HK40009174A - Tamper resistant immediate release formulations - Google Patents

Description

Tamper-resistant immediate release formulations

The application is a divisional application of Chinese patent applications with application numbers of 201380012104.8(PCT/IB2013/000444), application dates of 3 months and 1 day in 2013 and invented name of 'damage-resistant immediate release type preparation'.

[ technical field ] A method for producing a semiconductor device

The present invention relates to the field of tamper-resistant (tampering) and abuse-resistant pharmaceutical dosage forms.

[ background of the invention ]

Pharmaceutical products are sometimes the subject of abuse. For example, a particular dose of opioid agonist, when administered parenterally, is more potent than the same dose of drug administered orally. Some formulations can be destroyed to provide the opioid agonist contained therein for illicit use. Opioid agonist formulations intended for oral use are sometimes crushed by drug abusers or extracted with a solvent (e.g., ethanol) to provide the opioid contained therein for illicit use (e.g., nasal or parenteral administration).

Attempts have been made in the past in the field to control the abuse risk associated with immediate release opioid analgesics. For example, a combination of pentazocine (pentazocine) and naloxone (naloxone) is applied to tablets sold in the United states, such as Sanofi-WinthropNx。Nx contained pentazocine hydrochloride equivalent to 50mg base and naloxone hydrochloride equivalent to 0.5mg base.Nx is useful for relieving moderate to severe pain. The amount of naloxone in this combination, when taken orally, has low activity and little intervention in the pharmacological activity of pentazocine. However, naloxone in this amount exerts a significant antagonistic effect on narcotic analgesics when administered parenterally. Thus, the inclusion of naloxone is intended to inhibit the abuse forms of oral pentazocine that can occur when the dosage form is dissolved and injected. Thus, this dosage form has a lower risk of parenteral abuse than previous oral pentazocine formulations. Fixed combination therapy comprising tilidine (50mg) and naloxone (4mg) was marketed in germany since 1978 for the treatment of severe pain (N, Goedecke). The principle of combining these drugs is effective pain relief and morphine receptor antagonism via naloxone induction to prevent tiridine addiction. Fixed combination of buprenorphine (buprenorphine) and naloxone in 1991Nx,Reckitt&Colman) for the treatment of pain.

There remains a need in the art for an immediate release dosage form comprising an abuse-prone drug that is resistant to parenteral as well as to nasal abuse. In the case of opioid analgesics, there remains a need for tamper-resistant immediate release formulations that do not rely on the inclusion of antagonists in the formulation to deter parenteral and nasal abuse.

[ summary of the invention ]

It is an object of certain embodiments of the present invention to provide an immediate release solid oral dosage form comprising an active agent (such as an opioid analgesic) that is tamper resistant.

It is an object of certain embodiments of the present invention to provide an immediate release solid oral dosage form comprising an active agent, such as an opioid analgesic, which is less susceptible to parenteral abuse than other dosage forms.

It is an object of certain embodiments of the present invention to provide an immediate release solid oral dosage form comprising an active agent, such as an opioid analgesic, which is less susceptible to intranasal abuse than other dosage forms.

It is a further object of certain embodiments of the present invention to provide an immediate release solid oral dosage form comprising an active agent (such as an opioid analgesic) that is less susceptible to diversion than other dosage forms.

It is a further object of certain embodiments of the present invention to treat a disease or disorder (e.g., pain) in a patient in need thereof by administering to the human patient an immediate release solid oral dosage form disclosed herein.

It is a further object of certain embodiments of the present invention to provide a method of treating pain in a human patient in an immediate release solid oral dosage form comprising an opioid analgesic while reducing the abuse liability of the dosage form.

It is a further object of certain embodiments of the present invention to provide a method of manufacturing an immediate release solid oral dosage form of an active agent (e.g., an opioid analgesic) as disclosed herein.

It is a further object of certain embodiments of the present invention to provide the use of a drug, such as an opioid analgesic, in the manufacture of an anti-destructive dosage form disclosed herein for the treatment of a disease state, such as pain.

The above objects and others of the present invention are achieved by the present invention in which certain embodiments are directed to an immediate release solid oral dosage form comprising a plurality of particles, each particle comprising (i) an active agent, and (ii) a material sensitive to acidic pH, wherein the dosage form releases at least about 70% of the active agent within 45 minutes as measured by in vitro dissolution at 50rpm in usp apparatus 2 (paddle) at 37 ℃ in 500ml0.1N HCl.

In certain embodiments, the acidic pH sensitive material is less soluble in the pH range of about 6 to about 8.5 than in the pH range of about 1 to about 5.

In certain embodiments, the plurality of particles are dispersed in a substrate and compressed into a tablet or contained within a pharmaceutically acceptable capsule. The substrate may comprise at least one of a gelling agent, a disintegrant, or a filler.

In certain embodiments, the solid oral dosage forms disclosed herein release at least about 70 wt.%, or at least about 75 wt.%, or at least about 80 wt.%, or at least about 85 wt.%, or at least about 90 wt.%, or at least about 95 wt.% of the drug (e.g., opioid agonist) within 45 minutes by in vitro dissolution measurement at 50rpm in the United States Pharmacopeia (USP) apparatus 2 (paddle) at 37 ℃, in 500ml0.1N HCl.

In certain embodiments, the solid oral dosage forms disclosed herein release at least about 85%, at least about 90%, or at least about 95%, or at least about 98% by weight of the drug (e.g., opioid agonist) within 60 minutes by in vitro dissolution measurement at 50rpm in usp apparatus 2 (paddle) at 37 ℃ in 500ml0.1N HCl.

In other embodiments, the viscosity created by mixing a unit dose of the dosage form with about 0.5 to about 10ml of distilled water prevents or reduces the ability of the drug (e.g., opioid agonist) to be drawn up by a syringe or absorbed systemically when administered by the parenteral or nasal route.

In embodiments comprising first and second active agents, the viscosity resulting from mixing a unit dose of the dosage form with about 0.5 to about 10ml of distilled water prevents or reduces the ability of the first active agent, the second active agent, or both to be drawn up by a syringe or to be absorbed systemically when administered by the parenteral or nasal route.

In certain embodiments, the present invention relates to an immediate release solid oral dosage form comprising a plurality of particles, each particle comprising (i) an opioid agonist, and (ii) an acidic pH sensitive material, wherein the plurality of particles are dispersed in a substrate comprising (i) a gelling agent, and (ii) optionally a disintegrant, wherein the dosage form releases at least about 70% of the opioid agonist within 45 minutes as measured by in vitro dissolution at 50rpm in usp apparatus 2 (paddle) at 37 ℃ in 500ml0.1N HCl, and wherein the viscosity of the dosage form when administered by the parenteral or nasal route, mixed with about 0.5 to about 10ml distilled water, prevents or reduces the ability of the opioid agonist to be drawn up by a syringe or absorbed systemically.

In certain embodiments, the present invention relates to immediate release solid oral dosage forms comprising more than one active agent. For example, the immediate release solid oral dosage form may comprise a plurality of particles, each particle comprising (i) a core comprising a first active agent, (ii) a coating comprising a second active agent layered on the core, and (iii) an acidic pH sensitive material layered on the coated core, wherein the dosage form releases at least about 70% of the first active agent, the second active agent, or both within 45 minutes as measured by in vitro dissolution at 50rpm in usp apparatus 2 (paddle) at 37 ℃ in 500ml0.1N HCl. Contemplated combinations of active agents include, but are not limited to, opioid analgesics and non-opioid analgesics. Exemplary combinations include oxycodone (oxycodone) or a pharmaceutically acceptable salt thereof and acetaminophen; oxycodone or a pharmaceutically acceptable salt thereof and aspirin (aspirin); oxycodone or a pharmaceutically acceptable salt thereof and ibuprofen (ibuprofen); hydrocodone (hydrocodone) or a pharmaceutically acceptable salt thereof and acetaminophen; and hydrocodone or a pharmaceutically acceptable salt thereof and ibuprofen.

In certain embodiments, the present invention relates to a solid oral dosage form comprising a plurality of particles, each particle comprising (i) an opioid agonist, and (ii) a material sensitive to acidic pH, wherein the plurality of particles are dispersed in a substrate comprising a gelling agent and a disintegrant, wherein the dosage form releases at least about 70% of the opioid agonist within 45 minutes as measured by in vitro dissolution at 50rpm in usp apparatus 2 (paddle) at 37 ℃ in 500ml0.1N HCl, and wherein the dosage form mixed with about 0.5 to about 10ml of distilled water when administered by parenteral or nasal route prevents systemic absorption of the opioid agonist or reduces the ability of the opioid agonist to be absorbed systemically.

In certain embodiments, the present invention relates to a solid oral dosage form comprising a plurality of particles, each particle comprising (i) a core comprising a first active agent (e.g., a non-opioid analgesic such as acetaminophen, ibuprofen, or aspirin), (ii) a coating comprising a second active agent (e.g., an opioid agonist such as oxycodone, hydrocodone, or pharmaceutically acceptable salts thereof) laminated over the core, and (iii) a material sensitive to acidic pH laminated over the coated core, wherein the plurality of particles are dispersed over a substrate comprising a gelling agent and a disintegrant, wherein the dosage form releases at least about 70% of the opioid agonist within 45 minutes as measured by in vitro dissolution at 50rpm in usp apparatus 2 (paddle) at 37 ℃, in 500ml0.1NHCl, and wherein when administered by a parenteral or nasal route, the viscosity of the dosage form mixed with about 0.5 to about 10ml of distilled water prevents or reduces the ability of the opioid agonist to be absorbed systemically.

In certain embodiments, the present invention relates to a method of making an immediate release solid oral dosage form comprising (i) preparing a plurality of particles, each particle comprising an active agent and a material sensitive to acidic pH, and (ii) dispersing the plurality of particles in a matrix, wherein the dosage form releases at least about 70% of the active agent within 45 minutes by in vitro dissolution measurement in usp apparatus 2 (paddle) at 50rpm at 37 ℃ in 500ml0.1N HCl.

In certain embodiments, the present invention relates to a method of preparing an immediate release solid oral dosage form comprising (i) granulating an active agent and a material sensitive to acidic pH to obtain granules, and (ii) compressing the granules into a tablet or containing the granules in a capsule, wherein the dosage form releases at least about 70% of the active agent within 45 minutes by in vitro dissolution measurement at 50rpm in usp apparatus 2 (paddle) at 37 ℃ in 500ml0.1N HCl.

In certain embodiments, the invention relates to a method of making a dosage form as disclosed herein that releases at least about 70 wt.%, or at least about 75 wt.%, or at least about 80 wt.%, or at least about 85 wt.%, or at least about 90 wt.%, or at least about 95 wt.% of the drug (e.g., opioid agonist) within 45 minutes as measured by in vitro dissolution at 50rpm in usp apparatus 2 (paddle) at 37 ℃ in 500ml0.1N HCl.

In certain embodiments, the invention relates to a method of making a solid oral dosage form as disclosed herein that releases at least about 85%, or at least about 90%, or at least about 95%, or at least about 98% by weight of the drug (e.g., opioid agonist) within 60 minutes as measured by in vitro dissolution at 50rpm in usp apparatus 2 (paddle) at 37 ℃ in 500ml0.1N HCl.

In certain embodiments, the invention relates to a method of making a solid oral dosage form as disclosed herein, the method comprising (a) preparing a plurality of particles, each particle comprising (i) a core comprising a first active agent (e.g., a non-opioid analgesic), (ii) a coating comprising a second active agent (e.g., an opioid analgesic), and (iii) an acidic pH sensitive material laminated to the coated core, wherein the dosage form releases at least about 70% of the first active agent, the second active agent, or both active agents within 45 minutes by in vitro dissolution measurement at 50rpm in usp apparatus 2 (paddle) at 37 ℃ in 500ml0.1N HCl.

In other embodiments, the invention relates to a method of making a dosage form as disclosed herein, wherein the viscosity resulting from mixing a unit dose of the dosage form (crushed or uncrushed) with about 0.5 to about 10ml of distilled water prevents or reduces the ability of the drug (e.g., opioid agonist) to be drawn up by a syringe or absorbed systemically when administered by parenteral or nasal route.

