US20150118300A1 - Immediate Release Abuse-Deterrent Granulated Dosage Forms - Google Patents

Immediate Release Abuse-Deterrent Granulated Dosage Forms Download PDF

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Publication number
US20150118300A1
US20150118300A1 US14/333,986 US201414333986A US2015118300A1 US 20150118300 A1 US20150118300 A1 US 20150118300A1 US 201414333986 A US201414333986 A US 201414333986A US 2015118300 A1 US2015118300 A1 US 2015118300A1
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US
United States
Prior art keywords
dosage form
immediate release
core
abuse deterrent
form according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/333,986
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English (en)
Inventor
Dinesh K. Haswani
Derek V. Moe
Victoria A. O'Neill
Manuel A. Vega Zepeda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cima Labs Inc
Original Assignee
Cima Labs Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=51263565&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20150118300(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Cima Labs Inc filed Critical Cima Labs Inc
Priority to US14/333,986 priority Critical patent/US20150118300A1/en
Priority to PCT/US2014/054061 priority patent/WO2015065586A1/en
Priority to US14/477,354 priority patent/US20150118301A1/en
Priority to US14/484,793 priority patent/US20150118295A1/en
Assigned to CIMA LABS INC. reassignment CIMA LABS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HASWANI, DINESH K., VEGA ZEPEDA, MANUEL A., MOE, DEREK V., O'NEILL, VICTORIA A.
Priority to US15/032,658 priority patent/US20160250203A1/en
Priority to AU2014342412A priority patent/AU2014342412B2/en
Priority to PE2016000556A priority patent/PE20160606A1/es
Priority to CA2900858A priority patent/CA2900858C/en
Priority to JP2016552219A priority patent/JP6659925B2/ja
Priority to MX2016005482A priority patent/MX384376B/es
Priority to PCT/US2014/062887 priority patent/WO2015066172A1/en
Priority to US14/527,215 priority patent/US9707224B2/en
Priority to CN201480059281.6A priority patent/CN105682647A/zh
Priority to HK16112327.1A priority patent/HK1223856A1/zh
Priority to KR1020167013870A priority patent/KR102363573B1/ko
Priority to EA201690874A priority patent/EA032013B1/ru
Priority to EP14858628.2A priority patent/EP3062778A4/en
Priority to US14/539,231 priority patent/US9757371B2/en
Publication of US20150118300A1 publication Critical patent/US20150118300A1/en
Priority to IL245125A priority patent/IL245125B/en
Priority to ZA2016/04451A priority patent/ZA201604451B/en
Priority to CL2016001031A priority patent/CL2016001031A1/es
Priority to US15/908,013 priority patent/US10568881B2/en
Priority to US16/751,043 priority patent/US11207318B2/en
Priority to US17/527,528 priority patent/US11844796B2/en
Abandoned legal-status Critical Current

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    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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Definitions

  • the present invention relates to the field of oral dosage forms that contain abuse-deterrent features, in particular including immediate release dosage forms that contain a drug that is commonly susceptible to abuse.
  • Pharmaceutical products including both prescription and over-the-counter pharmaceutical products, while useful for improving health of a person in need, are also susceptible to intentional and unintentional abuse and overdosing.
  • Examples of commonly abused active pharmaceutical ingredients include psychoactive drugs, anxiolytics, sedative hypnotics, stimulants, depressants, and analgesics such as narcotic analgesics, among others.
  • a complete list of specific drug compounds that are commonly abused would be lengthy; a short listing of some classes of drugs commonly abused includes opioids and morphine derivatives, barbiturates, amphetamines, ketamine, and other drugs that can cause psychological or physical dependence.
  • Some common techniques for intentionally abusing a drug begin with an abuser obtaining a solid dosage form such as an orally administered tablet or capsule, and crushing the solid dosage form into a powder.
  • the powder may be administered by an abuser by nasal insufflation (i.e., “snorting”) to introduce the drug to the abuser's bloodstream intranasally.
  • the crushed dosage form may be combined with a solvent that is capable of dissolving the drug (active pharmaceutical ingredient, or “API”), and the solvent with the dissolved drug may be injected directly into an abuser's bloodstream.
  • an abuser might simply ingest multiple units (e.g., tablets) of the dosage form together, e.g., simultaneously. Each one of the multiple dosage form units—immediately releases an amount of drug to produce a short-term concentration spike of the drug in the user's bloodstream and a desired “high” in the user.
  • the pharmaceutical industry has identified various mechanisms of adapting drug compositions and oral dosage forms that can be useful to discourage abuse of oral dosage forms.
  • Pharmaceutical companies have studied dosage forms that contain a nasal irritant or an effervescent agent, which can cause irritation or pain in a nasal passage if the dosage form is crushed and then snorted, thus discouraging abuse by nasal insufflation.
  • Another possible abuse deterrent may be addition of an emetic agent which can deter abuse by causing emesis on ingestion of multiple doses.
  • Another abuse deterrent involves adding an antagonist of an API to a dosage form that will substantially block the effect of the drug.
  • the following description relates to oral dosage forms that are useful for immediate release of an active pharmaceutical ingredient or “API.”
  • the dosage form can be designed to release the API as desired in an immediate release dosage form, and can also include one or a combination of feature that will prevent or deter abuse of the API.
  • the abuse deterrent features described herein can be included singly or in any combination in an immediate release dosage form.
  • a dosage form as described can include a gelling polymer to prevent or compromise abuse practices wherein the dosage form is crushed and then combined with a small amount of a solvent to produce a liquid composition that contains a concentrated amount of API and that can be delivered to an abuser using a syringe.
  • the gelling polymer can be any polymer useful to achieve this functionality, and can be placed in the dosage form at any location to allow the gelling polymer to perform as described and still allow immediate release of the API.
  • a gelling polymer can be included in a core of a coated of core-shell particle or in a matrix of a dosage form that suspends the core-shell particles.
  • the core may contain any amount of gelling polymer, such as from 0 to 100 percent gelling polymer based on a total weight of the core.
  • the core in a core-shell particle may comprise a filler, e.g., up to 100 percent filler, such as a sugar sphere or microcrystalline cellulose sphere (up to 100 percent microcrystalline cellulose spheres such as those available under the trade name Celphere®).
  • Another type of abuse deterrent feature can be a wax that alone or with other ingredients, e.g., the gelling polymer, is effective in compromising abuse practices wherein a dosage form is crushed and combined with a solvent to produce a liquid composition that can be abused by nasal insufflation or delivered to an abuser using a syringe.
  • the wax can additionally inhibit or prevent an abuser from grinding the dosage form into a powder because upon grinding the wax will smear as opposed to fracturing or powdering.
  • wax can be included in a dosage form at any location that allows the wax to function as an abuse deterrent feature while not interfering with an immediate release profile of the API.
  • a wax can be included in a core of a coated particle.
  • a core may contain any amount of wax, such as from 0 to 100 percent wax based on a total weight of the core, such as up to 50, 75, or 80 weight percent wax based on a total weight of the core.
  • Still another type of abuse deterrent feature can be a filler or binder that alone or in combination with other ingredients can compromise abuse practices wherein a dosage form is being crushed and combined with a small amount of a solvent to produce a liquid composition that can be delivered to an abuser using a syringe.
  • the filler or binder can inhibit or prevent an abuser from grinding the dosage form into a powder because upon grinding, the polymeric filler or binder will smear as opposed to fracturing or powdering.
  • the filler or binder can be included in a dosage form in any manner and location that allows the filler or binder to function as an abuse deterrent feature while not interfering with an immediate release profile of the API.
  • a filler or binder can be included in a core of a coated particle.
  • a core may contain any amount of polymeric filler or binder such as from 0 to 100 percent filler or binder on a total weight of the core, or up to 50, 75, or 80 weight percent filler or binder based on a total weight of the core.
  • Yet another type of abuse deterrent feature can be a film layer that surrounds or covers API in a dosage form and that is optionally resistant to being dissolved by one or more of the solvents commonly used by abusers to dissolve an API for injection, including water and C 1 -C 4 alcohols such as ethanol, methanol, and mixtures thereof.
  • the film layer may be prepared from any film material that is disposed as a continuous layer on a coated particle at a location to enclose and surround the API.
  • Examples of film layers can optionally and preferably provide properties of a solvent-resistant film, which is a film that is slow or difficult to dissolve in a limited or small volume of one the solvents commonly used by abusers to dissolve API of a dosage form.
  • an abuser may grind the dosage form and combine the ground dosage form with a solvent (as described) in an attempt to produce a solution that contains the concentrated API and the solvent, and that may be efficiently injected or snorted.
  • a solvent as described
  • a solvent-resistant film layer that surrounds API of a dosage form can prevent an abuser from easily accessing and so manipulating the API.
  • an immediate release dosage form can include these features in a coated particle, such as a core-shell particle.
  • An exemplary core-shell particle can include a core and one or more layers surrounding the core.
  • the API may be included in the core, or in one or more layers surrounding the core, or in both the core and one or more layers surrounding the core.
  • the core can include any one or more of: a gelling polymer, wax, binder, or filler, alone or in combination. Alternately, the core may comprise a microcrystalline cellulose or sugar sphere.
  • a film layer may surround and enclose the core, or an API-containing layer that is disposed around the core.
  • the film layer may preferably be a solvent-resistant film in the form of a continuous coating that covers the core, which contains API, or that covers an API-containing layer or coating disposed around the core.
  • a coated particle as described herein can be useful in a dosage form that includes one or more optional abuse deterrent features, and a matrix such as a compressed matrix that is formed to allow for immediate release of the API present in the coated particles.
  • An exemplary matrix composition may comprise additional gelling polymer, disintegrant, or both additional gelling polymer and disintegrant.
  • additional gelling polymer as used above means an amount of gelling polymer that is in addition to an amount of gelling polymer present in the coated particles.
  • the additional gelling polymer may be the same or different in nature, chemistry, molecular weight, etc., as compared to the gelling polymer that is included in the coated particles.
  • a disintegrant as a component of the matrix may be useful to facilitate release of the API of the dosage form, e.g., API present in the coated particles.
  • the active pharmaceutical ingredient included in the dosage form, especially in the coated particle surrounded by a film layer can be any active pharmaceutical ingredient desired to be administered orally, and may in particular be a type of active pharmaceutical ingredient that is commonly susceptible to abuse.
  • active pharmaceutical ingredients that are considered to be commonly susceptible to abuse include psychoactive drugs, tranquilizers, sedative hypnotics, anxiolytics, stimulants, depressants, and narcotic analgesics, among others.
  • Certain more specific classes of drugs commonly abused includes opioids, barbiturates, benzodiadepines, amphetamines, as well as many other drugs that are known to cause psychological or physical dependence.
  • Dosage forms of the present description can be useful as immediate release dosage forms, and may also include abuse deterrent features as described.
  • the abuse deterrent features can discourage or prevent abuse by nasal insufflation, by injection, and can also be effective to prevent or significantly limit the success of abuse by the common methods (especially with immediate release oral dosage forms) of orally taking multiple dosage form units together.
  • the final mode of abuse (sometimes referred to herein as “multi-tablet dosing”) is often particularly difficult to deter, especially in immediate release oral dosage forms, making these described dosage forms particularly useful as abuse-resistant oral immediate release dosage forms.
  • Embodiments of the described dosage forms can be effective in the absence of other types of abuse deterrent features such as nasal irritants, emetic agents, bittering agents, and effervescent agents, to inhibit nasal insufflation or other forms of abuse, or the inclusion of drug antagonists of the subject drug.
  • abuse deterrent features such as nasal irritants, emetic agents, bittering agents, and effervescent agents
  • the invention relates to an immediate release dosage form that includes core-shell particles.
  • the core-shell particles include: an inner core containing a gelling polymer; at least one layer surrounding the core, the at least one layer including a film layer surrounding the core; and an active pharmaceutical ingredient.
  • the active pharmaceutical ingredient is also surrounded by the film layer that surrounds the core.
  • the invention in another aspect, relates to an immediate release dosage form that includes core-shell particles.
  • the core-shell particles includes a core and an active pharmaceutical layer surrounding the core.
  • the active pharmaceutical layer contains an active pharmaceutical ingredient.
  • the core contains less than 5 weight percent of a total amount of the active pharmaceutical ingredient in the core-shell particles.
  • the invention in yet another aspect relates to an immediate release dosage form that contains core-shell particles.
  • the core-shell particles include: a core and an active pharmaceutical ingredient.
  • the dosage form further includes a matrix.
  • the matrix includes disintegrant and an additional amount of gelling polymer.
  • FIGS. 1A , 1 B, and 1 C illustrate embodiments of core-shell particles as described, in cross section.
  • FIGS. 2A and 2B illustrate embodiments of core-shell particles as described, in cross section.
  • FIG. 3 is a perspective view of an embodiment of a dosage form as described.
  • FIG. 4 shows a plot of Multiple Tablet oral Abuse Resistance (Supratherapeutic Dosing)—Dissolution of Hydrocodone Bitartrate in 0.1N HCl media as a function of time.
  • FIG. 5 shows a plot of multiple tablet oral abuse resistance (supratherpeutic dosing)—dissolution of acetaminophen in 0.1N HCl media as a function of time.
  • FIG. 6 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing)—dissolution of hydrocodone bitartrate in 0.1N HCl media as a function of time.
