WO2017192608A1

WO2017192608A1 - Immediate release drug formulation combining opioid and nonopioid analgesics with abuse deterrence and overdose protection

Info

Publication number: WO2017192608A1
Application number: PCT/US2017/030667
Authority: WO
Inventors: Siva Ram Kiran VAKA; Kanji Meghpara; Dipen Desai; Wantanee Phuapradit; Navnit H. Shah; Atsawin THONGSUKMAK
Original assignee: Kashiv Pharma LLC
Current assignee: Kashiv Biosciences LLC
Priority date: 2016-05-03
Filing date: 2017-05-02
Publication date: 2017-11-09
Anticipated expiration: 2018-11-03

Abstract

The present disclosure provides solid immediate release (IR) dosage forms, including particulate and multi-particulate dosage forms, with abuse deterrent and overdose protection characteristics. In certain embodiments, the dosage form is multi¬ particulate, comprising: a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix, an optional seal coat, a functional coat layer(s), and an over coat, wherein the functional coat layer(s) comprises a nonionic water-insoluble polymer, and a cationic polymer that dissolves at a pH of less than about 5; a second population of particulates comprising a therapeutically effective amount of acetaminophen (APAP) embedded in a polymer matrix, an optional seal coat, a functional coat layer(s), and an over coat, wherein the functional coat layer(s) comprises a cationic polymer that dissolves at a pH of less than about 5 and an optional nonionic water-insoluble polymer; and a third population of particulates comprising an alkaline agent, and an optional pH-stabilizing agent, wherein the alkaline agent raises the gastric pH when three or more dosage units are ingested, and the pH-stabilizing agent maintains the elevated pH. The dosage forms, including particulate and multi-particulate dosage forms, are designed to accomplish the desired combination of analgesia, abuse deterrence, and overdose protection.

Description

IMMEDIATE RELEASE DRUG FORMULATION COMBINING OPIOID AND NONOPIOID ANALGESICS WITH ABUSE DETERRENCE AND OVERDOSE PROTECTION

This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/331,311, filed May 3, 2016, the disclosure of which is incorporated by reference herein in its entirety.

1. FIELD OF THE INVENTION

The present disclosure relates to tamper and/or overdose resistant immediate release ("IR") pharmaceutical dosage forms having both opioid and nonopioid analgesics, and processes of manufacture related to same.

2. BACKGROUND

Governmental reports state that prescription drug abuse is the fastest growing drug problem in the United States, and a survey indicated that nearly one-third of people age twelve and above who used drugs illicitly for the first time in 2009 began with the nonmedical use of a prescription drug. For example, prescription opioid analgesics can be abused by: swallowing whole in excessive quantities (e.g., multi-tablet dosing); crushing and swallowing; crushing and inhaling nasally ("snorting"); crushing and smoking; or crushing, dissolving, and injecting the prescription drug.

Abuse can involve some physical manipulation of a dosage form so that larger amounts of immediately available drugs can be taken orally, nasally, or by intravenous injection. Reports of overdosing and death from prescription pain products rose sharply in the early 2000s ("Death from Prescription Opioid Overdose" Prescription Drug Overdose Data; Centers for Disease Control and Prevention;

www.cdc.gov/drugoverdose/data/overdose.html; retrieved 02 MAR 2016).

The U.S. Food and Drug Administration (FDA) describes the science of abuse deterrence as relatively new and rapidly evolving. In April 2015, the FDA published a draft guidance document for the evaluation and labeling of abuse-deterrent opioid products. Categories of abuse-deterrent formulations were described as: 1. Physical barriers to prevent chewing, crushing, cutting, grating or grinding, and chemical barriers to resist extraction of the active ingredient with common solvents such as water, alcohol, and organic liquids;

2. Agonist/antagonist combinations that interfere with, reduce, or defeat the euphoria associated with abuse;

3. Aversion, by incorporating a substance that produces an unpleasant effect when the dosage form is altered before ingestion, or is ingested in a high dose;

4. Delivery systems that provide abuse resistance through release characteristic design or a mode of administration; 5. New molecular entities and prodrugs that lack opioid activity until acted upon in the gastrointestinal system;

6. Combinations of two or more of the foregoing; and

7. Novel approaches not captured by the other categories.

In March 2016, the FDA published a guidance document describing general procedures for developing and evaluating abuse deterrence of generic solid oral opioid products formulated to incorporate physical or chemical barriers,

agonists/antagonists, aversive agents, or combinations of these technologies. The FDA recommends the following evaluations, involving all potential routes of abuse, of the abuse deterrence of generic solid oral opioid drug products:

1. Injection (parenteral route) - evaluate the extractability and syringeability of intact and mechanically manipulated products.

2. Ingestion (oral route) - evaluate extractability, dissolution, and where applicable, the rate and extent of a product's absorption for intact and mechanically or chemically manipulated products. 3. Insufflation (nasal route) - evaluate nasal availability and likability of mechanically manipulated and insufflated products.

4. Smoking (inhalation route) - evaluate the ability to sublimate intact and mechanically or chemically manipulated products. Researchers have combined various classes of analgesics to provide better pain relief to patients, such as combining an opioid analgesic with a nonopioid analgesic. For example, a combination of oxycodone hydrochloride and acetaminophen (APAP) is commercially available as PERCOCET^®; and a combination of hydrocodone bitartrate and APAP is available as VICODIN^®. In addition, in various countries, codeine has been formulated in combination with different nonopioid analgesics, including APAP, aspirin, and ibuprofen. Other combination products, such as tramadol with APAP, are known in the art.

In randomized controlled trials, the combination product oxycodone / acetaminophen at low dosages for the treatment of chronic pain in rheumatoid arthritis ("RA") patients was proven to be a good alternative to nonsteroidal anti-inflammatory drugs (NSAIDs), allowing the reduction of their consumption, while keeping RA therapy stable (Raffaeli et al. (2010) "Oxycodone/acetaminophen at low dosage: an alternative pain treatment for patients with rheumatoid arthritis" J. OpioidManag. 6(l):40-46). PERCOCET^® was statistically superior to immediate release ("IR") oxycodone hydrochloride in various outcome measures of pain relief (U.S. Patent No. 8,658,631).

It is postulated that the combination of two analgesic drugs with complementary mechanisms of action results in enhanced analgesia due to an additive effect, an "opioid-sparing" effect, and improved side effect and safety profiles (U.S. Patent No. 8,658,631). The improved safety profile results from the administration of reduced doses of each of two analgesics with different side effects, rather than administration of an equieffective dose of a single agent.

As noted in the April 2015 FDA Guidance, abuse-deterrent technologies have not yet proven successful at deterring the most common form of abuse: swallowing a number of intact capsules or tablets (e.g., multi -tablet dosing).

Therefore, a need remains for improved formulations of opioids, including opioid / APAP combinations, that make it difficult— if not impossible— for individuals to abuse or misuse opioids, not only by snorting and/or extraction of drug but also by ingesting multiple doses. In particular, new formulations are needed that can be used for IR pharmaceutical products containing such combinations. The need for improved formulations includes avoiding the toxicities associated with all forms of multi-tablet overdose, whether intentional or unintentional (e.g., accidental / inadvertent misuse by patients or caregivers). Such formulations should combine overdose protection (ODP) and abuse deterrence in a single dosage form, and thereby address multiple health-related concerns, especially because these combinations include APAP as well as habit-forming opioid compounds for which there is a high propensity for abuse and overdose. These combination dosage forms must also allow both pharmaceutical ingredients (e.g., opioid and nonopioid (e.g., APAP) ingredients) to be soluble in the gastrointestinal tract and have the desired pharmacological activities when ingested as instructed, while providing abuse deterrence and overdose protection of opioids. In the case of opioid / APAP combinations, the pharmacological activities are related to analgesic effects.

3. SUMMARY OF THE INVENTION

In certain embodiments, the disclosure provides abuse-deterrent and/or overdose-resistant IR pharmaceutical particulate dosage forms (pharmaceutical composition) containing at least one population of particulates. In certain embodiments, the particulate dosage form can comprise an intragranular component comprising one population of particulates containing at least one opioid and at least one nonopioid analgesic, e.g., Active Particulates (containing opioid and nonopioid analgesics in a matrix), and an extragranular component comprising an alkaline agent and, optionally, a pH-stabilizing agent.

In certain embodiments, the disclosure provides abuse-deterrent and/or overdose-resistant IR pharmaceutical multi-particulate dosage forms (pharmaceutical compositions) containing at least two different populations of particulates. For example, the multi-particulate dosage form can comprise: (1) opioid and nonopioid analgesic- containing Active Particulates and (2) Triggering Particulates comprising an alkaline agent and, optionally, a pH-stabilizing agent. The multi-particulate dosage form can be in the form of a capsule, a tablet, or any other dosage form as disclosed herein.

In certain embodiments, the multi-particulate dosage forms of the disclosure contain at least three different populations of particulates. For example, the multi-particulate dosage form can comprise: (1) opioid-containing "Opioid Particulates," (2) nonopioid analgesic-containing "APAP Particulates," and (3) Triggering Particulates comprising an alkaline agent and, optionally, a pH-stabilizing agent. The multiparticulate dosage form can be in the form of a capsule, a tablet, or any other dosage form as disclosed herein.

In certain embodiments, the disclosure provides abuse-deterrent and/or overdose-resistant IR pharmaceutical tablet dosage forms (pharmaceutical compositions) comprising an intragranular component and an extragranular component. The intragranular component (or separate intragranular components) comprises at least one opioid and at least one nonopioid analgesic, and the extragranular component comprises at least one alkaline agent and, optionally, at least one pH-stabilizing agent, e.g., an envelope or a coating of an alkaline agent and, optionally, a pH-stabilizing agent.

In certain embodiments, the disclosure provides abuse-deterrent and/or overdose-resistant IR pharmaceutical tablet, capsule or other dosage forms comprising APAP Particulates, crush-resistant Opioid Particulates, and Triggering Particulates, the latter comprising an alkaline agent and, optionally, a pH-stabilizing agent.

In certain embodiments, the disclosure provides abuse-deterrent and/or overdose-resistant IR pharmaceutical tablet, capsule or other dosage forms comprising crush-resistant particulates comprising at least one opioid (Opioid Particulates), and particulates comprising at least one nonopioid analgesic (e.g., APAP, ibuprofen) (APAP Particulates); the particulates are partially, substantially, or completely surrounded by an envelope/coating of an alkaline agent and, optionally, a pH-stabilizing agent.

In certain embodiments, the disclosure provides abuse-deterrent and/or overdose-resistant IR pharmaceutical tablet, capsule or other dosage forms comprising crush-resistant particulates comprising at least one opioid and at least one nonopioid analgesic (Active Particulates); the particulates are partially, substantially, or completely surrounded by an envelope/coating of an alkaline agent and, optionally, a pH-stabilizing agent.

In certain embodiments, the disclosure provides a solid, oral, immediate release, multi-particulate combination dosage form with abuse deterrent and overdose protection characteristics comprising: a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix; an optional seal coat; a functional coat comprising at least one of functional coat layers FC 0, FC 1, and FC 2; and an over coat; where the first population seal coat comprises a nonionic water- soluble polymer; the at least one of FC 0, FC 1, and FC 2 comprises a cationic polymer that dissolves at a pH of less than about 5 and an optional nonionic water-insoluble polymer; and the first population over coat comprises a nonionic water-soluble polymer; a second population of particulates comprising a therapeutically effective amount of acetaminophen (APAP) embedded in a polymer matrix; an optional seal coat; a functional coat comprising at least one of functional coat layers APAP FC 0, APAP FC 1, and APAP FC 2; and an over coat; the second population seal coat comprises a nonionic water-soluble polymer; where the at least one of APAP FC 0, APAP FC 1, and APAP FC 2 comprises a cationic polymer that dissolves at a pH of less than about 5 and an optional nonionic water-insoluble polymer; and where the second population over coat comprises a nonionic water-soluble polymer; and a third population of particulates comprising an alkaline agent and an optional pH-stabilizing agent; where the alkaline agent elevates gastric pH to a value greater than 5 when three or more dosage units are ingested; and where the pH-stabilizing agent maintains an elevated pH above 5.

In certain embodiments, FC 1 and/or APAP-FC 1 comprise a rate-controlling nonionic water-insoluble polymer and a cationic polymer that acts as a pore former at a pH of less than about 5.

In other embodiments, the wt% ratio of the nonionic polymer to the cationic polymer is in the range of from about 50:50 to about 98:2. In certain embodiments, the wt% ratio of the nonionic polymer to the cationic polymer is about 60:40. In certain embodiments, the wt% ratio of the nonionic polymer to the cationic polymer is about 80:20.

In certain embodiments, the nonionic polymer present in FC 0, FC 1, FC 2, APAP FC 0, APAP FC 1, and/or APAP FC 2 is selected from the group consisting of cellulose acetate, cellulose acetate-based polymers, ethylcellulose, and polyvinyl acetate polymers. In other embodiments, the nonionic polymer is cellulose acetate.

In certain embodiments, the cationic polymer present in FC 0, FC 1, FC 2, APAP

FC 0, APAP FC 1, and/or APAP FC 2 is a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

In certain embodiments, the polymer matrix of the first population of particulates and the polymer matrix of the second population of particulates comprise a nonionic polymer, an anionic polymer, and/or a cationic polymer.

In certain embodiments, the cationic polymer is a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

In other embodiments, the polymer matrix of the first population of particulates comprises a nonionic polymer. In certain embodiments, the nonionic polymer is selected from the group consisting of a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups (ammonium methacrylate copolymer), hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, ethylcellulose, cellulose acetate butyrate, cellulose acetate, polyvinyl acetate polymers, polyethylene oxide polymers, and mixtures thereof. In certain embodiments, the nonionic polymer is a mixture of a polyethylene oxide polymer and hydroxypropyl methylcellulose.

In certain embodiments, the polymer matrix of the second population of particulates comprises a cationic polymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

In some embodiments, the nonionic polymer in the over coat of the first population of particulates and in the over coat of the second population of particulates is hydroxypropyl methylcellulose.

In certain embodiments, FC 0, FC 2 APAP FC 0, and/or APAP FC 2 comprise a cationic polymer that acts as a pore former at a pH of less than about 5.

In certain embodiments, the alkaline agent present in the third population of particulates is selected from the group consisting of aluminum hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium carbonate , sodium carbonate, potassium bicarbonate, sodium bicarbonate, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine, L- lysine, and combinations thereof. In certain embodiments, the alkaline agent is magnesium hydroxide.

In certain embodiments, the pH-stabilizing agent is present and is dibasic calcium phosphate.

In certain embodiments, the polymer matrix of the first population of particulates and the polymer matrix of the second population of particulates further comprise an antioxidant, a plasticizer, and/or a surfactant.

In certain embodiments, the opioid is selected from the group consisting of oxycodone, oxymorphone, hydromorphone, hydrocodone, buprenorphine, codeine, phenazocine, tilidine, tramadol, meperidine, sufentanil, prodine, methadone,

pentazoxine, tapentadol, morphine, fentanyl, and pharmaceutically acceptable salts thereof. In other embodiments, the opioid is selected from the group consisting of oxycodone, oxymorphone, hydromorphone, hydrocodone, and pharmaceutically acceptable salts thereof.

In certain embodiments, the disclosure provides a dosage form further comprising a fourth population of particulates comprising a viscosity-building polymer comprising a nonionic polymer and/ or an anionic polymer. In some embodiments, the nonionic polymer is a polyethylene oxide polymer. In other embodiments, the anionic polymer is a carbomer. In certain embodiments, abuse deterrent characteristics comprise syringeability resistance, extractability resistance in aqueous and/or hydro-organic solvents, and heat stability of the dosage form, where the heat stability comprises maintaining the abuse deterrent characteristics of the dosage form after the exposure to heat. In other embodiments, the abuse deterrent characteristics of the dosage form comprise resistance to crushability and resistance to grindability of the first population of particulates.

The present disclosure also provides methods of preparing a solid, oral, immediate release, multi-particulate dosage form with abuse deterrent and overdose protection characteristics, comprising: preparing a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix; an optional seal coat; a functional coat comprising at least one functional coat layers FC 0, FC 1, and FC 2; and an over coat; where the first population seal coat comprises a nonionic water-soluble polymer; where the at least one of FC 0, FC 1, and FC 2 comprises a cationic polymer that dissolves at a pH of less than about 5 and an optional nonionic water-insoluble polymer; and where the first population over coat comprises a nonionic water-soluble polymer; preparing a second population of particulates comprising a therapeutically effective amount of APAP embedded in a polymer matrix; an optional seal coat; a functional coat comprising at least one of functional coat layers APAP FC 0, APAP FC 1, and APAP FC 2; and an over coat; where the second population seal coat comprises a nonionic water-soluble polymer; where the at least one of APAP FC 0, APAP FC 1, and APAP FC 2 comprises a cationic polymer that dissolves at a pH of less than about 5 and an optional nonionic water- insoluble polymer; and where the second population over coat comprises a nonionic water-soluble polymer; preparing a third population of particulates comprising an alkaline agent and an optional pH-stabilizing agent; where the alkaline agent elevates gastric pH to a value greater than 5 when three or more dosage units are ingested; and where the pH-stabilizing agent maintains an elevated pH above 5; and combining the first, second, and third populations of particulates into a tablet, tablet-in-tablet, multilayered tablet, or a capsule.

In certain embodiments, the disclosure provides a solid, oral, immediate release, multi-particulate combination dosage form with abuse deterrent and overdose protection characteristics comprising: a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix; an optional seal coat; a functional coat comprising at least one of functional coat layers FC 0, FC 1, and FC 2; and an over coat; where the first population seal coat comprises a nonionic water- soluble polymer; where the at least one of FC 0, FC 1, and FC 2 comprises a cationic polymer that dissolves at a pH of less than about 5 and an optional nonionic water- insoluble polymer; and where the first population over coat comprises a nonionic water- soluble polymer; a second population of particulates comprising a therapeutically effective amount of APAP embedded in a polymer matrix; and an optional seal coat; where the second population seal coat comprises a nonionic water-soluble polymer; and a third population of particulates comprising an alkaline agent and an optional pH- stabilizing agent; where the alkaline agent elevates gastric pH to a value greater than 5 when three or more dosage units are ingested; and where the pH-stabilizing agent maintains an elevated pH above 5.

In certain embodiments, the disclosure provides a solid, oral, immediate release, multi-particulate combination dosage form with abuse deterrent and overdose protection characteristics comprising: a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix; an optional seal coat; a functional coat comprising at least one of functional coat layers FC 0, FC 1, and FC 2; and an over coat; where the first population seal coat comprises a nonionic water- soluble polymer; where the at least one of FC 0, FC 1, and FC 2 comprises a cationic polymer that dissolves at a pH of less than about 5 and an optional nonionic water- insoluble polymer; and where the first population over coat comprises a nonionic water- soluble polymer; a second population of particulates comprising an alkaline agent and an optional pH-stabilizing agent; where the alkaline agent elevates gastric pH to a value greater than 5 when three or more dosage units are ingested; and where the pH- stabilizing agent maintains an elevated pH above 5; and a therapeutically effective amount of APAP.

In certain embodiments, the disclosure provides a solid, oral, immediate release, multi-particulate tablet dosage form comprising Opioid Particulates coated with an optional seal coat, a functional coat layer(s), and an over coat; uncoated APAP

Particulates; and Triggering Particulates.

In certain embodiments, the disclosure provides a solid, oral, immediate release, multi-particulate tablet dosage form comprising Opioid Particulates coated with an optional seal coat, a functional coat layer(s), and an over coat; APAP Particulates coated with an optional seal coat; and Triggering Particulates. In certain embodiments, the disclosure provides a solid, oral, immediate release, multi -particulate tablet dosage form comprising Opioid Particulates coated with an optional seal coat, a functional coat layer(s), and an over coat; APAP Particulates; and Triggering Particulates.

In certain embodiments, the disclosure provides a solid, oral, immediate release, multi-particulate bilayer tablet dosage form comprising a first layer comprising Opioid Particulates coated with an optional seal coat, a functional coat layer(s), and an over coat, and APAP Particulates coated with an optional seal coat, a functional coat layer(s), and an over coat; and a second layer comprising Triggering Particulates.

4. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts a schematic representation of an Opioid Particulate (e.g., an Opioid Granule) according to certain embodiments.

Figure 2 shows the dissolution profiles of hydrocodone bitartrate from hydrocodone bitartrate / APAP tablets (Eq 10 mg/325 mg tablets from Example 24; one, three, and six dosage units), in a two-stage dissolution method: the first stage is in pH 1.6 for 30 minutes, followed by a second stage in pH 6.8 for 120 minutes(Example 25).