In describing the present invention, the following terms are used as follows. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" or "an active agent" includes a single active agent and a mixture of two or more different active agents, reference to "a gelling agent" or "a gelling agent" includes a single gelling agent and a mixture of two or more different gelling agents, and the like.

The terms "active agent," "active ingredient," "pharmaceutical agent," and "drug" as used herein refer to any substance intended to produce a therapeutic, prophylactic, or other desired effect, whether or not approved by a governmental agency for this purpose. These terms with respect to a particular agent encompass all pharmaceutically active forms of that agent, including the free base form of the agent, as well as all pharmaceutically acceptable salts, complexes, stereoisomers, crystalline forms, co-crystals, ethers, esters, hydrates, solvates, and mixtures thereof, wherein the form is pharmaceutically active.

The term "therapeutically effective" as used herein refers to the amount of drug or the rate of drug administration required to produce the desired therapeutic result.

The term "prophylactically effective" as used herein refers to the amount of a drug or the rate of drug administration required to produce a desired prophylactic result.

The term "stereoisomers" as used herein is a collective term for all isomers of individual molecules, which differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds having one or more chiral centers that are not mirror images of each other (diastereomers).

The term "enantiomer" or "enantiomer" refers to a molecule that does not overlap completely with its mirror image, which turns plane polarized light by a certain angle in one direction, and thus is optically active, and the mirror image turns plane polarized light by the same angle in the opposite direction.

The term "chiral center" refers to a carbon atom to which four different groups are attached.

The term "racemic" refers to a mixture of enantiomers.

The term "resolution" refers to the separation or concentration or exclusion of one of the two enantiomeric forms of a molecule.

The term "patient" refers to an individual, particularly a human, who exhibits clinical signs of a particular symptom or symptoms, suggesting a need for treatment, who has been prophylactically or prophylactically treated for a condition, or who has been diagnosed as having a condition to be treated. The term "subject" encompasses the definition of the term "patient" and does not exclude subjects who are completely normal in every respect or in a particular disorder.

Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts (such as hydrochloride, hydrobromide, sulfate, phosphate and the like), organic acid salts (such as formate, acetate, trifluoroacetate, maleate, tartrate and the like), sulfonates (such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like), amino acid salts (such as arginate, aspartate, glutamate and the like), metal salts (such as sodium, potassium, cesium and the like), alkaline earth metals (such as calcium, magnesium and the like), organic amine salts (such as triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N' -benzhydrylethylenediamine and the like).

The term "ppm" as used herein refers to "parts per million". In the case of 14-hydroxycodeinone, "ppm" represents parts per million of 14-hydroxycodeinone in a particular sample product. The amount of 14-hydroxycodeinone may be determined by any method known in the art, preferably HPLC analysis using UV detection.

The term "laminated" refers to complete or partial coverage onto a substrate (e.g., an inert core).

The term "bioavailability" is defined for purposes of this invention as the degree to which a drug (e.g., oxycodone) is absorbed from a unit dosage form. Bioavailability also refers to AUC (i.e. area under plasma concentration/time curve).

The term "C_max"means the highest plasma concentration achieved during the dosing interval.

The term "T_max"means that the highest plasma concentration (C) is reached_max) Time of (d).

The term "patient population" or "individual population" or "healthy individual population" means that the discussion (or claims) refers to at least two patients, individuals, or healthy individuals; at least six patients, individuals, or healthy individuals; or average pharmacokinetic parameters of at least twelve patients, individuals or healthy individuals.

For the purposes of the present invention, the formulations disclosed herein are preferably dose-proportional. Pharmacokinetic parameters (e.g., AUC and C) in dose proportional formulations_max) And/or in vitro release increases linearly from one dose intensity to another dose intensity. Thus, the pharmacokinetic and in vitro parameters for a particular dose can be derived from the parameters for different doses of the same formulation.

[ description of the drawings ]

FIG. 1 is a graphical illustration of a formulation of the present invention.

FIG. 2 is another graphical illustration of a formulation of the present invention.

Fig. 3 is a graphical illustration of a method of making an embodiment of the present invention.

Figure 4 is a graphical illustration of the pharmacokinetic results of example 5.

Fig. 5 is a graphical illustration of dissolution data for formulation 6B of example 8.

Fig. 6 is a graphical illustration of dissolution data for formulation 6C of example 8.

Figure 7 is a graphical illustration of dissolution data for formulation 7 of example 8.

Fig. 8 is a flow chart of a manufacturing method for layering a first active agent with a second active agent.

Fig. 9 is a flow chart of a manufacturing method for laminating an acidic pH sensitive substance on a substrate according to an embodiment of the present invention.

Fig. 10 is a flow chart of a method of making a tablet according to an embodiment of the present invention.

FIG. 11 is a graphical illustration of the elution data of example 10.

Detailed Description

[ embodiment ] A method for producing a semiconductor device

Particle-based formulations of active agents utilize different substances to control the release of the active agent following oral administration. For example, polymer-based active agent formulations may be differentially released based on pH dependence, designed to release the active agent over an extended period of time, or to release the active agent at a specific point in time in the gastrointestinal system.

In addition, gelling agents are contemplated for use in pharmaceutical formulations to protect against abuse of dosage forms containing drugs that are susceptible to abuse. One form of abuse is crushing the controlled release dosage form to release the drug contained therein for illicit use, such as parenteral administration or absorption via mucosal surfaces. When a dosage form containing a gelling agent is crushed and then mixed with a solution, the resulting viscosity may inhibit the drug from being drawn up by a syringe, thereby preventing parenteral abuse. Likewise, when the crushed dosage form is applied to a mucosal surface (e.g., the nasal cavity), the composition will gel upon contact with mucosal moisture, thereby inhibiting absorption.

Controlled release dosage forms of drugs of abuse are of high interest in the hope of developing tamper resistant technology, as crushing the dosage form may release an amount of active agent that is intended to be released for an extended period of time (e.g., between 12 and 24 hours).

Immediate release dosage forms may also be abused, becoming a public safety issue when administered via an unintended route. One of the problems to overcome by incorporating a polymer and/or gelling agent into an immediate release dosage form is the controlled release profile, i.e., the agent may impart said controlled release profile to the dosage form when incorporated in an amount sufficient to inhibit breakage.

In some instances, immediate release dosage forms may be abused without crushing, for example, by contacting the entire dosage form with a liquid to dissolve the active agent contained therein. This problem can be particularly acute with a complete immediate release dosage form in the form of granules, because the dosage form has a large surface area and increased dissolution.

Immediate release dosage forms play an important role in the management of both acute and chronic conditions (e.g., pain management of opioid analgesics). It is therefore important to provide a tamper resistant dosage form of the drug susceptible to abuse to maintain its immediate release characteristics. In certain embodiments, the immediate release profile is that the dosage form releases at least about 70% by weight (w/w) of the drug within 45 minutes as measured by in vitro dissolution of usp apparatus 2 (paddle) at 37 ℃ of 500ml0.1nhcl or simulated enzyme free gastric fluid (SGF) at 50 rpm. In other embodiments, the immediate release profile is such that the dosage form releases at least about 70% by weight of the drug within 45 minutes as measured by in vitro dissolution of the usp apparatus 1 (basket) at 37 ℃ in 900ml distilled water at 50 rpm.

In certain embodiments, the present invention relates to an immediate release solid oral dosage form comprising a plurality of granules, each granule comprising: (i) an active agent, and (ii) an acidic pH sensitive material, wherein the dosage form releases at least about 70% of the active agent within 45 minutes as measured by in vitro dissolution of usp apparatus 2 (paddle) at 37 ℃ in 500ml simulated 0.1N HCl or simulated gastric fluid without enzyme (SGF) at 50 rpm. Alternatively, this embodiment may release at least about 70% w/w of the drug in 45 minutes as measured by the United states Pharmacopeia apparatus 1 (basket) in 900ml of distilled water at 37℃ and 50rpm for in vitro dissolution.

In certain embodiments, the present invention relates to an immediate release solid oral dosage form comprising a plurality of granules, each granule comprising: (i) an active agent susceptible to abuse, such as an opioid agonist, and (ii) an acidic pH sensitive material, wherein the plurality of particles are dispersed in a matrix comprising (i) a gelling agent, and (ii) optionally a disintegrant, wherein the dosage form releases at least about 70% of the active agent within 45 minutes as measured by in vitro dissolution of the dosage form in usp apparatus 2 (paddle) at 37 ℃ of 500ml of 0.1N HCl or simulated enzyme-free gastric fluid (SGF) at 50 rpm. Alternatively, this embodiment may release at least about 70% w/w of the drug in 45 minutes as measured by in vitro dissolution of the United states Pharmacopeia apparatus 1 (basket) in 900ml of distilled water at 37℃ and 50 rpm.

In certain embodiments, the release rate of the active agent (e.g., opioid agonist) in water is slower than in 0.1 NHCL. For example, the amount of active agent released at one or more time points selected from 5, 10, 15, 30, 45, or 60 minutes by an in vitro dissolution measurement in 500ml of distilled water at 37 ℃ by usp apparatus 2 (paddle) at 50rpm is less than the amount of active agent released at the same time point as determined by an in vitro dissolution measurement in 900ml of 0.1N HCl at 37 ℃ by usp apparatus 1 (basket). In certain embodiments, the ratio of the amount released in water to the amount released in 0.1NHCl at each time point is about 1:10 to less than 1:1, about 1:5 to about 9:10, about 3:10 to about 4:5, or about 2:5 to about 7:10 or about 1:2 to about 3: 5. In other embodiments, the ratio is about 1:10, about 9:10, about 3:10, about 9:10, about 1:2, about 9:10, about 7:10, about 9:10, or about 4:5 to about 9: 10. In other embodiments, the ratio is about 1:10, about 1:5, about 3:10, about 2:5, about 1:2, about 3:5, about 7:10, about 4:5, or about 9: 10.

The unit dose of the immediate release dosage form of the present invention may include, but is not limited to, from about 2 to about 75 particles, from about 10 to about 50 particles, or from about 15 to about 25 particles. In other embodiments, a unit dose of an immediate release dosage form of the present invention may include, but is not limited to, about 50 to about 500 particles, about 75 to about 350 particles, about 100 to about 300 particles, or about 150 to about 250 particles.

The particles used in the present invention may have an average diameter of from about 0.1mm to about 10mm, from about 0.5mm to about 8mm, from about 1mm to about 6mm, or from about 2mm to about 4 mm.

In certain embodiments comprising a gelling agent, the viscosity of the dosage form (crushed or intact) mixed with about 0.5 to about 10ml of distilled water prevents or reduces the ability of the active agent to be pumped up by a syringe or absorbed systemically when administered by parenteral or nasal routes.

In certain embodiments, with respect to the plurality of particles of the present invention, each particle comprises (i) a core comprising the active agent, and (ii) an acidic pH sensitive material layered on the core. In this embodiment, the core may comprise (i) an inert excipient (such as a sugar sphere) layered with the active agent or (ii) the active agent dispersed in a pharmaceutically acceptable excipient. Alternatively, the core may comprise the active agent but no excipient or very little excipient.

In other embodiments, with respect to the plurality of particles, each particle comprises (i) a core comprising an inert excipient, and (ii) a coating comprising the active agent and a substance sensitive to acidic pH laminated on the core.

In other embodiments, with respect to the plurality of particles, each particle comprises the active agent dispersed in a substance sensitive to acidic pH (e.g., in a mixed or particulate form). In this embodiment, the particles may have an optional coating, such as a film coating.

In other embodiments, each core of the plurality of particles may comprise another active agent in place of, or in addition to, the inert excipient. For example, a first active agent can be used as a substrate for coating a second active agent thereon. The first active agent may be a substantially pure active pharmaceutical ingredient, or may be mixed with a pharmaceutically acceptable excipient prior to coating with the second active agent. The first active agent used as a matrix may be in the form of, for example, a powder or granules. The second active agent can be applied to the first active agent by any method, such as spray coating.