  • FIG. 7 shows a plot of multiple tablet oral abuse resistance (supratherpeutic dosing)—dissolution of acetaminophen in 0.1N HCl media as a function of time
  • FIG. 8 shows a plot of multiple tablet oral abuse resistance (supratherapeutic dosing)—dissolution of hydrocodone bitartrate in 0.1N HCl media as a function of time.
  • FIG. 9 shows a plot of multiple tablet oral abuse resistance (supratherpeutic dosing)—dissolution of acetaminophen in 0.1N HCl media as a function of time.
  • the present description relates to immediate release dosage forms that include one or more abuse deterrent features for reducing the potential for a) parenteral abuse, b) abuse by nasal insufflation (“snorting”), and c) abuse by simultaneous oral ingestion of multiple oral dosage form units (tablets or capsules) of a drug.
  • abuse deterrent features are achieved by preparing the dosage form to include certain structural features and certain ingredients that have now been determined to effectively prevent an abuser from realizing the intended biological effect of the drug abuse by using certain presently-common methods used to abuse the API.
  • a dosage form prepared to contain one or more of the described abuse deterrent features, as a deterrent to abuse of one or more API that is commonly susceptible to abuse, can still be constructed to provide immediate release of the one or more API upon normal therapeutic use by oral ingestion.
  • expressions such as “abuse deterrent” and “preventing” or “deterring” or “inhibiting” practices and processes associated with the abuse and overdose of drugs relate to features of the claimed formulations that provide significant physical and chemical impediments to these practices and processes.
  • the objective in such deterrence includes both making abuse practices significantly more difficult to carry out, and making any product resulting from an attempt to carry out such abuse practices on the claimed formulations significantly less desirable, less profitable, and less abusable to the potential abuser.
  • immediate release refers to a dosage form that upon oral ingestion by a human releases substantially all of a contained active pharmaceutical ingredient into a gastrointestinal tract for biological uptake in a short time.
  • in vitro methods of measuring a release profile of a dosage form, for the purpose of determining whether a dosage form exhibits an immediate release or dissolution profile are known in the pharmaceutical arts.
  • examples of dosage forms as described herein can be measured to be capable of releasing substantially all of a total amount of at least one type of active pharmaceutical ingredient (e.g., an API commonly susceptible to abuse) contained in the dosage form (e.g., at least 75, 80, or 90 weight percent of the total amount of the API in a dosage form) into a solution (e.g., acidic aqueous solution) of a suitable pH within 240 minutes, e.g., in less than 180 minutes, less than 90 minutes, or less than 60, 30, 15, or 5 minutes.
  • a solution e.g., acidic aqueous solution
  • a release profile of a dosage form of the present description may be measured by a method that exposes the dosage form to a volume of up to 900 milliliters (e.g., 300 milliliters, or 900 milliliters, based on various test methods) of hydrochloric acid (0.01 to 0.1N) (e.g., aqueous hydrochloric acid) at a pH of from 1 to 2, and at a temperature of 37 degrees Celsius.
  • hydrochloric acid e.01 to 0.1N
  • aqueous hydrochloric acid e.g., aqueous hydrochloric acid
  • Dosage forms as described can be formulated to provide an immediate release profile of an API, and can also be prepared to include effective or advantageous abuse deterrent features that are effective to deter abuse of the same API (e.g., one that is commonly susceptible to abuse) that exhibits the immediate release profile.
  • effective or advantageous abuse deterrent features that are effective to deter abuse of the same API (e.g., one that is commonly susceptible to abuse) that exhibits the immediate release profile.
  • the combination of immediate release of an API with broad abuse resistance of the same API for multiple abuse modalities including multi-tablet dosing, as described herein, is not believed to be previously known.
  • dosage forms as described herein can provide an immediate release profile of an API, and can at the same time include abuse deterrent features that provide general abuse deterrence or abuse resistance of the same API.
  • the dosage forms can also be more specifically characterized as resistant to certain common methods of abuse, such as 1) abuse by injection (e.g., by steps that include grinding a dosage form and dissolving API of the dosage form), 2) abuse by nasal insufflation (e.g., also by grinding and optionally dissolving API of a dosage form), and 3) abuse by multi-tablet dosing by oral consumption, meaning simultaneous oral ingestion of multiple or excessive quantities of orally administered dosage forms such as tablets or capsules.
  • the third mode of abuse, multi-tablet dosing is particularly common with immediate release dosage forms and is particularly difficult to defend against by design of a dosage form structure or by formulation. Accordingly, that the presently-described dosage forms can be effective to prevent or deter abuse (or even accidental overdose) by the mode of multi-tablet dosing can be a particularly useful feature of the dosage forms described herein.
  • in vitro testing of exemplary dosage forms as described herein indicates that exemplary dosage forms provide deterrence against abuse by multi-tablet dosing. More specifically, in vitro testing of exemplary dosage forms was performed by conducting dissolution testing of one or more dosage forms (tablets) in 300 milliliters of 0.1NHCL maintained at 37 degrees Celsius using a 50 RPM paddle speed. See, Example 26 (a) and FIGS. 4 and 5 herein. As shown at FIGS. 4 , 5 , 6 , 7 , 8 and 9 , the amount (percentage per tablet) of API (opioid) or APAP (acetaminophen) released in the media is reduced with an increase in the number of tablets.
  • API opioid
  • APAP acetaminophen
  • the tested dosage forms are effective to prevent increased levels of API uptake in an individual who would accidentally ingest multiple tablets, preventing or reducing the risk of an unintentional overdose of the API.
  • the 1 tablet and 2 tablet dosage forms are as prepared in Example 3, infra
  • the 5 tablet, 8 tablet, and 12 tablet dosage forms are as prepared in Example 5, infra.
  • the tablets used in FIGS. 6 , 7 , 8 and 9 are as prepared as per Example 17.
  • a dosage form as described can include one or more gelling polymers.
  • a gelling polymer can act as an abuse deterrent feature by compromising abuse practices wherein an active pharmaceutical ingredient of a dosage form is being dissolved in a small volume of solvent or being accessible or easily isolatable if combined with solvent with the gelling polymer also present.
  • a gelling polymer can also deter or prevent abuse of an API in a dosage form by increasing the viscosity of a combination of the ground dosage form with solvent (especially a “small volume” of solvent) to a viscosity that is sufficiently high to prevent the combination or the API from being taken up by and injected using a syringe.
  • a preferred gelling polymer contained in a ground dosage form when exposed to a limited volume (or “small volume”) of solvent such as a C 1-4 alcohol (e.g., ethanol or methanol) or water, can form a non-injectable mass ranging from an insoluble mass, to a gel, to a viscous slurry, each of which exhibits a viscosity that substantially prevents either uptake by or injection from a needle of a hypodermic syringe.
  • solvent such as a C 1-4 alcohol (e.g., ethanol or methanol) or water
  • Suitable gelling polymers include one or a combination of polymers that, as part of a dosage form, upon contact of the dosage form with a small volume of solvent, will absorb the solvent and swell to form a viscous or semi-viscous substance that significantly reduces or minimizes the amount of free solvent that can contain an amount of a solubilized API and that can be drawn into a syringe.
  • the gelled polymer can also reduce the overall amount of drug extractable with the solvent by entrapping the drug in a gel matrix.
  • the gelling polymer can be present in the dosage form at a location and in an amount that together allow the gelling polymer to produce a viscous gel in the event of an abuser grinding the dosage form and combining the crushed dosage form with a solvent.
  • the gelling polymer, as present in the dosage form will preferably not interfere with desired dissolution of the dosage form, the desired release (immediate release) of API from the dosage form, or the uptake of the API by a patient ingesting the intact immediate release dosage form for an intended therapeutic purpose.
  • An exemplary location for the gelling polymer is in a coated particle that also includes active pharmaceutical ingredient, such as in a core or in a layer coated to surround the core; wherein an amount of active pharmaceutical ingredient is contained in either the core, or a layer coated to surround the core, or is contained in both.
  • Another exemplary location is within a matrix used to form a compressed tablet, a capsule (e.g., a compressed capsule), a caplet, or another type of dosage form that contains a coated particle that contains active pharmaceutical ingredient.
  • the gelling polymer can be present in a dosage form at any desired amount and at any portion of, or location in a dosage form structure.
  • the amount of gelling polymer can be any useful amount, meaning an amount that can produce an abuse-resistant viscous mixture or gel if the dosage form is crushed, ground, powdered, etc., and mixed with solvent.
  • a useful amount of total gelling polymer in a dosage form may be in a range from 0.5 to 90 weight percent gelling polymer based on a total weight of the dosage form, e.g., from 0.7 to 20, or 2 to 15 weight percent gelling polymer based on total weight of the dosage form.
  • total gelling polymer can be present in one or more locations of the dosage form, to achieve the specified total amount, such as in a portion at a coated particle (e.g., core), a matrix (e.g., compressed matrix) structure that supports and contains the coated particles, or in both the coated particles and the matrix.
  • a coated particle e.g., core
  • a matrix e.g., compressed matrix
  • a core (uncoated) of a core-shell particle can contain any useful amount of gelling polymer, such from 0 up to and including 100 percent gelling polymer in a core of a core-shell particle, e.g., from 10 to 95 weight percent gelling polymer based on a total weight of the core, such as from 40 to 85 or 50 to 75 weight percent gelling polymer based on total weight core.
  • an amount of gelling polymer present in a core of a core shell polymer may be, e.g., in a range from 0.5 to 15 weight percent gelling polymer (present in the core) per total weight of the dosage form, such as from 1 to 10 weight percent gelling polymer (present in the core) per total weight dosage form.
  • An amount of gelling polymer present in a matrix of a dosage form may be any desired amount, such as an amount in a range from 0.5 to 15 weight percent gelling polymer (as excipient in a matrix) based on a total weight of the dosage form, such as from 1 to 10 weight percent gelling polymer (present as excipient in a matrix) based on total weight dosage form.
  • a useful gelling polymer can be any polymeric material that exhibits the ability to retain a significant fraction of adsorbed solvent in its molecular structure, e.g., the solvent being a solvent otherwise useful by an abuser to extract API from a dosage form or a crushed or powdered dosage form, the solvent for example being water or a C 1 to C 4 alcohol such as ethanol or methanol, etc.
  • examples of gelling polymers include materials that can swell or expand to a very high degree when placed in contact with such a solvent. The swelling or expansion may cause the gelling polymer to experience from a two- to one-thousand-fold volume increase from a dry state.
  • gelling polymers include swellable polymers sometimes referred to as osmopolymers or hydrogels.
  • the gelling polymer may be non-cross-linked, lightly crosslinked, or highly crosslinked.
  • the crosslinking may involve covalent or ionic bonds with the polymer possessing the ability to swell in the presence of a solvent, and when cross-linked will not dissolve in the solvent.
  • a gelling polymer upon dissolution or dispersion in an aqueous solution or dispersion (e.g., water) at a concentration of 2% w/w (based on the dry material), creates a solution/dispersion with a viscosity of from about 100 to about 200,000 mPa ⁇ s (e.g., 4,000 to 175,000 mPa ⁇ s, and 4,000 to 50,000 mPa ⁇ s) as measured at 20 degrees Celsius (+/ ⁇ 0.2 degree Celsius) using the analysis method described in the USP 33 monograph for hypromellose (incorporated herein by reference).
  • an aqueous solution or dispersion e.g., water
  • a concentration of 2% w/w based on the dry material
  • suitable gelling polymers include pharmaceutically acceptable polymers that undergo an increase in viscosity upon contact with a solvent, as described.
  • Various examples of polymers are known to be useful in this manner, generally including natural and synthetic starches (i.e., modified or pregelatinized modified starch), natural and synthetic celluloses, acrylates, and polyalkylene oxides.
  • natural starches include natural starches include corn starch, potato starch, rice starch, tapioca starch and wheat starch, hydroxypropyl starch such as hydroxypropyl corn starch, hydroxypropyl pea starch and hydropropyl potato starch (derivative of natural starch).
  • Examples of synthetic starches include acetylated distarch adipate, waxy maize basis, acid-treated maize starch, acid-treated waxy maize starch, distarch phosphate, waxy maize basis, oxidized waxy maize starch, and sodium octenyl succinate starch.
  • Examples of celluloses include carboxymethylcellulose calcium, carboxymethylcellulose sodium, ethycellulose, methylcellulose, cellulose ethers such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxyethylmethyl cellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose sodium, and low substituted hydroxypropyl cellulose.
  • Examples of acrylates include Eudragit RS, RL, NE, NM.
  • Examples of polyalkylene oxides include polyethylene oxide such as POLYOX N10, N80, N60K, WSR-1105 LEO, or WSR-301 LEO, or WSR-303 LEO.
  • suitable gelling polymers include polyethylene oxide, polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethylmethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, polyacrylic acid and polyvinyl carboxy polymers such as those commercially available under the trade name Carbopol®, and other high molecular weight polymers capable of attaining a viscosity level effective to prevent uptake in a syringe, if combined with a small volume of solvent as described.
