.; and (c) a second agent that has a melting
temperature greater than or equal to about 100.degree. C., or (d) a
polyethylene glycol having an average molecular weight between
about 3000 Daltons and about 4000 Daltons.
2. The capsule of claim 1 comprising an active substance
susceptible to abuse; a controlled release agent that has a melting
temperature less than or equal to about 70.degree. C.; and a second
agent that has a melting temperature greater than or equal to about
100.degree. C.
3. The capsule of claim 1 comprising an active substance
susceptible to abuse; a controlled release agent that has a melting
temperature less than or equal to about 70.degree. C.; and a
polyethylene glycol having an average molecular weight between
about 3000 Daltons and about 4000 Daltons.
4. The capsule of claim 1, wherein the controlled release agent is
selected from the group consisting of glyceryl behenate, behenoyl
polyoxylglycerides, glycerol monostearate, glycerol esters of sat.
C8-C18 fatty acids, glycerol esters of sat. C12-C18 fatty acids,
lauroyl polyoxylglycerides/PEG-32 glyceryl laurate, stearoyl
polyoxylglyceride, PEG-32 glyceryl stearate, saturated
polyglycolized glycerides, glycerol disterate/glyceryl
palmitostearate, and hard fats.
5. The capsule of claim 1, wherein the second agent is selected
from the group consisting of hydroxypropyl methylcellulose,
polyvinyl alcohol, polyvinylpyrrolidone, cellulose ethers,
cellulose esters and acrylic resins.
6. The capsule of claim 1, wherein the controlled release agent is
stearoyl polyoxylglyceride.
7. The capsule of claim 1, wherein the second agent is
polyvinylpyrrolidone.
8. The capsule of claim 1, wherein the controlled release agent is
from about 15 wt % to about 70 wt % of the capsule.
9. The capsule of claim 1, wherein the second agent is from about 5
wt % to about 20 wt % of the capsule.
10. The capsule of claim 1, wherein the polyethylene glycol is from
about 10 wt % to about 40 wt % of the capsule.
11. The capsule of claim 1, wherein the active substance is
hydrocodone.
12. The capsule of claim 1, wherein the active substance is
oxycodone HCl.
13. The capsule of claim 1, wherein the active substance is
oxymorphone HCl.
14. The capsule of claim 1, wherein the active substance is
hydromorphone HCl.
15. The capsule of claim 1, further comprising a dye.
16. The capsule of claim 15, wherein the dye comprises FD&C
Blue #1, FD&C Yellow #6, and FD&C Red #40.
17. The capsule of claim 15, wherein the dye reduces abuse via
extracting and injecting.
18. The capsule of claim 1, wherein the capsule comprises at least
about 2.5 wt % of the active substance.
19. The capsule of claim 1, wherein the capsule is prepared by
filling a capsule body with a heated homogenized suspension
comprising the active substance, the controlled release agent, the
second agent or the polyethylene glycol.
20. The capsule of claim 1, wherein the capsule comprises about 10
mg, about 20 mg, about 40 mg, or about 80 mg of the active
substance, and exhibits an extended release of the active
substance.
21. The capsule of claim 1, wherein the contents of the capsule are
solid at 40.degree. C./75% relative humidity.
22. A process for the production of an extended release, abuse
deterrent capsule comprising at least one active substance
susceptible to abuse comprising: (a) preparing a homogenized
suspension of: (i) the at least one active substance susceptible to
abuse; (ii) a controlled release agent that has a melting
temperature less than or equal to about 100.degree. C.; and (iii) a
second agent that has a melting temperature greater than or equal
to about 100.degree. C.; or (iv) a polyethylene glycol having an
average molecular weight between about 3000 Daltons and about 4000
Daltons; and (b) dispensing the homogenized suspension into a
capsule body to produce the capsule.
23. The process of claim 22, wherein the controlled release agent
is stearoyl polyoxylglyceride.
24. The process of claim 22, wherein the second agent is
polyvinylpyrrolidone.
25. The process of claim 22, wherein the active substance is
hydrocodone.
26. The process of claim 22, wherein the active substance is
oxycodone HCl.
27. The process of claim 22, wherein the active substance is
oxymorphone HCl.
28. The process of claim 22, wherein the active substance is
hydromorphone HCl.
29. The process of claim 22, wherein the capsule is formed by
joining a capsule body with a capsule cap.
30. A method of treating pain comprising administering to a subject
in need thereof a therapeutically effective amount of the capsule
of claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 62/066,298 filed Oct. 20, 2014, the disclosure of
which is incorporated herein by reference in their entirety.
FIELD OF THE TECHNOLOGY
[0002] The present disclosure relates to an oral, extended release,
abuse deterrent dosage form. The dosage form contains active
pharmaceutical ingredient (API) suspended in a wax matrix which is
difficult to extract in order to reduce abuse by non-oral
administration routes, e.g. intranasal and/or intravenous. The
dosage form also contains a controlled release agent with a
relatively low melting temperature, for example, stearoyl
polyoxylglyceride and a second agent, for example,
polyvinylpyrrolidone (PVP) or a polyethylene glycol (PEG). The low
melting temperature allows the controlled release agent to
homogenize the API and other excipients within a wax suspension
without degrading the API. The composition is designed to allow for
extended release of the active ingredient while deterring abuse and
maintaining stability of the dosage form at elevated
temperatures.
BACKGROUND
[0003] FDA-approved drugs are provided in many different forms
based on the type of active substance, the indication treated and
the preferred route of administration. These forms include enteral
formulations (e.g., tablets, capsules or pills), parenteral
formulations (e.g., injectable formulations such as intravenous,
subcutaneous, intramuscular and intraarticular), liquid
formulations (e.g., elixirs), lyophilized formulations and topical
formulations. A majority of the FDA-approved drugs are currently
available in enteral form, as either a tablet or capsule. Several
formulations have been investigated for deterring abuse, either by
oral ingestion of the drug with alcohol, or by non-oral
administration routes such as intranasal and/or intravenous
administration. However a need still exists for extended release
abuse deterrent dosage forms.
SUMMARY
[0004] The present disclosure relates to an extended release, abuse
deterrent capsule including an active substance susceptible to
abuse, a controlled release agent, such as a stearoyl
polyoxylglyceride, that has a melting temperature less than or
equal to about 70.degree. C., and a PEG having an average molecular
weight between about 3000 Daltons and about 4000 Daltons or a
second agent having a high melting temperature and potentially a
high molecular weight, such as a soluble polyvinylpyrrolidone.
[0005] The present disclosure also relates to a process for the
production of an extended release, abuse deterrent capsule
including at least one active substance susceptible to abuse
including preparing a homogenized suspension of the at least one
active substance susceptible to abuse, a controlled release agent
such as a stearoyl polyoxylglyceride that has a melting temperature
less than or equal to about 70.degree. C., and a PEG having an
average molecular weight between about 3000 Daltons and about 4000
Daltons, or a second agent having a high melting temperature and
potentially a high molecular weight, such as a soluble
polyvinylpyrrolidone; and dispensing the homogenized suspension
into a capsule body to produce the dosage form.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] FIG. 1 shows cross sections of a capsule filling machine
including the body segment, the cap disc, the hopper, the pumping
box, the substation roller, and capsule bodies.
[0007] FIG. 2A shows solutions of grey dye before filtering. FIG.
2B shows solutions of grey dye after filtering.
[0008] FIG. 3 shows unfiltered solutions of the dosage forms in 190
proof ethanol after shaking at 250 rpm for 3 hours.
[0009] FIG. 4 shows syringe-filtered solutions of the dosage forms
in 190 proof ethanol after shaking at 250 rpm for 3 hours.
[0010] FIG. 5 shows the difference in dissolution between an intact
and ground extended release, abuse deterrent capsule containing 80
mg of active.
[0011] FIG. 6 shows the difference in dissolution between an intact
and ground extended release, abuse deterrent capsule containing 80
mg of active.
[0012] FIG. 7 shows the difference in dissolution between an intact
and ground extended release, abuse deterrent capsule containing 10
mg of active.
[0013] FIG. 8 shows the difference in dissolution between an intact
and ground extended release, abuse deterrent capsule containing 40
mg of active.
DETAILED DESCRIPTION
[0014] Abuse of prescription drugs, particularly opioids, is a
serious and growing public health concern. To address this concern,
new formulations are being developed that contain abuse-deterrent
properties. Abuse deterrent properties include properties that make
product manipulation more difficult or make abuse of the
manipulated product less attractive or rewarding.
[0015] Recently the FDA issued a guidance for industry related to
formulations having abuse deterrent properties. Guidance for
Industry: Abuse Deterrent Opioids--Evaluation and Labeling, U.S.
Department of Health and Human Services, FDA, CDER, April 2015, the
entire contents of which are incorporated herein by reference.
These guidelines separate abuse deterrent formulations into six
categories, including: physical/chemical barriers,
agonist/antagonist combinations, aversion, delivery system,
prodrug, or a combination of the aforementioned. As described by
the FDA guidance, the categories are:
[0016] Physical/Chemical barriers--Physical barriers can prevent
chewing, pulverizing, cutting, grating, or grinding. Chemical
barriers can resist extraction of the opioid using common solvents
like water, alcohol, or other organic solvents. Physical and
chemical barriers can change the physical form of an oral drug
rendering it less amenable to abuse.
[0017] Agonist/Antagonist combinations--An opioid antagonist can be
added to interfere with, reduce, or defeat the euphoria associated
with abuse. The antagonist can be sequestered and released only
upon manipulation of the product. For example, a drug product may
be formulated such that the substance that acts as an antagonist is
not clinically active when the product is swallowed but becomes
active if the product is crushed and injected or snorted.
[0018] Aversion--Substances can be combined to produce an
unpleasant effect if the dosage form is manipulated prior to
ingestion or a higher dosage than directed is used.
[0019] Delivery System (including depot injectable formulations and
implants)--Certain drug release designs or the method of drug
delivery can offer resistance to abuse. For example, a
sustained-release depot injectable formulation that is administered
intramuscularly or a subcutaneous implant can be more difficult to
manipulate.