In other embodiments, the core may comprise a first active agent layered on an inert excipient and the second active agent layered on the core. Alternatively, the first active agent can be dispersed in a pharmaceutically acceptable excipient to form a plurality of matrices, and the second active agent can be layered on the matrices. An optional inner layer of a film forming substance (such as hydroxypropyl methylcellulose or polyvinyl alcohol) may be laminated between the first and second active agents.

In other embodiments, the core may comprise an inert excipient layered with a coating comprising a mixture of the first active agent and the second active agent. Alternatively, both the first and second active agents may be dispersed in a pharmaceutically acceptable excipient to form a plurality of matrices, and the acidic pH sensitive material may be layered on the matrices.

The acidic pH sensitive material of the present invention may be a polymer. In certain embodiments, the polymer is soluble at a pH of about 1 to about 5. In other embodiments, the polymer is insoluble at a pH of about 6 to about 8.5. In other embodiments, the polymer is less soluble in the pH range of about 6 to about 8.5 than in the pH range of about 1 to about 5.

In certain embodiments, the acidic pH sensitive substance provides less dissolution of the active agent (e.g., opioid agonist) in an amount of solvent typically used for illicit extraction (e.g., 0.5 to about 10ml of water) than the dissolution in the gastric system following administration. This was tested by in vitro dissolution using usp apparatus 2 (paddle) at 37 ℃ and 50rpm in 500ml distilled water and usp apparatus 1 (basket) at 37 ℃ and 900ml 0.1N HCl at 50 rpm. The ratio of the amount released in water to the amount released in 0.1N HCl at one or more time points selected from 5, 10, 15, 30, 45, or 60 minutes is from about 1:10 to less than 1:1, from about 1:5 to about 9:10, from about 3:10 to about 4:5, or from about 2:5 to about 7:10, or from about 1:2 to about 3: 5. In other embodiments, the ratio is about 1:10, about 9:10, about 3:10, about 9:10, about 1:2, about 9:10, about 7:10, about 9:10, or about 4:5 to about 9: 10. In other embodiments, the ratio is about 1:10, about 1:5, about 3:10, about 2:5, about 1:2, about 3:5, about 7:10, about 4:5, or about 9: 10.

The polymer used in the present invention may be, for example, polyacrylate, polysaccharide, ion exchange resin, or a mixture thereof.

Examples of polyacrylates (or salts) that can be used in the present invention are copolymers comprising amino and/or alkylamino and/or dialkylamino groups, for example copolymers comprising methyl methacrylate and diethylaminoethyl methacrylate, such as Kollicoat Smartseal30 available from BASFAnother example is a copolymer comprising methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate, such as Eudragit E available from Evonik(granules) or Eudragit E(powder preparation). In certain embodiments, the polyacrylate (or salt) is applied to the particle in an amount that provides a weight increase of about 10% (w/w) to about 90% (w/w), or about 20% (w/w) to about 80% (w/w), or about 30% (w/w) to about 70% (w/w), or about 40% (w/w) to about 60% (w/w).

An example of a polysaccharide that can be used in the present invention is chitosan.

Examples of ion exchange resins useful in the present invention include polacrilex resin (polacrilex resin), polacrilin (polacrilin) salts, sodium polystyrene sulfonate, cholestyramine resin (cholestyramine resin), or mixtures thereof.

In embodiments where the base material comprises a gelling agent, the amount of the gelling agent may be from about 0.25% to about 50% (w/w) or from about 0.25% to about 10% (w/w) of the total amount of the dosage form.

The gelling agent used in the immediate release dosage forms of the present invention may be selected from sugars, sugar-derived alcohols (e.g., mannitol, sorbitol, and the like), starches, starch derivatives, cellulose derivatives (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose), attapulgite (attapulgite), bentonite (bentonite), dextrin, alginates, carrageenan, gums (e.g., tragacanth, acacia, guar gum, and xanthan gum), pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer (carbomer), carbopol (carbopol), polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, alcaligenes polysaccharide (curdlan), furcellaran, albumen powder, lactalbumin, soy protein, chitosan, talc, gelatin, Surfactants, mixed surfactant/wetting agent systems, emulsifiers, other polymeric materials, or mixtures thereof. In certain embodiments, the gelling agent is xanthan gum. In other embodiments, the gelling agent is pectin. The pectin or pectic substance includes pectate esters (or salts) and crude natural pectin purified or isolated from sources such as apple, citrus or beet residues, which sources are esterified or de-esterified (e.g., by alkali or enzymes), if desired. Pectin can also be derived from citrus fruits such as lime, lemon, grapefruit, and tangerine. In particular embodiments, the gelling agent may be selected from pregelatinized starches (e.g., available from Asahi Kasei)) Hydroxyethyl group, hydroxyethyl groupCellulose (e.g. available from Ashland inc) Guar gum (e.g., available from Ashland inc) Xanthan gum, alginates, carrageenan, polyethylene oxide or mixtures thereof.

The gelling agent is preferably included in the dosage form such that the viscosity of the dosage form (crushed or intact) mixed with about 0.5 to about 10ml of distilled water prevents or reduces the ability of the active agent (e.g., opioid agonist) to be drawn up by a syringe or absorbed systemically when administered by the parenteral or nasal route. The viscosity can be, for example, from about 10cP to about 100cP, from about 25cP to about 75cP, at least about 20cP, at least about 40cP, or at least about 60 cP.

In certain embodiments, the immediate release dosage form of the present invention comprises a weight of gelling agent that does not exceed the weight of the drug (e.g., opioid agonist). In other embodiments, the immediate release dosage form of the present invention comprises less gelling agent by weight than the weight of the drug. In other embodiments, the immediate release dosage form of the present invention comprises a weight of gelling agent in excess of the weight of the drug.

In certain embodiments, the immediate release dosage forms of the invention comprise a weight ratio of gelling agent to drug (e.g., opioid agonist) of about 10:1 to about 1:10, about 5:1 to about 1:5, about 3:1 to about 1:3, about 1:1 to about 1:1.5, about 1.5:1 to about 1:1, about 1:1.25, or about 1.25: 1.

In embodiments where the base material comprises a disintegrant, the amount of disintegrant may be from about 0.2% to about 25% (w/w) or from about 1% to about 10% (w/w) of the total amount of the dosage form.

The disintegrant may be selected from croscarmellose sodium, starch, sodium starch glycolate, crospovidone, or a mixture thereof.

In embodiments where the base material comprises a filler, the filler may be present in an amount of about 15% to about 95% (w/w) or about 25% to about 50% (w/w) of the total amount of the dosage form.

The filler may be a sugar, for example selected from sucrose, glucose, lactose, fructose, mannitol, cellulose derivatives and mixtures thereof. In certain embodiments, the filler can be lactose (e.g., Fast available from Foremost Farms)) Or microcrystalline cellulose (e.g., available from FMC BioPolymer))。

In certain embodiments, the particles of the dosage form may be layered with a barrier layer. The barrier layer may be included, for example, to provide stability or to prevent migration of the active agent into the substrate. In embodiments employing a barrier layer, the substance and/or amount of the substance used preferably does not substantially interfere with the release profile of the active agent from the dosage form. The substance of the barrier layer may be, for example, an acrylic polymer, a cellulose polymer or a vinyl polymer. Preferred barrier layers of the present invention include hydroxypropyl methylcellulose, polyvinyl alcohol, povidone, or mixtures thereof. In certain embodiments, the barrier layer is applied to the particles in an amount that provides a weight gain of about 1% (w/w) to about 10% (w/w), or about 4% (w/w) to about 7% (w/w).

The dosage form of the present invention may include an aversive agent (aversive) to further prevent illegal use of the active agent contained therein. The aversive agent can be included in the plurality of particles, the substrate, or both components of the dosage form. The aversive agent may be, for example, an emetic, an antagonist, a bittering agent, a stimulant, or mixtures thereof.

The emetic agent may be selected from, for example, methyl cephaeline (methaphenine), cephaeline (cephaeline), emidine hydrochloride (emetine hydrochloride), cephaeline (pseudomycin), O-methyl cephaeline (O-methyl pseudomycin), emetamine (emetamine), ipecamine (ipecamine), hydrogenated ipecamine (hydro-ipecamine), ipecamic acid (ipecamine acid), and mixtures thereof. In a particular embodiment, the emetic is ipecac.

The antagonist may be selected from, for example, naltrexone (naltrexone), naloxone (naloxone), nalmefene (nalmefene), cyclazocine (cyclazacine), levorphanol (levallorphan), their pharmaceutically acceptable salts and mixtures thereof.

The bitterant may be selected from, for example, flavoring oils, flavoring aromatics, oleoresins, plant extracts, leaf extracts, flower extracts, fruit extracts, sucrose derivatives, sucralose (chlorosucrose) derivatives, quinine sulfate, denatonium benzoate, and mixtures thereof. In certain embodiments, the bitterant is spearmint oil, peppermint oil, eucalyptus oil, nutmeg oil, allspice oil, dried nutmeg skin (mace), dried nutmeg skin oil, bitter almond oil, menthol, and mixtures thereof. In other embodiments, the bitterant is extracted from a fruit selected from the group consisting of lemon, orange, lime, grapefruit, and mixtures thereof. In a particular embodiment, the bittering agent is denatonium benzoate.

The stimulant may be selected from, for example, a surfactant, capsaicin (capsaicin), or a capsaicin analog. The capsaicin analog is selected from resiniferatoxin (resiniferatoxin), tinyatoxin (tinyatoxin), heptanoyl isobutylamide, heptanoyl guaiacyl amide, isobutylamide, guaiacyl amide, dihydrocapsaicin, homovanillyl octyl ester, nonanoyl vanillyl amide, or mixtures thereof.

The surfactant may be selected from poloxamer (poloxamer), sorbitan monoesters, glyceryl monooleate, sodium lauryl sulfate or mixtures thereof.

In certain embodiments, the immediate release solid oral dosage forms of the invention release, e.g., at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the active agent (such as an opioid agonist) within 45 minutes as measured by in vitro dissolution measurement in usp apparatus 2 (paddle) at 37 ℃ of 500ml0.1n HCl or Simulated Gastric Fluid (SGF) without enzymes at 50 rpm.

In certain embodiments, the immediate release solid oral dosage forms of the invention release, e.g., at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the active agent (e.g., opioid agonist) within 60 minutes as measured by in vitro dissolution measurement in usp apparatus 2 (paddle) at 37 ℃ of 500ml0.1n HCl or simulated gastric fluid without enzymes (SGF) at 50 rpm.

In certain embodiments, the immediate release solid oral dosage forms of the invention release, e.g., at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the active agent (e.g., opioid agonist) within 45 minutes as measured by in vitro dissolution of the united states pharmacopeia apparatus 1 (basket) in 900ml of distilled water at 37 ℃ at 50 rpm.

In certain embodiments, the immediate release solid oral dosage forms of the invention release, e.g., at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the active agent (e.g., opioid agonist) within 60 minutes as measured by in vitro dissolution of usp apparatus 1 (basket) in 900ml of distilled water at 37 ℃ at 50 rpm.

In certain embodiments, the immediate release solid oral dosage form of the invention has a release, as measured by in vitro dissolution measurement in usp apparatus 2 (paddle) at 37 ℃ in 500ml distilled water at 50rpm, of, for example, one or more of the following: (i) at least about 15%, at least about 25%, or at least about 35% of the active agent (e.g., opioid agonist) is released at 15 minutes, or (ii) at least about 25%, at least about 35%, or at least about 45% of the active agent is released at 30 minutes.

In certain embodiments, the immediate release solid oral dosage forms of the invention release, e.g., (i) about 15% to about 70% of the active agent (e.g., opioid agonist) at 15 minutes, (ii) about 25% to about 80% of the active agent at 30 minutes, and release at least about 90% of the active agent at 45 minutes, as measured by in vitro dissolution measurement in usp apparatus 2 (paddle) at 37 ℃ of 500ml0.1n HCl or simulated gastric fluid without enzymes (SGF) at 50 rpm.

