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WO2024261775A1 - Forme posologique combinée d'antagoniste et de médicament - Google Patents

Forme posologique combinée d'antagoniste et de médicament Download PDF

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Publication number
WO2024261775A1
WO2024261775A1 PCT/IN2024/050851 IN2024050851W WO2024261775A1 WO 2024261775 A1 WO2024261775 A1 WO 2024261775A1 IN 2024050851 W IN2024050851 W IN 2024050851W WO 2024261775 A1 WO2024261775 A1 WO 2024261775A1
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WIPO (PCT)
Prior art keywords
antagonist
drug
dosage form
particulates
retarding
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Jayendrakumar Dasharathlal PATEL
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Individual
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Individual
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893—Tablet coating processes

Definitions

  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • the U.S. Food and Drug Administration 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).
  • 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.
  • 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 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • ingestion of multiple units of the combination dosage form (e.g., multiple tablets or capsules) together results in the alkalizing agent increasing the pH of the gastric fluid very rapidly to above about 5.5.
  • said combination dosage form further comprises at least one pH-stabilizing agent to maintain or stabilize the increased pH caused by the alkalizing agent.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • an effective amount of the antagonist would be released to antagonize the drug’s effect by neutralizing or blocking the drug effect.
  • 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
  • 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.
  • 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.
  • 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.
  • release rate e.g., immediate or extended
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • drug used interchangeably herein to refer to a chemical compound that induces a desired pharmacological or physiological effect or biological activity.
  • 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.
  • 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.
  • racemic refers to a mixture of equal parts of enantiomers.
  • said drug is in either salt or base form.
  • 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.
  • 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.
  • 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.
  • multi-particulate 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.
  • 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.
  • 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.
  • 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.
  • reverse enteric coat refers to a coat comprising a reverse enteric polymer.
  • reverse enteric polymer 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • enteric coat refers to a coat comprising an enteric polymer.
  • enteric polymer 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.
  • the pH at which said "enteric polymer” will dissolve in the normal physiological pH of the intestinal fluid is greater than about 5.
  • 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).
  • 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).
  • 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.
  • alkalizing 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.
  • 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.
  • 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.
  • 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.
  • a pH-stabilizing agent(s) maintains the pH of the gastric fluid at a pH greater than about 5.5 for a finite time.
  • gelling ingredient refers to an ingredient that increases the viscosity of aqueous or non-aqueous media.
  • water-insoluble polymer refers to a polymer generally insoluble in water (across all pH) and physiological fluids.
  • water-insoluble material refers to a pharmaceutically acceptable excipient, including polymers that are generally insoluble in water and physiological fluids.
  • water-soluble polymer refers to a polymer generally soluble in water and physiological fluids.
  • water-soluble material refers to a pharmaceutically acceptable excipient, including polymers that are generally soluble in water and physiological fluids.
  • 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.
  • the term "effective amount" refers to an amount that produces the intended effect of a drug or antagonist.
  • the intended effect is to treat a disease condition or therapeutic condition in the patient.
  • 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.
  • in-vitro 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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:
  • 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
  • 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,
  • 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 (
  • 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.
  • 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.
  • the immediate or extended-release particulate of the nonretarding particulates 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 the method of preparation does not limit the scope of the presently disclosed subject matter.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • the immediate or extended-release particulate of the retarding particulates comprising the antagonist 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.
  • 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.
  • 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.
  • 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.
  • the antagonist as such in particle(s) form;
  • 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.
  • 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.
  • 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.
  • the antagonist as such in particle(s) form
  • the water insoluble coat can be non-porous yet permeable to at least one antagonist, or it may be porous.
  • 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.
  • 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.
  • 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.
  • said intermediate coat comprising a reverse enteric polymer, a water-soluble material, a water insoluble material, or any combination thereof.
  • each coated particulate of the non-retarding particulates further comprising an outer coat surrounding the reverse enteric coat.
  • said outer coat comprising a reverse enteric polymer, a water-soluble material, a water-insoluble material, or any combination thereof.
  • each coated particulate of the non-retarding particulates further comprising nonfunctional coat surrounding the reverse enteric coat or the outer coat.
  • said nonfunctional coat comprising essentially water-soluble material, optionally with colorant.
  • 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.
  • said intermediate coat comprising a reverse enteric polymer, a water-soluble material, a water-insoluble material, or any combination thereof.
  • each coated particulate of the retarding particulates further comprising an intermediate coat surrounding the reverse enteric coat and prior to applying the enteric coat.
  • said intermediate coat comprising a reverse enteric polymer, a water-soluble material, a water insoluble material, or any combination thereof.
  • each coated particulate of the retarding particulates further comprising an outer coat surrounding the enteric coat.
  • said outer coat comprising an enteric polymer, a water-soluble material, a water-insoluble material, or any combination thereof.
  • each coated particulate of the retarding particulates further comprising a non-functional coat surrounding the enteric coat or the outer coat.
  • said non-functional coat comprising essentially water-soluble material, optionally with colorant.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a seed core such as a non-pareil seed, sugar sphere, microcrystalline cellulose sphere, silicon dioxide, magnesium silicate, calcium silicate, etc.
  • said coated particulate of the antagonist is not of critical importance and thus does not limit the scope of the presently disclosed subject matter.
  • said coated particulate further comprising an intermediate coat surrounding the particulate prior to applying the water-insoluble coat.
  • 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.
  • each coated particulate of the deterrent particulates further comprising a non-functional coat surrounding the water-insoluble coat or the outer coat.
  • said non-functional coat comprising essentially water-soluble material, optionally with colorant.
  • said combination dosage form further comprising at least one pH- stabilizing agent.
  • the pH-stabilizing agent acts to maintain or stabilize the increased pH caused by the alkalizing agent.
  • 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.
  • 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.
  • 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.
  • 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.
  • the drug is present in an amount ranging from about 0.1% to about 75% w/w of the combination dosage form.
  • 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.
  • 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.
  • the drugs are prone to abuse, misuse, and/or overdose.
  • 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, kerato
  • 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.
  • the drug can be an opioid in a free base form or a pharmaceutically acceptable salt thereof.
  • 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,
  • 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, methylpheni
  • amphetamines
  • 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
  • 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, F
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • effectual amount is used herein to refer to an amount that is not sufficient to completely antagonize the drug’s therapeutical effect.
  • 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.
  • effectual amount is used herein to refer to an amount that is sufficient to block the drug’s therapeutic effect.
  • 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.
  • 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,
  • 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, pro
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • the alkalizing agent particulates are coated with the reverse-enteric coat (comprises reverse-enteric polymer) or non-functional coat (comprises water- soluble particle)
  • 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 antacid
  • said combination dosage form further comprises at least one pH- stabilizing agent.
  • the pH-stabilizing agent acts to maintain or stabilize the increased pH caused by the alkalizing agent.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pH- stabilizing agent is a combination of dibasic calcium phosphate/tricalcium phosphate.
  • the ratio of dibasic calcium phosphate to tricalcium 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.
  • the pH-stabilizing agent is anhydrous dibasic calcium phosphate.
  • 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.
  • 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.
  • 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.
  • overdose protection properties activate when multiple units of the combination dosage form are ingested together.
  • 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.
  • multiple dosage units or “multiple units” also meant to include more than one unit, most preferably more than two units.
  • ingestion of multiple units of the combination dosage form 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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); polyviny
  • 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).
  • gelling ingredient 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.
  • 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.
  • 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.
  • solvents e.g., water
  • volumes of solvent e.g., 2-10 ml
  • the extractability can also be tested by determining the amount of drug present in the withdrawn liquid.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • surfactant examples 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, sphingomyel
  • 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.
  • 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
  • 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.
  • 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).
  • 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.
  • ingredients have more than one functionality in the composition.
  • 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.
  • the combination dosage form further comprising any functional ingredient mentioned in the Handbook of Pharmaceutical Excipients, 7 th
  • 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.
  • 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.
  • "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.
  • 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.
  • 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).
  • 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).
  • 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).