  • Suitable gelling polymers can include, if of sufficiently high molecular weight: ethylcellulose, cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate and cellulose triacetate, cellulose ether, cellulose ester, cellulose ester ether, cellulose; acrylic resins comprising copolymers synthesized from acrylic and methacrylic acid esters, for example acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate
  • Exemplary gelling polymers can include natural polymers such as those derived from a plant or animal, as well as polymers prepared synthetically. Examples include polyhydroalkylcellulose having a molecular weight greater than 50,000; poly(hydroxy-alkylmethacrylate) having a molecular weight of from 5,000 to 5,000,000; poly(vinyl-pyrrolidone) having a molecular weight of from 100,000 to 3,000,000; anionic and cationic hydrogels; poly(electrolyte) complexes; poly(vinyl alcohol) having a low acetate residual; a swellable mixture of agar and carboxymethyl cellulose; a swellable composition comprising methyl cellulose mixed with a sparingly cross-linked agar; a polyether having a molecular weight of from 10,000 to 6,000,000; water-swellable copolymer produced by a dispersion of finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, or
  • polymers useful as a gelling polymer include pectin having a molecular weight ranging from 30,000 to 300,000; polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar; polyacrylamides; water-swellable indene maleic anhydride polymers; Good-rite® polyacrylic acid having a molecular weight of 80,000 to 200,000; Polyox® polyethylene oxide polymers having a molecular weight of 100,000 to 7,000,000; starch graft copolymers; Aqua-Keep® acrylate polymers with water absorbability of 400 times its original weight; diesters of polyglucan; a mixture of cross-linked polyvinyl alcohol and poly(-vinyl-2-pyrrolidone); poly(ethylene glycol) having a molecular weight of 4,000 to 100,000.
  • pectin having a molecular weight ranging from 30,000 to 300,000
  • polysaccharides such as agar, acacia
  • a gelling polymer may be, or may include, hydroxypropyl methyl cellulose (e.g., Hypromellose or HPMC), and hydroxy methyl cellulose, methyl cellulose, hydroxyethylmethyl cellulose, and sodium carboxymethyl cellulose.
  • HPMC hydroxypropyl methyl cellulose
  • HPMC Hypromellose
  • hydroxy methyl cellulose methyl cellulose, hydroxyethylmethyl cellulose, and sodium carboxymethyl cellulose.
  • the hydroxypropyl methyl cellulose can have a molecular weight ranging from 10,000 to 1,500,000.
  • suitable, commercially available hydroxypropyl methylcellulose polymers include HPMC K100M, Methocel K100LV and Methocel K4M.
  • a specific class of gelling polymer is the class of carbomer polymers, which are polymers derived from acrylic acid (e.g., acrylic acid homopolymers) and crosslinked with polyalcohol allyl ethers, e.g., crosslinked with polyalkenyl ethers of pentaerythritol or sucrose.
  • Carbomer polymers are hydrophilic and are not substantially soluble in water. Rather, these polymers swell when dispersed in water forming a colloidal, mucilage-like dispersion.
  • Carboxyl groups provided by acrylic acid residues of the polymer backbone are responsible for certain behavior of the polymers. Particles of this polymer can be viewed as a network structure of polymer chains interconnected by crosslinks.
  • the structure can swell in water by up to one thousand times of an original (dry) volume (and ten times an original diameter of polymer particles) to form a gel when exposed to a pH environment above 4-6.
  • the pKa of these polymers can be 6 ⁇ 0.5.
  • carboxylate groups pendant from the polymer backbone can ionize at a pH above 6, producing a repulsion between the negatively-charged particles, which adds to the swelling of the polymer if exposed to solvent at this pH range.
  • a dosage form as described herein can preferably include a pH adjuster in an amount and location within the dosage form to raise the pH of a carbomer polymer to at least 6, to substantially neutralize the carboxylate groups.
  • Carbomer polymers are often referred to in the art using alternative terminology such as, for example, carbomer homopolymer, acrylic acid polymers, carbomera, Carbopol, carboxy polymethylene, carboxyvinyl polymer, Pemulen, polyacrylic acid, and poly(acrylic acid),
  • the USP-NF lists three umbrella monographs i.e. for “carbomer copolymer,” for “carbomer homopolymer,” and for “carbomer interpolymer.”
  • carbopol (carbomer) polymers that may be useful as a gelling polymer can have an average equivalent weight of 76 per carboxyl group.
  • suitable commercially available carbomers include Carbopol® 934, 934P NF, Carbopol® 974P NF and Carbopol® 971P NF, Carbopol® 940, and Carbopol® 941, Carbopol® 71G, commercially available from Lubrizol. Examples of such polymers are described in U.S. Pat. Nos. 2,798,053 and 2,909,462, the entireties of which are incorporated herein by reference.
  • a gelling polymer e.g., Carbopol®
  • a gelling polymer can have a molecular weight and viscosity-increasing performance that will reduce or substantially inhibit an ability of an abuser to extract API from a combination of dosage form and a small volume of solvent, as described, while also being capable of being processed into a compressed dosage form.
  • a gelling polymer can also be characterized by viscosity of a solution prepared from the gelling polymer.
  • Product information for commercially available Carbopol® polymers reports that viscosities of different Carbopol® polymers are as follows:
  • Viscosity specified Type of Carbomer (cP) Carbomer Homopolymer Type A 4,000-11,000 (compendial name for Carbopol 71G, Carbopol 971P and Carbopol 981) Carbomer Homopolymer Type B 25,000-45,000 (compendial name for Carbopol 934P, and Carbopol 934) Carbomer Homopolymer Type C 40,000-60,000 (compendial name for Carbopol 980) (Type A and Type B viscosities measured using a Brookfield RVT, 20 rpm, neutralized to pH 7.3-7.8, 0.5 weight percent mucilage, spindle #5.)
  • xanthan gum polymers which includes natural polymers useful as hydrocolloids, and derived from fermentation of a carbohydrate.
  • a molecular weight of a Xanthan gum may be approximately 1,000,000.
  • Xanthan gum has been shown to provide particularly useful extraction resistance in a dosage form as described, and therefore may be preferred in dosage forms as described, especially if present in an amount of at least 2 or 3 weight percent based on a total weight of a dosage form.
  • the dosage form may optionally include another abuse deterrent in the form of a wax, such as a wax/fat material as described in Applicant's co-pending United States patent application 2008/0311205, the entirety of which is incorporated herein by reference.
  • the wax can be a solid wax material that is present in the dosage form at a location that inhibits an abuser from crushing, grinding, or otherwise forming the dosage form into a ground powder that might be abused by a nasal insufflation mode, or from which active pharmaceutical agent can be easily accessed and removed such as by dissolution or extraction using a solvent.
  • the wax may be present in the dosage form at a location and in an amount to also not interfere with desired uptake of the active pharmaceutical ingredient by a patient upon oral ingestion, in an immediate release dosage form.
  • An exemplary location is at a core of a core-shell particle, especially a core that also contains gelling polymer and that either may or may not contain active pharmaceutical ingredient.
  • Wax located at a core of a particle e.g., a core-shell particle
  • active pharmaceutical ingredient e.g., at a layer covering the core, or within the core
  • the active ingredient is inhibited or prevented from becoming thereafter dissolved in a solvent such as water or otherwise efficiently accessed by an abuser.
  • a core (uncoated) of a core-shell particle can contain any useful amount of wax, up to and including 100 percent wax, e.g., from 0.1 to 85 weight percent wax based on a total weight of the core, such as from 15 to 60 or 25 to 50 weight percent wax based on total weight core. More generally, a useful amount of wax in a dosage form (e.g., with the wax located in the coated particle, e.g., in the core) may be in a range from 0.05 to 15 weight percent wax based on total weight of a dosage form, e.g., from 0.1 to 10 or from 2 to 5 weight percent wax based on total weight of the dosage form.
  • the wax may be a wax (e.g., fat) material that is generally hydrophobic and that may be either solid or liquid at room temperature, preferably solid at room temperature (25 degrees Celsius).
  • Generally useful fats include those hydrophobic materials that are fatty acid-based compounds generally having a hydrophilic/lipophilic balance (HLB) of 6 or less, more preferably 4 or less, and most preferably 2 or less.
  • HLB hydrophilic/lipophilic balance
  • a fat can have any melting temperature, with preferred fats being solid at room temperature and having a melting point that is at least 30 degrees Celsius, e.g., at least 40 degrees Celsius, e.g., at least 50 degrees Celsius.
  • Useful fats include fatty acids and fatty esters that may be substituted or unsubstituted, saturated or unsaturated, and that have a chain length of at least 10, 12, or 14 carbons.
  • the esters may include a fatty acid group bound to any of an alcohol, glycol, or glycerol.
  • glycercols for example, mono-, di-, and tri-fatty substituted glycerols can be useful as well as mixtures thereof.
  • Suitable wax ingredients include fatty aced esters, glycerol fatty acid esters, fatty glyceride derivatives, waxes, and fatty alcohols such as, for example, glycerol behenate (a.k.a. glyceryl behenate, glycerin behenate, glycerol docosanoate) (e.g., COMPRITOL®), glycerol palmitostearate (PRECIROL®), glycerol monostearate, stearoyl macroglycerides (GELUCIRE® 50/13).
  • glycerol behenate a.k.a. glyceryl behenate, glycerin behenate, glycerol docosanoate
  • COMPRITOL® glycerol palmitostearate
  • PRECIROL® glycerol monostearate
  • stearoyl macroglycerides glycerol monostearate
  • waxes more generally include insect and animal waxes, vegetable waxes, mineral waxes, petroleum waxes, and synthetic waxes; particularly examples include beeswax, carnauba wax, condelilla wax, montan wax, ouricury wax, rice-bran wax, jojoba wax, microcrystalline wax, cetyl ester wax, cetyl alcohol, anionic emulsifying wax, nonionic emulsifying wax and paraffin wax.
  • the dosage form may optionally include another abuse deterrent in the form of a filler or binder material provided in a manner to compromising abuse practices wherein an abuser crushes, grinds, or otherwise forms the dosage form into a ground powder that might be abused by a nasal insufflation mode, or from which active pharmaceutical agent can be easily accessed and removed such as by dissolution or extraction using a solvent.
  • another abuse deterrent in the form of a filler or binder material provided in a manner to compromising abuse practices wherein an abuser crushes, grinds, or otherwise forms the dosage form into a ground powder that might be abused by a nasal insufflation mode, or from which active pharmaceutical agent can be easily accessed and removed such as by dissolution or extraction using a solvent.
  • the binder or filler may be present in the dosage form at a location and in an amount to also not interfere with desired uptake of the active pharmaceutical ingredient by a patient upon oral ingestion, in an immediate release dosage form.
  • An exemplary location is at a core of a core-shell particle.
  • Suitable filler or binder located at a core of a particle e.g., a core-shell particle
  • active pharmaceutical ingredient e.g., at a layer covering the core, or within the core
  • the active pharmaceutical ingredient is inhibiting or prevented from becoming thereafter dissolved in a solvent such as water or otherwise efficiently accessed by an abuser.
  • filler or binder When present within a core or particle of a dosage form, e.g., at a core of a core-shell particle, filler or binder may be present in any useful amount, such from 0 up to and including 100 percent filler or binder (singly or in combination) in a core of a core-shell particle, e.g., from 10 to 95 weight percent filler or binder (singly or in combination) based on total weight of the core, such as from 40 to 85 or 50 to 75 weight percent based on total weight core.
  • cores that contain high levels of filler include spherical particles that contain 100 percent sugar, and spherical particles that contain 100 percent microcrystalline cellulose.
  • Inert spherical filler products such as these, having useful particle sizes, are commercially available under the trade name Celphere®, and under the trade name Suglets® (sugar spheres, also containing starch), including as follows: CELPHERE SCP-100 (Particle size ( ⁇ m) 75-212); CELPHERE SCP-102 (Particle size ( ⁇ m) 106-212); CELPHERE SCP-203 (Particle size ( ⁇ m) 150-300); CELPHERE SCP-305 (Particle size ( ⁇ m) 300-500); CELPHERE SCP-507 (Particle size ( ⁇ m) 500-710); CELPHERE SCP-708 (Particle size ( ⁇ m) 710-850).
  • the particles sizes of these can be considered to be useful for any core as described herein, prepared of any single filler, gelling polymer, binder, any combination thereof, or any single or combination of materials combined with API.
  • a film layer or coating as part of a core-shell particle that is located over and surrounds an API.
  • the film layer can be any film layer capable of being applied as a film layer to core-shell particles, to surround API.
  • the film layer may be prepared from and will include any pharmaceutically acceptable film forming polymer material, such as one or more of a binder (e.g.
  • hydroxypropyl cellulose such as hydroxypropyl cellulose, poly(methyl methacrylates), ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyvinyl alcohol, and the like), a solvent-resistant layer, and a pH-sensitive layer (also sometimes referred to as a reverse enteric material or layer), e.g., Eudragit® RL.
  • the film layer may include any one of these materials alone (e.g., a film layer may include 100 percent of a single one of these types of materials), or a film layer may include a combination of two or more of these types of materials.
  • a solvent-resistant layer is a film layer that retards or prevent release of a drug in a solvent (e.g., one or more of water, ethanol, and methanol) while still allowing the drug to release normally in a gastrointestinal tract when ingested as an immediate release oral dosage form.
  • a solvent e.g., one or more of water, ethanol, and methanol
  • This type of abuse deterrent feature e.g., solvent-resistant film
  • the solvent-resistant film can dissolve in a human gastrointestinal tract with sufficient rapidity to allow for an immediate release profile.