In certain embodiments, the immediate release solid oral dosage form of the invention has a release of, for example, one or more of the following, as measured by in vitro dissolution measurement in usp apparatus 1 (basket) at 37 ℃ in 900ml distilled water at 50 rpm: (i) at least about 15%, at least about 25%, or at least about 35% of the active agent (e.g., opioid agonist) is released at 15 minutes, or (ii) at least about 25%, at least about 35%, or at least about 45% of the active agent is released at 30 minutes.

In certain embodiments, the immediate release solid oral dosage forms of the invention release, e.g., (i) about 15% to about 70% of the active agent (e.g., opioid agonist) in 15 minutes, (ii) about 25% to about 80% of the active agent in 30 minutes, and at least about 90% of the active agent in 45 minutes, as measured by in vitro dissolution of usp apparatus 1 (basket) in 900ml of distilled water at 37 ℃ at 50 rpm.

The immediate release dosage form of the present invention may be in the form of a compressed tablet or contained in a pharmaceutically acceptable capsule.

In a particular embodiment as depicted in fig. 1, an immediate release dosage form (10) of the present invention may comprise a plurality of particles (11), each particle comprising (i) an active agent (12) (e.g., an opioid agonist), and (ii) an acidic pH sensitive material (13) (e.g., chitosan, polyacrylate, or ion exchange resin), wherein the plurality of particles are dispersed in a matrix (14) comprising (i) a gelling agent, (ii) a disintegrant, and (iii) a filler, wherein the in vitro dissolution measurements are carried out by performing the in vitro dissolution measurements at 50rpm in a United states Pharmacopeia apparatus 2 (paddle) at 37 ℃ in 500ml of 0.1N HCl, the dosage form releases at least about 85% of the active agent within 45 minutes, and wherein when administered by parenteral or nasal route, the viscosity of the dosage form mixed with about 0.5 to about 10ml of distilled water prevents or reduces the ability of the active agent to be pumped up by a syringe or absorbed systemically.

In certain embodiments, the recovery of the active agent (e.g., opioid agonist) is, for example, less than about 10%, less than about 8%, less than about 6%, less than about 4%, less than about 2%, less than about 1%, less than about 0.8%, less than about 0.6%, less than about 0.4%, or less than about 0.2%, according to the syringability test by mixing or crushing and mixing the dosage form in 5mL of solvent and then sucking the resulting solution using an 271/2 gauge needle.

The solvent used in the penetration test may be, for example, tap water, distilled water, sterile saline, vinegar, or 40% ethanol. Likewise, in the needle penetration test, the solvent (either before or after mixing with the dosage form) may be heated using any heat source, such as a butane lighter.

In certain embodiments of the invention, the recovery of the drug is, for example, less than about 10%, less than about 8%, less than about 6%, less than about 4%, less than about 2%, less than about 1%, less than about 0.8%, less than about 0.6%, less than about 0.4%, or less than about 0.2% according to the heated and non-heated needle penetration test by mixing or crushing and mixing the dosage form in 5mL of solvent and then drawing the forming solution using an 271/2 gauge needle.

In certain embodiments, the ratio extracted from the unheated stability test to the heated stability test is about 1:5 to about 5:1, about 1:4 to about 4:1, about 1:3 to about 3:1, about 1:2 to about 2:1, about 1:1.5 to about 1.5:1, about 1:1.3 to about 1.3:1, or about 1:1.1 to about 1.1: 1.

Active agent

In certain embodiments, the active agent for use in the solid oral dosage forms of the present invention is selected from the group consisting of ACE inhibitors, adenohypophysis hormones, adrenergic neuron blockers, adrenal corticosteroids, inhibitors of adrenal corticosteroid biosynthesis, α -adrenergic agonists, α -adrenergic antagonists, selective α -2 adrenergic agonists, analgesics, antipyretics, anti-inflammatory agents, androgens, local and systemic anesthetics, anti-addiction agents, antiandrogens, antiarrhythmics, antiasthmaticsCholinergic agents, anticholinesterase agents, anticoagulants, antidiabetic agents, antidiarrheal agents, antidiuretic agents, antiemetics, prokinetic agents, antiepileptics, antiestrogens, antifungals, antihypertensive agents, antimicrobial agents, antimigraine agents, antimuscarinic agents, antineoplastic agents, antiparasitic agents, antiparkinson agents, antiplatelet agents, antiprogestins, schizophrenia agents, antithyroid agents, antitussive agents, antiviral agents, atypical antidepressants, azaspirocyclic decanediones, barbiturates, benzodiazepine salts or estersBenzothiadiazine, β -adrenal agonists, β -adrenal antagonists, selective β -1 adrenal antagonists, selective β -2 adrenal agonists, bile salts, agents that influence body fluid volume and composition, ketobutyric, agents that influence calcification, calcium channel blockers, cardiovascular drugs, cannabinoids, catecholamines and sympathomimetics, cholinergic agonists, cholinesterase reactivators, contraceptives, dermatological agents, diphenylbutylpiperidines, diuretics, ergot alkaloids, estrogens, ganglion blockers, ganglion stimulants, hydantoins, agents that control acid gastric juice and treat peptic ulcers, hematopoietic agents (hematogenic agents), histamine antagonists, hormones, 5-hydroxytryptamine antagonists, agents for treating hyperlipoproteinemia, hypnotics, sedatives, immunosuppressive agents, laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscular blockers, organic nitrates or esters, opioid agonists, opioid antagonists, pancreatic oxazines, phenothiazines, progestagens, prostaglandins, motility agents for treating diseases, testosterone, sodium hypothalamic disorders, transvascular antagonists, bronchodilators, vasopressive agents, bronchoconstrictors, broncholytics, bronchodilators, vasoconstrictors, or vasoconstrictors, or combinations thereof.

In certain embodiments, the active agent is susceptible to abuse (e.g., opioid analgesics such as opioid agonists). In said embodiment, the opioid analgesic is selected from the group consisting of alfentanil (alfentanil), allylamine (allylpropidine), anadoline (alphapropidine), anileridine (anileridine), benzylmorphine (benzylmorphine), bezilimide (bezitramide), buprenorphine (buprenorphine), butorphanol (butorphanol), lonicerazine (onicazine), codeine (codeine), desomorphine (desomorphine), dextromethorphan (dexomoramide), dezocine (dezocine), dinopropylamine (diampromide), diamorphine (diamorphine), dihydrocodeine (dihydromorphine), dihydromorphine (dihydromorphine), dimemethadone (dimedone), dimehypoxepinol (dimehypoxetol), thiomethamphetamine (diethylhexidone), ethicone (diethylphenazine), diethylphenazine (diethylphenazine), and mixtures thereof, Hydromorphone (oxymorphone), oxyperidine (hydroxypetidine), isometholone (isometholone), ketoximidone (ketobemidone), levorphanol (levorphanol), levorphanol (levophenicol), lofentanil (lofentane), meperidine (meperidine), meptazinol (meptazinol), metazocine (methazocine), methadone (methadone), metosone (metopon), morphine (morphine), mylorphine (myorphine), nalbuphine (nalbuphine), narbrorphine (narbepine), narcotine (narcotine), nicomorphine (normorphine), norlevorphanol (noroxymorphone), noroxymorphone (oxyphenone), oxyphenone (oxyphenoxyquinone), oxyphenone (oxyphenone), oxyphenone (oxyphenone), trimethine (promedol), propiverine (properine), propiram (propiram), dexpropoxyphene (propofol), sufentanil (supentinil), tilidine (tilidine), tramadol (tramadol), pharmaceutically acceptable salts thereof and mixtures of the foregoing. In certain embodiments, the opioid agonist is selected from codeine, fentanyl, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaceutically acceptable salts thereof, and mixtures of the foregoing.

In certain embodiments, the opioid agonist is oxycodone or a pharmaceutically acceptable salt thereof in an amount of, for example, about 2.5mg, 5mg, 7.5mg, 10mg, 15mg, 20mg, 25mg, or 30 mg.

In certain embodiments of the present invention wherein the active agent is oxycodone hydrochloride, the oxycodone hydrochloride used has an amount of 14-hydroxycodeinone of less than about 25ppm, less than about 15ppm, less than about 10ppm, less than about 5ppm, less than about 2ppm, less than about 1ppm, less than about 0.5ppm, or less than about 0.25 ppm.

WO 2005/097801A1, U.S. Pat. No. 7,129,248B2 and US2006/0173029A1, all incorporated herein by reference, describe processes for preparing oxycodone hydrochloride having a low content of 14-hydroxycodeinone.

In certain embodiments, the oral solid dosage forms of the present invention comprise an active agent that is an opioid antagonist (with or without an opioid agonist) — in such embodiments, the opioid antagonist is selected from the group consisting of amibendazole (amiphenazole), Naltrexone (Naltrexone), methylnaltrexone, naloxone (naloxone), nalbuphine (nalbuphine), nalmorphine (nalorphine), nalmorphine nicotinate, nalmefene (nalmefene), β -nicotinamide adenine dinucleotide (nadide), levallorphan (levalorphan), cycloxathiin (cyclozocine), pharmaceutically acceptable salts thereof, and mixtures thereof.

In certain embodiments, the solid oral dosage form of the present invention comprises an active agent that is a non-opioid analgesic. In said embodiment, the non-opioid analgesic is acetaminophen or a non-steroidal anti-inflammatory selected from the group consisting of: aspirin (as)pirin), celecoxib (celecoxib), ibuprofen (ibuprolen), diclofenac (diclofenac), naproxen (naproxen), benoxaprofen (benoxaprofen), flurbiprofen (flurbiprofen), fenoprofen (fenoprofen), flubufen (flubufen), ketoprofen (ketoprofen), indoprofen (indoprofen), pirprofen (piroprofen), carprofen (carprofen), oxaprozin (oxaprozin), pranoprofen (pranoprofen), miroprofen (muoprofen), trioxofen (trioxaprofen), suprofen (suprofen), amiprofen (amiprofen), tiaprofenic acid (tiaprofenic acid), fluprofen (fluprofen), cloth (bucloxacin), indomethacin (sulindac), sulindac (amiprofen), tiofenac (tiaprofenic acid), tiaprofenic acid (tiaprofenic acid), fluprofen (fluprofen), ibuprofen (butofenac), indomethacin (indomethacin), ibuprofen (sulindac), doxicac (indolecetic), thioctic acid (tetrachlorac), thioctic acid (tetrachlorvinpoc (fenac), doxicac (tetrachlor), clofenac (tetrachlor), clofenac (tetrachlorvinpoc (tetrachlor), clofenac (clofenamic acid (clofenac), clofenac (clofenamic acid (,_{Oxyunacic acid}(oxapinac), mefenamic acid (mefenamic acid), meclofenamic acid (meclofenamic acid), flufenamic acid (flufenamic acid), niflumic acid (niflumic acid), tolfenamic acid (tolfenamic acid), diflunisal (diflurisal), flufenisal (flufenisal), piroxicam (piroxicam), sudoxicam (sudoxicam), isoxicam (isoxicam), their pharmaceutically acceptable salts and mixtures of the above.

In other embodiments, the invention relates to the dosage forms disclosed herein that use an active agent such as benzodiazepine, barbiturate or an amphetamine, antagonists thereof, or combinations of the foregoing.

Benzodiazepines to be used in the present inventionPossibly selected from the group consisting of alprazolam (alprazolam), bromodiazam (brozepam), chlordiazepoxide (chloredizoxypode), lorazelate (clorazepate), diazepam (diazepam), estazolam (estazolam), flurazepam (flurazepam), halazepam (halazepam), katazoam (ketazolam), lorazepam (lorazepam), nitrazepam (nitrazepam), oxazepam (oxzepam), prazepam (prazepam), quazepam (quazepam), temazepam (temazepam), triazolam (triazolam), and oxazepamPharmaceutically acceptable salts, hydrates and solvates thereof and mixtures of the foregoing. Benzodiazepine antagonists that may be used in the present invention include, but are not limited to, flumazenil (flumazenil) and pharmaceutically acceptable salts, hydrates and solvates thereof.