5. DETAILED DESCRIPTION

There remains a need for improved IR dosage forms that make it difficult, if not impossible, for individuals to suffer the harmful, including fatal, sequelae of taking the dosage form in a manner other than intended by the manufacturer (for example, deliberate or inadvertent multi-tablet dosing). In certain embodiments, the present disclosure provides improved solid oral IR pharmaceutical particulate dosage forms comprising at least one population of particulates containing (1) an opioid, and (2) acetaminophen (APAP) and/or another nonopioid analgesic, and also comprising an alkaline agent and, optionally, a pH-stabilizing agent. In certain embodiments, the alkaline agent and, optionally, the pH-stabilizing agent can be contained within the particulates, or can be surrounding the particulates, of the population, or can be separate from the particulates in the dosage form. In certain embodiments, the present disclosure provides improved solid oral IR pharmaceutical multi-particulate dosage forms comprising at least two populations of particulates: (1) Opioid / APAP particulates, containing an opioid and APAP or another nonopioid analgesic; and (2) Triggering Particulates containing an alkaline agent and, optionally, a pH stabilizing agent. In certain embodiments, the multi-particulate dosage form contains at least three populations of particulates: (1) Opioid Particulates, containing an opioid; (2) APAP Particulates, containing APAP or another nonopioid analgesic; and (3) Triggering Particulates containing an alkaline agent and, optionally, a pH stabilizing agent. In certain embodiments, the IR pharmaceutical multi-particulate dosage forms of the disclosure contain at least four, at least five, at least six, at least seven, or at least eight different populations of particulates. Each population of particulates is designed for a specific function to accomplish the desired combination of analgesia, abuse deterrence, and overdose protection.

In certain embodiments, the IR pharmaceutical dosage forms contain an Opioid Particulate population (i.e., Opioid Granules and/or Opioid Pellets), which is a crush-resistant particulate population containing an opioid drug and at least one functional coat layer (e.g., FC 1) that only permits an immediate release of the opioid in an aqueous (or nonaqueous) environment with a pH of up to 5; this feature provides overdose protection (ODP), as described herein. In certain embodiments, the Opioid Particulates can further include a seal coat between the core (e.g., the polymer matrix of an Opioid Granule) and the functional coat layer(s). In certain embodiments, the Opioid Particulates can include an additional functional coat layer (referred to as FC 0) between the seal coat (or the core) and FC 1. In certain embodiments, the Opioid Particulates can include an additional functional coat (referred to as FC 2) on top of FC 1. In certain embodiments, FC 0 and FC 2 can further enhance the ODP features of the Opioid Particulates in the event of an overdose (e.g., the dosage form taken in doses above those prescribed or in a manner inconsistent with the manufacturer's instructions, e.g., three or more dosage units; more than two dosage units). In certain embodiments, FC 0 and FC 2 assist FC 1 in preventing or slowing release of the opioid from the Opioid Particulate in an aqueous (or nonaqueous) environment with a pH above 5. In certain embodiments, the Opioid Particulates can further include an over coat to maintain the controlled release of the opioid. In certain embodiments, the over coat prevents / reduces the interaction of EUDRAGIT^® E PO present in the functional coat(s) (e.g., FC 1) with, e.g., the alkaline agent(s) present in the dosage form (e.g., in the Triggering Particulates of the dosage form) to maintain the integrity of the functional coat for the controlled release of opioid.

In certain embodiments, APAP Particulates comprise one or more functional coats (e.g., APAP-FC 0; APAP-FC 1; and APAP-FC 2) In certain embodiments, APAP Particulates comprise a seal coat between the core (e.g., a polymer matrix containing APAP and EUDRAGIT E^® PO) and at least one functional coat (e.g., APAP-FC 1), the latter only allowing an immediate release of the acetaminophen (APAP) and/or another nonopioid analgesic in an aqueous (or nonaqueous) environment with a pH of up to 5, providing overdose protection (ODP). In certain embodiments, APAP-FC 1 comprises a cationic polymer (e.g., EUDRAGIT E^® PO). In certain embodiments, APAP-FC 1 comprises a nonionic polymer (e.g., cellulose acetate) and EUDRAGIT® E PO at a ratio of cellulose acetate : EUDRAGIT E^® PO between 20:80 and 70:30. In certain embodiments, APAP-FC 1 comprises cellulose acetate and

EUDRAGIT® E PO at a ratio of cellulose acetate : EUDRAGIT E^® PO between 1 : 99 and 99: 1. In certain embodiments, APAP Particulates can include an additional functional coat (referred to as APAP-FC 0) between the seal coat (or the core) and APAP-FC 1. In certain embodiments, APAP Particulates can include an additional functional coat (referred to as APAP-FC 2) on top of APAP-FC 1. In certain

embodiments, APAP-FC 0 and APAP-FC 2 can further enhance the ODP features of the APAP Particulates in the event of an overdose (e.g., three or more dosage units). In certain embodiments, APAP-FC 0 and/or APAP-FC 2 assist APAP-FC 1 in preventing or slowing release of the nonopioid analgesic, e.g., APAP, from the APAP Particulate in an aqueous (or nonaqueous) environment with a pH above 5. In certain embodiments, the APAP Particulates can further include an over coat to maintain the controlled release of APAP. In certain embodiments, the over coat prevents / reduces the interaction of EUDRAGIT^® E PO present in the functional coat(s) (e.g., at least one of APAP-FC 0, APAP-FC 1, and APAP-FC 2) with the alkaline agent(s) present in the dosage form (e.g., in the Triggering Particulates of the dosage form) to maintain the integrity of the functional coat for the controlled release of opioid. In certain embodiments, APAP Particulates do not comprise a functional coat.

In certain embodiments, the dosage form further contains a Triggering Particulate (e.g., Triggering Granule) containing an alkaline agent(s) that increases the pH of the aqueous (or nonaqueous) solution to a pH above 5 in the presence of, e.g., three or more dosage units. In certain embodiments, the Triggering Particulate also contains a pH-stabilizing agent(s) that maintains the increased pH above 5 for up to thirty minutes, or 45 minutes, or one hour, or 1.5 hours, or two hours. In certain embodiments, the increase in pH above 5 prevents or slows the release of the opioid(s) from the Opioid Particulates. In certain embodiments, the increase in pH above 5 prevents or slows the release of, e.g., APAP from the APAP Particulates.

In certain embodiments, the IR pharmaceutical dosage forms further comprise a Viscosity Enhancing Particulate (e.g., Viscosity Enhancing Granules) population containing a viscosity-building polymer that increases the viscosity of the aqueous or nonaqueous solution if tampered with or taken in doses above those prescribed or in a manner inconsistent with the manufacturer's instructions.

In certain embodiments, the pharmaceutical compounds for use in the present disclosure are those at risk for accidental (e.g., unintentional) or intentional overdose by the oral route (e.g., multi-tablet dosing), or other misuse by another route (e.g., intravenous, nasal, oral, rectal routes, etc.).

5.1. Definitions

The terms used in this specification generally have their ordinary meanings in the art, within the context of this disclosure and in the specific context where each term is used. Certain terms are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner in describing the compositions and methods of the disclosure and how to make and use them.

As used herein, the use of the word "a" or "an" when used in the specification and/or in conjunction with the term "comprising" in the claims can mean "one," but it is also consistent with the meaning of "one or more," "at least one," and

"one or more than one." Still further, the terms "having," "including," "containing," and "comprising" are interchangeable and one of skill in the art is cognizant that these terms are open-ended terms.

The term "about" or "approximately" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within three or more than three standard deviations, per the practice in the art. Alternatively, "about" can mean a range of up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, or within 5-fold, or within 2-fold, of a value. The term "drug," "compound," "active pharmaceutical ingredient," or "API" refers to a pharmaceutically active substance which includes, without limitation, drugs susceptible to abuse and/or overdose. In certain embodiments, the opioid has a solubility of greater than about 100 microgram/ml of physiological fluids (e.g., GI fluids, SGF). In certain embodiments, the drug is an opioid analgesic. In certain embodiments, the drug is a nonopioid analgesic (e.g., acetaminophen).

The term "opioid analgesic" includes single compounds and a mixture of compounds selected from the group of opioids and which provide an analgesic effect. For example, opioid analgesics can include, without limitation, an opioid agonist, a mixed opioid agonist-antagonist, and a partial opioid agonist. In certain embodiments, the opioid can be a stereoisomer, ether, salt, hydrate or solvate thereof. Opioid is also meant to encompass the use of all such possible forms as well as their racemic and resolved forms thereof, and all tautomers as well. The term "racemic" refers to a mixture of equal parts of enantiomers and which is optically inactive.

The term "acetaminophen" can be used interchangeably with "APAP" or

"paracetamol."

The term "immediate release" or "IR" refers to dosage forms that are formulated to allow the drug to dissolve in the gastrointestinal contents / fluids with no intention of delaying or prolonging the dissolution or absorption of the drug when taken as prescribed or in a manner consistent with manufacturer's instructions.

The term "extended release" or "ER" refers to dosage forms that are formulated to allow the drug to be available over a greater period of time after administration, thereby allowing a reduction in dosing frequency, as compared to a drug presented as a conventional dosage form (e.g., immediate release).

The term "particulate" refers to a discrete, small, repetitive unit of particles, granules, or pellets that include at least one excipient, and optionally an opioid.

The term "multi-particulate" refers to at least two different populations of particulates.

The term "dosage form" refers to an oral particulate solid drug delivery system that, in the present technology, includes at least one or two populations of particulates.

The term "dosage unit" refers to a tablet (e.g., single tablet, tablet-in- tablet, bilayer tablet, multilayer tablet, etc.), capsule, pill, or other solid dosage form. The term "coat" refers to a coating, layer, membrane, film, shell, capsule, filling in a capsule, or the like, and can partially, substantially, or completely surround or envelop a substance, particulate, granule, drug, dosage unit, or the like. For example, a coat can cover portions of the surface to which it is applied, e.g., as a partial layer, partial coating, partial membrane, partial film, or partial shell; it can, for example, be in the form of spheres and/or half spheres that partially, substantially, or completely cover a surface.

The term "surrounding" if used alone, without any qualifier, can be understood to mean "at least partially surrounding."

The term "acid labile coat" refers to a coat comprising component(s) that will dissolve or degrade (partially or completely) in an acidic environment (e.g. in a solution with an acidic pH). The acidic pH can be, for example, below 7, below 6, below 5, below 4, below 3, below 2, or below 1. Typically, the pH at which an acid labile coat of the present disclosure will dissolve is in the normal physiological pH of the stomach, such as from about 1 to about 5, from about 1 to about 4, or from about 2 to about 3. Typically, the acid labile coat dissolves or degrades more slowly, or to only a small extent, when present in a solution with a pH that is considered not acidic (e.g., nonacidic, e.g., at a pH above 5, above 6, or above 7). It will be understood that the acid labile coat can be prepared and designed to dissolve or degrade (partially or substantially) within any desired pH range, and to not dissolve or degrade (partially or substantially) within any desired pH range. For example, the acid labile coat can be designed to dissolve at any pH, e.g., below about 5; above that level, dissolution is inhibited, reduced or slowed. As the pH increases, the dissolution / degradation can slow further, and can stop nearly completely.

The term "alkaline agent" can be used to refer to an excipient that acts to increase the pH of, e.g., the gastric fluid (e.g., roughly pH 1.2-4.5) to a pH greater than 5. For example, alkaline agent can refer to substances that are capable of increasing the pH to greater than 4.5, greater than 5, greater than 5.5, etc. It also refers to basic substances and substances that can convert an acidic environment to a less acidic or a basic environment. Typically, these agents, when present in a sufficient amount, are able to raise the pH of the stomach to beyond physiological levels and thereby prevent, reduce, or inhibit dissolution of an acid labile substance or coat. Examples of alkaline agents include: aluminum hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum oxide, sodium oxide, potassium oxide, calcium oxide, magnesium oxide, calcium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine, L-lysine, and combinations thereof.

The term "pH-stabilizing agent" refers to salts of weak acids / weak bases that act to maintain or stabilize the elevated pH of gastric fluid caused by an alkaline agent. For example, a pH-stabilizing agent(s) can maintain the pH of the gastric fluid at a pH greater than 5 for a finite time.

The term "functional coating" or "functional coat" refers to a coating that affects the rate of release, in vitro or in vivo, of an active drug(s), e.g., an opioid(s) and/or acetaminophen (APAP) or another nonopioid analgesic(s). The term "functional coat" can include one or more "functional coat layers." The terms "functional coat" and "functional coat layer" can be used interchangeably herein.

The term "viscosity-building polymer" as used herein refers to a polymer or group of polymers that increase the viscosity of a solution if the dosage form is tampered with (e.g., by dissolution in a solvent) or taken in doses above those prescribed or in a manner inconsistent with the manufacturer's instructions.

The term "nonionic polymer" refers to a nonionic pH-independent polymer.

The term "nonionic water-insoluble polymer" refers to a nonionic pH- independent polymer generally insoluble in water, physiological fluids, and ethanol.

The term "nonionic water-soluble polymer" refers to a nonionic pH- independent polymer generally soluble in water, physiological fluids, and ethanol.

The term "cationic polymer" refers to a cationic pH-dependent polymer, generally soluble in, e.g., a gastric fluid or a simulated gastric fluid (e.g., a polymer, containing one or more cationic groups, soluble in, e.g., a gastric fluid or a simulated gastric fluid). Generally, such cationic polymers can serve as rate-controlling polymers.

The term "mini-tablet" refers to a tablet with a diameter equal to or smaller than 3 mm. They are filled into a capsule or compressed into a large tablet.

The terms "abuse-deterrent formulation," "abuse-deterrent composition," "abuse-resistant formulation," "abuse-resistant composition," or "ADF" are used interchangeably to refer to an oral dosage form that reduces the potential for abuse (e.g., improper administration) but delivers a therapeutically effective dose when administered as directed. For example, these terms generally refer to a dosage form that can be at least resistant to crushing, grinding, breaking, milling, melting, separating, cutting, extracting, dose dumping (e.g., alcohol dose dumping), and/or solubilizing for injection purposes. Improper administration includes, without limitation, tampering with the dosage form and/or administering the drug by any route other than that instructed. For example, and without limitation, improper administration includes snorting after grinding,

administration after heat treatment, oral administration after crushing, or parenteral administration after extraction with a solvent such as water, ethanol, isopropanol, acetone, acetic acid, vinegar, carbonated beverages, and the like, and combinations thereof.

The term "abuse" means the intentional, nontherapeutic use of a dosage form or opioid, to achieve a desirable psychological or physiological effect. For example, these terms refer to tampering with the dosage form and/or administering the drug in a manner inconsistent with the manufacturer's instructions. Methods of tampering or abuse include, but are not limited to, multi-tablet dosing (deliberate), crushing, grinding, melting, cutting, extracting, dose dumping (e.g., alcohol dose dumping), and solubilizing injection purposes

As used herein, "in a manner inconsistent with the manufacturer's instructions" is meant to include, but is not limited to, administering or consuming amounts greater than amounts described on the label or prescribed by a licensed physician, and/or altering by any means (e.g., crushing, breaking, milling, melting, separating, etc.) the dosage forms such that, for example, an opioid(s) can be crushed, ground, melted, cut, extracted, dose dumped (e.g., alcohol dose dumping), and/or solubilized for injection purposes.

The term "crush resistant" or "resistant to crushing" means, e.g., a granule or particulate (e.g., an Opioid Granule) that can deform but does not break into powder form when pressure, for example, greater than 500 N is applied, when using a suitable hardness tester.

The term "grinding" refers to a process of reducing one or more tablets into small fragments, e.g., in the form of powder, following a specific grinding pattern (e.g., two min grinding / one min rest / two min grinding) using, for example, an electrical grinding means (e.g., coffee grinder or IKA laboratory grinder).

The term "resistant to alcohol extraction" is used to refer to two or more dosage units (e.g., any form(s) of tablets or capsules) that at least fulfill the condition that in vitro dissolution, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid comprising 40% ethanol at 37°C, is provided that is characterized by the percent amount of active agent released at, e.g., 30 minutes (or, e.g., 60 min) of dissolution that deviates no more than 20% from the corresponding in vitro dissolution measured at the same time point in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without ethanol at 37°C.

The term "overdose protection" or "ODP" refers to a dosage form that reduces the potential for the detrimental consequences of overdose but delivers a therapeutically effective dose when administered as directed or prescribed by a licensed physician.

The term "overdose" refers to the administration of the dosage form in amounts or doses above those considered therapeutic (e.g., three or more dosage units; more than two dosage units); in a manner inconsistent with manufacturer's instructions; or in a manner not prescribed. Overdose can be intentional or unintentional (e.g., accidental).

As used herein, use of phrases such as "decreased," "reduced,"

"diminished," or "lowered" is meant to include at least a 10% change in the release of the drug with greater percentage changes being preferred for reduction in abuse potential and overdose potential. For example, but without limitation, the change can be greater than 10%, 15%, 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%, or increments therein.

5.2. Opioid Particulates

Opioid Particulates contain one or more opioids. In certain embodiments, the Opioid Particulates are Opioid Granules, Opioid Pellets, or a combination thereof. In certain embodiments, Opioid Granules can include an opioid, a polymer matrix (which in some embodiments can include a hydrophilic polyoxy ethylene (PEO) polymer, a cationic polymer, and/or an additional nonionic polymer), an antioxidant, a plasticizer, and/or a surfactant. The polymer matrix of, e.g., Opioid Granules, can be directly surrounded (optionally) by a seal coat. In certain embodiments, the seal coat can be made with a water-soluble nonionic polymer. The polymer matrix (in absence of seal coat)), or the seal coat (when present over the polymer matrix) is surrounded by one or more functional coats (e.g., FC 0, FC 1, and FC 2). In certain embodiments, the polymer matrix or seal coat surrounding the polymer matrix is directly surrounded by at least one functional coat (e.g., FC 1). In certain embodiments, FC 1 can include a water-insoluble nonionic polymer, as well as a cationic polymer that behaves as a pore former at pH below 5. In certain embodiments, the Opioid Particulates comprising FC 1 can further comprise FC 0, between the polymer matrix and FC 1. In certain embodiments, the Opioid Particulates comprising FC 1 can further comprise FC 2, coated over FC 1. In certain embodiments, FC 0 and/or FC 2 contain a cationic polymer and, optionally, a nonionic polymer. In certain embodiments, the Opioid Particulates further include an over coat that contains a water-soluble nonionic polymer and surrounds the functional coat(s).

In certain embodiments of Opioid Particulates, each of FC 0, FC 1, and/or FC 2 accomplishes the role of overdose protection (ODP) coupled with the alkaline agent and (optional) pH-stabilizing agent contained in one of the other granules (i.e.,

Triggering Granules, as described herein) present in the abuse deterrent formulation ("ADF") - overdose protection ("ODP") dosage form (tablets, capsules, etc.). In certain embodiments, FC 0 and/or FC 2 can provide enhanced ODP, in addition to that provided by FC 1, when coupled with the alkaline agent and (optional) pH-stabilizing agent contained in the Triggering Granules.

In certain embodiments, the Opioid Particulates are present in combination with particulates of at least one additional (nonopioid) pain-relieving agent having a complementary mechanism of action (i.e., "APAP Particulates").

5.2.1. Opioids

In certain embodiments, the Opioid Particulates contain at least one opioid. In certain embodiments, different populations of Opioid Particulates contain different opioids. In certain embodiments, the opioid has a solubility of greater than about 100 microgram/ml of physiological fluids (e.g., GI fluids, SGF).

As discussed in further detail herein, Opioid Particulates can be coated with at least one functional coat (e.g., FC 1). In some embodiments, FC 1 includes a nonionic polymer that is insoluble in water, and a cationic polymer that behaves as a pore former at a pH from about 1.2 to about 4.5 and is insoluble in fluids with a pH above about 5 (e.g., at a pH of about 5 or greater). Surprisingly, in some embodiments, it has been found that a functional coat containing, e.g., an 80:20 wt% ratio of the water- insoluble nonionic polymer to the pore former provides superior overdose protection (ODP) compared to a functional coat with, e.g., a 60:40 wt% ratio of the nonionic polymer to the pore former, while maintaining a therapeutically acceptable immediate release of the opioid when taken in a manner consistent with manufacturer's instructions, or in a manner prescribed (e.g., one or two dosage units are taken as intended or prescribed).

In certain embodiments, the opioid (or opioids) is present in the dosage form in an amount effective for the intended therapeutic purpose. Such amounts are well known in the art. The doses at which any of the presently known opioids embraced or contemplated by the present disclosure can be given safely and effectively for the intended therapeutic purpose are known to those of skill in the art. In certain

embodiments, the opioid is present in an amount of about 0.1% to about 95% w/w of the Opioid Particulate before the addition of the (optional) seal coat or any functional coat (i.e., about 0.1%> to about 95% w/w of the polymer matrix / core embedded with the opioid). In certain embodiments, the opioid is present in an amount of about 0.2% to about 90%, about 0.3% to about 85%, about 0.4% to about 80%, about 0.5% to about 75%, about 0.6% to about 70%, about 0.7% to about 65%, about 0.8% to about 60%, about 0.9% to about 55%, about 1% to about 50%, about 2.5% to about 45%, about 5% to about 40%, about 7.5% to about 35%, about 10% to about 30%, about 12.5% to about 25%), or about 15%> to about 20% w/w of the polymer matrix / core embedded with the opioid. In certain embodiments, the opioid is present in an amount of at least about 0.1%), at least about 0.2%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%), at least about 35%, at least about 40%, at least about 45%., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%), at least about 80%, at least about 85%, at least about 90%, or at least about 95% w/w of the polymer matrix / core embedded with the opioid.

In certain embodiments, opioids are drugs prone to abuse, misuse, and/or overdose. In certain embodiments, the opioid can be (for example, without limitation), alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydromorphodone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, nomiethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, pantopon, papaveretum, paregoric, pentazocine, phenadoxone, phendimetrazine, phendimetrazone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, propylhexedrine, sufentanil, tapentadol, tilidine, tramadol, and pharmaceutically acceptable salts thereof.

