HK1191570A

HK1191570A - Pharmaceutical composition comprising opioid agonist and sequestered antagonist

Info

Publication number: HK1191570A
Application number: HK14104935.4A
Authority: HK
Inventors: E．S．威尔森
Original assignee: 雅来制药有限责任公司
Priority date: 2011-02-02
Filing date: 2012-01-25
Publication date: 2014-08-01

Description

Pharmaceutical compositions comprising opioid agonists and sequestered antagonists

Technical Field

The present invention relates to pharmaceutical compositions comprising a plurality of multi-layered pellets having an oxycodone layer and a sequestering (sequencing) subunit comprising naltrexone and a blocking agent, in particular to pharmaceutical compositions comprising higher levels of naltrexone and related compositions and methods for use, for example, in preventing abuse of therapeutic agents. The compositions described herein also have a long oxycodone release T_maxAnd a flatter release profile of oxycodone over time.

Background

Opioids, also known as opioid agonists, are a class of drugs that exhibit opioid or morphine-like properties. Opioids were originally used as moderate-to-intense analgesics, but also have many other pharmacological effects, including lethargy, respiratory depression, mood changes, and mental cloudiness without loss of consciousness. Due to these other pharmacological effects, opioids have become dependent and abused subjects. Thus, a major problem associated with opioid use is the avoidance of these drugs in illicit users, such as addicts.

Previous attempts to control the abuse potential associated with opioid analgesics include, for example, by TalwinNx (from Sanofi-Winthrop, Canterbury, Australia) is a combination of pentazocine and naloxone in the form of tablets commercially available in the United states. TalwinNx contained pentazocine hydrochloride equivalent to 50mg of base and naloxone hydrochloride equivalent to 0.5mg of base. TalwinNx is useful for relieving moderate to severe pain. The amount of naloxone present in the combination has low activity when taken orally and minimally interferes with the pharmacological effect of pentazocine. However, this amount of naloxone administered parenterally has a significant antagonistic effect on narcotic analgesics. Thus, the inclusion of naloxone is intended to control the misuse of oral pentazocine, which occurs when the dosage form is dissolved and injected. Thus, the dosage form has a lower likelihood of parenteral misuse than previous oral pentazocine formulations. However, it is still the subject of misuse and abuse by the oral route (e.g. the patient takes multiple doses at once). Fixed combination therapy comprising telidine (50mg) and naloxone (4mg) has been used in Germany since 1978 for the control of severe pain (Valoron)N, Goedecke). The rationale for these drug combinations is effective pain relief and prevention of telidine addiction through naloxone-induced antagonism at the telidine receptor. New Zealand introduced a fixed combination of buprenorphine and naloxone in 1991 (Terngesic)Nx,Reckitt &Colman) to treat pain.

International patent application No. PCT/US01/04346(WO 01/58451) to Euroceltique, s.a. describes the use of a pharmaceutical composition comprising a substantially non-releasing opioid antagonist and a releasing opioid agonist as separate subunits combined into a pharmaceutical dosage form, such as a tablet or capsule. However, because the agonist and antagonist are in separate subunits, they can be easily separated. Furthermore, where agonists and antagonists are provided as separate subunits, it is more difficult to form tablets due to the mechanical sensitivity of some of the subunits containing the sequestering agent.

The benefits of abuse resistant dosage forms are particularly great for strong opioid agonists (e.g., morphine, hydromorphone, oxycodone, or hydrocodone) that provide valuable analgesia, but are easily abused. This is particularly beneficial for extended release opioid agonist products which contain, in each dosage unit, a large dose of the desired opioid agonist intended to be released over a period of time. Drug abusers take such sustained release products and crush, grind, extract or otherwise destroy the product so that all contents of the dosage form become immediately absorbable.

Such abuse resistant sustained release dosage forms are described in the prior art (see, e.g., U.S. application nos. 2003/0124185 and 2003/0044458). However, it is believed that a significant amount of the opioid antagonist or other antagonists found in these sequestered forms are released over time (typically less than 24 hours) due to the osmotic pressure accumulated in the core of the sequestered form as water permeates the sequestered form into the core. The high osmotic pressure inside the core of the sequestered form causes the opioid antagonist or antagonist to be pushed out of the sequestered form, thereby causing the opioid antagonist or antagonist to be released from the sequestered form. To the extent that the opioid antagonist has been sequestered for any extended period of time, the amount of antagonist sequestered is small relative to the sequestering subunit. For example, U.S. Pat. No.6,696,088 describes a sequestering subunit containing 2.3% naltrexone (3.3 mg out of a total of 140 mg). In addition, the formulation released 33% of naltrexone in 36 hours when subjected to the USP type II paddle test and the in vitro dissolution method. U.S. patent application No. 2010/0098771 describes a sequestering subunit containing 2.1% naltrexone, which has a 5.7% leak after 24 hours. U.S. patent No. 7,682,633 provides for sequestration of the antagonist, but the antagonist is 2.6% of the sequestering subunit.