Barbiturates to be used in the present invention include, but are not limited to, amobarbital (amobarbital), aleppobarbital (aprobarbital), butarbital (butarbital), butalbital (butarbital), methohexital (methohexital), mephobarbital (mephobarbital), methabarbital (methabarbital), pentobarbital (pentobarbital), phenobarbital (phenobarbital), secobarbital (secobarbital), and pharmaceutically acceptable salts, hydrates, and solvate mixtures thereof. Barbiturate antagonists that may be used in the present invention include, but are not limited to, amphetamines and pharmaceutically acceptable salts, hydrates, and solvates thereof.

Stimulants to be used in the present invention include, but are not limited to amphetamines such as amphetamine, dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate and their pharmaceutically acceptable salts, hydrates and solvates and mixtures thereof. Stimulant antagonists that may be used in the present invention include, but are not limited to, benzodiazepines and pharmaceutically acceptable salts, hydrates, and solvates as described herein.

In embodiments comprising a first active agent and a second active agent as disclosed herein (e.g., the first active agent is a substrate for coating the second active agent thereon), the first active agent can be a non-opioid analgesic and the second active agent can be an opioid agonist. Alternatively, the first active agent may be an opioid agonist and the second active agent may be a non-opioid analgesic. In particular embodiments, the non-opioid analgesic is acetaminophen or a non-steroidal anti-inflammatory drug (such as ibuprofen, aspirin, or diclofenac) and the opioid agonist is oxycodone, hydrocodone, or a pharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride or hydrocodone bitartrate).

The immediate release solid oral dosage form of the invention may contain, for example, from about 2.5mg to about 10mg oxycodone or a pharmaceutically acceptable salt thereof, from about 2.5mg to about 15mg hydrocodone or a pharmaceutically acceptable salt thereof, from about 325mg to about 650mg acetaminophen, from about 100mg to about 800mg ibuprofen, or from about 325mg to about 750mg aspirin.

A particular formulation may comprise about 2.5mg oxycodone, or a pharmaceutically acceptable salt thereof, and about 325mg acetaminophen; about 5mg oxycodone or a pharmaceutically acceptable salt thereof and about 325mg acetaminophen; about 7.5mg oxycodone or a pharmaceutically acceptable salt thereof and about 325mg acetaminophen; about 10mg oxycodone or a pharmaceutically acceptable salt thereof and about 325mg acetaminophen; about 7.5mg oxycodone or a pharmaceutically acceptable salt thereof and about 500mg acetaminophen; about 10mg oxycodone or a pharmaceutically acceptable salt thereof and about 650mg acetaminophen; about 5mg oxycodone or a pharmaceutically acceptable salt thereof and about 500mg acetaminophen; about 2.5mg oxycodone or a pharmaceutically acceptable salt thereof and about 300mg acetaminophen; about 5mg oxycodone or a pharmaceutically acceptable salt thereof and about 300mg acetaminophen; about 7.5mg oxycodone or a pharmaceutically acceptable salt thereof and about 300mg acetaminophen; about 10mg oxycodone or a pharmaceutically acceptable salt thereof and about 400mg acetaminophen; about 2.5mg oxycodone or a pharmaceutically acceptable salt thereof and about 400mg acetaminophen; about 5mg oxycodone or a pharmaceutically acceptable salt thereof and about 400mg acetaminophen; or about 7.5mg oxycodone or a pharmaceutically acceptable salt thereof and about 400mg acetaminophen.

Other formulations may comprise about 2.5mg oxycodone or a pharmaceutically acceptable salt thereof and about 325mg aspirin, about 5mg oxycodone or a pharmaceutically acceptable salt thereof and about 325mg aspirin, about 7.5mg oxycodone or a pharmaceutically acceptable salt thereof and about 325mg aspirin, about 10mg oxycodone or a pharmaceutically acceptable salt thereof and about 325mg aspirin, about 2.5mg oxycodone or a pharmaceutically acceptable salt thereof and about 500mg aspirin, about 5mg oxycodone or a pharmaceutically acceptable salt thereof and about 500mg aspirin, about 7.5mg oxycodone or a pharmaceutically acceptable salt thereof and about 500mg aspirin, about 10mg oxycodone or a pharmaceutically acceptable salt thereof and about 500mg aspirin. In certain embodiments, the formulation comprises about 4.8355mg oxycodone, or a pharmaceutically acceptable salt thereof, and 325mg aspirin.

Other formulations may contain about 5mg hydrocodone or a pharmaceutically acceptable salt thereof and about 500mg acetaminophen; about 10mg hydrocodone or a pharmaceutically acceptable salt thereof and about 660mg acetaminophen; about 7.5mg hydrocodone or a pharmaceutically acceptable salt thereof and about 750mg acetaminophen; about 5mg hydrocodone or a pharmaceutically acceptable salt thereof and about 325mg acetaminophen; about 7.5mg hydrocodone or a pharmaceutically acceptable salt thereof and about 325mg acetaminophen; about 10mg hydrocodone or a pharmaceutically acceptable salt thereof and about 325mg acetaminophen; about 7.5mg hydrocodone or a pharmaceutically acceptable salt thereof and about 650mg acetaminophen; about 10mg hydrocodone or a pharmaceutically acceptable salt thereof and about 750mg acetaminophen; about 10mg hydrocodone or a pharmaceutically acceptable salt thereof and about 500mg acetaminophen; about 5mg hydrocodone or a pharmaceutically acceptable salt thereof and about 400mg acetaminophen; about 7.5mg hydrocodone or a pharmaceutically acceptable salt thereof and about 400mg acetaminophen; or about 10mg hydrocodone or a pharmaceutically acceptable salt thereof and about 400mg acetaminophen.

The additional formulation may comprise about 2.5mg hydrocodone or a pharmaceutically acceptable salt thereof and about 200mg ibuprofen, about 5mg hydrocodone or a pharmaceutically acceptable salt thereof and about 200mg ibuprofen, about 7.5mg hydrocodone or a pharmaceutically acceptable salt thereof and about 200mg ibuprofen, or about 10mg hydrocodone or a pharmaceutically acceptable salt thereof and about 200mg ibuprofen.

Pharmacokinetic parameters

In preferred embodiments, the formulations of the invention comprise an opioid agonist (e.g., oxycodone hydrochloride) and preferably provide a Tmax of about 0.5 hours to about 6 hours, or about 1 hour to about 5 hours, or about 2 hours to about 4 hours, or about 2 hours to about 3 hours, or about 1 hour to about 3 hours, or about 2.5 hours.

In embodiments comprising oxycodone or a pharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride), the formulation preferably provides a Cmax of about 30ng/mL to about 50ng/mL, or about 35ng/mL to about 45ng/mL, or about 38 to about 42ng/mL, depending on the single dose of about 15mg administered to the individual; or providing a mean Cmax of about 30ng/mL to about 50ng/mL, or about 35ng/mL to about 45ng/mL, or about 38 to about 38ng/mL, based on administering a single dose of about 15mg to a population of individuals.

In embodiments comprising oxycodone or a pharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride), the formulation preferably provides a Cmax of about 20ng/mL to about 35ng/mL, or about 22ng/mL to about 32ng/mL, or about 25 to about 30ng/mL, depending on the single dose of about 10mg administered to the individual; or providing a mean Cmax of about 20ng/mL to about 35ng/mL, or about 22ng/mL to about 32ng/mL, or about 25 to about 30ng/mL, based on administering a single dose of about 10mg to a population of individuals.

In embodiments comprising oxycodone or a pharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride), the formulation preferably provides a Cmax of about 8ng/mL to about 20ng/mL, or about 10ng/mL to about 18ng/mL, or about 12 to about 16ng/mL, depending on the single dose of about 5mg administered to the individual; or providing a mean Cmax of about 8ng/mL to about 20ng/mL, or about 10ng/mL to about 18ng/mL, or about 12 to about 16ng/mL, based on administering a single dose of about 5mg to a population of individuals.

In embodiments comprising oxycodone or a pharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride), the formulation preferably provides a Cmax of about 4ng/mL to about 12ng/mL, or about 5ng/mL to about 10ng/mL, or about 6 to about 8ng/mL, based on administering to the subject a single dose of about 2.5 mg; or from about 4ng/mL to about 12ng/mL, or from about 5ng/mL to about 10ng/mL, or from about 6 to about 8ng/mL, in accordance with a single dose of about 2.5mg administered to a population of individuals.

In embodiments comprising oxycodone or a pharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride), the individual is administered a single dose of about 15mgThe formulation preferably provides an AUC of about 150ng x h/mL to about 350ng x h/mL, or about 200ng x h/mL to about 300ng x h/mL, or about 225ng x h/mL to about 275ng x h/mL_o-t(ii) a Or providing an average AUC of about 150ng h/mL to about 350ng h/mL, or about 200ng h/mL to about 300ng h/mL, or about 225ng h/mL to about 275ng h/mL, based on administering a single dose of about 15mg to a population of individuals_o-t。

In embodiments comprising oxycodone or a pharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride), the formulation preferably provides an AUC of about 100ng h/mL to about 300ng h/mL, or about 120ng h/mL to about 240ng h/mL, or about 150ng h/mL to about 200ng h/mL, upon administration of a single dose of about 10mg to an individual_o-t(ii) a Or providing an average AUC of about 100ng h/mL to about 300ng h/mL, or about 120ng h/mL to about 240ng h/mL, or about 150ng h/mL to about 200ng h/mL, based on administering a single dose of about 10mg to a population of individuals_o-t。

In embodiments comprising oxycodone or a pharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride), the formulation preferably provides an AUC of about 50ng h/mL to about 150ng h/mL, or about 60ng h/mL to about 120ng h/mL, or about 75ng h/mL to about 100ng h/mL, depending on the administration of a single dose of about 5mg to an individual_o-t(ii) a Or providing an average AUC of about 50ng h/mL to about 150ng h/mL, or about 60ng h/mL to about 120ng h/mL, or about 75ng h/mL to about 100ng h/mL, based on administering a single dose of about 5mg to a population of individuals_o-t。

In embodiments comprising oxycodone or a pharmaceutically acceptable salt thereof (e.g., oxycodone hydrochloride), the formulation preferably provides an AUC of about 20ng h/mL to about 100ng h/mL, or about 25ng h/mL to about 75ng h/mL, or about 30ng h/mL to about 50ng h/mL, depending on the individual administered a single dose of about 2.5mg_o-t(ii) a Or providing an average AUC of about 20ng h/mL to about 100ng h/mL, or about 25ng h/mL to about 75ng h/mL, or about 30ng h/mL to about 50ng h/mL, based on administering a single dose of about 2.5mg to a population of individuals_o-t。

Manufacturing method

The present invention also relates to a process for preparing the immediate release solid oral dosage form disclosed herein. In certain embodiments, the method comprises (i) preparing a plurality of particles, each particle comprising an active agent and a substance sensitive to acidic pH, and (ii) dispersing the plurality of particles in a matrix, wherein the dosage form releases at least about 85% of the active agent within 45 minutes as measured by in vitro dissolution at 50rpm in usp apparatus 2 (paddle) at 37 ℃ in 500ml0.1N HCl.

In another embodiment, the method comprises dispersing a plurality of particles in a matrix, each particle comprising an active agent and a substance sensitive to acidic pH, wherein the dosage form releases at least about 85% of the active agent within 45 minutes as measured by in vitro dissolution of the dosage form in usp apparatus 1 (paddle) at 37 ℃ in 500ml0.1N HCl at 50 rpm.

In certain embodiments, the substrate may comprise one or more of a gelling agent, a disintegrant, or a filler.

The particles may be prepared by layering a material sensitive to acidic pH on a core containing the active agent. The core may be prepared by layering the active agent in an inert excipient (such as microcrystalline cellulose beads or sugar spheres) or by dispersing the active agent in a pharmaceutically acceptable excipient. Alternatively, an active agent (e.g., acetaminophen) may be used in place of the inert excipient with an additional active agent (e.g., opioid agonist) layered thereon.

In other embodiments, the particles may be prepared by layering a core comprising an inert excipient with a coating comprising the active agent and a substance sensitive to acidic pH. In an alternative embodiment, the particles may be prepared by dispersing the active agent in a material that is sensitive to acidic pH.