In certain embodiments, the opioid can be oxycodone, hydrocodone, tapentadol, codeine, oxymorphone, hydromorphone, or pharmaceutically acceptable salts thereof. In certain embodiments, the opioid is oxycodone, hydrocodone, oxymorphone, hydromorphone, or codeine. In certain embodiments, the opioid is a pharmaceutically active salt of oxycodone, hydrocodone, oxymorphone, hydromorphone, or codeine.

Examples of pharmaceutically acceptable salts include, but are not limited to, citrate, oxalate, acetate, maleate, malonate, fumarate, succinate, tosylate, mesylate, hydrochloride, bitartrate, hydrobromide, sulfate, phosphate, methanesulfonate, toluenesulfonate or mixtures and/or forms thereof. In certain embodiments, the pharmaceutically acceptable salt is a hydrochloride salt; in certain other embodiments, the pharmaceutically acceptable salt is a bitartrate. Additional pharmaceutically acceptable salts can be found in P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zurich:Wiley- VCH/VHCA, 2002.

5.2.2. Opioid Granules

In certain embodiments, the Opioid Particulates are Opioid Granules. In certain embodiments, the Opioid Granules include an opioid, a polymer matrix that in some embodiments can include hydrophilic polyoxyethylene (PEO) polymer(s), a cationic polymer and/or a nonionic polymer, an antioxidant, a plasticizer and/or a surfactant. In certain embodiments, the Opioid Granules can include a seal coat layer and at least one functional coat (e.g., FC 1). In certain embodiments, the Opioid

Granules containing, e.g., FC 1 can further include FC 0 (optional) between the polymer matrix and FC 1, and/or FC 2 on top of FC 1. In certain embodiments, the Opioid Granules include an over coat, comprising a water-soluble nonionic polymer and surrounding the functional coat(s). In certain embodiments, at least one of FC 0, FC 1, and FC 2 includes a water-insoluble nonionic polymer (e.g., generally not soluble in physiological fluids, or in commonly used organic solvents such as ethanol) and a cationic polymer. The latter behaves as a pore former at a pH below 5, but swells and becomes semipermeable / less permeable at a pH above 5 (e.g., in intestinal fluids; in gastric fluid with an elevated pH), thereby substantially preventing or slowing release of the opioid at a higher pH. Generally, cationic polymers serving as pore formers provide a rate-controlling function regarding release.

In certain embodiments, the polymer matrix and a therapeutically effective amount of the opioid are contained in an inner core. In certain embodiments, the Opioid Granules can contain a plasticizer in the inner core, the outer coating layers (e.g., the seal coat, the functional coat(s), and/or the over coat), or both the inner core and the outer coating layers. In certain embodiments, the Opioid Granules can contain a surfactant in the inner core, the outer coating layers, or both the inner core and the outer coating layers.

In certain embodiments, Opioid Granules contain an opioid in an amount of about 0.1% to about 95% w/w of the uncoated Opioid Granules, i.e., the Opioid Granules before being coated with the (optional) seal coat and/or any functional coat. In certain embodiments, the Opioid Granules contain the opioid in an amount of about 0.2% to about 90%, about 0.3% to about 85%, about 0.4% to about 80%, about 0.5% to about 75%, about 0.6% to about 70%, about 0.7% to about 65%, about 0.8% to about 60%, about 0.9% to about 55%, about 1% to about 50%, about 2.5% to about 45%, about 5% to about 40%, about 7.5% to about 35%, about 10% to about 30%, about 12.5% to about 25%), or about 15%> to about 20% w/w of the uncoated Opioid Granule. In certain embodiments, the Opioid Granules contain the opioid in an amount of at least about 0.1%), at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.75%, at least about 1%, at least about 2.5%, at least about 5%, at least about 7.5%), at least about 10%, at least about 12.5%, at least about 15%, at least about 17.5%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%), at least about 45%, at least about 50%, at least about 55%, at least about 60%), at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% w/w of the uncoated Opioid Granule.

In certain embodiments, the opioid is oxycodone, or a pharmaceutically acceptable salt thereof. In certain embodiments, the opioid is oxycodone hydrochloride. In certain embodiments, the opioid is hydrocodone, or a pharmaceutically acceptable salt thereof. In certain embodiments, the opioid is hydrocodone bitartrate. In certain embodiments, the opioid is hydromorphone, or a pharmaceutically acceptable salt thereof. In certain embodiments, the opioid is hydromorphone hydrochloride. In certain embodiments, the opioid is oxymorphone.

In certain embodiments, the polymer matrix can comprise a nonionic polymer and/or a cationic polymer.

Representative nonionic polymers include, but are not limited to, a nonionic copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups (ammonium methacrylate copolymer, Type A, NF) (e.g., EUDRAGIT^® RL 100, RSI 00 (Evonik)); and nonionic polymers such as hydroxypropylcellulose (e.g., KLUCELE^®, L, J, G, M and H grades (Ashland)), hydroxypropyl methylcellulose (HPMC) (e.g., METHOCEL^® E, F, J, and K (Dow Chemicals)), hydroxyethylcellulose (e.g., NATRASOL L, G, M, and H grades (Ashland)), ethylcellulose (e.g., ETHOCEL^® 7FP, 10FP, 45FP, and 100FP (Dow

Chemicals) and N7, N10, N14, N22, N50, and N100 grades (Ashland)), cellulose acetate butyrate (e.g., CAB-381-0.5 (Eastman)), and cellulose acetate (CA-398-3, CA-398-6, CA-398-100, and CA-398-30 (Eastman)); polyvinyl acetate polymers (e.g., polyvinyl acetate-polyvinylpyrrolidone (Kollidon SR) and polyethylene oxide polymers (e.g., Polyox® WSR coagulant, Polyox® WSR- 301, Polyox® WSR-303). Exemplary polyoxyethylene oxide polymers include POLYOX™ WSR N-80, POLYOX™ WSR N- 750, POLYOX™ WSR N-3000, POLYOX™ WSR-205, POLYOX™ WSR N-l 105, POLYOX™ WSR N-12K, POLYOX™ WSR N-60K, POLYOX™ WSR N-301, POLYOX™ WSR Coagulant, POLYOX™ WSR N-303. The exemplary

polyoxyethylene oxide polymers provide different viscosities in an aqueous solution. In certain embodiments, the exemplary polyethylene oxide has an average molecular weight of about 1,000,000 (WSR-N-12K), about 4,000,000 (WSR-301), about 5,000,000 (WSR Coagulant), or about 7,000,000(WSR-303).

Representative cationic polymers include, but are not limited to,

(meth)acrylic polymers and (meth)acrylic copolymers (e.g., copolymers of alkyl

(meth)acrylates and copolymers of alkylamino(meth)acrylates); quaternary ammonium (meth)acrylic polymers. Representative cationic polymers include, but are not limited to, cationic polymers that are soluble in gastric fluid, but swell and become permeable at a pH above about 5. In some embodiments, the cationic polymer matrix comprises EUDRAGIT E PO, which has a molecular weight about 47,000 and a glass transition temperature about 48°C.

In some embodiments, the polymer matrix (i.e., the polymer matrix without an opioid embedded within) can be present in the Opioid Granules in a range of about 1.0% to about 95% w/w based on the total weight of the uncoated Opioid Granule; in some embodiments, from about 15% to about 90% w/w based on the total weight of the uncoated Opioid Granule; and in some embodiments, from about 30% to about 75% w/w based on the total weight of the uncoated Opioid Granule. In certain embodiments, the polymer matrix can be present in an amount of at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%), at least about 35%, at least about 40%, at least about 45%, at least about 50%), at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% w/w based on the total weight of the uncoated Opioid Granule.

In certain embodiments, a plasticizer can be added to increase the elasticity of the polymer in the polymer matrix of the Opioid Granules. In certain embodiments, the plasticizer makes, or participates in making, the Opioid Granule crush- resistant. In certain embodiments, the plasticizer is soluble in both aqueous and nonaqueous solvents that are commonly used to extract opioids and other abuse-prone drugs from commercial formulations. In certain embodiments, the plasticizer acts as an aversion agent. In certain embodiments, the plasticizer acts as a tissue irritant that causes discomfort if administered in conjunction with an opioid with which it is coextracted.

Representative plasticizers include, but are not limited to liquid esters, (e.g., triethyl citrate, propylene glycol, polyethylene glycols, triacetin, diethylene glycol monoethyl ether, dibutyl sebacate, and diethyl phthalate). In certain embodiments, the dielectric constant values of the plasticizer are in a range of about 5 to about 60. In certain embodiments, the dielectric constant values of the plasticizer are in a range of about 10 to about 40.

In certain embodiments, the plasticizer can be present in an amount that is sufficient to make the Opioid Granules substantially crush-resistant, but not in quantities that negatively impact the dissolution of the opioid when taken in a manner consistent with the manufacturer's instructions or in a manner prescribed. In certain embodiments, the plasticizer can be present in amounts that result in discomfort to the abuser when the plasticizer is co-eluted with the opioid and administered in a manner inconsistent with the manufacturers and/or physicians instructions. In certain embodiments, the amount of plasticizer provides an adequate rubbery state and elongation property to the polymer to achieve crush-resistance, making it difficult to pulverize the Opioid Granules into a fine powder, thereby deterring abuse.

In certain embodiments, the plasticizer can be present in a range of about

0.1% to about 30% w/w of the uncoated Opioid Granules. In certain embodiments, the plasticizer can be present in a range from about 2.0% to about 15% w/w of the uncoated Opioid Granules. In certain embodiments, the plasticizer can be present in an amount of about 0.2% to about 27.5%, about 0.3% to about 25%, about 0.4% to about 22.5%, about 0.5% to about 20%, about 0.6% to about 17.5%, about 0.7% to about 15%, about 0.8% to about 12.5%, about 0.9% to about 10%, about 1% to about 7.5%, or about 2.5% to about 5% w/w of the uncoated Opioid Granule. In certain embodiments, the plasticizer can be present in an amount of at least about 0.1%, at least about 0.2%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%), at least about 25%, or at least about 30% w/w of the uncoated Opioid Granule. In certain embodiments, the plasticizer can be present in an amount of about 2%, about 3%, about 4%), about 6%, or about 8% w/w of the uncoated Opioid Granule.

In certain embodiments, the Opioid Granule polymer matrix further comprises at least one surfactant. In certain embodiments, the pharmaceutically acceptable surfactants that are useful in the practice of the present disclosure are soluble in oils, co-solvents, or aqueous media. In certain embodiments, the surfactant component helps in modulating the solubility of the opioid. In certain embodiments, the surfactant helps to reduce the abuse potential by a dual mechanism. First, it elicits the irritant response when administered "as is" by nasal or injection routes, and second, by co-eluting with the drug when extracted with commonly used solvents, such as aqueous and organic solvents. Surfactants produce tissue irritation when applied to nasal mucosa and will cause local irritation at an injection site. Further, docusate sodium (as an exemplary surfactant) is commonly used as a stool softener/laxative, so while providing some relief for opioid-induced constipation at the intended dose, docusate sodium can cause undesirable gastrointestinal effects if large quantities are ingested. Similar gastrointestinal effects can be obtained by ingesting other surfactants. In certain embodiments, the surfactant is present in an amount that results in discomfort to the abuser when the surfactant is co-eluted with the opioid. The hydrophilic-lipophilic balance ("HLB") values of the surfactants are in a range of about 4 to about 30. Types of surfactants that can be useful in the practice of the present disclosure include nonionic surfactants (e.g., esters of fatty acids, especially of C8-C24 and preferably of C16-C22, and fatty acid esters of polyols such as glycerol or sorbitol); sorbitan fatty acid esters ethoxylated with from 2 to 30 moles of ethylene oxide;

polyethylene glycol fatty acid esters; polyethyleneglycol esters and polyethyleneglycol ethers; and poly ethoxylated carboxylic acids (e.g., PEG-35 castor oil, PEG-40 castor oil, steareth-2 (e.g., Brij 72, Uniqema), steareth-21 (e.g., Brij 721, Uniqema), ceteareth-25 (e.g., Cremophor A25, BASF Cooperation), PEG-7 hydrogenated castor oil (e.g., Cremophor W07, BASF Cooperation), and PEG-30 dipolyhydroxystearate (e.g., Arlacel P 135, Uniqema)); block copolymers based on ethylene oxide and propylene oxide (e.g., PLURONIC® (e.g., 188 or 407 (BASF)); dioctyl sodium sulfosuccinate (docusate sodium); sodium lauryl sulfate; PEG-32 glyceryl laurate; PEG-32 glyceryl

palmitostearate; PEG-8 glyceryl caprylate/caprate; PEG-6 glyceryl caprylate/caprate; macrogol 15 hydroxystearate; poly oxy ethylene 20 sorbitan monolaurate (polysorbate 20); poly oxy ethylene 20 sorbitan monooleate (polysorbate 80); sorbitan monolaurate; sorbitan monooleate; and polyoxyl 40 stearate. Anionic surfactants (e.g., alkyl ether sulfates and sulfosuccinates), can also be useful. Alternatively cationic and amphoteric surfactants such as phospholipids, lysophospholipids, and PEGylated phospholipids can also be used. Additional useful surfactants include vitamin E and derivatives thereof, e.g., PEGylated derivatives of vitamin E, such as tocopherol PEG succinate, tocopheryl PEG sebacate, tocopheryl PEG dodecanodioate, tocopheryl PEG suberate, tocopheryl PEG azelaate, tocopheryl PEG citraconate, tocopheryl PEG methylcitraconate, tocopheryl PEG itaconate, tocopheryl PEG maleate, tocopheryl PEG glutarate, tocopheryl PEG glutaconate, tocopheryl PEG fumarate, tocopheryl PEG phthalate, tocotrienol PEG succinate, tocotrienol PEG sebacate, tocotrienol PEG dodecanodioate, tocotrienol PEG suberate, tocotrienol PEG azelaate, tocotrienol PEG citraconate, tocotrienol PEG methylcitraconate, tocotrienol PEG itaconate, tocotrienol PEG maleate, tocotrienol PEG glutarate, tocotrienol PEG glutaconate, tocotrienol PEG fumarate and tocotrienol PEG phthalate (see, e.g., USPAP 2014/0271593).

In certain embodiments, the surfactant can be present in a range of about

0.01% to about 15%) w/w of the uncoated Opioid Granules. In certain embodiments, the surfactant can be present in a range from about 0.15% to about 5%> w/w of the uncoated Opioid Granules. In certain embodiments, the surfactant can be present in an amount of about 0.025 to about 12.5%, about 0.05% to about 10%, about 0.075% to about 7.5%, about 0.1% to about 5%, about 0.25% to about 2.5%, or about 0.5% to about 1% w/w of the uncoated Opioid Granules. In certain embodiments, the surfactant can be present in an amount of about 0.2%, about 0.5%, about 2%, or about 2.2%, w/w of the uncoated Opioid Granules.

In certain embodiments, certain combinations of aversion agents (e.g., plasticizer and surfactant) can be used to deter abuse. Examples of such combinations include triethyl citrate and docusate sodium (DOSS™), propylene glycol and DOSS™, polyethylene glycol (PEG-400) and DOSS™, PEG-400, PEG-40, PEG-40 castor oil, Polyoxyl 40 hydrogenated castor oil, (Cremaphor RH40), PEG 35 castor oil, and Polyoxyl 35 hydrogenated castor oil (Cremaphor EL).

In certain embodiments, the polymer matrix of the Opioid Granules further contains an antioxidant. In certain embodiments, the antioxidant is present in an amount sufficient to suppress temperature-induced degradation of high molecular weight PEO upon hot melt extrusion (HME). Polymer degradation can result in an uncontrolled release profile, particularly when active material is embedded in a matrix of PEO; this can be another cause of oxidative degradation of pharmacologically active ingredients by, e.g., radicals. When adding an excipient, such as butylated hydroxytoluene (BHT), in order to attempt to stabilize high molecular weight PEO polymer, it should be taken into consideration that such an excipient should be stable at elevated temperatures, e.g., HME temperatures used during manufacture of Opioid Granules, or used by an abuser to defeat the extended release properties of the dosage form. Antioxidants for use in the present disclosure include, but are not limited to, ascorbic acid and its salts, tocopherols, sulfite salts such as sodium metabisulfite or sodium sulfite, sodium sulfide, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, and propyl gallate. In certain embodiments, the antioxidant can be present in a range of about 0.01% to about 2% w/w of the uncoated Opioid Granules. In certain embodiments, the antioxidant can be present in a range of about 0.025% to about 1%, about 0.05% to about 0.75%, about 0.075%) to about 0.5%, or about 0.1 to about 0.75% w/w of the uncoated Opioid

Granules. In certain embodiments, the antioxidant can be present in about 0.2%, about 0.3%), about 0.4%, or about 0.5% w/w of the uncoated Opioid Granules.

In certain embodiments, the Opioid Granules can be prepared in several ways known to those in the art, including hot-melt extrusion, film melt, granulation, melt granulation, extrusion spheronization, and rotor or roller compaction. In certain embodiments, the opioid granules, containing PEO polymers, prepared by granulation, extrusion (e.g., HME), spheronization, rotor, or roller compaction process can require curing at a temperature above the melting point of the PEO polymers. In certain embodiments, the Opioid Granules can be prepared by an HME process. In an HME process, a thermoplastic carrier polymer(s) (e.g., a nonionic polymer and/or a cationic polymer) is combined with an opioid, a plasticizer, a surfactant, as well as any optional ingredients (e.g., an ion exchange polymer(s), an alkaline agent, and/or a viscosity- building agent(s)) to form a powdery mixture. The mixture is introduced into one or two rotating screws that convey the powder into a heated zone where shear forces compound the materials until a molten mass is achieved. Hot-melt extrusion equipment typically includes an extruder, auxiliary equipment for the extruder, downstream processing equipment, and other monitoring tools used for performance and product quality evaluation. The extruder is typically composed of a feeding hopper, barrels, single or twin screws, and the die and screw-driving unit. The auxiliary equipment for the extruder mainly includes a heating / cooling device for the barrels, a conveyer belt to cool down the product, and a solvent-delivery pump. The monitoring devices on the equipment include temperature gauges, a screw-speed controller, an extrusion torque monitor, and pressure gauges. In certain embodiments, different shaped dies can be used. For example, extrudates can be produced by extruding the material through round- shaped dies into cooled rolls, wherein the extruded strands are cut into short cylinders using a pelletizer.

The pelletized extruded strands are subjected to an appropriate size reduction process(es) using co-mill or fitz mill or micropulverizer with coolant processing aids such as dry ice or liquid nitrogen.

In certain embodiments, the sizes of Opioid Granules, before or after attempted grinding, are significantly large enough to prevent the granules from being snorted. In certain embodiments, the mean size distribution of the Opioid Granules can be from about 125 μπι to about 1000 μπι, and in some embodiments from about 250 μπι to about 750 μπι (as measured by weight frequency distribution using a sieving method). In certain embodiments, the mean particle size of the Opioid Granules is about 400 μπι to about 600 μπι. In certain embodiments, the mean particle size of the Opioid Granules is about 500 μπι. 5.2.3. Opioid Pellets

In certain embodiments, the Opioid Particulates are Opioid Pellets. In certain embodiments, the Opioid Pellets include an opioid and a functional coat(s). In certain embodiments, at least one of FC 0, FC 1, and FC 2 contain at least one cationic polymer and, optionally, a nonionic water-insoluble polymer. In certain embodiments, the Opioid Pellets can further include a seal coat (optional) between the polymer matrix and a functional coat(s). In certain embodiments, the Opioid Pellets further include an over coat, comprising a water-soluble nonionic polymer, on top of the functional coat(s). In certain embodiments, FC 1 includes a water-insoluble nonionic polymer, and a cationic polymer that is soluble in gastric fluids (e.g., at a pH less than about 5). The latter behaves as a pore former at a pH below about 5, but swells and becomes semipermeable at a pH above about 5 (e.g., in intestinal fluids; in gastric fluid with an elevated pH), thereby substantially preventing or slowing release of the opioid at a higher pH.

In certain embodiments, the core of the Opioid Pellets can be preformed pellets. By way of example, but not limitation, the pellet core can be made from microcrystalline cellulose (MCC cellets) and/or alkaline agents / ion exchange resins. In certain embodiments, the pellet core comprises MCC cellets containing cured POLYOX.

In certain embodiments, the shape of the pellets can be round, oval, or oblong.

In certain embodiments, that pellet core has a density of about 0.3 to about 1.0 mg/cm³.

In certain embodiments, the pellet core can be about 25 mg to about 500 mg. In certain embodiments, the pellet core can be about 50 mg to about 475 mg, about 75 mg to about 450 mg, about 100 mg to about 425 mg, about 125 mg to about 400 mg, about 150 mg to about 375 mg, about 175 mg to about 350 mg, about 200 mg to about 325 mg, about 225 mg to about 300 mg, or about 250 mg to about 275 mg.

In certain embodiments, the pellet core can be about 25% to about 90% w/w of the uncoated Opioid Pellet, i.e., the Opioid Pellet before being coated with the (optional) seal coat and/or any functional coat(s). In certain embodiments, the pellet core can be about 27.5% to about 87.5%, about 30% to about 85%, about 32.5% to about 82.5%, about 35% to about 80%, about 37.5% to about 77.5%, about 40% to about 75%, about 42.5% to about 72.5%, about 45% to about 70%, about 47.5% to about 67.5%, about 50% to about 65%>, about 52.5% to about 62.5%, or about 55% to about 60%> w/w of the uncoated Opioid Pellet.

