WO2024261775A1 - A drug-antagonist combination dosage form - Google Patents

Abstract

The presently disclosed subject matter relates to a drug-antagonist combination dosage form, a method for preparing the dosage form, and a method of administering the dosage form to treat a disease or therapeutic condition. The presently disclosed subject matter provides an oral, multi-particulate, extended-release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists, wherein the dosage form provides two-stage protection in an overdose condition: the first stage is to retard the release of the drug from the dosage forms, and the second stage is to make the antagonist available in an effective amount if the dosage forms fail to retard the drug release in the overdose condition.

Description

A DRUG- ANTAGONIST COMBINATION DOSAGE FORM

FIELD

[0001] A presently disclosed subject matter relates to a drug-antagonist combination dosage form, a method for preparing the dosage form, and a method of administering the dosage form to treat a disease or therapeutic condition. In certain embodiments, the present disclosed subject matter provides two-stage protection in overdose conditions: the first stage is to retard the release of the drug from the combination dosage form, and the second stage is to make the antagonist available in an effective amount if the dosage form fails to retard the drug release in overdose condition. In certain embodiments, the present disclosed subject matter reduces the liking of improper administration of the drug-antagonist combination dosage for non-therapeutic purposes, such as abuse to achieve a pleasurable (hedonic) experience (a desirable psychological, physiological, or euphoric effect).

BACKGROUND

[0002] Overdosing any pharmaceutical formulation is fatal and causes death. Longer pharmaceutical treatment can also generate a drug tolerance, and thus the drug is required to be administered in a higher dose. But along with potential therapeutic benefits, some pharmaceutical drugs also produce a pleasurable (hedonic) experience when administered in high doses. For example, an estimated 11% of adult Americans experience daily pain, and millions are treated with prescription opioids for chronic pain. Unfortunately, opioids also carry the potential to inadvertently cause issues like slowing of breathing and sedation, as well as a sensation of euphoria through the release of endorphins that might contribute to abuse or misuse. Those taking opioids for analgesia specifically may also develop a tolerance to the opioid doses that once gave them relief, causing them to experiment with higher doses to achieve the same level of relief. This also increases the risk of adverse effects associated with opioid overuse. The problem is further exacerbated in the case of extended-release dosage forms containing potent drugs susceptible to abuse, since the extended-release preparations have a higher dose of the drug incorporated into them. This makes a higher amount of the drug available to the abuser through overdose or administration of the preparation in manipulated form, such as grating, grinding, extraction with an appropriate solvent, application of force, etc., for abuse through inhalation, injection, swallowing, and smoking.

[0003] The United States is in the midst of an unprecedented prescription drug abuse epidemic, as classified by the Centres for Disease Control and Prevention (CDC) and the World Health Organisation (WHO). An estimated 52 million Americans use prescription drugs for nonmedical reasons at least once in their lifetimes, with some using prescription drugs for recreational purposes. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), more than 6.5 million people above the age of 11 used prescription drugs for non-medical reasons in 2013. In 2018, about 9.9 million Americans reported misuse of prescription opioid analgesics, and clinicians are increasingly becoming more concerned and aware of the propensity for patient addiction. According to the CDC, more than 106,000 people in the U.S. died from drug-related overdoses in 2021, including illicit drugs and prescription opioids. In 2017, the economic impact of opioid use disorder and fatal opioid overdoses exceeded $1 trillion.

[0004] There have previously been attempts in the art to control the abuse potential associated with the drug, such as those that require the inclusion of an antagonist of the drug that is not orally active but substantially blocks the euphoric (and analgesic) effect of the drug if one attempts to dissolve the drug and administer it parenterally. Prescription drugs (e.g., oxycodone, hydrocodone, oxymorphone, hydromorphone, codeine, fentanyl, and morphine) and heroin are opioid receptor agonists. They can effectively modify the perception of pain pathways within the brain and spinal cord. With larger doses, respiratory depression can occur, limiting adequate oxygenation of the blood, which reduces oxygen availability to the brain and heart, leading to unresponsiveness, anoxia, cyanosis, and death. This respiratory depression is reversible until death occurs; for example, it can be reversed with the drug’s antagonist, e.g., naloxone. Naloxone is an antagonist that displaces drugs such as opioids from the opioid receptors and blocks the binding of the opioids for 20-90 minutes (Hawk et al., 2015).

[0005] The U.S. Food and Drug Administration (FDA) describes the science of abuse deterrence as relatively new and rapidly evolving. The need remains for improved formulations that make it difficult, if not impossible, for individuals to abuse or misuse the drug, not only by crushing, grinding, cutting, chewing, snorting, and/or extraction of drug, but also by ingesting multiple doses (overdose). Therefore, new/improved extended-release pharmaceutical formulations and dosage forms are needed to prevent, inhibit, reduce, or reduce and/or delay the effects of overdose by ingesting multiple units of the dosage form, either intentionally or unintentionally. These dosage forms must also allow the drug to be soluble and absorbable in the gastrointestinal tract and have the desired pharmacological / therapeutical effect when ingested as directed.

SUMMARY

[0006] In certain embodiments, the presently disclosed subject matter relates to a drug-antagonist combination dosage form, a method for preparing the dosage form, and a method of administering the dosage form to treat a disease or therapeutic condition. In certain embodiments, the present disclosed subject matter reduces the liking of improper administration of the drug-antagonist combination dosage form or a drug contained in the drug-antagonist combination dosage form for non-therapeutic purposes, such as abuse to achieve a pleasurable (hedonic) experience (a desirable psychological, physiological, or euphoric effect).

[0007] In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended-release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists, wherein the dosage form provides two-stage protection in an overdose condition: the first stage is to retard the release of the drug from the dosage forms, and the second stage is to make the antagonist available in an effective amount if the dosage forms fail to retard the drug release in the overdose condition. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended-release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists, wherein the antagonist shows a dose-dependent effect. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended- release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists that releases the effective amount of the drug to produce its intended therapeutic effect and makes the antagonist available in an amount that is not sufficient to suppress the drug’s intended therapeutic effect when a single or prescribed units of said combination dosage form is administered in an intact form to a subject. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended-release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists that releases the effective amount of the drug to produce its intended therapeutic effect and makes the antagonist available in an amount that is not sufficient to suppress the drug’s intended therapeutic effect but sufficient to reduce the side/adverse effect associated with the drug when a single or prescribed units of said combination dosage form is administered in an intact form to a subject. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended-release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists that retard the release of the drug when multiple units of said combination dosage form are administered together. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended- release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists that releases the antagonist in an effective amount to reduce the drug's liking effect when multiple units of said combination dosage form are administered together.

[0008] In certain embodiments, an oral, multi-particulate, extended-release, drug-antagonist combination dosage form with overdose protection property comprising: a) a therapeutically effective amount of at least one drug, wherein the said at least drug is included in non-retarding particulates, b) a biphasic amount of at least one antagonist, wherein a first phase amount of the said at least one antagonist is included in non-retarding particulates and a second phase amount of the said antagonist is included in retarding particulates, and c) an alkalizing agent; wherein the combination dosage form does not release the said at least one antagonist in an effective amount to block the said drug’s intended therapeutic effect when administered to a subject in a single or prescribed units in an intact form, but it retards the release of the said drug or releases the said at least one antagonist in an effective amount to reduce the drug's liking effect when administered in multiple or non-prescribed units in the intact form.

[0009] In certain embodiments, an oral, multi-particulate, extended-release, drug-antagonist combination dosage form with overdose protection property comprising: a) a therapeutically effective amount of at least one drug, wherein the said at least one drug is included in non-retarding particulates, b) at least one antagonist, wherein the said at least one antagonist is included in retarding particulates, and c) an alkalizing agent; wherein the combination dosage form does not release the said at least one antagonist in an effective amount to block the said at least one drug’s intended therapeutic effect when administered to a subject in a single or prescribed units in an intact form, but it retards the release of the said at least one drug or releases the antagonist in an effective amount to reduce the drug's liking effect when administered in multiple or non-prescribed units in the intact form.

[0010] In certain embodiments, an oral, multi-particulate, extended-release, drug-antagonist combination dosage form with overdose protection property comprising: a) a therapeutically effective amount of at least one drug, wherein the said at least one drug is included in non-retarding particulates, b) a first antagonist, wherein the said first antagonist is included in the said non-retarding particulates, c) a second antagonist, wherein the said second antagonist is included in retarding particulates, and d) an alkalizing agent; wherein the combination dosage form does not release the said first and the said second antagonist in an effective amount to block the said at least one drug’s intended therapeutic effect when administered to a subject in a single or prescribed units in an intact form, but it retards the release of the said at least one drug or releases at least one of the said first and the said second antagonist in an effective amount to reduce the said at least one drug's liking effect when administered in multiple or non-prescribed units in the intact form.

[0011] In certain embodiments, an oral, multi-particulate, extended-release, drug-antagonist combination dosage form with overdose protection property comprising: a) a therapeutically effective amount of at least one drug, wherein the said at least one drug is included in non-retarding particulates, b) at least one antagonist, wherein the said at least one antagonist is included in the said non-retarding particulates, and c) an alkalizing agent; wherein the combination dosage form does not release the antagonist in an effective amount to block the said at least one drug’s intended therapeutic effect when administered to a subject in a single or prescribed units in an intact form, but it retards the release of the said at least one drug or releases the antagonist in an effective amount to reduce the said at least one drug's liking effect when administered in multiple or non-prescribed units in the said intact form.

[0012] In certain embodiments, the amount of the drug included in the non-retarding particulates or the combination dosage form is at least sufficient to produce its intended therapeutic purpose in a subject in need thereof. In certain embodiments, the drug is associated with abuse syndromes, therefore, said drug may, for example, be selected from opioids, opiates, CNS depressants or sedatives, anxiolytics, narcotics, tranquillizers, barbiturates, hormones, CNS stimulants, cannabinoids, nicotine-like compounds, glutamate antagonists, N-methyl-D-aspartate (NMD A) antagonists, or drugs that can cause psychological and/or physical dependence. Drugs that are preferred include those classified as Schedule I, II, III, IV, and V drugs based upon the substance's medicinal value, harmfulness, and potential for abuse or addiction under the Control Substance Act of the United States.

[0013] In certain embodiments, the selection of the antagonist is based on the drug used in the combination dosage form, and it may vary according to the therapeutic class of the drug. In certain embodiments, the antagonists useful in the presently disclosed subject matter include, but are not limited to, antagonists for opioids, non-opioid, central nervous system (CNS) depressants, stimulants, tranquillizers, barbiturates, hormones, cannabinoids, nicotine-like compounds, cold and cough drugs such as pseudoephedrine, glutamate antagonists, N-methyl-D-aspartate (NMD A) antagonists,

[0014] In certain embodiments, the alkalizing agent is included in the combination dosage form in an amount that results in about little or no major incremental change in the pH of the gastric fluids (the pH remains below about 5.5) upon ingestion of a single (e.g., one tablet or capsule) or prescribed unit(s) of the combination dosage form. In certain embodiments, overdose protection properties remain inactivate when single or prescribed unit(s) of the combination dosage form are ingested, i.e., release of the drug from the single or prescribed unit(s) of the combination dosage form(s) maintains its actual release properties [i.e., there is no or about minimal effect on the drug release] after ingestion of the said single or prescribed unit(s) of the combination dosage form. In certain embodiments, ingestion of multiple units of the combination dosage form (e.g., multiple tablets or capsules) together (overdose) results in the alkalizing agent increasing the pH of the gastric fluid very rapidly to above about 5.5. In certain embodiments, said combination dosage form further comprises at least one pH-stabilizing agent to maintain or stabilize the increased pH caused by the alkalizing agent. In certain embodiments, the overdose protection properties activated by the increased pH (at pH of at least greater than about 5.0) after ingestion of multiple units of the combination dosage form (e.g., multiple tablets or capsules) together, which results in modulation of the release properties of at least one of the drug and the antagonist from at least one of the non-retarding particulates and the retarding particulates contains in the combination dosage form. In certain embodiments, the activation of overdose properties causes the retardation of the release of the drug from the non-retarding particulates or releases the antagonist from at least one of the non-retarding particulates and the retarding particulates in an effective amount to reduce the drug's liking effect and/or the potential detrimental consequences of the drug in the event of overdose.

[0015] In certain embodiments, the combination dosage form further comprising water-soluble material, water insoluble material, gelling ingredient, anti-crushing ingredient, diluent, glidant, surfactant, stabilizer, binder, lubricant, disintegrant, plasticizer, anti-oxidant or stabilizer, anti-tacking agent, sweetener, or any combination thereof in an amount of about 0.00001% to about 85% w/w of the combination dosage form or respective particulates (non-retarding or retarding particulates), wherein some ingredient has more than one functionality in the composition (combination dosage form).