In an alternative embodiment, the immediate release dosage form of the present invention may be prepared by (i) granulating an active agent and a material sensitive to acidic pH to obtain granules, and (ii) compressing the granules into tablets or containing the granules in capsules, wherein the dosage form releases at least about 85% of the active agent within 45 minutes as measured by in vitro dissolution in usp apparatus 1 (paddle) at 37 ℃ in 500ml0.1N HCl at 50 rpm.

The process may also incorporate one or more of a gelling agent, a disintegrant, or a filler. The filler may be spray dried using a solution comprising the active agent and a substance sensitive to acidic pH to obtain a spray dried composition as shown in figures 2 and 3. The spray dried granules may then be granulated with the gelling agent and the disintegrant and other excipients and then compressed into a unit dosage form as further described in figures 2 and 3.

Method of treatment

The present invention further relates to a method of treating a disease or disorder comprising administering to a patient in need of treatment any of the immediate release solid oral dosage forms described herein. In certain embodiments, the patient is treated for pain, diarrhea, or constipation.

The types of pain that can be treated with the immediate release solid oral dosage form of the invention include pain caused by: pancreatitis, kidney stones, headaches, dysmenorrhea, musculoskeletal pain, sprains, visceral pain, ovarian cysts, prostatitis, cystitis, interstitial cystitis, inflammatory bowel disease, post-operative pain, toothache, post-operative pain, migraine, trigeminal dysmenorrhea, burn and scald and/or wound pain, pain associated with trauma, neuropathic pain, post-herpetic dysmenorrhea, pain associated with musculoskeletal disease, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, periarticular pathologies, tumor pain, bone metastasis pain, HIV pain, or myocardial infarction pain. In certain embodiments, the immediate release solid oral dosage form of the present invention may be used to treat "breakthrough pain" (i.e., a short period of pain that occurs suddenly and cannot be alleviated with the patient's general pain management).

The treatment methods of the present invention may comprise administering a solid oral dosage form as described herein in combination with another pharmaceutical composition. In certain embodiments, the other pharmaceutical composition is administered to treat the same disorder or disease. In other embodiments, the other pharmaceutical composition is administered to treat a different disorder or disease.

In certain embodiments, the treatment methods of the invention further comprise monitoring the condition of the patient's metabolism of the active agent, or the patient's response to the active agent. In certain embodiments, the method of treatment further comprises altering the amount of the solid oral dosage form based on the monitoring. In certain embodiments, certain baseline measurements are taken on the patient prior to administering the solid oral dosage form to the patient.

The following examples are set forth to aid in understanding the invention and should not be construed as specifically limiting the invention and the claims set forth herein. Such variations of the invention, including substitutions of all now known or later developed equivalents, which are within the purview of one skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered within the scope of the invention as incorporated herein.

Example 1

Formulations 1A to 1O are gelled substrates that can be used in the present invention to disperse active agent particles comprising a material sensitive to acidic pH. The formulations were prepared according to the following general method (which may be varied using the particles of the invention in place of naloxone):

the method comprises the following steps:

1. items 1 to 5 (naloxone, lactose, microcrystalline cellulose (MCC), gelling polymer and crospovidone, respectively) were passed through a 20 mesh screen, charged into a V-blender and mixed for 10 minutes.

2. Item 6 (magnesium stearate) was passed through a 30 mesh screen and mixed for 3 minutes in the above V-blender.

3. The above mixture of step 2 was compressed into tablets (round) of a target weight of 500mg and a target hardness of 3 to 5kp using a rotary tablet press from Stokes, Fette or Killian.

Tables 1A to 1O show the formulations of examples 1A to 1O, respectively.

TABLE 1A

TABLE 1B

TABLE 1C

TABLE 1D

TABLE 1E

TABLE 1F

TABLE 1G

TABLE 1H

TABLE 1I

TABLE 1J

TABLE 1K

TABLE 1L

TABLE 1M

TABLE 1N

TABLE 1O

Example 2

Formulations 2A (bolus) and 2B (tablet) were prepared according to the following general method:

methods of preparing 2A and 2B:

1. add item 2 (naloxone) and items 5 (talc) to 6 (water) and mix for about 30 minutes in a mixing vessel such as a V-blender.

2. While still stirring, item 3 (an aqueous dispersion of a copolymer comprising methyl methacrylate and diethylaminoethyl methacrylate (Kollicoat smart 30D)) and item 4 (triethyl citrate) were added to the above drug suspension, and stirring was continued for at least 2 hours. Homogenization was carried out for 5 minutes and screening was carried out through a 200 mesh screen before spraying.

3. The microcrystalline cellulose spheres of item 1 were charged to a spray dryer (GPCG-3 fluid bed dryer). The apparatus is set to spray the coating suspension of step 2 at about 5-15 g/min.

4. After the spraying step is completed, the formed particles (beads) or pellets are further dried at about 40 ± 5 ℃ for about 30 minutes.

5. The coated granules of example 2A were collected after successive passes through 40 and 100 mesh screens to remove agglomerate fines.

6. The coated granules were mixed with the other excipients from example 2B (lactose, microcrystalline cellulose, gelling polymers, crospovidone and magnesium stearate) and compressed into tablets with a target weight of 500mg and a target hardness of 3 to 5kp using a rotary tablet press from Stokes, Fette or Killian.

Tables 2A and 2B show the formulations of examples 2A and 2B, respectively.

TABLE 2A

TABLE 2B

Numbering	Composition (I)	mg/tablet	％
				1	Drug layered MCC pellet of example 2A	250.00	50.000
2	Lactose monohydrate (Fast Flo 316)	216.00	43.200
				3	Avicel pH 102	0.00	0.000
4	Pregelatinized starch (Swelstar MX-1)	5.00	1.000
				5	Polyvinylpolypyrrolidone (Croospovidone)	25.00	5.000
6	Magnesium stearate	3.75	0.750
					Total of	500	100.0

The dissolution of example 2B was measured under the following conditions:

the method comprises the following steps: united states pharmacopoeia equipment 2 (Paddle type)

Paddle speed: 75rpm

Medium: distilled water or 0.1N HCl

Volume: 500ml of

Sampling interval: 5. 10, 15, 30, 45 and 60 minutes.

Table 2C shows the dissolution data for example 2B in water and 0.1N HCl.

TABLE 2C

Example 3

Formulations 3A (bolus) and 3B (tablet) were prepared according to the following general method:

methods of preparing 3A and 3B:

1. add items 5 (talc) to 6 (water) and mix for about 30 minutes in a mixing vessel such as a V-blender.

2. While stirring, item 3 (aqueous dispersion of copolymer comprising methyl methacrylate and diethylaminoethyl methacrylate) and item 4 (triethyl citrate) were added to the above suspension. Stirring was continued for at least 2 hours.

3. The coating suspension was divided into two portions (first portion 500ml, second portion 2500 ml). Add item 2 (naloxone) to the first portion and continue stirring.

4. The first and second partial coating suspensions were homogenized for about 5 minutes and screened through a 200 mesh screen prior to spraying.

5. The spray dryer (GPCG-3 fluid bed dryer) was charged with item 1 (microcrystalline cellulose spheres) and the appropriate operating parameters for the instrument were set. The coating suspension of step 4 is sprayed at about 5-15 g/min, starting with the first portion and then with the second portion.

6. After the spraying operation is completed, the drying of the pellet is continued at about 40 ± 5 ℃ for about 30 minutes.

7. The coated granules of example 3A were collected after sieving through 40 mesh and 100 mesh sieves, respectively, to remove agglomerate fines.

8. The coated granules were mixed with the other excipients from example 3B (lactose, microcrystalline cellulose, gelling polymers, crospovidone and magnesium stearate) and compressed into tablets with a target weight of 500mg and a target hardness of about 3 to 5kp using a rotary tablet press from Stokes, Fette or Killian.

Tables 3A and 3B show the formulations of examples 3A and 3B, respectively.

TABLE 3A

TABLE 3B

Numbering	Composition (I)	mg/tablet	％	Batch numbering
					1	Drug layered MCC pellet of example 3A	330.00	66.000	Example 3A
2	Lactose monohydrate (Fast Flo 316)	136.00	27.200	8511071661
					3	Avicel pH 102	0.00	0.000	p211823096
4	Pregelatinized starch (Swelstar MX-1)	5.00	1.000	9111
					5	Polyvinylpolypyrrolidone (Croospovidone)	25.00	5.000	54752224U0
6	Magnesium stearate	3.75	0.750	C005160
						Total of	500	100.0

The dissolution test of example 3B was performed under the following conditions:

the method comprises the following steps: united states pharmacopoeia equipment 2 (Paddle type)

Paddle speed: 75rpm

Medium: distilled water or 0.1N HCl

Volume: 500ml of

Sampling interval: 5. 10, 15, 30, 45 and 60 minutes.

Table 3C shows the dissolution data for example 3B in water and 0.1N HCl.

TABLE 3C

Example 4

Formulations 4A (drug-layered pellets), 4B (acrylic coated pellets with Kollicoat Smartseal 30D), 4C (acrylic coated pellets with Eudragit E100), 4D (tablets) and 4E (tablets) were prepared according to the following general procedure:

methods of making 4A, 4B, 4C, 4D, and 4E:

4A: drug layer coating

Item 3 (povidone) to item 4 (water) were dissolved to prepare a binder solution, and item 2 (naloxone) was added to the binder to prepare a coating solution. The above coating solution was sprayed onto item 1 (MCC balls) using GPCG-3. The drug-layered pellets were used for further coating in the following examples 4B and 4C.

4B and 4D: kollicoat Smartseal30D top stack pellet and tablet

1. Add items 4 (talc) to 5 (water) and mix for about 30 minutes.

2. While stirring, add item 2 (Kollicoat Smartseal 30D) and item 3 (triethyl citrate) to the suspension and continue stirring for at least 2 hours.

3. The coating suspension was homogenized for about 5 minutes and sieved through a 200 mesh screen before spraying.

4. The drug stack MCC spheres of item 1 were loaded into a spray dryer (GPCG-3 fluid bed dryer). The coating suspension of item 3 is sprayed at about 5 to 15 g/min.

5. After the spraying step is completed, the drying of the pellet is continued at 40 ± 5 ℃ for about 30 minutes.

6. The coated granules of example 4B were collected after sequentially passing through 40 mesh and 100 mesh screens to remove agglomerate fines.

7. The coated granules were mixed with the other excipients from example 4D (lactose, microcrystalline cellulose, gelling polymers, crospovidone, and magnesium stearate) and compressed into tablets with a target weight of about 500mg and a target hardness of about 3 to 5kp using a rotary tablet press from Stokes, Fette, or Killian.

4C and 4E: eudragit E100 top-laminated pellet and tablet

1. Mix items 3, 4 and 5 (IPA, acetone and water) to make the solvent system.

2. Add Eudragit E100 item 2 to half of the solvent system of step 1. Stirring was continued until dissolved.

3. Add items 6 and 7 (triethyl citrate and talc) to the other half of the solvent system of step 1 and homogenize for about 10 minutes.

4. Adding the suspension of the step 3 to the solution of the step 2, and continuing stirring. The suspension was passed through a 0.5mm screen before spraying.

5. Item 1 (drug stacked MCC spheres) was loaded into a spray dryer (GPCG-3 fluid bed dryer). The coating suspension of step 4 is sprayed at about 5 to 15 g/min.

6. After the spraying step was completed, the drying of the granules was continued at 40 ± 5 ℃ for about 30 minutes.

7. The coated granules of example 4C were collected after successively passing them through 40 mesh and 100 mesh screens to remove agglomerate fines.

8. The coated granules were mixed with the other excipients from example 4E (lactose, microcrystalline cellulose, gelling polymers, crospovidone and magnesium stearate) and compressed into tablets with a target weight of 500mg and a target hardness of about 3 to 5kp using a rotary tablet press from Stokes, Fette or Killian.

Tables 4A to 4E show the formulations of examples 4A to 4E, respectively.

