WO2018044895A1

WO2018044895A1 - Immediate release dosage forms with abuse deterrence and alcohol resistance

Info

Publication number: WO2018044895A1
Application number: PCT/US2017/049128
Authority: WO
Inventors: Sagar RANE; Joel Deacon FORD; Randal A. SEBURG
Original assignee: Cima Labs Inc
Current assignee: Cima Labs Inc
Priority date: 2016-08-29
Filing date: 2017-08-29
Publication date: 2018-03-08
Anticipated expiration: 2019-02-28

Abstract

The disclosure is directed to immediate release dosage forms comprising an active agent portion comprising an active pharmaceutical agent and about 30% to about 99%, based on the weight of the dosage form, of an alcohol resistant agent. The dosage forms can include an admixture of a plurality of particles comprising an active pharmaceutical agent and the alcohol resistant agent, or can include a central core portion that comprises the active agent portion, and an outer layer comprising the alcohol resistant agent that surrounds the central core. The dosage forms prevent dose dumping of the pharmaceutical agents when administered to the patient. Also provided are methods of treating patients comprising administering to the patient an immediate release dosage form as described herein.

Description

IMMEDIATE RELEASE DOSAGE FORMS WITH ABUSE DETERRENCE AND ALCOHOL RESISTANCE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority to U.S. Provisional App. No. 62/380,566, filed August 29, 2016, the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD

[0002] This disclosure relates to immediate release pharmaceutical compositions and dosage forms which suppress release of an active pharmaceutical agent in the presence of alcohol.

BACKGROUND

[0003] In today's society, the use of pharmaceutical drugs in combination with alcohol is a frequent occurrence. Even though their combination may be unintentional, the result in doing so can range from minor hospitalization to death. Although a single dose of a drug combined with alcohol may have serious consequences, it is more common for multiple doses of a drag to lead to liver damage or death when intentionally or inadvertently ingested with alcohol.

[0004] In sustained, modified, or delayed release formulations, serious complications can happen due to "dose dumping,'¹ i.e., rapid release of the drug from product upon the ingestion of alcohol in combination with intact or crushed drug tablets that are designed for sustained, modified, or delayed release of drug. In such cases, patients ingest a veiy high concentration of the drug which can cause the blood concentrations to greatly exceed threshold for toxicity.

[0005] Sustained/modified/deiayed release drugs are available as compositions which cannot easily be crushed with the expectation that the drug will enter the bloodstream when taken orally. However, such compositions do not prevent inadvertent or intentional interactions with alcohol.

[0006] In immediate release products, serious complications can also happen due to synergistic effects of the drug and alcohol on the body when they are consumed together. Such interactions are a common cause of death in patients who combine alcohol with pharmaceutical drugs. For example, pharmaceutical agents s benzodiazepines act synergistically with alcohol, and can result in serious side effects when taken together. In this example, both the drug (benzodiazepine) and alcohol suppress the central nervous system and their synergistic effect can cause subjects to stop breathing or lose consciousness.

[0007] As such, new compositions and dosage forms that suppress release of an active pharmaceutical agent in the presence of alcohol are needed.

SUMMARY

[0008] The present disclosure is directed to immediate release dosage forms comprising an admixture of a plurality of particles comprising an active pharmaceutical agent and about 30% to about 90%, based on the weight of the dosage form, of an alcohol resistant agent. With these dosage forms, the ratio of the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vo% 0.1N aqueous HC1 at 37 °C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N aqueous HC1 without ethanol is less than about 0.9.

[0009] Also disclosed are immediate release dosage forms comprising an active agent portion comprising an active pharmaceutical agent; and about 30% to about 99%, based on the weight of the dosage form, of an alcohol resistant agent; wherein the ratio of the active pharmaceutical agent released from the dosage form after 1 hour, when measured by

the USP 2 Paddle method at 50 ipm in 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N aqueous HCI at 37°C to the active pharmaceutical agent released from the dosage form after 1 hour- when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N aqueous HCI without ethanol at 37°C,

or,

the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.0 IN aqueous HCI at 37°C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 0.01N aqueous HCI without ethanol at 37°C,

or,

the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0.1N aqueous HCI at 37°C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N aqueous HCl without ethanol at 37°C,

or,

the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0.01N aqueous HCl at 37°C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0.01N aqueous HCl without ethanol at 37°C,

is less than about 0.9.

[0010] Methods of making these immediate release dosage forms are described.

Methods of treating patients using these immediate release dosage forms are also described.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a graph illustrating the release of hydrocodone bitartrate from tablets in 0.1 N HCl (♦) and 40 vol.% ethanol/60 vol.% 0.1 N HCl (■).

[0012] FIG. 2 is a graph illustrating the release of hydrocodone bitartrate from a single tablet in 0.1 N HCl (4) and 40 vol.% ethanol/60 vol.% 0.1 N HCl (■) and twelve tablets in 0.1 N HCl (0) and 40 vol.% ethanol/60 vol.% 0.1 N HCl (□).

[0013] FIG. 3 is a graph illustrating the release of hydrocodone bitartrate from a prior art formulation in 0.1 N HCl (4) and 40 vol.% ethanol/60 vol.% 0.1 N HCl (■).

[0014] FIG. 4 is a graph illustrating the release of diphenhydramine HCl from tablets in 0.1 N HCl (4) and 40 vol.% ethanol/60 vol.% 0.1 N HCl (■).

[0015] FIG. 5 is a graph illustrating the release of diphenhydramine HCl from tablets in 0.1 N HCl (4) and 40 vol.% ethanol/60 vol.% 0.1 N HCl (■).

[0016] FIG. 6 is a graph illustrating the release of diphenhydramine HCl from tablets in 0.1 N HCl (4) and 40 vol.% ethanol/60 vol.% 0.1 N HCl (■).

[0017] FIG. 7 is a graph illustrating the release of diphenhydramine HCl from tablets in 0.1N HCI.

[0018] FIG. 8 is a graph illustrating the release of diphenhydramine HCl from tablets in 20 vol.% ethanol/80 vol.% 0.1 N HCl.

[0019] FIG. 9 is a graph illustrating the release of diphenhydramine HCl from tablets in 0.1N HCL [0020] FIG. 10 is a graph illustrating the release of diphenhydramine HC1 from tablets in 20 vol.% ethanol/80 vol.% 0.1 N HCL

[0021] FIG. 11 is a graph illustrating the release of diazepam from tablets in 0. IN HC1.

[0022] FIG. 12 is a graph illustrating the release of diazepam from tablets in 20 vol.% ethanol/80 vol.% 0.1 N HCL

[0023] FIG. 13 is a graph illustrating the release of diazepam from tablets in 0. IN HCL

[0024] FIG. 14 is a graph illustrating the release of diazepam from tablets in 20 vol.% ethanol/80 vol.% 0.1 N HCL

[0025] FIG. 15 is a graph illustrating the release of diazepam from tablets in 20 vol.% ethanol/80 vol.% 0.1 N HC1, or in 40 vol.% ethanol/60 vol.% 0.1 N HC1

[0026] FIG, 16 is a graph illustrating the release of alprazolam from tablets in 0. IN

HCL

[0027] FIG. 17 is a graph illustrating the release of alprazolam from tablets in 20 vol.% ethanol/80 vol.% 0.1 N HC1.

[0028] FIG. 18 is a graph illustrating the release of alprazolam from tablets in 0. IN

HCL

[0029] FIG. 19 is a graph illustrating the release of alprazolam from tablets in 20 vol.% ethanol/80 vol.% 0.1 N HC1.

[0030] FIG. 20 is a graph illustrating the release of phenobarbital from tablets in 0.01N

HCL

[0031] FIG. 21 is a graph illustrating the release of phenobarbital from tablets in 20 vol.% ethanol/80 vol.% 0.01 N HCL

[0032] FIG. 22 is a graph illustrating the release of diphenhydramine HC1 from tablets in 0. IN HCL

[0033] FIG. 23 is a graph illustrating the release of diphenhydramine HC1 from tablets in 20 vol.% ethanol/80 vol.% 0.1 N HCL

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0034] The present disclosure may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures and examples, which form a part of this disclosure. It is to be understood that this disclosure is not limited to the specific compositions or methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed disclosure. Also, as used in the specification including the appended claims, the singular forms "a," "an," and "the" include the plural, and reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. All ranges are inclusive and combinable.

[0035] The immediate release dosage forms described herein include more than one component. It will be understood by those of skilled in the art that in preparing any of the dosage forms described herein, the weight percent value of all components does not exceed 100 wt.%.

[0036] The modifier "about" should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 2 to about 4" also discloses the range "from 2 to 4." When used to modify a single number, the term "about" may refer to plus or minus 10% of the indicated number and includes the indicated number. For example, "about 10%" may indicate a range of 9% to 1 1%, and "about 1" means from 0.9 to 1.1.

[0037] It is to be appreciated that certain features of the disclosure which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. Fuither, reference to values stated in ranges includes each and every value within that range.

[0038] The term "immediate release" as used herein refers a dosage form that, upon oral ingestion by a human, releases substantially all of a contained active pharmaceutical agent, by weight, into a portion of the gastrointestinal ti'act (e.g., the stomach or the intestine, preferably the stomach) for biological uptake in a short time. In vitro methods of measuring a release profile of a dosage form, for the purpose of determining whether a dosage form exhibits an immediate release or extended release dissolution profile, are known in the pharmaceutical arts. By such methods, examples of immediate release dosage forms as described herein can be measured to be capable of releasing substantially all of a total amount of at least one type of active pharmaceutical ingredient (e.g., an API commonly susceptible to abuse) contained in the dosage form (e.g., at least about 80, or about 90 wt.% of the total amount of the API in a dosage form) into a solution (e.g., acidic aqueous solution) of a suitable pH within about 120 minutes, e.g., in less than about 60 minutes, less than about 45 minutes, or less than about 30, about 15, about 10, or about 5 minutes. For example, a release profile of a dosage form of the present description may be measured by a method that exposes the dosage form to a volume of up to about 900 mL (e.g., about 300 mL, or about 900 mL, based on various test methods) of hydrochloric acid (about 0.01 to about 0.1N) (e.g., aqueous hydrochloric acid) at a pH of from about 1 to about 2, and at a temperature of about 37 °C.

[0039] The term "extended release¹¹ as used herein refers to the slow release of the contained active pharmaceutical agent(s) over several hours into the gastrointestinal tract (e.g., the stomach or the intestine) and colon for biological uptake over a long time. In vitro methods of measuring a release profile of a dosage form, for the purpose of determining whether a dosage form exhibits an immediate release or extended release dissolution profile, are known in the pharmaceutical arts. By such methods, examples of extended release dosage forms as described herein can be measured to be capable of releasing slowly substantially all of a total amount of at least one type of active pharmaceutical ingredient (e.g., an API commonly susceptible to abuse) contained in the dosage form (e.g., at least about 80, or about 90 wt.% of the total amount of the API in a dosage form) into a solution (e.g., acidic aqueous solution, neutral and basic aqueous solution) of a suitable pH over a time period of about 1440 minutes, or about 720 minutes, or about 360 minutes, or about 180 minutes. For example, a release profile of a dosage form of the present description may be measured by a method that exposes the dosage form to a volume of up to about 900 mL (e.g., about 300 mL, or about 900 mL, based on various test methods) of hydrochloric acid (about 0.01 to about 0. IN) (e.g., aqueous hydrochloric acid) at a pH of from about 1 to about 2, or phosphate buffer at a pH of about 6.8 to 7.5 and at a temperature of about 37 °C.

[0040] In some embodiments, the immediate release dosage form has an immediate release profile and an extended release profile. In other embodiments, the immediate release dosage form has an immediate release profile defined as not less than 90% of API released in 60 minutes, and an extended release profile defined as not more than 85% released in 60 minutes.

[0041] According to some embodiments of the dosage forms (designated "type I", as described more fully below), the ratio of the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N or 0.0 IN aqueous HCl at 37 °C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N or 0.0 IN aqueous HCl without ethanol is less than about 0.9, i.e., about 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0,03, 0.02, 0.01, or 0.0. In some embodiments, the ratio is less than about 0.83. In other embodiments, the ratio is about 0.1 to about 0.9. In further embodiments, the ratio is about 0, 14 to about 0.83.

[0042] Throughout the present disclosure, when the description of a release profile of a dosage form includes reference to a medium containing ethanol and "0. IN or 0.01N aqueous HCl", then one of the two recited concentrations of aqueous HCl is present in the ethanol- containing medium; and, for that described release profile, the same concentration of aqueous HCl applies to the medium that does not contain ethanol. For example, if the ethanol-containing medium includes 0.01N aqueous HCl, then the ethanol-free medium to which the description of the release profile refers must also include 0.01N aqueous HCL Likewise, if the ethanol- containing medium includes 0.1N aqueous HCl, then the ethanol-free medium to which the description of the release profile refers must also include 0.1N aqueous HCl.

[0043] In other embodiments, the type I dosage forms will release about 95% or more of the active pharmaceutical agent by weight from the dosage form after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising about 0.1N or 0.01N aqueous HCl without ethanol, at about 37 °C. In addition, the dosage form will release less than about 80% of the active pharmaceutical agent by weight after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0. IN or 0.01N aqueous HCl at about 37 °C.

[0044] In further embodiments, the type I dosage forms will release about 90% or more of the active pharmaceutical agent by weight after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 0. IN or 0.01N aqueous HCl without ethanol at about 37 °C. In addition, the dosage form will release less than about 75% of the active pharmaceutical agent by weight after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N or 0.01N aqueous HCl at about 37 °C.

[0045] In yet other embodiments, the type I dosage forms will release about 80% or more of the active pharmaceutical agent by weight from the dosage form after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 0. IN or 0.01N aqueous HCl without ethanol at about 37°C. In addition, the immediate release dosage form will release less than about 65% of the active pharmaceutical agent by weight from the dosage form after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N or 0.01N aqueous HCl at about 37 °C.

[0046] In further embodiments, the type I dosage forms will release about 75% or more of the active pharmaceutical agent by weight after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 0.1N or 0.01N aqueous HCl without ethanol at about 37 °C. In addition, the dosage form will release less than about 62.5% of the active pharmaceutical agent by weight after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 40% ethanol: 60 vol.% 0.1N or O.OIN aqueous HCl at about 37 °C.

[0047] In further embodiments, the type I dosage forms will release about 95% or more of the active pharmaceutical agent by weight after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 0. IN or 0.01N aqueous HCl without ethanol at about 37 °C. In addition, the dosage form will release less than about 13.5% of the active pharmaceutical agent by weight after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 40% ethanol: 60 vol.% 0. IN or 0.01N aqueous HCl at about 37 °C.

[0048] In yet other embodiments, the type I dosage forms will release from about 75% or more, about 80% or more, about 90% or more, or 95% or more or about 75% to about 95% (e.g., about 75%, about 80%, about 85%, about 90% or about 95% of the active pharmaceutical agent by weight from the dosage form after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 0.1N or 0.01N aqueous HCl without ethanol at about 37°C provided that the ratio of the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N or 0.01N aqueous HCl at 37 °C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N or 0.01N aqueous HCl without ethanol is less than about 0.9. In addition, the immediate release dosage form will release less than 80%, for example, less than about 80%, preferably less than about 70%, about 60% or about 50%, more preferably less than about 50%, or from about 10% to about 79% of the active pharmaceutical agent by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or about 80% of the active pharmaceutical agent by weight) from the dosage form after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N or 0.0 IN aqueous HCl at about 37 °C provided that the ratio of the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N or 0.0 IN aqueous HCl at 37 °C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N or 0.0 IN aqueous HCl without ethanol is less than about 0.9.

[0049] In certain other embodiments (designated "type II", described more fully below), the ratio of the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% O. IN or 0.0 IN aqueous HCl at 37 °C to the active pharmaceutical agent released from the dosage form after I hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N or 0.01N aqueous HCl without ethanol is less than about 0.9, i.e., about 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.03, 0.02, 0.01, or 0.0. In some embodiments, the ratio is less than about 0.4. In other embodiments, the ratio is about 0.1 to about 0.9. In further embodiments, the ratio is about 0.0 to about 0.5, about 0.0 to about 0.4, about 0.0 to about 0.3, about 0.0 to about 0.2, about 0.0 to about 0.15, or 0.0 to about 0.1.

[0050] In further embodiments, the type II dosage forms release less than 80% of the active pharmaceutical agent by weight after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0.1N or 0.0 IN aqueous HCl at 37°C; and, the dosage forms release 95% or more of the active pharmaceutical agent by weight after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 rnL of an aqueous solution comprising 0.1N or 0.0 IN aqueous HCl without ethanol at 37°C.

[0051] In yet other embodiments, the instant type II dosage forms release less than 60% of the active pharmaceutical agent by weight after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0.1N or 0.01N aqueous HCl at 37°C; and, the dosage forms release 90% or more of the active pharmaceutical agent by weight after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N or 0.01N aqueous HCl without ethanol at 37°C. [0052] In further embodiments, the type IT dosage forms release less than 50% of the active pharmaceutical agent by weight after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.%) 0.1N or 0.01N aqueous HCl at 37°C; and, the dosage forms release 80%> or more of the active pharmaceutical agent by weight after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N or 0.01N aqueous HCl without ethanol at 37°C.

[0053] In yet other embodiments, the type II dosage forms will release from about 75% or more, about 80% or more, about 90% or more, or 95% or more or about 75% to about 95% (e.g., about 75%, about 80%, about 85%, about 90% or about 95% of the active pharmaceutical agent by weight from the dosage form after about 1 hour when measured by the USP 1 Basket (10 mesh screen) method at about 50 rpm in about 900 mL of an aqueous solution comprising 0.1N or 0.0 IN aqueous HCl without ethanol at about 37°C provided that the ratio of the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0.1N or 0.01N aqueous HCl at 37 °C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N or 0.01N aqueous HCl without ethanol is less than about 0.9. In addition, the immediate release dosage form will release less than 80%, for example, less than about 80%, preferably less than about 70%, about 60% or about 50%, more preferably less than about 50%, or from about 10% to about 79% of the active pharmaceutical agent by weight (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or about 80% of the active pharmaceutical agent by weight) from the dosage form after about 1 hour when measured by the USP 1 Basket (10 mesh screen) at about 50 rpm in about 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0. IN or 0.01N aqueous HCl at about 37 °C provided that the ratio of the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0.1N or 0.01N aqueous HCl at 37 °C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N or 0.01N aqueous HCl without ethanol is less than about 0.9. [0054] The immediate release dosage forms may also reduce the risk of an overdose resulting from simultaneous oral ingestion of multiple units of the oral dosage form and may be in the absence or presence of alcohol. In other embodiments, the immediate release dosage form reduces the potential for abuse by simultaneous oral ingestion of multiple units of the oral dosage form. In further embodiments, the immediate release dosage form demonstrates an immediate release profile when administered in therapeutic doses, but which demonstrates an extended release profile when administered in supratherapeutic doses.