  • this type of solvent-resistant film covers and encloses API of a core-shell particle and acts as a film barrier or retardant to prevent or retard access to the API by use of solvent.
  • a solvent-resistant film is one that does not readily or immediately dissolve in a small volume of a solvent of the type often used by an abuser to dissolve an API, such as any one of water or a C 1 -C 4 alcohol such as ethanol or methanol.
  • a “small volume” refers to an amount of such a solvent that can contain an amount of dissolved API that is sufficiently concentrated to be useful to an abuser to realize the intended biological effect of the drug abuse, and that is also capable of being administered for abuse of the API, e.g., a volume that can contain an amount (concentration) of API that is effective to achieve a desired “high” if administered by injection or nasal insufflation, the volume also being sufficiently small to allow the volume to be administered by injection or nasal insufflation.
  • an API in the dosage form must be capable of being accessed and dissolved at sufficient concentration by an abuser without undue complication, into a “small volume” of solvent, which is a volume that can be administered by injection or by nasal insufflation.
  • a “small volume” of solvent means 50 milliliters or less, or 20 milliliters or less, or 10 milliliters or less, or 5 milliliters or less (volumes which could be injected or used for nasal insufflation).
  • a solvent-resistant film layer can be a film placed on a core-shell particle that is difficult to dissolve in a “small volume” of water or a C 1 -C 4 alcohol such as ethanol or methanol, e.g., that does not immediately dissolve in one or more of water or any one of a C 1 -C 4 alcohol such as methanol or ethanol.
  • the solvent-resistant film thereby retards or prevents an abuser from accessing an API portion of a core-shell particle if the core-shell particle is placed in one of these solvents.
  • the solvent-resistant film need not be completely or substantially insoluble in any one of these solvents, or in all of the solvents, and it must be capable of allowing the API to be accessed with sufficient rapidity, in a gastrointestinal tract, for the dosage form to be useful as an immediate release dosage form.
  • a particular example of a solvent-resistant film is a film that exhibits solubility properties that depend on the pH of a solvent.
  • An example of a solvent-resistant film may be a film that is substantially or completely insoluble at a pH that is greater than a pH condition of a human stomach, and that is sufficiently soluble at a pH condition of a stomach (and gastrointestinal tract) to allow the film to dissolve and release API with sufficient rapidity that the dosage form can be useful as an immediate release oral dosage form.
  • a pH-sensitive layer is a type of solvent-resistant film, and can be disposed in a dosage form to surround an active pharmaceutical ingredient and inhibit or prevent access to and dissolution of the active pharmaceutical ingredient in a solvent outside of a stomach (e.g., at a neutral pH environment), while still allowing the active pharmaceutical ingredient to be efficiently released from an immediate release dosage form at a lower pH environment of a user's stomach.
  • This type of abuse deterrent feature can prevent or significantly impede an abuser's access to an active pharmaceutical agent of a dosage form (e.g., at the core of a core-shell particle or in a layer disposed on the core, or in both the core and the layer disposed on the core) by use of a solvent that is outside of a stomach and that does not have a relatively acidic pH, such as water or a C 1 -C 4 alcohol such as ethanol, methanol, etc., or a mixture thereof, having a pH that is higher than a pH found in a human stomach, for example a pH greater than 4; greater than 5; or greater than 5.5; or greater than 6.
  • a pH-sensitive layer may be useful as a solvent-resistant film, placed in a dosage form as a layer of a core-shell particle to surround, cover, or enclose a portion of the core-shell particle that contains active pharmaceutical ingredient.
  • an active pharmaceutical ingredient may be located as desired at a core or at a layer outside of an uncoated or coated core; a solvent-resistant film in the form of a pH-sensitive layer may be disposed as a separate layer surrounding or covering the portion of the core-shell particle that contains the active pharmaceutical ingredient.
  • the pH-sensitive layer may be in direct contact with (adjacent to) a core or a layer that includes active pharmaceutical ingredient; alternately a core-shell particle may include one or more intermediate layers between a pH-sensitive layer and a core or layer that includes active pharmaceutical ingredient.
  • a useful pH-sensitive layer may include a polymer or other material that can be placed as a layer of a particle as described herein, such as to cover a more inner layer or core that contains active pharmaceutical ingredient, to form a pH-sensitive film surrounding or covering active pharmaceutical ingredient.
  • the pH-sensitive film can be solubilized by exposure to a liquid that exhibits a pH that may be present in a stomach of a user of the dosage form, such as a pH below 6 or below 5.5.
  • the pH-sensitive layer can contain polymer that is not easily or substantially soluble at a pH that is higher than a pH found in a human stomach, e.g., a pH greater than 6; by being insoluble at a pH greater than 6, the pH-sensitive polymer will not dissolve in many solvents easily available and commonly used by an abuser to extract a water-soluble drug from a dosage form such as water, ethanol, methanol, etc.
  • pH-sensitive polymer useful in a pH-sensitive layer include the class of reverse enteric polymers that contain cationic-functional groups and that exhibit pH-dependent solubility as described herein.
  • examples include polymers that contain basic functional groups such as amino groups, and that exhibit solubility at pH conditions found in a (human) stomach but not at relatively higher pH conditions, e.g., not above a pH of 4, 5, or 5.5, or not above a pH of 6.
  • pH-sensitive polymers include copolymers of dimethyl aminoethyl methacrylates, and neutral methacrylic acid esters; e.g., dimethyl aminoethyl methacrylate, butyl methacrylates, and methyl methacrylates, such as at a ratio of 2:1:1.
  • Examples of such polymers are commercially available under the trade name Eudragit® E-100, Eudragit® E PO, Eudragit® E 12.5, and similar amino-functional pH-sensitive polymers.
  • a preferred pH-sensitive polymer is the polymer Eudragit E100, but any polymer that is sufficiently hydrophilic at a low pH and hydrophobic at a higher pH to exhibit pH-dependent solubility as described, may also be effective if otherwise acceptable for use in a pharmaceutical dosage form, for example as a non-toxic ingredient of an oral dosage form.
  • Reverse enteric compositions are also described in EP 1694724 B1, titled “pH Sensitive Polymer and Process for Preparation Thereof.”
  • a solvent-resistant film layer When present as a coating of a particle that contains active pharmaceutical ingredient, a solvent-resistant film layer may be present at any amount useful as an abuse deterrent feature, such as in a range from 0.1 to 90 weight percent of a total weight of a core-shell particle, e.g., from 3 to 50 or 4 to 40 weight percent solvent-resistant polymer per total weight core-shell particle. More generally, a useful amount solvent-resistant film layer or polymer in a dosage form may be in a range from 1 to 50 weight percent solvent-resistant film layer or polymer based on a total weight of a dosage form, e.g., from 2 to 30 or from 3 to 15 weight percent solvent-resistant polymer based on total weight dosage form.
  • a dosage form as presently described can also preferably include a disintegrant, which functions to cause the dosage form to expand and break up during use, e.g., at conditions of a human stomach, to allow active pharmaceutical ingredient of the dosage form to be released in a manner to achieve an immediate release profile.
  • Disintegrants are known ingredients of pharmaceutical dosage forms, with various examples being known and commercially available.
  • disintegrants include compositions of or containing sodium starch glycolate, starch (e.g., maize starch, potato starch, rice starch, tapioca starch, wheat starch, corn starch and pregelatinized starch), croscarmellose sodium, crospovidone (crosslinked polyvinyl N-pyrrolidone or PVP) (polyplasdone XL-10), sodium starch glycolate (EXPLOTAB® or PRIMOJEL®), any combination of two or more of the foregoing, and other pharmaceutically acceptable materials formed into particles having a having particle size, density, etc., to allow processing of the disintegrant into a useful immediate release dosage form.
  • starch e.g., maize starch, potato starch, rice starch, tapioca starch, wheat starch, corn starch and pregelatinized starch
  • croscarmellose sodium crospovidone (crosslinked polyvinyl N-pyrrolidone or PVP) (polyplasdone
  • the disintegrant can be present in an immediate release dosage form at any location that allows the disintegrant to function as desired, to expand within the intact dosage form, upon ingestion, to cause the ingested dosage form to break apart and allow for desired immediate release of active pharmaceutical ingredient from the dosage form, in a stomach.
  • One useful location for a disintegrant can be as a component of an excipient used to contain core-shell particles that contain active pharmaceutical ingredient, as described herein, in a dosage form such as a compressed tablet or capsule.
  • disintegrant When included as an excipient of a dosage form, disintegrant may be present in an amount useful to achieve immediate release of an API of a dosage form.
  • useful amounts of disintegrant in an immediate release dosage form as described herein may be in a range from 0.5 to 50 weight percent disintegrant based on a total weight of the dosage form, e.g., from 1 to 30 weight percent disintegrant based on total weight of the dosage form.
  • the amount of disintegrant in a matrix of a dosage form can be consistent with these amounts, e.g., disintegrant can be included in a matrix (e.g., total of a dosage form that is other than the coated particles or API) of a dosage form in an amount in a range from 0.5 to 50 weight percent disintegrant based on a total weight of the matrix, e.g., from 1 to 30 weight percent disintegrant based on total weight matrix.
  • a matrix e.g., total of a dosage form that is other than the coated particles or API
  • a dosage form as described can also include any of various known and conventional pharmaceutical excipients that may be useful to achieve desired processing and performance properties of an immediate release dosage form.
  • excipients include fillers, binders, lubricants, glidants, coloring agents, pH-adjusters, etc., and can be included in core-shell particles or in a matrix (e.g., compressed matrix) of a tablet or capsule.
  • a matrix e.g., compressed matrix
  • a pH-adjuster can be included in an immediate release dosage form as described, for example at a location to affect pH at a specific location of the dosage form that is only a portion of a total dosage form.
  • a pH-adjuster in the form of a base may be included at a location of a gelling polymer that contains acid functionalities, to neutralize the acid functionalities.
  • the amount of pH-adjuster included at the location of the gelling polymer can be an amount effective to neutralize the acid functionalities of the gelling polymer at that location.
  • a component of a dosage form as described that includes an acid-functional gelling polymer such as a carbopol may include a base in an amount and location to neutralize the acid functionalities of that polymer.
  • the pH-adjuster can be located at a location effective to cause such neutralization, e.g., at the location of the dosage form that contains the acid-functional gelling polymer, for example at a core of a core-shell particle or as part of an excipient that includes acid-functional gelling polymer and that functions to bind particles together as a dosage form.
  • fillers examples include lactose, starch, dextrose, sucrose, fructose, maltose, mannitol, sorbitol, kaolin, microcrystalline cellulose, powdered cellulose, calcium sulfate, calcium phosphate, dicalcium phosphate, lactitol or any combination of the foregoing.
  • a filler will have a molecular weight that does not result in a substantial viscosity increase or formation of a gel as described herein for a gelling polymer, if combined with a solvent such as water.
  • a filler may be present in any portion of a dosage form as described, including a core-shell particle; the filler may be present in a core, in a layer containing an active pharmaceutical ingredient that is disposed on the core, in a solvent resistant film, at a matrix, or in two or more of these portions of the dosage form.
  • the filler may be present at any one or more of these portions of a dosage form in an amount to provide desired processing or functional properties of a portion of the dosage form and of the entire dosage form.
  • the amount of total filler in a dosage form can also be as desired to provide desired functionality, including an immediate release profile, for example in an amount in a range from 0 to 80 weight percent filler based upon the total weight of the dosage form, e.g. from 5 to 50 percent filler based on total weight dosage form.
  • binders examples include polymeric material such as alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, starch, pregelatinized starch, polyvinyl alcohol, polyethylene oxide, polyvinylpyrrolidone, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and any combination of two or more of these.
  • polymeric material such as alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, starch, pregelatinized starch, polyvinyl alcohol, polyethylene oxide, polyvinylpyrrolidone, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and any combination of two or more of these.
  • a binder may be a water soluble material; as compared to non-binder ingredients such as a gelling polymer, a binder is of a molecular weight that does not result in formation of a gel or a highly viscous composition upon combining with a small volume of water.
  • a binder can exhibit a relatively low molecular weight as compared to a gelling polymer, and a relatively lower viscosity (e.g., when measured in a 2% aqueous solution).
  • Polymer useful as a binder may typically have a molecular weight of less than 50,000, e.g., less than 30,000, or than 10,000.
  • a binder may be present in any portion of a dosage form as described, including a core or a film or coating of a core-shell particle, or as part of an excipient to contain or bind core-shells particles in a dosage form.
  • Filler may be included in a core of a core-shell particle in combination with active pharmaceutical ingredient, gelling polymer or both; as part of an active pharmaceutical layer located over a core or another layer of a core-shell particle; as part of a solvent-resistant film; or within an excipient useful to bind particles into a dosage form.
  • a binder may be present at any one or more of these portions of an immediate release dosage form as described, in an amount to provide desired processing or functional properties in each portion of the dosage form and of the overall dosage form.
  • the amount of total binder in a dosage form can also be as desired to provide desired functionality, including immediate release functionality, for example in an amount in a range from 0.1 to 10 weight percent binder based on a total weight of a dosage form, e.g., from 0.5 to 7 weight percent binder based on total weight dosage form.