[0016] In certain embodiments, the multiarticulate of the combination dosage form can be filled into a capsule, compressed to form a larger tablet, or uniformly suspended in a liquid vehicle. In certain embodiments, the preferable size of particulate can be less than about 5mm, less than 4mm, less than 3mm, less than 2mm, less than 1.5mm, or any size between 5 microns to 5mm. In certain embodiments, the combination dosage form can be formulated in the form of a sprinkle formulation. The sprinkle formulation is useful for children and other patients who have difficulty swallowing the conventional solid dosage form.

DETAILED DESCRIPTION

[0017] The terms used in this specification generally have their ordinary meanings in the art, within the context of the presently disclosed subject matter, and in the specific context where each term is used. Certain terms are discussed below or elsewhere in the specification to provide additional guidance to the practitioner in describing the compositions and methods of the presently disclosed subject matter and how to make and use them.

[0018] As used herein, the use of the word "a" or "an" when used in conjunction with the term "comprising" (such as comprising a drug, comprising an antagonist, comprising an alkalizing agent, comprising a coat, and like) in the claims and/or the specification can mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." Still further, the terms "having," "including", "include," "containing", "comprising," and "comprises" are interchangeable, and one of skill in the art is cognizant that these terms are open-ended terms. [0019] The terms "drug-antagonist combination dosage form", "combination dosage unit", “composition”, "combination dosage form", "unit dosage form," "dosage form," "dosage unit," or "strength", are used interchangeably to refer to a pharmaceutical composition comprising a combination of a predetermined amount of at least one drug, at least one antagonist, and other inactive ingredients, and that is suitable as unitary dosage for single-time administration to human patients to treat the therapeutic condition(s).

[0020] The term "overdose" or "drug overdose" refers to administering a combination dosage form in multiple units (or non-prescribed units) in an intact form or in a single unit (or prescribed units) in a manipulated form by a subject. Typically, overdoses can be intentional or unintentional (e.g., accidental). The term "multiple units" means a plurality of units of the drug-antagonist combination dosage form, wherein the overall content of at least one drug originally contained in the plurality of units of the drugantagonist combination dosage form is greater than the maximum daily recommended dose of the drug, greater than the maximum single-time recommended administrable dose of the drug by a manufacturer, or greater than the maximum single-time prescribed dose of the drug by a licensed physician. The term "prescribed units" or “therapeutically effective units” means the number of unit(s) (e.g., one or more than one unit) of the drug-antagonist combination dosage form prescribed by a licensed physician or recommended by a manufacturer to treat an intended therapeutic condition. The term "non-prescribed units" means a greater number of units of the drug-antagonist combination dosage form than those prescribed by a licensed physician or recommended by the manufacturer.

[0021] The term "overdose protection properties" refers to a feature of a drug-antagonist combination dosage form that reduces a drug-linking effect and/or the potential detrimental consequences of the drug in the event of an overdose of said drug-antagonist combination dosage form. The term "drug liking effect" refers to the pleasurable (hedonic) experience (a desirable psychological, physiological, or euphoric effect) in the event of an overdose of the drug. Typically, the overdose protection properties mean the property of the drug-antagonist combination dosage form to retard the release of the drug or release the antagonist in an effective amount to reduce the drug-linking effect and/or the potential detrimental consequences of the drug in the event of an overdose.

[0022] In certain embodiments, the present disclosed subject matter reduces the liking of improper administration of the drug-antagonist combination dosage form or a drug contained in the drugantagonist combination dosage form for non-therapeutic purposes, such as abuse to achieve a pleasurable (hedonic) experience (a desirable psychological, physiological, or euphoric effect). The term "abuse" means the intentional improper administration of a drug-antagonist combination dosage form for a nontherapeutic use, such as to achieve a pleasurable (hedonic) experience (a desirable psychological, physiological, or euphoric effect). The term "improper administration" includes overdose of the drugantagonist combination dosage form, the administration of a manipulated form of the drug-antagonist combination dosage form, or administering the drug-antagonist combination dosage form in a manner inconsistent with the manufacturer's instructions. The term "manipulated dosage form" or "manipulated form" includes altering the physical form of the drug-antagonist combination dosage form in any way prior to administration via any route, i.e., oral, parenteral, nasal, and/or rectal. Various methods to alter the physical form of the dosage form include physical and/or chemical tampering. The term physical tampering includes, with or without heat treatment or freezing, at least one of crushing, grinding, melting, cutting, and the like. Thus, if an individual were to crush or grind up the combination dosage form in an attempt to take it parenterally, orally for overdose (dose dumping), or by snorting it through the nose, in order to obtain the drug’s liking effect, such as a euphoric "high," an effective amount of the antagonist would be released to antagonize the drug’s effect by neutralizing or blocking the drug effect. The term chemical tampering includes extracting the drug from the dosage form, dose dumping (e.g., compromising the extended-release properties of the drug), alcohol dose dumping (such as consuming the dosage form with up-to 40% w/w alcoholic drink), and solubilizing the dosage form for injection purposes. The term "in a manner inconsistent with the manufacturer's instructions" is meant to include, but is not limited to, overdose (consuming the dosage form in amounts greater than the amount(s) described on the label or prescribed by a licensed physician), and/or administering single (prescribed) or multiple units after altering the intact physical form of the dosage forms (e.g., manipulated dosage form) by any means such as physical and/or chemical tampering as described previously.

[0023] The term "immediate release" refers to the release property of at least one of a drug and an antagonist contained within a drug-antagonist combination dosage form, wherein said drug-antagonist combination dosage form is formulated to allow at least one of the drug and the antagonist to dissolve immediately in the gastrointestinal fluid/contents with no intention of delaying or prolonging the absorption when administered by a subject.

[0024] The term "extended release" refers to the release property of at least one of a drug and an antagonist contained within a drug-antagonist combination dosage form, wherein said drug-antagonist combination dosage form is formulated to allow at least one of the drug and the antagonist to dissolve at a slower rate over a greater period of time, e.g., for a period of at least 2 hours, 4 hours, 8 hours, 12 hours, and more, in the gastrointestinal fluid/contents when administered by a subject. The term "extended release" also includes the release of the at least one of the drug and the antagonist at any release rate (e.g., immediate or extended) after the predetermined lag time or in the predetermined location of the intestinal tract (other than the stomach or gastric region, such as enteric-coated or enteric formulation for release in the intestinal region) after administration.

[0025] The term "about" or "approximately" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, "about" can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, the term can also mean within an order of magnitude, preferably within five-fold, and more preferably within two-fold, of a value.

[0026] The terms "retarded", "retard", "retarding", "retardation" "diminish", or "lower" are interchangeable and generally have their ordinary meanings in the specific context where each term is used in the presently disclosed subject matter. For example, with respect to an antagonist, retard means to include delay, hold, no release, or a progressively slower release rate than the drug’s release rate in a normal dosing condition (such as administration of the drug-antagonist combination dosage form as directed by a physician or as instructed by the manufacturer). In the normal dosing condition, a greater percentage (%w/w) of the antagonist’s release retardation from the drug-antagonist combination dosage form is preferred, such as, but without limitation, greater than 1%, 5%, 15%, 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%, or increments therein. With respect to a drug, retard means to include delay, hold, no release, or a progressively slower release rate, such as at least a 10% change in the original release rate of a drug from the drug-antagonist combination dosage form in an overdose condition. In the overdose condition, a greater percentage (%w/w) change in the release rate (higher retardation) of the drug from the drug-antagonist combination dosage form is preferred, such as, but without limitation, greater than 15%, 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%, or increments therein.

[0027] The terms "drug", "active substance", "active ingredient", "active agent", "pharmacologically active agent", "physiologically active agent", "drug substance", "drug in physiologically active form", or "pharmaceutically acceptable derivatives of the drug substance" are used interchangeably herein to refer to a chemical compound that induces a desired pharmacological or physiological effect or biological activity. The terms pharmaceutically acceptable derivatives of the drug substance mentioned herein include, but are not limited to, salts, ethers, stereo-isomer solvates, polymorphs, hydrates, complexes with one or more molecules, complexes with one or more cationic or anionic ingredients, drug-ion exchange resin complexes, prodrugs, active metabolites, analogues, homologues, and the like. The term drug substance is also meant to encompass the use of all such possible forms as well as their racemic and resolved forms thereof and all tautomers as well. The term "racemic" refers to a mixture of equal parts of enantiomers. In certain embodiments, said drug is in either salt or base form. In some embodiments, said drug is present in powder form, in amorphous form, in crystalline form, in micronized form, in complexes with one or more molecules, in combination of two or more active substances, or any combination thereof. In some embodiments, said drug is present in the form of a pharmaceutically acceptable derivative, wherein the pharmaceutically acceptable derivative is a drug-ion exchange resin, complexes with one or more cationic or anionic ingredients, or is coated on a seed core. In certain embodiments, said drug is associated with abuse syndromes; therefore, said drug may, for example, be selected from opioids, opiates, CNS depressants or sedatives, anxiolytics, narcotics, tranquillizers, barbiturates, hormones, CNS stimulants, cannabinoids, nicotine-like compounds, glutamate antagonists, N-methyl-D-aspartate (NMDA) antagonists, or drugs that can cause psychological and/or physical dependence. Drugs that are preferred include those classified as Schedule I, II, III, IV, and V drugs based upon the substance's medicinal value, harmfulness, and potential for abuse or addiction under the Control Substance Act of the United States.

[0028] The term "multi-particulate", “particles”, “coated particles”, or "particulates" is used interchangeably to refer to a discrete, small, repetitive unit of particle, granule, pellet, bead, mini-tablet, mini-capsule, complex, or any combination thereof that comprises at least one material (such as an inactive ingredient, polymer, pharmaceutical additive, etc.) and, optionally, at least one of a drug, an antagonist, and an alkalizing agent. The multiarticulate can be filled into a capsule, compressed to form a larger tablet, or uniformly suspended in a liquid vehicle. In certain embodiments, the preferable size of particulate can be less than about 5mm, less than 4mm, less than 3mm, less than 2mm, less than 1.5mm, or any size between 5 microns to 5mm.

[0029] The term "coat" refers to a coating, layer, membrane, film, etc. applied to a surface and, in certain embodiments, can partially, substantially, or completely surround, envelop, cover, enclose, or encase the surface (e.g., an outer surface of core(s) or intermediated coated parti cle(s)) to which it is applied. For example, a coat can cover portions of the surface to which it is applied, e.g., as a partial layer, partial coating, partial membrane, or partial film, or it can completely cover the surface to which it is applied. [0030] The term "reverse enteric coat," as used herein, refers to a coat comprising a reverse enteric polymer. The term "reverse enteric polymer," as used herein, refers to a polymer that is soluble at the pH of acidic gastric fluids but is insoluble, or alternatively, swells or gels at the pH of the small intestine. Typically, the pH at which said "reverse enteric polymer" will dissolve in the normal physiological pH (e.g., the range of normal physiological pH values) of the acidic gastric fluid is below about 5. Typically, the reverse enteric polymer swells, gels, dissolves or degrades more slowly, or to only a small extent, when present in a solution with a pH that is slightly less acidic or not acidic, such as at a pH above about 5, above about 6, or above about 7. It will be understood that the reverse enteric polymer can be used to prepare a coat that is designed to dissolve or degrade (partially or substantially) within any desired pH range and not dissolve or degrade (partially or substantially) within any desired pH range. For example, the coat comprising said reverse enteric polymer can be designed to dissolve at pH, e.g., below about 5, but above that pH level, its dissolution is inhibited, reduced, retarded, or slowed. As the pH increases, the dissolution/degradation can slow further and may stop nearly completely. The coat comprising said reverse enteric polymer affects the rate of release, in vitro or in vivo, of said drug and/or an antagonist. [0031] The term "enteric coat", as used herein, refers to a coat comprising an enteric polymer. The term "enteric polymer", as used herein, refers to a polymer that is soluble at the pH of intestinal fluids but is insoluble, or alternatively, swells or gels, at the pH of acidic gastric fluid. Typically, the pH at which said "enteric polymer" will dissolve in the normal physiological pH of the intestinal fluid is greater than about 5. Typically, the enteric polymer remains stable in the highly acidic pH environment of the stomach but breaks down/dissolves at a less acidic (relatively more basic) pH (such as > about 5). For example, an enteric coat will not dissolve in the stomach (at < about 5) but will break down/dissolve in the basic pH environment of the small intestine (at > about 5). In addition, an enteric coat will break down/dissolve in the stomach if the environment of the stomach becomes less acidic (i.e., relatively more basic, such as a pH rise greater than about 5), as can occur in the presently disclosed subject matter in the overdosing condition when multiple or non-prescribed units release sufficient alkalizing agent.

