AU2018253567A1 - Extruded extended release abuse deterrent pill - Google Patents

Abstract

Abstract The present disclosure relates to an oral, extended release, abuse deterrent pill containing at least one active pharmaceutical ingredient susceptible to abuse which is homogenously spread throughout a matrix used to deter abuse. The pill can be prepared using a hot melt extrusion process and a forming unit. The formed pill meets regulatory guidelines for extended release formulations and is abuse deterrent to parenteral administration due at least to particle size, viscosity, or purity limitations.

Description

invention be limited to the specific values recited when defining a range.

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2018253567 25 Oct 2018 [00111] 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 [00112] Example 1 [00113] Initial testing was performed using abuse deterrent formulations containing acetaminophen. Acetaminophen was utilized as a tracer in place of oxycodone HC1 for early experiments due to its availability, similar dissolution/solubility profile and cost-effectiveness. Extended release abuse deterrent pills containing acetaminophen in place of oxycodone HC1 were manufactured according to the following formulation as provided in Tables 5-6.

Table 5 - Exemplary Extended Release Abuse Deterrent Pill Formulation Ranges

Components	% Wt.
Active Substance	5.0-40.0
Matrix/Controlled Release Agent	20.0 - 70.0
Plasticizer (8K Da)	20.0 - 70.0

Table 6 - Exemplary Extended Release Abuse Deterrent Pill Formulation Ranges

Components	% Wt.
Active Substance	5.0-40.0
Polyvinyl Acetate	25.0 - 50.0
Polyvinylpyrrolidone	5.0-15.0
Sodium Lauryl Sulfate	0.1-0.75
Silica	0.01-0.2
Polyethylene Glycol (8k Da)	2.0-15.0
Antioxidants	0.0-2.0
Dye	0.0-2.0

[00114] Abuse deterrent pills containing acetaminophen were made by blending the formulation components in a Turbula T2F mixer shaker at 30 RPM for 5 minutes.

[00115] Extrusion was performed by means of a twin screw extruder of type Steer Omega 20. To achieve a uniform extrudate with good processing capabilities a medium sheer screw design was used at a relatively slow screw speed (150RPM). The temperature profile was designed to immediately melt the melting excipients (e.g., PEO, polyethylene glycol, and/or PVAc).

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Thereafter, the temperature was adjusted to be at or above the melting temperature of the melting excipients of the formulation at standard pressure to achieve mixing, decrease viscosity, and limit high torque forces on the extruder. Adequate mixing was achieved by maintaining high pressures in the extruder.

[00116] At times, the die was heated above the general melt temperature of the extrudate. It was found that at die temperatures at the melt temperature of the extrudate, the portion of the extrudate in contact with the inside die surface sheared off due to friction. An increase in die temperature decreased this frictional force and allowed the extrudate to slide along the die producing a glossy, uniform extrudate. Operating temperatures and pressures are provided in Table 7. The temperature and pressure zones in Table 7 correspond to the zones shown in Figure 1.

Table 7 - Extrusion Temperature and Pressure

	Temp	Pressure
Zone 1	60-70 °C
Zone 2	60-70 °C
Zone 3	70-80 °C
Zone 4	70-80 °C
Zone 5	80-90 °C
Zone 6	90-100 °C
Zone 7	90-100 °C
Die	100-125 °C
Melt Pressure		30-150 bar

[00117] The temperature profile, feed rate, and die size all have an effect on the pressure produced on the die head. A die size of 6 mm was used. The temperature profile was kept relatively static. The feed rate was adjusted to maintain a consistent and high pressure on the die head of about 50 bar.

[00118] For the experiment, a Carver Press was used to form the extrudate into a pill form. The Carver Press is a manual hydraulic press, utilizing a free standing set of Natoli upper and lower punches that meet at a die. Dedicated tooling was made for the experiment in order to produce 200-400 mg pills.

[00119] The extrudate was hand cut, based on weight (200-400 mg). The die was placed on top of the bottom punch, the cut extrudate was placed in the die cavity, and the top punch placed

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2018253567 25 Oct 2018 through the top section of the die. The cut extrudate was formed into a pill at around 1 +/- 0.5 metric tons of force, using the Carver Press and Natoli die set.

[00120] Dissolution Testing [00121] The abuse deterrent pills containing acetaminophen were tested for dissolution. Additional pills were formed and tested containing oxycodone HC1 as the active substance. 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. Japanese Sinker Baskets (Part Number PSCUSBSKJPMAG) were utilized. A 1.5 mL sample was pulled at 1 hour, 4 hours, and 12 hours (Dissolution Test 2 according to the USP monograph on Oxycodone Hydrochloride ExtendedRelease Tablets) and submitted for HPLC analysis. HPLC conditions were modified from the USP monograph in order to observe the release of acetaminophen or oxycodone HC1. The HPLC conditions were as follows: Injection Volume: 20 pL (acetaminophen), 30 pL (oxycodone); Flow Rate 1.5 mL/min (acetaminophen), 1.7 mL/min (oxycodone); Detection: UV at 295 nm (acetaminophen), UV at 225 nm (oxycodone); Column Temp: 25 °C; Autosampler Temperature: ambient; Gradient: Isocratic; and Runtime: 5 minutes. In another embodiment, the dissolution 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. Japanese Sinker Baskets (Part Number PSCUSBSK-JPMAG) were utilized. A 1.5 mL sample was pulled at 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours (Dissolution Test 1 according to the USP monograph on Oxycodone Hydrochloride Extended-Release Tablets) and submitted for HPLC analysis. HPLC conditions were modified from the USP monograph in order to observe the release of oxycodone HC1. The HPLC conditions were as follows: Injection Volume: 30 pL; Flow Rate 1.7 mL/min; Detection: UV at 225 nm; Column Temp: 25 °C; Autosampler Temperature: ambient; Gradient: Isocratic; and Runtime: 5 minutes. The specifications for dissolution testing are provided in Tables 1-4.

[00122] In order to determine the extended release characteristics of a pill, the effect of varying the wt% of the controlled release agent (e.g., PVAc/ PVP or HPMC) in the formulation was tested. In the initial phase of testing, PVAc/PVP was tested as a duel matrix/controlled

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2018253567 25 Oct 2018 release agent. The general formulation as provided in Tables 5 and 6 was tested for dissolution with the wt% of PVAc/PVP offset by the plasticizer.

[00123] Figure 4 shows the dissolution for four formulations having a different wt% of PVAc/PVP (30-60 wt. %). The higher the PVAc/PVP content, the slower the release of active substance at the 1,4, and 12 hour time points, thus wt% of PVAc/PVP has a direct correlation to release profile.

[00124] Abuse Deterrent Testing [00125] The abuse deterrent pills were tested for resistance to pulverizing/grinding using a coffee grinder analysis. The tested formulations contained materials mentioned in Tables 5 and 6. Three (3) pills for each specific wt% of PEO were selected and placed in a commercially available coffee grinder (Mr. Coffee®, model number IDS55). The coffee grinder was run for about 30 seconds with occasional pulsing. The grinded pills were submitted to a particle size analysis using an ATM L3P sonic sifter separator (screen size 35 Mesh) for 2 minutes. The 35 Mesh corresponds to a sieve size of 500 pm. The wt% of particles above 500 pm was used as a metric for measuring abuse deterrence against pulverization and grinding for subsequent insufflation.

[00126] The combination of PVAc and PVP was tested for its application in a matrix agent for abuse deterrence in formulations mentioned in Tables 5 and 6. In formulations with more than 40%, 50%, and 60% of PVAc/PVP, less than 45% of the particles were above 500 pm after being pulverized in the coffee grinder for 30 seconds. The PVAc/PVP alone does not have enough deterrence against pulverization when it is used as a duel matrix/controlled release agent. [00127] Example 2 [00128] Due to Example 1 having low abuse deterrence from pulverization, a separate matrix agent was needed which could act to prevent pulverization of the pill while not having a large effect on dissolution profile. PEO was selected for its ability to prevent pulverization due to entanglement of polymer chain lengths. Extended release abuse deterrent pills were manufactured according to Tables 8 and 9.

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Table 8 - Exemplary Extended Release Abuse Deterrent Pill Formulation Ranges

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Components	% Wt.
Active Substance	5.0-40.0
Matrix Agent (50K - 150K Da)	8.0-35.0
Controlled Release Agent	8.0-60.0
Plasticizer (8k Da)	0.0-22.0

Table 9 - Exemplary Extended Release Abuse Deterrent Pill Formulation Ranges

Components	% Wt.
Active Substance	5.0-40.0
Polyethylene Oxide (50K - 150K Da)	23.0 -27.0
Polyvinyl Acetate	25.0 - 50.0
Polyvinylpyrrolidone	5.0-15.0
Sodium Lauryl Sulfate	0.1-0.75
Silica	0.01-0.2
Polyethylene Glycol (8k Da)	1.0-15.0
Antioxidants	0.0-2.0
Dye	0.0-2.0

[00130] The formulations for extended release abuse deterrent pills described in Tables 8 and 9 underwent the same manufacturing procedure and dissolution testing as described in Example 1. Figure 5 shows the dissolution of six formulations containing three wt%s of 100K Dalton PEO at two wt%s of PVAc/PVP. The PVAc/PVP is believed to be the controlled release rate modifying agent for this formulation with the 100K Dalton PEO having no effect on controlled release of the drug.

[00131] Abuse Deterrent Testing [00132] The abuse deterrent pills were tested for resistance to pulverizing / grinding using a coffee grinder analysis. The tested formulations contained materials mentioned in Tables 8 and 9. The tests were performed in the same manner as described in Example 1 and the same 500 pm particle size was used as a metric for measuring abuse deterrence against pulverization and grinding for subsequent insufflation. .

[00133] The addition of 100K Dalton PEO to the abuse deterrent pills with PVAc/PVP significantly increased the percentage particles over the 500 pm size after the coffee grinder testing. This suggests that the 100K Dalton PEO helps to make the pills more abuse deterrent.

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PCT/US2014/070942 [00134] With 10-15% 100K Dalton PEO in the formulation the percentage of particles over

500 pm increased to 70-80% and if the PEO percentages were 20-25% the particles over 500 pm increased to over 80% in most cases after grinding, see Table 10. In Table 10, the PVAc/PVP and a plasticizer were adjusted to complete the rest of the formulations.