  • lubricants include inorganic materials such as talc (a hydrated magnesium silicate; polymers, such as, PEG 4000; fatty acids, such as stearic acid; fatty acid esters, such as glyceride esters (e.g., glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate); sugar esters (e.g., sorbitan monostearate and sucrose monopalmitate); glyceryl dibehenate (Compritol® 888 ATO); and metal salts of fatty acids (e.g., magnesium stearate, calcium stearate, and zinc stearate).
  • talc a hydrated magnesium silicate
  • polymers such as, PEG 4000
  • fatty acids such as stearic acid
  • fatty acid esters such as glyceride esters (e.g., glyceryl monostearate, glyceryl tribehenate, and gly
  • Lubricant may be included in an immediate release dosage form as described, in any useful amount, such as an amount in a range from 0.1 to 10 weight percent lubricant based on a total weight of a dosage form, e.g., from 0.5 to 7 weight percent lubricant based on total weight dosage form.
  • glidants examples include colloidal silicon dioxide, untreated fumed silica (e.g., as available under the trade name Cab-O-Sil®), and crystalline or fused quartz. Glidant may be included in an immediate release dosage form as described, in any useful amount.
  • coloring agents include FD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxide and mixtures thereof.
  • a coloring agent may be incorporated into a dosage form by blending the coloring agent any other ingredient. Alternately, coloring agent may be applied to an outer surface of a dosage form.
  • APIs that can be particularly useful can be those types of active pharmaceutical ingredients that can be subject to abuse, addiction, overdosing, or two or more of these; such APIs can be located in the dosage form at a location to cause the API to be subject to abuse deterrent features of the core-shell particle, e.g., at a core or inner layer of a core-shell particle.
  • Drugs commonly susceptible to abuse include sedative-hypnotics, stimulants (e.g., central nervous system ((CNS) stimulants), anxiolytics, antipsychotics, dissociative anesthetics, and narcotic analgesics including but not limited to drugs that can cause psychological or physical dependence on the drug.
  • stimulants e.g., central nervous system ((CNS) stimulants
  • anxiolytics e.g., central nervous system ((CNS) stimulants
  • anxiolytics e.g., antipsychotics
  • dissociative anesthetics e.g., narcotic analgesics
  • narcotic analgesics including but not limited to drugs that can cause psychological or physical dependence on the drug.
  • An API can include any therapeutically acceptable drug salt, drug derivative, drug analog, drug homologue, or polymorph of an active pharmaceutical ingredient.
  • Sedative hypnotics include, for example, barbiturates, for example phenobarbital, methobarbital, amobarbital, pentobarbital, and secobarbital and pharmaceutically acceptable salts thereof; benzodiazepines, for example diazepam, chlorodiazepoxide, lorazepam, triazolam, temazepam, alprazolam and flurazepam and pharmaceutically acceptable salts thereof; phenothiazines, such as for example, alimemazine, chlorpromazine, thioridazine, and pharmaceutically acceptable salts thereof, and sleep medications, such as for example, zolpidem, zaleplon, and eszopiclone and pharmaceutically acceptable salts thereof.
  • barbiturates for example phenobarbital, methobarbital, amobarbital, pentobarbital, and secobarbital and pharmaceutically acceptable salts thereof
  • benzodiazepines for example diaze
  • Anxiolytics include, for example, benzodiazepines, for example diazepam, chlordiazepoxide, estazolam, lorazepam, triazolam, alprazolam, clonazepam and flurazepam and pharmaceutically acceptable salts thereof.
  • benzodiazepines for example diazepam, chlordiazepoxide, estazolam, lorazepam, triazolam, alprazolam, clonazepam and flurazepam and pharmaceutically acceptable salts thereof.
  • CNS Stimulants include, for example, amphetamines, such as for example, dextroamphetamine, levoamphetamine (benzadrine), methamphetamine (methadrine), pseudoephedrine, and Adderall (amphetamine mixed salts) and pharmaceutically acceptable salts thereof, and non-amphetamine psychostimulants such as methylphenidate, modafinil and armodafinil and pharmaceutically acceptable salts thereof.
  • amphetamines such as for example, dextroamphetamine, levoamphetamine (benzadrine), methamphetamine (methadrine), pseudoephedrine, and Adderall (amphetamine mixed salts) and pharmaceutically acceptable salts thereof
  • non-amphetamine psychostimulants such as methylphenidate, modafinil and armodafinil and pharmaceutically acceptable salts thereof.
  • Narcotic analgesics include opioids such as, for example, buprenorphine, butorphanol, codeine, dihydrocodeine, dihydromorphine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, methadone, fentanyl, meperidine, tramadol, propoxyphene, and pharmaceutically acceptable salts thereof.
  • opioids such as, for example, buprenorphine, butorphanol, codeine, dihydrocodeine, dihydromorphine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, methadone, fentanyl, meperidine, tramadol, propoxyphene, and pharmaceutically acceptable salts thereof.
  • Antipsychotic agents can include, for example, phenothiazines as listed above, butyrophenones, such as, for example, droperidol and haloperidol, dibenzoxazepines such as loxapine, and atypical antipsychotic agents such as aripiprazole, clozapine, olanzapine, quetiapine, risperidone ziprasidone, paliperidone and remoxipride.
  • phenothiazines as listed above
  • butyrophenones such as, for example, droperidol and haloperidol
  • dibenzoxazepines such as loxapine
  • atypical antipsychotic agents such as aripiprazole, clozapine, olanzapine, quetiapine, risperidone ziprasidone, paliperidone and remoxipride.
  • muscle relaxants such as for example cyclobenzaprine and pharmaceutically acceptable salts thereof
  • cannabinols e.g., ⁇ 1 -cannabidiol. ⁇ 2 -cannabidiol, ⁇ 3 -cannabidiol, ⁇ 3,7 -cannabidiol, ⁇ 4 -cannabidiol, ⁇ 5 -cannabidiol, and ⁇ 6 -cannabidiol
  • cannabinoids such as dronabinol, delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), nabilone, dexanabinol, ajulemic acid, cannabinor, rimonabant and taranabant, and pharmaceutically acceptable salts thereof
  • dissociative anesthetic agents such as ketamine and Esketamine, and pharmaceutically acceptable salts thereof.
  • the amount of active pharmaceutical ingredient included in an immediate release dosage form can be any useful amount, as is known and as may be found in relevant literature such as Goodman & Gillman's, The Pharmacological Basis of Therapeutics, 9th ed. pages 219-222, 361-396, 521-535 1996.
  • typical therapeutic amounts of oxycodone range 5 mg, 10 mg, or up to 400 mg, for the hydrochloride salt.
  • the active pharmaceutical ingredient can be present in such dosage form in an amount normally prescribed, typically 0.5 to 25 percent on a dry weight basis, based on the total weight of the dosage form.
  • narcotic analgesics such as opioids in a single unit dosage form, such as at a level from about 1 to about 500 mg, or from about 1 to about 250 mg, or from about 1 to about 100 mg; for example, 2.5, 5, 7.5, 10, 15, 20, or 30, milligram (mg) per dosage form unit.
  • a dosage form contains any appropriate amount of an API to provide a therapeutic effect.
  • the present invention is also directed to methods of treatment, comprising orally administering an effective amount of the herein described immediate release abuse deterrent dosage form.
  • Also provided herein is a method for treating sleep disorders in a subject in need thereof by administering an effective amount of the herein described immediate release abuse deterrent dosage form containing an API that is a sedative hypnotic drug such as a barbiturate,
  • Also provided herein is a method for treating anxiety in a subject in need thereof by administering a an effective amount of the herein described immediate release abuse deterrent dosage form containing an API that is an anxiolytic drug such as a benzodiazepine,
  • Also provided herein is a method for treating psychoses in a subject in need thereof by administering a an effective amount of the herein described immediate release abuse deterrent dosage form containing an API that is an antipsychotic drug such as questiapine,
  • an “effective amount” of when used in connection with composition described herein is an amount sufficient to produce a therapeutic result in a subject in need thereof.
  • a therapeutic result can include, but is not limited to treating or preventing pain, sleep disorders, anxiety or psychotic symptomology by a subject.
  • a dosage form as described can optionally include one or more additional APIs of a type that is not commonly susceptible to abuse.
  • This additional APIs may be any suitable or desired API, such as those in the class of non-steroidal analgesic drugs.
  • non-steroidal analgesic drugs refers to drugs that include those commonly referred to as non-steroidal anti-inflammatory drugs, or “NSAIDS,” and acetaminophen, which is non-steroidal, but does not act via an inflammation mechanism. Accordingly, the term “non-steroidal analgesic drugs” would include acetaminophen, and also include NSAIDS such as aspirin, ibuprofen, and naproxen.
  • the dosage form also exhibits immediate release properties with respect to these not-commonly-subject-to-abuse APIs.
  • these APIs can be present in the dosage form at any useful level, typically 0.5 to 25, e.g., 1 to 10 weight percent of the API on a dry weight basis, based on a total weight of the dosage form, e.g., at a level of or between 5, 25, 50, 75, 100, 125, 150, 175, 200, 300, 325, 500, 750 or up to or exceeding 1000 milligram (mg) per dosage form unit.
  • a dosage form contains an appropriate amount of an API to provide a therapeutic effect.
  • An immediate release dosage form as described can include one or more of the described abuse deterrent features, alone or in combination; e.g., one or more of: gelling polymer as part of a core-shell particle (e.g., at a core of the core-shell particle); wax as part of a core-shell particle (e.g., at a core of the core-shell particle); binder or filler as part of a core-shell particle (e.g., at a core of the core-shell particle); a film layer that may optionally be a solvent-resistant film (e.g., pH-sensitive film) as part of a core-shell layer; or gelling polymer as a component of an excipient or binder used to hold core-shell particles together as part of in an immediate release dosage form.
  • a solvent-resistant film e.g., pH-sensitive film
  • some dosage forms include nasal irritant to discourage or prevent abuse by nasal insufflation.
  • the nasal irritant can be a mucous membrane irritant or nasal passageway irritant that, if inhaled through a nasal passageway when contained in a ground or powdered dosage form, can induce pain or irritation of the abuser's nasal passageway tissue.
  • examples include surfactants such as sodium lauryl sulfate, poloxamer, sorbitan monoesters, and glyceryl monooleates.
  • dosage forms can include an emetic agent, to cause vomiting.
  • Certain particular embodiments of dosage forms of the present description do not require and can specifically exclude an emetic agent.
  • some dosage forms include an effervescent agent that acts as a deterrent to abuse by nasal insufflation.
  • the effervescent includes an acidic component and a basic component that release a gas such as oxygen or carbon dioxide when combined in the presence of an aqueous media, such as upon nasal insufflation.
  • the acid source may be, for example, citric acid, tartaric acid, malic acid, maleic acid, lactic acid, glycolic acid, ascorbic acid, fumaric acid, adipic acid, succinic acid, salts thereof, and combinations thereof.
  • the base may be, for example, a carbonate or bicarbonate. Dosage forms of the present description do not require, and can specifically exclude, an effervescent in the form of an acid and a base that can combine to a gas such as oxygen or carbon dioxide.
  • Still other dosage forms include a biologically active chemical compound that functions as an antagonist to an active pharmaceutical ingredient.
  • An antagonist may prevent the potential abuse of a dosage form in a manner, including the method of consuming multiple or several or more dosage form units at once.
  • Antagonist agents are compounds that block or negate the effect of an active pharmaceutical ingredient, and are available and known for various classes of drugs including opioids and other pharmaceutical agents.
  • antagonist agents for opioids include compounds such as naltrexone, naloxone, nalmefene, cyclazacine, levallorphan.
  • Specific examples of antagonist agents and methods for preparing antagonist agents for incorporation into a dosage form are provided in U.S. Pat. Nos. 7,682,633 and 7,658,939, which are incorporated herein by reference.
  • an immediate release dosage form that includes an opioid and that includes one or more abuse deterrent feature as described herein (e.g., a gelling polymer, wax, solvent-resistant film, or a combination thereof), can be formulated to not contain and to specifically exclude an agonist of an API that is also included in the dosage form, e.g., an opioid antagonist in a dosage form containing an opioid.
  • an opioid e.g., a gelling polymer, wax, solvent-resistant film, or a combination thereof
  • a dosage form can include particles 10 A, 10 B that contain API.
  • the particle e.g., coated particle or “core-shell” particle
  • the particle can include a core 12 (or “uncoated core”), which may be coated with one or more layer, film or coating, e.g., 14 , 16 , or any additional layer or coating that is coated over, underneath, or intermediate to these.
  • Particle 10 A, 10 B can contain one or more of the ingredients described herein, such as any one or more of API (especially an API that is susceptible to abuse), a gelling polymer, optional wax, optional solvent-resistant layer, as well as one or more additional layer or layers under, over, or intermediate to these layers or between either layer and the core.
  • Each layer can be present in size or amount (e.g., thickness) that will result in a useful immediate release dosage form having one or more of the presently described abuse deterrent features.
  • Other optional components of a core or layer of particle 10 can be filler, binder, other excipient, or solvent (not more than a residual amount, if any) such as water or ethanol for use in preparing the coated particle, and that is substantially removed after formation of the core, coating, or coated particle.
  • the core 10 A, 10 B can include any amount of the different ingredients of: a gelling polymer (e.g.
  • filler as described herein such as sugar (mannitol) or microcrystalline cellulose (e.g., from 0 to 100 percent of a core), binder (e.g., from 0 to 100 percent of a core), and wax (e.g., from 0 to 100 percent of a core).