[0032] The term "alkalizing agent", "alkaline agent", or "buffering agent" can be used to refer to an excipient that acts to increase the pH of, e.g., the gastric fluid (e.g., roughly about pH 1.2-5) to a pH greater than about 5.5. For example, the alkaline agent can refer to substances that are capable of increasing the pH to greater than 5.0, greater than 5.5, greater than 6.0, etc. It also refers to basic substances and substances that can convert an acidic environment to a less acidic or basic environment. Typically, these agents, when present in a sufficient amount, such as in an overdosing condition, are able to raise the pH of the stomach to beyond their physiological level, such as greater than about 5, and thereby prevent, reduce, or inhibit the dissolution/solubilization of a reverse enteric coat.

[0033] The term "pH-stabilizing agent" refers to salts of weak acids or weak bases that act to maintain or stabilize the elevated pH of gastric fluid caused by the alkaline agent. For example, a pH-stabilizing agent(s) maintains the pH of the gastric fluid at a pH greater than about 5.5 for a finite time.

[0034] The term "gelling ingredient", as used herein, refers to an ingredient that increases the viscosity of aqueous or non-aqueous media. [0035] The term "water-insoluble polymer" refers to a polymer generally insoluble in water (across all pH) and physiological fluids. The term "water-insoluble material" refers to a pharmaceutically acceptable excipient, including polymers that are generally insoluble in water and physiological fluids.

[0036] The term "water-soluble polymer" refers to a polymer generally soluble in water and physiological fluids. The term "water-soluble material" refers to a pharmaceutically acceptable excipient, including polymers that are generally soluble in water and physiological fluids.

[0037] The term "antagonist" is used herein to refer to an agent that, when available in an effective amount, reduces the drug-linking effect and/or potential detrimental consequences of an overdose of a drug.

[0038] The term "effective amount" refers to an amount that produces the intended effect of a drug or antagonist. With respect to the drug, the intended effect is to treat a disease condition or therapeutic condition in the patient. With respect to the antagonist, the intended effect is to elicit (a) a desired drugliking effect in the subject that is not directly related to treating a disease condition and/or (b) potential detrimental consequences of an overdose of the drug, such as death. The effective amounts of different drugs and antagonists vary from each other, and thus those skilled in the art can adjust such amounts in accordance with standard practices as needed to treat a specific subject and/or condition/disease.

[0039] The term "in-vitro dissolution", "in-vitro dissolution testing", or "dissolution" refers to testing to evaluate the rate and extent of release of a drug and an antagonist from single or multiple units of the drug-antagonist combination dosage form in 50ml/100ml/500ml/900 ml of 0.1N/0.01N/0.001N HC1 at 37°±1°C, with or without sinker, in either USP Apparatus 2 (paddle) at 50 rpm, USP Apparatus 1 (basket) at 100 rpm, USP apparatus 7 (5-30 DPM). The in-vitro dissolution in 50ml/100ml/500ml/900 ml of 0.1N/0.01N/0.001N HC1 can be used to mimics the in vivo performance of single or multiple units of the combination dosage form(s) in the stomach environment.

[0040] The "%w/w", "wt.%", or "%wt." refers to percentage by weight.

[0041] The term "biphasic amount" refers to the distribution (in any proportion) of the overall dose or amount of an antagonist into two different phases or two different particulates (such as non-retarding or retarding particulates or both). For example, a first phase amount of the antagonist is included in nonretarding particulates and a second phase amount of the antagonist is included in retarding particulates or any particulates other than the non-retarding particulates.

[0042] In certain embodiments, the presently disclosed subject matter relates to a drug-antagonist combination dosage form, a method for preparing the dosage form, and a method of administering the dosage form to treat a disease or therapeutic condition. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended- release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists, wherein the dosage form provides two- stage protection in an overdose condition: the first stage is to retard the release of the drug from the dosage forms, and the second stage is to make the antagonist available in an effective amount if the dosage forms fail to retard the drug release in the overdose condition. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended-release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists, wherein the antagonist shows a dose-dependent effect. It is well known that below the minimum effective concentration, an antagonist or a drug should not produce its desired pharmacologic response. The presently disclosed subject matters utilize this principle. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended- release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists, wherein the amount of the antagonist included in the combination dosage form is not sufficient to suppress the drug’s intended therapeutic effect when a single or prescribed units of said combination dosage form is administered in an intact form to a subject. In certain embodiments, the presently disclosed subject matter provides an oral, multiparticulate, extended-release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists that releases the effective amount of the drug to produce its intended therapeutic effect and makes the antagonist available in an amount that is not sufficient to suppress the drug’s intended therapeutic effect when a single or prescribed units of said combination dosage form is administered in the intact form to a subject. It is further reported that below the minimum effective concentration, an antagonist does not produce its desired drug antagonism pharmacologic response but may reduce a side/adverse effects associated with the drug, for example, TARGINIQ ER is US FDA approved (currently discontinued) combination product consisting of oxycodone, an opioid agonist, and naloxone, an opioid antagonist, indicated for the management of severe pain, wherein the oxycodone is incorporated in an amount that is sufficient to treat sever pain but the amount of naltrexone is not sufficient to antagonize the drug therapeutic effect but is sufficient to reduce the side/adverse effect associated with oxycodone such as oxycodone induced constipation. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended-release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists that releases the effective amount of the drug to produce its intended therapeutic effect and makes the antagonist available in an amount that is not sufficient to suppress the drug’s intended therapeutic effect but sufficient to reduce the side/adverse effect associated with the drug when a single or prescribed units of said combination dosage form is administered in an intact form to a subject. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended-release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists, wherein the amount of the antagonist included in the combination dosage form is sufficient to reduce the drug’s liking effect when a single or prescribed units of said combination dosage form is administered in the manipulated form to a subject. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended-release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists that retard the release of the drug when multiple units of said combination dosage form are administered together. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended- release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists, wherein the amount of the antagonist included in the combination dosage form is sufficient to reduce the drug’s liking effect when multiple units of said combination dosage form are administered together. In certain embodiments, the presently disclosed subject matter provides an oral, multi-particulate, extended-release, drug-antagonist combination dosage form comprising one or more drugs and one or more antagonists that release the antagonist in an effective amount to reduce the drug's liking effect when multiple units of said combination dosage form are administered together.

[0043] In certain embodiments, an oral, multi-particulate, extended-release, drug-antagonist combination dosage form with overdose protection property comprising: a) a therapeutically effective amount of at least one drug, b) a biphasic amount of at least one antagonist, and c) an alkalizing agent; wherein the drug and a first phase amount of the antagonist are included in non-retarding particulates, wherein said non-retarding particulates comprising coated particulates, wherein each coated particulate comprising:

(a) an immediate or extended-release particulate comprising at least one of the drug and the antagonist, and

(b) a reverse enteric coat surrounding the immediate or extended-release particulate, wherein the reverse enteric coat comprises a reverse enteric polymer and optionally a water insoluble material; wherein a second phase amount of said antagonist is included in retarding particulates, wherein said retarding particulates comprising coated particulates, wherein each coated particulate comprising:

(a) an immediate or extended-release particulate comprising the antagonist,

(b) a reverse enteric coat surrounding the particulate, wherein the reverse enteric coat comprising a reverse enteric polymer and optionally a water insoluble material, and (c) an enteric coat surrounding said reverse enteric coat, wherein the enteric coat comprising an enteric polymer, and optionally, a water insoluble material; wherein said combination dosage form when subjected to in-vitro dissolution testing at 37°±1°C in 900ml of 0.01N HC1 in a USP Apparatus 2 (paddle) at 50 rpm or a USP Apparatus 1 (basket) at 100 rpm, the non- retarding particulates of the combination dosage form releases the first phase amount of the antagonist with the drug at the same or different release rate and the retarding particulates of the combination dosage form retards the release of the second phase amount of the antagonist.

[0044] In certain embodiments, an oral, multi-particulate, extended-release, drug-antagonist combination dosage form with overdose protection property comprising: a) a therapeutically effective amount of at least one drug, b) at least one antagonist, and c) an alkalizing agent; wherein the drug is included in non-retarding particulates, wherein said non-retarding particulates comprising coated particulates, wherein each coated particulate comprising: a) an immediate or extended-release particulate comprising at least one drug, and b) a reverse enteric coat surrounding the particulate, wherein the reverse enteric coat comprising a reverse enteric polymer, and optionally, a water insoluble material; wherein the antagonist is included in retarding particulates, wherein said retarding particulates comprising coated particulates, wherein each coated particulate comprising: a) an immediate or extended-release particulate comprising at least one antagonist, b) a reverse enteric coat surrounding the particulate, wherein the reverse enteric coat comprising a reverse enteric polymer, and optionally, a water insoluble material, and c) an enteric coat surrounding the reverse enteric coat, wherein the enteric coat comprising an enteric polymer, and optionally, a water insoluble material; wherein the combination dosage form when subjected to in-vitro dissolution testing at 37°±1°C in 900ml of 0.01N HC1 in a USP Apparatus 2 (paddle) at 50 rpm or a USP Apparatus 1 (basket) at 100 rpm, the non-retarding particulates of the combination dosage form releases the drug, and the retarding particulates of the combination dosage form retard the release of the antagonist.

[0045] In certain embodiments, an oral, multi-particulate, extended-release, drug-antagonist combination dosage form with overdose protection property comprising: a) a therapeutically effective amount of at least one drug, b) a first antagonist, c) a second antagonist, and d) an alkalizing agent; wherein the drug and the first antagonist are included in non-retarding particulates, wherein the non-retarding particulates comprising coated particulates, wherein each coated particulate comprising: a) an immediate or extended-release particulate comprising the drug, the first antagonist, or combination thereof, and b) a reverse enteric coat surrounding the particulate, wherein the reverse enteric coat comprising a reverse enteric polymer, and optionally, a water insoluble material; wherein the second antagonist is included in retarding particulates, wherein the retarding particulates comprising coated particulates, wherein each coated particulate comprising: a) an immediate or extended-release particulate comprising the second antagonist, b) a reverse enteric coat surrounding the particulate, wherein the reverse enteric coat comprising a reverse enteric polymer, and optionally, a water insoluble material, and c) an enteric coat surrounding the reverse enteric coat, wherein the enteric coat comprising an enteric polymer, and optionally, a water insoluble material; wherein the combination dosage form when subjected to in-vitro dissolution testing at 37°±1°C in 900ml of 0.01N HC1 in a USP Apparatus 2 (paddle) at 50 rpm or a USP Apparatus 1 (basket) at 100 rpm, the non-retarding particulates of the combination dosage form releases the first antagonist with the drug at the same or different release rate and the retarding particulates of the combination dosage form retard the release of the second antagonist.

[0046] In certain embodiments, an oral, multi-particulate, extended-release, drug-antagonist combination dosage form with overdose protection property comprising: a) a therapeutically effective amount of at least one drug, b) at least one antagonist, and c) an alkalizing agent; wherein the drug and the antagonist are included in non-retarding particulates, wherein the nonretarding particulates comprising coated particulates, wherein each coated particulate comprising: a) an immediate or extended-release particulate comprising at least one of the drug and the antagonist, and b) a reverse enteric coat surrounding the particulate, wherein the reverse enteric coat comprising a reverse enteric polymer, and optionally, a water insoluble material; wherein said combination dosage form when subjected to in-vitro dissolution testing at 37°±1°C in 900ml of 0.01N HC1 in a USP Apparatus 2 (paddle) at 50 rpm or a USP Apparatus 1 (basket) at 100 rpm, the non-retarding particulates of the combination dosage form releases the antagonist with the drug at the same or different release rate.

[0047] In certain embodiments, the non-retarding particulates, the retarding particulates, and alkalizing agent particulates can be prepared in several ways known to those in the art, including various granulation approaches such as wet granulation, dry granulation, melt granulation, top spray granulation, hot melt extrusion process, compression, film melt, granulation, melt granulation, extrusion spheronization, coating, imprinting, or any combination thereof.