In certain embodiments, Opioid Pellets contain an opioid in an amount of about 0.1%) to about 95% w/w of the uncoated Opioid Pellets, i.e., the Opioid Pellets before being coated with the (optional) seal coat and/or any functional coat(s). In certain embodiments, the Opioid Pellets contain the opioid in an amount of about 0.2% to about 90%, about 0.3% to about 85%, about 0.4% to about 80%, about 0.5% to about 75%, about 0.6% to about 70%, about 0.7% to about 65%, about 0.8% to about 60%, about 0.9% to about 55%, about 1% to about 50%, about 2.5% to about 45%, about 5% to about 40%, about 7.5% to about 35%, about 10% to about 30%, about 12.5% to about 25%o, or about 15% to about 20% w/w of the uncoated Opioid Pellet. In certain embodiments, the Opioid Pellets contain the opioid in an amount of at least about 0. 1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.75%), at least about 1%, at least about 2.5%, at least about 5%, at least about 7.5%o, at least about 10%, at least about 12.5%, at least about 15%, at least about 17.5%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%), at least about 45%, at least about 50%, at least about 55%, at least about 60%), at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% w/w of the uncoated Opioid Pellet.

In certain embodiments, the opioid is oxycodone, or a pharmaceutically acceptable salt thereof. In certain embodiments, the opioid is oxycodone hydrochloride. In certain embodiments, the opioid is hydrocodone, or a pharmaceutically acceptable salt thereof. In certain embodiments, the opioid is hydrocodone bitartrate. In certain embodiments, the opioid is hydromorphone, or a pharmaceutically acceptable salt thereof. In certain embodiments, the opioid is hydromorphone hydrochloride. In certain embodiments, the opioid is oxymorphone. In certain embodiments, the opioid is codeine, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the opioid can be absorbed by the pellet core. In certain embodiments, Opioid Pellets can be made by coating the opioid upon the cellet (to form a pellet core). In certain embodiments, the opioid can be dissolved into a suitable solvent system to either be absorbed by the pellet core or sprayed onto the pellet core. In certain embodiments, the solvent is water, an alcohol, an organic liquid, or a combination thereof. In certain embodiments, the alcohol is dehydrated alcohol. In certain embodiments, the solvent is a mixture of water and an alcohol. In certain embodiments, the solvent is a mixture of water and dehydrated alcohol. In certain embodiments, the components of a solvent mixture can be added at the same time or in different steps or stages.

In certain embodiments, solvents that can be used in processes of preparing dosage forms of the present disclosure (i.e., Particulates, e.g., Opioid

Particulates, APAP Particulates, Active Particulates) include, but are not limited to, water, methanol, ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, di ethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, N,N- dimethylformamide, tetrahydrofuran, and any mixtures thereof.

In certain embodiments, the Particulate coating can also contain additives such as coloring agents, talc and/or magnesium stearate, which are well known in the coating arts. In certain embodiments, the excipients added to a Particulate solution can include, but are not limited to hydroxypropylmethylcellulose (HPMC) (e.g., methocel E5 Premium LV), lactose, polyvinylpyrrolidone (PVP), magnesium stearate, and talc. In certain embodiments, the excipients can be present in an amount of about 0.1 % to about 30% w/w of the uncoated Particulate. In certain embodiments, the Particulates contain excipients in an amount of about 0.2% to about 27.5%, about 0.3% to about 25%, about 0.4% to about 22.5%, about 0.5% to about 20%, about 0.6% to about 17.5%, about 0.7% to about 15%, about 0.8% to about 12.5%, about 0.9% to about 10%, about 1% to about 7.5%), or about 2.5% to about 5% w/w of the uncoated Particulate. In certain

embodiments, the Particulates contain excipients in an amount of at least about 0.1%, at least about 0.2%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%), at least about 15%, at least about 20%, at least about 25%, or at least about 30% w/w of the uncoated Particulate.

5.3. APAP Particulates

In certain embodiments, the Opioid Particulates (as discussed above) are present in combination with particulates of at least one additional (nonopioid) pain relieving agent having a complementary mechanism of action (i.e., APAP Particulates). APAP Particulates contain one or more nonopioid pain relieving agent(s). In certain embodiments, APAP Particulates are APAP Granules. In certain embodiments, APAP Particulates are APAP Pellets. In certain embodiments, the additional pain-relieving agent is acetaminophen (APAP). In certain embodiments, APAP Particulates include acetaminophen embedded in a polymer matrix (core) comprising a cationic polymer and/or a nonionic polymer, a glidant, a surfactant, and/or a plasticizer. In certain embodiments, the polymer matrix of APAP Particulates containing, e.g., acetaminophen, can be directly surrounded by a seal coat (optional). In certain embodiments, the seal coat can be made with a water-soluble nonionic polymer. In certain embodiments, the polymer matrix (when a seal coat is absent), or the seal coat (when present over the polymer matrix) can be directly surrounded by at least one functional coat layer (e.g., APAP-FC 0, APAP-FC 1, and APAP-FC 2). In certain embodiments, the APAP

Particulates can include a seal coat and at least one functional coat layer (e.g.,

APAP-FC 1). In certain embodiments, the APAP Particulates comprising APAP-FC 1 can further comprise APAP-FC 0, between the polymer matrix and APAP-FC 1. In certain embodiments, the APAP Particulates comprising APAP-FC 1 can further comprise APAP-FC 2, coated over APAP-FC 1. In certain embodiments, APAP-FC 0 and/or APAP-FC 2 contain a cationic polymer and, optionally, a nonionic polymer. In certain embodiments, the APAP Particulates further include an over coat that contains a water-soluble nonionic polymer and surrounds the functional coat(s).

In certain embodiments, at least one of APAP-FC 0, APAP-FC 1, and

APAP-FC 2 can include a cationic polymer that behaves as a pore former at pH below 5 and a water-insoluble nonionic polymer. In certain embodiments, APAP-FC 1 includes a cationic polymer and, optionally, a water-insoluble nonionic polymer. In certain embodiments, APAP-FC 0, APAP-FC 1, and APAP-FC 2 can include different ratios of water-insoluble nonionic polymer and cationic polymer. In certain embodiments, the latter behaves as a pore former at a pH below 5, but swells and becomes semipermeable at a pH above 5 (e.g., in intestinal fluids; in gastric fluid with an elevated pH), thereby substantially preventing or slowing release of the nonopioid agent at higher pH. In certain embodiments, APAP Particulates of the present disclosure do not comprise any functional coat.

In certain embodiments, the APAP Particulates can be coated with a functional coat (e.g., one or more of APAP-FC 0, APAP-FC 1, and APAP-FC 2). In certain embodiments, APAP-FC 1 contains Eudragit® E PO. In certain embodiments, APAP-FC 1 contains cellulose acetate (CA) and Eudragit® E PO in a wt% ratio from about 0.1 :99.9 to 99.9:0.1.

In certain embodiments of APAP Particulates, APAP-FC 0, APAP-FC 1, and/or APAP-FC 2 accomplish the role of overdose protection (ODP) coupled with the alkaline agent and (optional) pH-stabilizing agent contained in one of the other granules (i.e., Triggering Granules) present in the abuse deterrent formulation ("ADF") - overdose protection ("ODP") tablets or capsules. In certain embodiments, APAP-FC 0, and APAP-FC 2 can provide enhanced ODP, in addition to that provided by APAP-FC 1, when coupled with the alkaline agent and (optional) pH-stabilizing agent contained in the Triggering Granules.

In certain embodiments of APAP Particulates, a therapeutically effective amount of acetaminophen and the polymer matrix are contained in an inner core. In certain embodiments, the APAP Particulates can contain a glidant in the inner core, the outer coating layers (e.g., the seal coat, the functional coat(s), and/or the over coat), or both the inner core and the outer coating layers. In certain embodiments, the APAP

Particulates can contain a plasticizer and/or a surfactant in the seal coat, in the functional coat(s), or in both the seal coat and the functional coat(s). In certain embodiments, the APAP Particulates can be made by mixing acetaminophen with EUDRAGIT® E PO in the granule core.

In certain embodiments, APAP Particulates can be prepared in several ways known to those of skill in the art, including hot-melt extrusion, film melt, granulation, melt granulation, extrusion spheronization, and rotor or roller compaction.

In certain embodiments, acetaminophen is present in APAP Particulates. In certain embodiments, acetaminophen is present in the particulate or multi-particulate dosage form in an amount effective for supplementing the intended therapeutic purpose of the opioid. These amounts are well known in the art. The doses at which

acetaminophen can be given safely and effectively for the intended therapeutic purpose are known to those of skill in the art. In certain embodiments, acetaminophen is present in an amount of about 0.1% to about 95% w/w of the APAP Particulate before the addition of the seal coat, the functional coat(s), and the over coat (i.e., about 0.1% to about 95% w/w of the polymer matrix embedded with acetaminophen). In certain embodiments, acetaminophen is present in an amount of about 0.2% to about 90%, about 0.3% to about 85%, about 0.4% to about 80%, about 0.5% to about 75%, about 0.6% to about 70%, about 0.7% to about 65%, about 0.8% to about 60%, about 0.9% to about 55%, about 1% to about 50%, about 2.5% to about 45%, about 5% to about 40%, about 7.5% to about 35%, about 10% to about 30%, about 12.5% to about 25%, or about 15% to about 20%) w/w of the polymer matrix embedded with acetaminophen. In certain embodiments, acetaminophen is present in an amount of at least about 0.1%, at least about 0.2%), at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%), at least about 40%, at least about 45%., at least about 50%, at least about 55%), at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% w/w of the polymer matrix embedded with acetaminophen.

5.3.1. APAP and Other Nonopioid Analgesics

APAP Particulates contain one or more nonopioid analgesic agent(s). In certain embodiments, nonopioid analgesics include, without limitation, acetaminophen (APAP), aspirin, ibuprofen, naproxen, meloxicam, celecoxib, and ketoprofen.

The nonopioid analgesic is present in the dosage form in an amount effective for the intended therapeutic purpose. These amounts are well known in the art. Indeed, the doses at which any of the presently known nonopioid analgesics embraced by the present disclosure can be given safely and effectively for the intended therapeutic purpose are known to those of skill in the art. In certain embodiments, the nonopioid analgesic is present in an amount of about 0.1% to about 95% w/w of the APAP

Particulate before the addition of the (optional) seal coat, the functional coat(s), and the over coat (i.e., about 0.1% to about 95% w/w of the polymer matrix / cellets embedded with the nonopioid analgesic, e.g., acetaminophen). In certain embodiments, the nonopioid analgesic is present in an amount of about 0.2% to about 90%, about 0.3% to about 85%, about 0.4% to about 80%, about 0.5% to about 75%, about 0.6% to about 70%, about 0.7% to about 65%, about 0.8% to about 60%, about 0.9% to about 55%, about 1% to about 50%, about 2.5% to about 45%, about 5% to about 40%, about 7.5% to about 35%, about 10% to about 30%, about 12.5% to about 25%, or about 15% to about 20%) w/w of the polymer matrix / core embedded with the nonopioid analgesic. In certain embodiments, the nonopioid analgesic is present in an amount of at least about 0.1%), at least about 0.2%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%), at least about 80%, at least about 85%, at least about 90%, or at least about 95% w/w of the polymer matrix / core embedded with the nonopioid analgesic. 5.4. Seal Coats for Opioid and APAP Particulates

In certain embodiments, the Opioid Particulates and/or APAP Particulates can be seal coated. In some embodiments, the seal coat can be disposed between the inner polymer matrix core (e.g., the polymer matrix with opioid or acetaminophen embedded within) or the pellet core (e.g., cellet embedded with or sprayed with opioid or acetaminophen), and at least one functional coat (e.g., FC 1 (Opioid Particulates) or APAP-FC 1 (APAP Particulates)). In certain embodiments, the seal coat can be made with a water-soluble nonionic polymer. In certain embodiments, the nonionic polymer that can be included in the seal coat is a cellulose ether polymer (e.g., a water-soluble methylcellulose and/or hydroxypropyl methylcellulose polymer). In certain

embodiments, the amount of the polymer ranges from about 5% to about 100% w/w of the total weight of the composition of the seal coat (also noted within as "seal coat composition"); in certain embodiments from about 30% to about 95% w/w based on the total weight of the seal coat composition; and in certain embodiments from about 50% to about 75%) w/w based on the total weight of the seal coat composition. In certain embodiments, the amount of the polymer ranges from about 10% to about 95%, about 15% to about 90%, about 20% to about 85%, about 25% to about 80%, about 30% to about 75%, about 35% to about 70%, about 40% to about 65%, about 45% to about 60%, or about 50% to about 55% w/w of the total weight of the seal coat composition.

In certain embodiments, the seal coat composition also can include additional excipients such as an anti-tacking agent (e.g., talc, magnesium trisilicate, colloidal silicon dioxide (e.g., CAB-O-SIL^®)) and a plasticizer. In certain embodiments, the amount of the additional excipients, when present, can range from about 0.1% to about 40%), or from about 0.5% to about 10% w/w of the total weight of the seal coat composition. In certain embodiments, the additional excipients are present at about 0.5% or about 4% w/w based on the total weight of the seal coat composition. In certain embodiments, the additional excipients are present from about 0.25% to about 35%, about 0.5% to about 30%, about 0.75% or about 25%, about 1% or about 20%, about 2.5% or about 15%, or about 5% or about 10% w/w based on the total weight of the seal coat composition.

In certain embodiments, the seal coat composition can also include an amount of the opioid, which can be therapeutically effective in and of itself, as well as the plasticizer and/or the surfactant, as well as other excipients and ingredients such as one or more solvents (both aqueous and organic, e.g., ethanol), as well as other excipients that can also be included in the seal coat composition.

In certain embodiments, the seal coat can be present in a range of about 0.1%) to about 40%) w/w of the uncoated Opioid Particulates / APAP Particulates, i.e., the Opioid Particulates / APAP Particulates before being coated with the seal coat. In certain embodiments, the seal coat can be present in a range from about 5% to about 25% w/w of the uncoated Opioid Particulates / APAP Particulates. In certain embodiments, the seal coat can be present in an amount of about 5% or about 15% w/w of the uncoated Opioid Particulates / APAP Particulates. In certain embodiments, the seal coat can be present in a range of about 0.2% to about 37.5%, about 0.3% to about 35%, about 0.4% to about 32.5%, about 0.5% to about 30%, about 0.6% to about 27.5%, about 0.7% to about 25%, about 0.8% to about 22.5%, about 0.9% to about 20%, about 1% to about 17.5%, about 2.5% to about 15%, about 5% to about 12.5%, or about 7.5% to about 10% w/w of the total weight of the uncoated Opioid Particulates / APAP Particulates. In certain embodiments, the seal coat can be present in an amount of at least about 0.1%, at least about 0.2%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%), at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, or at least about 40% w/w of uncoated Opioid Particulates / APAP Particulates.

5.5. Functional Coats for Opioid and APAP Particulates

In certain embodiments, Opioid Particulates are coated with a functional coat(s) (e.g., FC 1). In certain embodiments, e.g., FC 1 includes a water-insoluble nonionic polymer, and a cationic polymer (e.g., a cationic polymer that is soluble in gastric fluids) that behaves as a pore former at pH below 5.

In certain embodiments, a functional coat(s) of the Opioid Particulates can comprise at least a water-insoluble nonionic polymer, e.g., cellulose acetate, cellulose acetate-based polymers (e.g. OP ADR Y^® CA, cellulose acetate butyrate, cellulose acetate propionate, and the like), polyvinyl acetate polymers, polyvinyl acetate-based copolymers (e.g., KOLLIDON^® SR), ethylcellulose (e.g., ETHOCEL™),

EUDRAGIT^® RL 100, EUDRAGIT^® RL PO, EUDRAGIT^® RS 100,

EUDRAGIT^® RS PO, EUDRAGIT^® NE 30 D, EUDRAGIT^® NE 40 D, and the like, or a blend thereof; and/or a cationic polymer (e.g., dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate copolymer (e.g., EUDRAGIT^® E PO)).

In certain embodiments, a functional coat(s) of Opioid Particulates comprises cellulose acetate and a dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate copolymer. In certain embodiments, the dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate copolymer is

EUDRAGIT^® E PO.

In certain embodiments, a functional coat comprising cellulose acetate ("CA") and/or CA-based polymer blends, together with the pH-dependent (cationic) pore former, becomes semipermeable to almost impermeable at a pH above about 5, thereby significantly reducing drug release. In certain embodiments (e.g., embodiments related to opioids having a solubility of greater than about 100 microgram/ml of physiological fluids (e.g., GI fluids, SGF)), the ratio of CA to pore former (i.e., CA : pore former) in a functional coat(s) can be from about 70:30 to about 98:2 wt% ratio. In certain embodiments, the ratio of CA to pore former can be from about 72.5:27.5 to about 95:5, about 75:25 to about 92.5:7.5, about 77.5:22.5 to about 90: 10, about 80:20 to about

87.5: 12.5, or about 82.5: 17.5 to about 85: 15 wt% ratio. In certain embodiments, the ratio of CA to pore former can be about 71 :29, about 72:28, about 73 :27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81 : 19, about 82: 18, about 83 : 17, about 84: 16, about 85: 15, about 86: 14, about 87: 13, about 88: 12, about 89: 11, about 90: 10, about 91 :9, about 92:8, about 93 :7 about 94:6 about 95:5, about 96:4, about 97:3, or about 98:2 wt% ratio. In certain embodiments, the ratio of CA to pore former can be about 80:20 wt% ratio. In certain embodiments (e.g., embodiments related to opioids having a solubility of less than about 100 microgram/ml of physiological fluids), the amount of pore former in the ratio of CA to pore former can exceed the amount of pore former used for opioids having a solubility of greater than about 100 microgram/ml of physiological fluids (for example, the ratio of CA to pore former can be from about 50:50 to about 70:30).

In certain embodiments, the water-insoluble nonionic polymer is a polyvinyl acetate polymer ("PVA polymer") or a PVA-based polymer or copolymer. In certain embodiments, the PVA-based polymer along with the cationic pore former becomes almost impermeable at a pH above 5, thereby significantly reducing drug release. In certain embodiments, the ratio of PVA-based polymer to pore former (i.e., PVA-based polymer: pore former) in a functional coat(s) can be from about 70:30 to about 98:2 wt% ratio. In certain embodiments, the ratio of PVA-based polymer to pore former can be from about 72.5:27.5 to about 95:5, about 75:25 to about 92.5:7.5, about 77.5:22.5 to about 90: 10, about 80:20 to about 87.5: 12.5, or about 82.5: 17.5 to about 85: 15 wt% ratio. In certain embodiments, the ratio of PVA-based polymer to pore former can be about 71 :29, about 72:28, about 73 :27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81 : 19, about 82: 18, about 83 : 17, about 84: 16, about 85: 15, about 86: 14, about 87: 13, about 88: 12, about 89: 11, about 90: 10, about 91 :9, about 92:8, about 93 :7 about 94:6 about 95:5, about 96:4, about 97:3, or about 98:2 wt% ratio. In certain embodiments, the ratio of PVA-based polymer to pore former can be about 80:20 wt% ratio. In certain embodiments (e.g., embodiments related to opioids having a solubility of less than about 100 microgram/ml of physiological fluids), the amount of pore former in the ratio of PVA-based polymer to pore former can exceed the amount of pore former used for opioids having a solubility of greater than about 100 microgram/ml of physiological fluids (for example, the ratio of PVA-based polymer to pore former can be from about 50:50 to about 70:30).

In certain embodiments, APAP Particulates are coated with a functional coat(s) (e.g., FC 1). In certain embodiments, the APAP Particulates are coated with a functional coat(s) (e.g., APAP-FC 1). In certain embodiments, e.g., APAP-FC 1 includes a cationic polymer (e.g., a cationic polymer that is soluble in gastric fluids) and, optionally, a water-insoluble nonionic polymer. In certain embodiments, e.g.,

APAP-FC 1 of APAP Particulates comprises EUDRAGIT^® E PO. In certain

embodiments, e.g., APAP-FC 1 includes cellulose acetate (CA) and dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate copolymer (e.g.,

EUDRAGIT^® E PO) in a wt% ratio from about 1 :99 to about 70:30.

EUDRAGIT^® E PO is soluble in gastric fluid up to about pH 5. Above about pH 5, EUDRAGIT^® E PO is swellable and permeable. The uniqueness of the chemical properties of EUDRAGIT^® E PO contributes to its dual roles in the overdose protection imparted by the present technology. It is soluble in aqueous fluids with a pH below 5 (e.g., including in normal gastric fluid); thus, upon oral administration,

EUDRAGIT^® E PO allows for the release of nonopioid analgesic from the APAP Particulates, when the gastric fluid is unmodified. However, when the pH of the gastric fluid is increased above 5 (e.g., when three or more dosage units of the present disclosure are ingested), the EUDRAGIT^® E PO in, e.g., APAP-FC 1 no longer dissolves. The elevated pH prevents the EUDRAGIT^® E PO from dissolving, which leads to decreased release of nonopioid analgesic from the APAP Particulates. Together these processes regulate (i.e., significantly reduce) the release of the nonopioid analgesic based on the pH of the gastric environment. In certain embodiments, APAP Particulates are not coated with any functional coat (e.g., "naked" APAP Particulates).