[0020] Prodrug--A prodrug that lacks opioid activity until
transformed in the gastrointestinal tract can be unattractive for
intravenous injection or intranasal routes of abuse.
[0021] Combination--Two or more of the above methods can be
combined to deter abuse.
[0022] An opioid analgesic submitted for abuse deterrent
formulation (ADF) labeling must show conformance to one or more of
these categories. The present disclosure relates to an abuse
deterrent dosage form for oral administration, which provides
extended release of an active pharmaceutical substance and conforms
to one or more of these categories. In one embodiment, the abuse
deterrent dosage form of the present disclosure conforms to at
least one of the six FDA categories. In another embodiment, the
abuse deterrent dosage form of the present disclosure conforms to
at least two of the six FDA categories. In another embodiment, the
abuse deterrent dosage form of the present disclosure conforms to
at least three of the six FDA categories. In another embodiment,
the abuse deterrent dosage form of the present disclosure conforms
to at least four of the six FDA categories. In another embodiment,
the abuse deterrent dosage form of the present disclosure conforms
to at least five of the six FDA categories.
[0023] For example, an abuse deterrent dosage form of the present
disclosure can reduce abuse by the incorporation of at least one
barrier, e.g., chemical and/or physical barrier. The barrier can be
designed to prevent abuse based on extraction and/or purification
of the API from the dosage form. Preferably, the barrier prevents
or reduces the effectiveness of these methods. As used herein, the
phrase "abuse deterrent" means that the active substance cannot
readily be separated from the formulation in a form suitable for
abuse by such means as, for example, extraction. Abuse deterrent
measures render it difficult to transform the dosage form into a
purified, abusable powder or extract for non-oral administration,
such as intranasal or intravenous.
[0024] In one embodiment, the present disclosure relates to an
oral, extended release, abuse deterrent dosage form including (a)
an active substance susceptible to abuse; (b) a controlled release
agent such as a stearoyl polyoxylglyceride that has a melting
temperature less than or equal to about 70.degree. C.; and (c) a
second agent having a high molecular weight such as a soluble
polyvinylpyrrolidone with a nominal K-value of about 90.
[0025] In another embodiment, the present disclosure relates to an
oral, extended release, abuse deterrent dosage form including (a)
an active substance susceptible to abuse; (b) a controlled release
agent such as a stearoyl polyoxylglyceride that has a melting
temperature less than or equal to about 70.degree. C.; and (c) a
polyethylene glycol having an average molecular weight between
about 3000 Daltons and about 4000 Daltons.
[0026] Active Substance Susceptible to Abuse
[0027] As used herein, the term "active substance" or "active
substance susceptible to abuse" means any opioid or opioid related
compound subject to potential abuse. The active substance may
include, without limitation, alfentanil, allylprodine,
alphaprodine, anileridine, benzylmorphine, bezitramide,
buprenorphine, butorphanol, clonitazene, codeine, cyclazocine,
desomorphine, dextromoramide, dezocine, diampromide,
dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,
ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,
fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,
isomethadone, ketobemidone, levallorphan, levophenacylmorphan,
levorphanol, lofentanil, meperidine, meptazinol, metazocine,
methadone, metopon, morphine, myrophine, nalbulphine, narceine,
nicomorphine, norpipanone, opium, oxycodone, oxymorphone,
papvretum, pentazocine, phenadoxone, phenazocine, phenomorphan,
phenoperidine, piminodine, propiram, propoxyphene, sufentanil,
tilidine, tramadol, tapentadol, and pharmaceutically acceptable
salts and mixtures thereof.
[0028] In particular embodiments, the active substance can be
hydrocodone or oxycodone.
[0029] The wt % of the active substance may vary depending on the
active substance, stability, release profile and bioavailability.
In some embodiments, the dosage form includes at least about 0.1 wt
%, 0.2 wt %, 0.3 wt %, 0.4 wt %, 0.5 wt %, 0.6 wt %, 0.7 wt %, 0.8
wt %, 0.9 wt %, 1.0 wt %, 1.1 wt %, 1.2 wt %, 1.3 wt %, 1.4 wt %,
1.5 wt %, 2 wt %, 2.5 wt %, 3 wt %, 4 wt %, 5 wt %, 6 wt %, 7 wt %,
7.5 wt %, 8 wt %, 9 wt %, 10 wt %, 11 wt %, 12 wt %, 13 wt %, 14 wt
%, 15 wt %, 16 wt %, 17 wt %, 18 wt %, 19 wt %, 20 wt %, 21 wt %,
22 wt %, 23 wt %, 24 wt %, 25 wt %, 26 wt %, 27 wt %, 28 wt %, 29
wt %, 30 wt %, 31 wt %, 32 wt %, 33 wt %, 34 wt %, 35 wt %, 36 wt
%, 37 wt %, 38 wt %, 39 wt %, 40 wt %, 41 wt %, 42 wt %, 43 wt %,
44 wt %, 45 wt %, 46 wt %, 47 wt %, 48 wt %, 49 wt %, 50 wt %, 51
wt %, 52 wt %, 53 wt %, 54 wt %, 55 wt %, 56 wt %, 57 wt %, 58 wt
%, 59 wt %, 60 wt %, 65 wt %, 69 wt %, 70 wt %, 75 wt %, 80 wt %,
85 wt %, 88 wt %, 90 wt %, or 95 wt % of the active substance. Any
of these values may be used to define a range for the wt % of the
active substance depending on the application. For example, the
amount of active substance in the dosage form may range from about
0.10 wt % to about 60 wt %. Particularly, the amount of active
substance in the dosage form may range from about 0.1 wt % to about
1.5 wt %, from about 5 wt % to about 30 wt %, from about 15 wt % to
about 20 wt %, from about 15 wt % to about 30 wt %, from about 40
wt % to about 60 wt %, from about 40 wt % to about 50 wt %, or from
about 42 wt % to about 46 wt %.
[0030] For example, the dosage form may be a 100 mg capsule
including about 5 mg, about 10 mg, about 15 mg, about 20 mg, or
about 30 mg of active substance (e.g. oxycodone HCl). In other
embodiments, the dosage form may be a 150 mg capsule including
about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, or
about 45 mg of active substance (e.g. oxycodone HCl). In other
embodiments, the dosage form may be a 200 mg capsule including
about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg,
about 40 mg, about 50 mg, about 60 mg, about 70 mg or about 80 mg
of active substance (e.g. oxycodone HCl). In other embodiments, the
dosage form may be a 250 mg capsule including about 2.5 mg, about 5
mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 30
mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80
mg, about 90 mg or about 100 mg of an active substance (e.g.
oxycodone HCl). In other embodiments, the dosage form may be a 275
mg capsule including about 2.5 mg, about 5 mg, about 7.5 mg, about
10 mg, about 15 mg, about 20 mg, about 30 mg, about 45 mg, about 50
mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg or about 100
mg of an active substance (e.g. oxycodone HCl). In other
embodiments, the dosage form may be a 500 mg capsule including
about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg,
about 20 mg, about 30 mg, about 45 mg, about 50 mg, about 60 mg,
about 70 mg, about 80 mg, about 90 mg or about 100 mg of an active
substance (e.g. oxycodone HCl). In other embodiments, the dosage
form may be a 700 mg capsule including about 2.5 mg, about 5 mg,
about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg,
about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg,
about 90 mg or about 100 mg of an active substance (e.g.
hydrocodone).
[0031] Controlled Release Agent
[0032] The controlled release agent may include a compound selected
from the group consisting of Compritol.RTM. ATO 888 (glyceryl
behenate), Compritol.RTM. HD5 ATO (behenoyl polyoxylglycerides),
Geleol.TM. mono and di glycerides(glycerol monostearate), and
Gelucire.RTM. 33/01(glycerol esters of sat. C8-C18 fatty acids),
Gelucire.RTM. 39/01 & 43/01 (glycerol esters of sat. C12-C18
fatty acids), Gelucire.RTM. 44/14 (lauroyl
polyoxylglycerides/PEG-32 glyceryl laurate), Gelucire.RTM. 50/13
(stearoyl polyoxylglyceride), Gelucire.RTM. 53/10 (PEG-32 glyceryl
stearate), Gelucire .RTM. 62/02 (saturated polyglycolized
glycerides), Precirol.RTM. ATO 5 (glycerol disterate/glyceryl
palmitostearate), or Suppocire.RTM. pellets (hard fats).
[0033] The Gelucire.RTM. molecules are described utilizing a two
part number: the first number indicates the melting temperature of
the molecule; the second refers to the HLB number or
Hydrophilic-Lipophilic Balance number which denotes if the molecule
is hydrophobic or hydrophilic. This HLB number ranges from 0-14
with <10 being hydrophobic and >10 being hydrophilic.
Hydrophilic molecules work through a swelling and disintegration
mechanism of release whereas hydrophilic molecules work though
erosion/diffusion. In certain embodiments the Gelucire.RTM.
molecules used in this present disclosure are hydrophilic. In other
embodiments, Gelucire.RTM. molecules used in this present
disclosure are hydrophobic. In certain embodiments, a combination
of hydrophobic and hydrophilic molecules are used.
[0034] The total wt % of the controlled release agent in the dosage
form may vary depending on the active substance, stability, and
release profile. In some embodiments, the controlled release agent
is at least about 5 wt %, 10 wt %, 15 wt %, 20 wt %, 25 wt %, 30 wt
%, 35 wt %, 36 wt %, 37 wt %, 38 wt %, 39 wt %, 40 wt %, 41 wt %,
42 wt %, 43 wt %, 44 wt %, 45 wt %, 46 wt %, 47 wt %, 48 wt %, 49
wt %, 50 wt %, 51 wt %, 52 wt %, 53 wt %, 54 wt %, 55 wt %, 56 wt
%, 57 wt %, 58 wt %, 59 wt %, 60 wt %, 61 wt %, 62 wt %, 63 wt %,
64 wt %, 65 wt %, 66 wt %, 67 wt %, 68 wt %, 69 wt %, 70 wt %, 71
wt %, 72 wt %, 73 wt %, 74 wt %, 75 wt %, 76 wt %, 77 wt %, 78 wt
%, 79 wt %, 80 wt %, 85 wt %, 88 wt %, 90 wt %, or 95 wt % of the
dosage form. Any of these values may be used to define a range for
the wt % of the controlled release agent in the dosage form. For
example, in some embodiments, the wt % of the controlled release
agent in the dosage form ranges from about 15 wt % to about 60 wt %
or from about 30 wt % to about 40 wt %.