[0048] In any of the previous embodiments, the immediate or extended-release particulate of the nonretarding particulates comprising at least one of the drug and the antagonist (here "antagonist" refers to any antagonist such as an antagonist, first antagonist, or antagonist from the first phase amount as discussed in any of the previous embodiments) can be prepared by any method known to those of skill in the art, and therefore the method of preparation does not limit the scope of the presently disclosed subject matter. For example, the immediate-release particulate comprising at least one of the drug and the antagonist can be prepared by any method known to those of skill in the art, and therefore a method of fabricating said immediate-release particulate does not limit the scope of the presently disclosed subject matter. In one example, said immediate-release particulate includes a matrix system (such as mini-tablets or beads such as pellets prepared by the extrusion and spheronization technique), in which at least one of the drug and the antagonist is embedded (suspended or dispersed) within the matrix of at least one of a water-soluble material and a water-insoluble material. In another example, the immediate- release particulate includes an inert core. The inert core may be prepared using techniques known to those skilled in the art, including, but not limited to, the drug or the antagonist as such in particle(s) form; a forming complexation of the drug or the antagonist with ion-exchange resin (drug/antagonist-ion exchange resin complex); by preparing granule(s) comprising at least one of the drug, the antagonist, water soluble material and water insoluble material; prepared by building a coat (by any methods such as drug layering technique or spraying coating solution/dispersion) of at least one of the drug and the antagonist on a seed core (such as a non-pareil seed, sugar sphere, microcrystalline cellulose sphere, silicon dioxide, magnesium silicate, calcium silicate, etc.,); prepared by extrusion-spheronisation technique using other suitable ingredients; by adsorbing a solution comprising at least one of the drug and the antagonist, and optionally at least one of water soluble material and water insoluble material, on a seed core or porous material such as colloidal silica, cellulose particles; and like. Therefore, a method of fabricating said immediate-release particulate is not of critical importance and thus does not limit the scope of the presently disclosed subject matter. Similarly, the extended-release particulate comprising at least one of the drug and the antagonist can be prepared by any method known to those of skill in the art, and therefore a method of fabricating said extended-release particulate does not limit the scope of the presently disclosed subject matter. In one example, said extended-release particulate includes a matrix system (such as mini-tablets or beads such as pellets prepared by the extrusion and spheronization technique), in which at least one of the drug and the antagonist is embedded (suspended or dispersed) within the matrix of at least one of the water-insoluble material and the water-soluble material. In another example, said extended-release particulate includes a reservoir system in which an inert core comprising at least one of the drug and the antagonist is surrounded by a water insoluble coat. The inert core may be prepared using techniques known to those skilled in the art, including, but not limited to, the drug or the antagonist as such in particle(s) form; a forming complexation of the drug or the antagonist with ion-exchange resin (drug/antagonist-ion exchange resin complex); by preparing granule(s) comprising at least one of the drug, the antagonist, water soluble material and water insoluble material; prepared by building a coat (by any methods such as drug layering technique or spraying coating solution/ dispersion) of at least one of the drug and the antagonist on a seed core (such as a non-pareil seed, sugar sphere, microcrystalline cellulose sphere, silicon dioxide, magnesium silicate, calcium silicate, etc.,); prepared by extrusion-spheronisation technique using other suitable ingredients; by adsorbing a solution comprising at least one of the drug and the antagonist, and optionally at least one of water soluble material and water insoluble material, on a seed core or porous material such as colloidal silica; and like. In certain embodiments, the water insoluble coat can be non-porous, yet permeable to at least one of the drug and the antagonist, or it may be porous. In certain embodiments, the water-insoluble coat can be permeable or porous, wherein the porosity of the coat may be adjusted by incorporating a pore former in the coating film. In certain embodiments, the pore former includes water-soluble material, and the amount of pore former in the water-insoluble coat is not more than about 75% w/w of the water-insoluble coat. Therefore, a method of fabricating said extended-release particulate is not of critical importance and thus does not limit the scope of the presently disclosed subject matter.

[0049] In any of the previous embodiments, the immediate or extended-release particulate of the retarding particulates comprising the antagonist (here "antagonist" refers to any antagonist such as an antagonist, second antagonist, or antagonist from the second phase amount as discussed in any of the previous embodiments) can be prepared by any method known to those of skill in the art, and therefore the method of preparation does not limit the scope of the presently disclosed subject matter. For example, the immediate release particulate comprising the antagonist can be prepared by any method known to those of skill in the art, and therefore a method of fabricating said immediate-release particulate does not limit the scope of the presently disclosed subject matter. In one example, said immediate-release particulate includes a matrix system (such as mini-tablets or beads such as pellets prepared by the extrusion and spheronization technique), in which at least one antagonist is embedded (suspended or dispersed) within the matrix of at least one of a water-soluble material and a water-insoluble material. In another example, the immediate-release particulate includes an inert core. The inert core may be prepared using techniques known to those skilled in the art, including, but not limited to, the antagonist as such in particle(s) form; a forming complexation of the antagonist with ion-exchange resin (antagonist-ion exchange resin complex); by preparing granule(s) comprising at least one of the antagonist, water soluble material and water insoluble material; prepared by building a coat (by any methods such as drug layering technique or spraying coating solution/dispersion) of at least one antagonist on a seed core (such as a non-pareil seed, sugar sphere, microcrystalline cellulose sphere, silicon dioxide, magnesium silicate, calcium silicate, etc.,); prepared by extrusion-spheronisation technique using other suitable ingredients; by adsorbing a solution comprising at least one antagonist, and optionally at least one of water soluble material and water insoluble material, on a seed core or porous material such as colloidal silica, cellulose particles; and like. Therefore, a method of fabricating said immediate-release particulate is not of critical importance and thus does not limit the scope of the presently disclosed subject matter. Similarly, the extended-release particulate comprising at least one antagonist can be prepared by any method known to those of skill in the art, and therefore a method of fabricating said extended-release particulate does not limit the scope of the presently disclosed subject matter. In one example, the extended-release particulate includes a matrix system (matrix particles such as mini-tablets, or beads such as pellets prepared by the extrusion and spheronization technique, or matrix coat surrounding the inert core or placebo particle or bead), in which at least one antagonist is embedded (suspended or dispersed) within the matrix of at least one of the water-insoluble material and the water-soluble material. In another example, the extended-release particulate includes a reservoir system, in which an inert core comprising at least one antagonist is surrounded by a water insoluble coat. The inert core may be prepared using techniques known to those skilled in the art, including, but not limited to, the antagonist as such in particle(s) form; a forming complexation of the antagonist with ionexchange resin (antagonist-ion exchange resin complex); by preparing granule(s) comprising at least one of the antagonist, water soluble material and water insoluble material; prepared by building a coat (by any methods such as drug layering technique or spraying coating solution/dispersion) of at least one antagonist on a seed core (such as a non-pareil seed, sugar sphere, microcrystalline cellulose sphere, silicon dioxide, magnesium silicate, calcium silicate, etc.,); prepared by extrusion-spheronisation technique using other suitable ingredients; by adsorbing a solution comprising at least one antagonist, and optionally at least one of water soluble material and water insoluble material, on a seed core or porous material such as colloidal silica; and like. In certain embodiments, the water insoluble coat can be non-porous yet permeable to at least one antagonist, or it may be porous. In certain embodiments, the water- insoluble coat can be permeable or porous, wherein the porosity of the coat may be adjusted by incorporating a pore former in the coating film. In certain embodiments, the pore former includes water- soluble material, and the amount of pore former in the water-insoluble coat is not more than about 75% w/w of the water insoluble coat. Therefore, a method of fabricating said extended-release particulate is not of critical importance and thus does not limit the scope of the presently disclosed subject matter.

[0050] In some embodiments, each coated particulate of the non-retarding particulates further comprising an intermediate coat surrounding the immediate or extended-release particulate and prior to applying the reverse enteric coat. In certain embodiments, said intermediate coat comprising a reverse enteric polymer, a water-soluble material, a water insoluble material, or any combination thereof. In some embodiments, each coated particulate of the non-retarding particulates further comprising an outer coat surrounding the reverse enteric coat. In certain embodiments, said outer coat comprising a reverse enteric polymer, a water-soluble material, a water-insoluble material, or any combination thereof. In some embodiments, each coated particulate of the non-retarding particulates further comprising nonfunctional coat surrounding the reverse enteric coat or the outer coat. In certain embodiments, said nonfunctional coat comprising essentially water-soluble material, optionally with colorant.

[0051] In some embodiments, each coated particulate of the retarding particulates further comprising an intermediate coat surrounding the immediate or extended-release particulate and prior to applying the reverse enteric coat. In certain embodiments, said intermediate coat comprising a reverse enteric polymer, a water-soluble material, a water-insoluble material, or any combination thereof. In some embodiments, each coated particulate of the retarding particulates further comprising an intermediate coat surrounding the reverse enteric coat and prior to applying the enteric coat. In certain embodiments, said intermediate coat comprising a reverse enteric polymer, a water-soluble material, a water insoluble material, or any combination thereof. In some embodiments, each coated particulate of the retarding particulates further comprising an outer coat surrounding the enteric coat. In certain embodiments, said outer coat comprising an enteric polymer, a water-soluble material, a water-insoluble material, or any combination thereof. In some embodiments, each coated particulate of the retarding particulates further comprising a non-functional coat surrounding the enteric coat or the outer coat. In certain embodiments, said non-functional coat comprising essentially water-soluble material, optionally with colorant.

[0052] In certain embodiments, at least one of the reverse enteric coat, the enteric coat, the water insoluble coat, the intermediate coat, and the outer coat can be present in a range of about 0.1% to about 75% w/w of the total weight of the combination dosage form.

[0053] In certain embodiments, the composition of at least one of the reverse enteric coat, the enteric coat, the water-insoluble coat, the intermediate coat, and the outer coat further includes plasticizer. The selection of plasticizer mainly depends on the polymer used for the respective coat, and thus the plasticizers can be the same or different from each other in a similar or different coating composition. In certain embodiments, the amount of the plasticizer, when present in any of the coat compositions, can range from about 0.0001% to about 50% w/w of the total weight of the respective coat composition or the combination dosage form.

[0054] In certain embodiments, the composition of at least one of the reverse enteric coat, the enteric coat, the water-insoluble coat, the intermediate coat, and the outer coat further includes an anti-tacking agent. A selection of the anti-tacking agent mainly depends on the polymer used for the respective coat, and thus the anti-tacking agents can be the same or different from each other in similar or different coating compositions. In certain embodiments, the amount of the anti-tacking agent, when present in any of the coat compositions, can range from about 0.0001% to about 50% w/w of the total weight of the respective coat composition or the combination dosage form.

[0055] In certain embodiments, the composition of at least one of the reverse enteric coat, the enteric coat, the water-insoluble coat, the intermediate coat, and the outer coat further includes surfactant. In certain embodiments, the amount of the surfactant, when present in any of the coat compositions, can be at least 0.0001% w/w of the total weight of the respective coat composition or the combination dosage form.

[0056] In certain embodiments, the composition of at least one of the reverse enteric coat, the enteric coat, the water-insoluble coat, the intermediate coat, and the outer coat further includes at least one of the drug and the antagonist. In certain embodiments, the amount of at least one of the drug and the antagonist, if present in any of the coat compositions, can range from about 0.0001% to about 50% w/w of the total weight of the respective coat composition or the combination dosage form.

[0057] In certain embodiments, the composition of at least one of the reverse enteric coat, the enteric coat, the water-insoluble coat, the intermediate coat, and the outer coat further includes one or more solvents (both aqueous and/or organic) and/or one or more other excipients.

[0058] In certain embodiments, said combination dosage form further comprising deterrent particulates, wherein said deterrent particulates comprising coated particulates, wherein each coated particulate comprising: (a) a particulate comprising an antagonist, and (b) a water-insoluble coat surrounding said particulate, wherein the water-insoluble coat comprising an essentially water-insoluble material. The water-insoluble coat retards the release of the antagonist. The particulate comprising the antagonist can be prepared by any method known to those of skill in the art, and therefore, a method of fabricating said particulate does not limit the scope of the presently disclosed subject matter. For example, said particulate of the antagonist includes a matrix system (such as matrix particles like mini-tablets, or beads such as pellets prepared by the extrusion and spheronization technique, or a matrix coat surrounding the inert core particle (placebo pellet or bead)), in which the antagonist is embedded (suspended or dispersed) within the matrix of at least one of water-soluble material and water-insoluble material. In another example, said particulate of the antagonist includes an inert core. The inert core may be prepared using techniques known to those skilled in the art, including, but not limited to, the antagonist as such in particle(s) form; the antagonist in granule(s) form; a forming complexation of the antagonist with ionexchange resin (antagonist-ion exchange resin complex); prepared by building a coat of the antagonist on a seed core (such as a non-pareil seed, sugar sphere, microcrystalline cellulose sphere, silicon dioxide, magnesium silicate, calcium silicate, etc.) by layering of the antagonist; spraying a solution or dispersion of the antagonist onto the seed cores; prepared by extrusion-spheronization technique using other suitable ingredients; and like. Therefore, a method of fabricating said particulate of the antagonist is not of critical importance and thus does not limit the scope of the presently disclosed subject matter. In a further embodiment, said coated particulate further comprising an intermediate coat surrounding the particulate prior to applying the water-insoluble coat. In a further embodiment, said coated particulate further comprising an outer coat surrounding the said water-insoluble coat. The intermediate coat and/or the outer coat comprising at least one of water-soluble material and water-insoluble material. In some embodiments, each coated particulate of the deterrent particulates further comprising a non-functional coat surrounding the water-insoluble coat or the outer coat. In some embodiments, said non-functional coat comprising essentially water-soluble material, optionally with colorant.