[0055] The immediate release dosage forms of the disclosure include one or more alcohol resistant agents, as described herein, that provide for immediate release of an active pharmaceutical agent when the dosage forms are administered in the absence of alcohol. But in the presence of alcohol, the described dosage forms retard the release of the active

pharmaceutical agent by, for example, impeding the wetting and/or disintegration of the dosage form.

[0056] As used herein, "alcohol" refers to a Ci to C₄ alcohol, such as methanol, ethanol, or isopropanol. Ethanol is the most commonly encountered alcohol.

[0057] "Pharmaceutically acceptable" refers to physiologically tolerable materials, which do not typically produce an allergic or other adverse reaction when administered to a human.

[0058] "Pharmaceutically acceptable salts" are those derived from acids or bases (i.e., an acid addition salt or base addition salt, which salt is therapeutically active, non-toxic and otherwise acceptable for administration to a patient. Acid addition salts may be formed from drug compounds having an ionizable basic moiety by using a suitable acid reagent. Suitable acid reagents for forming an acid addition salt include inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like, as well as organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesuifonic, ethane disulfonic, oxalic, isethionic, and the like. Base addition salts may be formed from drug compounds having an ionizable acidic moiety by using a suitable base reagent. Suitable base reagents for forming a base addition salt include inorganic bases such as alkali metal hydroxides such as sodium or potassium hydroxide, alkaline earth metal hydroxides such as calcium or magnesium hydroxide; and also include organic bases such as ammonia or amines such as triethyl amine or meglumine. [0059] "Pharmaceutically acceptable excipients" inciude, but not limited to, diluents, disintegrates, binders and lubricants. Preferably, the excipients meet the standards of the National Formulary ("NF") or United States Pharmacopoeia ("USP").

[0060] "Pharmaceutical dosage form" refers to a final formulation that can be administered to a patient to treat a disease, condition, or disorder in the patient. The particular dosage form may be selected by those skilled in the art from solid dosage forms. In some embodiments, the pharmaceutical dosage form is a solid dosage form.

[0061] "Therapeutically effective amount" refers to an amount of an active

pharmaceutical agent described herein which is sufficient to inhibit, halt, or cause an

improvement in a disorder or condition being treated in a particular subject or subject population. In certain embodiments, in a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by government guidelines for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.

[0062] "Supratherapeutic amount" refers to an amount of an active pharmaceutical agent described herein which exceeds the recommended amount, under government guidelines, as determined by one skilled in the pharmaceutical and medical arts. The supratherapeutic amount typically results in one or more adverse effect in a patient after administration including, without limitation, death. The particular adverse effect depends on the particular active pharmaceutical agent and patient. In some embodiments, a supratherapeutic amount exceeds a recommended dosage over a period of hours. In other embodiments, a supratherapeutic amount exceeds a recommended dosage over a period of at least about 1, 2, 3, 4, 5, 6, 7 8, 9, 10, I I, 12, 13, 14, 15 16, 17, 18, 19, 20, 21, 22, 23, or 24 or more hours. The supratherapeutic amount will depend on the particular active pharmaceutical agent selected for use herein, disease, or patient, among others. In some embodiments, the "supratherapeutic dose" corresponds to administration of five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, or twelve or more individual dose units, e.g., tablets, simultaneously. In further embodiments, a supratherapeutic dose is five or more dosage forms. In other embodiments, a supratherapeutic dose includes administering multiple individual dose units simultaneously. In further embodiments, a supratherapeutic dose includes administering multiple doses sequentially over a short time interval, e.g., over an interval of less than 60 minutes, less than 30 minutes, less than 15 minutes, less than 5 minutes or less than one minute. [0063] "Treatment" refers to the acute or prophylactic diminishment or alleviation of at least one symptom or characteristic associated or caused by a disorder being treated. In certain embodiments, treatment can include diminishment of several symptoms of a disorder or complete eradication of a disorder.

[0064] Immediate release dosage forms are described herein and are useful in controlling the systemic release of active pharmceutical agents in a patient. These immediate release dosage forms release the active pharmaceutical agent when taken as directed (i.e., when taken without alcohol), but inhibit release of the active pharmaceutical agent when taken, or combined, either purposefully or accidentally, with alcohol. The immediate release dosage forms suppress release of the active pharmaceutical agent in the presence of any alcohol concentration, but particularly high alcohol concentrations, i.e., at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% alcohol by volume or greater. The immediate release dosage forms also deter or prevent abuse by multiple routes such as intravenous, nasal, and oral ingestion of a single intact dosage form, multiple intact dosage forms, or any number of crushed dosage forms. The immediate release dosage forms also resist abuse when potential abusers attempt to chemically extract the active pharmaceutical agent using common solvents such as esters such as ethyl acetate or methyl acetate, ketones such as methylethyl ketone (MEK) or acetone, alcohols such as methanol, ethanol, or isopropanol, and other readily available organic sol vents that could potentially be used for such extraction.

[0065] In some embodiments, the immediate release dosage forms are effective in preventing accidental or intentional fatality in a subject when taken as a single dose or in multiple doses. The multiple doses may be taken all at once or consecutively, provided that the end result is a contraindicated supratherapeutic dose. When multiple doses of the immediate release dosage forms are orally taken by a subject, a slower rate of release of the active pharmaceutical agent as compared to currently available dosage forms was observed.

Advantageously, the slower rate of release for multiple tablets occured in the presence or absence of alcohol. The slowing effects of the immediate release dosage forms are also observed when contacting alcohol. In these embodiments, when single or multiple doses are taken by a patient who has ingested alcohol, will ingest alcohol or are consuming alcohol concurrently with the immediate release dosage form, the single or multiple doses have a slower rate of release of the active pharmacweutical agent as compared to currently available dosage forms. Accordingly, the administi'ation of a single immediate release dosage form or multiple doses of the immediate release dosage forms (a supratherapeutic dose) can provide the addititional time needed to obtain emergency assistance and prevent intentional or accidental death.

Dosage Forms

[0066] The immediate release dosage forms described herein can be formulated for oral delivery to the patient using methods known in the art. In some embodiments, the immediate release dosage form is in the form of a tablet. In other embodiments, the immediate release dosage form is a in the form of a compressed tablet. In yet further embodiments, the immediate release dosage form is in the form of a caplet.

[0067] Regardless of the physical form, certain the dosage forms of the disclosure contain particles. As used herein, the term "particles" refers to granules, spheroids, beads, or pellets that comprise an active pharmaceutical agent and form the "core" of the dosage form. The disclosed particles can be prepared using any of the components and/or methods described herein. For example, the particles can comprise cellulose and cellulose derivatives (e.g., hydi'oxypropyl methyicellulose ("HPMC" or "hypromellose"), ethyl cellulose, microcrystalline cellulose, and combinations thereof), lipids (e.g., fatty acid esters such as glyceryl behenate, COMPRITOL), polyvinylpyrrolidones, and the like. Particles of the disclosure can be prepared using, for example, a high shear granulator. In other embodiments, the particles may be prepared according to U.S. Patent Application Publication No. 2015/01 18303, the entirety of which is incorporated by reference herein.

[0068] In some embodiments, the particles of the disclosure comprise an active pharmaceutical agent The active pharmaceutical agents used in the immediate release dosage forms of the disclosure can be agents that are known in the ait to be abused generally, or subject to abuse with alcohol. The active pharmaceutical agents used in the immediate release dosage forms of the disclosure can also be agents that are contraindicated for administration with alcohol, i.e., that an adverse side effect is known to occur if the active pharmaceutical agent is administered with alcohol (for example, metronidazole).

[0069] The active pharmaceutical agent may be selected by one skilled in the art depending on the condition being treated. Selection of the active pharmaceutical agent may also depend on other factors including, without limitation, components of the composition, mode of delivery, severity of the condition being treated, the patient's age and weight, and any other active ingredients used in the composition. In some embodiments, the immediate release dosage form contains one active pharmaceutical agent. In other embodiments, the immediate release dosage form contains two active pharmaceutical agents. In further embodiments, the immediate release dosage form contains three or more active pharmaceutical agents.

[0070] In some embodiments, the active pharmaceutical agent is an analgesic, stimulant, depressant, antihistamine, anesthetic, antidepressant, anti-anxiety agent, sedative, anxiolytic, antipsychotic, cannabinol, cannabinoid, antibiotic, or muscle relaxant As those skilled in the art will appreciate, some active pharmaceutical agents useful in the described immediate release dosage forms may have one mechanism of action or two or more mechanisms of action. For example, a single active pharmaceutical agent may be categorized as both an antihistamine and a sedative.

[0071] Analgesics which may be included in the immediate release dosage forms include narcotics, non-steroidal anti-inflammatory drugs, and narcotic analgesics such as opioids. In some embodiments, the active pharmaceutical agent is an opioid agonist. The opioid agonist may be selected by those skilled in the art from agents such as buprenorphine, butorphanol, codeine, dextropropoxyphene, dihydrocodeine, dihydroetorphine, dihydromorphine, dipipanone, etorphine, fentanyl, fentanyl derivatives, heroin, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, morphine sulphate, nalbuphine, oxycodone, oxymorphone, propoxyphene, tramadol, or pharmaceutically acceptable salts thereof. In some embodiments, the dosage forms may also include an opioid antagonist, for example, naltrexone.

[0072] In further embodiments, more than one active pharmaceutical agent may be included in the particles described herein or in the immediate release dosage forms described herein. For example, when an opioid is present as an active pharmaceutical agent, an additional active pharmaceutical agent may be included and selected from, for example, one or more of a non-steroidal anti-inflammatory drug, analgesic/antipyretic, or opioid antagonist. Examples of non-steroidal anti-inflammatory drugs include, without limitation, aspirin, ketoprofen, naproxen, or ibuprofen. An example of an analgesic/antipyretic includes, without limitation, paracetamol. Examples of opioid antagonists include, without limitation, naloxone or naltrexone

[0073] Muscle relaxants which may be included in the immediate release dosage forms include, without limitation, cyclobenzaprine, carisoprodol, diazepam, metaxalone, or methocarbamol.

[0074] Sedatives which may be included in the immediate release dosage forms include, without limitation, barbiturates such as phenobarbital, methobarbital, amobarbital, pentobarbital, and secobarbital, allobarbital, aprobarbital, alphenal, barbital, and brallobarbital; benzodiazepines such as diazepam, clonazepam, chlorodiazepoxide, lorazepam, triazolam, temazeparn, alprazolam and flurazepam; phenothiazines such as alimemazine, chlorpromazine, or thioridazine; and sleep medications such as Zolpidem, zaleplon, and eszopiclone; or pharmaceutically acceptable salts thereof.

[0075] Antihistamines which may be included in the immediate release dosage forms include, without limitation, astemizole, azatadine, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyproheptadine, desloratadine, dexchlorpheniramine, diphenhydramine, fexofenadine, hydroxyzine, levocetirizine, loratadine, phenindamine, promethazine, terfenadine, tripelennamine, triprolidine, or pharmaceutically acceptable salts thereof. In some embodiments, the antihistamine is diphenhydramine.

[0076] Antidepressants which may be included in the immediate release dosage forms include, without limitation, amitriptyline, amoxapine, bupropion, desipramine, desvenlafaxine, escitalopram, doxepin, duloxetine, fluoxetine, imipramine, isocarboxazid, italopram, levomilnacipran, lurasidone, lamotrigine, chlordiazepoxide, mirtazapine, nortriptyline, olanzapine, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, veniafaxine, vilazodone, vortioxetine, or

pharmaceutically acceptable salts thereof.

[0077] Anti-anxiety agents which may be included in the immediate release dosage forms include, without limitation, alprazolam, amitriptyline/chlordiazepoxide,

arnitriptyline/perphenazine, aspirin/meprobamate, atenolol, bupropion, buspirone,

chlordiazepoxide, clonazepam, clonidine, clonidine, clorazepate, desvenlafaxine, diazepam, doxepin, duloxetine, escitalopram, gabapentin, halazepam, hydroxyzine, lamotrigine, lorazepam, meprobamate, mirtazapine, nadolol, nefazodone, oxazepam, oxcarbazepine, paroxetine, phenytoin, prochlorperazine, propranolol, risperidone, tramadol, trazodone, trifluoperazine, veniafaxine, vilazodone, or pharmaceutically acceptable salts thereof.

[0078] Anxiolytics which may be included in the immediate release dosage forms include, without limitation, benzodiazepines such as diazepam, chlordiazepoxide, estazolam, lorazepam, triazolam, alprazolam, clonazepam and flurazepam or pharmaceutically acceptable salts thereof.

[0079] Stimulants which may be included in the immediate release dosage forms include, without limitation, amphetamines such as dextroamphetamine, levoamphetamine, methamphetamine, pseudoephedrine, and Adderall and non-amphetamine psychostimulants such as methylphenidate, modafmil, armodafinil, or pharmaceutically acceptable salts thereof. [0080] Antipsychotic agents which may be included in the immediate release dosage forms include, without limitation, phenothiazines, butyrophenones such as droperidol and haloperidol, dibenzoxazepines such as loxapine, and atypical antipsychotic agents such as aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, paliperidone, remoxipride, or pharmaceutically acceptable salts thereof.

[0081] Anesthetics which may be included in the immediate release dosage forms include, without limitation, ketamine, esketamine, or pharmaceutically acceptable salts thereof.

[0082] Antibiotics which may be included in the immediate release dosage forms include, without limitation, metronidazole, tinidazoie, and trimethoprim-sulfamethoxazole, or pharmaceutically acceptable salts thereof.

[0083] The active pharmaceutical agents which are suitable also include such active pharmaceutical agents wherein the molecular structures include isotopes of carbon, hydrogen and nitrogen atoms occurring on those structures. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium. Isotopes of carbon include C-13. Isotopes of nitrogen include N- 15.

[0084] Accordingly, one or more atom within the chemical structure of any active pharmaceutical agent discussed herein may be an isotope. In some embodiments, any hydrogen atom or group of hydrogen atoms may be replaced by an isotope of hydrogen, i.e., deuterium. In other embodiments, any carbon atom or group of carbon atoms may be replaced by an isotope of carbon, i.e., ¹³C. In further embodiments, any nitrogen atom or group of nitrogen atoms may be replaced by an isotope of nitrogen, i.e., ^I5N.

[0085] As used herein, an active pharmaceutical agent that is termed "isotopically- enriched" means that the abundance of deuterium, ¹³C, or ¹⁵N at any relevant site of the compound is substantially more than the abundance of deuterium, ¹³C, or ^I5N naturally occurring at that site in an amount of the compound. A relevant site in a compound as used above is a site which would be designated as "H" or "C" or "N" in a chemical structure representation of the compound when not enriched. The expression, "naturally occurring," as used above refers to the abundance of the particular atom which would be present at a relevant site in a compound if the compound was prepared without any affirmative synthesis step to enrich the abundance of a different isotope. Thus, in one example in a "deuterium-enriched" compound, the abundance of deuterium at any relevant site in the chemical structure of the active pharmaceutical agent can range from an amount that is substantially more than the natural abundance of deuterium (about 0.01 15%) all the way up to 100%, for example, from about 1% to about 100%, or from about 10% to about 100%, or from about 50% to about 100%, or from about 90% to about 100%.

[0086] Similarly, for a "ⁱ³C-ermched" compound, the abundance of ¹³C at any relevant site in the chemical structure of the API can range from an amount that is substantially more than the natural abundance of ¹³C (about 1.109%) all the way up to 100%, for example, from about 5% to about 100%, or from about 10% to about 100%, or from about 50% to about 100%, or from about 90% to about 100%. Similarly for a "^I5N-enriched" compound, the abundance of ¹⁵N at any relevant site in the chemical structure of the API can range from an amount that is substantially more than the natural abundance of ¹⁵N (about 0.364%) all the way up to 100%, for example, from about 1% to about 100%, or from about 10% to about 100%, or from about 50% to about 100%, or from about 90% to about 100%. Isotopically-enriched compounds can generally be prepared by conventional techniques known to those skilled in the ait. Such isotopically-enriched compounds can also be prepared by adapting conventional processes as described in the scientific literature for synthesis of API's disclosed herein as suitable for formulation according to the invention, and using an appropriate isotopicaUy-substituted reagent (or reagents) in place of the corresponding non isotopically-substituted reagent(s) employed in the conventional synthesis of the non-isotopically-enriched compounds. Examples of ways to obtain a deuterium-enriched compound include exchanging hydrogen with deuterium or synthesizing the compound with deuterium-enriched starting materials.

[0087] The amount of the active pharmaceutical agent included in the immediate release dosage form described herein may be determined by one of skilled in the art, i.e., can be any useful amount. In some embodiments, the amount of the active pharmaceutical agent may be determined using The Physician's Desk Reference, 70^1h Edition, 2016. In some embodiments, the amount of the active pharmaceutical agent is sufficient to induce a beneficial therapeutic response in the patient over time. The beneficial dose can vary from patient to patient depending upon the patient's condition, body weight, surface area, and side effect susceptibility, among others. Administration can be accomplished via single or divided doses.

[0088] Dosage forms according to the present disclosure may be those in which (I) an active agent portion is present in the dosage form as a plurality of particles, and the plurality of particles are admixed with the alcohol resistant agent, thereby forming an admixture, or (Π) the active agent portion forms a central core of the dosage form, and the alcohol resistant agent is contained within an outer layer that surrounds the central core. Detailed descriptions of dosage forms according to type I and of dosage forms according to type II are respectively provided below under appropriate headings. Descriptions of possible types of alcohol resistant agents, active pharmaceutical agents, gelling agents, neutralizing agents, binders, disintegrants, glidants, lubricants, fillers, pH sensitive polymers, and other excipients that are provided in the section pertaining to dosage forms according to type I are equally applicable to dosage forms according to type II.

I. Dosage Forms in Which an Active Agent Portion Is Present In the Dosage Form as a Plurality Of Particles, and the Plurality of Particles Are Admixed With the Alcohol Resistant Agent, Thereby Forming an Admixture

[0089] In some embodiments, the active pharmaceutical agent is dispersed within the particles or core to form "active particles." For example, in these embodiments, the active pharmaceutical agent can be combined with the other paiticle components during the paiticle preparation process. In these embodiments, the active particles can comprise from about 10% to about 80%, by weight of the active paiticle, of the active pharmaceutical agent(s). For example, the active particles can comprise about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or about 80%, by weight of the active paiticle, of the active pharmaceutical agent(s).