In certain embodiments, if three or more dosage units are taken, release of the opioid from the dosage form is significantly reduced. In certain embodiments, the release is reduced by 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%), or increments therein. In certain embodiments, the release is reduced from about 30% to about 90%, about 40% to about 80%, or about 50% to about 70%.

In certain embodiments, the composition of the functional coating (e.g., FC 1 of Opioid Particulates and/or, e.g., APAP-FC 1 of APAP Particulates) can also include an anti-tacking agent (e.g., talc, magnesium trisilicate, colloidal silicon dioxide (e.g., CAB-O-SIL^®)) and/or a plasticizer.

In certain embodiments, the functional coating prevents the extraction of the opioid and/or the nonopioid analgesic in water and in water / alcohol mixtures.

In certain embodiments, a functional coat(s) for Opioid Particulates, e.g.,

FC 1, can be present in a range of about 5% to about 70% w/w of the uncoated or seal coated Opioid Particulates (i.e., the polymer matrix with opioid embedded within, also including the optional seal coat, if present). In certain embodiments, e.g., FC 1 can be present in a range of about 10% to about 65%, about 15% to about 60%, about 20% to about 55%), about 25% to about 50%, about 30% to about 45%, or about 35% to about 40% w/w of the uncoated or seal coated Opioid Particulates. In certain embodiments, e.g., FC 1 can be present in a range of about 5% to about 10%, about 5.25% to about 9.75%, about 5.5% to about 9.5%, about 5.75% to about 9.25%, about 6% to about 9%, about 6.25% to about 8.75%, about 6.5% to about 8.5%, or about 6.75% to about 8.25% w/w of the uncoated or seal coated Opioid Particulates. In certain embodiments, e.g.,

FC 1 can be present in a range from about 10% to about 35% w/w of the uncoated or seal coated Opioid Particulates. In certain embodiments, e.g., FC 1 can be present in an amount of about 15% or about 25% w/w of the uncoated or seal coated Opioid

Particulates. In certain embodiments, , a functional coat(s) for APAP Particulates, e.g., APAP-FC 1, can be present in the range of about 5% to about 50% of the seal coated APAP Particulates. In certain embodiments, e.g., APAP-FC 1 can be present in a range of about 10%) to about 65%>, about 15%> to about 60%>, about 20% to about 55%, about 25% to about 50%, about 30% to about 45%, or about 35% to about 40% w/w of the uncoated or seal coated APAP Particulates. In certain embodiments, e.g., APAP-FC 1 can be present in the range of about 10% to about 20% of the seal coated APAP

Particulates.

In certain embodiments, functional coated Opioid Particulates and/or APAP Particulates can be with more than one functional coat(s) (e.g., FC 0, FC 1, FC 2, APAP-FC 0, APAP-FC 1, APAP-FC 2) to further enhance ODP features. In certain embodiments, a functional coat(s) can comprise a cationic polymer (e.g.,

Eudragit® E PO). In certain embodiments, a functional coat(s) can comprise a cationic polymer and a nonionic polymer. In certain embodiments, the composition of functional coat(s) can also include an anti-tacking agent (e.g., talc, magnesium trisilicate, colloidal silicon dioxide (e.g., CAB-O-SIL^®)) and/or a plasticizer.

In certain embodiments, FC 2 can be present in a range of about 5% to about 100%) w/w of the functional FC 1 -coated Opioid Particulates (i.e., the polymer matrix with opioid embedded within, the FC 1, and also including the optional seal coat, if present). In certain embodiments, the FC 2 can be present in a range from about 10% to about 40% w/w of the FC 1 -coated Opioid Particulates. In certain embodiments, FC 2 can be present in a range from about 12.5% to about 37.5%, about 15% to about 35%, about 17.5% to about 32.5%, about 20% to about 30%, or about 22.5% to about 27.5% w/w of the FC 1 -coated Opioid Particulates.

In certain embodiments, the functional coated APAP Particulates can further be coated with a second functional coat (APAP-FC 2) to further enhance the ODP feature. In certain embodiments, APAP-FC 1 in APAP Particulates comprises

EUDRAGIT^® E PO and cellulose acetate. In these embodiments, APAP-FC 1 is further coated with a second functional coat (i.e., APAP-FC 2) comprising EUDRAGIT^® E PO and, optionally, a nonionic polymer. In certain embodiments, APAP-FC 2 is 100% w/w of EUDRAGIT^® E PO.

In certain embodiments, Opioid Particulates and/or APAP Particulates can comprise one, two, or three functional coats (e.g., FC 0, FC 1, FC 2, APAP-FC 0, APAP-FC 1, APAP-FC 2). In certain embodiments, Opioid Particulates and/or APAP Particulates can comprise more than three functional coats (e.g., four or five functional coats). In certain embodiments, any one or more of the functional coats (in either or both of Opioid Particulates and APAP Particulates) can comprise a cationic polymer(s) in the absence of a water-insoluble nonionic polymer. In certain embodiments, any one or more of the functional coats (in either or both of Opioid Particulates and APAP

Particulates) can comprise a cationic polymer(s) in the presence of a water-insoluble nonionic polymer; in such embodiments, the ratio of nonionic polymer to cationic polymer can be from about 0.1 :99.9 to about 99.9:0.1.

5.6. Over Coats for Opioid and APAP Particulates In certain embodiments, the functional coated Opioid Particulates (i.e., comprising FC 0, FC 1, and/or FC 2) and functional coated APAP Particulates (i.e., comprising APAP-FC 0, APAP-FC 1, and/or APAP-FC 2) include an over coat to prevent / minimize the interaction of a cationic polymer, e.g., EUDRAGIT^® E PO (present in the functional coat(s)) with the alkaline agent present in the Triggering Particulates. The over coat can include a water-soluble nonionic polymer (e.g., hydroxypropyl methylcellulose). In certain embodiments, "naked" APAP Particulates include an overcoat. In certain embodiments, naked APAP Particulates do not include an overcoat.

In certain embodiments, the composition of the over coat can also include additional excipients such as an anti-tacking agent (e.g., talc, magnesium trisilicate, colloidal silicon dioxide (e.g., CAB-O-SIL^®)) and a plasticizer.

In certain embodiments, the over coat can be present in a range of about 5% to about 50% w/w of the functional coated Opioid Particulates and/or APAP

Particulates (i.e., the polymer matrix with opioid embedded within, the functional coat(s), and the seal coat, if present). In certain embodiments, the over coat can be present in a range of about 10% to about 30%, about 10% to about 35%, about 15% to about 25%, about 10% to about 45%, about 15% to about 40%, about 20% to about 35%, or about 25% to about 30% w/w of the functional coated Opioid Particulates and/or APAP Particulates.

5.7. Crushability and Grindability Resistance

In certain embodiments, the Opioid Particulates (e.g., Opioid Granules) and APAP Particulates are at least partially crush-resistant and grind-resistant. In certain embodiments, Opioid Particulates and APAP Particulates are substantially

indistinguishable, noncrushable, and nongrindable, thereby making it difficult to isolate and abuse the opioid content. For example, Opioid Granules resist abuse via, but not limited to, crushing or grinding and swallowing; crushing or grinding and inhaling or insufflating nasally ("snorting"); crushing or grinding and smoking; and crushing or grinding, dissolving, and injecting (subcutaneously (i.e., skin popping), intravenously, or intramuscularly). In certain embodiments, the Opioid Granules cannot be ground or crushed into particles small enough to be effectively snorted or injected. In certain embodiments, the APAP Particulates cannot be efficiently separated from Opioid Particulates. In certain embodiments, the opioid/ APAP dosage form, when taken in doses above therapeutically effective amounts (e.g., three or more dosage units;

overdosed), taken in a manner inconsistent with the manufacturer's instructions, and/or in a manner not prescribed, can cause severe liver damage; this can deter the abuser. In certain embodiments, the Opioid Granules and APAP Particulates cannot be pulverized into fine powder by mechanical grinding.

In certain embodiments, a plasticizer can be added to increase the elasticity of the polymer in Opioid Particulates (e.g., Opioid Granules), thereby making the granules both crush-resistant and grind-resistant. In certain embodiments, a plasticizer (e.g., triethyl citrate) present in the core of an Opioid Granule makes the Opioid Granule crush-resistant and grind-resistant. In certain embodiments, the plasticizer present in a functional coat (e.g., FC 1 and FC 2) makes the functional coat crush -resistant and grind-resistant (i.e., the coat remains intact after attempted crushing or grinding).

The resistance of the Opioid Granules to crushing and grinding is provided, at least in part, by vitamin E, which prevents degradation of PEO during hot- melt extrusion (HME). Thus, heating during HME, in the presence of vitamin E, provides a curing process to the PEO in the core, making the plastic extrudates difficult to grind by conventional milling methods, as well as difficult to crush into powder. In addition, further resistance of the Opioid Granules to crushing and grinding is provided by the presence of PEO (with vitamin E) and UPMC in the core. Opioid Granules produced by HME and containing PEO and HPMC, followed by cryogenic milling, are not grindable by either common household grinders or analytical laboratory grinders, and are crush-resistant. The crush-resistance of the Opioid Granules can be determined by a measurement of crushing strength required to deform the granules without any evidence of fragmentation or breaking into smaller pieces or powder using an Instron Tester or equivalent.

Abuse deterrence can be tested by examining the mean particle size following the physical manipulation of the Opioid Granule. For example, the Opioid Granules can be subjected to grinding in a coffee grinder, mill, mortar and pestle, a food processor, a blender, etc. For example, Opioid Granules can be placed in a coffee grinder (e.g., Hamilton Beach Coffee Grinder) and ground for several cycles (e.g., at a 10 cup setting for 8 cycles of 30 seconds each).

The mean particle size of the granules after grinding can be measured using sieve analysis that gathers granules of the same size into groups based on particle size. The weight of the particles in each group can be measured and compared to the unground sample.

In certain embodiments, the mean particle size after grinding the Opioid

Granules is preferably greater than 500 μιη (with a range of about 250 μιη to about 1000 μιη) (as measured by weight frequency distribution using sieving method), which is larger than the maximum particle size of about 125 μιη that can be inhaled through the nose. In certain embodiments, the mean particle size after grinding the Opioid Granules is greater than about 500 μπι, and difficult to snort (i.e., nasal insufflation). In certain embodiments, the mean particle size after grinding the Opioid Granules is greater than about 150 μπι, about 175 μπι, about 200 μπι, about 225 μπι, about 250 μπι, about 275 μπι, about 300 μπι, about 325 μπι, about 350 μπι, about 375 μπι, about 400 μπι, about 425 μπι, about 450 μπι, about 475 μπι, about 500 μπι, about 525 μπι, about 550 μπι, about 575 μπι, about 600 μπι, about 625 μπι, about 650 μπι, about 675 μπι, or about 700 μιη.

5.8. Triggering Particulates

In certain embodiments, the Triggering Particulates can be Triggering Granules. In certain embodiments, the Triggering Particulates can be Triggering Pellets. In certain embodiments, the Triggering Particulates can contain a combination of at least one alkaline agent (e.g., magnesium hydroxide (e.g., three or more dosage units increase the gastric pH from about 1.6 to greater than about 5)) and, optionally, at least one pH- stabilizing agent (e.g., di and/or tricalcium phosphate (e.g., three or more dosage units maintain the newly increased gastric pH of greater than about 5 for up to or about 1 hour to about 2 hours)). Ingestion of one or two dosage units (i.e., one or two tablets, capsules, etc.) results in little or no increase in pH of the gastric fluids. In certain embodiments, ingestion of multiple dosage units (e.g., three or more; more than two) results in the alkaline agent increasing the pH very rapidly above about 5. In certain embodiments, the pH-stabilizing agent acts to maintain or stabilize the increased pH caused by the alkaline agent. For example, ingestion of multiple dosage units results in (a) a rapid increase in pH caused by the alkaline agent; (b) modulation of pore formation in the functional coat; and (c) a decrease in the rate of release of the opioid (e.g., oxycodone, hydrocodone) from the Opioid Particulate. In certain embodiments, upon ingestion of multiple dosage units (e.g., three or more), the pH of the gastric fluid increases very rapidly above a pH of about 5 in about 1 to about 5 minutes. In certain embodiments, the increase in the pH of the gastric fluid upon taking multiple dosage units occurs in about 2 to about 3 minutes.

In certain embodiments, the alkaline agent for use in the Triggering Particulates include, but are not limited to, aluminum hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum oxide, sodium oxide, potassium oxide, calcium oxide, magnesium oxide, calcium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine, L-lysine, and combinations thereof. In certain embodiments, the alkaline agent is magnesium hydroxide.

In certain embodiments, the alkaline agent is present in an amount such that when a single dosage unit is taken, it does not alter the pH of the gastric fluid. In certain embodiments, the alkaline agent is present in an amount from about 30% to about 90% w/w of total Triggering Particulates. In certain embodiments, the alkaline agent is present in an amount from about 35% to about 85%, about 40% to about 80%, about 40% to about 70%, about 45% to about 75%, about 50% to about 70%, about 55% to about 65%), or about 70% to about 90% w/w of the total Triggering Particulate. In certain embodiments, the alkaline agent is present in an amount of about 50% or about 60%) w/w of total Triggering Particulate.

In certain embodiments, the pH-stabilizing agent for use in the Triggering Particulates include, but are not limited to, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, calcium phosphate, dibasic calcium phosphate, dihydroxyaluminum aminoacetate, dihydroxyaluminum glycine, magnesium glycinate, sodium potassium tartrate, tribasic sodium phosphate, tricalcium phosphate, and combinations thereof. In certain embodiments, the pH- stabilizing agent is a combination of dibasic calcium phosphate / tricalcium phosphate. In certain embodiments, the ratio of dibasic calcium phosphate to tricalcium phosphate (i.e., dibasic calcium phosphate : tricalcium phosphate) is about 1 : 1 to about 1 :5 wt% ratio. In certain embodiments, the ratio of dibasic calcium phosphate to tricalcium phosphate is about 1 : 1.25 to about 1 :4.75, about 1 : 1.5 to about 1 :4.5, about 1 : 1.75 to about 1 :4.25, about 1 :2 to about 1 :4, about 1 :2.25 to about 1 :3.75, about 1 :2.5 to about 1 :3.5, or about 1 :2.75 to about 1 :3.25 wt% ratio. In certain embodiments, the pH- stabilizing agent is anhydrous dibasic calcium phosphate.

In certain embodiments, the pH-stabilizing agent is present in an amount that when a single dosage unit is taken, it does not alter the pH of the gastric fluid, but when multiple dosage units are taken (e.g., three or more dosage units), the pH- stabilizing agent maintains the elevated pH levels caused by the alkaline agent. In certain embodiments, the pH-stabilizing agent is present in an amount sufficient to maintain or stabilize the pH of the gastric fluid above 5 for up to 5 hours. In certain embodiments, the pH-stabilizing agent is present in an amount sufficient to maintain the pH of the gastric fluid above 5 for about 1 to about 2 hours. In certain embodiments, the pH-stabilizing agent is present in an amount sufficient to maintain the pH of the gastric fluid above 5 for at least about 1 hour, at least about 1.25 hours, at least about 1.5 hours, at least about 1.75 hours, at least about 2 hours, at least about 2.25 hours, at least about 2.5 hours, at least about 2.75 hours, at least about 3 hours, at least about 3.25 hours, at least about 3.5 hours, at least about 3.75 hours, at least about 4 hours, at least about 4.25 hours, at least about 4.5 hours, at least about 4.75 hours, at least about 5 hours.

In certain embodiments, the pH-stabilizing agent is present in an amount from about 10% to about 60% w/w of total Triggering Particulates. In certain embodiments, the pH-stabilizing agent is present in an amount from about 12.5% to about 57.5%, about 15% to about 55%, about 15% to about 40%, about 17.5% to about 52.5%, about 20% to about 50%, about 22.5% to about 47.5%, about 25% to about 45%, about 27.5% to about 42.5%, about 30% to about 40%, or about 32.5% to about 37.5% w/w of total Triggering Particulates. In certain embodiments, the pH-stabilizing agent is present in an amount of about 20% or about 30% w/w of total Triggering Particulates. In certain embodiments, the alkaline agent and the pH-stabilizing agent (combined) (e.g., included in the Triggering Particulates) are present in an amount of less than 60% w/w (i.e., 60 wt%) of the total dosage form (or pharmaceutical composition). In certain embodiments, the alkaline agent and the pH-stabilizing agent (combined) are present in an amount of less than 60%, less than 55%, less than 50%, less than 45%, less than 44%, less than 43%, less than 42%, less than 41%, less than 40%, less than 39%, less than 38%, less than 37%, less than 36%, less than 35%, less than 34%, less than 33%, less than 32%, less than 31%, less than 30%, less than 29%, less than 28%, less than 27%, less than 26%, less than 25%, less than 24%, less than 23%, less than 22%, less than 21%, less than 20%, less than 19%, less than 18%, less than 17%, less than 16%), or less than 15%, w/w of the total dosage form (or pharmaceutical composition).

In certain embodiments, the Triggering Particulates include a binder, a disintegrant, filler (or diluents), and/or a lubricant.

Binders according to the present disclosure include, but are not limited to, hydroxypropyl celluloses in various grades, hydroxypropyl methylcelluloses in various grades, polyvinylpyrrolidones in various grades, copovidones, powdered acacia, gelatin, guar gum, carbomers, methylcelluloses, polymethacrylates, and starches.

Disintegrants according to the present disclosure include, but are not limited to, carmellose calcium, carboxy methyl starch sodium, croscarmellose sodium, crospovidone (crosslinked homopolymer of N-vinyl-2- pyrrolidone), low-substituted hydroxypropyl celluloses, sodium starch glycolate, colloidal silicon dioxide, alginic acid and alginates, acrylic acid derivatives, and various starches.

Lubricants according to the present disclosure include, but are not limited to, magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and any combinations thereof.

The Triggering Particulates can be prepared by any granulation method known to those of skill in the art. For example, the Triggering Particulates can be made by dry granulation (e.g., direct blend, compacting and densifying the powders), wet granulation (e.g., addition of a granulation liquid onto a powder bed under the influence of an impeller or air), or melt granulation, roller compaction. The granulation product obtained can be milled to achieve uniform granules. The granules obtained can be subsequently coated with an aqueous dispersion. In certain embodiments, the mean particle size distribution of the Triggering Particulates is about 100 μιη to about 1000 μιη. In certain embodiments, the mean particle size distribution of the Triggering Particulates is about 150 μιη to about 950 μπι, about 200 μιη to about 900 μπι, about 250 μιη to about 850 μπι, about 300 μιη to about 800 μπι, about 350 μιη to about 750 μπι, about 400 μιη to about 700 μπι, about 450 μπι to about 650 μπι, or about 500 μιη to about 600 μιη.

5.9. Viscosity Enhancing Particulates

In certain embodiments, the Viscosity Enhancing Particulates can be Viscosity Enhancing Granules. Viscosity Enhancing Granules increase the viscosity of the dosage form when added to a solution, thus impeding the ability to extract the opioid from the dosage form or to pass the solution through a needle for injection purposes.

In certain embodiments, the increase in viscosity can also reduce the potential absorption of the opioid when taken in amounts in excess of two dosage units (e.g., three or more dosage units). As the viscosity of the solution in the GI tract increases, the opioid is eventually entrapped in a polymer gel matrix and the dosage form is transformed from an IR formulation to an extended-release formulation. It is believed that the ingestion of increasing quantities of the formulation will not proportionally increase the maximum concentration (C_max) to reach the full potential of abusive effects (e.g., euphoria, sedation, and/or relaxation) of the opioid. In addition, it will take a longer time to reach maximum concentration (T_max). The result will be a reduced desirability of deliberately abusing or overdosing on the opioid.

In certain embodiments, the Viscosity Enhancing Granules contain a viscosity-building polymer. In certain embodiments, the viscosity-building polymer is present in an amount that is sufficient to increases the viscosity of the surrounding fluid in the GI tract if multiple doses, e.g., three or more dosage units, are taken for abuse purpose and/or prevents syringeability by rapidly forming a gelatinous mass that resists passage through a needle when subjected to about 10 ml aqueous or nonaqueous media.

In certain embodiments, the Viscosity Enhancing Granules include a polymer matrix that can include a nonionic polymer (e.g., polyethylene oxide (PEO) polymers such as POLYOX® WSR coagulant, POLYOX® WSR-301, POLYOX® WSR-303) and/or pH-dependent polymers (e.g., anionic polymers such as carbomers (e.g., Carbopol 934P, Carbopol 971P, Carbopol 974P)). In certain embodiments, Viscosity Enhancing Granules include an antioxidant, a plasticizer and/or a surfactant, each of which can be the same or different from those used in the Opioid Granules. In certain embodiments, the Viscosity

Enhancing Granules matrix further includes a glidant (e.g., talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch and tribasic calcium phosphate). In certain embodiments, the Viscosity Enhancing Granules matrix further includes a disintegrant.

In certain embodiments, the viscosity-building polymer is present in an amount that does not retard the release of the opioid from a single dose administration, but does slow down the release of the opioid after multiple dosage units are taken (e.g., three or more dosage units). In certain embodiments, the viscosity-building polymer is present in an amount from about 2% to about 60% w/w of total Viscosity Enhancing Granules. In certain embodiments, the viscosity-building polymer is present in an amount from about 5% to about 55%, about 10% to about 50%, about 15% to about 45%, about 20% to about 40%, or about 25% to about 35% w/w of total Viscosity

Enhancing Granules. In certain embodiments, the viscosity -building polymer is present in an amount of about 15% or about 20% w/w of total Viscosity Enhancing Granules.