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Table 10 - Effect of 100K Dalton PEO on the Pulverization of the Pills

100K Dalton PEO (% in formulation)	ADF properties (% Particles >500 pm)
0%	13%-45%
10%-15%	71%-76%
20%-25%	79-95%

[00135] The effect of 100K Dalton PEO on pulverization was independent of the PVAc/PVP wt%. The coffee grinder analysis was performed on formulations with 15% wt 100K Dalton PEO and with PVAc/PVP having a wt% varied from 38%, 50% and 60 %. The percentage of particles over 500 pm was between 70-75% for all three PVAc/PVP wt%, suggesting that PEO was controlling the resistance to pulverization. See Table 11.

Table 11 - Effect of Changes in PVAc/PVP % on the Pulverization in a Formulation with 15% PEO

PVAc/PVP (% in formulation)	ADF properties (% Particles >500 pm)
37.89%	71%
50%	75%
60%	73%

[00136] The percentage of the active ingredient in the formulation was also tested to see if there would be any reduction in the pulverization of the pills with increased level of active ingredient. The test formulation contained 15 wt% 100K Dalton PEO and either 5 wt%, 20 wt% or 40 wt% active ingredient. The PVAc/PVP and plasticizer were used to complete the rest of the formulation. The effect of the dosing percentage on the pulverization level is shown in Table 12. As shown in Table 12, the percentage of the active ingredient did not affect the ADF properties of the formulation when the PEO percentage was held constant.

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Table 12 - Effect of Dosing Percentage on the Pulverization Levels

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Active Ingredient (% in formulation)	ADF properties (% Particles >500 pm)
5%	73-75%
20%	76%
40%	71%

[00137] These formulations meet or exceed the metrics for abuse deterrent properties with regards to pulverization and grinding. The inclusion of 10 - 15 wt% of 100K Dalton PEO in the formulation results in good abuse deterrent properties and 20 - 25 wt% of 100K Dalton PEO in the formulation results in excellent abuse deterrent properties against insufflation.

[00138] Example 3 [00139] Testing was also performed using abuse deterrent formulations containing HPMC as a controlled release rate modifying agent. Acetaminophen was utilized as a tracer in place of oxycodone HCI for these experiments due to its availability, similar dissolution/solubility profile and cost-effectiveness. Extended release abuse deterrent pills containing acetaminophen in place of oxycodone HCI were manufactured according to the following formulation as provided in Tables 13 and 14. These were produced using the same manufacturing and dissolution method described in Example 1.

Table 13 - Exemplary Extended Release Abuse Deterrent Pill Formulation Ranges

Components	% Wt.
Active Substance	5.0-40.0
Matrix Agent (100K - 350K Da)	15.0-40.0
Controlled Release Agent	10.0-50.0
Plasticizer (8k Da)	0.0-40.0

Table 14 - Exemplary Extended Release Abuse Deterrent Pill Formulation Ranges

Components	% Wt.
Active Substance	5.0-40.0
Polyethylene Oxide (100K - 350K Da)	20.0-31.0
Hydroxypropyl Methylcellulose	15.0-42.0
Polyethylene Glycol (8k Da)	5.0-40.0
Antioxidants	0.0-2.0
Dye	0.0-2.0

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2018253567 25 Oct 2018 [00140] Initial testing using 300K Dalton PEO with HPMC was done to test the effect of PEO on dissolution. The wt% of the PEO was varied while maintaining the HPMC wt%. Figure 6 shows the dissolution profile of four formulations with varied wt% of 300K Dalton PEO (50 - 80 wt %). These results show very similar dissolution profiles at higher wt% 300K Dalton PEO in the formulation (i.e., 60, 70, and 80 wt %). The 50 wt % formulation exhibited a faster release profile. This experiment indicates that 300K Dalton PEO does not have a molecular weight high enough to provide controlled release of the active substance.

[00141] Additional testing was done to test the controlled release effects of varying the wt% of HPMC in the formulation while holding 300K Dalton PEO constant. Formulations were manufactured according to Tables 13 and 14. Figure 7 shows the dissolution profile of 5 formulations with varying wt% of HPMC (30 - 66 wt %).

[00142] The results show very similar data points at the 1 hour time point regardless of wt% of HPMC. At the 4 hour time point, the release profile is inversely proportional to the wt% of HPMC, which ceases to change at 50 wt%. This experiment shows there is a direct correlation between wt% of HPMC and the release rate of active substance below 50 wt % of HPMC.

[00143] Abuse Deterrence Testing [00144] The abuse deterrent pills were tested for resistance to pulverizing I grinding using a coffee grinder analysis in the same manner as described in Example 1. The tested formulations contained materials mentioned in Tables 13 and 14. The same 500 pm metric was used as a marker for abuse deterrence against pulverization and grinding for insufflation..

[00145] Abuse deterrent pills containing 300K Dalton PEO were tested for resistance to pulverizing / grinding using the coffee grinder analysis. All of the formulations containing > 29 wt% 300K Dalton PEO have a 90% or higher weight percentage of particles over the size of 500 pm after pulverization in a coffee grinder (92% - 100%). Table 15 below outlines the results.

[00146] Additional testing was done on pills that were formulated using 300K Dalton PEO with a larger final pill weight. Formulations were made with 300 mg and 400 mg pill weights and showed there was no appreciable change in the particle size distribution compared to a similar 200 mg formulation. Table 15 details the results of this experiment.

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Table 15 - Coffee Grinder Analysis for Higher Pill Weight Experiments

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Pill Weight	ADF properties (% Particles >500 pm)
200 mg	92%-100%
300 mg	93%-96%
400 mg	94%-98%

[00147] The percentage of HPMC was varied to test the effect on the ability of the pill to prevent pulverization. Formulations of 29% and 60% 300K Dalton PEO were used as constants while the HPMC levels were varied. The plasticizer was used to fill the percentages of the formulations to maintain the same pill weight. It was found that the wt% of HPMC had no effect on the pulverization results. When the wt% of HPMC was varied from 5%-66% the wt% of particles greater than 500 pm following the coffee grinder analysis was 92% or higher. The results are outlined in Table 16.

Table 16 - Effect of HPMC on Abuse deterrence properties

Percentage of HPMC	ADF properties (% Particles >500 pm)
5%-25% (60% PEO)	95%-100%
30%-66% (29% PEO)	92%- 98%

[00148] All formulations met or exceeded the metric for abuse deterrent properties with regards to pulverization and grinding. Pills containing >29-60 wt% 300K Dalton PEO and 5 66 wt% HPMC as the extended release agent are difficult to pulverize or grind into a form that could be insufflated.

[00149] Example 4 [00150] Formulations using oxycodone HCI as an active substance were manufactured according to Tables 13 and 14 in a similar method described in Example 1 with a theoretical dosage of 10 mg. Three pills listed as percent active dissolved at a given time point are shown in Table 17.

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Table 17: 10 mg Oxycodone HCI Dissolution Data

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	1 Hour
	Average	Pill 1	Pill 2	Pill 3
Actual	25.83	25.077	27.657	24.753
RLD Specification	18%-28%

	4 Hours
	Average	Pill 1	Pill 2	Pill 3
Actual	64.46	62.229	68.13	63.023
RLD Specification	44%-65%

	12 Hours
	Average	Pill 1	Pill 2	Pill 3
Actual	93.20	90.976	93.664	94.961
RLD Specification	77-95%

[00151] The results show the average percent of active dissolved at each time point is within specification of the Reference List Drug for a 10 mg extended release oxycodone HCI pill.

[00152] Similarly, a formulation utilizing a theoretical dosage of 80 mg oxycodone HCI was made in accordance with Tables 13 and 14. Three pills were subjected to dissolution testing listed as percent active dissolved at the given time point, shown in Table 18.

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Table 18: 80 mg Oxycodone HCI Dissolution Data

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	1 Hour
	Average	Pill 1	Pill 2	Pill 3
Actual	38.17	36.406	38.629	39.473
USP Specification	31%-51%

	4 hours
	Average	Pill 1	Pill 2	Pill 3
Actual	70.91	66.43	71.54	74.772
USP Specification	61%-81%

	12 hours
	Average	Pill 1	Pill 2	Pill 3
Actual	92.06	87.937	91.308	96.938
USP Specification	> 85%

[00153] These results show the dissolution at the 1,4, and 12 hour time points for the 80 mg formulation listed in Tables 13 and 14 are within the criteria defined by the USP for an 80 mg oxycodone HCI ER tablet.

[00154] Abuse Deterrence Testing [00155] The abuse deterrent pills were tested for resistance to pulverizing / grinding using a coffee grinder assay in the same manner as described in Example 1. The tested formulations contained materials mentioned in the rest of this example containing oxycodone HCI as the active substance. The same 500 pm particle size was used as a metric for measuring abuse deterrence against pulverization and grinding for subsequent insufflation [00156] It was found that the abuse deterrent pills performed the equal to or better than previous pulverization tests performed in Examples 1-3. The 10 mg and 80 mg dosage pills were tested to confirm the ability to prevent abuse via pulverization. Both 100K Dalton PEO and 300K Dalton PEO were also tested using oxycodone HCI as the active ingredient. It was found

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Table 19.

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Table 19 - Oxycodone HCI pill Pulverization results.

Experiment	ADF properties (% Particles >500 pm)
10 mg Pill	85%-96%
80 mg Pill	75%-93%

[00157] Exemplary oxycodone HCI formulations are provided in Figures 8-11. Figure 8 shows exemplary formulations having 10 mg to 80 mg active substance and 100K Dalton PEO. The wt % values for PEO, PVAc/PVP (combined and separate) and PEG listed in Figure 8 may be varied up to +/- 1% and +/- 3% within each formulation. For example, the 10 mg dosage form may contain about 23 wt% to about 27 wt% PEO, about 53 wt% to about 57 wt% PVAc/PVP, and about 12 wt% to about 16 wt% PEG. Figure 9 shows exemplary formulations having 5 mg to 40 mg active substance and 100K Dalton PEO. The wt % values for PEO, PVAc/PVP (combined and separate) and PEG listed in Figure 9 may also be varied up to +/- 1% and +/- 3% within each formulation. Figure 10 shows exemplary formulations having 5 mg to 80 mg active substance and 300K Dalton PEO. The wt % values for PEO, HPMC and PEG listed in Figure 10 may be varied up to +/- 1% and +/- 3% within each formulation.