[0090] In other embodiments, the particles are coated with an "active coating layer" to form "coated particles", wherein the active coating layer comprises the active pharmaceutical agent. For example, in these embodiments, the active pharmaceutical agent can be combined with one or more pharmaceutically acceptable excipients to form an active coating solution. The active coating solution can be applied to the particles using methods known in the art, for example, spray coating, to form an active coating layer on the particles. In these embodiments, the coated particles can comprise from about 10% to about 80%, by weight of the coated paiticle, of the active pharmaceutical agent(s). For example, the coated particles can comprise at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, or about 95%, by weight of the coated particle, of the active pharmaceutical agent. In other embodiments, the coated particles comprise at least about 95% by weight of the coated particle, of the active pharmaceutical agent.

[0091] In further embodiments, the active pharmaceutical agent is dispersed within the particles and contained within the coating.

[0092] In other embodiments, the total amount of active pharmaceutical agent can be both in an active coating layer and dispersed within the particles. In these embodiments, the particles are coated with an active coating layer comprising a first portion of the active pharmaceutical agent. Also in these embodiments, a second portion of the active pharmaceutical agent is dispersed within the particles. In these embodiments, about 1 to about 99 wt.% of the active pharmaceutical agent is in the active coating layer, with the remainder of the active pharmaceutical agent being dispersed within the particles. In other embodiments, about 1 to about 75 wt.% of the active pharmaceutical agent is in the active coating layer, with the remainder of the active pharmaceutical agent being dispersed within the particles. In other embodiments, about 1 to about 50 wt.% of the active pharmaceutical agent is in the active coating layer, with the remainder of the active pharmaceutical agent being dispersed within the particles. In other embodiments, about I to about 25 wt.% of the active pharmaceutical agent is in the active coating layer, with the remainder of the active pharmaceutical agent being dispersed within the particles,

[0093] In the immediate release dosage forms of the disclosure, the particles that comprise an active pharmaceutical agent are admixed with an alcohol resistant agent, as defined herein. In further embodiments, the particles can be coated with one or more alcohol resistant agents, prior to being admixed with one or more additional alcohol resistant agents.

[0094] The present disclosure encompasses two types of alcohol resistant agents, referred to herein as "A-type" agents and "B-type" agents. Some immediate release dosage forms of the disclosure will include only A-type alcohol resistant agent(s). Some of the dosage forms of the disclosure can comprise about 30% to about 90%, based on the weight of the dosage form, of the A-type alcohol resistant agents. For example, the dosage forms of the disclosure can comprise about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or about 90%, based on the weight of the dosage form, of the A-type alcohol resistant agent(s),

[0095] Some immediate release dosage forms of the disclosure will include only B-type alcohol resistant agent(s). Some of the dosage forms of the disclosure can comprise about 30% to about 90%, based on the weight of the dosage form, of the B-type alcohol resistant agents. For example, the dosage forms of the disclosure can comprise about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or about 90%, based on the weight of the dosage form, of the B-type alcohol resistant agent(s).

[0096] Other immediate release dosage forms of the disclosure will include a combination of one or more A-type agents and one or more B-type agents. Accordingly, some of the dosage forms of the disclosure can comprise about 30% to about 90%, based on the weight of the dosage form, of the combination of A-type agent and B-type agent. For example, the dosage forms of the disclosure can comprise about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or about 90%, based on the weight of the dosage form, of the combination of A-type agent(s) and B-type agent(s). [0097] As used herein, A-type alcohol resistant agents are those that do not gel in water but that gel with increasing concentration of alcohol (e.g., ethanol) in water-alcohol mixtures. The gelling action in water-alcohol mixture slows dosage form disintegration and wetting, resulting in slow release of the active pharmaceutical agent in water-alcohol mixtures. The higher the alcohol concentration in the water-alcohol mixture, the more the A-type agents will gel. In contrast, with A-type agents, there is a relatively rapid release and relatively rapid dosage form disintegration in 0.1 N HC1 or 0.01 N HC1 (that does not include alcohol), which is commensurate with dosage forms intended for immediate release of the active pharmaceutical agent. Preferred A-type agents are copolymers comprising ethyl acrylate and methyl methacrylate. In other embodiments, A-type agents are copolymers comprising ethyl acrylate, methyl methacrylate, and methacrylic acid ester with quaternaiy ammonium group salts.

Preferred A-type agents included, for example, EUDRAGIT RS, EUDRAGIT RL, EUDRAGIT NE, EUDRAGIT NM, Kollicoat EMM and other derivatives of the poly(methyl methacrylate) family, which are commercially available from Evonik Industries, Essen, Germany, and BASF SE, Ludwigshafen, Germany.

[0098] B-type agents are those that do not gel in alcohol (e.g., ethanol) and may be classified into two subtypes, i.e., Bl-type and B2~type agents. B l-type agents are soluble or freely soluble in water. In some embodiments, Bl-type agents allow the dosage forms to wet more quickly in water, resulting in relatively rapid dosage form disintegration and release of the active pharmaceutical agent. The B2-type agents are those that are insoluble, slightly soluble or sparingly soluble in water. One of skill in the art would be able to utilize common techniques to determine if a B-type reagent was a B 1 -type or B2-type.

[0099] In water-alcohol mixtures, however, the B-type agents prevent the dosage form from wetting rapidly and as a result, the release of the active pharmaceutical agent from the dosage form is slowed or delayed. In some embodiments, the B-type agents are granular. With B-type agents, there is a relatively rapid release and relatively rapid dosage form disintegration in 0.1 N HC1 or 0.01 N HC1 (that does not include alcohol), which is commensurate with dosage forms intended for immediate release of the active pharmaceutical agent. Preferred B-type agents are ionic, insoluble in alcohol, and may be soluble or insoluble in water. Examples of B~ type agents include ammonium phosphate monobasic, ammonium phosphate dibasic, ammonium sulfate, ammonium citrate tribasic, ammonium citrate dibasic, barium acetate, barium citrate, barium phosphate, calcium citrate tetrahydrate, calcium magnesium citrate, calcium citrate malate, calcium fumarate anhydrous, calcium fumarate trihydrate, calcium lactate anhydrous, calcium malate, calcium silicate, calcium succinate, calcium carbonate, calcium citrate tetrahydrate, calcium citrate anhydrous, calcium hydroxide, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate monobasic anhydrous, calcium phosphate tribasic, calcium sulfate, calcium sulfate dihydrate, copper carbonate, copper citrate hemitrihydrate, copper gluconate, cupric oxide, cupric sulfate anhydrous, cupric sulfate pentahydrate, ferric ammonium citrate, ferrous ammonium sulfate, ferric citrate, ferric phosphate hydrate, ferric phosphate anhydrous, ferrous citrate dibasic, ferrous fumarate, ferrous gluconate, ferrous lactate dihydrate, magnesium ascorbate, magnesium aspartate monobasic dihydrate, magnesium aspartate dibasic, magnesium citrate tribasic hydrate, magnesium citrate tribasic anhydrous, calcium magnesium citrate, magnesium gluconate, magnesium lactate anhydrous, magnesium lactate dihydrate, magnesium malate trihydrate, magnesium phosphate dibasic, magnesium phosphate tribasic, magnesium phosphate tribasic pentahydrate, magnesium sulfate, magnesium sulfate heptahydrate, manganese ascorbate, manganese citrate, manganese gluconate dihydrate, manganese lactate, manganese sulfate monohydrate, potassium carbonate, dipotassium citrate, potassium gluconate anhydrous, potassium nitrate, potassium phosphate dibasic, potassium phosphate dibasic anhydrous, potassium phosphate monobasic, potassium sulfate, sodium acetate trihydrate, sodium bisulfate monohydrate, sodium carbonate anhydrous, sodium carbonate monohydrate, sodium formate, sodium nitrate, sodium phosphate monobasic anhydrous, sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, sodium phosphate dibasic dihydrate, sodium phosphate dibasic heptahydrate, sodium phosphate tribasic dodecahydrate, sodium pyrophosphate decahydrate, sodium succinate anhydrous, sodium sulfate anhydrous, sodium sulfate decahydrate, strontium nitrate, zinc ascorbate monohydrate, zinc citrate dihydrate, zinc citrate trihydrate, zinc gluconate, zinc lactate dihydrate, zinc oxide, zinc phosphate tribasic tetrahydrate, zinc sulfate heptahydrate, zinc sulfate monohydrate, or a mixture thereof. Preferred B-type agents that can be used within the disclosed dosage forms include, for example, calcium phosphate, sodium phosphate, calcium sulfate, calcium citrate, calcium acetate, barium sulfate, barium citrate, or a mixture thereof. In some embodiments, the B-type agent is a B2-type agent such as monobasic calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, or a mixture thereof. In other embodiments, the B-type agent is a B2-type agent such as a hydrate of calcium phosphate. In further embodiments, the B- type agent is anhydrous calcium phosphate. In yet other embodiments, the B-type agent is anhydrous dicalcium phosphate. In still further embodiments, the B-type agent is a dihydrate of dibasic calcium phosphate dihydrate. In some embodiments, the B-type agent is calcium sulfate dihydrate. In further embodiments, the B-type agent is a Bl-type agent such as granular dibasic sodium phosphate dihydrate. In other embodiments, the B-type agent is a B2-type agent such as calcium sulfate.

[00100] In addition to the active pharmaceutical agent and the alcohol resistant agent, the immediate release dosage forms of the disclosure may comprise one or more

pharmaceutically acceptable excipients. The excipients can be included in the particles described herein and in the final dosage forms described herein. The excipients may be included in the dosage forms in intragranular forms, extragranular forms, or combinations thereof. The term "intragranular" and "extragranulai'¹¹ as used herein are known in the art of formulations. An intragranular form of an excipient is added before granule/particle formation. In some embodiments, an extragranular form of a component described herein is added to the granules/particles of the formulation prior to compression. In other embodiments, an extragranulai- portion of one or more component described herein breaks the composition into granules/particles and the intragranular portion disintegrates the granules/particles to release the active agent.

[00101] The selection of the particular excipient for use in the immediate release dosage forms can depend on the particular active pharmaceutical agent to be delivered. One would be able to select one or more suitable excipients using skill in the art and the teachings herein. In some embodiments, the excipients may be selected from those described in Handbook of Pharmaceutical Excipients, 5th ed. (2006). In other embodiments, the excipient is a standard tableting excipient. In other embodiments, the excipient includes, without limitation, one or more of a gelling agent/polymer, neutralizing agent, disintegrant, glidant, binder, filler, lubricant, support, embittering agent, gas-releasing agent, coloring agent, metallic pigment, flavor, sweetener, pH adjuster, emetic agent, effervescent agent, or a combination thereof.

[00102] For example, in some embodiments, the immediate release dosage forms can further comprise a gelling agent that is not an A-type alcohol resistant agent or a B-type alcohol resistant agent. Such gelling agents are present in an amount that does not affect the alcohol resistance of the immediate release dosage forms. The gelling agent may include, without limitation, an acrylic acid and methacrylic acid copolymer, a methyl methacrylate copolymer, a carbomer polymer, an ethoxy ethyl methacrylate, a cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, agar, acacia, algin, cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, cellulose ether, cellulose ester, cellulose ester ether, cellulose, ethylcelluiose, glycidyl methacrylate copolymer, guar, hydroxy methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylmethyl cellulose, karaya, methacrylic acid alkylamide copolymer, methyl cellulose, ethyl cellulose, polyethylene oxide, polyvinyl alcohol poly(methyl methacrylate), polymethacrylate, poly(methyl

methacrylate) copolymer, polyacrylamide, poly(aciylic acid), poly(methacrylic acid), poly (methacry lie acid anhydride), sodium carboxymethyl cellulose, tragacanth, polyacrylamide, water-sweliable indene maleic anhydride polymer, and combinations thereof. In some embodiments, the gelling agent is EUDRAGIT E-100, EUDRAGIT E PO, EUDRAGIT E 12.5, and similar amino-functional pH-sensitive polymers. In other embodiments, the gelling agent is the polymer EUDRAGIT El 00. In further embodiments, the gelling agent is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

[00103] The binder for use herein as an excipient is selected to ensure cohesion of the active pharmaceutical agent ingredient with the other components of the immediate release dosage form. Examples of binders include, without limitation, gum arabic, gum tragacanth, gum arable, methyl cellulose, ethyl cellulose, carboxymethylcellulose, sodium

carboxymethylcellulose, gelatin, starch, pregelatinized starch, maltodextrins, PEG 4000 and 6000 in alcoholic solution, polyvidone in aqueous or alcoholic solution, saccharose, glucose, sorbitol, saccharose, dextrin, polyvinylpyrrolidone (PVP or polyvidone), HPMC,

methylcellulose, hydroxymethyl cellulose, gum lac, hydroxypropyl cellulose (HPC), cellulose, polyols (mannitol, sorbitol, maltito! or xylitol), alginates such as alginic acid, polyglycolysed glycerides, macrogolglycerides, acrylic derivatives, microcrystallme cellulose (MCC), ethylcellulose, polyvinyl alcohol, polyethylene oxide, polyacrylamides, poly vinyloxoazolidone, or combinations thereof. In some embodiments, the binder is HPMC, ethyl cellulose, MCC, PVP or combinations thereof.

[00104] Lubricants may be utilized in the immediate release dosage form and selected by one of skill in the ait. The excipient may also include a lubricant selected from, without limitation, sodium lauryl sulfate, sodium oleate, talc, silicone derivatives, waxes, talc, PEG 4000, stearic acid, glyceride esters such as glyceryl monostearate, glyceryl behenate, glyceryl tribehenate, and glyceryl dibehenate, sugar esters such as sorbitan monostearate and sucrose monopalmitate, and metal salts of fatty acids such as magnesium stearate, calcium stearate, and zinc stearate. In some embodiments, the lubricant is glyceryl behenate.

[00105] The lubricant included in the immediate release dosage form may depend on the particular A-type or B-type agent utilized in the dosage form and the water solubility of the immediate release dosage form resulting therefrom. In some embodiments, the immediate release dosage form contains an A-type agent and one or more lubricants. In other embodiments, the immediate release dosage form contains a Bl-type agent and one or more lubricants. In further embodiments, the immediate release dosage form contains a B2-type agent and one or more lubricants, which lubricant is selected to ensure that disintegration of the immediate release dosage form in water is not suppressed. In one example, when the immediate release dosage form contains a B2-type agent, an inorganic lubricant such as talc may be selected. In another example, when the immediate release dosage form contains a B2-rype agent, the lubricant is not a lipid-based lubricant such as magnesium stearate, stearic acid, or sodium stearyl fumarate.

[00106] One of skill in the art would be able to determine the amount of lubricant to include in the immediate release dosage form depending on desired alcohol resistance, dissolution, among others. In some embodiments, the immediate release dosage form contains no more than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 wt% of a lubricant, such as talc.

[00107] Embittering agents may also be selected for use as an excipient and include, without limitation, denatonium benzoate, extracts of, gentian, quinine, caffeine, brucine, quassin, propylthiouracil, phenylthiocarbamide, astringent compounds such as tannins, grapefruit flavor and bitter cocoa flavor.

[00108] In addition to the fillers recited above, examples of fillers that may be useful in an immediate release dosage form as described may include lactose, starch, dextrose, sucrose, fructose, maltose, mannitol, sorbitol, kaolin, microcrystalline cellulose, powdered cellulose, calcium sulfate, calcium phosphate, dicalcium phosphate, lactitol or any combination.

[00109] A gas-releasing compound may be used as an excipient, e.g., a carbonate or bicarbonate such as sodium bicarbonate, sodium carbonate, sodium glycine carbonate, potassium bicarbonate, magnesium carbonate and calcium carbonate.

[00110] Coloring agents may be used as an excipient and selected from, without limitation, neutral red, brilliant blue FDC, conventional food colorings such as Coloring E131 , fruit and vegetable extracts, or mixtures thereof.

[00111] Metallic pigments may optionally be included in the formulations described herein. Examples of metallic pigments include, without limitation, and titanium dioxide-based pigments.

[00112] Glidants may further be included in the immediate release dosage forms include without limitation, colloidal silicon dioxide, untreated fumed silica, and crystalline or fused quartz. [00113] Disintegrants may include, without limitation, sodium starch glycolate, starch (e.g., maize starch, potato starch, rice starch, tapioca starch, wheat starch, com starch and pregelatinized starch), croscarmellose sodium, crospovidone (crosslinked polyvinyl N- pyrrolidone or PVP), polyplasdone XL- 10, or sodium starch glycolate.

[00114] A pH-adjuster can also be included in an immediate release dosage form as described, for example at a location to affect pH at a specific location of the dosage form that is only a portion of a total dosage form.

[00115] The immediate release dosage form may further include a flavor and/or sweetener as an excipient. Examples of flavors/sweeteners include those traditionally used as food additives. In some embodiments, the sweeteners include, without limitation, E951 aspartame, E420 sorbitol, E421 mannitol, E950 acesulfame K, E954 saccharin, stevia or thaumatine.

[00116] In some embodiments, the pharmaceutically acceptable excipient comprises HPMC, ethyl cellulose, glyceryl behenate, MCC, a PVP, or a mixture thereof.

[00117] A non-functional coating agent may be included in the immediate release dosage forms of the disclosure by forming a coating layer on the particles or the final dosage forms of the disclosure. Such coating agents may include, without limitation, wax derivatives (natural or synthetic products consisting of esters of fatty acids and alcohols), plasticizers (film- forming agents), gum lac, polyvinylpyrrolidone, glycol polyethylene, cellulose derivatives such as HPMC or HPC, saccharose, alginates, glycerides of fatty acids and methacrylic polymers.

[00118] The immediate release dosage forms described herein may also contain an enteric coating. Agents which may be utilized to form such an enteric coating include, without limitation, methacrylic polymers such as EUDRAGIT L, gum lac or HPMCP (hydroxypropyl methylcellulose phthalate-hypromellose phthalate).