  • sugar mannitol
  • microcrystalline cellulose e.g., from 0 to 100 percent of a core
  • binder e.g., from 0 to 100 percent of a core
  • wax e.g., from 0 to 100 percent of a core
  • core-shell particles 10 are believed to be new and inventive, certain method steps useful to prepare these novel coated particles may be known. Available methods include certain methods and processing steps known to be useful for preparing particles and coated particles in the pharmaceutical arts.
  • a core-shell particle 10 can be prepared by an initial step of mixing ingredients of core 12 with a solvent such as water or ethanol and forming the mixture into a spherical core particle by known methods. The particle may be dried and separated by size, and then one or more coating in the form of a continuous film or layer can be applied to the core, optionally successively to produce multiple layers surrounding the core.
  • General processing to produce a multi-layer coated particle can include a series of steps such as compounding, mixing, granulation, wet milling, coating (by any method such as fluidized bed coating, spray coating, etc.), and one or more drying steps such as by use of a fluidized bed or other drying method. Intermittently between core-forming and coating steps, e.g., after a drying step, coated or uncoated particles can be sorted or separated based on size to produce a composition or a collection of particles having a desired size range and distribution.
  • an immediate release dosage form as described can include a core-shell particle 10 A that includes a core 12 A that contains only a minor amount of API or that contains an insubstantial amount of API.
  • Core 12 A may contain less than 5 weight percent, e.g., less than 1 or less than 0.5 weight percent active pharmaceutical ingredient based on a total weight of the core of the core-shell particle.
  • core 12 A may contain less than 5 weight percent of a total amount of pharmaceutical ingredient in a core-shell polymer, e.g., less than 5, less than 1, or less than 0.5 weight percent active pharmaceutical ingredient based on total weight of API in the core-shell particle.
  • a major portion of API can be contained outside of core 12 A, e.g., in an API layer 16 , which can contain at least 50, at least 75, or at least 90 weight percent of a total amount of the API in a core-shell polymer.
  • Core 12 A can include binder, gelling polymer (e.g., HPMC), wax, or filler, optionally alone or in combination, each in an amount to allow the materials of the core to function as one or more abuse deterrent feature as described herein. See the examples included herewith for examples of useful amounts and ranges of amounts of these ingredients.
  • gelling polymer e.g., HPMC
  • wax e.g., wax
  • filler optionally alone or in combination, each in an amount to allow the materials of the core to function as one or more abuse deterrent feature as described herein. See the examples included herewith for examples of useful amounts and ranges of amounts of these ingredients.
  • core 12 A contains gelling polymer, wax, binder, or filler, or any combination of these, and no API (meaning not more than an insignificant amount, such as less than 0.5 or less than 0.1 weight percent based on the weight of core 12 A).
  • core 12 A, not containing API can be coated with a coating layer that contains API, e.g., an active pharmaceutical layer or API layer 16 A.
  • API e.g., an active pharmaceutical layer or API layer 16 A.
  • core-shell particle 10 A includes core 12 A, which does not contain any API, and API layer 16 A, which contains an amount of API, such as a total amount of API (e.g., API commonly susceptible to abuse) to be contained in a dosage form prepared from particles 10 A.
  • API layer 16 A can contain one or more ingredients as described herein useful to form API layer 16 A as a layer over an outer surface of core 12 A.
  • API in API layer 16 A can be a type of API that is commonly susceptible to abuse, such as an opioid, and can account for all of or most of (e.g., at least 70, at least 80, at least 90, or at least percent) the total amount of that type of API in the core-shell particles and in the dosage form; in this embodiment the core can contain less than 10, less than 5, or less than 1 percent of the total amount of API in the core-shell particles, and less than 10, 5, or 1 percent of the total amount of API in the dosage form.)
  • Useful non-API ingredients in an API layer can include a binder along with the API.
  • the API and binder can be carried in a solvent (e.g., water, ethanol, or both) and coated and dried to form a preferably continuous film layer on an outer surface of core 12 A, i.e., API layer 16 A. See the examples included herewith for examples of useful amounts and ranges of amounts of these ingredients.
  • a solvent e.g., water, ethanol, or both
  • a core-shell particle 10 A can also optionally include a film layer, e.g., a solvent-resistant layer (e.g., a pH-sensitive layer) 14 A as described herein.
  • a film layer e.g., a solvent-resistant layer (e.g., a pH-sensitive layer) 14 A as described herein.
  • a dosage form as described can include a core-shell particle 10 B that includes a core 12 B that does contain a useful amount of API, such as an amount of API useful in an immediate release dosage form having one or more abuse deterrent features as described herein, prepared to include particles 10 B. See FIGS. 2A and 2B .
  • core 12 B of particle 10 B can contain a gelling polymer, optional wax, optional binder or filler, and an amount of API.
  • core 12 B contains gelling polymer, optional wax, optional binder, and API.
  • core 12 B, containing API can optionally be coated with solvent-resistant layer (e.g., a pH-sensitive layer) 14 B as described herein for use in an immediate release dosage form.
  • solvent-resistant layer e.g., a pH-sensitive layer
  • a coated particle 10 that includes API can be included in any of a variety of dosage forms, examples including a compressed tablet or compressed capsule, a suppository, capsule, caplet, pill, gel, soft gelatin capsule, etc.
  • a dosage form 12 can be prepared as a compressed tablet or compressed capsule.
  • Tablet or capsule 12 can contain core-shell particles 10 (e.g., 10 A or 10 B) distributed within a matrix 20 , compressed to form the compressed tablet or capsule 12 .
  • Core-shell particles 10 A or 10 B can be as described herein, generally or specifically, and can contain an amount of API suited to provide a desired dosage upon ingestion of tablet or capsule 12 ; e.g., matrix 20 does not include any substantial amount of API.
  • Matrix 20 can include ingredients useful in combination with the core-shell particles 10 A, 10 B, to produce an immediate release dosage form.
  • useful excipients of an immediate release dosage form can include ingredients that allow the dosage form to break up or disintegrate upon ingestion and facilitate exposure to fluid in a stomach, such as a useful amount of disintegrant.
  • examples of such excipients for such a dosage form can also include one or more ingredients that act as an abuse deterrent feature, such as a gelling polymer as described herein.
  • Other excipients can be useful for processing to form a compressed dosage form, and also may allow the compressed dosage form to function as an immediate release dosage form, with one or more abuse deterrent features.
  • the following non-limiting examples show various dosage forms as described herein.
  • the described and exemplified dosage forms can be made from methods that include granulating, coating, and compressing steps as follows.
  • the blending, compression and bottling process for hydrocodone and acetaminophen tablets manufactured using the coated intermediate is as follows:
  • Granules were manufactured in a high shear granulator, where hypromellose and glyceryl behenate were dry mixed for 3 minutes. Then, a 10% hydroalcoholic solution of ethylcellulose N10 was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of ethylcellulose was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.
  • a size reduction mill Granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.
  • coated granules were prepared according to Example 1 above and mixed with paracetamol and other excipients (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • paracetamol and other excipients carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • the prepared coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Coated granules were prepared according to the procedure described in Example 1. The prepared coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, red iron oxide, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, red iron oxide, microcrystalline cellulose
  • Microcrystalline cellulose particles were layered in a bottom spray fluid bed coater with a 12% aqueous solution of oxycodone hydrochloride and HPMC 2910.
  • the oxycodone hydrochloride layered particles were then coated in a bottom spray fluid bed coater with 25% alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate. The resulting coated particles were subsequently used for further blending and compression process.
  • coated particles were mixed with other excipients (crospovidone and lactose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into oxycodone tablets.
  • excipients crospovidone and lactose
  • coated spheres were mixed with acetaminophen and other excipients (mannitol, microcrystalline cellulose, binder and crospovidone) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into oxycodone tablets.
  • Coated spheres were prepared as in Example 7, and mixed with acetaminophen and other excipients (mannitol, microcrystalline cellulose, xanthan gum and crospovidone) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone tablets.
  • acetaminophen and other excipients mannitol, microcrystalline cellulose, xanthan gum and crospovidone
  • Coated spheres were prepared as in Example 7, and mixed with acetaminophen and other excipients (mannitol, microcrystalline cellulose, carbopol, sodium bicarbonate and crospovidone) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into tablets.
  • acetaminophen and other excipients mannitol, microcrystalline cellulose, carbopol, sodium bicarbonate and crospovidone
  • Oxycodone tablet composition Component mg/tablet Core Shell composition (above) 250 APAP 325 gelatin 12.14 lactose 84.9 carbopol 30 microcrystalline cellulose 120 crospovidone 150 sodium bicarbonate 18 magnesium stearate 10 Total 1000.04
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into oxycodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Oxycodone/acetaminophen tablet composition Component mg/tablet Core Shell composition (above) 250 APAP 325 gelatin 12.14 mannitol 82.9 xanthan gum 50 microcrystalline cellulose 120 crospovidone 150 magnesium stearate 10 Total 1000.04
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (xanthan gum, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into oxycodone/acetaminophen tablets.
  • excipients xanthan gum, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Oxycodone/acetaminophen tablet composition Component mg/tablet Core Shell composition (above) 250 APAP 325 Gelatin 12.14 Mannitol 52.9 Carbopol 50 microcrystalline cellulose 120 Crospovidone 150 sodium bicarbonate 30 magnesium stearate 10 Total 1000.04
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into oxycodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • excipients carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Granules were prepared and coated as described in Example 1. The coated granules were then mixed with Paracetamol and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and coloring agents) and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and the mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • Armodafinil tablet composition Armodafinil: Components (mg/tab) 50 mg 150 mg 200 mg hypromellose 64.26 36 48 Compritol 888 ATO 17.85 10 14 ethylcellulose 10.71 10 14 armodafinil 50 150 200 Eudragit E-100 21 30 40 Mannitol Ez 17 25 25 Carbopol 71g 50 50 50 50 microcrystalline cellulose 100 125 125 crospovidone 150 200 200 sodium bicarbonate #1 30 30 30 30 magnesium stearate non- 71 25 32 bovine Lutrol F68 (1:5) 150 200 200 sodium lauryl sulphate (3%) 23 30 40 Alcohol SDA-3A, * * * * anhydrous * purified water * * * * * Total Tablet Weight 754.82 921 1018 * Removed during Processing Granules are prepared and coated as described in Example 1.
  • coated granules are then mixed with the other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes.
  • the other excipients include butylene glycol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Magnesium stearate non-bovine
  • Phenobarbital granule compositions 15 mg Dose 30 mg Dose 60 mg Dose 100 mg Dose mg/g mg/tab mg/g mg/tab mg/g mg/tab mg/g mg/tab Granulation Hypromellose 450 19.31 450 38.57 450 77.18 450 128.57 Phenobarbital 350 15.02 350 30 350 60.03 350 100 Compritol 125 5.36 125 10.71 125 21.44 125 35.71 888 ATO Ethylcellulose 75 3.22 75 6.43 75 12.86 75 21.43 Alcohol SDA-3A, * * * * * * * * * * Anhyd.
  • Granules are prepared and coated as described in Example 1.
  • the coated granules are then mixed with the other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes.
  • Magnesium stearate (non-bovine) is then added to lubricate the blend and the mixture is blended for an additional 5 minutes prior to compressing into phenobarbital tablets.
  • coated granules are then mixed with the other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes.
  • the other excipients include butylene glycol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose
  • Magnesium stearate non-bovine
  • Granules are prepared and coated as described in Example 1.
  • the coated granules are then mixed with the other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes.
  • Magnesium stearate (non-bovine) is then added to lubricate the blend and the mixture is blended for an additional 5 minutes prior to compressing into hydrocodone tablets.
  • Coated granules were prepared according to the Example 1 above.
  • the prepared coated granules were then mixed with Paracetamol and other excipients (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, colorants such as FD and C blue, red iron oxide or yellow iron oxide are premixed and blended in a bin blender for 30 minutes.
  • Paracetamol and other excipients carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, colorants such as FD and C blue, red iron oxide or yellow iron oxide are premixed and blended in a bin blender for 30 minutes.
  • Magnesium stearate was then added to lubricate the blend and the resulting mixture was blended for an additional 5 minutes prior to compressing into hydrocodone/acetaminophen tablets.
  • the Dosage form (intact and crushed) prepared according to Examples 3 above (10/325 mg hydrocodone bitartrate/Acetaminophen tablet) was taken up in a small volume of water and extracted to simulate the amount of hydrocodone that was available to abusers via intravenous (IV) route.
  • the resultant mixture was assessed for ability to draw the mixture through a filter material into a syringe for IV injection.
  • Various needle sizes and extraction volumes were evaluated. Filtrates were assayed by HPLC for content of hydrocodone bitartrate.
  • the dosage form prepared according to Example 3 above (10/325 mg hydrocodone bitartrate/Acetaminophen tablets) was crushed using a pestle and mortar and placed in 10 mL of simulated nasal fluid at 37° C., with gentle agitation to simulate the amount of hydrocodone bitartrate available for abuse by nasal insufflation. Aliquots were removed at 10 and 30 minutes for analysis of hydrocodone bitartrate by HPLC. The amount of hydrocodone bitartrate extracted from crushed tablets for simulated nasal insufflation is provided in the table below.
  • This method is for the determination of hydrocodone bitartrate released from simulated nasal fluid extractions of hydrocodone bitartrate extended-release tablets.