[0035] In certain embodiments, the controlled release agent has a
melting temperature of about 100.degree. C., 99.degree. C.,
98.degree. C., 97.degree. C., 96.degree. C., 95.degree. C.,
94.degree. C., 93.degree. C., 92.degree. C., 91.degree. C.,
90.degree. C., 89.degree. C., 88.degree. C., 87.degree. C.,
86.degree. C., 85.degree. C., 84.degree. C., 83.degree. C.,
82.degree. C., 81.degree. C., 80.degree. C., 79.degree. C.,
78.degree. C., 77.degree. C., 76.degree. C., 75.degree. C.,
74.degree. C., 73.degree. C., 72.degree. C., 71.degree. C.,
70.degree. C., 69.degree. C., 68.degree. C., 67.degree. C.,
66.degree. C., 65.degree. C., 64.degree. C., 63.degree. C.,
62.degree. C., 61.degree. C., 60.degree. C., 59.degree. C.,
58.degree. C., 57.degree. C., 56.degree. C., 55.degree. C.,
54.degree. C., 53.degree. C., 52.degree. C., 51.degree. C.,
50.degree. C., 49.degree. C., 48.degree. C., 47.degree. C.,
46.degree. C., 45.degree. C., 44.degree. C., 43.degree. C.,
42.degree. C., 41.degree. C., 40.degree. C., 39.degree. C.,
38.degree. C., 37.degree. C., 36.degree. C., 35.degree. C.,
34.degree. C., 33.degree. C., 32.degree. C., 31.degree. C. or
30.degree. C. In certain embodiments, the controlled release agent
has a melting temperature that is less than equal to about
100.degree. C., 99.degree. C., 98.degree. C., 97.degree. C.,
96.degree. C., 95.degree. C., 94.degree. C., 93.degree. C.,
92.degree. C., 91.degree. C., 90.degree. C., 89.degree. C.,
88.degree. C., 87.degree. C., 86.degree. C., 85.degree. C.,
84.degree. C., 83.degree. C., 82.degree. C., 81.degree. C.,
80.degree. C., 79.degree. C., 78.degree. C., 77.degree. C.,
76.degree. C., 75.degree. C., 74.degree. C., 73.degree. C.,
72.degree. C., 71.degree. C., 70.degree. C., 69.degree. C.,
68.degree. C., 67.degree. C., 66.degree. C., 65.degree. C.,
64.degree. C., 63.degree. C., 62.degree. C., 61.degree. C.,
60.degree. C., 59.degree. C., 58.degree. C., 57.degree. C.,
56.degree. C., 55.degree. C., 54.degree. C., 53.degree. C.,
52.degree. C., 51.degree. C., 50.degree. C., 49.degree. C.,
48.degree. C., 47.degree. C., 46.degree. C., 45.degree. C.,
44.degree. C., 43.degree. C., 42.degree. C., 41.degree. C.,
40.degree. C., 39.degree. C., 38.degree. C., 37.degree. C.,
36.degree. C., 35.degree. C., 34.degree. C., 33.degree. C.,
32.degree. C., 31.degree. C. or 30.degree. C. Any of these values
may be used to define a range for the melting temperature of the
controlled release agent. For example, the controlled release agent
may have a melting temperature from about 90.degree. C. to about
50.degree. C. or from about 60.degree. C. to about 40.degree.
C.
[0036] In one embodiment, the controlled release agent melts at a
relatively low temperature under a process that incorporates as
little oxygen as possible during melting and homogenization. For
example, the stearoyl polyoxylglyceride requires a melting
temperature of at least 70.degree. C. with incorporation of as
little oxygen as possible during melting and homogenization. The
melted controlled release agent, and optionally the PEG, can create
a suspension which incorporates other components of the dosage
form, such as the second agent, which melts at a higher
temperature.
[0037] Second Agent
[0038] The second agent may be selected from the group consisting
of hydroxypropyl methylcellulose (HPMC), polyvinyl acetate,
polyvinylpyrrolidone, cellulose ethers, cellulose esters, acrylic
resins, and derivatives thereof, and combinations thereof.
Particularly, the second agent may be selected from ethylcellulose,
hydroxypropyl methylcellulose, hydroxypropylcellulose,
hydroxymethylcellulose, poly(meth)acrylic acid,
polyvinylpyrrolidone and derivatives thereof, such as the salts,
amides or esters, and combinations thereof.
[0039] The total wt % of the second agent in the dosage form may
vary depending on the active substance, stability, and release
profile. In some embodiments, the second agent is at least about 5
wt %, 10 wt %, 15 wt %, 20 wt %, 25 wt %, 30 wt %, 35 wt %, 36 wt
%, 37 wt %, 38 wt %, 39 wt %, 40 wt %, 41 wt %, 42 wt %, 43 wt %,
44 wt %, 45 wt %, 46 wt %, 47 wt %, 48 wt %, 49 wt %, 50 wt %, 51
wt %, 52 wt %, 53 wt %, 54 wt %, 55 wt %, 56 wt %, 57 wt %, 58 wt
%, 59 wt %, 60 wt %, 61 wt %, 62 wt %, 63 wt %, 64 wt %, 65 wt %,
66 wt %, 67 wt %, 68 wt %, 69 wt %, 70 wt %, 71 wt %, 72 wt %, 73
wt %, 74 wt %, 75 wt %, 76 wt %, 77 wt %, 78 wt %, 79 wt %, 80 wt
%, 85 wt %, 88 wt %, 90 wt %, or 95 wt % of the dosage form. Any of
these values may be used to define a range for the wt % of the
second agent in the dosage form. For example, in some embodiments,
the wt % of the second agent in the dosage form ranges from about 5
wt % to about 60 wt % or from about 10 wt % to about 35 wt %.
[0040] In certain embodiments, the second agent has a melting
temperature of about 100.degree. C., 110.degree. C., 120.degree.
C., 130.degree. C., 135.degree. C., 140.degree. C., 145.degree. C.,
150.degree. C., 155.degree. C., 160.degree. C., 165.degree. C.,
170.degree. C., 180.degree. C., 190.degree. C., 200.degree. C.,
210.degree. C., 220.degree. C., 230.degree. C., 240.degree. C.,
250.degree. C., 260.degree. C., 270.degree. C., 280.degree. C.,
290.degree. C., 300.degree. C., 310.degree. C., 320.degree. C.,
330.degree. C., 340.degree. C., 350.degree. C., 360.degree. C.,
370.degree. C., 380.degree. C., 390.degree. C., 400.degree. C.,
410.degree. C., 420.degree. C., 430.degree. C., 440.degree. C.,
450.degree. C., 460.degree. C., 470.degree. C., 480.degree. C.,
490.degree. C., 500.degree. C., 600.degree. C., 700.degree. C.,
800.degree. C., 900.degree. C. or 1000.degree. C. In certain
embodiments, the second agent has a melting temperature greater
than or equal to about 100.degree. C., 110.degree. C., 120.degree.
C., 130.degree. C., 135.degree. C., 140.degree. C., 145.degree. C.,
150.degree. C., 155.degree. C., 160.degree. C., 165.degree. C.,
170.degree. C., 180.degree. C., 190.degree. C., 200.degree. C.,
210.degree. C., 220.degree. C., 230.degree. C., 240.degree. C.,
250.degree. C., 260.degree. C., 270.degree. C., 280.degree. C.,
290.degree. C., 300.degree. C., 310.degree. C., 320.degree. C.,
330.degree. C., 340.degree. C., 350.degree. C., 360.degree. C.,
370.degree. C., 380.degree. C., 390.degree. C., 400.degree. C.,
410.degree. C., 420.degree. C., 430.degree. C., 440.degree. C.,
450.degree. C., 460.degree. C., 470.degree. C., 480.degree. C.,
490.degree. C., 500.degree. C., 600.degree. C., 700.degree. C.,
800.degree. C., 900.degree. C. or 1000.degree. C. Any of these
values may be used to define a range for the melting temperature of
the second agent. For example, the second agent may have a melting
temperature from about 100.degree. C. to about 200.degree. C. or
from about 135.degree. C. to about 165.degree. C.
[0041] In certain embodiments, the dosage form of the present
disclosure does not include a second agent.
[0042] Polyethylene Glycol
[0043] The compositions of the present disclosure can also contain
one or more polyethylene glycols. In some embodiments, the PEG has
an average molecular weight of 3000, 3050, 3100, 3150, 3200, 3250,
3300, 3350, 3400, 3450, 3500, 3550, 3600, 3650, 3700, 3750, 3800,
3850, 3900, 3950 or 4000 Daltons. Any of these values may be used
to define a range for the average molecular weight of the second
PEG. For example, the PEG may have an average molecular weight
between about 3100 Daltons and about 3900 Daltons, between about
3200 Daltons and about 3800 Daltons, between about 3300 Daltons and
about 3700 Daltons, between about 3400 Daltons and about 3600
Daltons, between about 3000 Daltons and 3200 Daltons, between about
3200 Daltons and about 3400 Daltons, between about 3600 Daltons and
about 3800 Daltons, or between about 3800 Daltons and about 4000
Daltons.