[0059] In certain embodiments, said combination dosage form further comprising at least one pH- stabilizing agent. In certain embodiments, the pH-stabilizing agent acts to maintain or stabilize the increased pH caused by the alkalizing agent. In certain embodiments, the pH-stabilizing agent is included in the combination dosage form in an amount that results in about little or no major incremental change (maintaining the pH below about 5.5) in the pH of 900 ml of 0.01N HC1 when said combination dosage form is subjected to in-vitro dissolution testing. In certain embodiments, the pH-stabilizing agent is present in an amount that does not alter the pH of the gastric fluid in a normal dosing condition, but maintains or extends the elevated pH levels caused by the alkaline agent in the overdose condition. In certain embodiments, the pH-stabilizing agent is present in an amount sufficient to maintain or extend the pH of the gastric fluid above about 5.5 in the overdose condition for a period of at least about 0.5 hour, at least about 1 hour, preferably at least about 2 hours, more preferable at least about 3 hours, and most preferably at least about 5 hours.

[0060] In certain embodiments, the amount of the drug included in the non-retarding particulates or the combination dosage form is at least sufficient to produce its intended therapeutic purpose in a subject in need thereof. These amounts are well known in the arts. Indeed, the doses at which any of the presently known drugs embraced by the present can be given safely and effectively for the intended therapeutic purpose are known to those of skill in the art. In certain embodiments, the drug is present in an amount ranging from about 0.1% to about 75% w/w of the combination dosage form. In certain embodiments, the drug is present in an amount of about 0.2% to about 75%, about 0.3% to about 70%, about 0.4% to about 65%, about 0.5% to about 60%, about 0.6% to about 60%, about 0.7% to about 55%, about 0.8% to about 50%, about 0.9% to about 45%, about 1% to about 40%, about 2.5% to about 40%, about 5% to about 40%, about 7.5% to about 35%, about 10% to about 35%, about 12.5% to about 35%, or about 15% to about 35% w/w of the combination dosage form. In certain embodiments, the drug is present in an amount of at least about 0.1%, at least about 0.2%, at least about 0.5%, at least about 1%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% w/w of the combination dosage form.

[0061] In certain embodiments, the drugs are prone to abuse, misuse, and/or overdose. In certain embodiments, the drug can include, without limitation, members of the therapeutic categories such as analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, antiviral agents, anticoagulants, anti-depressants, anti-diabetic agents, anti-epileptic agents, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarial agents, anti-migraine agents, anti- muscarinic agents, anti-neoplastic agents, erectile dysfunction improving agents, immunosuppressants, anti-protozoa agents, anti-thyroid agents, anti-anxiolytic agents, sedatives, hypnotics, neuroleptics, 0- blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-Parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid-regulating agents, anti-angina agents, cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, nonessential fatty acids, and any combinations of two or more thereof.

[0062] In certain embodiments, the drug is associated with abuse syndromes; therefore, said drug may, for example, be selected from opioids, opiates, CNS depressants or sedatives, anxiolytics, narcotics, tranquillizers, barbiturates, hormones, CNS stimulants, cannabinoids, nicotine-like compounds, glutamate antagonists, N-methyl-D-aspartate (NMD A) antagonists, or drugs that can cause psychological and/or physical dependence. Drugs that are preferred include those classified as Schedule I, II, III, IV, and V drugs based upon the substance's medicinal value, harmfulness, and potential for abuse or addiction under the Control Substance Act of the United States.

[0063] In certain embodiments, the drug can be an opioid in a free base form or a pharmaceutically acceptable salt thereof. For example, but not limited to, the opioid can be alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydromorphodone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, nomiethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, pantopon, papaveretum, paregoric, pentazocine, phenadoxone, phendimetrazine, phendimetrazone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, propylhexedrine, sufentanil, tapentadol, tilidine, tramadol, pharmaceutically acceptable salts thereof.

[0064] In certain embodiments, the drug can include, but are not limited to, benzodiazepines (e.g., bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam), barbiturates (e.g., amobarbital, aprobarbital, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital), and stimulants, such as amphetamines (e.g., amphetamine, dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate), as well as dronabinol, glutethimide, methylprylon, ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline, levomethadyl, benzphetamine, chlorphentermine, diethylpropion, phentermine, mebutamate, chlortermine, phenylacetone, dronabinol, nabilone, chloral hydrate, ethclorovynol, paraldehyde, midazolam, and dextropropoxyphene, or pharmaceutically acceptable salts thereof.

[0065] In certain embodiments, the drug can include, but are not limited to, 1-(1- Phenylcyclohexy l)pyrrolidine, 1 -(2-Pheny lethyl)-4-pheny 1-4-acetoxypiperidine, 1 - [ 1 -(2-Thieny 1)- cyclohexyl]piperidine, l-[l-(2-Thienyl)cyclohexyl]pyrrolidine, 1 -Methyl-4-phenyl-4-propionoxy- piperidine, 1 -Phenylcyclohexylamine, 1-Piperidinocyclohexanecarbonitrile, 2,5-Dimethoxy-4- ethylamphetamine, 2,5-Dimethoxyamphetamine, 2C-B-(4-bromo-2,5-dimethoxypenethylamine), 2C-D (2,5-dimethoxy-4-methylphenethylamine), 2C-I (4-iodo-2,5-dimethoxy-phenethylamine), 2C-T-2 (2,5- dimethoxy-4-ethylthiophenethylamine), 2C-T-4 (2,5-dimethoxy-4-isopropyl thiophenethylamine), 2C- T-7 (2,5-dimethoxy-4-(n)-propylthiopenethylamine), 3,4-Methylene-dioxymethamphetamine, 3,4,5- Trimethoxy amphetamine, 3,4-Methylenedioxyamphetamine, 3,4-Methylenedioxy-N- ethylamphetamine, 3 -Methylfentanyl, 3 -Methylthiofentanyl, 4-Bromo-2,5-dimethoxyamphetamine, 4- Bromo-2,5-dimethoxyphenethylamine, 4-Methoxyamphetamine, 4-Methyl-2,5- dimethoxyamphetamine, 4-Methylaminorex (cis isomer), 5-MeO-DMT (5-Methoxy-N,N- diisopropyltryptamine), 5-MeO-DMT (5-Methoxy-N,N-dimethyltryptamine), 5-Methoxy-3,4- methylenedioxyamphetamine, Acetorphin, Acetorphine, Acetyl-alpha-methylfentanyl, Acetyl-alpha- methylfentanyl, Acetyldihydrocodeine, Acetylmethadol, Acetylmethadol, anileridine, Alfentanil, Allobarbital, Allylprodin, Allylprodine, Alphacetylmethadol except levo-alphacetylmethadol, Alphaethyltryptamine, Alphameprodine, Alphamethadol, Alphamethadol, Alpha-Methylfentanyl, Alpha- Methylthiofentanyl, Alphaprodine, Alprazolam, Amfepramon, Amfetaminil, Amineptin, Aminorex, Amobarbital, amfepramone, Amphetamine, amphetaminil, Amylnitrit (all isomers of the amyl group), Anabolic steroids, Anileridine, apocodeine, Aprobarbital, Barbital, Barbituric acid derivative, BDB (3,4- methylenedioxyphenyl)-2-butanamine), Benzethidin, Benzethidine, Benzoylecgonine, Benzphetamine, Benzphetamine, Benzylmethylketon, Benzylmorphine, Betacetylmethadol, Beta-Hydroxy-3 - methylfentanyl, Beta-Hydroxyfentanyl, Betameprodine, Betameprodine, Betamethadol, Betaprodine, Bezitramide, Boldenone, Brolamfetamin, Bromazepam, Brotizolam, Bufotenine, Buprenorphine, Butabarbital, Butalbital, Butobarbital, Butorphanol, BZP (A 2)(l-benzylpiperazin), Camazepam, Cannabis, Carfentanil, carfentanyl, Catha edulis, Cathine, Cathinone, Chloral betaine, Chloral hydrate, Chlordiazepoxide, Chlorhexadol, Chlorotestosterone (same as clostebol), Chlorphentermine, Clobazam, Clonazepam, Clonitazene, Clorazepate, Clortermine, Clostebol, Clotiazepam, Cloxazolam, Coca Leaves, Cocaine, Codeine, Codeine &isoquinoline alkaloid, Codeine methylbromide, Codeine-N-oxide, Codoxim, cyclorphan, Cyclobarbital (Hexemal NFN), cyclazocine, Cyprenorphine, Dehydrochlormethyltestosterone, Delorazepam, Desomorphine, Dexamfetamine, dexamphetamine, dexmethylphenidate, Dexfenfluramine, Dextromoramide, dextromethorphan, Dextropropoxyphene, dezocine, Diacetylmorphine, diamorphone, Diampromide, diapromide, Diazepam, Dichloralphenazone, Diethylpropion, Diethylthiambutene, Diethyltryptamine, Difenoxin, Dihydrocodeine,

Dihydroetorphine, Dihydromorphine, Dihydrotestosterone, dimephetanol, Dimenoxadol, Dimepheptanol, Dimethylthiambutene, Dimethyltryptamine, Dioxaphetyl butyrate, Diphenoxylate, Dipipanone, Diprenorphine, Dronabinol, Drostanolone, Drotebanol, Ecgonine, eptazocine, Estazolam, Ethchlorvynol, Ethinamate, ethoheptazine, Ethyl loflazepate, Ethylestrenol, Ethylmethylthiambutene, Ethylmorphine, Eticyclidin, Etilamfetamine, Etonitazene, Etorphine, Etoxeridine, Etryptamine, Fencamfamin, Fenethylline, Fenetylline, Fenfluramine, Fenproporex, Fentanyl, Fludiazepam, Flunitrazepam, Fluoxymesterone, Flurazepam, Formebolone, Fungi and Spores of the species PsilocypeSemilanceata, Furethidine, Gammahydroxybutanic acid, Glutethimide, Halazepam, Hallucinogens, Haloxazolam, Heroine, Hydrocodone, Hydrocodone &isoquinoline alkaloid, Hydromorphinol, Hydromorphone, Hydroxypethidine, Ibogaine, Isobutylnitrit, Isomethadone, Ketamine, Ketazolam, Ketobemidone, lefetamine, Levamfetamine, levallorphan, Levoalphacetylmethadol, Levo-methamphetamine, Levomethorphan, Levomoramide,