[00158] Additional oxycodone HCI formulations having 10 mg and 80 mg active substance were prepared having varying amounts of excipients as provided in Figure 11. The formulations were evaluated for dissolution profile and abuse deterrent properties, as described above. Formulations exhibiting an acceptable dissolution profile and abuse deterrent property are identified (e.g., experiments 5, 9, 11, 20 and 23) in Figure 11. Formulations comprising PEO, PVAc/PVP or HPMC, and PEG which vary up to +/- 1% and +/- 3% within each formulation are contemplated by the present disclosure. For example, an 80 mg dosage form may contain about 27 wt% to about 31 wt% 300K Dalton PEO, about 35 wt% to about 39 wt% HPMC and about 27 wt% to about 31 wt% PEG.

[00159] Example 5

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2018253567 25 Oct 2018 [00160] Active substance dose dumping of extended release dosage forms in ethanol is another way drug products can be abused. With regards to dose dumping in alcohol, to be classified as abuse deterrent a drug product should be able to resist dumping the active substance in a media containing alcohol. Dose dumping is commonly defined as the “unintended, rapid drug release in a short period of time of the entire amount or a significant fraction of the drug contained in a modified release dosage form.” To test a real life scenario, a media was created which consisted of 90% simulated gastric fluid (the oxycodone HCI dissolution media) and 10% ethanol or 810 mL Simulated Gastric Fluid (SGF) and 90 mL ethanol (EtOH). This is an equivalent environment to the stomach of a person who has consumed 7.22 fluid ounces of 80 proof alcohol. Rapid drug release was defined as a significant increase in dissolved drug at the 60 minute time point. Experiments were based on formulations detailed in Tables 8, 9, 13 and 14.

[00161] Results for the PEO and PVAc/PVP matrix tablets show a negligible difference in dissolution in alcoholic environments. Reference Table 20 for results. The largest increase in dissolution is only 1.82%. The formulations containing PEO and HPMC show only a slightly reduced amount of dissolved active substance at the 60 minute time point. These results suggest the presence of alcohol may actually decrease the release rate of active substance. The formulation of the present disclosure is not subject to alcohol dose dumping. The formulation of the present disclosure exhibits less than about a 50% increase, or about a 40% increase, or about a 30% increase, or about a 20% increase, or about a 10% increase, or about a 5% increase of active substance released in a simulated alcoholic gastric fluid environment. The formulation of the present disclosure is also not subject to ineffective release in alcoholic environments.

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Table 20 - Extended Release Alcohol Dose Dumping Study

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PEO/PVAc/PVP Dissolution at 60 Minutes

Media	Pilll	Pill 2	Pill 3	Average	Variance from Baseline
100% SFG	22.81	25.09	25.54	24.48
90% SGF : 10% EtOH	25.03	25.31	25.91	25.42	0.94
PEC	)/PVAc/PVP Dissolu,	tion at 60 Minutes
Media	Pill 1	Pill 2	Pill 3	Average	Variance from Baseline
100% SFG	16.29	19.24	18.45	17.99
90% SGF : 10% EtOH	19.33	20.31	19.80	19.81	1.82

PEO/PVAc/PVP Dissolution at 60 Minutes
Media	Pilll	Pill 2	Pill 3	Average	Variance from Baseline
100% SFG	27.71	25.66	28.95	27.44
90% SGF : 10% EtOH	26.33	25.94	26.68	26.32	-1.13

PEO/HPMC Dissolution at 60 Minutes

Media	Pill 1	Pill 2	Pill 3	Average	Variance from Baseline
100% SFG	25.077	27.657	24.753	25.83
90% SGF : 10% EtOH	23.106	23.661	22.741	23.17	-2.66

PEO/HPMC Dissolution at 60 Minutes
Media	Pill 1	Pill 2	Pill 3	Average	Variance from Baseline
100% SFG	25.248	27.483	28.865	27.20
90% SGF : 10% EtOH	20.808	23.64	23.347	22.60	-4.60

[00162] Extraction Example [00163] 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. A study was conducted to investigate the effect of dyes in the formulations of the present disclosure. Extraction products from whole or cut formulations were

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2018253567 25 Oct 2018 visually inspected to determine abuse deterrence following alcohol extraction, and also following subsequent filtration.

[00164] 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., >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).

[00165] In this study, 190 proof ethanol was utilized as an extraction solvent. A commercially available coffee filter was used to filter out any particulate matter of several drug products. The resulting solution was analyzed for physical appearance. The difference in physical appearance (if any) between drug products which are dyed or coated was evaluated.

[00166] Experimental: Oxycodone lOmg and 80mg (Extended Release) as described in the present disclosure, Opana® ER 5mg (reformulated) (Endo Health Solutions); Opana® ER 40mg (reformulated) (Endo Health Solutions); OxyContin® lOmg (reformulated) (Purdue Pharma); OxyContin® 40mg (reformulated) (Purdue Pharma); OxyContin® 60mg (reformulated) (Purdue Pharma); OxyContin® 80mg (reformulated) (Purdue Pharma). A summary of all of the samples tested is provided in the table below.

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Table 21: List of Samples Tested

Dosage Units Descriptions
Sample	Sample Name	Manufac. Process	Manufac. Process Color	API	Release Timeframe
4	Present Disclosure ER lOmg	Extrusion	Dye	Oxycodone	Extended
5	Present Disclosure ER 80mg	Extrusion	Dye	Oxycodone	Extended
6	Opana® ER 5mg	Extrusion	Coating	Oxymorphone	Extended
7	Opana® ER 40mg	Extrusion	Coating	Oxymorphone	Extended
8	OxyContin® lOmg	Compress & Cure	Coating	Oxycodone	Controlled
9	OxyContin® 40mg	Compress & Cure	Coating	Oxycodone	Controlled
10	OxyContin® 60mg	Compress & Cure	Coating	Oxycodone	Controlled
11	OxyContin® 80mg	Compress & Cure	Coating	Oxycodone	Controlled

[00167] The formulations of the samples of the present disclosure tested, i.e., samples 4 and 5, are provided in the table below.

Table 22: Formulations of Samples Tested

Component	Sample 4	Sample 5
Oxycodone HC1	5.00%	33.33%
PEO, 100K Daltons	40.00%	40.00%
HPMC, K100M	37.50%	20.00%
PEG, 8K Daltons	15.75%	4.67%
Citric Acid	1.00%	1.00%
Dye	0.75%	1.00%
Total weight	200 mg	240 mg
Release characteristics	ER	ER

[00168] In additional embodiments of the present disclosure, the amount of active substance in the formulation can range from about 0.50 Wt% to about 40 Wt%. Particularly, the amount of active substance in the formulation may range from about 1.0 Wt% to about 35 Wt%, or from

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2018253567 25 Oct 2018 about 5.0 Wt% to about 33 Wt%. In additional embodiments of the present disclosure, the amount of plasticizer (e.g., PEG) can range from about 0.25 Wt% and about 20 Wt% plasticizer.

[00169] For each sample, both whole and cut dosage units were tested. For whole dosage units, two (2) whole dosage units were placed in a 25mL Erlenmeyer flask containing 1 OmL of EtOH. For cut dosage units, all cut pieces of the dosage unit were placed in similar flasks. Cut dosage units were cut into about 8 pieces using diagonal pliers. Each flask was sealed with parafilm and shaken on a platform shaker for at least 10 hours at about 150rpm. The resulting solution was filtered through a coffee filter to remove any particulate matter. The filtered solution was collected in a 50mL Nessler color comparison tube. After 30 minutes, each sample tube was visually examined for color (if any), clarity/turbidity, and if any noticeable difference in filtered solution volume exists (i.e., a significant decrease from the original lOmL EtOH). The results for the whole and cut dosage units are provided in the two tables below.

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Table 23: Whole Dosage Unit Extraction Data

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Visual Examination - Whole Dosage Units
Sample	Sample Name	Color Change	Color Observed	Intensity	Notes (clarity/turbidity, volume change, etc.)
4	Present Disclosure ER lOmg	Yes	Blue	Dark	Clear, ~3mL volume decrease
5	Present Disclosure ER 80mg	Yes	Green	Dark	Clear, ~4mL volume decrease
6	Opana® ER 5mg	No	None	None	Clear, no volume change
7	Opana® ER 40mg	Yes	Yellow	Faint	Clear, no volume change
8	OxyContin® lOmg	Yes	White	Faint	Slightly turbid, no volume change
9	OxyContin® 40mg	Yes	White	Faint	Slightly turbid, no volume change
10	OxyContin® 60mg	Yes	Red	Faint	Slightly turbid, no volume change
11	OxyContin® 80mg	Yes	Blue	Faint	Slightly turbid, no volume change

Table 23: Cut Dosage Unit Extraction Data

Visual Examination - Cut Dosage Units
Sample	Sample Name	Color Change	Color Observed	Intensity	Notes (clarity/turbidity, volume change, etc.)
4	Present Disclosure ER lOmg	Yes	Blue	Dark	Clear, ~3mL volume decrease
5	Present Disclosure ER 80mg	Yes	Green	Dark	Clear, ~4mL volume decrease
6	Opana® ER 5mg	No	None	None	Clear, ~lmL volume decrease
7-	Opana® ER 40mg	Yes	Yellow	Faint	Clear, ~lmL volume decrease
8	OxyContin® lOmg	Yes	White	Faint	Slightly turbid, ~lmL volume decrease
9	OxyContin® 40mg	Yes	White	Medium	Turbid, ~lmL volume decrease
10	OxyContin® 60mg	Yes	Red	Medium	Turbid, ~2mL volume decrease
11	OxyContin® 80mg	Yes	Blue	Faint	Turbid, slight volume change

[00170] During filtration, samples passed through the filter at various rates. For example, samples 6-11 took approximately 20 seconds for the entire volume to completely pass through the coffee filter. Samples 4 and 5 took approximately 60 minutes for the entire volume to completely pass through the coffee filter. After filtration, samples 4-5 were uniform in color after sitting for approximately 30 minutes, while samples 8-11 had significant sediment at the bottom of the comparison tubes. Samples 6 and 7 had no noticeable sediment but were significantly less colored than the batches of the present disclosure.