[0044] The total wt % of PEG in the dosage form may vary depending
on the active substance, stability, and release profile. In some
embodiments, the PEG is at least about 5 wt %, 10 wt %, 15 wt %, 20
wt %, 25 wt %, 30 wt %, 35 wt %, 36 wt %, 37 wt %, 38 wt %, 39 wt
%, 40 wt %, 41 wt %, 42 wt %, 43 wt %, 44 wt %, 45 wt %, 46 wt %,
47 wt %, 48 wt %, 49 wt %, 50 wt %, 51 wt %, 52 wt %, 53 wt %, 54
wt %, 55 wt %, 56 wt %, 57 wt %, 58 wt %, 59 wt %, 60 wt %, 61 wt
%, 62 wt %, 63 wt %, 64 wt %, 65 wt %, 66 wt %, 67 wt %, 68 wt %,
69 wt %, 70 wt %, 71 wt %, 72 wt %, 73 wt %, 74 wt %, 75 wt %, 76
wt %, 77 wt %, 78 wt %, 79 wt %, 80 wt %, 85 wt %, 88 wt %, 90 wt
%, or 95 wt % of the dosage form. Any of these values may be used
to define a range for the wt % of PEG in the dosage form. For
example, in some embodiments, the wt % of PEG in the dosage form
ranges from about 30 wt % to about 50 wt % or from about 20 wt % to
about 60 wt %.
[0045] Dye
[0046] The composition can also include one or more dyes. A dye is
useful in deterring abuse by discouraging the abuser from
intravenous injection. For example, extraction of the dye along
with the active ingredient would result in a colored solution that
would discourage the abuser from intravenous injection. Thus, in
certain embodiments, the dye reduces abuse by extracting and
injecting. The dye may be selected from known dyes suitable for use
in pharmaceutical formulations or approved by the FDA for such use.
For example, the dye may be FD&C Blue No. 2 or a 50/50 Wt %
solution of FD&C Blue No. 2 in PEG. In another embodiment, the
dye may be a grey dye including FD&C Blue #1, FD&C Yellow
#6, and FD&C Red #40. The dye may be in a 90% PEG 3350 blend.
In certain embodiments, 14 mg of dye blend is used in each capsule
or about 1.4 mg of concentrated dye. In certain embodiments a grey
dye is used since it is visually deterring and non-transparent. The
dosage form may include about 0.10 wt %, 0.20 wt %, 0.30 wt %, 0.40
wt %, 0.50 wt %, 1 wt %, 2 wt %, 3 wt %, 4 wt %, 5 wt %, 6 wt %, 7
wt %, 8 wt %, 9 wt %, 10 wt %, 11 wt %, 12 wt %, 13 wt %, 14 wt %,
15 wt %, 16 wt %, 17 wt %, 18 wt %, 19 wt %, or 20 wt % dye. Any of
these values may be used to define a range for the wt % of the dye.
For example, the dosage form may contain between about 0.10 wt %
and about 15 wt % dye. Particularly, the dosage form may contain
between about 0.20 wt % and about 1.5 wt % dye, about 0.50 wt % and
about 1.0 wt % dye, or about 7 to about 14 wt % dye. In certain
embodiments, the dosage form may include about 1 mg, 1.4 mg, 2 mg,
3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13
mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg,
23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg or 30 mg of dye. In
another embodiment, the dosage form of the present disclosure
excludes a dye.
[0047] Other Excipients
[0048] The composition can also include a preservative or
antioxidant. The preservative or antioxidant reduces or limits the
degradation or deterioration of the abuse deterrent dosage form.
The addition of a preservative or antioxidant in the dosage form
may be necessary to prevent premature degradation of the active
substance over the shelf life of the dosage form.
[0049] The preservative or antioxidant may be selected from
preservatives or antioxidants known to one skilled in the art for
use in pharmaceutical formulations, such as citric acid, ascorbic
acid, ascorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, erythorbic acid, hypophosphorous acid, lactobionic
acid, monothioglycerol, potassium metabisulfite, propyl gallate,
racemethionine, sodium bisulfite, sodium formaldehyde sulfoxylate,
sodium metabisulfite, sodium sulfite, sodium thiosulfate, stannous
chloride, sulfur dioxide and tocopherols. The formulation, or
dosage form, may contain between about 0.1 wt % and about 2.0 wt %,
or about 0.25 wt % and about 0.75 wt % of preservative or
antioxidant. In another embodiment, the dosage form of the present
disclosure excludes a preservative or antioxidant.
[0050] In some embodiments, the dosage form includes one or more
excipients that form a gel in the presence of an alcohol. The
alcohol gelling/thickening agent reduces or limits the potential
for abuse by preventing extraction of the active substance from the
dosage form. For example, when introduced to an alcohol solution,
the components of the dosage form (e.g., active substances,
stearoyl polyoxylglyceride, PEG, PVP) may become trapped in a
gel/viscous liquid which prevents extraction and subsequent alcohol
evaporation to produce a pure active substance. In one embodiment,
the alcohol gelling/thickening agent does not form a gel in the
presence of water. The dosage form may contain between about 0.1 wt
% to 40 wt % alcoholic gelling/thickening agent. In another
embodiment, the dosage form of the present disclosure does not
contain an alcohol gelling/thickening agent.
[0051] The alcohol gelling/thickening agent may be a gelling or
thickening agent known to one skilled in the art for use in
pharmaceutical formulations, such as acacia, alginic acid,
bentonite, calcium acetate, carbomers, carboxymethylcellulose,
ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropyl
cellulose, magnesium aluminum silicate, methylcellulose,
poloxamers, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl
acetate, sodium alginate, sorbitol derivatives, tragacanth, or
xanthan gum.
[0052] The dosage form may additionally include at least one
additive independently selected from surfactants, solubilizers,
emulsifiers, bulking agents, poloxamers, lubricants, flavorings or
combination thereof.
[0053] Abuse Deterrence
[0054] One of the most common means of abuse of an orally
administered opioid analgesic involves the manipulation of the oral
dosage form in order to achieve rapid delivery of the active
substance from the dosage form. With regards to extended release
formulations, abusers attempt to manipulate the dosage form to
cause instantaneous release of the active substance originally
intended to be delivered over 6-12 hours. This is a common method
taken by abusers referred to as "dose dumping" which can be
utilized through decreasing particle size or use of a solvent. Dose
dumping results in a rapid release of higher than intended levels
of active substance into the body, resulting in a euphoric high. In
order for physical manipulation, such as chewing, grinding, or
pulverizing, to be used as an effective means of abuse, the
original dosage form must be manipulated so as to decrease the
particle size of the drug which can be effectively insufflated
and/or swallowed. Traditionally, decreasing the particle size of a
dosage form will increase the rate of dissolution due to an
increase of surface area on which a solution or solvent can act.
One way to prevent abuse by physical manipulation is by capturing
the active substance susceptible to abuse in a matrix which is
dissolved at a similar rate regardless of particle size. This will
inhibit abusers from achieving a euphoric high by limiting the
amount of active substance available at one time. In some
embodiments, the formulation of the present disclosure will
maintain an extended release profile regardless of particle size.
This delay in the rapid onset of active substance available is
thought to decrease abuse by oral, intranasal, and intravenous
pathways.
[0055] The dosage form of the present disclosure allows for
manipulation by chewing, grinding or pulverizing using common
equipment, such as a coffee grinder. For example, the formulation
of the present disclosure contains no long chain polymers and as a
result, can be easily ground into a powdered form. However, the
formulation of the present disclosure deters abuse by limiting the
amount of active substance available at one time regardless of
particle size. The formulation prevents the active substance, or at
least substantial portions of the active substance, from being
immediately released when introduced to an aqueous environment. As
a result, the dosage form is said not to be able to be prepared for
abuse via swallowing or insufflation.
[0056] The dosage form of the present disclosure can also
significantly limit the extraction of the active substance by
common solvents (e.g., cold water or distilled aqueous ethanol)
from the formulation. For example, the formulation deters abuse by
limiting the ability of persons to extract the active substance
from the dosage form (either intentionally or unintentionally),
such that the active substance cannot easily be concentrated for
parenteral administration. For example, if the dosage form is
attempted to be extracted with alcohol or an aqueous solution, the
stearoyl polyoxylglyceride, PVP, PEG and/or dye or combinations
thereof will also be extracted and cannot be separated from the
active substance, preventing the preparation of pure drug for
intravenous administration. Extraction with a solution would result
in a grey/black/brown liquid containing the stearoyl
polyoxylglyceride, PVP, PEG, dye or combinations thereof, and the
active substance. If an abuser tries to evaporate or burn off the
liquid to form a powder, the stearoyl polyoxylglyceride and PEG
melt before the alcohol and/or water evaporated, so that the
extraction essentially becomes a melted wax with suspended API,
which forms a solid once returned to room temperature. This
prevents an abuser from separating out the extended release
excipients and thereby, allows the dosage form to maintain an
extended release profile. These properties allow for an oral drug
delivery system that satisfies at least one of the categories in
the FDA guidance (e.g., "physical and chemical barriers can change
the physical form of an oral drug rendering it less amenable to
abuse"). The abuse deterrent dosage form may also include, but does
not require, the incorporation of other deterrents such as
antagonists or irritants.
[0057] In one embodiment, the controlled release agent includes
stearoyl polyoxylglyceride. The dosage form of the present
disclosure can be rendered abuse deterrent by incorporating
stearoyl polyoxylglyceride in the dosage form. The stearoyl
polyoxylglyceride can deter extraction of the active substance with
an alcohol in order to form a purified powder containing the active
substance. For example, since stearoyl polyoxylglyceride melts and
forms a wax before the alcohol burns off, an abuser may not be able
to obtain a powder containing the active substance. The addition of
a PEG to the dosage form may also deter abuse since it is soluble
in water and alcohol and melts before either can be flashed off.
Addition of a dye to the dosage form may result in a colored
solution after extraction of the active substance, deterring
intravenous injection. By varying the quantity of stearoyl
polyoxylglyceride and/or PVP or PEG present within a dosage form,
the characteristics of the dosage form can be manipulated in a way
to create a wide array of abuse deterrent capsules having extended
release profiles.