TABLE 4A

TABLE 4B

TABLE 4C

TABLE 4D

Numbering	Composition (I)	mg/tablet	％
				1	Drug layered MCC pellet of example 4B	300.00	60.000
2	Lactose monohydrate (Fast Flo 316)	166.00	33.200
				3	MCC(Avicel pH 102)	0.00	0.000
4	Pregelatinized starch (Swelstar MX-1)	5.00	1.000
				5	Polyvinylpolypyrrolidone (Croospovidone)	25.00	5.000
6	Magnesium stearate	3.75	0.750
					Total of	500	100.0

TABLE 4E

Numbering	Composition (I)	mg/tablet	％
				1	Drug layered MCC pellet of example 4C	300.00	60.000
2	Lactose monohydrate (Fast Flo 316)	166.00	33.200
				3	MCC(Avicel pH 102)	0.00	0.000
4	Pregelatinized starch (Swelstar MX-1)	5.00	1.000
				5	Polyvinylpolypyrrolidone (Croospovidone)	25.00	5.000
6	Magnesium stearate	3.75	0.750
					Total of	500	100.0

The dissolution tests of examples 4D and 4E were carried out under the following conditions:

the method comprises the following steps: united states pharmacopoeia equipment 2 (Paddle type)

Paddle speed: 75rpm

Medium: distilled water or 0.1N HCl

Volume: 500ml of

Sampling interval: 5. 10, 15, 30, 45 and 60 minutes.

Table 4F shows the dissolution data for example 4D, and Table 4G shows the dissolution data for example 4E.

TABLE 4F

TABLE 4G

Example 5A

Formulations of formula 5A (oxycodone hydrochloride tablets USP (5mg and 10mg)) and 5B (oxycodone hydrochloride tablets USP (20mg and 30mg)) were prepared according to the following general method:

1: medicine layer:

oxycodone hydrochloride and povidone (PVP) were dissolved in pure water in a 50 gallon stainless steel tank and the drug layer coating solution was prepared using an overhead stirrer. This solution was applied to MCC spheres using GPCG-60 equipped with an 18 inch Wurster insert. The resulting drug layered particles were screened using a Sweco screen fitted with US140 mesh and US 50 mesh screens.

2: polymer coating:

polymer coating suspensions (Eudragit E PO, Sodium Lauryl Sulfate (SLS), stearic acid and talc) were prepared in a 100 gallon stainless steel tank using an overhead stirrer and applied to oxycodone hydrochloride drug layered particles using GPCG-60 equipped with an 18 inch Wurster apparatus. After the polymer coating was complete, the particles were screened using a Sweco screen fitted with US140 mesh and US 40 mesh screens.

3: mixing:

the polymer coated particles and excipients (lactose monohydrate, crospovidone, pregelatinized starch (swelstartmx-1), FD & C yellow No. 6 (only 20mg and 30mg dose)) were passed through a US 25 mesh screen into a V-blender at 10 cubic feet and stirred for 10 minutes. Magnesium stearate was passed through a US 30 mesh screen into a V-blender and lubricated for 3 minutes to form the final mixture.

4: pressing:

the final blend was compressed to the desired tablet strength using a Manesty 700 rotary tablet press.

Tables 5A and 5B show the formulations of formulations 5A and 5B, respectively.

Example 5B

The dissolution of formulation 5A (15mg tablet) was measured under the following conditions:

the method comprises the following steps: united states pharmacopoeia equipment 2 (Paddle type)

Paddle speed: 50rpm

Medium: 0.1N HCl

Volume: 900ml of

Sampling interval: 5. 10, 15, 30, 45 and 60 minutes.

Table 5C below shows dissolution data for formulation 5A (15mg) in 0.1N HCl.

TABLE 5C

Example 5C

18 healthy subjects (8 males, 10 females) participated in the study, randomized to receive formulation 5A (15mg), and 17 subjects (94.4%) completed the study as planned. 17 individuals (94.4%) received their assigned dose of the test study drug and 18 individuals (100%) received their assigned dose of the reference study drug. 18 individuals were included in the safety population and 17 individuals were included in the Pharmacokinetic (PK) population.

Demographic study: individuals represent a healthy adult male and female population with an age distribution of 18 to 43 years. The mean (SD) age was 29.6(7.78) years and the mean (SD) Body Mass Index (BMI) was 26.5(2.64) kg/m². The ethnic group was 10 (55.6%) black and 8 (44.4%) white.

The methodology is as follows: the study was a single-center, randomized, open-label, single-dose, two-phase, crossover study to evaluate single-dose test (T) formulation oxycodone hydrochloride Immediate Release (IR)15mg tablets (formula 5A) andthe Pharmacokinetics (PK) and relative bioavailability of 15mg tablets (reference drug) (R) in healthy adult male and female subjects under satiating conditions. Each individual was randomly grouped into one of two treatment sequences (T-R, R-T) according to a randomized grouping plan established prior to the start of the study.

There was a 7 day rest period between each single dose administration. The subjects were all administered on the same day, i.e., on day 1 of phase 1, and the other formulation was administered on the same day, i.e., on day 8 of phase 2.

During phases 1 and 2, subjects received a single dose of naltrexone 50mg using about 240mL of ambient water at 12 hours (+ -1 hour) and 1 hour (+ -10 minutes) prior to receiving each study drug dose, and 12 hours (+ -30 minutes) after each study drug dose.

After an overnight fast of at least 10 hours, the subject had a high-fat breakfast within about 5 minutes before taking the drug. Then at about 8 am (+ -1 hour), the subject received a single dose of the reference or test formulation orally using about 240mL of normal temperature water.

Continuous blood samples for determination of oxycodone plasma concentrations and PK analysis were obtained at time 0 (within 90 minutes prior to dosing) on day 1 and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24 and 36 hours post-dosing. Individuals were discharged from the study facility approximately 36 hours after receiving their study drug dose. At phase 2, i.e., day 8 after the 7 day drug withdrawal period, subjects changed to receiving another formulation and the same study procedure was performed.

Individuals who completed two treatment sessions, did not significantly violate the study procedure, and provided plasma drug concentration data were included in the PK analysis cohort. The plasma oxycodone concentration levels are summarized using descriptive statistics. Plasma oxycodone PK parameters (AUC)_0-t、AUC_0-inf、C_max、t_max、t_1/2And K_el) Summary is listed according to treatment. The relative bioavailability of the test and reference formulations is based on the AUC of oxycodone_0-、AUC_0-infAnd C_maxAnd (6) determining. Log-transformed PK parameters AUC_0-、AUC_0-infAnd C_maxAnalysis was performed using analysis of variance (ANOVA), involving sequence, formulation and duration items as fixed effects, and individuals within the sequence as random effects. The arithmetic mean, geometric mean, ratio of geometric means and 90% Confidence Interval (CI) for the ratio of test to reference study drug are shown.

Graphs of mean plasma oxycodone concentration levels versus time for each treatment group are shown in figure 4 and table 5D below.

TABLE 5D

The results of the pharmacokinetic parameters for the PK population are shown in table 5E below.

TABLE 5E

Dissolution and pharmacokinetic results show that the drug release rate of the dosage form is the same as the reference drug.

Example 6

Formulation 6A (drug-layered granule), 6B (Eudragit E)Coated granules) and 6C (tablets) were prepared according to the following general method:

method of making formulation 6A: drug layer coating

Item 3 (povidone) to item 4 (water) were dissolved to prepare a binder solution, and item 2 (naloxone) was added to the binder solution to prepare a coating solution. The above coating solution is sprayed onto item 1 (acetaminophen (APAP) particles) using a suitable spray dryer such as a GPCG-3 spray dryer from Glatt technologies.

Method of making formulation 6B: naloxone-APAP particles with Eudragit E PO top-stacking (45% weight gain)

1. APAP granules were layered with the drug described in 5A for further coating.

2. Add items 3 and 4 (sodium lauryl sulfate (SLS) and stearic acid) to item 6 (water) and continue stirring until dissolved.

3. Add item 2 (Eudragit E PO) to the above solution and continue stirring until a slightly yellow solution is formed.

4. Add item 5 (talc) to the polymer solution and continue stirring for at least 30 minutes.

5. Item 1 (drug-layered APAP granules) was loaded into a GPCG-3 fluid bed dryer setting the machine and spray step 3 (coating suspension) to 5-15 g/min. Samples were collected as needed.

6. After the spraying step is completed, the drying of the granules is continued at about 40 ± 5 ℃ for about 15 minutes.

7. The coated granules were collected after sieving through 40 mesh and 140 mesh screens to remove agglomerate fines.

Method of making formulation 6C: tablet comprising Eudragit E PO top-stacked naloxone-APAP granules

1. Items 1 to 4 (coated naloxone-APAP granules, lactose, pregelatinized starch, and crospovidone) were passed through a 20 mesh screen and mixed for 10 minutes.

2. Item 5 (magnesium stearate) was passed through a 30 mesh screen into the above mixture (blend) and mixed for about 3 minutes.

3. Compressing into a tablet in the form of a capsule having a target weight of about 750mg and a target hardness of about 5-10 kp.

Tables 6A to 6C show the formulations of formulations 6A to 6C, respectively. Table 6D shows the amounts of pregelatinized starch and crospovidone in various formulations prepared according to example 6C.

TABLE 6A

TABLE 6B

TABLE 6C

TABLE 6D

Example 7

Formulation 7 was prepared according to the following general method:

the method comprises the following steps:

1. items 1 to 5 (naloxone, APAP, lactose, pregelatinized starch, and crospovidone) were passed through a 20 mesh screen and mixed for about 10 minutes.

2. Item 6 (magnesium stearate) was passed through a 30 mesh screen into the above mixture and mixed for about 3 minutes.

3. Compressed into caplet (caplet) tablets having a target weight of about 750mg and a target hardness of about 5-10 kp.

Table 7 shows the formulation of formulation 7. Table 7A shows the amounts of pregelatinized starch and crospovidone in various formulations prepared according to example 7.

TABLE 7

TABLE 7A

Example 8

Dissolution of formulation 6B, formulation 6C and formulation 7 was measured under the following conditions:

the method comprises the following steps: united states pharmacopoeia equipment 2 (Paddle type)

Paddle speed: 50rpm

Medium: distilled water or 0.1N HCl

Volume: 900ml of

Sampling interval: 5. 10, 15, 30 and 45 minutes.

Tables 8A, 8B, and 8C below (and figures 5, 6, and 7) show dissolution data for formulations 6B, 6C, and 7 in water and 0.1N HCl.

TABLE 8A (formulation 6B: EudragitEPO coated naloxone-APAP granules)

Polymer Eudragit E PO coating naloxone loaded-APAP particles (formulation 6B) showed pH dependent dissolution profile of naloxone in different dissolution media. Dissolution in 0.1N HCl released > 80% naloxone in 5 min. The dissolution of naloxone in water was slower than in 0.1N HCl.

Table 8B (formulation 6C: formulation containing Eudragit EPO coated naloxone-APAP particles, 1% Swelstar and 5% crospovidone)

Formulation 6C was prepared using coated naloxone-APAP particles (formulation 6B), 1% Swelstar, 5% crospovidone, and other excipients. Naloxone dissolved in 0.1N HCl reached 94% in 45 minutes. However, in water, the dissolution test showed that 9% naloxone was released at 45 minutes.

Table 8C (formulation 7: formulation with uncoated naloxone, APAPJSOU, 5% Swelstar and 5% crospovidone)

Formulation 7 was prepared using non-coated active agents (naloxone and APAP), 5% Swelstar, 5% crospovidone, and other excipients. Naloxone dissolves slower in 0.1N HCl than in water, indicating that the gelling polymer alone may not impart abuse-resistant properties to the opioid combination drug product based on its preferential dissolution.

Example 9

Evaluation of oxycodone hydrochloride abuse-resistant immediate Release tablets of the invention (example 5A) with reference to the drug Listing (RLD) productThe syringeability and extractability of the tablet (15 mg). Roxicodone is a commercially available oxycodone hydrochloride immediate release tablet.