Viscosity Enhancing Granules can be prepared by any granulation method known to those of skill in the art. For example, the Viscosity Enhancing Granules can be made by dry granulation (e.g., direct blend, compacting and densifying the powders), wet granulation (e.g., addition of a granulation liquid onto a powder bed under the influence of an impeller or air), melt granulation, hot-melt extrusion, extrusion spheronization, or rotor granulation. The granulation product obtained can be milled to achieve uniform granules. The granules obtained can be subsequently coated with an aqueous dispersion.

In certain embodiments, the mean particle size distribution of the

Viscosity Enhancing Granules is about 125 μιη to about 1000 μιη. In certain

embodiments, the mean particle size distribution of the Viscosity Enhancing Granules is about 150 μιη to about 950 μιτι, about 200 μιη to about 900 μιτι, about 250 μιη to about 850 μιη, about 250 μιη to about 750 μιτι, about 300 μιη to about 800 μιτι, about 350 μιη to about 750 μιτι, about 400 μιη to about 700 μιτι, about 450 μιη to about 650 μιτι, or about 500 μιη to about 600 μιη. 5.10. Particulate and Multi-particulate Dosage Forms

The present disclosure combines ADF and ODP properties in single solid oral IR dosage form and thus addresses multiple health-related concerns, especially regarding habit-forming opioids compounds for which there is a high propensity for abuse (e.g., opioids). In certain embodiments, the abuse deterrence and/or overdose protection activates after the ingestion of three or more dosage units (e.g., three or more tablets/capsules). In certain embodiments, the abuse deterrence and/or overdose protection activates when multiple dosage units are taken at once. In certain

embodiments, the abuse deterrence and/or overdose protection can activate when the multiple dosage units are taken in tandem. In certain embodiments, release of the opioid after ingesting one to two dosage units results in the dosage form maintaining its (their) IR characteristics (i.e., there is no effect on the release of the opioid from the dosage form(s)). In certain embodiments, if three or more dosage units are taken, release of the opioid from the dosage form is significantly reduced. In certain embodiments, the release is reduced by 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%), or increments therein. These dosage forms, however, are not intended to be used as an extended release or sustained release dosage form.

In certain embodiments, the IR pharmaceutical dosage form is a particulate dosage form. In certain embodiments, the IR pharmaceutical dosage form is a multi-particulate dosage form containing at least two different populations of

particulates. In certain embodiments, the IR pharmaceutical dosage form is a multiparticulate dosage form containing at least three different populations of particulates. In certain embodiments, the IR pharmaceutical dosage form contains at least four different populations of particulates. In certain embodiments, the IR pharmaceutical dosage form contains at least five, at least six, at least seven, or at least eight different populations of particulates. Each population of particulates is designed for a specific function to accomplish the desired combination of abuse deterrence and overdose protection qualities.

In certain embodiments, the pharmaceutical dosage forms contain at least one population of Opioid Particulates (e.g., Opioid Pellets and/or Opioid Granules), one population of APAP Particulates (e.g., APAP Pellets and/or Granules), and at least one population of Triggering Particulates (e.g., Triggering Pellets and/or Granules). In certain embodiments, the alkaline agent of the Triggering Particulates increases the pH of the aqueous or nonaqueous solution to above pH 5 in the presence of three or more dosage units, and the pH-stabilizing agent of the Triggering Particulates maintains the increased pH above 5 for up to two hours. In certain embodiments, the functional coat(s) (e.g., including partial and/or complete acid labile coat(s)) of the Opioid Particulates (and/or the APAP Particulates) only allows the release of the opioid (and/or the nonopioid analgesic) in an aqueous or nonaqueous environment with a pH below 5 and prevents or slows the release of the opioid in a pH above 5. Typically, the acid labile coat(s) (or portion(s) thereof) dissolves or degrades more slowly or to a very low extent when present in a solution with a pH that is not acidic (e.g., considered not acidic). In certain embodiments, the acid labile coat(s) (or portion(s) thereof) can be designed to dissolve at any pH below about 5; however, above that pH level, dissolution is inhibited, reduced or slowed. As the pH increases, the dissolution can slow further and can stop nearly completely.

In certain embodiments, the pharmaceutical dosage forms further contain at least one population of Viscosity Enhancing Particulates (e.g., Viscosity Enhancing Pellets and/or Granules). In certain embodiments, the pharmaceutical dosage forms contain at least one population of Opioid Particulates in combination with at least one population of APAP Particulates, at least one population of Triggering Particulates, and at least one population of Viscosity Enhancing Particulates. In certain embodiments, the Viscosity Enhancing Particulates are present in an amount of from about 2% to about 50% of the total weight of the dosage form.

In certain embodiments, the pharmaceutical dosage forms can contain at least one population of pH-dependent Viscosity Modifying Particulates. In certain embodiments, pH-dependent Viscosity Modifying Particulates are pH-dependent Viscosity Modifying Granules comprising pH-dependent viscosity building polymer (e.g., a carbomer such as Carbopol 934P, Carbopol 971P, and Carbopol 974P). In certain embodiments, the pH-dependent viscosity building polymer can be present in an amount that does not retard the release of the opioid from a single dose administration, but does slow down the release of the opioid after multiple dosage units are taken. In certain embodiments, the pH-dependent Viscosity Modifying Granules can be present in an amount from about 0.5 %> w/w to about 15% w/w of the total weight of the dosage form. In certain embodiments, the pH-dependent Viscosity Modifying Granules can be present in an amount from about 0.75 %> w/w to about 12.5%, about 1% to about 10%, or about 2.5%) to about 7.5%> w/w of the total weight of the dosage form. In certain embodiments, the pharmaceutical dosage forms contain at least one population of pH-dependent Viscosity Modifying Particulates (e.g., pH-dependent Viscosity Modifying Pellets and/or Granules). In certain embodiments, the

pharmaceutical dosage forms contain at least one population of Opioid Particulates in combination with at least one population of APAP Particulates, at least one population of Triggering Particulates, and at least one population of pH-dependent Viscosity

Modifying Particulates. In certain embodiments, the pharmaceutical dosage forms contain at least one population of Opioid Particulates in combination with at least one population of APAP Particulates, at least one population of Triggering Particulates, at least one population of Viscosity Enhancing Particulates, and at least one population of pH-dependent Viscosity Modifying Particulates.

In certain embodiments, the pharmaceutical dosage forms can contain at least one population of Ion Exchange Resin Granules (e.g., Amberlite™ IRP 64, Amberlite™ IRP 69). The ion exchange resins of the Ion Exchange Resin Granules form a matrix or complex with the drug and thus can alter the release of drug. In certain embodiments, the ion exchange resin can be present in an amount that binds to the opioid if the dosage form is tampered with, thereby preventing the release of the opioid from the dosage form. In certain embodiments, the Ion Exchange Resin Granules can be present in a concentration of about 1-5 M, or about 1-3 M, based on the total molarity of the drug susceptible to abuse.

In certain embodiments, the pharmaceutical dosage forms further contain at least one population of Ion Exchange Resin Particulates (Ion Exchange Resin Pellets and/or Granules). In certain embodiments, the pharmaceutical dosage forms contain at least one population of Opioid Particulates in combination with at least one population of APAP Particulates, at least one population of Triggering Particulates, and at least one population of Ion Exchange Resin Particulates. In certain embodiments, the

pharmaceutical dosage forms contain at least one population of Opioid Particulates in combination with at least one population of APAP Particulates, at least one population of Triggering Particulates, at least one population of Viscosity Enhancing Particulates, and at least one population of Ion Exchange Resin Particulates. In certain embodiments, the pharmaceutical dosage forms contain at least one population of Opioid Particulates in combination with at least one population of APAP Particulates, at least one population of Triggering Particulates, at least one population of Viscosity Enhancing Particulates, at least one population of pH-dependent Viscosity Modifying Particulates, and at least one population of Ion Exchange Resin Particulates.

In certain embodiments, a singular particulate population (e.g., a population combining an opioid(s) and a nonopioid analgesic(s) (e.g., APAP) in a single particulate), or a plurality of particulate populations (i.e., a multi-particulate population) can be blended with other excipients and additives and compressed into a dosage form, e.g., a tablet/mini-tablet, tablet-in-tablet, bilayer tablet, or multilayer tablet, or loaded into a capsule, or the like. In certain embodiments, additional solid IR dosage forms, including additional particulate, tablet, and/or capsule coating regimens, are

contemplated. A nonlimiting set of examples follows.

In certain embodiments, the formulation is a single particulate dosage form comprising a single population of particulates containing a mixture of opioid and APAP, the particulates being compressed into a tablet/mini-tablet or filled in a capsule, and at least one alkalinizing coat surrounding the tablet and/or capsule.

In certain embodiments, the multi-particulate dosage form is a two particulate dosage form comprising a first population of particulates containing a mixture of opioid and APAP, and a second population of particulates containing at least one alkaline agent and, optionally, at least one pH-stabilizing agent (Triggering Particulates); the two particulate populations are compressed into a tablet/mini-tablet or filled in a capsule.

In certain embodiments, the multi-particulate dosage form is a three particulate dosage form comprising a first population of particulates containing an opioid(s) (Opioid Particulates), a second population of particulates containing APAP (or another nonopioid analgesic(s) (APAP Particulates), and a third population of

particulates containing at least one alkaline agent and, optionally, at least one pH- stabilizing agent (Triggering Particulates); the three particulate populations are compressed into a tablet/mini-tablet or filled in a capsule.

In certain embodiments, the tablet/mini-tablet is further coated with an acid labile coat and, optionally, an alkalinizing coat on top of the acid labile coat.

In certain embodiments, Opioid Particulates contain an alkaline agent and, optionally, a pH-stabilizing agent in the polymer matrix.

In certain embodiments, the size of Opioid Particulates and, optionally, APAP Particulates is increased (e.g., from about 400 micrometers to about 2-3 mm) to provide enhanced control of release of opioid and/or APAP, e.g., in an ODP setting, In certain embodiments, the Opioid Particulates and APAP Particulates can have various functional coat(s) or sets of functional coats (e.g., without limitation, combinations of FC 0, FC 1, and/or FC 2; APAP-FC 0, APAP-FC 1, and/or

APAP-FC 2).

In certain embodiments, the Opioid Particulates and/or APAP Particulates have a seal coat (optional) on top of the polymer matrix.

In certain embodiments, the Opioid Particulates and/or APAP Particulates have an over coat on top of the functional coat(s).

In certain embodiments, capsules contain coated Opioid Particulates, coated / uncoated APAP Particulates, and Triggering Particulates.

In certain embodiments, capsules contain Triggering Particulates, and mini-tablets made from coated Opioid Particulates and coated / uncoated APAP

Particulates.

In certain embodiments, capsules contain mini-tablets of coated Opioid Particulates and coated / uncoated APAP Particulates, and mini-tablets of Triggering Particulates.

In certain embodiments, capsules contain coated Opioid Pellets, coated / uncoated APAP Particulates, and Triggering Particulates.

In certain embodiments, capsules contain (1) mini-tablets comprising coated Opioid Particulates, coated / uncoated APAP Particulates, and at least a portion of Triggering Particulates; and (2) a remaining portion of Triggering Particulates.

In certain embodiments, the dosage form is a bilayer tablet comprising a first layer comprising a blend of coated Opioid Particulates and coated / uncoated APAP Particulates, and a second layer comprising Triggering Particulates; the two layers are compressed into a bilayer tablet.

In certain embodiments, the dosage form is a bilayer tablet comprising a first layer comprising a coated (tablet) layer comprising a blend of uncoated Opioid Particulates and uncoated APAP Particulates, and a second layer comprising Triggering Particulates; the two layers are compressed into a bilayer tablet.

In certain embodiments, the dosage form is a tablet-in-tablet dosage form comprising an inner tablet comprising coated Opioid Particulates and coated / uncoated APAP Particulates, and an outer tablet, partially, substantially, or completely

surrounding the inner tablet, comprising Triggering Particulates.

In certain embodiments, the dosage form is a tablet-in-tablet dosage form comprising an inner coated tablet comprising uncoated Opioid Particulates and uncoated APAP Particulates, and an outer tablet, partially, substantially, or completely

surrounding the inner tablet, comprising Triggering Particulates.

In certain embodiments, the dosage form is a capsule dosage form comprising coated or uncoated compressed tablets comprising an opioid, a nonopioid analgesic, and Triggering Particulates.

In certain embodiments, the tablet / capsule dosage form disintegrates rapidly once in contact with an aqueous medium. In certain embodiments, the capsule can be a soft or hard gelatin capsule. In certain embodiments, the capsule itself does not alter the release of the opioid.

In certain embodiments, the Opioid Particulates are present in an amount from about 10% to about 80%> w/w of the total weight of the dosage form. In certain embodiments, the Opioid Particulates are present in an amount from about 15%> to about 75%, about 20% to about 70%, about 25% to about 65%, about 30% to about 60%, about 35%) to about 55%, or about 40% to about 50% w/w of the total weight of the dosage form. In certain embodiments, the Opioid Particulates are present in an amount from about 50% to about 80%, about 60% to about 80%, or about 70% to about 80% w/w of the total weight of the dosage form. In certain embodiments, the Opioid Particulates are present in an amount from about 10%> to about 50%, about 20% to about 50%, about 30%) to about 50%), or about 40% to about 50% w/w of the total weight of the dosage form. In certain embodiments, the Opioid Particulates are present in an amount of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%), at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%), or at least about 80% w/w of the total weight of the dosage form.

In certain embodiments, the APAP Particulates are present in an amount from about 10% to about 80% w/w of the total weight of the dosage form. In certain embodiments, the APAP Particulates are present in an amount from about 15% to about 75%, about 20% to about 70%, about 25% to about 65%, about 30% to about 60%, about 35%) to about 55%, or about 40% to about 50% w/w of the total weight of the dosage form. In certain embodiments, the APAP Particulates are present in an amount from about 50% to about 80%, about 60% to about 80%, or about 70% to about 80% w/w of the total weight of the dosage form. In certain embodiments, the APAP Particulates are present in an amount from about 10% to about 50%, about 20% to about 50%, about 30%) to about 50%), or about 40% to about 50% w/w of the total weight of the dosage form. In certain embodiments, the APAP Particulates are present in an amount of at least about 10%), at least about 15%, at least about 20%, at least about 25%, at least about 30%), at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%), or at least about 80% w/w of the total weight of the dosage form.

In certain embodiments, the Triggering Granules are present in an amount from about 20% to about 42% w/w of the total weight of the dosage form. In certain embodiments, the Triggering Granules are present in an amount from about 22% to about 40%, about 24% to about 38%, about 26% to about 36%, about 28% to about 34%, or about 30% to about 32% w/w of the total weight of the dosage form. In certain embodiments, the Triggering Granules are present in an amount from about 20% to about 42%, about 22% to about 42%, about 24% to about 42%, about 26% to about 42%, about 28% to about 42%, about 30% to about 42%, about 32% to about 42%, about 34% to about 42%, about 36% to about 42%, about 38% to about 42%, or about 40% to about 42%) w/w of the total weight of the dosage form. In certain embodiments, the Triggering Granules are present in an amount of at least about 20%, at least about 22%, at least about 24%), at least about 26%, at least about 28%, at least about 30%, at least about 32%), at least about 34%, at least about 36%, at least about 38%, at least about 40%, or at least about 42% w/w of the total weight of the dosage form.

In certain embodiments, the Viscosity Enhancing Granules are present in an amount from about 2% to about 50% w/w of the total weight of the dosage form. In certain embodiments, the Viscosity Enhancing Granules are present in an amount from about 5%) to about 45%, about 10% to about 40%, about 15% to about 35%, or about 20%) to about 30%) w/w of the total weight of the dosage form.

In certain embodiments, the pH-dependent Viscosity Modifying Granules are present in an amount from about 0.5% to about 15% w/w of the total weight of the dosage form. In certain embodiments, the pH-dependent Viscosity Modifying Granules are present in an amount from about 0.75 % to about 12.5%, about 1% to about 10%, or about 2.5%) to about 7.5% w/w of the total weight of the dosage form. In certain embodiments, the Ion Exchange Resin Granules are present in a concentration of about 1-5 M and in some embodiments from about 1-3 M, based on the total molarity of the drug susceptible to abuse.

5.11. Syringeability and Extractability Resistance, and Heat Stability

In certain embodiments, the particulate and multi-particulate dosage forms of the present disclosure provide several additional abuse-deterrent properties, including syringeability resistance, extractability resistance, and heat stability. For example, the multi-particulate dosage forms resist abuse via, but not limited to, extraction of the opioid from the dosage form, syringeability of the opioid from the dosage form, and destabilization of the several abuse-deterrent attributes by various heat treatment-related manipulations. In certain embodiments, the combination of these additional properties, along with the aforementioned resistance to crushability and grindability of the Opioid Particulates, strongly deter or prevent abuse of the particulate / multi-particulate dosage forms of the disclosure.

In certain embodiments, resistance to extractability is provided by, e.g., carbomers in the Opioid Particulates of the dosage form. In certain embodiments, carbomers (such as Carbopol 934P, Carbopol 97 IP, Carbopol 974P), as well as other anionic polymers that are viscosity-enhancing agents, form gel and increase viscosity in aqueous and/or alcoholic media, such as those media used by abusers attempting extraction of opioid from a given dosage form. In certain embodiments, the gelling effect of, e.g., carbomers is greatly enhanced in the alkaline pH resulting from the alkaline agent released from the Triggering Granules (e.g., in attempted extraction, or in the stomach when three or more dosage units are ingested); or the alkaline agent when present in the polymer matrix. In certain embodiments, carbomers in the core form gel and further diminish drug release, e.g., permeation from the core of Opioid Particulates into the GI fluid, or into aqueous media attempting to be drawn into a syringe. In certain embodiments, polymers present in the functional coat(s), e.g., EUDRAGIT^® E PO, are also involved in decreasing permeation of the opioid from the Opioid Particulates, e.g., when extraction is attempted. The alkaline agent(s) present in the dosage forms produce a rapid rise in the pH of aqueous media (e.g., in attempted extraction, or in the stomach when three or more dosage units are ingested). The polymers present in the functional coats, e.g., EUDRAGIT^® E PO, become less permeable in this alkaline media; thus the release of opioid from the dosage form is slowed or blocked. In certain embodiments, resistance to syringeability is provided by polyoxy ethylene (PEO) polymers and HPMC in the Opioid Particulates (e.g., in the core of the Opioid Granules). The gelling characteristics of these molecules, when exposed to aqueous media, provide resistance to syringeability as the bore of the needle is blocked by the viscous nature of the diluted dosage form. In addition, carbomers included in the dosage form (e.g., in the core of the Opioid Granules) provide further resistance to syringeability; in response to the rapidly rising pH induced by, e.g., Mg(OH)₂ in aqueous media, carbomer-based gelling is greatly enhanced, further diminishing drug release. In certain embodiments, carbomers included in the dosage form (e.g., in the core of the Opioid Granules) provide further resistance to syringeability in response to the rising pH induced by the interaction of aqueous media with Mg(OH)₂ present in the core. Thus, less drug permeates into the aqueous media, and less drug is available to be drawn into the syringe. In certain embodiments, polymers present in the functional coats, e.g., EUDRAGIT^® E PO, are also involved in resistance to syringeability. The alkaline agent(s) present in the dosage form produces a rapid rise in the pH of aqueous media. The polymers present in the functional coats, e.g., EUDRAGIT^® E PO, become less permeable in this alkaline media and slow or block release of opioid from the dosage form. Thus, attempts to draw fluid containing the opioid into a syringe are impeded in this manner as well.

In certain embodiments, acetaminophen present in APAP Particulates causes considerable irritation when injected and thereby provides resistance to abuse by injection.

Further resistance to extractability and syringeability are provided by one or more properties of the dosage form. For example, resistance is provided by the gelling characteristics of polyoxyethylene (PEO) polymers and HPMC in the Opioid Particulates (e.g., in the core of the Opioid Granules) when exposed to aqueous media; such gelling results in less drug permeating into the aqueous media by extraction, and less drug being available to be drawn into a syringe. In addition, carbomers and alkaline agent(s) included in the matrix core of the dosage form (e.g., in the core of the Opioid Particulates) provide further resistance to syringeability; in response to the rapidly rising pH induced by Mg(OH)₂ in aqueous media; carbomer-based gelling is greatly enhanced, diminishing drug release. Also in response to the elevated pH induced by Mg(OH)₂ (present in the Triggering Particulates), the functional coats remain relatively intact, further diminishing drug release from the dosage form. These unique properties of the dosage form are also prominent in a physiological setting involving accidental overdose (or deliberate abuse) comprising ingestion of multiple dosage units of the dosage forms of the disclosure.