  • Solvent A (0.1% HFBA in H 2 O): Combine 1 mL of HFBA and 1 L of HPLC grade water, and mix well. Solvent A is stable for 14 days. Proportionate volumes may be prepared.
  • Mobile Phase 70:30 Solvent A:MeOH: Combine 700 mL of Solvent A and 300 mL of MeOH, and mix well. Prepared solutions are stable for 1 month. Proportionate volumes may be prepared.
  • the HPLC pump may be used to mix the mobile phase.
  • Diluent/Medium 0.1 N HCl
  • Proportionate volumes may be prepared.
  • Injector Flush 50:50 MeOH:H2O: Combine 500 mL of MeOH and 500 mL of HPLC grade water, and mix well. 50:50 MeOH:H 2 O is stable for 1 month. Proportionate volumes may be prepared.
  • Working Standard Solution Pipette 15 mL of each stock standard solution into separate 50-mL volumetric flasks. Dilute to volume with 0.1 N HCl diluent, and mix well. These working standard solutions are approximately 90 micrograms/mL (as anhydrous hydrocodone bitartrate) and are stable for 43 days under ambient laboratory conditions (unprotected from light). Proportionate volumes may be prepared.
  • the dosage form prepared according to Example 3 and 5 above was evaluated for multiple tablet oral abuse resistance by stirring the selected number of tablets in 300 mL of 0.1N HCl. Dissolution was performed using USP Apparatus II at 50 rpm and 37° C. One to twelve tablets were added to the vessel simultaneously and aliquots were removed after 5, 10, 15, 30, 60, 120, 240 and 360 minutes of agitation and analyzed for hydrocodone bitartrate ( FIG. 4 ) and APAP ( FIG. 5 ) by HPLC. The results were plotted against time and appear in FIGS. 4 and 5 .
  • the dosage form prepared according to Example 17 above was evaluated for multiple tablet oral abuse resistance by stirring the selected number of tablets in 300 mL of 0.1N HCl. Dissolution was performed using USP Apparatus II at 50 rpm and 37° C. One to twelve tablets were added to the vessel simultaneously and aliquots were removed after 5, 10, 15, 30, 60, 120, 240 and 360 minutes of agitation and analyzed for hydrocodone bitartrate ( FIG. 6 ) and APAP ( FIG. 7 ) by HPLC. The results were plotted against time and appear in FIGS. 6 and 7 .
  • the dosage form prepared according to Example 17 above was evaluated for multiple tablet oral abuse resistance by stirring the selected number of tablets in 300 mL of 0.1N HCl. Dissolution was performed using USP Apparatus II at 50 rpm and 37° C. One to twelve tablets were added to the vessel simultaneously and aliquots were removed after 5, 10, 15, 30, 60, 120, 240 and 360 minutes of agitation and analyzed for hydrocodone bitartrate and APAP by HPLC. The results were plotted against time and appear in FIG. 8 (hydrocodone bitartrate) and FIG. 9 (APAP).
  • Coated esketamine granules are prepared as per the process described in Example 1 with slight variation from Example 1 in components as illustrated below.
  • coated granules prepared per Example 27 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and the resulting mixture was blended for additional 5 minutes prior to compressing into tablets.
  • Coated esketamine granules are prepared as per the process described in Example 1 with slight variation from Example 1 in components as illustrated in the Table below.
  • Coated granules prepared per Example 29 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate is added to lubricate the blend and the resulting mixture was blended for additional 5 minutes prior to compressing into tablets.
  • Esketamine granules are manufactured using a process similar to that described in Example 1 above with some modification to the process.
  • the active ingredient instead of being layered on the granules resides in the core where it is granulated with other excipients as per the Table below, and is subsequently coated with Eudragit E-100.
  • Granules are manufactured in a high shear granulator where hypromellose, Esketamine hydrochloride and glyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added.
  • the granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying.
  • Esketamine hydrochloride granules are then coated in a bottom spray fluid bed coater with 25% alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate (2:1). The coated granules are subsequently used in blending and compression process.
  • Coated granules prepared per Example 31 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and blended in a V-blender for 30 minutes. Magnesium stearate is added to lubricate the blend and the resulting mixture was blended for additional 5 minutes prior to compressing into tablets.
  • Esketamine hydrochloride tablet composition Components (mg/tablet) 28 mg 56 mg 84 mg hypromellose 36 72 108 gyceryl behenate 10 20 30 ethylcellulose 6 12 18 esketamine hydrochloride 28 56 84 Eudragit E-100 11.7 23.4 35.1 mannitol 17 17 20.1 carbopol 50 50 50 microcrystalline cellulose 100 100 100 crospovidone 150 150 150 sodium bicarbonate 30 30 30 magnesium stearate 12 20 30 Total Tablet Weight 450.7 550.4 655.2
  • Esketamine granules are manufactured using a process similar to that described in Example 1 and Example 32 above with some modification to the process.
  • the active ingredient is granulated with other excipients per the table below, and is subsequently coated with Eudragit E-100.
  • Granules containing Esketamine hydrochloride are manufactured in a high shear granulator where hypromellose, esketamine hydrochloride and glyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and then loaded into fluid bed for drying.
  • a size reduction mill Granules containing Esketamine hydrochloride
  • the granules are then coated in a bottom spray fluid bed coater with 25% alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate (2:1). The resulting coated granules are subsequently used for blending and compression process.
  • coated granules prepared per Example 33 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Esketamine hydrochloride tablet compositions Components (mg/tab) 200 mg 300 mg 400 mg Hypromellose 48 72 96.4 Glyceryl behenate 14 21 27.6 Ethylcellulose 14 21 27.6 Esketamine hydrochloride 200 300 400 Eudragit E-100 40 61 81 Mannitol 25 25 25 Carbopol 75 75 75 Microcrystalline cellulose 125 125 125 Crospovidone 300 300 300 Sodium bicarbonate 45 45 45 Magnesium stearate 140 150 160 Total Tablet Weight 1026 1195 1362.6
  • Coated Zolpidem tartrate granules are prepared as per the process described in Example 1 as per the composition illustrated in the Table below.
  • Coated zolpidem granules are prepared as per the process described in Example 35 above.
  • the coated granules are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Zolpidem tartrate tablet compositions Components (mg/tab) 5 mg 10 mg hypromellose 25.5 51.1 glyceryl behenate 11 21.9 ethylcellulose 6 12 zolpidem tartrate 5 10 Hypromellose 2910 2.5 5 Eudragit E-100 33.4 66.7 mannitol 70 70 carbopol 50 50 microcrystalline cellulose 95 94 crospovidone 100 100 sodium bicarbonate 30 30 magnesium stearate 21.6 39.3 Total Tablet Weight 450 550 550
  • Quetiapine granules are manufactured using a process similar to that described in Example 1 above with some modification to the process.
  • the Quetiapine fumarate instead of being layered on the granules, resides in the core where it granulated along with other excipients per Table 70 (Granulation) and is subsequently coated with Eudragit E-100 and magnesium stearate.
  • Granules are manufactured in a high shear granulator where hypromellose, Quetiapine fumarate, a portion of the Lutrol, sodium lauryl sulphate and glyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and then loaded into fluid bed for drying.
  • a size reduction mill Granules are then wet milled using a size reduction mill (Granumill) and then loaded into fluid bed for drying.
  • the quetiapine fumarate granules are then coated in a bottom spray fluid bed coater with alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • the resulting coated granules are then used in blending and compression process.
  • coated granules prepared per Example 37 above are subsequently mixed with other components (carbomer, crospovidone, remaining portion of Lutrol, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Quetiapine fumarate tablet compositions 25 mg 50 mg 100 mg (mg/ (mg/ (mg/ Components (mg/tablet) tablet) tablet) tablet) hypromellose 16 32 63 glyceryl behenate 9 18 36 ethylcellulose 5 11 22 quetiapine fumarate 25 50 100 Eudragit E-100 27 53 107 mannitol 17 17 20.1 carbopol 50 50 50 microcrystalline cellulose 100 100 100 100 crospovidone 150 150 150 200 sodium bicarbonate 30 30 30 magnesium stearate 18 31 63 Lutrol 45 51 62 sodium lauryl sulphate 6 12 24 Total Tablet Weight 498 605 877.1
  • Quetiapine granules are manufactured using a process similar to that described in Example 1 and with some modification to the process.
  • the Quetiapine fumarate instead of being layered on the granules, resides in the core where it is granulated along with other excipients per Table 72 and is subsequently coated with Eudragit E-100.
  • Granules are manufactured in a high shear granulator where hypromellose, Quetiapine fumarate, sodium lauryl sulphate, portion of Lutrol and glyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and then loaded into fluid bed for drying.
  • a size reduction mill Granules are then wet milled using a size reduction mill (Granumill) and then loaded into fluid bed for drying.
  • Quetiapine Fumarate granules are then coated in a bottom spray fluid bed coater with alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate. The resultant coated granules are subsequently used for blending and compression process.
  • coated granules prepared as per Example 39 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, and remaining portion of Lutrol) and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Quetiapine fumarate tablet compositions Components (mg/tab) 200 mg 300 mg 400 mg hypromellose 48 72.5 97 glyceryl behenate 14 20.8 28 ethylcellulose 14 20.8 28 quetiapine fumarate 200 300 400 Eudragit E-100 40 74 99 mannitol 25 25 25 carbopol 50 65 65 microcrystalline cellulose 125 125 125 crospovidone 200 275 275 sodium bicarbonate 45 45 45 magnesium stearate 36 48 64 Lutrol 78 91.6 105 sodium lauryl sulphate 34 51.2 69 Total Tablet Weight 909 1213.9 1425
  • Coated hydromorphone granules are prepared as per the process described in Example 1 with slight variation from Example 1 in components as illustrated below.
  • Coated hydromorphone granules are prepared as per the process described in Example 1 and Example 41 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Coated methamphetamine granules are prepared according to the process described in Example 1.
  • Methamphetamine hydrochloride granule composition % w/w Granulation hypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL 100 Layering methamphetamine hydrochloride 5 polymer granules (EC, HPMC and 92.5 Compritol) Hypromellose 2910 2.5 TOTAL 100 Coating methamphetamine layered 50 granules Eudragit E-100 33 magnesium stearate 17 TOTAL 100
  • Coated methamphetamine granules are prepared as per the process described in Example 1 and Example 43 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Methamphetamine hydrochloride tablet composition Components (mg/tablet) 5 mg hypromellose 55.6 glyceryl behenate 23.8 ethylcellulose 13.1 methamphetamine hydrochloride 5 Hypromellose 2910 2.5 Eudragit E-100 66.7 mannitol 70 carbopol 50 microcrystalline cellulose 95 crospovidone 100 sodium bicarbonate 30 magnesium stearate 39 Total Tablet Weight 550.7
  • Coated oxymorphone granules are prepared as per the process described in Example 1.
  • Coated oxymorphone granules are prepared as per the process described in Example 1 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Oxymorphone hydrochloride tablet compositions Components (mg/tablet) 5 mg 10 mg hypromellose 25.5 51.1 glyceryl behenate 11 21.9 ethylcellulose 6 12 oxymorphone hydrochloride 5 10 Hypromellose 2910 2.5 5 Eudragit E-100 33.4 66.7 mannitol 70 70 carbopol 45 45 microcrystalline cellulose 95 94 crospovidone 100 100 sodium bicarbonate 27 27 magnesium stearate 21.6 39.3 Total Tablet Weight 442 542
  • Coated oxycodone granules are prepared as per the process described in Example 1.
  • Coated oxycodone granules are prepared as per the process described in Example 1 and Example 47 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Oxycodone hydrochloride tablet compositions Components (mg/tablet) 5 mg 15 mg 30 mg hypromellose 25.5 76.6 153.3 glyceryl behenate 11 32.8 65.7 ethylcellulose 6 18.1 36.1 oxycodone hydrochloride 5 15 30 Hypromellose 2910 2.5 7.5 15 Eudragit E-100 33.4 100.1 200.1 mannitol 70 37.29 70 carbopol 45 50 50 microcrystalline cellulose 95 130 94 crospovidone 100 150 200 sodium bicarbonate 27 30 30 magnesium stearate 21.6 57 110 Total Tablet Weight 442 704.39 1054.2
  • Coated morphine granules are prepared as per the process described in Example 1.
  • Morphine Sulfate tablet compositions % w/w Granulation hypromellose 60 glyceryl behenate 26 ethylcellulose 14 TOTAL 100 Layering morphine sulphate 10 polymer granules (EC, HPMC and 85 Compritol) Hypromellose 2910 5 TOTAL 100 Coating morphine layered granules 50 Eudragit E-100 33 magnesium stearate 17 TOTAL 100
  • Coated morphine granules are prepared as per the process described in Example 1 and Example 49 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Morphine sulphate tablet compositions Components (mg/tablet) 6 mg 15 mg 30 mg hypromellose 30.6 76.6 153.3 glyceryl behenate 13.1 32.8 65.7 ethylcellulose 7.2 18.1 36.1 morphine sulphate 6 15 30 Hypromellose 2910 3 7.5 15 Eudragit E-100 40.02 100.1 200.1 mannitol 70 70 70 carbopol 45 50 50 microcrystalline cellulose 95 130 94 crospovidone 100 150 200 sodium bicarbonate 27 30 30 magnesium stearate 24.5 57 110 Total Tablet Weight 461.42 737.1 1054.2
  • Coated granules containing mixed amphetamine salts are prepared as per the process described in Example 1.