[00119] The immediate release dosage forms of the disclosure may further comprise a pH sensitive layer. The pH sensitive layer may be applied to any component of the immediate release dosage form. In some embodiments, the pH sensitive layer is applied to the particles. In other embodiments, the pH sensitive layer is applied to the coating. In further embodiments, the pH sensitive agent may be selected from those readily used in the art. The pH-sensitive film can be solubilized by exposure to a liquid that exhibits a pH that may be present in a stomach of a user of the dosage form, such as a pH below 6 or below 5.5. The pH-sensitive layer can contain a polymer that is not easily or substantially soluble at a pH that is higher than a pH found in a human stomach, e.g., a pH greater than 6, by being insoluble at a pH greater than 6, the pH- sensitive polymer will not dissolve in many solvents easily available and commonly used by an abuser to extract a water-soluble drug from a dosage form such as water, ethanoi, methanol, etc. In some embodiments, the pH sensitive layer is insoluble in water at a pH greater than 5 and is soluble in water at a pH less than 5. In other embodiments, the pH sensitive layer contains a pH sensitive agent which is insoluble in water at a pH greater than 5 and is soluble in water at a pH less than 5.

[00120] Useful pH-sensitive layers may include a polymer or other material that can be placed as a layer to form a pH-sensitive film. Examples of pH-sensitive polymers useful in a pH-sensitive layer include the class of reverse enteric polymers that contain cationic-functional groups and that exhibit pH-dependent solubility as described herein. Examples include polymers that contain basic functional groups such as amino groups, and that exhibit solubility at pH conditions found in a (human) stomach. In some embodiments, any polymer that is sufficiently hydrophilic at a low pH and hydrophobic at a higher pH to exhibit pH-dependent solubility as described may also be effective if otherwise acceptable for use in a pharmaceutical dosage form, for example as a non-toxic ingredient of an oral dosage form. More specific examples of such pH-sensitive polymers include copolymers of dimethyl aminoethyl methacrylates, and neutral methaciylic acid esters; e.g., dimethyl aminoethyl methaciylate, butyl methacrylates, and methyl methacrylates, such as at a ratio of 2: 1 : 1, Examples of such polymers are commercially available under the trade name Eudragit® E-100, Eudragit® E PO, Eudragit® E 12,5, and similar amino-functional pH-sensitive polymers. Reverse enteric compositions are also described in European Patent No. 1694724, "pH Sensitive Polymer and Process for Preparation Thereof, which is incorporated by reference.

[00121] The immediate release dosage form may be prepared using common compression/compaction techniques. One of skill in the ait would be able to select suitable compression parameters, such as compression pressure, based on the pharmaceutically active agent and excipients to provide an immediate release dosage form described herein. In some embodiments, the compression/compaction techniques are designed to provide a dosage form that provides the release profile described herein, but does not fall apart prior to or during use. The compression pressure may also depend on the selected alcohol resistant agent. In some embodiments, the compression pressure is not critical and does not affect the overall performance and alcohol resistance of the immediate release dosage form. The compression pressure is selected to produce an immediate release dosage form that remains intact, dissolves upon exposure to water and provides the desired alcohol resistance. In some embodiments, the compression pressure is at least about 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000 17,000, 18,000, 19,000, 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000, 28,000, or 29,000 to about 30,000 lb/in².

Dosage Forms Comprising Type A Alcohol Resistant Agents

[00122] In some embodiments of the disclosure, the particles comprising an active pharmaceutical agent are admixed with one or more A-type alcohol resistant agents. The A-type alcohol resistant agents used in these embodiments of the disclosure can be any of the A-type alcohol resistant agents described herein. Preferred A-type agents are copolymers comprising ethyl acrylate and methyl methacrylate. In more preferred embodiments, A-type agents are copolymers comprising ethyl acrylate, methyl methacrylate, and methacrylic acid ester with quaternary ammonium group salts. Exemplary A-type agents for use in these embodiments include, for example, EUDRAGIT RS, EUDRAGIT RL, EUDRAGIT NE, EUDRAGIT NM, and other derivatives of the poly(methyl methacrylate) family.

[00123] In these embodiments, the one or more A-type alcohol resistant agents will comprise about 35% to about 55%, by weight of the dosage form. For example, these dosage forms comprise about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or about 55%, based on the weight of the dosage form, of the A-type alcohol resistant agent.

[00124] The particles used in these embodiments can be "active particles," that is, particles wherein the active pharmaceutical agent is dispersed within the particles. These embodiments can comprise from about 5% to about 70%, by weight of the dosage form, of the active particles. For example, the dosage forms of the disclosure can comprise about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or about 70%, by weight of the dosage form, of the active particles. The active particles used in these

embodiments can optionally be coated with one or more pharmaceutically acceptable excipients prior to admixture with the one or more A-type alcohol resistant agents. The active particles may also be coated as described in the following.

[00125] The particles used in these embodiments can be "coated particles," that is, particles which are coated with an active coating layer that comprises the active pharmaceutical agent. These dosage forms can comprise from about 5% to about 70%, by weight of the dosage form, of the coated particles. For example, the dosage forms of the disclosure can comprise about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or about 70%, by weight of the dosage form, of the coated particles. The coated particles used in these embodiments can optionally be further coated with one or more pharmaceutically acceptable excipients prior to admixture with the one or more A-type alcohol resistant agents.

[00126] The immediate release dosage forms may comprise a "plurality" of the particles described herein. The phrase "plurality of particles" refers to particles, regardless of their form, which contain the active pharmaceutical agent. In some embodiments, the plurality of particles includes active particles. In other embodiments, the plurality of particles includes coated particles. In further embodiments, the plurality of particles includes active and coated particles. In still other embodiments, the plurality of particles lacks an active pharmaceutical agent, i.e., placebo particles. In yet further embodiments, the plurality of particles can include all active particles, or a combination of active particles and placebo particles, where each type of particle may optionally be coated.

[00127] In certain of embodiments, the particles can optionally be coated with one or more alcohol resistant agents prior to being admixed with the one or more A-type alcohol resistant agents. In preferred aspects of these embodiments, the particles are coated with an A- type alcohol resistant agent, for example, a copolymer comprising ethyl acrylate and methyl methacrylate. In more preferred embodiments, the A-type agents coated onto the particles are copolymers comprising ethyl acrylate, methyl methacrylate, and methacrylic acid ester with quaternary ammonium group salts. Exemplary A-type agents for use in coatings of these embodiments include, for example, EUDRAGIT RS, EUDRAGIT RL, EUDRAGIT NE, EUDRAGIT NM, and other derivatives of the poly (methyl methacrylate) family.

[00128] With A-type agents, the compression force utilized to prepare the immediate release dosage form is not critical and may be high or low, as long as it is sufficient to produce an immediate release dosage form that remains intact, dissolves upon exposure to water and provides the desired alcohol resistance. In some embodiments, the compression force utilized with A-type agents has minimal or no impact on the immediate release dosage form, i.e., final performance, dissolution, hardness, among others.

Dosage Forms Comprising Type B Alcohol Resistant Agents

[00129] In some embodiments of the disclosure, the particles comprising an active pharmaceutical agent are admixed with one or more B-type alcohol resistant agents. In some embodiments, the plurality of particles are admixed with one B-type alcohol resistant agent. In other embodiments, the plurality of particles are admixed with two B-type alcohol resistant agents. [00130] Any of the described B-type alcohol resistant agents can be used in these embodiments of the disclosure. Preferred B-type agents include, for example, a calcium phosphate (e.g., monobasic calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate), a calcium sulfate (e.g., calcium sulfate dihydrate), and a sodium phosphate (e.g., dibasic sodium phosphate dihydrate), as well as combinations thereof. In some embodiments, the B-type alcohol resistant agent is a B I -type agent. In other embodiments, the B-type alcohol resistant agent is a B2-type agent. In further embodiments, the B-type alcohol resistant agent is calcium phosphate, calcium sulfate, or a combination thereof and the lubricant is talc, preferably 2 wt.% or less of talc. In still other embodiments, the B-type alcohol resistant agent is calcium sulfate and the lubricant is sodium lauryl sulfate and sodium oleate, or other salt mixtures.

[00131] In these embodiments of the disclosure, the dosage forms comprise about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 to about 90%, about 70% to about 90% or about 80% to about 90%, based on the weight of the dosage form, of the one or more B-type alcohol resistant agents. For example, these dosage forms can comprise about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or about 90%, based on the weight of the dosage form, of the one or more B-type alcohol resistant agents.

[00132] The particles used in these embodiments can be "active particles," that is, particles wherein the active pharmaceutical agent is dispersed within the particle. These embodiments can comprise from about 5% to about 70%, by weight of the dosage form, of the active particles. For example, the dosage forms of the disclosure can comprise about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or about 70%, by weight of the dosage form, of the active particles. The active particles used in these

embodiments can be uncoated or coated with one or more pharmaceutically acceptable excipients prior to admixture with the one or more B-type alcohol resistant agents.

[00133] Alternatively, the particles used in these embodiments can be coated with an active coating layer, to form "coated particles", that comprises the active pharmaceutical agent in the coating. The coated particles may be formed by coating particles lacking the active pharmaceutical agent or particles having the active pharmaceutical agent therein, i.e., the active particles. These dosage forms can comprise from about 5% to about 70%, by weight of the dosage form, of the coated particles. For example, the dosage forms of the disclosure can comprise about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or about 70%, by weight of the dosage form, of the coated particles. The coated particles used in these embodiments can optionally be further coated with one or more pharmaceutically acceptable excipients prior to admixture with the one or more B-type alcohol resistant agents.

[00134] In certain of embodiments, the particles can optionally be coated with one or more alcohol resistant agents prior to being admixed with the one or more B-type alcohol resistant agents. Preferably the particles are coated with an A-type alcohol resistant agent, for example, a copolymer comprising ethyl acrylate and methyl methacrylate, prior to admixture with the one or more B-type alcohol resistant agents. In more preferred embodiments, the A- type agents coated onto the particles are copolymers comprising ethyl acrylate, methyl methacry late, and methacrylic acid ester with quaternary ammonium group salts. Exemplary A- type agents for use in coatings of these embodiments include, for example, EUDRAGIT RS, EUDRAGIT RL, EUDRAGIT NE, EUDRAGIT NM, and other derivatives of the poly(methyl methacrylate) family.

[00135] With B-type agents, the compression force utilized to prepare the immediate release dosage form may differ depending on the selected B-type agent and may be high or low. In some embodiments, the compression force utilized with B-type agents, such as Bl-type agents, has a lower limit, but no upper limit. In other embodiments, the compression force required for B-type agents, such as B2-rype agents, has an upper limit, but a minimal lower limit. In further embodiments, the compression forces required for B-type agents has lower and upper limits.

Dosage Forms Comprising A~Type Alcohol Resistant Agents and B-Type Alcohol Resistant Agents

[00136] In some embodiments of the disclosure, the plurality of particles comprising an active pharmaceutical agent are admixed with one or more A-type alcohol resistant agents and one or more B-type alcohol resistant agents. In some embodiments, the plurality of particles are admixed with one A-type alcohol resistant agent and one B-type alcohol resistant agent. In some embodiments, the plurality of particles are admixed with two A-type alcohol resistant agents and one B-type alcohol resistant agent In some embodiments, the plurality of particles are admixed with one A-type alcohol resistant agent and two B-type alcohol resistant agents. In some embodiments, the plurality of particles are admixed with two A-type alcohol resistant agents and two B-type alcohol resistant agents.

[00137] The A-type alcohol resistant agents used in these embodiments of the disclosure can be any of the A-type alcohol resistant agents previously described. Preferred A- type agents are copolymers comprising ethyl acrylate and methyl methacrylate. In more preferred embodiments, A-type agents are copolymers comprising ethyl acrylate, methyl methacrylate, and methacrylic acid ester with quaternary ammonium group salts. Exemplary A- type agents for use in these embodiments include, for example, EUDRAGIT RS, EUDRAGIT RL, EUDRAGIT NE, EUDRAGIT NM, Koilicoat EMM and other derivatives of the poIy(methyl methacrylate) family

[00138] Any of the described B-type agents can be used in these embodiments of the disclosure. Preferred B-type agents include, for example, calcium phosphate (e.g., dibasic calcium phosphate dihydrate, dicalcium phosphate), calcium sulfate (e.g., calcium sulfate dihydrate), ferric phosphate, manganese citrate, calcium citrate, and sodium phosphate (e.g., dibasic sodium phosphate dihydrate), as well as combinations thereof.

[00139] In some of these embodiments, the plurality of particles comprising an active pharmaceutical agent are admixed with a first alcohol resistant agent that is an A-type alcohol resistant agent and a second alcohol resistant agent that is a B-type alcohol resistant agent. In these embodiments, the first alcohol resistant agent is an A-type alcohol resistant agent that is a copolymer comprising ethyl acrylate and methyl methacrylate. Also in these embodiments, the second alcohol resistant agent is a B-type alcohol resistant agent that is a calcium phosphate, a sodium phosphate, calcium sulfate, calcium citrate, calcium acetate, barium sulfate, barium citrate, or a mixture thereof.

[00140] In other of these embodiments, the plurality of particles comprising an active pharmaceutical agent are admixed with a first alcohol resistant agent that is an A-type alcohol resistant agent and a second alcohol resistant agent that is a B-type alcohol resistant agent. In these embodiments, the first alcohol resistant agent is an A-type alcohol resistant agent that is a copolymer comprising ethyl acrylate, methyl methacrylate, and methacryiic acid ester with quaternary ammonium group salts. Also in these embodiments, the second alcohol resistant agent is a B-type alcohol resistant agent that is a calcium phosphate, a sodium phosphate, calcium sulfate, calcium citrate, calcium acetate, barium sulfate, barium citrate, or a mixture thereof,

[00141] The combination of A-type and B-type alcohol resistant agents will comprise about 35% to about 55%, by weight of the dosage form. For example, these dosage forms comprise about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,or about 55%, based on the weight of the dosage form, of the combination of A-type and B-type alcohol resistant agents. [00142] The particles used in these embodiments can be "active particles," that is, particles wherein the active pharmaceutical agent is dispersed within the particles. These embodiments can comprise from about 5% to about 70%, by weight of the dosage form, of the active particles. For example, the dosage forms of the disclosure can comprise about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or about 70%, by weight of the dosage form, of the active particles. The active particles used in these

embodiments can optionally be coated with one or more pharmaceutically acceptable excipients prior to admixture with the one or more A- and B-type alcohol resistant agents.

[00143] Preferably, the particles used in these embodiments can be coated with an active coating layer, to form "coated particles", that comprises the active pharmaceutical agent. These dosage forms can comprise from about 5% to about 70%, by weight of the dosage form, of the coated particles. For example, the dosage forms of the disclosure can comprise about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or about 70%, by weight of the dosage form, of the coated particles. The coated particles used in these embodiments can optionally be further coated with one or more pharmaceutically acceptable excipients prior to admixture with the one or more A- and B-type alcohol resistant agents.

[00144] In certain of embodiments, the particles can optionally be coated with one or more alcohol resistant agents prior to being admixed with the one or more A- and B-type alcohol resistant agents. Preferably the particles are coated with an A-type alcohol resistant agent, for example, a copolymer comprising ethyl acrylate and methyl methacrylate, prior to admixture with the one or more A- and B-type alcohol resistant agents. In more preferred embodiments, the A-type agents coated onto the particles are copolymers comprising ethyl acrylate, methyl methacrylate, and methacry lie acid ester with quaternary ammonium group salts. Exemplary A- type agents for use in coatings of these embodiments include, for example, EUDRAGIT RS, EUDRAGIT RL, EUDRAGIT NE, EUDRAGIT NM, and other derivatives of the poiy(methyl methacrylate) family.

[00145] With A-type agents, the compression force utilized to prepare the immediate release dosage form is not critical and may be high or low. In some embodiments, the compression force utilized with A-type agents has minimal or no impact on the immediate release dosage form, i.e., final performance, dissolution, hardness, among others.

With B-type agents, the compression force utilized to prepare the immediate release dosage fonn may differ depending on the selected B-type agent and may be high or low. In some embodiments, the compression force utilized with B-type agents, such as Bl-type agents, has a lower limit, but no upper limit. In other embodiments, the compression force required for B-type agents, such as B2-type agents, has an upper limit, but a minimal lower limit. In further embodiments, the compression forces required for B-type agents has lower and upper limits. II. Dosage Forms Wherein the Active Agent Portion Forms a Central Core of the Dosage Form, and the Alcohol Resistant Agent Is Contained Within an Outer Layer That

Surrounds the Central Core

[00146] The present disclosure also pertains to a second type of dosage forms in which the active agent portion forms a centi'al core of the dosage form, and the alcohol resistant agent (i.e., of type A, type B, or any combination thereof) is contained within an outer layer that surrounds the central core. This configuration may be referred to as a tablet-in-tablet arrangement. In a preferred embodiment, these dosage forms are prepared by blending the components of the central core together, compressing the components together to form a central core (which may be referred to as an "inner tablet"), blending at least some the components of the outer layer together, dispensing the blended components of the outer layer into a compression die, adding the central core to the die, optionally dispensing one or more additional components into the die, and applying a final compression in order to form the final "tablet-in-tablet" dosage form.

[00147] In addition to the active agent, the central core of such dosage forms may include a gelling agent, a neutralizing agent, a binder, a disintegrant, a glidant, a lubricant, a filler, a pH sensitive polymer, or a combination thereof. For example, the central core of the dosage forms may include a gelling agent, a binder, a lubricant, and a filler. As noted above, the preceding description of types of gelling agent, neutralizing agent, binder, disintegrant, glidant, lubricant, filler, and pH sensitive polymer that appears in the section pertaining to the dosage forms of type I pertains equally to the types of gelling agent, neutralizing agent, binder, disintegrant, glidant, lubricant, filler, and pH sensitive polymer that may be used in the dosage forms of type II. The same can be said for the quantities, proportions, and combinations that are described above for the possible gelling agent, neutralizing agent, binder, disintegrant, glidant, lubricant, filler, and pH sensitive polymer.

[00148] The central core portion of the dosage forms may comprise about 10-70% by weight of the total weight of a given dosage form. For example, the central core portion may be present in an amount of about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70% by weight of the dosage form. [00149] The gelling polymer may be of the type that primarily undergoes gelation above or below a certain ambient pH (a "pH-sensitive gelling polymer"), or that undergoes gelation independently of ambient pH conditions (a "non-pH sensitive gelling polymer"). When the central core of the instant dosage forms contain a gelling agent, it may include a pH sensitive gelling agent, a non-pH sensitive gelling agent, or both. For example, the central core may include a carbopol (e.g., Carbopol 980, a pH-sensitive polymer that undergoes gelation at a pH that is, for example, higher than those in the gastric environment), hydroxy propyl

methylcellulose (e.g., HPMC K100M, which undergoes gelation upon exposure to an appropriate solvent independently of ambient pH conditions), or both. When present, pH-sensitive gelling polymer(s) may be present in the central core in an amount of about 0.25-10% by weight of the central core. For example, the amount of pH-sensitive gelling polymer may be about 0.25, 0.50, 0.75, 1, 2, 3, 4, 5 6, 7, 8, 9, or 10% by weight of the central core. The non-pH sensitive gelling polymer may be present in the central core in an amount of about 0.25%-l 0% by weight of the central core. For example, the amount of non-pH sensitive gelling polymer may be about 0,25, 0.50, 0.75, 1, 2, 3, 4, 5 6, 7, 8, 9, or 10%by weight of the central core.