5.12. Methods

In certain embodiments, the disclosure provides several methods of treatment, manufacture, etc., closely related to the pharmaceutical dosage forms and formulations. In certain embodiments, the disclosure is directed to a method of managing or treating pain with opioids and APAP, and discouraging their abuse or misuse. The method comprises orally administering to a subject in need thereof a solid, immediate release, multi-parti culate combination dosage form with abuse deterrent and overdose protection properties comprising: (1) a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix, a seal coat (optional), a functional coat comprising at least one of FC 0, FC 1, and FC 2, and an over coat; wherein the seal coat comprises a nonionic water- soluble polymer; wherein the at least one of FC 0, FC 1, and FC 2 comprise at least one cationic polymer that dissolves at a pH of less than about 5 and, optionally, a nonionic water-insoluble polymer; and wherein the over coat comprises a nonionic water-soluble polymer; (2) a second population of particulates comprising a therapeutically effective amount of acetaminophen (APAP) embedded in a polymer matrix, a seal coat (optional), a functional coat comprising at least one of APAP-FC 0, APAP-FC 1, and APAP-FC 2, and an over coat; wherein the seal coat comprises a nonionic water-soluble polymer; wherein the at least one of APAP-FC 0, APAP-FC 1, and APAP-FC 2 comprise at least one cationic polymer that dissolves at a pH of less than about 5 and, optionally, a nonionic water-insoluble polymer; and wherein the over coat comprises a nonionic water-soluble polymer; and (3) a third population of particulates comprising an alkaline agent and, optionally, a pH-stabilizing agent; wherein the alkaline agent raises the gastric pH to a value greater than 5 when three or more dosage units are ingested, and the stabilizing agent maintains the elevated pH above 5.

In certain embodiments, the disclosure is directed to a method of preparing a solid, oral, immediate release, multi -parti culate dosage form with abuse deterrent and overdose protection characteristics, comprising: (1) preparing a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix, a seal coat (optional), a functional coat comprising at least one of FC 0, FC 1, and FC 2, and an over coat; wherein the seal coat comprises a nonionic water-soluble polymer; wherein the at least one of FC 0, FC 1, and FC 2 comprise at least one cationic polymer that dissolves at a pH of less than about 5 and, optionally, a nonionic water-insoluble polymer; and wherein the over coat comprises a nonionic water-soluble polymer; (2) preparing a second population of particulates comprising a therapeutically effective amount of APAP embedded in a polymer matrix, a seal coat (optional), a functional coat comprising at least one of APAP-FC 0, APAP-FC 1, and APAP-FC 2, and an over coat; wherein the seal coat comprises a nonionic water-soluble polymer; wherein the at least one of APAP-FC 0, APAP- FC 1, and APAP-FC 2 comprise at least one cationic polymer that dissolves at a pH of less than about 5 and, optionally, a nonionic water-insoluble polymer; and wherein the over coat comprises a nonionic water-soluble polymer; (3) preparing a third population of particulates comprising an alkaline agent and, optionally, a pH-stabilizing agent; wherein the alkaline agent raises the gastric pH to a value greater than 5 when three or more dosage units are ingested, and the stabilizing agent maintains the elevated pH above 5; and (4) combining the first, second, and third populations of particulates into a tablet, tablet-in-tablet, multilayered tablet, or a capsule.

In certain embodiments of the method, the cationic polymer present in the FC 1 of the first population of particulates, and in the APAP-FC 1 of the second population of particulates acts as a pore former in those functional coats (or functional coat layers) at the nonionic polymer to cationic polymer wt% ratio of from about 50:50 to about 98:2.

In certain embodiments of the method, the wt% ratio of the nonionic polymer to the cationic polymer in the FC 1 or in the APAP-FC 1 is about 60:40.

In certain embodiments of the method, the wt% ratio of the nonionic polymer to the cationic polymer in the FC 1 or in the APAP-FC 1 is about 80:20.

In certain embodiments of the method, the FC 0, FC 2, APAP-FC 0, and/or APAP-FC 2 comprise a cationic polymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

In certain embodiments of the method, the overcoat in the first population of particulates and/or in the second population of particulates is the outermost layer.

In certain embodiments of the method, the polymer matrix of the first population of particulates and/or the second population of particulates comprises a cationic polymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

In certain embodiments, the method further comprises preparing a fourth population of particulates comprising a viscosity-building polymer comprising a nonionic polymer and/or an anionic polymer.

In certain embodiments, the disclosure is directed to a method for providing overdose protection from opioid overdose. The method comprises orally administering to a subject a multi-parti culate solid oral immediate release opioid and nonopioid (e.g., APAP) analgesic combination dosage form with abuse deterrent and overdose protection properties, as described in the present disclosure.

In certain embodiments, the disclosure is directed to a method for providing analgesia by administering immediate release opioid and nonopioid agonist combination dosage form to a subject in an overdose protection formulation without impeding release of the opioid when taken as directed. The method comprises orally administering to the subject a multi -parti culate solid oral immediate release opioid and nonopioid (e.g., APAP) analgesic combination dosage form with abuse deterrent and overdose protection properties, as described in the present disclosure.

In certain embodiments, the disclosure comprises a dosing regimen comprising orally administering to a subject in need thereof, a pharmaceutical composition comprising a multi-particulate solid oral immediate release opioid and nonopioid (e.g., APAP) analgesic combination dosage form with abuse deterrent and overdose protection properties. In certain embodiments, the pharmaceutical composition comprises Opioid Particulates comprising therapeutically effective amount of at least one opioid, or a pharmaceutically acceptable salt thereof, embedded in a polymer matrix, wherein the individual particulates are coated with an acid labile coat; APAP Particulates comprising acetaminophen; and Triggering Particulates comprising an alkaline agent and, optionally, a pH-stabilizing agent. In certain embodiments, the dosing regimen comprises administering one or two dosage units of the pharmaceutical composition every 4 to 6 hours as needed for pain. In certain embodiments, the opioid is oxycodone hydrochloride. In certain embodiments, the opioid is hydrocodone bitartrate. In certain embodiments, the dosing regimen comprises administering 5 to 20 mg of oxycodone hydrochloride and 325 mg of APAP every 4 to 6 hours. In certain embodiments, the dosing regimen comprises administering 10 mg of hydrocodone bitartrate and 325 mg of APAP every 4 to 6 hours. The following examples are offered to more fully illustrate the disclosure, not to be construed as limiting the scope thereof.

6. EXAMPLES

Example 1: Crush-Resistant Oxycodone Hydrochloride Granule Cores

5 Oxycodone hydrochloride granule cores were prepared for use in a 5 mg,

10 mg, 15, mg, and 30 mg oxycodone hydrochloride dosage form.

Table 1: Formulation of Oxycodone Hydrochloride Granule Core

Manufacturing Procedure:

1. Oxycodone hydrochloride, polyethylene oxide, microcrystalline cellulose,

hypromellose, Kollidon SR, and docusate sodium were added to a high shear granulator and mixed into a uniform powder mix using an impeller and a chopper.

2. A solution of dl-a-tocopherol solution and triethyl citrate was sprayed onto the

powder mix from step #1 to achieve a uniform blend. 3. The blend from step #2 was granulated by hot-melt extrusion.

4. The granules from step #3 were processed using cryomilling to a mean particle size of about 500 μιη.

Example 2: Crush-Resistant Hydromorphone Hydrochloride Granule Cores

Hydromorphone hydrochloride granule core was prepared for use in an 8 mg hydromorphone hydrochloride dosage form.

Table 2: Formulation of Hydromorphone Hydrochloride Granule Cores

Manufacturing Procedure:

1. Hydromorphone hydrochloride, polyethylene glycol, hypromellose, Kollidon® SR, and docusate sodium were added to a high shear granulator and mixed into a uniform powder mix using an impeller and a chopper.

2. A solution of dl-a-tocopherol solution and triethyl citrate was sprayed onto the powder mix from step #1 to achieve a uniform blend.

3. The blend from step #2 was granulated by hot-melt extrusion.

Example 3: Crush-Resistant Hydrocodone Bitartrate Granule Cores

Hydrocodone bitartrate granule core was prepared for use in a 10 mg hydrocodone bitartrate dosage form. Table 3: Formulation of Hydrocodone Bitartrate Granule Cores

Components Granule 1 Granule 2

(mg/dose) (mg/dose)

Kollidon^® SR 2.36 4.71

Triethyl citrate 0.10 0.20

Docusate sodium 1.62 3.24

dl-a-Tocopherol 1.00 2.00

Total 50. 00 100.00

Manufacturing Procedure:

1. Hydrocodone bitartrate, polyethylene oxide, hypromellose, Kollidon® SR, and

docusate sodium were added to a high shear granulator and mixed into a uniform powder mix using an impeller and a chopper.

2. A solution of dl- a-tocopherol solution and triethyl citrate was sprayed onto the

powder mix from step #1 to achieve a uniform blend.

3. The blend from step #2 was granulated by hot-melt extrusion.

4. The granules from step #3 were processed cryomilling to a mean particle size of about 500 μιη.

Example 4: Crush-Resistant Oxymorphone Hydrochloride Granule Cores (Active Granules)

Oxymorphone hydrochloride granule cores are prepared according to procedures similar to those in Examples 1-3.

Example 5: Acetaminophen (APAP) Granules

Acetaminophen (APAP) Granules were prepared with a mean particle size of 500 μιη.

Table 4: Formulation of APAP Granules

Manufacturing Procedure:

1. Eudragit® EPO, Colloidal silicon dioxide were added to Acetaminophen in a high shear granulator and mixed to achieve a uniform powder mix using impeller and

5 chopper.

2. A mixer from step #1 was screened pass through US standard #30 (600 μιη).

3. A mixer from step #2 was mixed to achieve a uniform blend using an impeller and chopper.

4. The blend from step #3 was granulated by hot-melt extrusion.

10 5. The granules from step #4 were processed using milling to a mean particle size of

500 μιη.

Example 6: Seal Coating of Oxycodone Hydrochloride Granule Cores

Oxycodone hydrochloride active granule cores were coated with a seal coat.

15 Table 5: Formulation of Seal Coated Oxycodone Hydrochloride Granule Cores

Components Seal Coated Seal Coated Seal Coated Seal Coated Oxycodone HC1 Oxycodone HC1 Oxycodone HC1 Oxycodone HC1 Granule 1 Granule 2 Granule 3 Granule 4 mg/dose mg/dose mg/dose mg/dose

Solvent system for coating

Purified water NA NA NA NA

Dehydrated NA NA NA NA

alcohol

Total 120.00 120.00 120.00 120.00

Coating Procedure:

1. Hypromellose was added to dehydrated alcohol in a stainless steel container and

mixed to form a uniform dispersion.

2. To the dispersion from step #1 , the purified water was added and mixed until a clear 5 solution formed.

3. To the solution from step #2, triethyl citrate was added followed by the addition of

colloidal silicon dioxide and mixed to form a homogenous dispersion.

4. The oxycodone granules from Example 4 were coated using a Wurster fluid bed

coater with an inlet air temperature of 40°-50°C, and sufficient air volume for

10 fluidization.

5. When the product temperature reached 30° C, the dispersion from step #3 was

sprayed onto the granules while maintaining the product temperature of 28°-30°C and sufficient air volume for the fluidization, until the target coating weight gain (20 mg) was achieved.

15 6. The coated granules from step #5 were dried.

Example 7: Seal Coating of Hydromorphone Hydrochloride Granule Cores

Hydromorphone hydrochloride active granule cores (Example 5) were coated with a seal coat.

Table 6: Formulation of Seal Coated Granules

Active Granule cores 50.00

(Hydromorphone

hydrochloride)

Hypromellose (Methocel 8.89

E5 Premium LV)

Triethyl citrate 0.89

Colloidal silicon dioxide 0.22

(Cab-O-Sil (M-5P)

Solvent system for coating

Purified water NA

Dehydrated alcohol NA

Total 60.00

Coating Procedure:

1. Hypromellose was added to dehydrated alcohol in a stainless steel container and mixed to form a uniform dispersion.

2. To the dispersion from step #1, the purified water was added and mixed until a clear solution formed.

3. To the solution from step #2, triethyl citrate was added followed by the addition of colloidal silicon dioxide and mixed to form a homogenous dispersion.

4. The granules were coated using a Wurster fluid bed coater with an inlet air

temperature of 40°-50°C, and sufficient air volume for fluidization.

5. When the product temperature reached 30° C, the dispersion from step #3 was

sprayed onto the granules while maintaining the product temperature of 28°-30°C and sufficient air volume for the fluidization, until the target coating weight gain (10 mg) was achieved.

6. The coated granules from step #5 were dried.

Example 8: Seal Coating of Hydrocodone Bitartrate Granule Cores

Hydrocodone bitartrate active granule cores (Granule 2, Example 6) were coated with a seal coat.

Table 7: Formulation of Seal Coated Granules

Active Granule Cores 100.00

(Hydrocodone bitartrate)

Hypromellose (Methocel 17.78

E5 Premium LV)

Tri ethyl citrate 1.78

Colloidal silicon dioxide 0.44

(Cab-O-Sil (M-5P)

Solvent system for coating

Purified water NA

Dehydrated alcohol NA

Total 120.00

Coating Procedure:

3. To the solution from step #2, tri ethyl citrate was added followed by the addition of colloidal silicon dioxide and mixed to form a homogenous dispersion.

4. The granules were coated using a Wurster fluid bed coater with an inlet air

temperature of 40°-50°C, and sufficient air volume for fluidization.

5. When the product temperature reached 30° C, the dispersion from step #3 was

6. The coated granules from step #5 were dried.

Example 9: Functional Coating of Seal Coated Oxycodone Hydrochloride Granules

Seal coated oxycodone hydrochloride granules(Granules 1-4, Example 12) were coated with a first functional coat FC 1 comprising a mixture of rate controlling polymers, e.g., cellulose acetate (CA) and EUDRAGIT^® E PO, in a ratio of CA:

EUDRAGIT^® E PO of 60:40, and a second functional coat FC 2 comprising

EUDRAGIT^® E PO as the sole rate controlling polymer. Table 8: Formulation of Functional Coated Active Granules

Coating Procedure:

1. EUDRAGIT^® E PO was added to acetone in a stainless steel container and mixed until a clear solution formed.

5 2. To the solution from step #1, cellulose acetate was added and mixed until a clear solution formed.

3. The purified water was added to the solution from step #2 and mixed for ~5 minutes. 4. To the solution from step #3, dibutyl sebacate was added followed by colloidal silicon dioxide and continued mixing until a homogenous dispersion was obtained.

5. The seal coated granules were further coated using a Wurster fluid bed coater with an inlet air temperature of 40°-50°C and sufficient air volume for fluidization.

6. When the product temperature reached 30°C, the dispersion from step #4 was

sprayed onto the seal coated granules while maintaining the product temperature of 28°-30°C and sufficient air volume for the fluidization, until the target coating weight gain (36 mg) was achieved.

7. The coated granules from step #6 were dried to FC 1 coated granules.

The FC 1 coated granules were further coated with a second functional coat (FC 2) as follows:

1. EUDRAGIT^® E PO was added to acetone in a stainless steel container and mixed until a clear solution form.

2. The purified water was added to the solution from step #1 and mixed for ~5 minutes.

3. To the solution from step #3, polyethylene glycol was added followed by talc and mixed until a homogenous dispersion was obtained.

4. The FC 1 coated granules were further coated using a Wurster fluid bed coater with an inlet air temperature of 40°-50°C, and sufficient air volume for fluidization.

5. When the product temperature reached 30°C, the dispersion from step #4 was

sprayed onto the FC 1 coated granules while maintaining the product temperature of 28°-30°C and sufficient air volume for the fluidization, until the target coating weight gain (93.6 mg) was achieved.

6. The coated granules from step #6 were dried to FC 2 coated granules.

Example 10: Functional Coating of Seal Coated Hydromorphone Hydrochloride Granules

Seal coated hydromorphone hydrochloride granules were coated with a first functional coat layer FC 1 comprising a mixture of rate controlling polymers, e.g., cellulose acetate (CA) and EUDRAGIT^® E PO, in a ratio of CA:EUDRAGIT^® E PO of 60:40, and a second functional coat layer FC 2 comprising EUDRAGIT^® E PO as the sole rate controlling polymer. Table 9: Formulation of Functional Coated Hydromorphone Hydrochloride Granules

Coating Procedure:

1. EUDRAGIT® E PO was added to acetone in a stainless steel container and mixed until a clear solution formed.

2. To the solution from step #1, cellulose acetate was added and mixed until a clear solution formed.

3. The purified water was added to the solution from step #2 and mixed for ~5 minutes.

4. To the solution from step #3, dibutyl sebacate was added followed by colloidal

silicon dioxide and continued mixing until a homogenous dispersion was obtained.

6. When the product temperature reached 30°C, the dispersion from step #4 was

sprayed onto the seal coated granules while maintaining the product temperature of 28°-30°C and sufficient air volume for the fluidization, until the target coating weight gain (18 mg) was achieved.

7. The coated granules from step #6 were dried to FC 1 coated granules. The FC 1 coated granules were further coated with a second functional coat layer (FC 2) as follows:

2. Isopropyl alcohol was added to the solution from step #1 and mixed for ~5 minutes.

5. When the product temperature reached 30°C, the dispersion from step #4 was

sprayed onto the FC 1 coated granules while maintaining the product temperature of 28°-30°C and sufficient air volume for the fluidization, until the target coating weight gain (46.80 mg) was achieved.

6. The coated granules from step #6 were dried to FC 2 coated granules.

Example 11: Functional Coating of Seal Coated Hydrocodone Bitartrate Granules

Seal coated hydrocodone bitartrate granules were coated with a first functional coat layer FC 1 comprising a mixture of rate controlling polymers, e.g., cellulose acetate (CA) and EUDRAGIT^® E PO, in a ratio of CA:EUDRAGIT^® E PO of 60:40, and a second functional coat layer FC 2 comprising EUDRAGIT^® E PO as the sole rate controlling polymer.

Table 10: Formulation of Functional Coated Hydrocodone Bitartrate Granules

Components Functional Coated Hydrocodone Bitartrate

Granules 2

(mg/dose)

EUDRAGIT^® E PO 72.00

Polyethylene glycol 7.20

Talc 14.40

Solvent System for Coating

Acetone NA

Isopropyl alcohol NA

Total 249.60

Coating Procedure:

3. Isopropyl alcohol was added to the solution from step #2 and mixed for ~5 minutes.

6. When the product temperature reached 30°C, the dispersion from step #4 was

7. The coated granules from step #6 were dried to FC 1 coated granules.

The FC 1 coated granules were further coated with a second functional coat layer (FC 2) as follows:

1. EUDRAGIT® E PO was added to acetone in a stainless steel container and mixed until a clear solution form.

4. The FC 1 coated granules were further coated using a Wurster fluid bed coater with an inlet air temperature of 40°-50°C, and sufficient air volume for fluidization. 5. When the product temperature reached 30°C, the dispersion from step #4 was sprayed onto the FC 1 coated granules while maintaining the product temperature of 28°-30°C and sufficient air volume for the fluidization, until the target coating weight gain (93.60 mg) was achieved.

5 6. The coated granules from step #6 were dried to FC 2 coated granules.

Example 12: Over Coating of Functional Coated Oxycodone Hydrochloride Granules

Functional coated oxycodone hydrochloride granules were coated with an over coat.

10 Table 11: Formulation of Over Coated Active Granules

Coating Procedure:

2. To the dispersion from step #1, the purified water was added and mixed until a 15 clear solution formed.

3. To the solution from step #2, triethyl citrate was added followed by the addition of talc and mixed to form a homogenous dispersion.

4. The granules were coated using a Wurster fluid bed coater with an inlet air

temperature of 40°-50°C, and sufficient air volume for fluidization.

20 5. When the product temperature reached 30° C, the dispersion from step #3 was sprayed onto the granules while maintaining the product temperature of 28°-30°C and sufficient air volume for the fluidization, until the target coating weight gain (36.44 mg) was achieved.

6. The coated granules from step #5 were dried.

Example 13: Over Coating of Functional Coated Hydromorphone Hydrochloride Granules

Functional coated hydromorphone hydrochloride granules were coated with an over coat.

Table 12: Formulation of Over Coated Active Granules

Coating Procedure:

1. Methocel was added to dehydrated alcohol in a stainless steel container and mixed to form a uniform dispersion.

4. The granules were coated using a Wurster fluid bed coater with an inlet air

temperature of 40°-50°C, and sufficient air volume for fluidization.

5. When the product temperature reached 30° C, the dispersion from step #3 was sprayed onto the granules while maintaining the product temperature of 28°-30°C and sufficient air volume for the fluidization, until the target coating weight gain (18.72 mg) was achieved. 6. The coated granules from step #5 were dried.

Example 14: Over Coating of Functional Coated Hydrocodone Bitartrate Granules

Functional coated Hydrocodone bitartrate granules were coated with an over coat.

Table 13: Formulation of Over Coated Active Granules

Coating Procedure:

1. Methocel was added to dehydrated alcohol in a stainless steel container and

mixed to form a uniform dispersion.

4. The granules were coated using a Wurster fluid bed coater with an inlet air

temperature of 40°-50°C, and sufficient air volume for fluidization.

5. When the product temperature reached 30° C, the dispersion from step #3 was sprayed onto the granules while maintaining the product temperature of 28°-30°C and sufficient air volume for the fluidization, until the target coating weight gain (37.44 mg) was achieved.

6. The coated granules from step #5 were dried. Example 15: Triggering Granules

Triggering Granules were prepared as described below.

Table 14: Formulation of Triggering Granules

Manufacturing Procedure:

1. Magnesium hydroxide was added to anhydrous dibasic calcium phosphate (-50%), crospovidone, hydroxypropyl cellulose, and sodium lauryl sulfate in a high shear granulator and mixed using an impeller and chopper to achieve a uniform blend.