[0058] The controlled release agent, e.g. stearoyl
polyoxylglyceride, can also be capable of allowing extended release
of the active substance, providing abuse deterrence, and/or
ensuring the formation of a solid dosage form that is stable at
elevated temperatures, for example 40.degree. C. The dosage form of
the present disclosure can accomplish one or more of the above
capabilities by using a mixture of a controlled release agent
having a relatively low melting temperature, and a second agent
having a relatively high melting temperature or a controlled
release agent having a relatively low melting temperature, and/or a
PEG. For example, the dosage form can include a controlled release
agent having a melting temperature less than or equal to about
70.degree. C., and a high molecular weight PVP or a controlled
release agent that has a melting temperature less than or equal to
about 70.degree. C., and a PEG having an average molecular weight
about 3000 Daltons and 4000 Daltons.
[0059] Extended Release
[0060] The abuse deterrent composition of the present disclosure is
capable of extended release of the active substance. The dosage
form may be manufactured to provide a composition exhibiting an
extended release profile of at least one active substance. As used
herein, "extended release" refers to a dosage form that releases
the active substance or a pharmaceutically acceptable salt thereof,
into the gastrointestinal tract of the user over a period of 6-12
hours. Particularly, the active substance is released continuously
the period of 6-12 hours. In one embodiment, the amount of active
substance released from the dosage form, e.g. oxycodone HCl, by
exposure to simulated gastric fluid within 6-12 hours is about 85%.
The formulation of the present disclosure exhibits an extended
release profile that matches the reference listed drug for extended
release active substance.
[0061] In different embodiments, the amount of active substance
released from the dosage form by exposure to simulated gastric
fluid, or other dissolution media known to one skilled in the art,
is shown in Tables 1 and 2. The values in Tables 1 and 2 represent
acceptable USP criterion and may differ from values associated with
the RLD specifications. Each individual amount (approx. range)
value for each column in Tables 1 and 2 (e.g., 1, 2, 3, 4, 5, 6 and
7) can be used with any other individual amount at other time
points to define a release profile.
TABLE-US-00001 TABLE 1 Exemplary Release Profiles (e.g. 10, 20, 40,
80 mg active) 1 2 3 4 5 Time Amount Amount Amount Amount Amount
(Hours) (approx. range) (approx. range) (approx. range) (approx.
range) (approx. range) 1 22% and 28% 20% and 28% 22 and 30% 20% and
30% 20% and 40% 2 37% and 45% 35% and 45% 37% and 50% 35% and 50%
35% and 55% 4 58% and 72% 55% and 72% 58% and 75% 55% and 75% 55%
and 80% 6 75% and 80% 70% and 80% 75% and 85% 70% and 85% 70% and
90% 8 NLT 75% NLT 75% NLT 80% NLT 80% NLT 85% 12 NLT 75% NLT 80%
NLT 80% NLT 85% NLT 90%
TABLE-US-00002 TABLE 2 Exemplary Release Profile 6 7 (e.g., 10, 20
and 40 mg active) (e.g., 80 mg active) Time Amount Amount (Hours)
(approx. range) (approx. range) 1 20% and 40% 25% and 45% 2 35% and
55% 45% and 65% 4 55% and 75% 65% and 85% 6 70% and 90% NLT 80% 8
NLT 80%
[0062] Process
[0063] In another embodiment, the present disclosure relates to a
process for the production of an oral, extended release, abuse
deterrent dosage form including preparing a homogenized suspension
of at least one active substance susceptible to abuse, a controlled
release agent, and a second agent and/or a PEG. The PEG can have an
average molecular weight between about 3000 Daltons and about 4000
Daltons. The controlled release agent can have a melting
temperature of less than or equal to 70.degree. C. The second agent
can have a melting temperature greater than or equal to 100.degree.
C. The process can further include dispensing the homogenized
suspension into a capsule to produce the dosage form. In some
embodiments, the capsule is formed by joining a capsule body with a
capsule cap. In some embodiments of the processes described herein,
the active substance is hydrocodone. In other embodiments, the
active substance is oxycodone HCl. In certain embodiments, the
abuse deterrent dosage forms of the present disclosure are
capsules. The abuse deterrent dosage forms of the present
disclosure may be produced by liquid filled encapsulation. Liquid
filled encapsulation is a process in which active pharmaceutical
ingredients are suspended or emulsified in a carrier matrix and
filled into capsules. The capsules are usually made of hard gelatin
or hydroxypropyl methylcellulose. One of the advantages of this
dosage form is that it requires fewer excipients and processing
steps than other traditional compressed solid dosage forms. The
internal solid phase active pharmaceutical ingredient (e.g.
oxycodone or hydrocodone) can be suspended in an external fluid
phase. (e.g., a stearoyl polyoxylglyceride and/or PEG). In one
embodiment, stearoyl polyoxylglycerides are used to liquid fill
capsules because they are thermoplastics that melt at temperatures
below the melting point of the hard gelatin capsule (<70.degree.
C.) and are solids at room temperature. If the filling material is
liquid at room temperature, a banding process would need to follow.
This process adds a gelatin band around the point where the two
capsule ends join to create a unified capsule body to prevent any
leakage. In some embodiments, the formulation of the present
disclosure can include a band.
[0064] An exemplary liquid fill process is described. The liquid
fill process can begin by dispensing excipients (e.g., stearoyl
polyoxylglyceride, PVP, PEG and stabilizers/preservatives) and API
according to theoretical percent weights of the final capsule fill
weight. Following this step, the controlled release agent, e.g.
stearoyl polyoxylglyceride pellets, can be added to a homogenizing
mixing kettle which heats them above their melting point via
jacketing on the kettle. When the controlled release agent, e.g.
stearoyl polyoxylglyceride, is completely fluid, the API and other
excipients can be mixed in to form a homogenized suspension. This
occurs with the aid of mechanical agitation by way of several
internal stirring arms and the homogenizer built into the kettle.
Once a homogenized suspension is attained (newer kettles can be
equipped with NIR probes to indicate when this occurs), the
suspension can be pumped through jacketed hoses (to maintain the
internal kettle temperature to prevent solidification in the hose)
to a hopper on the capsule filling machine. An illustration of a
capsule filling machine is provided in FIG. 1. The capsule filling
hopper can also be jacketed to heat the suspension to prevent
solidification. The capsule filling machine can contain a separate
hopper which operators can fill with hard gelatin capsules. The
hopper can feed into a rectifying drum which aligns all capsules in
the same direction. Once aligned, the capsules sit vertically in a
cap disk which allows for separation of the body and cap via
vacuum. To fill the capsule, a positive displacement piston pump
can be used to draw the product in from the jacketed hopper and
dispense the suspension into the capsule body through a set of
changeable nozzles. Fill weight adjustment can be achieved by
varying the piston stroke of the pump. Changes can be made
throughout the process due to accommodate frequent in-process
capsule weight checks.
[0065] Once the capsule body is filled, the capsule body and cap
can be joined via pusher pins which raise the capsule body upwards
and into the capsule cap, which are held in place above the capsule
body by a joining block. The pusher pins then push the unified
capsule out of the cap disk and are discharged from the machine.
The capsules are allowed to cool at room temperature on trays and
are each weight checked via a capsule weigh checking machine.
Following this, the capsules are then placed into a final output
drum. Automatic capsule filling machines have the ability to
produce 500 to 150,000 capsules an hour with a very high degree of
accuracy.
[0066] In some embodiments, the present disclosure relates to a
dosage form as described herein prepared by filling a capsule body
with a heated homogenized suspension including an active substance,
a controlled release agent, a second agent and/or a PEG. In some
embodiments, the homogenized suspension including an active
substance, a controlled release agent, and a second agent and/or a
PEG wherein the suspension melts at a temperature of about
42.degree. C., 43.degree. C., 44.degree. C., 45.degree. C.,
46.degree. C., 47.degree. C., 48.degree. C., 49.degree. C.,
50.degree. C., 51.degree. C., 52.degree. C., 53.degree. C.,
54.degree. C., 55.degree. C., 56.degree. C., 57.degree. C.,
58.degree. C., 59.degree. C., 60.degree. C., 61.degree. C.,
62.degree. C., 63.degree. C., 64.degree. C., 65.degree. C.,
66.degree. C., 67.degree. C., 68.degree. C., 69.degree. C.,
70.degree. C., 71.degree. C., 72.degree. C., 73.degree. C.,
74.degree. C., 75.degree. C., 76.degree. C., 77.degree. C.,
78.degree. C., 79.degree. C., 80.degree. C., 81.degree. C.,
82.degree. C., 83.degree. C., 84.degree. C., 85.degree. C.,
86.degree. C., 87.degree. C., 88.degree. C., or 90.degree. C. Any
of these values may be used to define a range of melting
temperatures for the homogenized suspension. For example, in
certain embodiments, the homogenized suspension has a melting
temperature between about 47.degree. C. and about 52.degree. C. In
particular embodiments, the homogenized suspension including an
active substance, a controlled release agent, a second agent and/or
a PEG melts at temperatures below 77.degree. C., i.e. the melting
point of the hard gelatin capsule. In another embodiment, the
present disclosure relates to a method of treating pain including
administering to an individual in need thereof a therapeutically
effective amount of a dosage form as described herein. The dosage
form provides rapid onset of analgesia for the treatment of
moderate to severe pain.
[0067] The disclosures of all cited references including
publications, patents, and patent applications are expressly
incorporated herein by reference in their entirety. Further, when
an amount, concentration, or other value or parameter is given as
either a range, preferred range, or a list of upper preferable
values and lower preferable values, this is to be understood as
specifically disclosing all ranges formed from any pair of any
upper range limit or preferred value and any lower range limit or
preferred value, regardless of whether ranges are separately
disclosed. Where a range of numerical values is recited herein,
unless otherwise stated, the range is intended to include the
endpoints thereof, and all integers and fractions within the range.
It is not intended that the scope of the invention be limited to
the specific values recited when defining a range.
[0068] The present invention is further defined in the following
Examples. It should be understood that these Examples, while
indicating preferred embodiments of the invention, are given by way
of illustration only.