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2018253567 25 Oct 2018 [00171] Approximately 5mL of the filtrate from each cut dosage form sample was passed through a 25mm, 0.2pm PTFE Titan syringe filter (Scientific Resources, Inc. Cat No. 42225-PC, Lot 709029003054). Each resulting solution was then assigned a number according to a scale of 0-5, with 0 (zero) representing a sample with no color and 5 representing a sample with a dark, significant color, (0 - no color; 1 - faint; 2 - light; 3 - medium; 4 - brilliant; and 5 - dark). Samples with at least light color, including dark coloration, can deter potential abusers from injecting or ingesting the filtered extract (e.g., colors 2 and above, 3 and above, 4 and above, or 5). The table below shows the color number assignments for the syringe filtered cut dosage unit solutions.

Table 25: Cut Dosage Unit Color Numbers

Visual Examination - Cut Dosage Units
Sample	Sample Name	Color Number
4	Present Disclosure ER lOmg	5
5	Present Disclosure ER 80mg	5
6	Opana® ER 5mg	0
7	Opana® ER 40mg	1
8	OxyContin® lOmg	0
9	OxyContin® 40mg	, 0
10	OxyContin® 60mg	0
11	OxyContin® 80mg	0

[00172] In some embodiments, the formulation of the present disclosure incorporates the dye throughout the entire dosage unit as opposed to incorporating the dye only in a coating. The dye can be water soluble, alcohol soluble or both. The dye can have a solubility in water, alcohol or both that is greater than about 0.01g/100 mL, about 0.1g/100 mL, about lg/100 mL or about 10g/100 mL. Traditional drug formulation dyes are not soluble, or significantly soluble, in water, alcohol or both. They are often formulated into the coatings of the drug formulations. In some embodiment, the dyes are water soluble, alcohol soluble or both, and are dyes that are approved for, or considered acceptable, for oral administration. In some instances, the solubility of the dye in alcohol is important because of the potential for compounding effects of, and interactions associated with, consuming both alcohol and the extracted API.

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PCT/US2014/070942 [00173] The following table lists the relative solubility of exemplary components of a formulation. A number of different dyes are listed along with their solubility information taken from the various literature sources and tested experimentally (200 proof ethanol and filtered through a 0.22 micrometer PTFE filter).

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Table 26: General Solubility of Exemplary Components

Exemplary Components	Water Solubility	Alcohol Solubility (Literature)	Alcohol Solubility (tested)
Oxycodone HC1	Yes	Yes	N/A
Polyethylene Oxide	Yes	No	N/A
Polyethylene Glycol	Yes	Yes	N/A
Hydroxypropylmethylcellulose	Yes	No	N/A
Microcrystalline Cellulose	No	No	N/A
Lactose	Yes	No	N/A
Blue #1	Yes	Yes	Yes
Blue #2	Yes	Yes	Yes
Yellow #5	Yes	Yes	Yes
Yellow #6	Yes	Yes	Yes
Red #40	Yes	Yes	Yes
Lake Dyes	No	No	N/A

[00174] The sediment observed at the bottom of the comparison tubes of the OxyContin® batches (samples 8-11) is indicative of a suspension rather than a solution. Typically, suspensions can be centrifuged or filtered to obtain a more clear solution (and in some cases, a colorless solution). Conversely, solutions cannot be further centrifuged or filtered using a common household coffee filter or a readily available syringe filter to obtain a more clear solution because the dye is completely dissolved in the solution. Dyed formulations can provide an additional mechanism of abuse deterrence than coated formulations.

[00175] 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%, or any range of these values (e.g., between about 0.1% and about 1.0% dye).

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2018253567 25 Oct 2018 [00176] It was also observed that a volume change occurred (~3-4mL decrease) for samples 4 and 5 following extended filtration time. Certain excipients (e.g., HPMC) can cause the resulting solution to become too viscous to fully pass through a coffee filter. Additional abuse deterrence (e.g., extended extraction time and volume loss) can be obtained by formulations including HPMC, or equivalents.

[00177] Additional Exemplary Formulations [00178] Additional exemplary formulations of the present disclosure are provided in the tables below.

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Table 27: Additional Exemplary Formulations

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Component	15 mg API	20 mg API	30 mg API	40 mg API	60 mg API
Oxycodone HCI	7.50%	10.00%	15.00%	20.00%	30.00%
PEO, 100K Daltons	40.00%	40.00%	40.00%	40.00%	40.00%
HPMC, K100M	33.00%	31.00%	29.00%	29.00%	28.00%
PEG, 8K Daltons	17.50%	17.85%	14.60%	9.25%	0.25%
Citric Acid	1.00%	1.00%	1.00%	1.00%	1.00%
Dye	1.00%	0.15%	0.40%	0.75%	0.75%
Total weight	200 mg	200 mg	200 mg	200 mg	200 mg
Release characteristics	ER	ER	ER	ER	ER

Table 28: Additional Exemplary Formulations

Component	10 mg API	80 mg API
Oxycodone HCI	4.0 - 6.0%	32.0-35.0%
PEO, 100K Daltons	38.0-42.0%	38.0 - 42.0%
HPMC, K100M	36.0 - 39.0%	18.0-22.0%
PEG, 8K Daltons	14.0- 17.0%	4.0 - 6.0%
Citric Acid .	0.8- 1.2%	0.8- 1.2%
Dye	0.6 - 0.9% or 0.5 - 1.0%	0.8- 1.2% or 0.5 - 1.5%
Release characteristics	ER	ER

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Table 29: Additional Exemplary Formulations

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Component
Hydrocodone Bitartrate	6.0-9.0%	8.0-12.0%	13.0-17.0%	18.0-22.0%	28.0-32.0%
PEO, 100K Daltons	38.0-42.0%	38.0-42.0%	38.0-42.0%	38.0-42.0%	38.0-42.0%
HPMC, K100M	31.0-35.0%	29.0-33.0%	27.0-31.0%	27.0-31.0%	26.0-30.0%
PEG, 8K Daltons	16.0-19.0%	16.0-19.0%	13.0-16.0%	8.0-11.0%	0.2-0.3%
Citric Acid	0.8-1.2%	0.8-1.2%	0.8-1.2%	0.8-1.2%	0.8-1.2%
Dye	0.8-1.2% or 0.75-1.25%	0.1-0.3% or 0.1-0.5%	0.3-0.5% or 0.3-0.8%	0.6-0.9% or 0.5-1.0%	0.6-0.9% or 0.5-1.0%
Release characteristics	ER	ER	ER	ER	ER

Table 30: Additional Exemplary Formulations

Component
Hydromorphone HCI	6.0-9.0%	8.0-12.0%	13.0-17.0%	18.0-22.0%	28.0-32.0%
PEO, 100K Daltons	38.0-42.0%	38.0-42.0%	38.0-42.0%	38.0-42.0%	38.0-42.0%
HPMC, K.100M	31.0-38.0%	29.0-35.0%	27.0-31.0%	27.0-31.0%	26.0-30.0%
PEG, 8K Daltons	16.0-19.0%	16.0-19.0%	13.0-16.0%	8.0-11.0%	0.2-5.0%
Citric Acid	0.8-1.2%	0.8-1.2%	0.8-1.2%	0.8-1.2%	0.8-1.2%
Dye	0.8-1.2% or 0.75-2.25%	0.1-0.3% or 1.0-2.5%	0.3-0.5% or 0.4-2.0%	0.6-0.9% or 0.5-2.5%	0.6-0.9% or 0.5-4.5%
Release characteristics	ER	ER	ER	ER	ER

[00179] Cutting Force Example [00180] The existing methodology used to evaluate abuse deterrence with regards to the cutting or breaking of a dosage form is based on the USP “tablet breaking force” test. This test defines “tablet breaking force” as the force required to cause tablets to fail (i.e., break) in a specific plane. The USP describes the test as follows “[t]he tablets are generally placed between two platens, one of which moves to apply sufficient force to the tablet to cause fracture. The platens should be parallel. Their faces should be polished smooth and precision-ground perpendicularly to the direction of movement. Perpendicularity must be preserved during platen movement, and the mechanism should be free of any bending or torsion displacements as the load is applied. The contact faces must be larger than the area of contact with the tablet.” Figure 12 shows equipment capable of executing traditional “tablet breaking force” analysis.

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2018253567 25 Oct 2018 [00181] The USP further explains the applications of tablet breaking force and why it is utilized in the industry. “Tablets must be able to withstand the rigors of handling and transportation experienced in the manufacturing plant, in the drug distribution system, and in the field at the hands of the end users (patients/consumers). Manufacturing processes such as coating, packaging, and printing can involve considerable stresses, which the tablets must be able to withstand. For these reasons, the mechanical strength of tablets is of considerable importance and is routinely measured.” The intent of these applications is for traditional formulations which may be subjected to forces which could break the tablets (i.e., vigorous shaking in a tablet bottle). The intent is not to address abuse deterrence potential. Furthermore, this test is only applicable to and instructive to evaluate tablet formulations. The test is not applicable to or instructive to evaluate pill, or other formulations, prepared by extrusion methodologies.

[00182] In formulations utilizing excipients such as PEO, and using such excipients in an extrusion process, the parameter “tablet breaking force” does not apply. For example, the long molecular chain lengths of the PEO (e.g., 100,000 Daltons - 7,000,000 Daltons) cause the drug product (relative to other traditional drug products) to be flattened, but never actually “fail” (i.e., break) when applying “tablet breaking force” in the traditional sense. The traditional application of “tablet breaking force” needs to be modified to evaluate formulations containing malleable excipients (such as PEO) for the “cutting force” of the dosage form, specifically dosage forms which are intended to deter abuse. The modification of the traditional “tablet breaking force” test presented in this study consists of a change from the “platens” utilized to cause the dosage forms to “fail” (i.e., break), namely from contact faces “larger than the area of contact with the tablet” to sharp planes which mimic commonly used tools for abuse. Figures 13,14 and 15 show reference attachments including a fracture wedge set (used to mimic common kitchen scissors, Figures 13 and 14 showing different views of the same set) and a razor blade (Figure 15).