2. The blend from step #1 was granulated by wet granulation.

3. The granules from step #2 were dried at 40°C using an air oven until the LOD was <1%.

4. Extragranular excipients (anhydrous dibasic calcium phosphate (-50%), croscarmellose sodium, magnesium stearate, colloidal silicon dioxide) were added to the dried granules and mixed using a V blender to achieve a uniform blend.

Example 16: Triggering Granules

Triggering Granules are prepared as described below. Table 15: Formulation of Triggering Granules

Manufacturing Procedure:

1. Magnesium hydroxide is added to (-50%), tri-calcium phosphate (~50%)„ crospovidone, hydroxypropyl cellulose (optional), and sodium lauryl sulfate in a high shear granulator and mixed using an impeller and chopper to achieve a uniform blend.

2. The blend from step #1 is granulated by wet granulation.

3. The granules from step #2 are dried at 40°C using a fluid bed dryer or an air oven until the LOD is <1%.

4. Extragranular excipients (tri-calcium phosphate (-50%), croscarmellose

sodium, magnesium stearate, colloidal silicon dioxide) are added to the dried granules and mixed using a V blender to achieve a uniform blend.

Example 17: Triggering Granules

Triggering Granules were prepared as described below.

Table 16: Formulation of Triggering Granules

Manufacturing Procedure:

1. Magnesium hydroxide was added to mannitol and crospovidone in a high shear granulator and mixed using an impeller and chopper to achieve a uniform blend.

2. The blend from step #1 was granulated using purified water.

3. The granules from step #2 were dried at 40°C using an forced air oven until the LOD was <1%.

Example 18: Viscosity Enhancing Granules

Viscosity Enhancing Granules were prepared with a mean particle size of

500 μιη.

Table 17: Formulation of Viscosity Enhancing Granules

Manufacturing Procedure:

1. POLYOX® WSR coagulant was added to hydroxypropyl methylcellulose K200M, KOLLIDON® SR, docusate sodium, and crospovidone / starch 1500 in a high shear granulator and mixed to achieve a uniform powder mix using impeller and chopper.

2. A solution of a-dl-tocopherol solution and triethyl citrate was sprayed onto the powder mix from step #1 to achieve a uniform blend.

5 3. Aerosil 200 was added to the blend from step #2 and mixed to achieve a

uniform blend using an impeller and chopper.

4. The blend from step #3 was granulated by hot-melt extrusion.

5. The granules from step #4 were processed using cryomilling to a mean particle size of 500 μιη.

Example 19: Viscosity Enhancing Granules

Viscosity Enhancing Granules were prepared as described below:

Table 18: Formulation of Viscosity Enhancing Granules

Manufacturing Procedure:

1. Poly ox® was added to hypromellose, Kollidon^® SR, docusate sodium, and (in

Granules 3 and 5) crospovidone / starch 1500 in a high shear granulator and mixed to achieve a uniform powder mix using impeller and chopper.

powder mix from step #1 to achieve a uniform blend.

3. Colloidal silicon dioxide / Aerosil 200 was added to the blend from step #2 and mixed to achieve a uniform blend using an impeller and chopper.

4. The blend from step #3 was granulated by hot melt extrusion.

Seal Coating Procedure:

4. The granules were coated using a Wurster fluid bed coater with an inlet air

temperature of 40°-50°C, and sufficient air volume for fluidization. When the product temperature reached 30° C, the dispersion from step #3 was sprayed onto the granules while maintaining the product temperature of 28°-30°C and sufficient air volume for the fluidization, until the target coating weight gain (12.49 mg) was achieved.

5. The coated granules from step #5 were dried.

Example 20: Opioid and APAP (Eq 10 mg / 325 mg) Capsule Dosage Form

Capsules filled with coated Opioid Particulates, APAP Particulates, and Triggering Particulates. Table 19: Formulation composition of oxycodone HCl or hydrocodone bitartrate, and APAP combination (Eq 10 mg / 325 mg) capsule dosage form

Manufacturing Procedure:

1. A uniform blend of Opioid Particulates, APAP Particulates, and Triggering Particulates is made using a V-blender.

2. Based on the fill weight, the blend from Step #1 is filled into capsules.

Example 21: Opioid and APAP (Eq 10 mg / 325 mg) Capsule Dosage Form

Coated Opioid Particulates and APAP Particulates are compressed into tablets, and filled into capsules along with Triggering Particulates.

Table 20: Formulation composition of oxycodone HCl or hydrocodone bitartrate, and APAP combination (Eq 10 mg / 325 mg) capsule dosage form

Manufacturing Procedure:

1. A uniform blend of coated Opioid Particulates, APAP Particulates,

microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose and croscarmellose sodium is made using a V-blender.

To the blend from step #1, magnesium stearate is added and the mixture further blended for 3 minutes. 3. The blend from step #2 is compressed into tablets using a tablet press.

4. The compressed tablets along with the Triggering Particulates are filled into capsules.

Example 22: Opioid and APAP (Eq 10 mg / 325 mg) Bilayer Tablet Dosage Form

Coated Opioid Particulates, coated APAP Particulates, and Triggering Particulates are compressed into bilayer tablets.

Table 21: Formulation composition of oxycodone HCl or hydrocodone bitartrate, and APAP combination (Eq 10 mg / 325 mg) bilayer tablet dosage form

Manufacturing Procedure:

1. A uniform blend of coated Opioid Particulates, coated APAP Particulates, microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose and croscarmellose sodium is made using a V-blender.

2. To the blend from step #1, magnesium stearate is added and the mixture is further blended for 3 minutes using V-blender.

3. Similarly, a uniform blend of Triggering Particulates is made by mixing magnesium hydroxide granules and croscarmellose sodium using a V-blender.

4. To the blend from step #3, magnesium stearate is added and the mixture is further blended for 3 minutes using V-blender.

5. The two blends (i.e., from step #2 and step #4) are layered on each other during compression to form bilayer tablets. Example 23: Opioid and APAP (Eg 10 mg / 325 mg) Capsule Dosage Form

Coated Opioid Particulates and coated APAP Particulates are compressed into a first tablet population. Triggering Particulates are compressed into a second tablet population. The two tablet populations are filled into capsules. Table 22: Formulation composition of oxycodone HCl or hydrocodone bitartrate, and APAP combination (Eq 10 mg / 325 mg) capsule dosage form

Manufacturing Procedure:

1. A uniform blend of coated Opioid Particulates, APAP Particulates,

2. To the blend from step #1, magnesium stearate is added and blended for 3 minutes using V-blender and then compressed into tablets using a tablet press.

4. To the blend from step #3, magnesium stearate is added and the mixture is further blended for 3 minutes using V-blender and then compressed into tablets using a tablet press.

5. Tablets from step #2 and step #4 are filled into capsules.

Example 24: Hydrocodone Bitartrate and APAP (Eg 10 mg / 325 mg) Tablet Dosage Form

Tablets were manufactured as described below. Table 23: Formulation composition of Hydrocodone Bitartrate / Acetaminophen tablets (Eq 10 mg / 325 mg)

Manufacturing Procedure:

1. A uniform blend of over coated Hydrocodone bitartrate granules, APAP granules, triggering granules, and microcrystalline cellulose was made using a V-blender

2. Croscarmellose sodium and colloidal silicon dioxide were mixed and the mixture was passed through US standard #30 (όθθμιτι), and added to B-blender containing the blend from step #1 and blended for 3 minutes.

3. To the blend from step #2, magnesium stearate was added and blended for 3 minutes using V-blender.

4. The blend from step #3 was compressed into tablets using a tablet press.

Example 25: In Vitro Overdose Protection (ODP) Studies with Opioid Formulation containing 10 mg of Hydrocodone Bitartrate

In order to examine the ability of the dosage form to prevent the release of its active agent (e.g., an opioid) when taken in doses above therapeutically effective amounts (e.g., three or more dosage units; overdosed), taken in a manner inconsistent

with the manufacturer's instructions, or taken in another manner not prescribed, an in vitro dissolution test was conducted using a USP Apparatus II at pH 1.6 for 30 minutes followed by pH 6.8 for 120 minutes. In order to mimic physiological conditions, the total volume of the dissolution medium was kept at 250 ml at pH 1.6 acid medium, and then at 300 ml at pH 6.8 (as detailed below). Figure 2 shows dissolution profiles (% drug release) of hydrocodone bitartrate for 1, 3, and 6 hydrocodone / APAP tablets.

1. Hydrocodone bitartrate / APAP tablets from Example 24 were added to a 250 ml acid-adjusted dissolution medium at pH 1.6, and the dissolution of the tablets was measured for 30 minutes.

2. Buffer (50 mL of 60 mM phosphate buffer) was added to the solution from step #1, and the dissolution of the tablet was measured for an additional 120 minutes.

3. Samples were withdrawn from the solutions of steps #1 and #2 at intervals as shown in Figure 4.

4. The samples obtained from step #3 were analyzed, using FIPLC, for the percent release of hydrocodone.

5. Steps #1-4 were repeated for addition of 3 and 6 dosage units (i.e., 3 and 6 tablets).

Example 26: In Vitro Abuse Deterrent Studies

In order to examine abuse resistance (e.g., ability to withstand grinding) of Opioid Particulates, an in vitro physical manipulation test is conducted.

The results demonstrate the nongrindable and/or noncrushable nature of the Opioid Particulates. After grinding, the weight % of fine particles (i.e., particle size of below 125 μπι; "fines fraction") remains very low, thereby preventing the abuser from easily snorting the opioid, even after tampering with the dosage form by grinding.

Grinding Procedure:

1. 5000 mg of Opioid Particulates are added to a Hamilton Beach Coffee Grinder (Model 80365) using the following settings:

Settings: 10 cups

Number of cycles: 8

Cycle time: 30 seconds

2. Opioid Particulates are ground for 8 cycles, and a total grind time of 12 minutes (including wait times as noted below) to form a ground mixture of granules. The grinding procedure consists of :

1) Grind 2 cycles

2) Wait for 1 minute

3) Grind 2 cycles

4) Wait for 1 minute 5) Grind 2 cycles

6) Wait for 1 minute

7) Grind for 2 cycles

8) Wait for 5 minutes

3. The ground mixture of granules and powder is then added to the stack of sieves of the Gilson Sonic Siever (Model GA-6) for sieve analysis. A tray is used to gather the fine particles, and the fine particles are transferred to the stack of sieves.

4. The ground mixture of granules is sieved for 5 minutes. 5. The weights obtained in each sieve are compared to the weight of intact

Opioid Particulates as noted in step #1.

Example 27: In Vitro Abuse Deterrent (AD) Studies

In order to examine the abuse resistance of Opioid Particulates, in vitro physical manipulation tests are conducted.

Ground Opioid Particulates form a gelatinous mass with 2-10 mL of water, which resists passage through a 27 gauge needle.

Ground Opioid Particulates are also resistant to extraction with water and 40% ethanol (alcohol dose dumping).

AD properties of Opioid Particulates (e.g., resistance to extractability, resistance to syringeability) are not defeated, even with preheat treatment in an oven (e.g., 100°C for 2 hours) or microwave (e.g., 1200 W (at 80°C) for 15 minutes) before grinding.

The present disclosure is well adapted to attain the ends and advantages mentioned, as well as those that are inherent therein. The particular embodiments disclosed above are illustrative only, as the present disclosure can be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein. Furthermore, no limitations are intended to the details of construction or design herein shown, other than as described in the claims below. It is therefore evident that the particular illustrative embodiments disclosed above can be altered or modified, and all such variations are considered within the scope and spirit of the present disclosure. Various publications, patents, and patent application are cited herein, the contents of which are hereby incorporated by reference in their entireties.

Claims

CLAIMS:

1. A solid, oral, immediate release, multi-parti culate combination dosage form with abuse deterrent and overdose protection characteristics comprising:

a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix; an optional seal coat; a functional coat comprising at least one of functional coat layers FC 0, FC 1, and FC 2; and an over coat;

wherein the seal coat comprises a nonionic water-soluble polymer;

wherein the at least one of FC 0, FC 1, and FC 2 comprises a cationic polymer that

dissolves at a pH of less than about 5 and an optional nonionic water-insoluble polymer; and

wherein the over coat comprises a nonionic water-soluble polymer;

a second population of particulates comprising a therapeutically effective amount of acetaminophen (APAP) embedded in a polymer matrix; an optional seal coat; a functional coat comprising at least one of functional coat layers APAP-FC 0,

APAP-FC 1, and APAP-FC 2; and an over coat;

wherein the seal coat comprises a nonionic water-soluble polymer;

wherein the at least one of APAP-FC 0, APAP-FC 1, and APAP-FC 2 comprises a

cationic polymer that dissolves at a pH of less than about 5 and an optional nonionic water-insoluble polymer; and

wherein the over coat comprises a nonionic water-soluble polymer; and

a third population of particulates comprising an alkaline agent and an optional pH- stabilizing agent;

wherein the alkaline agent elevates gastric pH to a value greater than 5 when three or more dosage units are ingested; and

wherein the pH-stabilizing agent maintains an elevated pH above 5.

2. The dosage form of claim 1, wherein FC 1 and/or APAP-FC 1 comprise a rate- controlling nonionic water-insoluble polymer and a cationic polymer that acts as a pore former at a pH of less than about 5.

3. The dosage form of any of the preceding claims, wherein the wt% ratio of the nonionic polymer to the cationic polymer is in the range of from about 50:50 to about 98:2.

4. The dosage form of any of the preceding claims, wherein the wt% ratio of the nonionic polymer to the cationic polymer is about 60:40.

5. The dosage form of any of the preceding claims, wherein the wt% ratio of the nonionic polymer to the cationic polymer is about 80:20.

6. The dosage form of any of the preceding claims, wherein the nonionic polymer present in FC 0, FC 1, FC 2, APAP-FC 0, APAP-FC 1, and/or APAP-FC 2 is selected from the group consisting of cellulose acetate, cellulose acetate-based polymers, ethylcellulose, and polyvinyl acetate polymers.

7. The dosage form of any of the preceding claims, wherein the nonionic polymer is cellulose acetate.

8. The dosage form of any of the preceding claims, wherein the cationic polymer present in FC 0, FC 1, FC 2, APAP-FC 0, APAP-FC 1, and/or APAP-FC 2 is a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

9. The dosage form of any of the preceding claims, wherein the polymer matrix of the first population of particulates and the polymer matrix of the second population of particulates comprise a nonionic polymer, an anionic polymer, and/or a cationic polymer.

10. The dosage form of any of the preceding claims, wherein the cationic polymer is a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

11. The dosage form of any of the preceding claims, wherein the polymer matrix of the first population of particulates comprises a nonionic polymer.

12. The dosage form of any of the preceding claims, wherein the nonionic polymer is selected from the group consisting of a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups

(ammonium methacrylate copolymer), hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, ethylcellulose, cellulose acetate butyrate, cellulose acetate, polyvinyl acetate polymers, polyethylene oxide polymers, and mixtures thereof.

13. The dosage form of any of the preceding claims, wherein the nonionic polymer is a mixture of a polyethylene oxide polymer and hydroxypropyl methylcellulose.

14. The dosage form of any of the preceding claims, wherein the polymer matrix of the second population of particulates comprises a cationic polymer based on

dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

15. The dosage form of any of the preceding claims, wherein the nonionic polymer in the over coat of the first population of particulates and in the over coat of the second population of particulates is hydroxypropyl methylcellulose.

16. The dosage form of any of the preceding claims, wherein FC 0, FC 2

APAP-FC 0, and/or APAP-FC 2 comprise a cationic polymer that acts as a pore former at a pH of less than about 5.

17. The dosage form of any of the preceding claims, wherein the alkaline agent present in the third population of particulates is selected from the group consisting of aluminum hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium carbonate , sodium carbonate, potassium bicarbonate, sodium bicarbonate, ammonia, tertiary sodium phosphate, diethanolamine,

ethylenediamine, N-methylglucamine, L-lysine, and combinations thereof.

18. The dosage form of any of the preceding claims, wherein the alkaline agent is magnesium hydroxide.

19. The dosage form of any of the preceding claims, wherein the pH-stabilizing agent is present and is dibasic calcium phosphate.

20. The dosage form of any of the preceding claims, wherein the polymer matrix of the first population of particulates and the polymer matrix of the second population of particulates further comprise an antioxidant, a plasticizer, and/or a surfactant.

21. The dosage form of any of the preceding claims, wherein the opioid is selected from the group consisting of oxycodone, oxymorphone, hydromorphone, hydrocodone, buprenorphine, codeine, phenazocine, tilidine, tramadol, meperidine, sufentanil, prodine, methadone, pentazoxine, tapentadol, morphine, fentanyl, and pharmaceutically acceptable salts thereof.

22. The dosage form of any of the preceding claims, wherein the opioid is selected from the group consisting of oxycodone, oxymorphone, hydromorphone, hydrocodone, and pharmaceutically acceptable salts thereof.

23. The dosage form of any of the preceding claims, further comprising a fourth population of particulates comprising a viscosity-building polymer comprising a nonionic polymer and/ or an anionic polymer.

24. The dosage form of any of the preceding claims, wherein the nonionic polymer is a polyethylene oxide polymer.

25. The dosage form of any of the preceding claims, wherein the anionic polymer is a carbomer.

26. The dosage form of any of the preceding claims, wherein the abuse deterrent characteristics comprise syringeability resistance, extractability resistance in aqueous and/or hydro-organic solvents, and heat stability of the dosage form, wherein the heat stability comprises maintaining the abuse deterrent characteristics of the dosage form after the exposure to heat.

27. The dosage form of any of the preceding claims, wherein the abuse deterrent characteristics of the dosage form comprise resistance to crushability and resistance to grindability of the first population of particulates.

28. A method of preparing a solid, oral, immediate release, multi -particulate dosage form with abuse deterrent and overdose protection characteristics, comprising:

a. preparing a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix; an optional seal coat; a functional coat comprising at least one functional coat layers FC 0, FC 1, and FC 2; and an over coat;

wherein the seal coat comprises a nonionic water-soluble polymer;

wherein the at least one of FC 0, FC 1, and FC 2 comprises a cationic polymer that dissolves at a pH of less than about 5 and an optional nonionic water-insoluble polymer; and

wherein the over coat comprises a nonionic water-soluble polymer;

b. preparing a second population of particulates comprising a therapeutically effective amount of APAP embedded in a polymer matrix; an optional seal coat; a functional coat comprising at least one of functional coat layers APAP-FC 0,

APAP-FC 1, and APAP-FC 2; and an over coat;

wherein the seal coat comprises a nonionic water-soluble polymer;

wherein the at least one of APAP-FC 0, APAP- FC 1, and APAP-FC 2 comprises a cationic polymer that dissolves at a pH of less than about 5 and an optional nonionic water-insoluble polymer; and

wherein the over coat comprises a nonionic water-soluble polymer;

c. preparing a third population of particulates comprising an alkaline agent and an optional pH-stabilizing agent;

wherein the pH-stabilizing agent maintains an elevated pH above 5; and

d. combining the first, second, and third populations of particulates into a tablet, tablet- in-tablet, multilayered tablet, or a capsule.

29. A solid, oral, immediate release, multi-particulate combination dosage form with abuse deterrent and overdose protection characteristics comprising: a first population of particulates comprising a therapeutically effective amount of at least one opioid embedded in a polymer matrix; an optional seal coat; a functional coat comprising at least one of functional coat layers FC 0, FC 1, and FC 2; and an over coat;

wherein the seal coat comprises a nonionic water-soluble polymer;

wherein the over coat comprises a nonionic water-soluble polymer;

a second population of particulates comprising a therapeutically effective amount of

APAP embedded in a polymer matrix; and an optional seal coat;

wherein the seal coat comprises a nonionic water-soluble polymer; and

wherein the pH-stabilizing agent maintains an elevated pH above 5.

30. A solid, oral, immediate release, multi-particulate combination dosage form with abuse deterrent and overdose protection characteristics comprising:

wherein the seal coat comprises a nonionic water-soluble polymer;

wherein the over coat comprises a nonionic water-soluble polymer;

a second population of particulates comprising an alkaline agent and an optional pH- stabilizing agent; wherein the alkaline agent elevates gastric pH to a value greater than 5 when three or more dosage units are ingested; and

wherein the pH-stabilizing agent maintains an elevated pH above 5; and

a therapeutically effective amount of APAP.

31. A solid, oral, immediate release, multi-particulate tablet dosage form comprising Opioid Particulates coated with an optional seal coat, a functional coat layer(s), and an over coat; uncoated APAP Particulates; and Triggering Particulates.

32. A solid, oral, immediate release, multi-particulate tablet dosage form comprising Opioid Particulates coated with an optional seal coat, a functional coat layer(s), and an over coat; APAP Particulates coated with an optional seal coat; and Triggering

Particulates.

33. A solid, oral, immediate release, multi-particulate tablet dosage form comprising Opioid Particulates coated with an optional seal coat, a functional coat layer(s), and an over coat; APAP Particulates; and Triggering Particulates.

34. A solid, oral, immediate release, multi-particulate bilayer tablet dosage form comprising a first layer comprising Opioid Particulates coated with an optional seal coat, a functional coat layer(s), and an over coat, and APAP Particulates coated with an optional seal coat, a functional coat layer(s), and an over coat; and a second layer comprising Triggering Particulates.