EXAMPLES
Example 1
Extended Release ADF Oxycodone Hydrochloride Liquid Fill Capsules
with PEG
[0069] Extended release ADF Oxycodone Hydrochloride liquid fill
capsules including stearoyl polyoxylglyceride or glycerol ester of
sat. C12-18 fatty acids, and PEG 3350 were prepared and the release
profiles of the oxycodone were determined. The capsules were
prepared using the following exemplary procedure. Stearoyl
polyoxylglyceride or glycerol ester of sat. C12-18 fatty acids, PEG
3350 and grey dye were placed in a 150 mL stainless steel cup on a
hot plate, and allowed to melt completely under nitrogen blanket
with no agitation, Once melted, citric acid and Oxycodone HCl (and
other components, if present) were slowly added and mixed in. Once
the necessary minimum melt temperature of 70.degree. C. was
achieved, the melt was homogenized using a Silverson homogenizer
for a minimum of 10 minutes at setting 5 under a nitrogen blanket.
Following homogenization, the melt was allowed to cool to
<75.degree. C. Capsules were hand filled to weight using a metal
spatula. The melt was left on the hot plate to maintain liquid
state. The filled capsules and remaining melt were allowed to cool
and weights of good capsules and waste recorded. Table 3 list the
formulations prepared.
TABLE-US-00003 TABLE 3 Oxycodone Hydrochloride liquid fill
capsules. Wt % Wt % Wt % Wt % Wt % Wt % Wt % Component 1 2 3 4 5 6
7 Oxycodone 5 20 40 40 40 40 29.63 Stearoyl 87 72 52 0 0 0 52
polyoxylglyceride glycerol ester of sat. 0 0 0 52 42 32 0 C12-18
fatty acids PEG 3350 0 0 0 0 10 20 12.19 Grey Dye Blend 7 7 7 7 7 7
5.18 Citric Acid 1 1 1 1 1 1 1 Active, mg 10 40 80 80 80 80 80
Capsule Fill Wt, mg 200 200 200 200 200 200 270
[0070] Dissolution Testing
[0071] The extended release ADF oxycodone hydrochloride liquid fill
capsules in Table 3 were tested for dissolution. Dissolution
testing was performed with reference to USP Monograph on Oxycodone
Hydrochloride Extended-Release Tablets. These tests were performed
on a dissolution apparatus utilizing UPS <711> Apparatus I
(Baskets), with 900 mL Simulated Gastric Fluid (no enzymes) as
media and a basket speed of 100 rpm. A 1.5 mL sample was pulled at
each evaluated time point and submitted for HPLC analysis. HPLC
conditions were modified from the USP monograph in order to observe
the release of oxycodone HCl. The HPLC conditions were as follows:
Injection Volume: 30 .mu.L (oxycodone); Flow Rate 1.7 mL/min
(oxycodone); Detection: UV at 225 nm (oxycodone); Column Temp:
25.degree. C.; Autosampler Temperature: ambient; Gradient:
Isocratic; and Runtime: 5 minutes. The specifications for
dissolution testing are shown in Tables 1 and 2. The release
profiles are shown in the Table 4.
TABLE-US-00004 TABLE 4 Dissolution testing of Oxycodone
Hydrochloride liquid fill capsules (Average of 3 capsules)
Formulation 1 Hour 4 Hour 12 Hour 1 28.30 78.19 90.61 2 35.03 99.93
105.86 3 46.26 101.08 101.39 4 3.33 6.11 11.46 5 3.49 21.24 36.09 6
14.35 80.33 102.56 7 30.73 81.96 102.09
Example 2
Extended Release ADF Oxycodone Hydrochloride Liquid Fill Capsules
with HPMC
[0072] Additional formulations containing HPMC in place of PEG were
evaluated to determine the effect of HPMC on the active release
profiles. The formulations were prepared using the same procedure
of Example 1. The formulations are shown in Table 5. The release
profiles are shown in the Table 6.
TABLE-US-00005 TABLE 5 Oxycodone Hydrochloride liquid fill
capsules. Wt % Wt % Wt % Wt % Wt % Wt % Component 8 9 10 11 12 13
Oxycodone 5 5 5 5.714 5.714 5.714 Stearoyl 82 77 72 85.286 85.286
85.286 polyoxylglyceride HPMC 5 10 15 0 5 10 Grey Dye Blend 7 7 7 8
8 8 Citric Acid 1 1 1 1 1 1 Active, mg 10 10 10 10 10 10 Capsule
Fill Wt, mg 200 200 200 175 175 175
TABLE-US-00006 TABLE 6 Dissolution testing of Oxycodone
Hydrochloride liquid fill capsules (Average of 3 capsules)
Formulation 1 Hour 4 Hour 12 Hour 8 28.41 71.53 91.56 9 25.85 57.03
92.41 10 24.64 56.08 95.97 11 26.93 72.39 89.98 12 25.62 68.55
89.14 13 24.65 55.14 95.20
Example 3
Extended Release ADF Oxycodone Hydrochloride Liquid Fill Capsules
with HPMC and PEG 35,000
[0073] Additional formulations containing HPMC and PEG 35,000 were
evaluated to determine the effect of HPMC and PEG 35,000 on release
profiles. The formulations were prepared using the same procedure
of Example 1. The formulations are shown in Table 7. The release
profiles are shown in the Table 8.
TABLE-US-00007 TABLE 7 Oxycodone Hydrochloride liquid fill
capsules. Wt % Wt % Wt % Wt % Wt % Component 14 15 16 17 18
Oxycodone 5 5 5 5 5 Stearoyl 72 69.5 67 64.5 62 polyoxylglyceride
HPMC 10 10 10 10 10 PEG 35,000 5 7.5 10 12.5 15 Grey Dye Blend 7 7
7 7 7 Citric Acid 1 1 1 1 1 Active, mg 10 10 10 10 10 Capsule Fill
Wt, mg 200 200 200 200 200
TABLE-US-00008 TABLE 8 Dissolution testing of Oxycodone
Hydrochloride liquid fill capsules (Average of 3 capsules)
Formulation 1 Hour 4 Hour 12 Hour 14 22.95 57.51 95.62 15 20.55
61.23 101.46 16 19.94 65.35 103.32 17 17.58 66.51 108.84 18 19.17
68.23 105.68
Example 4
Extended Release ADF Oxycodone Hydrochloride Liquid Fill Capsules
with HPMC and PEG 3350
[0074] Additional formulations containing HPMC and PEG 3350 were
evaluated to determine the effect of HPMC and PEG 3350 on release
profiles. The formulations were prepared using the same procedure
of Example 1. The formulations are shown in Table 9. The release
profiles are shown in the Table 10.
TABLE-US-00009 TABLE 9 Oxycodone Hydrochloride liquid fill
capsules. Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % Component 19 20
21 22 23 24 25 26 Oxycodone 5 5 5 5 5 5 5 5 Stearoyl 72 67 62 57 52
47 42 37 polyoxyl- glyceride HPMC 10 10 10 10 10 10 10 10 PEG 3350
5 10 15 20 25 30 35 40 Grey Dye 7 7 7 7 7 7 7 7 Blend Citric Acid 1
1 1 1 1 1 1 1 Active, mg 10 10 10 10 10 10 10 10 Capsule Fill 200
200 200 200 200 200 200 200 Wt, mg
TABLE-US-00010 TABLE 10 Dissolution testing of Oxycodone
Hydrochloride liquid fill capsules (Average of 3 capsules)
Formulation 1 Hour 4 Hour 12 Hour 19 20.63 61.75 110.46 20 24.48
61.57 101.33 21 24.30 59.86 98.97 22 26.65 65.27 101.18 23 26.75
76.50 100.32 24 29.08 87.03 101.63 25 41.36 94.98 100.25 26 53.34
98.33 101.71
Example 5
Extended Release ADF Oxycodone Hydrochloride Liquid Fill Capsules
with HPMC and PEG 3350
[0075] Additional formulations containing higher amounts of HPMC
were evaluated to determine the effect of higher amounts of HPMC on
release profiles. The formulations were prepared using the same
procedure of Example 1. The formulations are shown in Table 11. The
release profiles are shown in the Table 12.
TABLE-US-00011 TABLE 11 Oxycodone Hydrochloride liquid fill
capsules. Wt % Wt % Wt % Wt % Component 27 28 29 30 Oxycodone 5 5 5
5 Stearoyl 37 32 32 27 polyoxylglyceride HPMC 15 20 15 20 PEG 3350
35 35 40 40 Grey Dye Blend 7 7 7 7 Citric Acid 1 1 1 1 Active, mg
10 10 10 10 Capsule Fill Wt, mg 200 200 200 200
TABLE-US-00012 TABLE 12 Dissolution testing of Oxycodone
Hydrochloride liquid fill capsules (Average of 3 capsules)
Formulation 1 Hour 4 Hour 12 Hour 27 26.54 66.50 104.11 28 27.86
67.73 100.10 29 32.88 74.41 98.08 30 29.06 75.94 103.35
[0076] Formulation 29 was further tested using the manufacturing
process described in Example 1. The capsules were evaluated for
dissolution to determine the effect of the formulations on
oxycodone release profiles. The release profiles are shown in the
Table 13.
TABLE-US-00013 TABLE 13 Dissolution testing of Oxycodone
Hydrochloride liquid fill capsules - Formulation 29 - (Average of 6
capsules) 10 mg ER Oxycodone Average 1 Hour Capsule 1 32.461
31.13267 Capsule 2 29.899 Capsule 3 32.632 Capsule 4 35.324 Capsule
5 29.656 Capsule 6 26.824 2 Hour Capsule 1 48.661 48.032 Capsule 2
46.852 Capsule 3 49.806 Capsule 4 51.354 Capsule 5 48.800 Capsule 6
42.716 3 Hour Capsule 1 61.805 63.325 Capsule 2 61.233 Capsule 3
63.324 Capsule 4 64.731 Capsule 5 62.759 Capsule 6 66.097 4 Hour
Capsule 1 74.006 75.886 Capsule 2 74.172 Capsule 3 75.773 Capsule 4
76.900 Capsule 5 75.773 Capsule 6 78.689 12 Hour Capsule 1 101.092
101.0475 Capsule 2 102.867 Capsule 3 93.646 Capsule 4 102.077
Capsule 5 101.977 Capsule 6 104.626
[0077] Table 14 provides exemplary formulations for 20 mg, 40 mg
and 80 mg doses of oxycodone.