[00150] The pH sensitive polymer may be of the type that is insoluble when the ambient pH is about 5 or higher. The pH sensitive polymer is distinct from a pH-sensitive gelling polymer, because the pH sensitive polymer is not a gelling polymer. An exemplary pH sensitive polymer is Eudragit E. The pH sensitive polymer may be present in the central core in an amount of about 2-90% by weight of the central core. For example, the amount of pH sensitive polymer may be about 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% by weight of the central core.

[00151] The outer layer of the dosage forms of type II may, in addition to an alcohol resistant agent, include a plurality of granules comprising a polymer. Such granules, when present, confer beneficial properties, such as alcohol resistance, and prevention of release of active pharmaceutical agents when a supratherapeutic number of the dosage forms are ingested by a subject. For example, when included in the outer layer in combination with an alcohol resistant agent of type Bl (described above), the granules can enhance the alcohol resistance properties of the dosage form as a whole. Preferably, when the granules are present in the outer layer, the alcohol resistant agent that is used in combination therewith is of a type that is not highly soluble in water. [00152] When present, the granules may be in an amount of about 5-10% by weight of the dosage form, and the alcohol resistant agent may be present in an amount of about 65-90% by weight of the dosage form.

[00153] The polymer in the granules may be a gelling agent. Accordingly, the granules may comprise a geiling agent. In some embodiments, the granules of the outer layer may contain hypromellose, ethyl cellulose, glyceryl behenate, magnesium stearate, microcrystalline cellulose, a polyvinylpyrrolidone, or any combination thereof. The granules may also or alternatively include one or more functional equivalents of hypromellose, ethyl cellulose, glyceiyl behenate, magnesium stearate, microcrystalline cellulose, or a polyvinylpyrrolidone. In some

embodiments, the granules comprise a combination of hypromellose, ethyl cellulose, and glyceiyl behenate.

[00154] Some embodiments of the granules in the outer layer further comprise an outer coating, such as a polymer coating, that inhibits dissolution of the outer layer and disintegration of the inner core when the dosage form is ingested with alcohol, and passes from a subject's stomach to the subject's intestinal tract without having released a majority of the active agent contained within the dosage form. The outer coating may include one or more pH sensitive agents, such as a pH sensitive agent that resists dissolution at an ambient pH that is higher than that which is present in a subject's stomach, e.g., that resists dissolution at a pH of about 5 or higher. As noted above, the presence of pH sensitive agents of this type can inhibit dissolution of the outer layer, and thereby of the inner core, under ambient pH conditions typically encountered in a subject's intestinal tract. The outer coating may further comprise one or more other excipients, such as a lubricant.

[00155] When the granules include a gelling agent, the gelling agent may be present in an amount of about 30-80% by weight of the granules. For example, the gelling agent may be present in an amount of about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% by weight of the granules. In certain embodiments, the gelling agent in the granules is in an amount of about 0- 35% by weight of the outer layer, and the alcohol resistant agent is present in an amount of about 30-90% by weight of the dosage form. For example, the gelling agent in the granules may be present in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, or 35% by weight of the outer layer. In such embodiments, the alcohol resistant agent may be present in an amount of about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% by weight of the dosage form. In these and other embodiments, the granules may be present in an amount of about 5-10% by weight of the dosage form, and the alcohol resistant agent may be present in an amount of about 65-90% by weight, such as 65, 70, 75, 80, 85, or 90% by weight, of the dosage form.

[00156] In some embodiments, the outer layer may include a certain amount of the active pharmaceutical agent, a second active pharmaceutical agent, or both. For example, the outer layer may include about 1-90% by weight of the total amount of the active pharmaceutical agent, with the remainder of the active pharmaceutical agent being present in the central core. To the extent that a second active pharmaceutical agent is present in the dosage form, the outer layer may optionally include about 1-90% by weight of the total amount of the second active pharmaceutical agent, with the remainder of the second active pharmaceutical agent being present in the central core. Thus, the outer layer may optionally include about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% by weight of the total amount of the active pharmaceutical agent in the dosage form. Likewise, the outer layer may optionally include about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% by weight of the total amount of any second active pharmaceutical agent in the dosage form.

[00157] In some embodiments of the type II dosage forms, a certain amount of the alcohol resistant agent may be present in the central core portion. For example, the central core may optionally include about 1-90% by weight of the total amount of alcohol resistant agent, with the remainder of the alcohol resistant agent being present in the outer layer. Thus, the central core may optionally include about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% by weight of the total amount of the alcohol resistant agent in the dosage form.

[00158] The present dosage forms of type II, i.e., in which the active agent portion forms a central core of the dosage form, and the alcohol resistant agent is contained within an outer layer that surrounds the central core, may release less than 80% of the active

pharmaceutical agent by weight after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0.1N or 0.01 N aqueous HC1 at 37°C; and, release 95% or more of the active

pharmaceutical agent by weight after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N or 0.01 N aqueous HC1 without ethanol at 37°C.

[00159] In certain embodiments, the dosage forms of type II release less than 60% of the active pharmaceutical agent by weight after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0. IN or 0.01 N aqueous HC1 at 3TC; and, release 90% or more of the active pharmaceutical agent by weight after 1 hour when measured by the USP 1 Basket (10 mesh scrcen) method at SO rpm in 900 mL of an aqueous sorption comprising 0.1N or 0.01 N aqueous Ha without ethanol at 37°C.

[00160] In further embodiments, the dosage forms release less than 50% of the active pharmaceutical agent by weight is released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at SO rpm in 900 mL of an aqueous solution comprising 20 voL% ethanol: 80 voL% 0.IN or 0Λ1 N aqueous HC1 at 37°C; and, release 80% or more of the active pharmaceutical agent by weight after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at SO rpm m 900 mL of an aqueous solution comprising 0. IN or 0.01 N aqueous HC1 without ethanol at 37°C.

Treatmeat Metkods

[00161] The immediate release dosage forms described herein provide methods of prwnHnj attenuating a *hntJmrm_l potentially Amgwnm nr fttnl, iwtWMfwrinti spilfft nf an active pharmaceutical agent in the bloodstream of a patient The methods may also prevent or attenuate the short-term coiicentration spike in the bloodstream of an abuser who consumes the drug for recreational purposes. In some embodiments, the patient has a history of drug abuse or ethanol abuse. The patient may self-administer the contraindicated dose intentionally or urum¾ntionalry.

[00162] The present disclosure also provides methods of treating a patient in need of treatment with an active pharmaceutical agent that is contraindicated for administration with ethanol. As used herein, "patient" or "subject" is intended to mean a mammal. Thus, the immediate release dosage forms described herein are applicable to human and nonhnman subjects. In certain embodiments, the immediate release dosage farms described herein are applicable to humans. In some embodiments, the patient has a history of drug abuse or ethanol abuse. It should be understood that the subject to be treated as described herein is

f-yngniTBH/iiWifiwH m nwwH nf+n*atmmtaWi m active pharmnr^trical agent that IS contraindicated for administration with ethanol.

[00163] Accordingly, the methods of using the immediate release dosage forms have a wide-sweeping use in the treatment of a variety of indications. The use of the immediate release dosage forms does not depend on the method of use. In some embodiments, the disorder or condition being treated is acute, chronic, or a combination thereof [00164] Accordingly, the methods include administering to the patient an immediate release dosage form described herein. The methods may also include identifying a patient in need of treatment with an active pharmaceutical agent, e.g., an active pharmaceutical agent that is contraindicated for administration with ethanol. Determination of the proper dosage of the active pharmaceutical agent discussed herein for a particular situation is within the skill of the practitioner. In some embodiments, the dosage form reduces the risk of an overdose by simultaneous oral ingestion of multiple units of the oral dosage form. In other embodiments, the dosage form demonstrates an immediate release profile when administered in therapeutic doses, but demonstrates an extended release profile when administered in supratherapeutic doses.

[00165] The present disclosure further provides methods of preventing abuse of a narcotic analgesic drug by administering an immediate release dosage form described herein to a subject.

[00166] Also provided are methods of preventing overdose by accidental or intentional administration of a supratherapeutic dose of a narcotic analgesic drug by administering to a subject in need thereof an immediate release dosage form described herein,

[00167] Further provided are methods of reducing the risk of overdose of an active pharmaceutical agent by administering to a subject in need thereof an immediate release dosage form described herein.

[00168] The methods described herein not only permit the safe administration of the active pharmaceutical agent, but they permit the active pharmaceutical agent to act for its intended purpose. Accordingly, the immediate release dosage forms may be used in methods of treating pain or discomfort, sleep disorders such as insomnia, anxiety such as generalized anxiety social anxiety and panic attacks, psychoses such as delusions, hallucinations, paranoia, disordered thoughts schizophrenia, and bipolar disorder, lethargy, fatigue, narcolepsy, eating disorders such as obesity, anorexia and bulimia, attentional disorders such as ADHD, nasal congestion, orthostatic hypotension, postural orthostatic tachycardia syndrome, itching sneezing, inflammatory responses, acne, depression such as major depressive disorder, bacterial infections, protozoan infections, convulsions, seizures, obsessive-compulsive disorder, muscle spasm, hyperreflexia, inflammation, and nausea; aid in smoking cessation; and to facilitate surgery such as causing temporary paralysis.

[00169] In some embodiments, methods for treating pain or discomfort in a subject in need thereof are provided and include administering an immediate release dosage form described herein. [00170] In other embodiments, methods for treating sleep disorders in a subject in need thereof are provided and include administering an immediate release dosage form described herein.

[00171] In further embodiments, methods for treating anxiety in a subject in need thereof are provided and include administering an immediate release dosage form described herein.

[00172] In yet other embodiments, methods for treating psychoses in a subject in need thereof are provided and include administering an immediate release dosage form described herein.

[00173] In certain embodiments, the present disclosure pertains to and includes at least the following aspects:

[00174]

Aspect 1. An immediate release dosage form comprising an admixture of:

a plurality of particles comprising an active pharmaceutical agent; and

about 30% to about 99%, based on the weight of the dosage form, of an alcohol resistant agent;

wherein the ratio of the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N aqueous HC1 at 37 °C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N aqueous HC1 without ethanol at 37 °C is less than about 0.9.

[00175]

Aspect 2. The immediate release dosage form of aspect 1, wherein said ratio is less than about 0.83.

[00176]

Aspect 3. The immediate release dosage form of aspect 1 or 2, wherein said ratio is about 0.1 to about 0.9.

[00177]

Aspect 4. The immediate release dosage form of any one of aspect I to 3, wherein said ratio is about 0.14 to about 0.83.

[00178] Aspect 5. The immediate release dosage form of aspect 1, wherein:

less than 80% of the active pharmaceutical agent by weight is released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 40 vol,% ethanol: 60 vol.% 0.1N aqueous HC1 at 37 °C; and

95% or more of the active pharmaceutical agent by weight is released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 0. IN aqueous HC1 without ethanol at 37 °C.

[00179]

Aspect 6. The immediate release dosage form of aspect 1, wherein:

less than about 75% of the active pharmaceutical agent by weight is released from the dosage form after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N aqueous HC1 at about 37 °C; and

about 90% or more of the active pharmaceutical agent by weight is released from the dosage form after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 0.1N aqueous HC1 without ethanol at about 37 °C.

[00180]

Aspect 7. The immediate release dosage form of aspect 1 , wherein:

less than about 65% of the active pharmaceutical agent by weight is released from the dosage form after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N aqueous HCI at about 37 °C; and

about 80% or more of the active pharmaceutical agent by weight is released from the dosage form after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 0.1N aqueous HCI without ethanol at about 37 °C.

[00181]

Aspect 8. The immediate release dosage form of aspect 1, wherein the active

pharmaceutical agent is dispersed within the particles. Aspect 9. The immediate release dosage form of aspect 1, wherein the particles are coated with an active coating layer comprising the active pharmaceutical agent.

[00182]

Aspect 10. The immediate release dosage form of aspect 1, wherein the particles are coated with an active coating layer comprising a first portion of the active pharmaceutical agent and wherein a second portion of the active pharmaceutical agent is dispersed within the particles.

[00183]

Aspect 1 1. The immediate release dosage form of any one of aspects 1 to 10, wherein the alcohol resistant agent admixed with said plurality of particles is a calcium phosphate, a sodium phosphate, calcium sulfate, calcium citrate, calcium acetate, barium sulfate, barium citrate, or a mixture thereof.

[00184]

Aspect 12. The immediate release dosage form of aspect 11, wherein the calcium phosphate is monobasic, dibasic, tribasic, or a mixture thereof.

[00185]

Aspect 13. The immediate release dosage form of aspect 11 or aspect 12, wherein the

calcium phosphate is a hydrate.

[00186]

Aspect 14. The immediate release dosage form of aspect 11 or aspect 12, wherein the

calcium phosphate is anhydrous.

[00187]

Aspect 15. The immediate release dosage form of any one of aspects 1 to 10, wherein the alcohol resistant agent admixed with said plurality of particles is calcium sulfate.

[00188]

Aspect 16. The immediate release dosage form of any one of aspects 1 to 10, wherein the alcohol resistant agent admixed with said plurality of particles is sodium phosphate.

[00189]

Aspect 17. The immediate release dosage form of any of the preceding aspects, comprising about 70% to about 90%, based on the wei ght of the dosage form, of the alcohol resistant agent.

[00190] Aspect 18. The immediate release dosage form of any of the preceding aspects, comprising about 80% to about 90%, based on the weight of the dosage form, of the alcohol resistant agent.

[00191]

Aspect 19. The immediate release dosage form of any one of aspects 1 to 10, wherein the alcohol resistant agent admixed with said plurality of particles is a copolymer comprising ethyl acrylate and methyl methacrylate.

[00192]

Aspect 20. The immediate release dosage form of any one of aspects 1 to 10, wherein the alcohol resistant agent admixed with said plurality of particles is a copolymer comprising ethyl acrylate, methyl methacrylate, and methacrylic acid ester with quaternary ammonium group salts.

[00193]

Aspect 21. The immediate release dosage form of any one of aspects 1 to 10, wherein the alcohol resistant agent admixed with said plurality of particles is a copolymer comprising ethyl acrylate and methyl methacrylate; a copolymer comprising ethyl acrylate, methyl methacrylate, and methacrylic acid ester with quaternary ammonium group salts; a calcium phosphate; a sodium phosphate; calcium sulfate; calcium citrate; calcium acetate; barium sulfate; barium citrate; or a mixture thereof.

[00194]

Aspect 22. The immediate release dosage form of aspect 21, wherein the alcohol resistant agent admixed with said plurality of particles is

a first alcohol resistant agent that is a copolymer comprising ethyl acrylate and methyl methacrylate; and

a second alcohol resistant agent that is a calcium phosphate, a sodium phosphate, calcium sulfate, calcium citrate, calcium acetate, barium sulfate, barium citrate, or a mixture thereof.

[00195]

Aspect 23. The immediate release dosage form of aspect 21, wherein the alcohol resistant agent admixed with said plurality of particles is

a first alcohol resistant agent that is a copolymer comprising ethyl acrylate, methyl

methacrylate, and methacrylic acid ester with quaternary ammonium group salts; and a second alcohol resistant agent that is a calcium phosphate, a sodium phosphate, calcium sulfate, calcium citrate, calcium acetate, barium sulfate, barium citrate, or a mixture thereof.

[00196]

Aspect 24. The immediate release dosage form of any one of aspects 21 to 23, comprising about 35% to about 55%, based on the weight of the dosage form, of the alcohol resistant agent.

[00197]

Aspect 25. The immediate release dosage form of any one of the preceding aspects, wherein the particles further comprise an alcohol resistant layer comprising an alcohol resistant agent.

[00198]

Aspect 26. The immediate release dosage form of aspect 25, wherein the alcohol resistant agent in the alcohol resistant layer is a copolymer comprising ethyl acrylate and methyl methacrylate.

[00199]

Aspect 27. The immediate release dosage form of aspect 25, wherein the alcohol resistant agent in the alcohol resistant layer is a copolymer comprising ethyl acrylate, methyl methacrylate, and methacrylic acid ester with quaternary ammonium group salts.

[00200]

Aspect 28. The immediate release dosage form of aspect 25, wherein the alcohol resistant agent in the alcohol resistant layer is a calcium phosphate, a sodium phosphate, calcium sulfate, calcium citrate, calcium acetate, barium sulfate, barium citrate, or a mixture thereof.

[00201]

Aspect 29. The immediate release dosage form of any one of aspects 25 to 28, wherein the alcohol resistant layer comprises about 35% to about 60% by weight of the layer, of the alcohol resistant agent.

[00202]

Aspect 30. The immediate release dosage form of any of the preceding aspects, wherein the active pharmaceutical agent is an analgesic, antihistamine, barbiturate, anesthetic, sedative, stimulant, antidepressant, or anti-anxiety agent.

[00203] Aspect 31. The immediate release dosage form of any one of the preceding aspects, wherein the active pharmaceutical agent is an opioid agonist, a benzodiazepine, a barbiturate, or diphenhydramine.

[00204]

Aspect 32. The immediate release dosage form of aspect 31, wherein the opioid agonist is oxycodone, oxymorphone, codeine, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, meperidine, buprenorphine, fentanyl, fentanyl derivatives, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, methadone, morphine, and propoxyphene and pharmaceutically acceptable salts thereof.

[0020S]

Aspect 33. The immediate release dosage form of aspect 31, wherein the benzodiazepine is diazepam, alprazolam, clonazepam, or lorazepam.

[00206]

Aspect 34. The immediate release dosage form of aspect 31 wherein the barbiturate is allobarbital, amobarbital, aprobarbital, alphenal, barbital, brallobarbital, pentobarbital, phenobarbital, or secobarbital.

[00207]

Aspect 35. The immediate release dosage form of any one of the preceding aspects, wherein the particles further comprise a pH sensitive layer that is insoluble in water at a pH greater than 5 and is soluble in water at a pH less than 5.

[00208]

Aspect 36. The immediate release dosage form of any one of the preceding aspects, wherein less than about 50% of the active pharmaceutical agent, by weight of the dosage form, is released after about 1 hour when measured by the USP 2 Paddie method at about 50 rpm in about 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N aqueous HC1 at about 37 °C.