  • Coated granules containing mixed amphetamine salts are prepared as per the process described in Example 1 and Example 51 above.
  • the coated granules are subsequently mixed with other components such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Coated granules containing Codeine phosphate are prepared as per the process described in Example 1 with some modifications to the composition as described below.
  • Coated granules containing codeine phosphate are prepared as per the process described in Example 1 and Example 53 above.
  • the coated granules are subsequently mixed with other active ingredient (paracetamol), and other components (carbomer, crospovidone, sodium bicarbonate, mannitol, colorant, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • active ingredient paracetamol
  • other components carbomer, crospovidone, sodium bicarbonate, mannitol, colorant, microcrystalline cellulose
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Coated granules containing methylphenidate hydrochloride are prepared as per the process described in Example 1.
  • Coated granules containing methylphenidate hydrochloride are prepared as per the process described in Example 1 and Example 55 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Methylphenidate hydrochloride tablet formulation Components (mg/tablet) 5 mg 20 mg hypromellose 25.5 102.15 glyceryl behenate 10.9 43.8 ethylcellulose 6.02 24.1 methylphenidate hydrochloride 5 20 Hypromellose 2910 2.5 10 Eudragit E-100 33.4 133.4 mannitol 70 70 carbopol 45 50 microcrystalline cellulose 95 150 crospovidone 100 160 sodium bicarbonate 27 30 magnesium stearate 21.5 75 Total Tablet Weight 441.82 868.45
  • Coated granules containing oxycodone hydrochloride were prepared and coated as per the process described in Example 1.
  • Granules were manufactured in a high shear granulator where Hypromellose and glyceryl behenate were dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose N10 was slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition was continued until the entire amount of ethylcellulose was added. The granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.
  • a size reduction mill Granules were then wet milled using a size reduction mill (Granumill) and were subsequently loaded into fluid bed for drying.
  • the prepared granules were then layered in a bottom spray fluid bed coater with a 12% aqueous solution of oxycodone hydrochloride and HPMC 2910 (2:1).
  • the oxycodone hydrochloride layered granules were then coated in a bottom spray fluid bed coater with 25% alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate (2:1). The resulting coated granules were subsequently used for further blending and compression process.
  • coated granules prepared according to the example 57 above were mixed with another active agent, Paracetamol, and other excipients (carbomer, crospovidone, sodium bicarbonate, mannitol, FD&C blue, microcrystalline cellulose), and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and blended for additional 5 minutes prior to compressing into oxycodone/APAP tablets.
  • Oxycodone hydrochloride tablet formulation Component % w/w oxycodone coated granules 20.0 Paracetamol* 33.7 mannitol 4.2 carbopol 5.0 microcrystalline cellulose 13.0 crospovidone 20.0 sodium bicarbonate 3.0 FD and C blue 0.06 magnesium stearate 1.0 Total 100 *Contains 95% acetaminophen and 5% gelatin
  • coated granules prepared according to the example 57 above were mixed with another active agent, Paracetamol, and other excipients (carbomer, crospovidone, sodium bicarbonate, mannitol, FD&C blue, microcrystalline cellulose), and blended in a V-blender for 30 minutes. Magnesium stearate was then added to lubricate the blend and blended for additional 5 minutes prior to compressing into oxycodone/APAP tablets.
  • Oxycodone/acetaminophen tablet formulations Component (% w/w) 5/325 mg 7.5/325 mg 10/325 mg oxycodone coated granules 12.5 16.7 20.0 paracetamol* 42.8 38.0 34.2 mannitol 3.7 4.37 3.79 carbopol 6.25 5.6 5 microcrystalline cellulose 12 12 13 crospovidone 18 19 20 sodium bicarbonate 3.75 3.3 3 Iron Oxide yellow 0.06 NA NA FD&C Blue # 2 NA 0.06 NA magnesium stearate 1.0 1.0 1.0 Total 100 100 100 *Contains 95% acetaminophen and 5% gelatin
  • Armodafinil granules are manufactured using a process similar to that described in Example 1 and with some modification to the process.
  • the active ingredient, Armodafinil instead of being layered on the granules, resides in the core where it is granulated along with other excipients as per Table 93, and is subsequently coated with Eudragit E-100.
  • Granules are manufactured in a high shear granulator where hypromellose, Armodafinil, povidone and glyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying.
  • a size reduction mill Granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying.
  • Armodafinil granules are then coated in a bottom spray fluid bed coater with alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • the resultant coated granules are subsequently used for blending and compression process.
  • coated granules prepared as per Example 60 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Phenobarbital granules are manufactured using a process similar to that described in Example 1 and with some modification to the process.
  • the active ingredient, Phenobarbital instead of being layered on the granules, resides in the core where it is granulated along with other excipients per the Table below, and is subsequently coated with Eudragit E-100.
  • Granules are manufactured in a high shear granulator where hypromellose, phenobarbital, povidone and glyceryl behenate are dry mixed for 3 minutes. Then a 10% hydroalcoholic solution of ethylcellulose is slowly added while maintaining the granulator impeller and chopper speed at pre-selected values that provide enough shear for granule formation and growth. Solution addition is continued until the entire amount of ethylcellulose is added. The granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying.
  • a size reduction mill Granules are then wet milled using a size reduction mill (Granumill) and subsequently loaded into fluid bed for drying.
  • the phenobarbital granules are then coated in a bottom spray fluid bed coater with alcoholic suspension of Eudragit E-100 copolymer and magnesium stearate.
  • the resultant coated granules are subsequently used for blending and compression process.
  • Phenobarbital granule formulations % w/w Granulation
  • coated granules prepared as per Example 62 above are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Phenobarbital tablet formulations 15 mg 30 mg 60 mg 100 mg (mg/ (mg/ (mg/ (mg/ Components tablet) tablet) tablet) tablet) hypromellose 3.8 7.5 15 25.01 glyceryl behenate 1 2 3.4 5.72 ethylcellulose 1 2 3.4 5.72 phenobarbital 15 30 60 100 Eudragit E-100 15 30 59 98.5 mannitol 20 20 20 20 20 20 20 20 carbopol 50 50 50 50 50 50 50 50 50 50 50 microcrystalline cellulose 75 100 100 100 crospovidone 130 130 200 200 sodium bicarbonate 30 30 30 30 30 30 magnesium stearate 12 20 36 59 povidone 2 4 7.7 12.9 Total Tablet Weight 354.8 425.5 584.5 706.85
  • Coated diazepam granules are prepared as per the process described in Example 1 with slight variation from Example 1 in components as illustrated in the Table below.
  • Coated diazepam granules are prepared as per the process described in Example 1 and Example 64 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose), and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.
  • Diazepam tablet formulations Components (mg/tablet) 2 mg 5 mg 10 mg hypromellose 22.2 55.6 111.2 glyceryl behenate 9.5 23.8 47.64 ethylcellulose 5.2 13.1 26.2 diazepam 2 5 10 Hypromellose 2910 1 2.5 5 Eudragit E-100 26.7 66.7 133.4 mannitol 70 70 70 carbopol 50 50 50 50 microcrystalline cellulose 95 95 94 crospovidone 120 120 150 sodium bicarbonate 30 30 30 magnesium stearate 18.1 38.6 74.6 Total Tablet Weight 449.7 570.3 802.04
  • Coated granules containing hydrocodone bitartrate are prepared as per the process described in Example 1.
  • Coated granules containing hydrocodone bitartrate are prepared as per the process described in Example 1 and Example 66 above.
  • the coated granules are subsequently mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and blended in a V-blender for 30 minutes.
  • Magnesium stearate is added to lubricate the blend and blended for additional 5 minutes prior to compressing into tablets.

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US14/333,986 US20150118300A1 (en) 2013-10-31 2014-07-17 Immediate Release Abuse-Deterrent Granulated Dosage Forms
PCT/US2014/054061 WO2015065586A1 (en) 2013-10-31 2014-09-04 Immediate release abuse-deterrent granulated dosage forms
US14/477,354 US20150118301A1 (en) 2013-10-31 2014-09-04 Immediate Release Abuse-Deterrent Granulated Dosage Forms
US14/484,793 US20150118295A1 (en) 2013-10-31 2014-09-12 Immediate Release Abuse-Deterrent Granulated Dosage Forms
EP14858628.2A EP3062778A4 (en) 2013-10-31 2014-10-29 Immediate release abuse-deterrent granulated dosage forms
AU2014342412A AU2014342412B2 (en) 2013-10-31 2014-10-29 Immediate release abuse-deterrent granulated dosage forms
US14/527,215 US9707224B2 (en) 2013-10-31 2014-10-29 Immediate release abuse-deterrent granulated dosage forms
EA201690874A EA032013B1 (ru) 2013-10-31 2014-10-29 Препятствующие злоупотреблению гранулированные лекарственные формы с немедленным высвобождением
PE2016000556A PE20160606A1 (es) 2013-10-31 2014-10-29 Formas de dosificacion granuladas disuasivas del abuso de liberacion inmediata
CA2900858A CA2900858C (en) 2013-10-31 2014-10-29 Immediate release abuse-deterrent granulated dosage forms
JP2016552219A JP6659925B2 (ja) 2013-10-31 2014-10-29 即放性乱用抑止性剤形
MX2016005482A MX384376B (es) 2013-10-31 2014-10-29 Formas de dosificación de liberación inmediata disuasivas del abuso, en forma de partículas recubiertas con capas múltiples que comprenden un analgésico narcótico susceptible de abuso o sobredosis.
PCT/US2014/062887 WO2015066172A1 (en) 2013-10-31 2014-10-29 Immediate release abuse-deterrent granulated dosage forms
US15/032,658 US20160250203A1 (en) 2013-10-31 2014-10-29 Immediate release abuse-deterrent granulated dosage forms
CN201480059281.6A CN105682647A (zh) 2013-10-31 2014-10-29 立即释放型滥用制止粒状剂型
HK16112327.1A HK1223856A1 (zh) 2013-10-31 2014-10-29 立即釋放型濫用制止粒狀劑型
KR1020167013870A KR102363573B1 (ko) 2013-10-31 2014-10-29 즉시 방출 남용 저지 입상 투여 형태
US14/539,231 US9757371B2 (en) 2013-10-31 2014-11-12 Immediate release abuse-deterrent granulated dosage forms
IL245125A IL245125B (en) 2013-10-31 2016-04-14 Immediate-release granulated dosage forms prevent abuse
ZA2016/04451A ZA201604451B (en) 2013-10-31 2016-04-22 Immediate release abuse-deterrent granulated dosage forms
CL2016001031A CL2016001031A1 (es) 2013-10-31 2016-04-29 Forma de dosificación de liberación inmediata que evita el abuso, que comprende partículas de núcleo recubiertas y una matriz; su uso para preparar un medicamento útil para prevenir, aliviar o aminorar un nivel de dolor y para prevenir el abuso de un fármaco analgésico narcótico, entre otros.
US15/908,013 US10568881B2 (en) 2013-10-31 2018-02-28 Immediate release abuse-deterrent granulated dosage forms
US16/751,043 US11207318B2 (en) 2013-10-31 2020-01-23 Immediate release abuse-deterrent granulated dosage forms
US17/527,528 US11844796B2 (en) 2013-10-31 2021-11-16 Immediate release abuse-deterrent granulated dosage forms

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US14/484,793 Abandoned US20150118295A1 (en) 2013-10-31 2014-09-12 Immediate Release Abuse-Deterrent Granulated Dosage Forms
US14/527,215 Active US9707224B2 (en) 2013-10-31 2014-10-29 Immediate release abuse-deterrent granulated dosage forms
US15/032,658 Abandoned US20160250203A1 (en) 2013-10-31 2014-10-29 Immediate release abuse-deterrent granulated dosage forms
US14/539,231 Active US9757371B2 (en) 2013-10-31 2014-11-12 Immediate release abuse-deterrent granulated dosage forms
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US14/527,215 Active US9707224B2 (en) 2013-10-31 2014-10-29 Immediate release abuse-deterrent granulated dosage forms
US15/032,658 Abandoned US20160250203A1 (en) 2013-10-31 2014-10-29 Immediate release abuse-deterrent granulated dosage forms
US14/539,231 Active US9757371B2 (en) 2013-10-31 2014-11-12 Immediate release abuse-deterrent granulated dosage forms
US15/908,013 Active US10568881B2 (en) 2013-10-31 2018-02-28 Immediate release abuse-deterrent granulated dosage forms
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US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
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US10568881B2 (en) 2020-02-25
US20150118302A1 (en) 2015-04-30
US9707224B2 (en) 2017-07-18
KR102363573B1 (ko) 2022-02-16
KR20160070839A (ko) 2016-06-20
MX2016005482A (es) 2016-12-16
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US20200155544A1 (en) 2020-05-21
US20150118303A1 (en) 2015-04-30
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US11844796B2 (en) 2023-12-19
US9757371B2 (en) 2017-09-12
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US20150118295A1 (en) 2015-04-30
US20150118301A1 (en) 2015-04-30
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US20160250203A1 (en) 2016-09-01
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US20180185354A1 (en) 2018-07-05
US11207318B2 (en) 2021-12-28

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