Levophenacylmorphan, Levorphanol, lisdexamphetamine, lofentanil, loperamide, Loprazolam, Lorazepam, Lormetazepam, Lysergic acid, Lysergic acid amide, Lysergic acid diethylamide, Marijuana, Mazindol, MBDN(N-methyl-l-(3,4-methylenedioxyphenyl)-2-butanamine), mCPP (l-(3- chlorphenyljpiperazine), Mebutamate, Mecloqualone, Medazepam, Mefenorex, MeOPP (l-(4- methoxyphenyljpiperazine), Meperidine intermediate, Meprobamate, meptazinol, Mescaline, Mesocarb, Mesterolone, Metamfetamine, Metazocine, Methadone, Methadone intermediate, Methamphetamine, Methandienone, Methandranone, Methandriol, Methandrostenolone, Methaqualone, Methcathinone, Methenolone, Methohexital, Methyldesorphine, Methyldihydromorphine, Methylphenidate, Methylphenobarbital (mephobarbital), Methyltestosterone, Methyprylone, Metopone, Mibolerone, Midazolam, Modafinil, Moramide-intermediate, Morpheridine, Morphine, morphine 3 -glucuronide, morphine 6-glucuronide, Morphine methylbromide, Morphine methylsulfonate, Morphine-N-oxide, Myrophine, N,N-Dimethylamphetamine, Nabilone, nalbuphine, Nalorphine, Nandrolone, narceine, N- Ethyl-1 -phenylcyclohexylamine, N-Ethyl-3-piperidyl benzilate, N-Ethylamphetamine, N-Hydroxy-3,4- methylenedioxyamphetamine, Nicocodeine, Nicocodine, Nicodicodine, Nicomorphine, Nimetazepam, Nitrazepam, N-Methyl-3-piperidyl benzilate, Noracymethadol, Norcodeine, Nordiazepam, Norethandrolone, Norlevorphanol, Normethadone, Normorphine, Norpipanone, ohmefentanyl, Opium, Oxandrolone, Oxazepam, Oxazolam, oxycodeine, Oxycodone, Oxymesterone, Oxymetholone, Oxymorphone, papaveretum, Para-Fluorofentanyl, Parahexyl, Paraldehyde, pethidine, Pemoline, Pentazocine, Pentobarbital, Petrichloral, Peyote, Phenadoxone, Phenampromide, Phenazocine, Phencyclidine, Phendimetrazine, Phenmetrazine, Phenobarbital, Phenomorphan, Phenoperidine, Phentermine, Phenylacetone, Pholcodine, Piminodine, Pinazepam, Pipradrole, Piritramide, PMMA (paramethyxymethyl amphetamine), Prazepam, prodine, Proheptazine, promedol, Properidine, Propiram, propheptazine, propoxyphene, Psilocybine, Psilocyn, Pyrovalerone, Quazepam, Racemethorphane, Racemoramide, Racemorphane, Remifentanil, Salvia divinorum, Salvinorin A, Secobarbital, Secobarbital, Sibutramine, SPA, Stanolone, Stanozolol, Sufentanil, Sulfondiethylmethane, Sulfonethylmethane, Sulfonmethane, Talbutal, Tapentadol, Temazepam, Tenamfetamin, Testolactone, Testosterone, Tetrahydrocannabinols, Tetrazepam, TFMPP (l-(3-triflourmethylphenyl)piperazine), Thebacon, Thebaine, Thiamylal, Thiofentanyl, Thiopental, Tiletamine, Tramadol, Zolazepam, Zolazepam, Tilidine, Trenbolone, Triazolam, Trimeperidine, Vinbarbital, Zaleplon, Zipeprol, Zolpidem, Zopiclon. [0066] In certain embodiments of the presently disclosed subject matter, the drug may also include a new chemical entity for which the amount of information is limited. In such cases, the dosage regimen needs to be evaluated based on preclinical and clinical trials.

[0067] In certain embodiments, the selection of the antagonist is based on the drug used in the combination dosage form, and it may vary according to the therapeutic class of the drug. Any antagonist, or a pharmaceutically acceptable salt thereof, or combinations thereof, may be used in accordance with the presently disclosed subject matter. In certain embodiments, the antagonist is present in an amount ranging from about 1% to about 50% w/w of the combination dosage form or the respective particulates (non-retarding or retarding particulates). In certain embodiments, the antagonist is present in an amount of about 0.2% to about 75%, about 0.3% to about 70%, about 0.4% to about 65%, about 0.5% to about 60%, about 0.6% to about 60%, about 0.7% to about 55%, about 0.8% to about 50%, about 0.9% to about 45%, about 1% to about 40%, about 1.5% to about 40%, about 2% to about 40%, about 2.5% to about 35%, about 3% to about 30%, about 3.5% to about 25%, or about 4% to about 20% w/w of the combination dosage form or the respective particulates (non-retarding or retarding particulates). In certain embodiments, the antagonist is present in an amount of at least about 0.1%, at least about 0.2%, at least about 0.5%, at least about 1%, at least about 2.5%, at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, or at least about 40% w/w of the combination dosage form. In some embodiments, the overall amount of the antagonist included in a single unit of the combination dosage form is an orally ineffectual amount to block the drug’s therapeutic effect. The term "ineffectual amount" is used herein to refer to an amount that is not sufficient to completely antagonize the drug’s therapeutical effect. In some embodiments, the overall amount of the antagonist included in a single unit of the combination dosage form is an orally effectual amount to block the drug’s therapeutic effect. The term "effectual amount" is used herein to refer to an amount that is sufficient to block the drug’s therapeutic effect. The phrase "the overall amount of the antagonist" means the total amount of the antagonist included in a single unit of the combination dosage form, i.e., the sum of the amount of the antagonist included in at least one of the non-retarding particulates and the retarding particulates. The effectual and ineffectual amount of the antagonist is varied according to the selection of antagonist agent, and thus those skilled in the art can adjust such amounts in accordance with standard practices as needed and, if required, based on preclinical and clinical trial output, to treat a specific subject and/or condition/disease.

[0068] In certain embodiments, the antagonists useful in the presently disclosed subject matter include, but are not limited to, antagonists for opioids, non-opioid, central nervous system (CNS) depressants, stimulants, tranquillizers, barbiturates, hormones, cannabinoids, nicotine-like compounds, cold and cough drugs such as pseudoephedrine, glutamate antagonists, N-methyl-D-aspartate (NMDA) antagonists, Some examples of antagonist agents include, but are not limited to, naloxone, naltrexone, nalmefene, nalide, nalmexone, naloxegol, nalorphine, naluphine, haloperidol, promethazine, fluphenazine, perphenazine, levomepromazine, cyclazocine, thioridazine, perazine, chlorpromazine, chlorprothixine, zuclopentixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, melperone, bromperidol, and like.

[0069] In certain embodiments of the presently disclosed subject matter, the antagonist may also include a new chemical entity for which the amount of information is limited. In such cases, the dosage regimen needs to be evaluated based on preclinical and clinical trials.

[0070] The above-mentioned drug and/or antagonist may also be included in the combination dosage form in the form of pharmaceutically acceptable salts, uncharged or charged molecules, molecular complexes, solvates, or anhydrates thereof, and, if relevant, isomers, enantiomers, racemic mixtures, and any mixtures thereof. Certain examples of the pharmaceutically acceptable salts include, but are not limited to, citrate, oxalate, acetate, maleate, malonate, fumarate, succinate, tosylate, mesylate, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, toluenesulfonate, or mixtures and/or forms thereof. Additional pharmaceutically acceptable salts can be found in P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Weinheim/Zurich: Wiley-VCH/VHCA, 2002, the disclosure of which is herein incorporated by reference in its entirety.

[0071] In certain embodiments, the alkalizing agent is included in the combination dosage form in an amount that results in about little or no major incremental change (maintaining the pH below about 5) in the pH of 900 ml of 0.0 IN HC1 when said combination dosage form is subjected to in-vitro dissolution testing. In some embodiments, the alkalizing agent is present in an amount of about 5% w/w to about 75% w/w; about 10% w/w to about 60% w/w; about 15% w/w to about 50% w/w; or about 25% w/w to about 55% w/w of the total weight of the combination dosage form or the alkalizing agent particulates. In certain embodiments, the alkalizing agent is present in an amount of at least about 5%, at least 10%, at least 15%, or at least 25% w/w of the combination dosage form or the alkalizing agent particulates. [0072] In certain embodiments, the alkalizing agent can be added to the said combination dosage form by any method known to those of skill in the art, and therefore the method of addition of the alkalizing agent to the dosage form does not limit the scope of the presently disclosed subject matter. For example, the alkalizing agent can be included in the form of powder, particulates, or a coat surrounding any type of coated particulates (such as non-retarding particulates or retarding particulates). In one embodiment, the alkalizing agent is present as separate particulates in the combination dosage form, wherein each particulate comprising the alkalizing agent and, optionally, at least one of diluent, glidant, binder, lubricant, and disintegrant. In another embodiment, the alkalizing agent particulates are coated with the reverse-enteric coat (comprises reverse-enteric polymer) or non-functional coat (comprises water- soluble particle)

[0073] In some embodiment, a suitable alkalizing agent includes, but are not to be limited, magnesium oxide, meglumine, sodium oxide, sodium hydroxide, sodium bicarbonate, sodium potassium tartrate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, potassium citrate, sodium citrate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, calcium phosphate, dibasic calcium phosphate, dihydroxyaluminumaminoacetate, dihydroxyaluminum sodium carbonate, glycine, magnesium glycinate, magnesium hydroxide, magnesium carbonate, sodium borate, aluminium oxide, aluminium hydroxide, ammonium carbonate, monoethanolamine, diethanolamine, triethanolamine, potassium hydroxide, calcium hydroxide, sodium phosphate dibasic, trolamine, sodium potassium tartrate, tribasic sodium phosphate, tricalcium phosphate and like. The alkalizing agents also include antacids or agents that inhibit acid secretion in the stomach, such as, but not limited to, histamines receptor antagonists and proton pump inhibitors.

[0074] In certain embodiments, said combination dosage form further comprises at least one pH- stabilizing agent. In certain embodiments, the pH-stabilizing agent acts to maintain or stabilize the increased pH caused by the alkalizing agent. In certain embodiments, the pH-stabilizing agent is included in the combination dosage form in an amount that results in about little or no major incremental change (maintaining the pH below about 5.5) in the pH of 900 ml of 0.01N HC1 when said combination dosage form is subjected to in-vitro dissolution testing. In certain embodiments, the pH-stabilizing agent is present in an amount that does not alter the pH of the gastric fluid in a normal dosing condition but maintains or extends the elevated pH levels caused by the alkaline agent in an overdose condition. In certain embodiments, the pH-stabilizing agent is present in an amount sufficient to maintain or extend the pH of the gastric fluid above about 5.5 in an overdose condition for a period of at least about 0.5 hour, at least about 1 hour, preferably at least about 2 hours, more preferable at least about 3 hours, and most preferably at least about 5 hours.

[0075] In certain embodiments, the combination dosage form further comprising pH-stabilizing agent in an amount ranging from about 1% to about 70% w/w of the combination dosage form. In certain embodiments, the pH-stabilizing agent is present in an amount of at least about 0.5%, at least 5%, at least 10%, at least 15%, or at least 20% w/w of the combination dosage form. In certain embodiments, the pH stabilizing agent can be added in the said combination dosage form by any method known to those of skill in the art, including in a similar way as discussed for the alkalizing agent previously, and therefore the method of addition of the pH stabilizing agent in the combination dosage form does not limit the scope of the presently disclosed subject matter.

[0076] In certain embodiments, the pH-stabilizing agents for use in the combination dosage form include, but are not limited to, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, calcium phosphate, dibasic calcium phosphate, dihydroxyaluminum aminoacetate, dihydroxyaluminum glycine, magnesium glycinate, sodium potassium tartrate, tribasic sodium phosphate, tricalcium phosphate, and combinations thereof. In certain embodiments, the pH- stabilizing agent is a combination of dibasic calcium phosphate/tricalcium phosphate. In certain embodiments, the ratio of dibasic calcium phosphate to tricalcium phosphate (i.e., dibasic calcium phosphate: tri calcium phosphate) is about 1 :0.1 to about 1 : 5 wt % ratio. In certain embodiments, the ratio of dibasic calcium phosphate to tri calcium phosphate is about 1 : 1.25 to about 1 :4.75, about 1 : 1.5 to about 1 :4.5, about 1 :1.75 to about 1 :4.25, about 1:2 to about 1:4, about 1:2.25 to about 1:3.75, about 1:2.5 to about 1:3.5, or about 1:2.75 to about 1:3.25 wt% ratio. In certain embodiments, the pH-stabilizing agent is anhydrous dibasic calcium phosphate.

[0077] In certain embodiments, overdose protection properties do not activate when single or prescribed unit(s) of the combination dosage form are ingested, i.e., release of the drug from the single or prescribed unit(s) of the combination dosage form(s) maintains its actual release properties [i.e., there is no or about minimal effect on the drug release] after ingestion of single or prescribed unit(s) of the combination dosage form. In certain embodiments, the alkalizing agent is included in the combination dosage form in an amount that results in about little or no major incremental change (the pH remains below about 5.5) in the pH of 900 ml of 0.01 N HC1 when said combination dosage form is subjected to the in-vitro dissolution testing in an amount of a single (e.g., a single tablet or capsule) or prescribed unit(s) per dissolution vessel. In certain embodiments, the alkalizing agent is included in the combination dosage form in an amount that results in about little or no major incremental change in the pH of the gastric fluids (the pH remains below about 5.5) upon ingestion of a single (e.g., one tablet or capsule) or prescribed unit(s) of the combination dosage form.