[00209]

Aspect 37. The immediate release dosage form of any one of the preceding aspects

comprising a second active pharmaceutical agent, preferably paracetamol.

[00210]

Aspect 38. The immediate release dosage form of any one of the preceding aspects wherein the admixture further comprises a gelling agent, a neutralizing agent, a disintegrant, a glidant, a lubricant, a filler, a pH sensitive polymer, or a combination thereof. [00211]

Aspect 39. The immediate release dosage form of any one of the preceding aspects, wherein the particles comprise hypromellose, ethyl cellulose, glyceryl behenate, magnesium stearate, microcrystalline cellulose, a polyvinylpyrrolidone, or a mixture thereof.

[00212]

Aspect 40. The immediate release dosage form of any one of the preceding aspects, wherein the dosage form is a caplet, pill, or compressed tablet.

[00213]

Aspect 41. The immediate release dosage form of any one of the preceding aspects, wherein the dosage form is a multi-layer tablet or caplet.

[00214]

Aspect 42. The immediate release dosage form according to any one of the preceding

aspects, wherein the dosage form reduces the risk of an overdose resulting from simultaneous oral ingestion of multiple units of the oral dosage form.

[00215]

Aspect 43. The immediate release dosage form according to any one of the preceding

aspects, wherein the dosage form reduces the potential for abuse by simultaneous oral ingestion of multiple units of the oral dosage form.

[00216]

Aspect 44. The immediate release dosage form of any one of the preceding aspects, that demonstrates an immediate release profile when administered in therapeutic doses, but which demonstrates an extended release profile when administered in supratherapeutic doses.

[00217]

Aspect 45. The immediate release dosage form of aspect 44, wherein the immediate release profile is defined as not less than 90% of API released in 60 minutes, and the extended release profile is defined as not more than 85% released in 60 minutes, wherein the release profiles may be evaluated by dissolution in 300 mL of 0.1N HC1 media using USP II apparatus at 50 RPM paddle speed and 37°C.

[00218]

Aspect 46. The immediate release dosage form of aspect 44, wherein the supratherapeutic dose is five or more dosage forms.

[00219] Aspect 47. The immediate release dosage form of aspect 1, wherein the ratio of the active pharmaceutical agent released from 12 dosage forms after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0. IN aqueous HCI at 37 °C to the active pharmaceutical agent released from 1 dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0.1N aqueous HCI at 37 °C is less than about 0.9.

[00220]

Aspect 48. A method of preventing abuse of a narcotic analgesic drug in a subject comprising administering an immediate release dosage form of any one of aspects 1 to 47 to said subject.

[00221]

Aspect 49. A method of preventing overdose by accidental or intentional administration of a supratherapeutic dose of a narcotic analgesic drug, comprising administering an immediate release dosage form of any one of aspects 1 to 47 to said subject.

[00222]

Aspect 50. A method of treating a patient, comprising administering to the patient an

immediate release dosage form of any one of aspects 1 to 47.

[00223]

Aspect 51. The method of aspect 50, fuilher comprising identifying that the patient is in need of treatment with an active pharmaceutical agent that is contraindicated for

administration with ethanol.

[00224]

Aspect 52. The method of aspect 50, wherein the active pharmaceutical agent is

contraindicated for administration with ethanol.

[00225]

Aspect 53. The method of any one of aspects 50 to 52, wherein the patient has a history of drug abuse or ethanol abuse.

[00226]

Aspect 54. The method of any one of aspects 50 to 53, wherein the dosage form demonstrates an immediate release profile when administered in therapeutic doses, but demonstrates an extended release profile when administered in supratherapeutic doses.

[00227] Aspect 55. The method according to aspect 54, wherein the supratherapeutic dose is five or more tablets.

[00228]

Aspect 56. A method of reducing the risk of overdose of an active pharmaceutical agent, comprising administering to a subject an immediate release dosage form of any one of aspects 1 to 47.

EXAMPLES

Example 1

[00229] Granules were manufactured in a high shear granulator, where hypromellose, hydrocodone bitartrate, and ethylcellulose were dry mixed for 2 minutes. Then, a 10 vol.% alcoholic solution of ethylcellulose N 10 was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of ethylcellulose was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for dtying.

Table 1 : Components for active granule formulation

[00230] The prepared granules were then coated in a bottom spray fluid bed coater with a mixture of Eudragit NE 30D and compritol in acetone. The resulting coated granules were subsequently used for further blending and compression process.

Table 2: Components for coated granule formulation

[00231] The coated granules were prepared described above and mixed with other excipients (sodium croscai-mellose, Eudragit RS) and blended in a V-blender for 30 minutes. Then the blend was compressed into 33 mg hydrocodone bitartrate, 600 mg tablets.

Table 3: 33 mg hydrocodone bitartrate Tablet Formulation

[00232] The following tests were conducted on the formulation.

[00233] (i) Dissolution (n=3) in 0.1N HC1 (timepoints: 0, 15, 30, 60, 240 minutes)

Table 4

[00234] (ii) Dissolution (n=3) in 40:60 ethanohO. IN HC1 (timepoints: 0, 15, 30, 60, 240 minutes)

Table 5

[00235] It was found that in 40 vol.% ethanol/60 vol.% 0.1 N HC1 media, a single tablet released less than 40 wt.% of hydrocodone in 4 hours, demonstrating significant alcohol resistance. See, e.g., Figure 1. It was also found that the compression pressure utilized to prepare the tablet had no impact on these results.

Example 2 [00236] Granules were manufactured in a high shear granulator, where hypromellose and glyceryl behenate were dry mixed for 3 minutes. Then, a 10 vol.% hydroalcoholic solution of ethylcellulose lSl lO was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of ethylcellulose was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.

Table 6: Components for core granule formulation

[00237] The prepared granules were then layered in a bottom spray fluid bed coater with a 12 vol.% aqueous solution of hydrocodone bitartrate and HPMC 2910.

Table 7: Components for layered granule formulation

[00238] The hydrocodone bitartrate layered granules were then coated in a bottom spray fluid bed coater with 25 vol.% alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate. The resulting coated granules were subsequently used for further blending and compression process,

Table 8: Components for coated granules formulation

[00239] The coated granules were prepared as described above and mixed with paracetamol and other excipients (carbomer, sodium bicarbonate, sodium croscarmellose, silicon dioxide, Eudragit RS, dicaicium phosphate) and blended in a V-blender for 30 minutes.

Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen, 1100 mg tablets.

Table 9: 10 mg hydrocodone/325 mg acetaminophen Tablet Formulation

[00240] The following tests were conducted on the formulation

[00241] (i) A single tablet dissolution (n=3) in 0. IN HC1 (timepoints: 0, 15, 30, 45, 60 minutes). Data shown is that of hydrocodone bitartrate.

Table 10

[00242] (ii) A single tablet dissolution (n=3) in 40:60 ethanokO. IN HC1 (timepoints: 0, 30, 60, 120, 240, 360 minutes). Data shown is that of hydrocodone bitartrate.

Table 11

Time (min) Dissolved (%)

0 0

30 10

60 15

[00243] (iii) 12 tablets multiple tablet abuse resistance (MTAR) (n=3) in 0. IN HCl (timepoints: 0, 15, 30, 45, 60, 120, 240, 360 minutes). Data shown is that of hydrocodone bitartrate.

Table 12

[00244] (iv) 12 tablet MTAR (n=3) in 40:60 ethanohO. IN HCl (timepoints: 0, 30, 60, 120, 240, 360 minutes). Data shown is that of hydrocodone bitartrate.

Table 13

[00245] It was found that in 40 vol.% ethanol/60 vol.% 0.1 N HCl media, a single tablet released less than 50 wt.% of hydrocodone in 4 hours, demonstrating significant alcohol resistance. The formulation also showed resistance to abuse by ingestion of multiple tablets, i.e., less than 75 wt.% of the dose from 12 tablets was released at 60 min. See, Figure 2.

Example 3 [00246] The coated granules were prepared as described in Example 2 and then utilized to prepare 10 mg hydrocodone bitartrate/325 mg acetaminophen tablets which are similar to the tablets discussed in US Patent Publication No. 2015/01 18303. Specifically, the coated granules were mixed with paracetamol and other excipients (mannitol, carbopol, microcrystalline cellulose, crospovidone, sodium bicarbonate, and iron oxide red 212P) and blended in a V- blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into

hy drocodone/acetaminophen tab lets.

Table 14: 10 mg Hydrocodone bitartrate/325 acetaminophen tablet formulation

[00247] The following tests were conducted on the formulation

[00248J (i) Dissolution (n=3) in 0.1N HC1 (timepoints: 0, 15, 30, 60, 120, 240 minutes). Data shown is that of hydrocodone bitartrate.

Table 15

[00249] (ii) Dissolution (n=3) in 40:60 ethanohO. IN HC1 (timepoints: 0, 15, 30, 60, 120, 240 minutes). Data shown is that of hydrocodone bitartrate. Table 16

[00250] It was found that there was immediate release of hydrocodone in 40 vol.% ethanol/60 vol.% 0.1 N HCI media, which was very similar to the release in 0.1 N HCI media. This demonstrated that the formulation does not show any alcohol resistance as compared to the formulation of Example 2. See, Figure 3. It was also found that the compression pressure utilized to prepare the tablet had no impact on these results.

Example 4

[00251] Granules were manufactured in a high shear granulator, where

diphenhydramine HCI and microciystalline cellulose were dry mixed for 2 minutes. Then, a 25 vol.% aqueous solution of povidone K30 was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of povidone was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.

Table 17: Components for active granule formulation

[00252] The prepared granules were then coated in a bottom spray fluid bed coater with a mixture of Eudragit E and magnesium stearate in ethanol. The resulting coated granules were subsequently used for further blending and compression process. Table 18: Components for coated granule formulation

[00253] The coated granules were prepared as described above and mixed with dibasic calcium phosphate dihydrate to create a homogenous blend. Then the blend was compressed into 27 mg diphenhydramine HCl, 1000 mg tablets.

Table 19: 27 mg Diphenhydramine HCl Tablet Formulation

[0Θ254] The following tests were conducted on the formulation

[00255] (i) Dissolution (n=3) in 0. IN HCl (timepoints: 0, 15, 30, 60, 240 minutes)

Table 20

[00256] (ii) Dissolution (n=3) in 40:60 ethanohO. IN HCl (timepoints: 0, 15, 30, 60, 120, 180, 240 minutes)

Table 21

Time (min) Dissolved (%)

0 0

15 43

30 58

45 69

60 77

120 94

180 103

[00257] It was found that in 40 vol.% ethanol/60 vol.% 0.1 N HCl media, a single tablet released less diphenhydramine much more slowly than 0.1 N HCl, demonstrating significant alcohol resistance. See, Figure 4. It was also found that the compaction pressure cannot exceed about 16,300 lb/in².

Example 5

[00258] Granules were manufactured in a high shear granulator, where

diphenliydramine HCl and microcrystalline cellulose were diy mixed for 2 minutes. Then, a 25 vol.% aqueous solution of povidone K30 was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of povidone was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.

Table 22: Components for active granule formulation

[00259] The prepared granules were then coated in a bottom spray fluid bed coater with a mixture of Eudragit E and magnesium stearate in ethanol. The resulting coated granules were subsequently used for further blending and compression process.

Table 23: Components for coated granule formulation

[00260] The coated granules were prepared as described above and mixed with calcium sulfate dihydrate to create a homogenous blend. Then the blend was compressed into 27 mg diphenhydramine HC1, 1000 mg tablets.

Table 24: 27 mg Diphenhydramine HC1 Tablet Formulation

[00261] The following tests were conducted on the formulation

[00262] (i) Dissolution (n=3) in 0. IN HC1 (timepoints: 0, 15, 30, 60, 240 minutes)

Table 25

[00263] (ii) Dissolution (n=3) in 40:60 ethanohO. IN HC1 (timepoints: 0, 15, 30, 60, 120, 180, 240 minutes)

Table 26

[00264] It was found that in 40 vol.% ethanol/60 vol.% 0.1 N HC1 media, a single tablet released less diphenhydramine much more slowly than 0.1 N HCI, demonstrating significant alcohol resistance. See, Figure 5. [00265] It was also found that the compression pressure cannot exceed about 26,100 lb/inch². When compression pressures exceeding about 26,100 lb/in² were utilized, the tablet stayed intact and did not disintegrate significantly in water. However, lower compression forces resulted in tablets having suppressed release in alcohol media (staying intact), but disintegrated in water media.

Example 6

[00266] Granules were manufactured in a high shear granulator, where hypromellose and glyceryl behenate were dry mixed for 3 minutes. Then, a 10 vol.% hydroalcohoiic solution of ethylcellulose N10 was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth.

Solution addition was continued until the entire amount of ethylcellulose was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.

Table 27: Components for core granule formulation

[00267] The prepared granules were then layered in a bottom spray fluid bed coater with a 25 vol.% aqueous solution of diphenhydramine HC1.

Table 28: Components for layered granule formulation

[00268] The diphenhydramine HC1 layered granules were then coated in a bottom spray fluid bed coater with 29.2% w/w suspension of Eudragit E-100 copolymer and magnesium stearate in acetone. The resulting coated granules were subsequently used for further blending and compression process. Table 29: Components for coated granules formulation

[00269] The coated gi'anules were prepared as described above and mixed with Dibasic sodium phosphate d (hydrate to create a homogenous blend. Then the blend was compressed into 72 mg diphenhydramine HCl, 1000 mg tablets.

Table 30: 72 mg Diphenhydramine HCl Tablet Formulation

[00270] The following tests were conducted on the formulation

[00271] (i) Dissolution (n=3) in 0. IN HCl (timepoints: 0, 15, 30, 60, 240 minutes)

Table 31

[00272] (ii) Dissolution (n=3) in 40:60 ethanohO. IN HCl (timepoints: 0, 5, 15, 30, 60, 120, 180, 240 minutes)

Table 32

Time (min) Dissolved (%)

0 0

5 10

15 18

30 26

45 33

60 39

[00273] It was found that in 40 vol.% ethanol/60 vol.% 0.1 N HC1 media, a single tablet released less diphenhydramine much more slowly than 0.1 N HQ, demonstrating significant alcohol resistance. See, Figure 6. It was also found that the compression pressure utilized to prepare the tablet had no impact of these results.

Example 7

[00274] Granules are manufactured in a high shear granulator, where hypromellose and glyceryl behenate are dry mixed for 3 minutes. Then, a 10 vol.% hydroalcoholic solution of ethylcellulose N10 is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and are subsequently loaded into fluid bed for drying.

Table 33: Components for core granule formulation

[00275] The prepared granules are then layered in a bottom spray fluid bed coater with a 1 vol.% ethanolic solution of diazepam.

Table 34: Components for layered granule formulation

[00276] The diazepam layered granules are then coated in a bottom spray fluid bed coater with 29.2% w/w suspension of Eudragit E-100 copolymer and magnesium stearate in acetone. The resulting coated granules are subsequently used for further blending and compression process. Table 35: Components for coated granules formulation

[00277] The coated granules are prepared as described above and mixed with dibasic sodium phosphate dihydrate to create a homogenous blend. Then the blend is compressed into 10 mg diazepam, 1000 mg tablets.

Table 36: 10 mg Diazepam Tablet Formulation

Example 8: Tri-layer diphenhydramine HCl tablets

[00278] Tri-layer diphenhydramine HCl tablets were prepared by compressing individual tablet layers together in a press.

[00279] A. Top and bottom layers

[00280] Ethylcellulose was blended with a lubricant (magnesium stearate) to create a homogeneous blend. The resulting blend was used to manufacture the top and bottom layers of the tri-layer tablet with ½ inch tooling.

Table 37: Composition of top and bottom layers of tri-layer diphenhydramine HCl tablets

[00281] B. Middle layer

[00282] Diphenhydramine HCl and sodium phosphate dibasic dihydrate, granular, were mixed to create a homogenous blend. The blend was used to manufactui'e the middle layer of the tri-layer tablet with 0.5 inch tooling.

Table 38: Composition of middle layer of tri-layer diphenhydramine HCl tablets

[00283] C. Tri-!ayer tablet

[00284] The tri- layer diphenhydramine HCl tablets were made by combining the top, middle, and bottom layers.

Table 39: Tri-layer diphenhydramine HCl tablets

Example 9: Diphenhydramine HCl Tablet-in-Tablet formulation with Calcium Sulfate in outer tablet

[00285] 9 A. Manufacture of 10 mg Diphenhydramine HCl Inner Tablet,

Diphenhydramine HCl inner tablets were manufactured by directly blending diphenhydramine HCl with other excipients prior to compressing into 1/4" round tablets. The composition for the diphenhydramine HCl tablets is shown in Table 40.

Table 40A: 10 mg Diphenhydramine HCl Inner Tablet Composition

[00286] 9B, Manufacture of 10 mg Diphenhydramine HCl Tablet-in-Tablet formulation with Calcium Sulfate outer tablet. The outer tablet material was used as either pure calcium sulfate or a blend containing lubricants/anti-tacking agents to improve the manufacturability of the dosage form while maintaining release characteristics provided by the pure component. The lubricated blend of calcium sulfate had the following composition: calcium sulfate (96.4% w/w), sodium lauryl sulfate (1.2% w/w), and sodium oleate (2.4% w/w) and was prepared by blending the three ingredients together in a tumble blender for 30 minutes.

[00287] In example 9A, tablet-in-tablet formulation with pure calcium sulfate as outer tablet was manufactured on a press by compressing 750 mg of pure calcium sulfate in a 112" round die around the inner tablet of Table 40 in the center. A compression pressure of about 25,000 lbs/in² was applied to form the final dosage unit.

[00288] In example 9B, tablet-in-tablet formulation with lubricated calcium sulfate as outer tablet was manufactured on a press by compressing 750 mg of lubricated calcium sulfate in a 1/2" round die around the inner tablet of Table 40A in the center. A compression pressure of about 12,733 lbs/in² was applied to form the final dosage unit.

[00289] Final Tablet-in-Tablet compositions are described in Table 40B.

Table 40B. 10 mg Diphenhydramine HCl Tablet-in-Tablet Compositions with Calcium Sulfate

Outer Tablet

[00290] The following tests were conducted on the formulations:

(i) Method 1 : A single tablet dissolution (n=3) in 0. IN HC1 (timepoints: 0, 10, 20, 30, 45, 60 minutes). Test method uses 900 mL media, 37°C media temperature, 10 mesh basket (USP apparatus 1) at a 50 rpm rotational speed. Results are shown in FIG. 7.