Materials and equipment:

small weighing ship

5mL syringe

20mL scintillation vial

Cotton

271/2 # needle

Clean glass mortar and pestle

Timer

The method comprises the following steps:

the tablets were milled/mixed using the following method:

1. the powder blend of 1 tablet or 1 tablet equivalent was placed in a 2oz. glass mortar.

2. The tablets are broken or ground or mixed 6 to 7 times with a glass pestle to break the tablet or mixture into small pieces.

3. The timer was started and the debris was ground using a vigorous rounding motion.

4. During grinding, the material on the side of the mortar was allowed to fall to the bottom by tapping the table with the mortar.

5. Milling was continued for 1 minute to form a uniform fine powder.

5mL of the appropriate extraction solvent was added to the vial, timed 30 seconds on hand shaking, and then poured into a small weigh boat containing a piece of pea-sized cotton. Using an 271/2 gauge needle and a 5mL syringe, the volume withdrawn over 5 minutes was recorded as much as possible by drawing fluid through the cotton with the syringe (T0 sample). And extracting a sample for testing. When it is desired to heat/boil the sample, the solution is heated while shaking until it just begins to boil, and then poured into a weighing boat containing cotton, following the same instructions as above.

At the 10 minute time point (T10 sample): the sample was heated to boil following the same procedure as above. The sample was allowed to stand in the vial for 10 minutes and then withdrawn.

The extraction solvent used was tap water, vinegar, 0.9% saline and 40% ethanol.

As a result:

the following table shows the penetration and extraction test results of oxycodone hydrochloride tablets 15mg in different media.

TABLE 9A Perfect and extraction test of oxycodone hydrochloride tablets in tap water (n ═ 2)

TABLE 9B Perfect and extraction test of oxycodone hydrochloride tablets in vinegar (n ═ 2)

TABLE 9C general penetration and extraction test of oxycodone hydrochloride tablets in 40% ethanol (n ═ 2)

TABLE 9 penetration and extraction test of oxycodone hydrochloride tablets in 0.9% saline (n ═ 2)

At time T0, the test formulation (example 5A, 15mg) significantly improved penetration and extraction compared to the reference product (oxycodone hydrochloride formulation (Roxicodone)15 mg). The extraction volume in the different media was reduced from about 3.6 to 4.6ml to 0.15 to 1.4 ml. The oxycodone extract also decreased from about 59.7-80.0% to 3.36-8.44%.

Example 10

Optimization experiment

Example 10A

The penetration and extraction of 15mg naloxone hydrochloride mixture (high dose naloxone particles with 1% Swelstar and 0.5% xanthan gum) was evaluated. This formulation was prepared according to the method described above (Swelstar with xanthan gum substituted for a portion) and the formulation is shown in table 10 below.

Watch 10

The results are shown in Table 10A below.

TABLE 10A naloxone hydrochloride concentrate (60% weight gain Eudragit EPO and 0.5% xanthan gum) at T0

Needle-through and extraction in different media (n ═ 2)

The dissolution profile of naloxone as a surrogate in this formulation is shown in figure 11. The dissolution media and conditions were as follows: 500ml medium, United states Pharmacopeia equipment 2 (paddle), 50 RPM. The drug loading was approximately 90% of the theoretical amount of the tablet.

Formulation yield results show that using a higher loading of 60% acid sensitive polymer Eudragit EPO and containing 0.5% xanthan gum, in addition to the standard 1% Swelstar, compared to other formulations as reviewed below, greatly reduces the amount of opioid drug extracted and meets very low penetration results.

Example 10B

The penetration and extraction of 20mg oxycodone hydrochloride mixtures (high dose oxycodone granules with different concentrations of Swelstar) were evaluated. The results are shown in tables 10B to 10E below. With the exception of the pressing step, the mixture was prepared according to example 5B.

TABLE 10B general acupuncture and extraction tests of 20mg oxycodone hydrochloride mixtures in tap water (n ═ 2)

TABLE 10C general acupuncture and extraction tests of 20mg oxycodone hydrochloride mixtures in vinegar (n ═ 2)

TABLE 10D general acupuncture and extraction tests of 20mg oxycodone hydrochloride mixtures in 40% ethanol (n ═ 2)

TABLE 10E penetration and extraction test of 20mg oxycodone hydrochloride mixture in 0.9% saline (n ═ 2)

Example 10C

The following table (tables 10F to 10I) shows the penetration of oxycodone hydrochloride tablets in different extraction media and the extraction results. The tablets were prepared according to example 5B, but with the addition of 0.5% silicon dioxideAnd a relative reduction in magnesium stearate.

TABLE 10 penetration and extraction test of oxycodone hydrochloride tablets in tap water (n ═ 2)

TABLE 10G penetration and extraction test of oxycodone hydrochloride tablets in vinegar (n ═ 2)

TABLE 10 penetration and extraction of oxycodone hydrochloride tablets in 40% ethanol (n ═ 2)

TABLE 10I penetration and extraction test of oxycodone hydrochloride tablets in 0.9% saline (n ═ 2)

The scope of the invention is not limited to the particular implementations disclosed in the examples, which are intended to illustrate some aspects of the invention, and any functionally equivalent implementations are within the scope of the invention. Indeed, many modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are within the scope of the appended claims.

Claims (10)

1. An immediate release solid oral dosage form comprising a plurality of granules, each granule comprising:

(i) an active agent, and

(ii) a substance sensitive to acidic pH;

wherein the plurality of particles are dispersed in a substrate comprising a gelling agent selected from the group consisting of pregelatinized starch, hydroxyethyl cellulose, guar gum, xanthan gum, alginates, carrageenans, and mixtures thereof, and

wherein the dosage form releases at least 70% of the active agent within 45 minutes as measured by in vitro dissolution at 50rpm in a paddle usp apparatus 2 at 37 ℃ in 500ml0.1N HCl.

2. An immediate release solid oral dosage form comprising a plurality of granules, each granule comprising:

(i) an opioid agonist, and

(ii) a substance sensitive to acidic pH;

wherein the plurality of particles are dispersed in a matrix comprising:

(i) a gelling agent selected from the group consisting of pregelatinized starch, hydroxyethyl cellulose, guar gum, xanthan gum, alginates, carrageenans, and mixtures thereof, and

(ii) a disintegrating agent, a disintegrating agent and a carrier,

wherein the dosage form releases at least 70% of the opioid agonist within 45 minutes as measured by in vitro dissolution in 500ml0.1N HCl at 50rpm in a paddle United states Pharmacopeia apparatus 2 at 37 ℃, and

wherein the viscosity of the dosage form mixed with 0.5 to 10ml of distilled water prevents or reduces the ability of the opioid agonist to be absorbed systemically when administered by the parenteral or nasal route.

3. A process for preparing an immediate release solid oral dosage form, the process comprising:

(i) preparing a plurality of particles, each particle comprising an active agent and a substance sensitive to acidic pH; and

(ii) dispersing the plurality of particles in a substrate, wherein the substrate comprises a gelling agent selected from the group consisting of pregelatinized starch, hydroxyethyl cellulose, guar gum, xanthan gum, alginates, carrageenans, and mixtures thereof, and

wherein the dosage form releases at least 70% of the active agent within 45 minutes as measured by in vitro dissolution at 50rpm in a paddle usp apparatus 2 at 37 ℃ in 500ml0.1N HCl.

4. An immediate release solid oral dosage form comprising a plurality of granules, each granule comprising:

(i) an opioid agonist, and

(ii) a substance sensitive to acidic pH;

wherein the plurality of particles are dispersed in a substrate comprising:

(i) a gelling agent selected from the group consisting of pregelatinized starch, hydroxyethyl cellulose, guar gum, xanthan gum, alginates, carrageenans, and mixtures thereof, and optionally

(ii) A disintegrating agent, a disintegrating agent and a carrier,

wherein the dosage form releases at least 70% of the opioid agonist within 45 minutes as measured by in vitro dissolution in 500ml0.1N HCl at 50rpm in a paddle United states Pharmacopeia apparatus 2 at 37 ℃, and

after mixing with 0.5 to 10ml of distilled water, a viscosity of 10cP to 100cP is provided.

5. An immediate release solid oral dosage form comprising a plurality of granules, each granule comprising:

(i) a core comprising an inert excipient and an active agent comprising an opioid agonist, wherein the active agent is layered on the inert excipient; and

(ii) an acidic pH sensitive substance laminated on the core, the acidic pH sensitive substance comprising a polyacrylate;

wherein the plurality of particles are dispersed in a substrate comprising a gelling agent selected from the group consisting of pregelatinized starch, hydroxyethyl cellulose, guar gum, xanthan gum, alginates, carrageenans, and mixtures thereof, and

wherein the viscosity of the dosage form mixed with 0.5 to 10ml of distilled water prevents or reduces the ability of the active agent to be absorbed systemically and when administered by parenteral or nasal route, and

wherein the dosage form releases at least 70% of the active agent within 45 minutes as measured by in vitro dissolution at 50rpm in a paddle usp apparatus 2 at 37 ℃ in 500ml0.1N HCl.

6. An immediate release solid oral dosage form comprising a plurality of granules, each granule comprising:

(i) a core comprising an inert excipient and an opioid agonist, wherein the opioid agonist is layered on the inert excipient; and

(ii) a material sensitive to acidic pH laminated on the core, the material comprising a polyacrylate;

wherein the plurality of particles are dispersed in a matrix comprising:

(i) a gelling agent selected from the group consisting of pregelatinized starch, hydroxyethyl cellulose, guar gum, xanthan gum, alginates, carrageenans, and mixtures thereof, and

(ii) a disintegrating agent, a disintegrating agent and a carrier,

wherein the dosage form releases at least 70% of the opioid agonist within 45 minutes as measured by in vitro dissolution in 500ml0.1N HCl at 50rpm in a paddle United states Pharmacopeia apparatus 2 at 37 ℃, and

wherein the viscosity of the dosage form mixed with 0.5 to 10ml of distilled water prevents or reduces the ability of the opioid agonist to be absorbed systemically when administered by the parenteral or nasal route.

7. A process for preparing an immediate release solid oral dosage form, the process comprising:

(i) preparing a plurality of particles, each particle comprising a core comprising an inert excipient and an active agent comprising an opioid agonist, wherein the active agent is layered on the inert excipient; and a material sensitive to acidic pH laminated on the core, the material comprising a polyacrylate; and

(ii) dispersing the plurality of particles in a substrate, wherein the substrate comprises a gelling agent selected from the group consisting of pregelatinized starch, hydroxyethyl cellulose, guar gum, xanthan gum, alginates, carrageenans, and mixtures thereof, and

wherein the viscosity of the dosage form mixed with 0.5 to 10ml of distilled water prevents or reduces the ability of the active agent to be absorbed systemically and when administered by parenteral or nasal route, and

wherein the dosage form releases at least 70% of the active agent within 45 minutes as measured by in vitro dissolution at 50rpm in a paddle usp apparatus 2 at 37 ℃ in 500ml0.1N HCl.

8. Use of the immediate release solid oral dosage form according to any of claims 1, 2 and 4-6 in the manufacture of a medicament for the treatment of a disease or condition.

9. An immediate release solid oral dosage form comprising a plurality of granules, each granule comprising:

(i) a core comprising an inert excipient and an opioid agonist layered on the inert excipient; and

(ii) an acidic pH sensitive substance laminated on the core, the acidic pH sensitive substance comprising a polyacrylate;

wherein the plurality of particles are dispersed in a substrate comprising:

(i) a gelling agent selected from the group consisting of pregelatinized starch, hydroxyethyl cellulose, guar gum, xanthan gum, alginates, carrageenans, and mixtures thereof, and optionally

(ii) A disintegrating agent, a disintegrating agent and a carrier,

wherein the dosage form releases at least 70% of the opioid agonist within 45 minutes as measured by in vitro dissolution in 500ml0.1N HCl at 50rpm in a paddle United states Pharmacopeia apparatus 2 at 37 ℃, and

after mixing with 0.5 to 10ml of distilled water, a viscosity of 10cP to 100cP is provided.

10. Use of an immediate release solid oral dosage form according to any of claims 1, 2, 4-6 and 9 for the manufacture of a medicament for the treatment of pain.