[0078] In certain embodiments, overdose protection properties activate when multiple units of the combination dosage form are ingested together. In certain embodiments, the alkalizing agent is included in the combination dosage form in an amount that is sufficient to increase the pH of 900 ml of 0.01 N HC1 above about 5.5 when said combination dosage form is subjected to in-vitro dissolution testing in an amount of multiple units (e.g., multiple tablets or capsules) per dissolution vessel. In certain embodiments, depending on the formulation development strategy, the term "multiple dosage units" or "multiple units" also meant to include more than one unit, most preferably more than two units. In certain embodiments, ingestion of multiple units of the combination dosage form (e.g., multiple tablets or capsules) together (overdose) results in the alkalizing agent increasing the pH of the gastric fluid very rapidly to above about 5.5, which retards the solubilization of the reverse enteric coat of the non-retarding particulates and solubilizes the enteric coat of the retarding particulates in the gastric fluid. Further, a pH-stabilizing agent, if added to the dosage form, acts to maintain or stabilize the increased pH caused by the alkalizing agent for a period of about 30 minutes or more. At this stage, the release of the drug (and antagonist, if present) from the non-retarding particulates and/or the antagonist from the retarding particulates in the gastric fluid is retarded by the reverse enteric coat. If the pH of gastric fluid decreases below about 5.5 before the particulates transit to the intestinal fluid from the gastric fluid, the reverse enteric coats of both particulates, the non-retarding particulates and the retarding particulates, are solubilized and release the antagonist in the effective amount together with the drug. If the particulates transit to the intestinal fluid from the gastric fluid before the pH of the gastric fluid decreases below about 5.5, the release of the drug (and antagonist, if present) from the non- retarding particulates and/or the antagonist from the non-retarding particulates in the intestinal fluid (where pH normally remains above about 5.5) is continued to be retarded by the reverse enteric coat (unless the pH of the intestinal fluid decreases below 5.5 in any of the intestinal parts). This means the invented combination dosage form provides two-stage protection in overdose conditions: the first stage is to retard the release of the drug from the combination dosage form, and the second stage is to make the antagonist available in an effective amount if the dosage form fails to retard the drug release in overdose condition.

[0079] In certain embodiments, the alkalizing agent and the pH-stabilizing agent (combined) are present in the combination dosage form in an amount of less than about 75% w/w of the dosage form. In certain embodiments, the alkaline agent and the pH-stabilizing agent (combined) are present in an amount of less than 60%, less than 55%, less than 50%, less than 45%, less than 44%, less than 43%, less than 42%, less than 41%, less than 40%, less than 39%, less than 38%, less than 37%, less than 36%, less than 35%, less than 34%, less than 33%, less than 32%, less than 31%, less than 30%, less than 29%, less than 28%, less than 27%, less than 26%, less than 25%, less than 24%, less than 23%, less than 22%, less than 21%, less than 20%, less than 19%, less than 18%, less than 17%, less than 16%, or less than 15% w/w of the dosage form (or pharmaceutical composition).

[0080] In some embodiments, the reverse enteric polymer is present in an amount of about 0.1% w/w to about 65% w/w; about 1% w/w to about 45% w/w; about 2% w/w to about 35% w/w; or about 3% w/w to about 25% w/w of the combination dosage form or respective particulates (non-retarding or retarding particulates). In certain embodiments, the reverse enteric polymer is present in an amount of less than 65%, less than 45%, less than 35%, less than 25%, less than 24%, less than 23%, less than 22%, less than 21%, or less than 20% w/w of the dosage form or respective particulates (non-retarding or retarding particulates). In some embodiments, the reverse enteric polymer includes, but are not limited to, polyvinylacetal diethylamino acetate (AEA), polymethacrylate or methacrylic acid and its derivatives, such as copolymers of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, copolymer of methyl methacrylate and diethylaminoethyl methacrylate. Suitable commercially available reverse enteric polymer grades include Eudragit EPO, Eudragit El 00, Eudragit 12.5, Kollicoat Smartseal 30D, Kollicoat Smartseal 100P or equivalent grade. Other than mentioned in the presently disclosed subject matter, the reverse enteric polymer also includes any ingredient, material, or polymer that is soluble at pH below about 5.5 (including degrade or digest by only stomach enzymes) but insoluble, or alternatively swells or gels, at pH above about 5.5.

[0081] In some embodiments, the enteric polymer is present in an amount of about 0.1% w/w to about 55% w/w; about 1% w/w to about 45% w/w; about 2% w/w to about 35% w/w; or about 3% w/w to about 25% w/w of the combination dosage form or respective particulates (retarding particulates). In certain embodiments, the enteric polymer is present in an amount of less than 55%, less than 45%, less than 35%, less than 25%, less than 24%, less than 23%, less than 22%, less than 21%, or less than 20% w/w of the dosage form or respective particulates (retarding particulates). In some embodiments, the enteric polymer includes, but are not limited to, at least one polymer selected from the group consisting of a copolymer of methacrylic acid and methyl methacrylate (1 : 1), a copolymer of methacrylic acid and methyl methacrylate (1 :2), a copolymer of methacrylic acid and ethyl acrylate (1: 1), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, crosslinked polyacrylic polymers, and polyvinyl acetate phthalate. In some embodiments, the enteric polymer includes, but are not limited to, acrylic acid derivatives such as eudragit S 100, eudragit FS, eudragit L 100, eudragit L 100-55, or mixtures thereof, cellulose esters such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose acetate succinate, HPMC phthalate, polyvinyl derivatives such as polyvinyl acetate phthalate, polysaccharide, shellac, zein, pectin, amylase starch and starch derivatives, and like. Other than mentioned in the presently disclosed subject matter, the enteric polymer also includes any ingredient, material, or polymer that is soluble at pH above about 5.5 (including degrade or digest by only intestine enzymes) but insoluble, or alternatively swells or gels, at pH below about 5.5.

[0082] In certain embodiments, the combination dosage form [at least one of the non-retarding particulates, retarding particulates, and alkalizing agent particulates (if incorporated as particulates) of the combination dosage form] further comprising water soluble material, water-insoluble material, gelling ingredient, anti-crushing ingredient, diluent, glidant, surfactant, stabilizer, binder, lubricant, disintegrant, plasticizer, anti-oxidant or stabilizer, anti-tacking agent, sweetener, or any combination thereof in an amount of about 0.0001% to about 85% w/w of the combination dosage form.

[0083] In certain embodiments, the combination dosage form further comprising the water-soluble material in an amount of about 0.0001% to about 85% w/w of the dosage form. Suitable water-soluble ingredients include, but are not limited to, polymer, sugar, salts, surfactant, salts of organic acid, acid, and polysaccharide. Water soluble polymers include, but are not limited to, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxymethylcellulose, hydroxymethylpropylcellulose, sodium carboxymethylcellulose, polyacrylamide derivatives, methacrylic acid derivatives, vinyl pyrrolidone polymers such as polyvinylpyrrolidone, starch derivatives, polyalkylene oxide and copolymer thereof, alkylene oxide homopolymers, gums of plant, animal, mineral, or synthetic origin, polyacrylic acid and copolymer thereof, polyvinyl alcohols, polyethylene glycol, poloxamer, and mixtures thereof. Preferred sugars include dextrose, glucose, arabinose, ribose, arabinose, xylose, lyxose, xylol, allose, altrose, inositol, glucose, sorbitol, mannose, gulose, glycerol, galactose, talose, trehalose, mannitol, erythritol, ribitol, xylitol, maltitol, isomalt, lactitol, sucrose, raffinose, maltose, fructose, lactose, dextrin, dextran, amylase and xylan. Water-soluble salts include sodium chloride, potassium chloride, calcium chloride or magnesium chloride, lithium chloride, lithium, sodium or potassium hydrogen phosphate, lithium, sodium or potassium dihydrogen phosphate, salts of organic acids such as sodium or potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, or sodium ascorbate. Preferred acids include ascorbic acid, 2-benzene carboxylic acid, benzoic acid, fumaric acid, citric acid, maleic acid, serbacic acid, sorbic acid, edipic acid, edetic acid, glutamic acid, toluene sulfonic acid, water-soluble amino acids such as glycine, leucine, alanine, or methionine, tartaric acid, and the like. Polysaccharides are polymeric carbohydrate molecules composed of long chains of monosaccharide units bound together by glycosidic linkages, which on hydrolysis give the constituent monosaccharides or oligosaccharides. They range in structure from linear to highly branched. Examples include storage polysaccharides such as starch and glycogen and structural polysaccharides such as cellulose and chitin.

[0084] In certain embodiments, the combination dosage form further comprising the water-insoluble material in an amount of about 0.0001% to about 85% w/w of the dosage form. The term "waterinsoluble material" refers to a component that is insoluble in water. Suitable water insoluble ingredients include natural, synthetic, or semi-synthetic ingredients. Natural, synthetic, or semi-synthetic waterinsoluble ingredients include, but are not limited to, cellulose derivatives, including cellulose acetate, cellulose acetate butyrate, cellulose triacetate, microcrystalline cellulose, ethyl cellulose, glycerol palmitostearate, wax include microcrystalline wax, beeswax, glycowax, castor wax, carnauba wax, glycerol monostearate, oil include hydrogenated vegetable oil, hydrogenated castor oil, vegetable oil, stearyl alcohol, acetylated hydrogenated soybean oil glycerides, castor oil, glycerol behenic acid ester, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, cetyl alcohol, natural and synthetic glycerides, fatty acids, fatty alcohol, lipid, methacrylic acid derivatives such polymethaacrylate and its copolymer (such as eudragit polymer); polyvinyl acetate, copolymers of vinyl pyrrolidone and vinyl acetate; vinyl acetate and copolymer thereof, ethyl vinyl acetate, modified starch like pregelatinised starch, polylactic acid or polyglycolic acid and copolymers thereof, methacrylates, cocoa butter, macrogol Stearate, diethylene glycol monostearate, polyoxyethylene 50 stearate, and mixtures thereof. [0085] In certain embodiments, the combination dosage form further comprising the gelling ingredient in an amount of not less than about 1% w/w, preferably not less than about 5% w/w of the dosage form or respective particulates (non-retarding or retarding or alkalizing agent particulates). The term "gelling ingredient", as used herein, refers to an ingredient that increases the viscosity of aqueous or non-aqueous media. A suitable gelling ingredient is at least one of a natural, semi-synthetic, or synthetic ingredient, which includes at least one of gum, polysaccharide, water soluble polymer, water soluble protein, and starch. Suitable gelling ingredient includes, but not limited to, xanthan gum, acacia gum, diutan gum, tragacanth, gellan gum, guar gum, fenugreek gum, locust bean gum, pullulan, welan gum, starch or its derivative, celluloseor its derivative (such as hydroxyethyl cellulose, hydroxypropylmethyl cellulose), polyalkylene oxide and its co-polymer such as polyethylene oxide, copolymer of ethylene oxide - propylene oxide, polycarboxylic acid such as polyacrylic acid, polypeptide such as gelatin, albumin, polylysine, soy protein, polyolefinic alcohol (such as polyvinyl alcohol), or a polyvinyl lactam such as, e.g., polyvinylpyrrolidone, polyvinyl caprolactam, alginic acid and its derivative, methacrylic acid and its copolymer, polyacrylic acid and copolymer thereof, and like. According to the presently disclosed subject matter, a more preferable gelling ingredient has a cloud point greater than about 85°C. Gelling ingredients having a cloud point greater than about 85°C resist separation of the drug substance from a dosage form by hot water having a temperature greater than about 90°C and thereby create complexity in efforts to get pure drug from the dosage form. In some embodiments, the gelling agent resists the syringeability and/or extractability of the drug using aqueous and/or hydro-organic solvents. The syringeability can be tested by examining the difficulty of drawing a solution of the dosage form, dissolved in varying types of solvents (e.g., water) and volumes of solvent (e.g., 2-10 ml) through, e.g., an 18-gauge syringe needle. The extractability can also be tested by determining the amount of drug present in the withdrawn liquid.

[0086] In certain embodiments, the combination dosage form further comprising the anti-crushing ingredient in an amount of not less than about 10% w/w of the dosage form or respective particulates (non-retarding or retarding particulates). The anti-crushing ingredients include thermoplastic materials such as polyalkylene oxide or its copolymer, polyvinyl acetate, polysaccharides such as starch or its derivative, cellulose or its derivatives, glycogen, or mixtures thereof. In some embodiments, crush resistant properties can be achieved by a thermal manufacturing process. In the thermal manufacturing process, heat is employed in at least one stage of the manufacturing process of the combination dosage form, and the temperature of the heat is at least about the melting or softening temperature of the anticrushing ingredient. Examples of thermal processes include hot melt extrusion (HME), melt granulation, curing the particulates at the melting or softening temperature, exposing the particulate components to heat during shaping into a particulate or dosage form, etc. In some embodiments, the anti-crushing ingredient resists crushing and grindability of the particulates, thereby allowing less than about 40% of the pulverized particulates pass through the #200 mesh sieve (as measured by weight frequency distribution using the sieving method for 5 minutes) when subjected to the pulverization in the coffee grinder for about 1 minute.

[0087] In certain embodiments, the combination dosage form further comprising the disintegrant in an amount of not less than about 1% w/w of the dosage form or respective particulates (non-retarding or retarding particulates). Suitable disintegrants include, but are not limited to, cellulose derivatives, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, ion-exchange resin, starch and its derivative, croscarmellose sodium, alginic acid, cross-linked polymers of polycarboxylic acid such as polacrilin potassium, insoluble polyvinylpyrrolidone such as crospovidone, and the like.