(ii) Method 2: A single tablet dissolution (n=3) in 80:20 0. IN HCi: Reagent Alcohol (timepoints: 0, 10, 20, 30, 45, 60, 120, 180, 240 minutes. Test method uses 900 mL media, 37°C media temperature, 10 mesh basket (USP apparatus 1) at a 50 rpm rotational speed. Results are shown in FIG. 8.

[00291] It was found that in both examples 9A and 9B a single tablet showed almost full release of the active in 30 minutes in 0.1 N HCI media and significantly suppressed release in 80 vol.% 0.1N HCl/20 vol.% reagent alcohol media. Thus, both formulations demonstrate significant alcohol resistance.

Example 10: Diphenhydramine HCI Table t-in-Tablet formulation with blends of salts (Calcium Sulfate/Manganese Citrate or Ferric Phosphate/Calciam Citrate) in outer tablet

[00292] 10A. Manufacture of 10 mg Diphenhydramine HCI Inner Tablet. See section 9 A of Example 9, above.

[00293] 10B. Manufacture of 10 mg Diphenhydramine HCI Tablet-in Tablet formulation with blend of salts (Calcium Sulfate/Manganese Citrate or Ferric Phosphate/Calcium Citrate) in outer tablet). The outer tablet material was a mixture of two salts of the following composition: calcium sulfate (75% w/w) and manganese citrate (25% w/w) or ferric phosphate (50% w/w) and calcium citrate (50% w/w). The mixture was prepared by blending the two inredients in a tumble mixer for 30 minutes.

[00294] In 1 OA, tablet-in-tablet formulation with a blend of calcium sulfate and manganese citrate as outer tablet was manufactured on a press by compressing 750 mg of the blend in a 1/2'¹ round die around the inner tablet of Table 40A in the center. A compression pressure of 25,466 lbs/in² was applied to form the final dosage unit.

[00295] In 10B, tablet-in-tablet formulation with a blend of ferric phosphate and calcium citrate as outer tablet was manufactured on a press by compressing 750 mg of the blend in a 1/2" round die around the inner tablet of Table 40A in the center. A compression pressure of 25,466 lbs/in² was applied to form the final dosage unit.

[00296] Final tablet-in-tablet compositions are described in Table 41 A.

Table 41 A. 10 mg Diphenhydramine HCi Tablet-in-Tablet Compositions with blend of salts (Calcium Sulfate/Manganese Citrate or Ferric Phosphate/Calcium Citrate) in outer tablet)

[00297] The formulations were tested under the methodologies described in Example 9. Results are shown in FIGS. 9 and 10.

[00298] It was found that in both examples 1 OA and 10B a single tablet showed almost full release of the active in 30 minutes in 0.1 N HCl media and significantly suppressed release in 80 vol.% 0.1N HCl/20 vol.% reagent alcohol media. Thus, both formulations demonstrate significant alcohol resistance.

Example 11: Diazepam Tablet-in-Tablet formulation with Calcium Sulfate in outer tablet

[00299] 11 A. Manufacture of 5 mg and 10 mg Diazepam Inner Tablets. Diazepam inner tablets 5 mg and 10 mg were manufactured using a common blend by blending diazepam with eudragit E PO and other excipients prior to compressing into tablets. The 10 mg dose inner tablet weighs 200 mg and is a 3/8" round tablet. The 5 mg dose inner tablets weighs 100 mg and is a 1/4" round tablet. The composition for the diazepam tablets are shown in Table 42A.

Table 42 A. 5 mg and 10 mg Diazepam Inner Tablet Composition

[00300] 1 IB. Manufacture of 5 mg and 10 mg Diazepam tablet-in-tablet formulation with Calcium Sulfate in outer tablet. Both 5 mg and 10 mg doses use pure calcium sulfate as outer tablet material.

[00301] In Example 11 A, a 10 mg diazepam tablet-in-tablet formulation with pure calcium sulfate as outer tablet was manufactured by compressing 700 mg of pure calcium sulfate in a 1/2" round die around the 10 mg inner tablet of Table 3 A in the center. A compression pressure of about 25,466 lbs/in² was applied to form the final dosage unit.

[00302] In Example 1 IB, a 5 mg diazepam tablet-in-tablet formulation with pure calcium sulfate as outer tablet was manufactured by compressing 750 mg of pure calcium sulfate in a 1/2" round die around the 5 mg inner tablet of Table 11A in the center. A compression pressure of about 25,466 lbs/in² was applied to form the final dosage unit.

[00303] Final tablet-in-tablet compositions are described in Table 42B.

Table 42B. 5 mg and 10 mg Diazepam Tablet-in-tablet compositions with Calcium Sulfate Outer tablet

[00304] The formulations were tested under the methodologies described in Example 9. Results are shown in FIGS. 11 and 12.

[00305] It was found that in both examples 1 1 A and 1 IB a single tablet showed almost full release of the active in 30 minutes in 0.1 N HCl media and significantly suppressed release in 80 vol.% 0.1N HCl/20 vol.% reagent alcohol media. Thus, both formulations demonstrate significant alcohol resistance.

Example 12: Diazepam Tablet-in-Tablet formulation with blend of Sodium Phosphate and coated polymer granules in outer tablet

[00306] 12 A. Manufacture of 5 mg and 10 mg Diazepam Inner Tablets. Diazepam inner tablets 5 mg and 10 mg were manufactured using a common blend by blending diazepam with eudragit E PO and other excipients prior to compressing into tablets. The 10 mg dose inner tablet weighs 200 mg and is a 3/8" round tablet. The 5 mg dose inner tablets weighs 100 mg and is a 1/4" round tablet. The composition for the diazepam tablets are shown in Table 43A.

Table 43 A. 5 mg and 10 mg Diazepam Inner Tablet Composition

[00307] 12B. Manufacturing of Polymer Granules. The polymer granules used in the outer tablet blend for tablet-in-tablets were manufactured in a high shear wet granulation process. The polymer granules batch formula is provided in Table 43B, below. The polymer granules manufactured were used in a subsequent coating process described in section 12C.

Table 43B. Components for polymer granule formulation

* Alcohol and water were removed from the polymer granules during processing.

[00308] Granules were manufactured in a high shear granulator, where hypromellose, glyceryl behenate, and a portion of ethylcellose were dry mixed. Then, a hydroalcoholic solution of ethylcellose (10% wt/wt) was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of ethylcellose was added and the granules formed. The granules were then wet milled using size reduction mill (Granumill) and were subsequently loaded into fluid bed for dtying.

[00309] 12C. Manufacturing of Coated Polymer Granules. The polymer granules from step 4B were subsequently coated in a bottom spray fluid bed coater with 32% acetone solution of Eudragit E 100 copolymer and magnesium stearate. The polymer granules were coated to an 18% weight gain. The composition of the coated polymer granules is described in Table 43C.

[00310] 12D, Manufacturing of 5 mg and 10 mg Diazepam Tablet-in-Tablet composition with blend of Sodium Phosphate and coated polymer granules in outer tablet. The outer tablet material was a mixture of coated polymer granules (10% w/w) and sodium phosphate (90% w/w) and was prepared by blending the two ingredients together in a tumble mixer for 30 minutes.

[00311] In example 12A, a 10 mg diazepam tablet-in-tablet formulation with the blend of coated polymer granules and sodium phosphate as outer tablet was manufactured on a press by compressing 850 mg of the blend in a 5/8" round die with the 10 mg inner tablet of Table 4A in the center. A compression pressure of about 16,297 lbs/in² was applied to form the final dosage unit,

[00312] In example 12B, a 5 mg diazepam tabiet-in-tabiet formulation with the blend of coated polymer granules and sodium phosphate as outer tablet was manufactured on a press by compressing 750 mg of the blend in a 1/2" round die with the 5 mg inner tablet of Table 43A in the center, A compression pressure of about 25,466 lbs/in² was applied to form the final dosage unit.

[00313] Final tablet-in-tablet compositions are described in Table 43D

Table 43D. 5 mg and 10 mg Diazepam Tabiet-in-Tablet composition with blend of Sodium

Phosphate and coated polymer granules in outer tablet

[00314] The formulations were tested under the methodologies described in Example 9. Results are shown in FIGS. 13 and 14.

[00315] A third test was conducted as follows. A single tablet dissolution (n=3) in 60:40 0.1N HCl: Reagent Alcohol (timepoints: 0, 10, 20, 30, 45, 60, 120, 180, 240 minutes. Test method used 900 mL media, 37°C media temperature, 10 mesh basket (USP apparatus 1) at a 50 rpm rotational speed. Dissolution testing is described only for Example 12 A. FIG. 15 includes example 12A in 80:20 (0.1N HCl: Reagent Alcohol) for reference.

[00316] It was found that in 80 vol.% 0. IN HCl/20 vol.% reagent alcohol media, a single tablet released less than 14 wt.% and 8 wt.% diazepam in 1 hour for the 10 mg dose (example 12 A) and the 5 mg dose (example 12B), respectively. By 2 hours both formulations had full release. Both formulations demonstrated significant alcohol resistance in the first hour in 20% alcohol. The formulas are expected to show slower release as the volume percent of alcohol increases as demonstrated for Example 12A in Figure 15. By 2 hours, the formula in 20% alcohol shows full release whereas in 40% alcohol the formula has only released 5% diazepam. After 4 hours the formula in 40% alcohol has only released 43% diazepam showing slower release as the concentration of alcohol increases.

Example 13: Alprazolam Tablet-in-Tablet formulation with blend of Sodium Phosphate and coated polymer granules in outer tab!et

[00317] 13A. Manufacture of 0.5 mg and 2 mg Alprazolam Inner Tablets.

Alprazolam inner tablets 0.5 mg and 2 mg were manufactured by directly blending diazepam with eudragit E PO and other excipients prior to compressing into 100 mg, 1/4" round tablets. The composition for the 2 mg and 0.5 mg tablets are shown in Table 44 A.

Table 44A. 0.5 mg and 2 mg Alprazolam Inner tablet Composition

[00318] J3B. Preparation of Sodium Phosphate/Coated Polymer Granule Blend. See Example 12, Steps 12B - 12D for the manufacture of the polymer granules, coated polymer granules, and sodium phosphate/coated polymer granule blend.

[00319] In example 13 A, a 2 mg alprazolam tablet-in-tablet formulation with the blend of coated polymer granules and sodium phosphate as outer tablet was manufactured on a press by compressing 750 mg of the blend in a 1/2" round die with the 2 mg inner tablet of Table 44A in the center. A compression pressure of about 25,466 lbs/in² was applied to form the final dosage unit.

[00320] In example 13B, a 0.5 mg alprazolam tablet-in-tablet formulation with the blend of coated polymer granules and sodium phosphate as outer tablet was manufactured on a press by compressing 750 mg of the blend in a 1/2" round die with the 0.5 mg inner tablet of Table 44A in the center. A compression pressure of about 25,466 lbs/in² was applied to form the final dosage unit.

[00321] The final tablet-in-tablet composition is shown in Table 44B.

Table 44B. 0.5 mg and 2mg Alprazolam Tablet-in-Tablet composition with blend of Sodium

Phosphate and coated polymer granules in outer tablet

[00322] The formulations were tested under the methodologies described in Example 9. Results are shown in FIGS. 16 and 17. Example 14: Alprazolam Tablet-in-Tablet formulation with Calcium Sulfate in outer tablet

[00323] 14A. Manufacture of 2 mg Alprazolam Inner Tablets. Alprazolam inner tablets were manufactured by directly blending alprazolam with eudragit E PO and other excipients prior to compressing into tablets. A 100 mg, 1/4" round tablet was designed for the 2 mg dose. The composition for the alprazolam tablets are shown in Table 45A.

Table 45A. 2 mg Alprazolam Inner Tablet Composition

[00324] 14B. Manufacture of 2 mg Alprazolam tablet-in-tablet formulation with Calcium Sulfate in outer tablet. The outer tablet material consisted of pure calcium sulfate.

[00325] A 2 mg alprazolam tablet-in-tablet formulation with pure calcium sulfate as outer tablet was manufactured by compressing 750 mg of pure calcium sulfate in a 1/2" round die around the 2 mg inner tablet of Table 45 A in the center. A compression pressure of about 25,466 lbs/in² was applied to form the final dosage unit.

[00326] Final tablet-in-tablet compositions are described in Table 45B.

Table 45B. 2 mg Alprazolam tablet-in-tablet composition with Calcium Sulfate Outer tablet

[00327] The formulations were tested under the methodologies described in Example 9. Results are shown in FIGS. 18 and 19.

Example 15: Phenobarbital Sodium Tablet-in-Tablet formulation with Calcium Sulfate in outer tablet

[00328] ISA. Manufacture of 15 mg and 100 mg Phenobarbital Sodium Inner Tablets. Phenobarbital Sodium inner tablets were manufactured by directly blending Phenobarbital Sodium with eudragit E PO and other excipients prior to compressing into tablets. The 100 mg dose inner tablet weighs 200 mg and is a 3/8" round tablet. The 15 mg dose inner tablets weighs 100 mg and is a 1/4" round tablet. The compositions for the Phenobarbital Sodium tablets are shown in Table 46A.

Table 46A. 15 mg and 100 mg Phenobarbital Sodium Inner Tablet Composition

[00329] 15B. Manufacture of 15 mg and 100 mg Phenobarbital Sodium tablet-in-tablet formulation with Calcium Sulfate in outer tablet. Both 100 mg and 15 mg doses use pure calcium sulfate as outer tablet material.

[00330] In Example 15 A, a 100 mg phenobarbital sodium tablet-in-tablet formulation with pure calcium sulfate as outer tablet was manufactured by compressing 700 mg of pure calcium sulfate in a 1/2" round die around the 100 mg inner tablet of Table 46A in the center, A compression pressure of about 25,466 lbs/in² was applied to form the final dosage unit. [00331] In Example 15B, a 15 mg phenobarbital sodium tablet-in-tablet formulation with pure calcium sulfate as outer tablet was manufactured by compressing 750 mg of pure calcium sulfate in a 1 /2" round die around the 15 mg inner tablet of Table 46A in the center. A compression pressure of about 25,466 lbs/in² was applied to form the final dosage unit.

[00332] Final tablet-in-tablet compositions are described in Table 46B.

Table 46B. 15 mg and 100 mg Phenobarbital tablet-in-tablet compositions with Calcium Sulfate outer tablet

[00333] The following tests were conducted on the formulations:

(i) Method 4: A single tablet dissolution (n=3) in 0.01N HC1 (timepoints: 0, 10, 20, 30, 45, 60 minutes). Test method uses 900 mL media, 37°C media temperature, 10 mesh basket (USP apparatus 1) at a 50 rpm rotational speed.

(ii) Method 5: A single tablet dissolution (n=3) in 80:20 0.01N HC1: Reagent Alcohol (timepoints: 0, 10, 20, 30, 45, 60, 120, 180, 240 minutes. Test method uses 900 mL media, 37°C media temperature, 10 mesh basket (USP apparatus 1) at a 50 rpm rotational speed.

[00334] Results are shown in FIGS. 20 and 21. It was found that in 80 vol.% 0.01N HCl/20 vol.% reagent alcohol media, a single tablet released less than 36 wt.% and 14 wt.% phenobarbital sodium in 1 hour for the 100 mg dose (example I SA) and the 15 mg dose (example 15B), respectively. After 4 hours of dissolution 92 wt.% and 84 wt.% phenobarbital sodium was released for the 100 mg and 15 mg doses, respectively. Both formulations demonstrated significant alcohol resistance within the first hour and slow release up to 4 hours.

Example 16: Diphenhydramine HCl Tablet-in-Tablet formulation with Calcium Sulfate or Calcium Citrate in outer tablet

[00335] 16A. Manufacture of 10 mg Diphenhydramine HCl inner tablets.

Diphenhydramine HCl inner tablets were manufactured by directly blending diphenhydramine HCl with Eudragit E PO and other excipients prior to compressing into 1/4" round tablets. The composition for the diphenhydramine HCl tablets is shown in Table 47 A.

Table 47A. 10 mg Diphenhydramine HCl Inner Tablet Composition.

[00336] 16B. Manufacture of 10 mg Diphenhydramine HCl tablet-in-tablet formulation with Calcium Sulfate or Calcium Citrate in outer tablet. The pure calcium sulfate or pure calcium citrate were used as outer tablet material.

[00337] In Example 16 A, a 10 mg diphenhydramine HCl tablet-in-tablet formulation with pure calcium sulfate as outer tablet was manufactured by compressing 750 mg of pure calcium sulfate in a 1/2" round die around the 10 mg inner tablet of Table 47A in the center. A compression pressure of about 25,466 lbs/in² was applied to form the final dosage unit.

[00338] In Example 16B, a 10 mg diphenhydramine HCl tablet-in-tablet formulation with pure calcium citrate as outer tablet was manufactured by compressing 750 mg of pure calcium citrate in a 1/2" round die around the 10 mg inner tablet of Table 47 A in the center. A compression pressure of about 40,744 lbs/in² was applied to form the final dosage unit.

[00339] Final tablet-in-tablet compositions are described in Table 47B.

Table 47B. 10 mg Diphenhydramine HCI Tablet-in-tablet compositions with Calcium Sulfate or

Calcium Citrate as Outer tablet

[00340] The formulations were tested under the methodologies described in Example 9. Results are shown in FIGS, 22 and 23.

Example 17: Diphenhydramine HCI Tablet-in-Tablet formulation with various salt blends {pure ferric phosphate, ferric phosphate/calcium sulfate or ferric phosphate/Calcium Sulfate/Talc) in outer tablet

[00341] 17A. Manufacture of 10 mg Diphenhydramine HCI inner tablets. See section 9A of Example 9.

[00342] 17B. Manufacture oflO mg Diphenhydramine HCI Tablet-in Tablet formulation with various salt blends (pure ferric phosphate, ferric phosphate/calcium sulfate, or Ferric phosphate/Calcium Sulfate/Talc) in outer tablet. The outer tablet material consists of either pure ferric phosphate (example 17A) or blend containing calcium sulfate (50% w/w) and ferric phosphate (50% w/w) (example 17B) or blend containing ferric phosphate (49% w/w), calcium sulfate (49% w/w), and talc (2% w/w) (example 17C). The blends are prepared by mixing all the ingredients together in a tumble blender for 30 minutes.

[00343] In example 17A, tablet-in-tablet formulation with pure ferric phosphate as outer tablet is manufactured on a press by compressing 750 mg of the material in a 1/2" round die around the inner tablet of Table 40A in the center, A compression pressure of about 10, 186 lbs/in² is applied to form the final dosage unit. [00344] In example 17B, tablet-in-tabiet formulation with a blend of ferric phosphate and calcium sulfate as outer tablet is manufactured on a press by compressing 750 mg of the blend in a 1/2" round die around the inner tablet of Table 40 A in the center. A compression pressure of 25,466 lbs/in² is applied to form the final dosage unit.