[00183] The purpose of this study was to perform and summarize the cutting force needed to cut different formulations of CII narcotic drug products. Texture analysis is the mechanical testing of pharmaceutical products in order to measure their physical properties. A Texture Analyzer XT2i can perform testing of numerous physical properties of pharmaceutical products, including cutting force. The cutting force needed to cut several different formulations of CII narcotic drug products utilizing different attachments on a Texture Analyzer (TE37) was investigated. Multiple tools were utilized to cut drug products with the intent of abuse including

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2018253567 25 Oct 2018 two attachments which mimic readily available tools used for abuse (e.g., a razor blade and kitchen scissors). The cutting force for all evaluated drug products was evaluated with each attachment.

[00184] Experimental: The samples tested include those samples listed in Table 21. The formulations of the samples of the present disclosure tested are listed in Tables 13 and 14. The Texture Analyzer, Model XT2i HR was operated at the following conditions: Pre Test Speed: lmm/s; Test Speed: 0.25mm/s; Post Test Speed: lOmm/s; Distance: 99.9% (% Strain); Trigger Type: Auto (Force = 0.2N) and Break Detect: Off. A sample size of N=10 was used for each sample per cutting attachment. The cutting force results of the CII narcotic drug products utilizing both cutting attachments (razor blade and fracture wedge set) were determined. Figure 16 shows the cutting force data tables for the razor blade and the fracture wedge set.

[00185] The individual maximum cutting force needed to cut any tested CII narcotic drug products utilizing the razor blade was 142 Newtons (N) (sample 7). The highest average cutting force needed to cut any tested CII narcotic drug products utilizing the razor blade was 13 IN (sample 7). The individual maximum cutting force needed to cut any tested CII narcotic drug products utilizing the fracture wedge set was 163N (sample 6). The highest average cutting force needed to cut any tested CII narcotic drug products utilizing the fracture wedge set was 156N (sample 6).

[00186] All of the tested CII narcotic drug products can indeed be cut, and therefore potentially be abused, with force which is substantially lower than what has been reported using the breaking strength test or equivalent (>500N, See U.S. Patent US 8,309,060) utilizing conventional means (i.e., common kitchen scissors or a razor blade). “Flattening” the tablets utilizing forces >500N (with traditional “tablet breaking force” definitions) does not address abuse deterrence potential in the tested CII narcotic drug products.

[00187] In one embodiment, the formulation of the present invention exhibits a cutting strength (i.e., force needed to cut the formulation) of greater than about 40 N, about 50 N, about 60 N,about 70 N, about 80 N, about 90 N, about 100 N, about 110 N, about 120 N, or about 130 N, or any range of these values (e.g., between about 40 N and about 120 N), as tested by either the Cutting Force - Razor Blade test or by the Cutting Force - Fracture Wedge Set test, or both.

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2018253567 25 Oct 2018 [00188] Samples 4 and 5 of the present disclosure exhibit improved cutting strength compared to the compress-and-cure samples (i.e., samples 8-11). Samples prepared via a compress-andcure procedure undergo dry mixing of the components only. These components are then compressed into a dosage form, and placing on a drying pan which applies heat to the dosage form. It is believed that compress-and-cure dosage forms are not melted or similarly liquefied to create significant homogeneity within the dosage form as compared to extrusion based procedures. The dosage formulations of the present invention are prepared by extrusion and, therefore, possess significant homogeneity as a result of the extrudate mixing within the extruder under melt flow conditions. The extrudate experiences high shear forces that produce the mechanical energy needed to ensure the required hardness and strength are achieved. The high shear forces can act on select components, for example PEO, to transform them into matrices that exhibit increased strength and stability.

[00189] Grinding Example [00190] The purpose of this study was to perform and summarize the grinding potential of different formulations of CII narcotic drug products. The Retsch Knife Mill GRINDOMIX GM200 was utilized to mimic a commercially available coffee grinder (Mr. Coffee) in order to grind CII drug products into a particle size that is suitable for intranasal abuse (insufflation). A commercially available coffee grinder was also evaluated for comparison purposes. Particle size analysis was conducted utilizing an ATM L3P Sonic Sifter, utilizing a 500 micrometer (pm) particle size sieve (35 mesh). For the purposes of this study, any particles less than 500pm in diameter were considered suitable for intranasal abuse. It is generally accepted as an industry standard that any particle greater than 500pm in diameter cannot be sufficiently absorbed by the blood vessels in the nasal passages.

[00191] 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 20,000rpm (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 (118mm vs. 60mm, when comparing the GM200 to a Mr. Coffee grinder, respectively) compensates for the approximate twofold decrease in top speed via the inversely proportional

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2018253567 25 Oct 2018 relationship of the two variables. Further, the torque provided by the GM200 is significantly higher than the torque provided by a Mr. Coffee grinder (0.860Nm (Newton meters) of the GM200 vs. 0.062Nm 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 abuse. The study evaluated the difference in particle sizes of several different formulations of CII narcotic drug products following modification (grinding) by the GM200 and Mr. Coffee grinder.

[00192] Experimental: The samples tested include those samples listed in Table 21. The formulations of the samples of the present disclosure tested are listed in Table 13 and 14. The following test equipment was used: Retsch Knife Mill GRINDOMIX GM200, Coffee Grinder (Mr. Coffee), ATM L3P Sonic Sifter, 500pm sieve (35 mesh) and a Shimpo Instruments Tachometer. The following testing conditions were used: Analysis speed: 10,000rpm (GM200), 20,000rpm (Mr. Coffee); Analysis time: 30 seconds; Sieve Size: 500pm (35 mesh); Analysis time: 2 minutes (no pulse). Each sample was prepared in triplicate (N=3).

[00193] For each sample, three (3) dosage units were weighed and tested. The following conditions were used with the GM200: a 30 second analysis time and a speed of 10,000rpm. Both parameters were set prior to each analysis. The composite sample was transferred to a tared weigh boat and the weight of the sample was recorded. The following equation was used to calculate the % sample loss:

Sample Loss (%) = 100 Analyzed Sample (mg) Sample Weight (mg) x 100) [00194] The weight of the 35 mesh sieve and sample pan was recorded. The testing apparatus was assembled with the 35 mesh sieve above the sample pan. The composite sample was transferred to the testing apparatus and analyzed utilizing the following parameters: 2 minute analysis time and no pulse. The analyzed 35 mesh sieve and sample pan were weighed. The % material remaining on the 35 mesh sieve (> 500pm) and in the sample pan (< 500pm) was calculated using the following equation:

Percent on Sieve (%) =

Weight of Sample on Sieve (mg) Total Weight of Sample on Sieve(mg)

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2018253567 25 Oct 2018 [00195] The procedure was repeated for the Mr. Coffee grinder in place of the GM200. The Mr. Coffee grinder has 1 operating speed (~20,000rpm). The particle size analysis and grinding results are shown in Figures 17. Figure 17 is a representation of particle size results (% >500pm) when comparing the tested Extended Release (ER) CII narcotic drug products between manufacturers.

[00196] Statistical significance was tested against a 95% confidence interval or a p-value of < 0.05. Combined OxyContin® batches provide statistically different (lower) amounts of particles >500pm than combined formulations of the present disclosure (e.g., ER samples and combined Opana® batches following grinding and particle size analysis as described in the protocol).

[00197] The results were combined per manufacturer, i.e. the present disclosure, Opana® ER batch results, and OxyContin® results, and analyzed as groups. The combined Opana® batches provide statistically similar amounts of particles >500pm as the combined formulations of the present disclosure (e.g., ER samples) following grinding and particle size analysis.

[00198] Alcohol Extraction Example [00199] The purpose of this study was to perform and summarize the results of an alcohol extraction, filtration, and purity testing of the resulting extraction solution for different formulations. Formulations of CII narcotic drug products can be modified from their intended dosage form in order to remove the full dose of the active substance from the dosage form. This is known as making the drug product “abusable.” Formulation development has occurred which is intended to reduce the ability of patients to modify the products into this “abusable” form. Extrusion and compress-and-curing are two methods for manufacturing CII drug products. Both methods, when formulated appropriately, possess characteristics which reduce the ability of patients to modify the products into an “abusable” form (when compared to traditional methods).

[00200] Twin Screw extrusion can be described as mixing a blended formulation by using shear forces. The co-rotating screws create shear/frictional forces through material contact between the two screws and between the screws and barrel wall. The shear forces work on the material based on its viscosity (inter-particulate friction) to create a homogenous polymer melt. The heated barrels control the melt by maintaining constant temperatures in the various zones of the extruder as well as add additional heat to maintain energy in the process. This happens in a

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2018253567 25 Oct 2018 simultaneous continuous process while the material is transferred through the extruder. The polymer melt can then be pushed through a die to form a uniform extrudate. This differs from compress-and-curing which can be described as initially compressing (with force) the blended formulation and then curing (with heat) after the compression in a separate sequential process to produce a finished drug product. CII drug products which utilize each manufacturing method are currently commercially available. In some embodiments, the formulation of the present disclosure is formed by an extrusion process under sufficient shear stresses to impart strength and stability to the formulation. The formulation can be prepared using an extruder wherein shear forces, pressure, and heating are applied together or separately in different zones of the extruder. In some embodiments, the formulation is prepared by reaching a melt flow temperature of the specific formulation in the extruder to assist in producing a uniform extrudate (i.e., localized uniformity). In other embodiments, the formulation is prepared using a compressand-cure process utilizing preceding, simultaneous, or subsequent heat.

[00201] Three principal methods of modifying CII drug products in order to make them “abusable” exist, namely cutting, grinding, and extraction. Cutting the dosage form can be performed in order to increase the surface area of the product prior to ingesting it in an effort to increase the rate of dissolution into the digestive tract. Cutting can also be used to increase the efficiency of grinding or extraction. Cutting alone, however, is not sufficient to render a formulation abuseable. Readily available tools used for cutting are razor blades and common kitchen scissors. Grinding the dosage form is performed in order to decrease the particle size of the product in an effort to insufflate (snort) for immediate release into the blood vessels of the nasal passages. Additional abuse pathways exist which follow the grinding of the product. A readily available tool used for grinding is a commercially available coffee grinder. Extraction is performed in order to dissolve the active substance of the dosage form into a liquid which can be filtered and subsequently swallowed, injected, or otherwise abused. A readily available tool used for extraction is high potency alcohol (i.e., >190 proof (95%)).