TABLE-US-00014 TABLE 14 Exemplary formulations of extended release
20 mg, 40 mg, and 80 mg ADF Oxycodone Hydrochloride liquid fill
capsules Oxycodone stearoyl PEG Citric Grey Dye Capsule Oxycodone
HCl polyoxylglyceride 3350 HPMC Acid Blend Fill Dose % % % % % %
(mg) 20 mg 10.00 27.00 40.00 15.00 1.00 7.00 200.00 40 mg 16.00
19.90 42.50 15.00 1.00 5.60 250.00 40 mg 16.00 17.40 45.00 15.00
1.00 5.60 250.00 80 mg 16.00 30.20 40.00 10.00 1.00 2.80 500.00 80
mg 16.00 55.20 15.00 10.00 1.00 2.80 500.00
Example 6
Extended Release ADF Oxycodone Hydrochloride Liquid Fill Capsules
with PVP or PEG 3350
[0078] Additional formulations containing PVP or PEG 3350 were
evaluated to determine the effect on release profiles. The
formulations were prepared using the same procedure of Example 1.
The formulations are shown in Table 15. The release profiles are
shown in the Table 16.
TABLE-US-00015 TABLE 15 Oxycodone Hydrochloride liquid fill
capsules. Wt % Wt % Wt % Wt % Component 31 32 33 34 Oxycodone 4 8
14.55 16 Stearoyl 69.40 65.40 66.86 45.20 polyoxylglyceride
Kollidon 90F (PVP) 20 20 12.5 0 PEG 3350 0 0 0 35 Grey Dye Blend
5.6 5.6 5.09 2.8 Citric Acid 1 1 1 1 Active, mg 10 20 40 80 Capsule
Fill Wt, mg 250 250 275 500
TABLE-US-00016 TABLE 16 Dissolution testing of Oxycodone
Hydrochloride liquid fill capsules (Average of 3 capsules)
Formulation 1 Hour 2 Hour 4 Hour 6 Hour 8 Hour 31 27.58 42.61 63.78
79.89 90.85 32 26.53 40.68 62.25 78.84 90.42 33 27.24 42.55 65.88
84.16 93.75 Specification 20%-40% 35%-55% 55%-75% 70%-90% >85%
(10, 20, 40 mg) 34 30.71 53.00 80.43 97.22 N/A Specification
25%-45% 45%-65% 65%-85% >85% N/A (80 mg)
[0079] The 10, 20, and 40 mg formulations of 31-33 are similar and
contain a controlled release agent (e.g., stearoyl
polyoxylglyceride) and a second agent (PVP). The second agent can
also act to decrease purity since it can be soluble in both water
and ethanol, as well as to slow dissolution in the presence of the
controlled release agent. Kollidon 90F is a high molecular weight
polyvinylpyrrolidone. The 90 is a nominal value that is a
calculated by the manufacturer based on viscosity and molecular
weight.
[0080] The 80 mg formulation contains only the controlled release
agent and PEG 3350. The second agent was excluded because in order
to reach a processable viscosity the fill weight had to be
increased to 500 mg. In some embodiments, a processable viscosity
is less than about 2500 cP at 75.degree. C. measured using a
Brookfield RVDV-II+ Pro digital viscometer equipped with a RV3
spindle at 50 RPM. This made the resulting capsule slug larger and
delayed the release dramatically with the controlled release agent
alone. The PEG was added to speed up the dissolution to achieve the
necessary endpoints. The PEG also decreases the purity.
[0081] In other embodiments, a processable viscosity is less than
about 2500, 2400, 2300, 2200, 2100, 2000, 1900, 1800, 1700, 1600,
1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600 or about 500
cP at 75.degree. C. measured using, for example, a Brookfield
RVDV-II+ Pro digital viscometer equipped with a RV3 spindle at 50
RPM. These values can be used to define a range, such as between
about 1500 and about 2000 cP at 75.degree. C.
Example 7
Evaluation of Dyes
[0082] Numerous dyes were evaluated for their potential to deter
intravenous abuse. Varying concentrations of FD&C Blue #2,
green (FD&C Blue #2 and FD&C Yellow #5), FD&C Yellow
#5, FD&C Red #40, and grey dye (FD&C Blue#1, FD&C
Yellow #6, FD&C Red #40) were evaluated by dissolving them in a
95% ethanol 5% purified water (190 proof) solution and passing the
solution through a syringe filter. After syringe filtering the dye
solutions were visually evaluated for color intensity and rated on
a scale of 0 to 5, with 0 indicating no color and 5 indicating
dark, significant color. As shown in Table 15 below, the blue and
green dyes exhibited the highest color intensity at low
concentrations, e.g. 0.25% w/w. Solutions of grey dye before and
after filtering are shown in FIGS. 2A and 2B, respectively. The
grey dye was particularly striking and less appealing. An
acceptable color scale designation after extraction of the dye is
.gtoreq.4 on a scale of 1 to 5, with 5 being the highest level of
color.
TABLE-US-00017 TABLE 17 Color intensity of dye solutions after
syringe filtering Batch Dye Color Number Number Color Dye (% w/w)
Dye (mg) Assignment* 66 Blue 0.25 1.75 4 67 Blue 0.50 3.50 5 68
Blue 0.75 5.25 5 69 Blue 1.00 7.00 5 70 Green 0.25 1.75 4 71 Green
0.50 3.50 4 72 Green 0.75 5.25 4 73 Green 1.00 7.00 4 74 Yellow
0.25 1.75 3 75 Yellow 0.50 3.50 4 76 Yellow 0.75 5.25 5 77 Yellow
1.00 7.00 5 78 Red 0.11 0.75 2 79 Red 0.21 1.50 3 80 Red 0.43 3.00
4 81 Red 0.63 4.44 5 82 Grey 0.25 1.75 2 83 Grey 0.50 3.50 2 84
Grey 0.75 5.25 4 85 Grey 1.00 7.00 4 86 Grey 2.00 14.00 5
Example 8
Abuse Deterrent Properties of Extended Release Liquid Fill Capsule
Oxycodone Formulations
[0083] Grinding--The purpose of grinding or chewing an extended
release dosage form is to break the extended release properties of
the dosage form and cause the active substance to "dump" or be
released in a relatively short amount of time. This is a common
method of abuse since it requires little to no equipment to perform
by an abuser. Once chewed or ground, the drug can be swallowed or
insufflated for immediate release of the active substance.
[0084] The purpose of this study was to show that the contents of
the capsule can maintain extended release properties and prevent
dose dumping regardless of particle size in order to prevent abuse
or misuse of the dosage form. The Retsch Knife Mill GRINDOMIX GM200
(TE96) was utilized to mimic a commercially available coffee
grinder (Mr. Coffee) in order to grind the drug product from a
capsule slug into a powder. The powder was then subjected to
dissolution testing similar to that of the intact capsule. For the
purposes of this study, any resulting powder which achieves a large
increase (i.e., double that of the original intact formulation) in
dissolution versus the intact capsule at the 1 or 2 hour mark is
considered suitable for intranasal or oral abuse.
[0085] The Retsch Knife Mill GRINDOMIX GM200 utilizes a circular
blade attachment to mimic commercially available coffee grinders.
The GM200 has a top speed of 10,000 revolutions per minute (rpm),
while commercially available coffee grinders have a top speed of
approximately 20,000 rpm (an approximate two-fold increase in speed
when comparing the GM200 to a Mr. Coffee grinder). However, the
approximate two-fold increase in blade diameter (118 mm vs. 60 mm,
when comparing the GM200 to a Mr. Coffee grinder, respectively)
compensates for the approximate twofold decrease in top speed via
the inversely proportional relationship of the two variables.
Further, the torque provided by the GM200 is significantly higher
than the torque provided by a Mr. Coffee grinder (0.860 Nm (Newton
meters) of the GM200 vs. 0.062 Nm of the Mr. Coffee grinder,
respectively), which additionally illustrates the ability (or lack
thereof) of the Mr. Coffee grinder to modify the drug products into
a particle size suitable for intranasal or oral abuse. The study
evaluated the difference in dissolution of ground forms of several
different formulations of oxycodone following modification
(grinding) by the GM200.
[0086] Experimental: The following test equipment was used: Retsch
Knife Mill GRINDOMIX GM200 (TE96). The following testing conditions
were used: Analysis speed: 10,000 rpm; Analysis time: 30 seconds;
The capsules, the formulations of which are listed in Table 18, are
emptied prior to grinding (grinding the capsule in addition to the
fill is unnecessary and not indicative of the pathway utilized by
an abuser). Approximately 5.0 g of emptied capsules were used to
create the powder. A tared empty capsule was then filled with the
powder to +/-5 mg of the original intact capsule fill weight. Each
sample was prepared in triplicate (N=3) and averaged to achieve a
percent drug dissolved at a given time point. The results are shown
in Table 19 and FIGS. 5-8.