[00345] In example 17C, tablet-in-tablet formulation with a blend of ferric phosphate, calcium sulfate, and talc as outer tablet is manufactured on a press by compressing 750 mg of the blend in a 1/2" round die around the inner tablet of Table 40A in the center. A compression pressure of 25,466 lbs/in² is applied to form the final dosage unit.

[00346] The final tablet-in-tablet compositions are described in Table 48A.

Table 48A. 10 mg Diphenhydramine HCl Tablet-in-Tablet Compositions with various salt blends (pure ferric phosphate, ferric phosphate/calcium sulfate, or Ferric phosphate/Calcium

Sulfate/Talc) in outer tablet

[00347] Those skilled in the art will appreciate that numerous changes and

modifications can be made to the preferred embodiments of the disclosure and that such changes and modifications can be made without departing from the spirit of the disclosure. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the disclosure.

Claims

WHAT IS CLAIMED IS:

1. An immediate release dosage form comprising:

an active agent portion comprising an active pharmaceutical agent; and

about 30% to about 99%, based on the weight of the dosage form, of an alcohol resistant agent; wherein the ratio of the active pharmaceutical agent released from the dosage form after 1 hour, when measured by

the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 40 voi.% ethanol: 60 vol.% 0. IN aqueous HCl at 37°C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 0. IN aqueous HCl without ethanol at 37°C,

or,

the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.01N aqueous HCl at 37°C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 0.01N aqueous HCl without ethanol at 37°C,

or,

the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0.1N aqueous HCl at 37°C to the active pharmaceutical agent released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N aqueous HCl without ethanol at 37°C,

or,

is less than about 0.9.

2. The immediate release dosage form of claim 1, wherein said ratio is less than about 0.83.

3. The immediate release dosage form of claim 1 or 2, wherein said ratio is about 0.0 to about 0.9.

4. The immediate release dosage form according to any one of claims 1 to 3, wherein said ratio is about 0.14 to about 0.83.

5. The immediate dosage form according to any preceding claim, wherein the active agent portion is present in the dosage form as a plurality of particles, and the plurality of particles are admixed with the alcohol resistant agent, thereby forming an admixture.

6. The immediate release dosage form of claim 5, wherein:

less than 80% of the active pharmaceutical agent by weight is released from the dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N aqueous HCl at 37 °C; and 95% or more of the active pharmaceutical agent by weight is released from the dosage fonn after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N aqueous HCl without ethanol at 37 °C.

7. The immediate release dosage form of claim 5, wherein:

less than about 75% of the active pharmaceutical agent by weight is released from the dosage form after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N aqueous HCl at about 37 °C; and

about 90% or more of the active pharmaceutical agent by weight is released from the dosage form after about 1 hour^* when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 0. IN aqueous HCl without ethanol at about 37 °C.

8. The immediate release dosage form of claim 5, wherein:

less than about 65% of the active pharmaceutical agent by weight is released from the dosage form after about 1 hour- when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N aqueous HCl at about 37 °C; and

about 80% or more of the active pharmaceutical agent by weight is released from the dosage form after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 0.1N aqueous HCl witliout ethanol at about 37 °C.

9. The immediate release dosage form of claim 5, wherein the active pharmaceutical agent is dispersed within the particles.

10. The immediate release dosage form of claim 5, wherein the particles are coated with an active coating layer comprising the active pharmaceutical agent.

1 1. The immediate release dosage form of claim 5, wherein the particles are coated with an active coating layer comprising a first portion of the active pharmaceutical agent and wherein a second portion of the active pharmaceutical agent is dispersed within the particles.

12. The immediate release dosage form according to any one of claims 5-1 1, wherein the particles comprise hypromellose, ethyl cellulose, glyceryl behenate, magnesium stearate, microcrystalline cellulose, a polyvinylpyrrolidone, or any combination thereof.

13. The immediate release dosage form according to any one of claims 5-12, wherein the admixture further comprises a gelling agent, a neutralizing agent, a binder, a disintegrant, a glidant, a lubricant, a filler, a pH sensitive polymer, or a combination thereof.

14. The immediate release dosage form according to any one of the preceding claims, wherein the dosage form is a caplet, pill, or compressed tablet.

15. The immediate release dosage form according to any one of the preceding claims, wherein the dosage form is a multi-layer tablet or caplet.

16. The immediate release dosage form according to any one of claims 5-15, wherein the particles further comprise a pH sensitive layer that is insoluble in water at a pH greater than 5.

17. The immediate release dosage form according to any one of claims 5-16, wherein less than about 50% of the active pharmaceutical agent, by weight of the dosage form, is released after about 1 hour when measured by the USP 2 Paddle method at about 50 rpm in about 900 mL of an aqueous solution comprising 40 vol.% ethanol: 60 vol.% 0.1N aqueous HCl at about 37 °C.

18. The immediate release dosage form according to any one of claims 5-17, wherein the particles further comprise an alcohol resistant layer comprising an alcohol resistant agent.

19. The immediate release dosage form of claim 18, wherein the alcohol resistant agent in the alcohol resistant layer is a copolymer comprising ethyl acrylate and methyl methacrylate.

20. The immediate release dosage form of claim 18, wherein the alcohol resistant agent in the alcohol resistant layer is a copolymer comprising ethyl acrylate, methyl methacrylate, and methacrylic acid ester with quaternary ammonium group salts.

21. The immediate release dosage form of claim 18, wherein the alcohol resistant agent in the alcohol resistant layer is a calcium phosphate, a sodium phosphate, calcium sulfate, calcium citrate, calcium acetate, barium sulfate, barium citrate, or a mixture thereof.

22. The immediate release dosage form according to any one of claims 18 to 21, wherein the alcohol resistant agent in the layer comprises about 35% to about 60% by weight of the total alcohol resistant agent in the dosage form.

23. The immediate release dosage form according to any one of claims 1-4, wherein the active agent portion forms a central core of said dosage form, and the alcohol resistant agent is contained within an outer layer that surrounds the central core.

24. The immediate release dosage form according to claim 23, wherein the central core further comprises a gelling agent, a neutralizing agent, a binder, a disintegrant, a glidant, a lubricant, a filler, a pH sensitive polymer, or a combination thereof.

25. The immediate release dosage form according to claim 24, wherein the central core comprises a gelling agent, a binder, a lubricant, and a filler.

26. The immediate release dosage form according to claim 24 or claim 25, wherein the central core comprises a pH sensitive gelling agent, a non-pH sensitive gelling agent, or both.

27. The immediate release dosage form according to claim 26, wherein the pH sensitive gelling agent is a carbopol, and the non-pH sensitive gelling agent is hydroxypropyl methylcellulose.

28. The immediate release dosage form according to claim 23, wherein the outer layer further comprises a plurality of granules comprising a polymer.

29. The immediate release dosage form according to claim 28, wherein the granules comprise a gelling agent.

30. The immediate release dosage form according to claim 28, wherein the granules comprise hypromellose, ethyl cellulose, glyceryl behenate, magnesium stearate, microcrystalline cellulose, a polyvinylpyrrolidone, or any combination thereof.

31. The immediate release dosage form according to claim 28, wherein the granules comprise hypromellose, ethyl cellulose, and glyceryl behenate.

32. The immediate release dosage form according to any one of claims 28-31 , wherein the granules further comprise an outer polymer coating.

33. The immediate release dosage form according to any one of claims 29-32, wherein the gelling agent in the granules is present in an amount of about 0-35% by weight of the outer layer, and the alcohol resistant agent is present in an amount of about 30-90% by weight of the dosage form.

34. The immediate release dosage form according to any one of claims 29-32, wherein the gelling agent is present in an amount of about 30-80% by weight of the granules.

35. The immediate release dosage form according to claim 34, wherein the granules are present in an amount of about 5-10% by weight of the dosage form, and the alcohol resistant agent is present in an amount of about 65-90% by weight of the dosage form.

3ό. The immediate release dosage form according to claim 28, wherein the active agent portion further comprises a gelling agent, a neutralizing agent, a binder, a disintegrant, a glidant, a lubricant, a filler, a pH sensitive polymer, or a combination thereof.

37. The immediate release dosage form according to claim 36, wherein the active agent portion comprises a gelling agent, a lubricant, and a binder.

38. The immediate release dosage form according to any one of claims 28-37, wherein the active agent portion comprises about 10-70% by weight of the dosage form.

39. The immediate release dosage form according to any one of claims 23 to 38, wherein less than 80% of the active pharmaceutical agent by weight is released from the dosage form after 1 hour when measured by the USP 1 Basket ( 10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0.1N aqueous HC1 at 37°C; and,

95% or more of the active pharmaceutical agent by weight is released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0. IN aqueous HC1 without ethanol at 37°C.

40. The immediate release dosage form according to any one of claims 23 to 38, wherein less than 60% of the active pharmaceutical agent by weight is released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0.1N aqueous HC1 at 37°C;

and,

90% or more of the active pharmaceutical agent by weight is released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N aqueous HC1 without ethanol at 37°C.

41. The immediate release dosage form according to any one of claims 23 to 38, wherein less than 50% of the active pharmaceutical agent by weight is released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 20 vol.% ethanol: 80 vol.% 0.1N aqueous HC1 at 37°C;

and,

80% or more of the active pharmaceutical agent by weight is released from the dosage form after 1 hour when measured by the USP 1 Basket (10 mesh screen) method at 50 rpm in 900 mL of an aqueous solution comprising 0.1N aqueous HC1 without ethanol at 37°C.

42. The immediate release dosage form according to any one of the preceding claims, wherein the alcohol resistant agent is a calcium phosphate, a sodium phosphate, a ferric phosphate, calcium sulfate, calcium citrate, calcium acetate, manganese citrate, barium sulfate, barium citrate, or any combination thereof.

43. The immediate release dosage form of claim 42, wherein the calcium phosphate is monobasic, dibasic, tribasic, or a mixture thereof.

44. The immediate release dosage form of claim 42 or claim 43, wherein the calcium phosphate is a hydrate.

45. The immediate release dosage form of claim 42 or claim 43, wherein the calcium phosphate is anhydrous.

46. The immediate release dosage form according to any one of the preceding claims, wherein the alcohol resistant agent is calcium sulfate or ferric phosphate.

47. The immediate release dosage form according to any one of the preceding claims, wherein the alcohol resistant agent is sodium phosphate, calcium citrate or manganese citrate.

48. The immediate release dosage form according to any one of the preceding claims, comprising about 30% to about 90%, based on the weight of the dosage form, of the alcohol resistant agent.

49. The immediate release dosage form according to any one of the preceding claims, comprising about 80% to about 90%, based on the weight of the dosage form, of the alcohol resistant agent

50. The immediate release dosage form according to any one of the preceding claims, wherein the alcohol resistant agent is a copolymer comprising ethyl acrylate and methyl methacrylate.

51. The immediate release dosage form according to any one of the preceding claims, wherein the alcohol resistant agent is a copolymer comprising ethyl acrylate, methyl methacrylate, and methacrylic acid ester with quaternary ammonium group salts.

52. The immediate release dosage form according to any one of the preceding claims, wherein the alcohol resistant agent is a copolymer comprising ethyl acrylate and methyl methacrylate; a copolymer comprising ethyl acrylate, methyl methacrylate, and methaciylic acid ester with quaternaiy ammonium group salts; a calcium phosphate; a sodium phosphate; calcium sulfate; calcium citrate; calcium acetate; barium sulfate; barium citrate; ferric phosphate;

manganese citrate; or a mixture thereof.

53. The immediate release dosage form of claim 52, wherein the alcohol resistant agent is a first alcohol resistant agent that is a copolymer comprising ethyl aery late and methyl methacrylate; and a second alcohol resistant agent that is a calcium phosphate, a sodium phosphate, calcium sulfate, calcium citrate, calcium acetate, barium sulfate, barium citrate, ferric phosphate, manganese citrate; or a mixture thereof.

54. The immediate release dosage form of claim 52, wherein the alcohol resistant agent admixed with said plurality of particles is

a first alcohol resistant agent that is a copolymer comprising ethyl acrylate, methyl methacryiate, and methacrylic acid ester with quaternary ammonium group salts; and

a second alcohol resistant agent that is a calcium phosphate, a sodium phosphate, calcium sulfate, calcium citrate, calcium acetate, barium sulfate, barium citrate, ferric phosphate manganese citrate; or a mixture thereof.

55. The immediate release dosage form according to any one of the preceding claims, wherein the active pharmaceutical agent is an analgesic, antihistamine, barbiturate, anesthetic, sedative, stimulant, antidepressant, or anti-anxiety agent.

56. The immediate release dosage form according to any one of the preceding claims, wherein the active pharmaceutical agent is an opioid agonist, a benzodiazepine, a barbiturate, or diphenhydramine.

57. The immediate release dosage form of claim 56, wherein the opioid agonist is oxycodone, oxymorphone, codeine, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, meperidine, buprenorphine, fentanyl, fentanyl derivatives, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, methadone, morphine, and propoxyphene and pharmaceutically acceptable salts thereof.

58. The immediate release dosage form of claim 56, wherein the benzodiazepine is diazepam, alprazolam, clonazepam, or lorazepam,

59. The immediate release dosage form of claim 56, wherein the barbiturate is allobarbital, amobarbital, aprobarbital, alphenai, barbital, brallobarbital, pentobarbital, phenobarbital, or secobarbital

60. The immediate release dosage form according to any one of the preceding claims comprising a second active pharmaceutical agent.

61. The immediate release dosage form according to claim 60, wherein the second active pharmaceutical agent is an analgesic, a stimulant, a depressant, an antihistamine, an anesthetic, an antidepressant, an anti-anxiety agent, a sedative, an anxiolytic, an antipsychotic, a cannabinol, a cannabinoid, an antibiotic, or a muscle relaxant.

62. The immediate release dosage form according to claim 60 or claim 61 , wherein the second active pharmaceutical agent is an analgesic.

63. The immediate release dosage form according to any one of the preceding claims, wherein the dosage form reduces the risk of an overdose resulting from simultaneous oral ingestion of multiple units of the oral dosage form.

64. The immediate release dosage form according to any one of the preceding claims, wherein the dosage form reduces the potential for abuse by simultaneous oral ingestion of multiple units of the oral dosage form.

65. The immediate release dosage form according to any one of the preceding claims, that demonstrates an immediate release profile when administered in therapeutic doses, but which demonstrates an extended release profile when administered in supratherapeutic doses.

66. The immediate release dosage form of claim 65, wherein the immediate release profile is defined as not less than 90% of API released in 60 minutes, and the extended release profile is defined as not more than 85% released in 60 minutes, wherein the release profiles may be evaluated by dissolution in 300 mL of 0. IN HCI media using USP II apparatus at 50 RPM paddle speed and 37°C.

67. The immediate release dosage form of claim 65, wherein the supratherapeutic dose is five or more dosage forms.

68. The immediate release dosage form of claim 65, wherein the ratio of the active pharmaceutical agent released from 12 dosage forms after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0.1N aqueous HCI at 37°C to the active phai-maceutical agent released from 1 dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0.1N aqueous HCI at 37°C is less than about 0.9.

69. The immediate release dosage form of claim 65, wherein the ratio of the active phannaceutical agent released from 12 dosage forms after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0. IN aqueous HC1 at 37°C to the active pharmaceutical agent released from 1 dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0.1N aqueous HC1 at 37°C is less than about 0.8.

70. The immediate release dosage form of claim 65, wherein the ratio of the active pharmaceutical agent released from 12 dosage forms after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0. IN aqueous HC1 at 37°C to the active pharmaceutical agent released from 1 dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0.1N aqueous HC1 at 37°C is less than about 0.7.

71. The immediate release dosage form of claim 65, wherein the ratio of the active pharmaceutical agent released from 12 dosage forms after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0.1N aqueous HC1 at 37°C to the active pharmaceutical agent released from 1 dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0.1N aqueous HC1 at 37°C is less man about 0.6.

72. The immediate release dosage form of claim 65, wherein the ratio of the active pharmaceutical agent released from 12 dosage forms after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0. IN aqueous HC1 at 37°C to the active pharmaceutical agent released from 1 dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0, IN aqueous HC1 at 37°C is less than about 0.4.

73. The immediate release dosage form of claim 65, wherein the ratio of the active pharmaceutical agent released from 12 dosage forms after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0.1N aqueous HQ at 37°C to the active pharmaceutical agent released from 1 dosage form after 1 hour when measured by the USP 2 Paddie method at 50 rpm in 900 mL of 0.1N aqueous HC1 at 37°C is less than about 0.3.

74. The immediate release dosage form of claim 65, wherein the ratio of the active pharmaceutical agent released from 12 dosage forms after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0. IN aqueous HC1 at 37°C to the active pharmaceutical agent released from 1 dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0. IN aqueous HCI at 37°C is less than about 0.2.

75. The immediate release dosage form of claim 65, wherein the ratio of the active pharmaceutical agent released from 12 dosage forms after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0.1N aqueous HC1 at 37°C to the active pharmaceutical agent released from 1 dosage form after 1 hour when measured by the USP 2 Paddle method at 50 rpm in 900 mL of 0.1N aqueous HC1 at 37°C is less than about 0.1.

76. A method of preventing abuse of a narcotic analgesic drug in a subject comprising administering an immediate release dosage form according to any one of claims 1 to 75 to said subject.

77. A method of preventing overdose by accidental or intentional administration of a supratherapeutic dose of a narcotic analgesic drug, comprising administering an immediate release dosage form according to any one of claims 1 to 75 to said subject.

78. A method of treating a patient, comprising administering to the patient an immediate release dosage form according to any one of claims 1 to 75.

79. The method of claim 78, further comprising identifying that the patient is in need of treatment with an active pharmaceutical agent that is contraindicated for administration with ethanol.

80. The method of claim 78, wherein the active pharmaceutical agent is contraindicated for administration with ethanol.

81. The method according to any one of claims 78-80, wherein the patient has a history of drug abuse or ethanol abuse.

82. The method according to any one of claims 78-81, wherein the dosage form demonstrates an immediate release profile when administered in therapeutic doses, but demonstrates an extended release profile when administered in supratherapeutic doses.

83. The method according to claim 82, wherein the supratherapeutic dose is five or more tablets.

84. A method of reducing the risk of overdose of an active pharmaceutical agent, comprising administering to a subject an immediate rele d age form according to any one of claims 1 to 75.