[00202] The purpose of this study was to determine the purity of an alcohol extraction sample using large volumes of high potency alcohol. For this experiment, 40 mg and 80 mg ER formulations of the present disclosure were compared to 40 mg and 80 mg OxyContin® of the RLD. Four (4) whole dosage units were ground using a Retsch Knife Mill GRINDOMIX GM200 at 10,000 RPM for 30 seconds. The samples were then placed in 40.0 mL of 190 proof

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2018253567 25 Oct 2018 ethanol. The samples were covered and shaken on a platform shaker at 250 RPM for 3 hours. 5.0mL of the resulting solution was pipetted off and placed in a beaker. The beaker was heated at ~100°C until all the ethanol evaporated. Once cooled, the residue was scrapped off, weighed, dissolved, and analyzed via a HPLC method validated for quantifying oxycodone HCI content. Figure 19 shows the percent purity of each of the 4 dosage forms following alcohol extraction. While it is assumed each dosage had -100% of label claim in the alcohol solution, the ER formulations of the present disclosure have a roughly 2-3 fold decrease in purity of alcohol extract. This is significant due to the fact the alcohol cannot be directly intravenously injected; formulations of a lower purity following alcohol extraction are thought to deter abuse via intravenous injection.

[00203] Small Volume Extraction Example [00204] The purpose of this study was to determine if the active substance can be extracted from a dosage form using a small volume of water (relative to a single dosage unit) in a relatively short amount of time. The use of small volumes of water is a common method for abuse since the materials are readily available and the waiting period is generally 1 hour or less. A dosage form able to prevent or reduce small volume extraction is another deterrent to abuse.

[00205] As a measure of whether a solution would be able to be intravenously injected by an abuser the viscosity of the resulting small volume extraction solutions is measured or calculated. An extended release 80mg dosage form of the present disclosure was compared to an 80mg OxyContin® (reformulated), a 40mg Opana® ER (reformulated), and a 30mg Roxicodone® IR dosage form. Ten (10) pills of each dosage form were cut in half and placed in 30mL of water at 90°C. Three (3) beakers of each dosage form were set up in order to test three time points: 30 minutes, 45 minutes, and 60 minutes. The samples were left unagitated. It is believed that nonagitation is a preferred method for extracting the active substance without increasing the solution viscosity. Agitation is believed to activate the high molecular weight, water soluble excipients. At each given time point, a ImL sample was taken for HPLC analysis of oxycodone HCI content and presented as percent of label claim. The remaining solution was subsequently decanted from the beaker for viscosity analysis via capillary viscometer at 25 °C. The results of the oxycodone HCI content and resulting viscosity are represented in Table 31 and Table 32, respectively. '

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Table 31: Aqueous Small Volume Extraction Oxycodone HC1 Content

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Product	Oxycodone HCI Content (% of Label Claim)
30 minutes	45 minutes	60 minutes
Roxicodone® 30mg	76.8	98.0	115.7
OxyContin® 80mg	34.0	48.9	59.1
Present Disclosure ER 80mg	34.0	43.8	52.5

Table 32: Aqueous Small Volume Extraction Viscosity

Product	Viscosity (Centistokes (cSt) @ 25°C)
30 minutes	45 minutes	60 minutes
Roxicodone® 30mg	1.0	1.0	1.0
OxyContin® 80mg	1.4	1.7	2.1
Opana® ER 40mg	1.3	2.4	2.4
Present Disclosure ER 80mg	22.3	60.8	70.3

Table 33: Aqueous Small Volume Extraction Drug Product Excipients

Product	Polyethylene Oxide Content	HPMC
Roxicodone® 30mg	N/A	N/A
OxyContin® 80mg	High MW PEO (>1,000,000 Daltons)	Yes
Opana® ER 40mg	High MW PEO (>1,000,000 Daltons)	Yes
Present Disclosure ER 80mg	Low MW PEO (<1,000,000 Daltons)	Yes

[00206] Following 30, 45, and 60 minutes, OxyContin® 80mg provided oxycodone HC1 content results which were 0.0% LC, 5.1% LC, and 6.6% LC (absolute) higher, respectively, than the present disclosure ER 80mg formulations. While the present disclosure ER 80mg releases less oxycodone HC1 when compared to OxyContin® 80mg ER, the difference at all three time points is small.

[00207] Following 30, 45, and 60 minutes, OxyContin® 80mg provided viscosity results not more than 3x that of Roxicodone® 30mg IR. Roxicodone® IR dosage form is a traditional

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018 directly compressed tablet with no abuse deterrent features. As a result, the Roxicodone® IR solution has no increased viscosity over a water only sample (~1 cSt). Following 30, 45, and 60 minutes, Opana® ER 40mg provided viscosity results relatively similar to OxyContin® 80mg with viscosities not more than 3x higher than Roxicodone® 30mg IR. Following 30, 45, and 60 minutes, present disclosure ER 80mg formulations provided an increase in viscosity of approximately 16x, 36x, and 33x, respectively, when compared to OxyContin® 80mg; approximately 17x, 25x, and 29x, respectively, when compared to Opana® ER 40mg; and 22x, 61x and 70x, respectively, when compared to Roxicodone® 30mg IR. The present disclosure 80mg dosage form of the present disclosure exhibits similar and/or reduced concentration of oxycodone HCI when compared to OxyContin® 80mg ER in small volume aqueous extraction and also provides a marked increase in viscosity over other extended release dosage forms at all three time points. The dosage forms of the present disclosure exhibit a 1.5x, 2x, 3x, 4s, 5x, lOx, 15x, 20x, 25x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, or lOOx increase in the small volume extraction viscosity as described herein over other dosage formulations that do not contain a low molecular weight matrix agents, e.g., about 50K to under 1M Daltons PEO, at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or about 60% HPMC (or equivalent), or both.

[00208] While this disclosure has been particularly shown and described with reference to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

Claims (22)

We claim:

1/22

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

1. An oral, extended release, abuse deterrent dosage formulation comprising:

(i) an active substance susceptible to abuse;

(ii) a matrix agent, wherein the matrix agent has an average molecular weight between about 5OK Daltons and IM Daltons;

(iii) a controlled release agent;

(iv) optionally, a plasticizer, a dye, or both;

wherein the active substance susceptible to abuse has an extended release profile, and wherein the formulation includes a physical barrier to reduce abuse.

2/22 στ

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

2. An oral, extended release, abuse deterrent dosage formulation comprising:

(i) an active substance susceptible to abuse; and (ii) a matrix agent, wherein the matrix agent has an average molecular weight between about 50K Daltons and 350K Daltons;

wherein the active substance susceptible to abuse has an extended release profile, and wherein the formulation includes a physical barrier to reduce abuse.

3/22

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

O

LL

3. The oral, extended release, abuse deterrent dosage formulation of claims 1 or 2, wherein the matrix agent has an average molecular weight between about 250K Daltons and 350K Daltons.

4/22 oj-c-ooooi^-comx-cocM

T“ V” T— uoqniossiQ % iours

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

4. The oral, extended release, abuse deterrent dosage formulation of claims 1 or 2, wherein the matrix agent has an average molecular weight between about 50K Daltons and 150K Daltons.

5 u- 79 75 lour ’’d^- ll σ> 92.06 ZL CN Τ- Ο cn CN 86 r— LL 33 o Γ- ΙΟ 5- CO T- X u co r— in σ> nt un NT o r- 44 LL ou h- Nt 67 r- X nJ- r- ' . CN CN CN 00 eo O O o o N- NT -3- t£> τ— co CN a o CN O T“ O) σ> CD m oo co 00 CO co in 1*4 in^- T— CO V- co CO CO CO CO r- CN uo in -27 m σ> 00 CN co CN CN iC o o o o © o © o T— r- V- 05 αΓ O) ω σ> E o co O) (Ran o T~ V (Rar CN σ>

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

5/22

2018253567 25 Oct 2018

O 05 00 S· «3 UO 't CO CN uoijniossiQ %

Hours

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

5. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the active substance is oxycodone, hydrocodone, hydromorphone, morphine, methadone, or pharmaceutically acceptable salts thereof.

WO 2015/095387

PCT/US2014/070942

6/22

2018253567 25 Oct 2018

Hours uoiiniossia %

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

6. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the active substance is present at about 5 to about 200 mg.

2018253567 25 Oct 2018

7/22

2018253567 25 Oct 2018

o ϋ □ υ o Σ Σ CL CL CL CL CL X X X X X 0^s VP 0^s SO 0^s VP 0^s 0^s o o o o CD co LO <£> CD ί ΐ 1 1 /> 1 1

O

LL

Hours uoijniossia %

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

7. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the matrix agent is selected from the group consisting of agar, alamic acid, alginic acid, carmellose, carboxymethylcellulose sodium, chitosan, copovidone, dextrin, gelatin, hydroxyethyl cellulose, hydroxypropyi cellulose, hydroxypropyi methylcellulose, methylcellulose derivatives, microcrystalline cellulose, polyacrylic acid, polyalkalene oxide, polyvinyl alcohol, povidone, propylene glycol alginate, a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, pullulan, silicon dioxide, sodium alginate, starch, and vinylpyrrolidone-vinyl acetate copolymers.

8/22

2018253567 25 Oct 2018

LL

80 Wt% 40.00% 25.00% 33.00% 2.00% xp 0^s χθ P -o P >5 09 P 4—< o o d o p in CO 00 o b- co CN N* xp P xp P* o'* xp P* as O o u*. CO in o o m LO LO CT) o CM CM CO 0% 0% 7% P ro E o ξ 20.0 o LO CN 46.6 co oo ω O) TO (0 p* Xp P P *Np P φ 30 P- o o oo CN Q 5.0 5.0 9.5 0.4 CM ”3* xp p xO o'·* P *p P O O o o o CN o o m LO d LO CN CN T“ CN LO xp xp P **p P P in 3? P o co § O LO r-' o in CN ro co LO LO co xP xp P· χθ P P o CM oo o O O o in § LO 25 55 φ c o E olido o F CD v_ o CD o CL O ......... o Dlyvinyl o Pills ient o X Φ c: o' o Φ col 8,0 CD Q. o TT Acetate / P< 200m Exci Oxycod hylene Oxi thylene Gl φ >1 >» >N C o o 0_ CL o CL

80 Wt% 40.00% 25.00% 26.40% 6.27% 0.26% 0.07% 2.00% 09 χθ P .00% .00% .67% 76% 33% 08% 17% g 30 25 32 o d N X© xp xp xP *p P 50 SS O o o o oo LO o in CN CO 00 O co η 25 ²⁵ v— CO O O o xP P* P* xp P* s? ©2 >5 -p o Ν' P O o o o CO co r~- oo oo r< CO 0.09' 33' CD E 20 25 37 d co ω ro «3 (A O Q 30 Xp P 4—» P o o .00% .67% 9.42% 40% 10% *p P CM N^- in 25 39 o d d 20 **P P 4—» .00% .00% .00% 98% 0.42% 11% xp P o in o 25 42 CT) d CM xO Xp P xp P xP P xp *p P m P O LO .00 43.17 .25 CO N o P v Ν' in r~’ 25 o d co o t— Xp P 00% .00% .33% .53% 44% 11% xP P OO n ·> LO 25 44 o r- d d n* o E_ o F cn o 000 φ Φ c Φ OOg Pills o’ TO /rrolidc Z5 CO ient ne H o Φ Φ o < relS ica col 8 ro Q_ o TT n Σ3 >> 200m O X LU Oxycod lene Oxi Polyviny 3lyvinyl f TO —J E Z3 TT co ylene Gl >> π o x: LL w Φ Cl) >> >, o o CL OL

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

8. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the matrix agent is polyethylene oxide.