TABLE-US-00018 TABLE 18 Oxycodone Hydrochloride liquid fill
capsules. Wt % Wt % Wt % Wt % Wt % Component 31 33 34 35 4-5
Oxycodone 4 14.55 16 16 29.09 Stearoyl 69.40 66.86 45.20 60.20
17.32 polyoxylglyceride glycerol ester of sat. 0 0 0 0 47.50 C12-18
fatty acids Kollidon 90F (PVP) 20 12.5 0 0 0 PEG 3350 0 0 35 20 0
Grey Dye Blend 5.6 5.09 2.8 2.8 5.09 Citric Acid 1 1 1 1 1 Active,
mg 10 40 80 80 80 Capsule Fill Wt, mg 250 275 500 500 275
TABLE-US-00019 TABLE 19 Grinding data for the Extended Release
Liquid Fill Capsule Oxycodone Formulations Batch Potency
Intact/Ground 1 h 2 h 4 h 6 h 8 h 35 80 mg Intact 28 51 80 97 N/A
Ground 51 78 99 100 Difference 23 27 20 2 34 80 mg Intact 23 40 61
77 N/A Ground 37 59 88 100 Difference 14 19 26 23 31 10 mg Intact
27 41 62 79 90 Ground 37 58 82 93 96 Difference 11 17 19 14 5 33 40
mg Intact 27 43 66 84 94 Ground 39 61 87 97 99 Difference 12 19 21
13 5
[0087] As shown in Table 19 and FIG. 5-8, the ground capsule does
slightly increase the rate of dissolution. The active substance,
however, does not "dump" because the increase is less than a 2 fold
increase in the early time points (e.g. 1 h and 2 h). The ground
formulations still maintain an sustained release profile. The
dosage form has a deterrent to abuse at least by physical
manipulation such as chewing, grinding, or pulverization.
[0088] Extraction--Color is one identifying characteristic of
commercial drug products. Color can be applied to the dosage form
in two ways: dye or coating. High potency alcohol (i.e.,
.gtoreq.190 proof (95%)) is one extraction solvent that can be used
by abusers for APIs which are insoluble in water or in order to
separate the API from other water soluble excipients. Dyes or
coatings can potentially be used to alter the physical appearance
of the extracted solution of drug product (i.e., turn the resulting
solution a noticeable color).
[0089] Accordingly, the inclusion of one or more dyes in a drug
formulation is one method to render a formulation abuse deterrent.
Significant discoloration of an extraction product from a
formulation subject to abuse can discourage a potential abuser from
using (e.g., injecting or ingesting) the extraction product.
[0090] A study is conducted to investigate the effect of dyes in
the formulations of the present disclosure. Extraction products
from whole formulations are visually inspected to determine abuse
deterrence following alcohol extraction. Capsules are added to a
flask containing 190 proof ethanol and shaken at 250 rpm for 3
hours. After 3 hours all capsule contents are fully dissolved.
Solutions are filtered with a syringe filter and then visually
analyzed for color intensity. FIGS. 3 and 4 show exemplary results
of the tests.
[0091] The amount of dye present in the formulation can be an
amount that produces an extract or a filtered extract using water,
alcohol or a combination of both with a color that is greater than
0, or greater than 1, or greater than 2, or greater than 3 or
greater than 4 on the visual scale disclosed, or similar scale. The
amount of dye can vary depending on the formulation and components
present. In some embodiments, the formulation can contain at least
0.1% dye, at least 0.2% dye, at least 0.3% dye, at least 0.4% dye,
at least 0.5% dye, at least 0.6% dye, at least 0.7% dye, at least
0.8% dye, at least 0.9% dye, at least 1.0% dye, at least 1.5% dye,
at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at
least 6.0%, at least 7.0%, at least 8.0%, at least 9.0%, at least
10.0%, at least 11.0%, at least 12.0%, at least 13.0%, at least
14.0%, or any range of these values (e.g. between about 0.1% and
about 1.0% dye).
[0092] Purity of the dosage form attainable in 190 proof ethanol
and water was also tested. Additional formulations containing
Gelucire.RTM. 50/13 (stearoyl polyoxylglyceride) were evaluated to
determine the effect of the components on purity of the extractable
API. The formulations were prepared using the same procedure of
Example 1. The formulations are shown in Table 19 & 22. The
purity data is shown in Tables 20 and 21. The composition of the
present disclosure can reduce or minimize the purity of the
resulting API extracted from the composition with alcohol, water or
combinations thereof to a purity less than about 75%, 70%, 65%,
60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or about 10%.
These values can also define a range, such as about 20% to about
50%.
TABLE-US-00020 TABLE 20 Purity data for the Extended Release Liquid
Fill Capsule Oxycodone Formulations % LC Water Passes Ethanol
25.degree. C. Batch Potency Dissolution Notes 25.degree. C.
70.degree. C. 90.degree. C. 25.degree. C. 5.degree. C. (pH 1.2) 36
40 No Gelucire .RTM. 50/13 14 N/A 96 30 27 26 no PVP 33 40 Yes
Gelucire .RTM. 50/13 26 108 177 62 42 56 PVP (12.5% w/w) 47 80 Yes
Gelucire .RTM. 50/13 10 N/A 94 73 58 52 & 43/01 1 hour,
unagitated, 5 mL/dosage unit
TABLE-US-00021 TABLE 21 Purity data for the Extended Release Liquid
Fill Capsule Oxycodone Formulations % Purity Water Passes Ethanol
25.degree. C. Batch Potency Dissolution Notes 25.degree. C.
70.degree. C. 90.degree. C. 25.degree. C. 5.degree. C. (pH 1.2) 36
40 No Gelucire .RTM. 50/13 9 N/A 15 23 25 20 no PVP 33 40 Yes
Gelucire .RTM. 50/13 10 13 15 21 20 14 PVP (12.5% w/w) 47 80 Yes
Gelucire .RTM. 50/13 27 N/A 50 61 57 56 & 43/01 Evaporated
residue
[0093] In some embodiments, the formulation is homogenous and does
not undergo any visible phase separation after all of the
formulation components are combined. For example, in a formulation
containing two components having drastically different HLB numbers,
a visible phase separation between two portions of the formulation
can occur. When a visible phase separation occurs, the formulation
is no longer homogenous. A non-homogeneous formulation can result
in a non-homogeneous dosage form. Similarly, a visible phase
separation can also occur when the formulation has a high content
of non-melting components. In formulations that cannot form a
single phase, e.g., formulations that becomes saturated to the
point of which the melt becomes a viscous paste, the formulation is
no longer homogeneous. For example, formulations containing over
10% of PEG 35K can become non-homogenous.
Example 9
Extended Release ADF Oxycodone Hydrochloride Liquid Fill Capsules
with Stearoyl Polyoxylglyceride
[0094] Additional formulations containing stearoyl
polyoxylglyceride were evaluated to determine the effect on release
profiles. The formulations were prepared using the same procedure
of Example 1. The formulations are shown in Table 22. The release
profiles are shown in the Table 23.
TABLE-US-00022 TABLE 22 Oxycodone Hydrochloride liquid fill
capsules. Wt % Wt % Component 36 47 Oxycodone 14.55 29.09 Stearoyl
79.36 17.32 polyoxylglyceride Glycerol esters of sat. 0 47.5
C12-C18 fatty acids Kollidon 90F (PVP) 0 0 PEG 3350 0 0 Grey Dye
Blend 5.09 5.09 Citric Acid 1 1 Active, mg 40 80 Capsule Fill Wt,
mg 275 275
TABLE-US-00023 TABLE 23 Dissolution testing of Oxycodone
Hydrochloride liquid fill capsules (Average of 3 capsules)
Formulation 1 Hour 2 Hour 4 Hour 6 Hour 8 Hour 36 25.98 43.93 72.57
88.49 95.55 47 33.12 49.33 70.47 84.19 N/A
Example 10
Extended Release ADF Oxycodone Hydrochloride Liquid Fill Capsules
with HPMC and PEG 3350
[0095] Additional formulations containing stearoyl
polyoxylglyceride, HPMC and PEG 3350 were evaluated to determine
the effect on release profiles. The formulations were prepared
using the same procedure of Example 1. The formulations are shown
in Table 24. The release profiles and viscosity are shown in the
Tables 25 and 26.
TABLE-US-00024 TABLE 24 Oxycodone Hydrochloride liquid fill
capsules. Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt % Wt %
Component 37 38 39 40 41 42 43 44 45 46 Oxycodone 5 5.405 16.00
14.55 14.55 14.55 16.00 16.00 16.00 16.00 Stearoyl 32 31.97 62.91
69.42 64.41 59.42 70.20 60.20 50.20 40.20 polyoxylglyceride HPMC 15
16.22 0 0 0 0 0 0 0 0 Kollidon 90F (PVP) 0 0 15.0 12.49 12.49 12.49
0 0 0 0 PEG 3350 40 37.84 0 0 5.0 10.0 10.0 20.0 30.0 40.0 Grey Dye
Blend 7 7.565 5.09 2.55 2.55 2.55 2.80 2.80 2.80 2.80 Citric Acid 1
1 1 1 1 1 1 1 1 1 Active, mg 10 10 80 80 80 80 80 80 80 80 Capsule
Fill Wt, mg 200 185 500 550 550 550 500 500 500 500
TABLE-US-00025 TABLE 25 Dissolution testing of Oxycodone
Hydrochloride liquid fill capsules (Average of 3 capsules)
Formulation 1 Hour 2 Hour 3 Hour 4 Hour 12 Hour 37 31.133 48.032
63.325 75.886 101.048 38 30.159 47.992 61.080 N/A N/A
TABLE-US-00026 TABLE 26 Viscosity of Oxycodone Hydrochloride liquid
fill capsules % Non- Viscosity % Melting Melting (cP) Formulation
Potency (mg) Components Components @ 75.degree. C. 31 10 75.00
25.00 1190 32 20 71.00 29.00 1490 33 40 71.96 28.04 1640 34 80
83.00 17.00 408 35 80 83.00 17.00 342 37 10 79.00 21.00 1520 38 10
77.38 22.62 2080 39 80 68.00 32.00 4010 40 80 71.96 28.04 1805 41
80 71.96 28.05 1910 43 80 83.00 17.00 465 45 80 83.00 17.00 502 46
80 83.00 17.00 520
[0096] The % Melting Components refers to the components that melt
at a relatively low temperature, such as below about 70.degree. C.
(or as otherwise provided herein), and can include the controlled
release agent, PEG, and dye blend. The % Non-Melting Components
refers to the components that melt at a relatively higher
temperature, such as above about 70.degree. C. (or as otherwise
provided herein), and can include the API, HPMC and PVP.
* * * * *