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Abstract

L'objet de la présente divulgation concerne une forme posologique combinant un médicament et un antagoniste, un procédé de préparation de la forme posologique et une méthode d'administration de la forme posologique pour le traitement d'une maladie ou d'une pathologie. La présente invention concerne une forme posologique combinée de médicament et d'antagoniste à libération prolongée, multiparticulaire et orale, comprenant un ou plusieurs médicaments et un ou plusieurs antagonistes, la forme posologique assurant une protection en deux étapes en cas de surdose : la première étape consiste à retarder la libération du médicament à partir des formes posologiques et la seconde étape consiste à rendre l'antagoniste disponible en quantité efficace si les formes posologiques ne parviennent pas à retarder la libération du médicament dans l'état de surdose.
PCT/IN2024/050851 2023-06-17 2024-06-16 Forme posologique combinée d'antagoniste et de médicament Pending WO2024261775A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2015145459A1 (fr) * 2014-03-26 2015-10-01 Sun Pharma Advanced Research Company Ltd. Forme pharmaceutique solide en réservoir revêtu anti-abus à libération immédiate

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015145459A1 (fr) * 2014-03-26 2015-10-01 Sun Pharma Advanced Research Company Ltd. Forme pharmaceutique solide en réservoir revêtu anti-abus à libération immédiate

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