9/22

2018253567 25 Oct 2018

40 Wt% 20.00% 25.00% 40.00% 15.00% p θ' p O X© o' p ©·> O O O o o co O O LO LO g in LO CN l< CM M V- X© O' sP O' xp o' p ©^ O o O o co CM O o o o g d LO LO o CM M^- CM CD Dosage(m LO Wt% 7.50% 25.00% 46.25% 21.25% X© sp sp sp 0^s o o o o § 5.0C o d 7.5 LO CM CM 'Μ^- CN X© X© o' xp o' P o'- 7.5 s’ o' LO r- co 5.00 8.13 3.13 CM CN X© X© O' x© o' p o· O' ©* o LO m m CO LO o rx Γ- LO 00 co CM CN 'M- CN ω CZ /mol olido o F Cj3 k. O 03 o CL o . o o _t/o HC o' o >> c o co CL ien Φ CZ CD ;etate / Polyt o C3 200mg Excip Oxycodo lene Oxid ylene Gly >» JZ < -CZ M—> Φ CD >> >. c o O CL lyvi CL o Q.

40 wt% 20.00% 25.00% 32.00% 7.60% 0.32% 0.08% 15.00% 30 X© o' 4—' .00% .00% .00% 08% 34% 09% .50% LO 25 34 CO o d Γ- 20 xp O' .00% .00% .00% x© © LO LO 36% 09% •sp o' o o o 25 36 00 d o o CM cn £ ω O) LO x© O' 7.50% .00% .00% 79% 37% 09% .25% re (A o O 25 37 OO o d CM x© x© P xp d* d- x© xp sP o O O O .00 .00 o' CO o 03 c· oo co d o' O o LO § LO 25 38 d 22 lo X© 0^s· 75% .00% .50% 14% 0.39% 10% sP O' co 5 co 25 38 CT) d 23 x© xp xO LO 50% O O o'- O O 26% 0.39% 10% LO l·-; CN 25 CT) CO 03 o 23 o E o F CD iOO g/i 000 Cl) Φ CZ CD 2 Pills U co S Ό Z3 co c Φ ne H o Φ Acet O u. >x rel S CD col 8 CD Q_ o u Q_ >. Z3 >> 0m ‘o X Oxycod X O CZ La ώ 0 o CM LU lene ( Polyv ilyvin dium ylene >» π o _CZ _CZ LL- CO M—· Φ CD >> >. o O 0_ (X

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

9. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the formulation contains about 15 wt% to about 40 wt% of matrix agent.

10/22

2018253567 25 Oct 2018

O *

o

LL

80 wt% 40.00% 29.00% 24.00% 7.00% xP O'*' X© o' xP O' -p o' . s5 O ro o o xZ* o o o o co o cn CO co CO CM CM p o' -p o' X© o' p o' 55 o O O o o LO •4—* o O o o LO d i-2 cn CM CN CN xP o' X© o' 55 Xp o' O' O O o o o O o o o OJ § d d CM d ε CN CN co T^- Φ cn ro « o p o' O x© o' O 0% 0% a o co O in o d p xt 2.0 CM CO CM Xp p p o' θ' o' o' O O o o o CN 0Ό 9.0 p co p LO CM co CM LO 55 -p O' xP o'- er* p o' O 0% § O in o cn o r-2 LO CO CM CO CM p χ© p 55 o' o' O O' O o' O o 5.0C o d p co 8.0 CM co CN o mol E CT> o cn o o o V) HCI o o' o o 2 8,0C ix CD CD co di o ro E Q. ’o dor Φ ;o »S0| £ o X o X Φ o o CN LU o >» o E ω X Φ o CZ o thylen CX >· X ethyle Φ >> >. o o CL 0.

40 Wt% 20.00% 29.00% 28.80% 22.20% o' Xp O' p o' -p o' o o o O o co o d p cn co d IO CM co CN xp O' -p 0^s· p o' p O' O o o O o CN 0.0 9.0 2.4 8.6 CN CO CN χθ «θ' sp o' p o' LO o5 0^s ro ro o cn £ 7.5C o d CM co co co CM d co Φ ro ro «Λ χθ Xp •X© o o' O' o' a O v- 5? § o' O o LO 9.00 4.20 1.80 CM CO CO X© x© O' -p «o' p o' 7.5 o' LO I> O co o S’ 9.0 4.6 2.6 CO CN co CO •p p x© -p 0^s o' O o' O o' o LfJ •4—· O in 9.0 v· LO 3.4 CN CM CO CO O mol £ cn o cn o o o JCO HCI 00,0 o x— 8,0C CL sipien φ co af o O) E dor Φ w _o ilyc o X o X Φ LU 20 LU o >> o E CD X Φ o o o len ί- ο. yle thy X XZ M—· Φ Φ >» o o □L CU.

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

10. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the controlled release agent is selected from the group consisting of polyvinyl acetate, polyvinylpyrrolidone, ethylcellulose, hydroxypropyi methylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and derivatives, or combinations thereof.

11/22

2018253567 25 Oct 2018 <

O

LL

ADF % >500pm 40 F 45 F 75 79 ⁷³ 95 93 85 12 Hour Average % 95.9 96.78 93.44 95.07 88.37 66.77 F 71.92 F 83.16 4 Hour Average % 66.10 F 58.96 56.23 62.67 54.17 40.42 F 44.49 61.75 1 Hour Average % 35.97 F 31.30F 29.56 F 28.83 F 24.48 19.89 23.13 32.24 F API % LO LO LO LO LO LO LO LO PEG 8000 45 35 30 20 ²⁰ 18-22 o LO OO PVAc/PVP % 50 09 50 50 09 58-62 09 55 53 PEO % o o m 25 lO 13-17 25 25 25 PEO Grade N/A V/N 100K 100K 100K 100K 100K 100K 10mg Experiment - CN eo NT in 5 (Range) co r-~ co

11. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the formulation contains about 8 wt% to about 60 wt% of controlled release agent.

WO 2015/095387

PCT/US2014/070942

12/22

2018253567 25 Oct 2018

CO

ADF % > 500pm 100 86 66 N/A V/N N/A 92 I 86 86 96 96 o^· .38 Σ3 o CD cn CO ’d^- 96.46 •rr h- LO LO V“ M V 103.7 04 56 CM X CM ro o co σ> cn 100 δ 94. 05 O v~ 90. 92. CO 05 u. Z3 e% LL LL LL LL LL LL LL in LL CD CO o cn o o 00 CO CO 05 LO 05 TT X CD o CO O CO co co Tf cn CD LO oi Q LO χ- in CM 'M· co 'M' > r- o- O- 05 r— xj- < LL LL LL 05 LL LL co Z3 O CO 05 LO 04 o cn 00 CO CD O CO o oo X CD o cn o 05 o co 05 st LO in CD CM 04 CM LO CM CD CD Ol > CD < sP o'* n LO LO LO ID LD LO LO LO LO LO in < o o o OO v- 00 LO LO LO O LO o CO to CM CD co 05 CO 1 EG 04 CO CM CM v— CM 27 CL o'- o Ol 05 o O o o LO o LO cd o Mh O o o- CO o T” V CM co CM co Mh 00 U) CD co m co CO □_ X a? o co o σ o o CD 05 05 co cn cn 05 co CD r— OO CD CD O- CM CM r*. CM CM CM |χ- LLl Ol CM CL Φ Ό 2 isC 5T 5T X :£ O o o <r> CO CO CO co o CD CD o o o co o o o co o o o © o co co co t— t— co co co co co LU CL , . ,- ___ c ω ω CD E ω σι 05 E co Tj- LO CD r- 00 05 o c CD CM co c CD σ CD ·*— *- *- τ^- 04 rr CM CM Ol rr V Q_ X o CO LU Ol CM

93 [ 95 93 lour .66 LO OO CD X CM LO CO CM 05 05 LL X X Σ3 0 0C5 05 o X CO CO co CO o CM CD LO X X X o CM co o X o CM co 05 A r— CM σ o O xj- 'M^- co o CO LO co CM co CM 05 05 05 CM CM CM ic CO CD o o σ o co co CO cn E ID CD cd CM CM CM OO

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

12. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the formulation contains about 29 wt% to about 60 wt% of a combination of polyvinyl acetate and polyvinylpyrrolidone as the controlled release agent.

2018253567 25 Oct 2018

13/22

FIG. 12

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

13. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the formulation contains about 15 wt % to about 45 wt % hydroxypropyl methylcellulose as the controlled release agent.

14/22

FIG. 13

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

INCORPORATED BY REFERENCE (RULE 20.6)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

14. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the plasticizer is selected from the group consisting of polyalkalene glycol, acetyltributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, propylene glycol, pullulan, sorbitol sorbitan solution, triacetin, tributyl citrate and triethyl citrate.

15. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the plasticizer is polyethylene glycol.

16/22

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

16. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the plasticizer is polyethylene glycol having an average molecular weight of less than about 1 OK Daltons.