[0088] In certain embodiments, the combination dosage form further comprising the plasticizer in an amount of less than about 25% w/w of the dosage form or respective particulates (non-retarding or retarding particulates). Suitable plasticizers include, but are not limited to, triacetin, triethyl acetate, acetylated monoglyceride, olive oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, polyethylene glycol, polypropylene glycol, and the like.

[0089] In certain embodiments, the combination dosage form further comprising the diluent in an amount of less than about 90% w/w of the dosage form or respective particulates (non-retarding or retarding particulates). Suitable diluents include, but are not limited to, sucrose, sorbitol, mannitol, various grades of lactose, various grades of microcrystalline cellulose, dextrins, maltodextrins, starches or modified starches, sodium phosphate, calcium phosphate, calcium carbonate, and like.

[0090] In certain embodiments, the combination dosage form further comprising the glidant in an amount of less than about 10% w/w of the dosage form or respective particulates (non- retarding or retarding particulates). Suitable glidants and lubricants may be incorporated, such as stearic acid, metallic stearates, talc, waxes, and glycerides with high melting temperatures, colloidal silica, colloidal silicon dioxide, sodium stearyl fumarate, polyethylene glycols, and alkyl sulphates.

[0091] In certain embodiments, the combination dosage form further comprising the surfactant in an amount of less than about 30% w/w of the dosage form or respective particulates (non-retarding or retarding particulates). Suitable surfactants include, but are not limited to, non-ionic surfactants, anionic surfactants, and cationic surfactants. Example of surfactant include, but are not limited to, ammonium lauryl sulfate, sodium lauryl sulfate, docusate (dioctyl sodium sulfosuccinate), perfluorooctanesulfonate, perfluorobutanesulfonate, alkyl-aryl ether phosphates, alkyl ether phosphates, sodium stearate, sodium lauroylsarcosinate, perfluorononanoate, perfluorooctanoate, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium bromide, phospholipids, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, sphingomyelins, poloxamer, fatty acid ester of glycerol, fatty acid ester of sorbitol such as tween and sorbitan, and like.

[0092] In certain embodiments, the combination dosage form further comprising the anti-tacking agent in an amount of less than about 10% w/w of the dosage form or respective particulates (non-retarding or retarding particulates). A suitable anti-tacking agent is selected from the group consisting of, but are not limited to, stearates, stearic acid, vegetable oil, waxes, a blend of magnesium stearate and sodium lauryl sulfate, boric acid, surfactants, sodium benzoate, sodium acetate, sodium chloride, DL-Leucine, polyethylene glycol, sodium oleate, sodium lauryl sulfate, magnesium lauryl sulfate, talc, starch, corn starch, amorphous silicon dioxide, syloid, metallic stearates, Vitamin E, Vitamin E TPGS, silica and combinations thereof.

[0093] In certain embodiments, the combination dosage form further comprising the binder in an amount of less than about 25% w/w of the dosage form or respective particulates (non-retarding or retarding particulates). Suitable binder include, but are not to be limited, cellulose derivatives include, but are not limited to be, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxymethylcellulose, hydroxymethylpropylcellulose, sodium carboxymethylcellulose, polyacrylamide derivatives, methacrylic acid derivatives, vinyl pyrrolidone polymers such as polyvinylpyrrolidone, starch derivative, polyalkylene oxide and copolymer thereof, alkylene oxide homopolymers, gums of plant, animal, mineral or synthetic origin, polyacrylic acid and copolymer thereof, polyvinyl alcohols, polyethylene glycol, poloxamer, and mixtures thereof.

[0094] In certain embodiments, the combination dosage form further comprising the sweetener in an amount of less than about 10% w/w of the dosage form or respective particulates (non- retarding or retarding particulates). Natural or synthetic sweeteners include, but are not limited to, mannitol, sorbitol, saccharose, saccharine, aspartame, acelsulphame K, or cyclamate.

[0095] In certain embodiments, the combination dosage form further comprising the anti-oxidant or stabilizer in an amount of less than about 10% w/w of the dosage form or respective particulates (nonretarding or retarding particulates). In certain embodiments, the antioxidant or stabilizer includes, but are not limited to, ascorbic acid and its salts, a-tocopherol, sulfite salts, sodium sulfide, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, propyl gallate, and the like.

[0096] In certain embodiments, some ingredients have more than one functionality in the composition. For example, polyethylene oxide can be used as an anti-crushing ingredient as well as a gelling ingredient with a cloud point greater than about 80°C.

[0097] In certain embodiments, the combination dosage form further comprising any functional ingredient mentioned in the Handbook of Pharmaceutical Excipients, 7^th The term "functional ingredient" refers to an ingredient that adds some functional characteristic, as mentioned in the application part (use of ingredient) of each ingredient in the Handbook of Pharmaceutical Excipients, to the composition.

[0098] In certain embodiments, the combination dosage form can be formulated in the form of a sprinkle formulation. Sprinkle formulations are useful for children and other patients, who have difficulty swallowing conventional solid dosage forms. The sprinkle formulation may be administered without the need to take it with water. The term "sprinkle formulation" includes any formulation that is suitable for oral administration, wherein the formulation is sprinkled upon any consumable item such as juice. According to the presently disclosed subject matter, "Sprinkle formulation" is composed of coated particulates of less than about 2.8 mm in size and can be administered orally with or without food or juice.

EXAMPLES

[0099] Certain aspects of the present disclosed subject matter may be better understood as illustrated by the following examples, which are meant by way of illustration and not limitation.

[0100] Example 1

0101] Manufacturing Procedure for 40mg Tapentadol HC1 extended-release formulation:

[0102] Follow the steps 1 - 4 to prepare non-retarding particulates (mini-tablets), the steps l-5 to prepare retarding particulates (mini-tablets), and the step 1 to prepare alkalizing agent particulates (mini-tablets).

Stepl: Preparation of Mini-Tablets (cores): Sift the core ingredients through suitable size sieve and mix it together for about 15minutes in appropriate size blender. Compress the blended material using a punch diameter of 1.5mm to form mini tablets.

Step 2: Extended-release Coat: Add the extended-release coat ingredients into organic or hydro- organic solvents to prepare the extended-release coating solution. Coat the step 1 mini-tablets with the extended-release coat solution till the target weight gain is achieved.

Step 3: Thermal Processing Step to Prepare crush resistant cores (Mini-Tablets): Cure the step (2) mini -tablets at 60-80°C bed temperature for period of 1 hour. Step 4: Reverse enteric coat: Add the reverse enteric coat ingredients into organic or hydro- organic solvents to prepare the reverse enteric coating solution. Coat the step 3 mini-tablets with the reverse enteric coat solution till the target weight gain is achieved.

Step 5: Enteric coat: Add the enteric coat ingredients into organic or hydro-organic solvents to prepare the enteric coating solution. Coat the step 3 mini-tablets with the enteric coat solution till the target weight gain is achieved.

Step 6: Preparation of Alkalizing agent mini-tablets (cores): Sift the core ingredients through suitable size sieve and mix it together for about 15minutes in appropriate size blender. Compress the blended material using a punch diameter of 1.5mm to form mini tablets.

[0103] Example !

0104] Manufacturing Procedure for 40mg Tapentadol HC1 extended-release formulation: Refer the manufacturing procedure of example 1: the steps 1 - 4 to prepare non-retarding particulates (minitablets), the steps 1-5 to prepare retarding particulates (mini-tablets), and the step 1 to prepare alkalizing agent particulates (mini-tablets).

[0105] Example 3

0106] Manufacturing Procedure for 40mg Tapentadol HC1 extended-release formulation: Refer the manufacturing procedure of example 1: the steps 1 - 4 to prepare non-retarding particulates (mini- tablets), the steps 1-5 to prepare retarding particulates (mini-tablets), and the step 1 to prepare alkalizing agent particulates (mini-tablets).

[0107] Example 4

0108] Manufacturing Procedure for 40mg Tapentadol HC1 extended- release formulation: Refer to the manufacturing procedure of example 1: the steps 1 - 4 to prepare non-retarding particulates (minitablets), and the step 1 to prepare alkalizing agent particulates (mini-tablets).

Claims

CLAIMS:

1. An oral, multi-particulate, extended-release, drug-antagonist combination dosage form with overdose protection property comprising: a) a therapeutically effective amount of at least one drug, b) a biphasic amount of at least one antagonist, and c) an alkalizing agent, wherein the drug and a first phase amount of the antagonist are included in non-retarding particulates, wherein said non-retarding particulates comprising coated particulates, wherein each coated particulate comprising: a. an immediate or extended-release particulate comprising at least one of the drug and the antagonist, and b. a reverse enteric coat surrounding the immediate or extended-release particulate, wherein the reverse enteric coat comprising a reverse enteric polymer and, optionally, a water-insoluble material; wherein a second phase amount of said antagonist is included in retarding particulates, wherein said retarding particulates comprising coated particulates, wherein each coated particulate comprising: a. an immediate or extended-release particulate comprising the antagonist, b. a reverse enteric coat surrounding the particulate, wherein the reverse enteric coat comprising a reverse enteric polymer, and optionally, a water-insoluble material, and c. an enteric coat surrounding said reverse enteric coat, wherein the enteric coat comprising an enteric polymer and, optionally, a water-insoluble material, wherein the said drug-antagonist combination dosage form when subjected to in-vitro dissolution testing at 37°±1°C in 900ml of 0.01N HC1 in a USP Apparatus 2 (paddle) at 50 rpm or a USP Apparatus 1 (basket) at 100 rpm, the non-retarding particulates of the combination dosage form releases the first phase amount of the antagonist with the drug at the same or different release rate and the retarding particulates of the combination dosage form retards the release of the second phase amount of the antagonist

2. The combination dosage form of claim 1, wherein the overall amount of the antagonist included in a single unit of the combination dosage form is an orally ineffectual amount to block the drug’s therapeutic effect.

3. The combination dosage form of claim 1 , wherein the alkalizing agent is included in form of powder, particulates, or a coat surrounding at least one of the non-retarding particulates and the retarding particulates.

4. The combination dosage form of claim 1 does not release the antagonist in an effective amount to block the drug’s intended therapeutic effect when administered to a subject in a single or prescribed units in an intact form, but it retards the release of the drug or releases the antagonist in an effective amount to reduce the drug's liking effect when administered in multiple or non-pr escribed units in an intact form.

5. An oral, multi-particulate, extended-release, drug-antagonist combination dosage form with overdose protection property comprising: a) a therapeutically effective amount of at least one drug, b) a first antagonist, c) a second antagonist, and d) an alkalizing agent, wherein the drug and the first antagonist are included in non-retarding particulates, wherein the non-retarding particulates comprising coated particulates, wherein each coated particulate comprising: a. an immediate or extended-release particulate comprising the drug, the first antagonist, or combination thereof, and b. a reverse enteric coat surrounding the particulate, wherein the reverse enteric coat comprising a reverse enteric polymer and optionally a water-insoluble material; wherein the second antagonist is included in retarding particulates, wherein the retarding particulates comprising coated particulates, wherein each coated particulate comprising: a. an immediate or extended-release particulate comprising the second antagonist, b. a reverse enteric coat surrounding the particulate, wherein the reverse enteric coat comprising a reverse enteric polymer and optionally a water-insoluble material, and c. an enteric coat surrounding the reverse enteric coat, wherein the enteric coat comprising an enteric polymer and, optionally, a water-insoluble material, wherein the said drug-antagonist combination dosage form when subjected to in-vitro dissolution testing at 37°±1°C in 900ml of 0.01N HC1 in a USP Apparatus 2 (paddle) at 50 rpm or a USP Apparatus 1 (basket) at 100 rpm, the non-retarding particulates of the combination dosage form releases the first antagonist with the drug at the same or different release rate and the retarding particulates of the combination dosage form retard the release of the second antagonist.

6. The combination dosage form of claim 5, wherein the overall amount of at least one of the first antagonist and the second antagonist included in a single unit of the combination dosage form is an orally ineffectual amount to block the drug’s therapeutic effect.

7. The combination dosage form of claim 5, wherein the alkalizing agent is included in form of powder, particulates, or a coat surrounding at least one of the non-retarding particulates and the retarding particulates. The combination dosage form of claim 5 does not release the first and the second antagonist in an effective amount to block the drug’s intended therapeutic effect when administered to a subject in a single or prescribed units in an intact form, but it retards the release of the drug or releases at least one of the first and the second antagonist in an effective amount to reduce the drug's liking effect when administered in multiple or non-prescribed units in an intact form.