17/22 <

co

LL

OxyContin ® 80mg 46 49 π 46 53 LO in 00 *4· 00 d^- 1* in 53 oo ^4- r- LO © c S3 O) <D £= P co to co 'M- to co to CM co CM co co xyCo 60r XT xfr xt LO M- LO M· co o © tin g TT = s= r^- CM o co co CD co CM CO xyCo 40r CO LO 'M -4- -M- 'M- m- CO 4* 4 co LO -xT CD O © tin g CM = P cd CO CM CM co co o v~ co CD m m LO χφ sT -m- 'M^- 4 4· m -M CM V~ S' Φ o O ro zor BI ame © ? m c oo o CO K- OO CD CM m LO oo CM v— 6.6 ro ₇ Opai ER4I CM co CM co CM M CO CM V 'M^- CO 0£ φ pie I v— T— V“* v~ T“· E o to LU to p ® TO ’’R 52 E CO LO co CD CO v— TO l·- co co IO r- □ Opar ER5 co CO co CO CO CM CM V— co CM LO υ v- V UJ S3) co p o CO co co o CO X— to TO co CO h- h- PMR 80i TO oo co oo r- TO O 00 oo 00 h- to oo in Q£ LU oj CO P r^- CD LO IO co o TO CM T— LO to >- PMR 10i r- r- OO co OO oo co r- 00 00 co OO I''· Φ «w E E Φ CO — o CD Q Replic CM CO TJ* LO CO co to O Minim Maxim 2 1 %RS

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

17. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the formulation contains about 0 wt% to about 40 wt% of plasticizer.

18/22

Cutting Force - Fracture Wedge Set | Sample Name OxyContin ® 80mg 97 I 97 99 I 96 v— σ> 97 I I 06 CM OT OT I 86 I 06 | 66 IO OT 3.4 OxyContin ® 60mg CO o V” CO o v~ 104 102 111 o o o τ— 104 102 ’d o 100 V o 5— 3.2 OxyContin ® 40mg CM σο 94 85 92 86 92 o o T“” 95 93 τ- ο 85 100 93 4.4 OxyContin ® 10 mg 144 153 156 157 160 m m v-* o XT 148 CM τ— h- CN v— 160 149 6.6 Opana® ER 40mg 132 CM τ— 143 138 142 137 143 144 150 3- 132 o LO T“ 'M' 3.5 Opana® ER 5mg 156 156 155 145 S in CO in V^- 158 163 158 145 co co τ— 156 3.3 PMRS ER 80mg ¹²⁷ T-· 108 124 CM v— o CO CM τ— oo s— 108 108 r*. CN LO 5.7 PMRS ER 10mg o 109 Π m T“* v~ o τ— O v— 105 o 96 o 92 92 un 105 6.7 Replicate - CN CO in CO 00 OT o Minimum Maximum Average %RSD

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

18. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the formulation further comprises at least one preservative or antioxidant

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018 selected from the group consisting of silica, sodium laurel sulfate, citric acid, butylated hydroxytoluene (BHT), ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), 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.

19/22 <

o ll

OxyContin ® 80mg 25.919 24.828 23.150 23.150 I 25.919 24.632 5.662 | 74.081 J 75.172 76.850 74.081 76.850 | 75.368 in co T— © c U 07 co CO IO IO CO OO CO -Μ^- r^> in Xt m CN £ £ co oo co co o> o· co CM V“ CO V o o >£ o § co 00 r- r-’ I** co V“ T— O> © 8.3 00 2.2 co 00 CN CN 00 © CM CO £ CM t— CN V V h- oo co h. 00 00 CN o © c 00 CO o 00 O o 00 CN r- o © CN © '<*> o> co Νφ NT h- CU co co co 00 co Xt* OxyCor 40m σ> σ> co CO σ> CO 6.3 6.5 8.0 6.0 6.8 6.8 © 00 to cd 't K“ CN V CN V* CO CO CO 00 00 © o 01 © CN c 2 ro .c '•P O) in IO W in 00 IO co in in 00 in O z b- r- 00 h- oo to CN o x— CN o T— V™ § ε o σ> xt σ> o T“ OI o io σ> o 00 CO x Φ 1° co o> co σ> co cd cd co T“ td cd cd CO s Q. CM cd co CN IO 07 oo r~ 07 oo 07 o Sarr o u z © S’ x— Xj o O oo re E 07 CD o o at CN in CN CN co CN 00 © CO Di c o r^- r*- CN CN h- O> r- IO CD CD IO co co 00 O 1 ω re't co CO CO xf* CO co CO cd co cd cd cd © M |jj cd cd CO cd cd cd CN 07 07 07 07 07 07 o k © co -1.728 -1.728 xfr CO co CM CO O O to 28 m ro 5 Φ re p ^f· o in CO 00 O 00 r~ o o Opan ER 5i 8.61 o o o 8.61 2.29 r· Tf CM V O X~ 91.3 100. 91.3 © 97.7 5.67 N at LU o) W CO r*- IO D) in f'- o Φ CO LO T~ co IO o co T— r~- 07 Γ-- co CN CO £ rz o OO CM o co CM r- co h- XT IO xt h- 07 1^· υ CM IO ’Xt CN m o id CN co CN O CN T- 07 Έ ro Q. 8 ilAld l·-' cd r< cd oo v~ 07 07 07 07 07 07 DC in to oo Xt O V” O v— LU α» CD co o co co b- CD h- 07 LC7 CM <O £ fY* <—* co xl· CD in -5.9' co XT .54 00 V 4.8 4.5 05. 4.5 05. '’fr od co iq PMI 11 in LO IO T“ xt CD 07 07 v- © cd o E E Φ E E Φ =3 Σ3 CD Q =3 CD Q 8 Q. Φ QC CM co Minim Maxim Avera (X) 0Ϊ o'*· CN CO Minim Maxim Avera %RS •^O 0^s ation st fe ϋ η o -o O o lqo _i to COLO v_ At

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

19. The oral, extended release, abuse deterrent dosage form of any of the preceding claims, wherein the dye comprises one or more FD&C dyes.

20/22 co hv—

O

LL

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SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

20. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the extended release profile of the active substance passes the criteria for the USP monograph or passes the criteria for the matching reference listed drug for extended release active substance.

21/22 o

o

CM

O

PMRS ER OxyContin® Opana® ER OxyContin® PMRS ER OxyContin’ 10mg 10mg 40mg 40mg 80mg 80mg

FIG. 18 ooooooooooo ocnoor-coLO'tcocMTLuiiQOS < sepiped %

SUBSTITUTE SHEET (RULE 26)

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

21. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claimsl, wherein the physical barrier is the formulation has at least 50 wt% of particles with a particle size greater than 0.5 mm following physical or mechanical manipulation of the formulation.

22. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the physical barrier is the formulations has at least a 2x increase in small volume extraction viscosity compared to similar dosage formulations.

23. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the purity of the drug following alcohol extraction is < 40%.

WO 2015/095387

PCT/US2014/070942

24. A directly-formed oral, extended release, abuse deterrent dosage form comprising an active substance susceptible to abuse, a matrix agent, a controlled release agent, a plasticizer, and a dye wherein the dosage form is directly formed from an extrusion process having a forming unit.

2018253567 25 Oct 2018

25. The directly-formed oral, extended release, abuse deterrent dosage formulation of claim 24, wherein the forming unit is a calendar, a rotary, or chain forming machine.

26. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims formed using a tablet press and cured using preceding, simultaneous, or subsequent heat.

27. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims formed using a hot melt extrusion process and a forming unit.

28. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein (i) the active substance is oxycodone present at about 5 to about 40 wt%;

(ii) the matrix agent is polyethylene oxide having an average molecular weight of about 50K to about 150K Daltons and present between about 8 wt% and 80 wt%;

(iii) the controlled release agent contains polyvinyl acetate, polyvinylpyrrolidone, or a combination thereof, and present between about 8 wt% and 60 wt%; and (iv) the plasticizer is polyethylene glycol having an average molecular weight of about 8K Daltons and present between about 0 wt% and 30 wt%, wherein the extended release profile of the active substance passes the criteria for the matching reference listed drug for extended release oxycodone; and wherein the formulation has at least 50 wt% of participles sized greater than 0.5 mm following physical or mechanical manipulation of the formulation.

WO 2015/095387

PCT/US2014/070942

29. The oral, extended release, abuse deterrent dosage formulation of claim 28, wherein the matrix agent is present between about 15 wt% and 30 wt%;

the controlled release agent is present between about 20 wt% and 60 wt%; and the plasticizer is present between about 2 wt% and 20 wt%.

2018253567 25 Oct 2018

30. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein the matrix agent is present between about 23 wt% and 27 wt%;

the controlled release agent is present between about 30 wt% and 55 wt%; and the plasticizer is present between about 2 wt% and 15 wt%.

31. The oral, extended release, abuse deterrent dosage formulation of any of the preceding claims, wherein (i) the active substance is oxycodone, hydrocodone, hydromorphone, morphine or methadone, and is present at about 5 wt% to about 40 wt%;

(ii) the matrix agent is polyethylene oxide having an average molecular weight of about 50K Daltons to about 350K Daltons and present between about 8 wt% and 80 wt%;

(iii) the controlled release agent is hydroxypropyl methylcellulose present at about 10 wt% to about 50 wt%; and (iv) the plasticizer is polyethylene glycol having an average molecular weight of about 8K Daltons and present between about 0 wt% and 40 wt%, wherein the extended release profile of the active substance passes the criteria for extended release oxycodone hydrochloride USP monograph or matching reference listed drug for extended release oxycodone; and wherein the formulation has at least 50 wt% of particles sized greater than 0.5 mm following physical or mechanical manipulation of the formulation.

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

32. The oral, extended release, abuse deterrent dosage formulation of claim 31, wherein the matrix agent is present between about 20 wt% and 35 wt%;

the controlled release agent is present between about 15 wt% and 45 wt%; and the plasticizer is present between about 5 wt% and 40 wt%.

33. The oral, extended release, abuse deterrent dosage formulation of claim 31, wherein the matrix agent is present between about 25 wt% and 30 wt%;

the controlled release agent is present between about 20 wt% and 40 wt%; and the plasticizer is present between about 10 wt% and 35 wt%.

WO 2015/095387

PCT/US2014/070942

2018253567 25 Oct 2018

22/22

Ajund %

FIG. 19

SUBSTITUTE SHEET (RULE 26)