Furthermore, when sequestering large amounts of opioid antagonist, the amount of opioid antagonist sequestered in prior art forms of abuse resistant sustained release dosage forms is limited by the leakage of the opioid antagonist from the dosage form. See, for example, U.S. patent application No. 2003/0004177.

In view of the foregoing disadvantages of the prior art sequestered forms, there is a need in the art for sequestered forms of opioid antagonists that provide a large amount of the antagonist to be sequestered, wherein the antagonist is not substantially released from the sequestered form over a long period of time. Disclosed herein are sequestered forms of such opioid antagonists. This and other objects and advantages and other features of the disclosed subject matter will be apparent from the description provided herein.

Summary of The Invention

Provided herein are pharmaceutical compositions comprising an antagonist, an agonist, a seal coat (seal coat), and a sequestering polymer, wherein the antagonist, agonist, seal coat, and at least one sequestering polymer are all components of a single unit, and wherein the seal coat forms a layer that physically separates the antagonist and the agonist from each other. Also provided herein are methods of making such pharmaceutical compositions. The pharmaceutical compositions described herein provide greater sequestration of opioid antagonists than the prior art.

The present invention provides a composition comprising a plurality of multilayer pellets comprising: a water-soluble core; an antagonist-containing layer comprising naltrexone hydrochloride coating the core; a sequestering polymer layer coating the antagonist-containing layer; an agonist layer comprising an opioid agonist coating the sequestering polymer layer; and a controlled release layer coating the agonist layer; wherein the naltrexone hydrochloride comprises at least 10% by weight of the opioid agonist, and wherein, when administered to a human, the agonist is substantially released and the naltrexone hydrochloride is substantially sequestered.

Also provided herein are compositions comprising a plurality of multilayer pellets comprising: a water-soluble core; an antagonist-containing layer comprising naltrexone hydrochloride coating the core; a sequestering polymer layer coating the antagonist-containing layer; an agonist layer comprising an opioid agonist coating the sequestering polymer layer; and a controlled release layer coating the agonist layer; wherein the weight of the naltrexone hydrochloride comprises at least 5% of the combined weight of the water-soluble core, the antagonist layer, and the sequestering polymer layer, and wherein, when administered to a human, the agonist is substantially released and the naltrexone hydrochloride is substantially sequestered.

Brief Description of Drawings

Figure 1 is a graphical representation of mean oxycodone plasma concentration versus time curves for immediate release oxycodone and extended release oxycodone/naltrexone compositions.

Figure 2 is a graphical representation of mean dose normalized oxycodone plasma concentration versus time curves for immediate release oxycodone and extended release oxycodone/naltrexone compositions.

FIG. 3 is a graphical representation of mean noroxycodone (noroxycodone) plasma concentration-time profiles for immediate release oxycodone and extended release oxycodone/naltrexone compositions.

FIG. 4 is a graphical representation of Drug preference Bipolar VAS mean (Drug weighing Bipolar VASMean) of raw scores (evaluable population).

Detailed Description

Provided herein are compositions and methods for administering multiple active agents to a mammal in a form and manner that minimizes the effect of any one active agent on another active agent in vivo. In certain embodiments, at least two active agents are formulated as part of a pharmaceutical composition. The first active agent can provide an in vivo therapeutic effect. The second agent can be an antagonist of the first agent and can be used to prevent misuse of the composition. For example, when the first active agent is an opioid, the second active agent can be an antagonist of the opioid. The composition remains intact and does not release the antagonist during normal use by the patient. However, when the composition is damaged (tamper), the antagonist may be released, thereby preventing the opioid from having its intended effect. In certain embodiments, both active agents may be contained in a single unit, such as a pellet, in the form of a layer. The active agent may be formulated, for example, as a controlled release composition with a substantially impermeable barrier to minimize release of the antagonist from the composition. In certain embodiments, the antagonist is released in an in vitro assay, but is not substantially released in vivo. The in vitro and in vivo release of the active agent from the composition can be measured by any of a variety of known techniques. For example, in vivo release can be determined by measuring plasma levels (i.e., AUC, Cmax) of the active agent or metabolite thereof.

In certain embodiments, one of the active agents is an opioid receptor agonist. Several opioid agonists are commercially available or in clinical trials, and may be administered as described herein to minimize the alcohol effect. Opioid agonists include, for example: alfentanil, allylmorphine, alfalidine, anileridine, benzylmorphine, bezilimide, buprenorphine, butorphanol, lonicerazine, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, dinolamine, dihydrocodeine, dihydroetorphine, dihydromorphine, dextromethorphan, dimemethadol, demewhat, dimethylthiodine, morelbutyl ester, dipiperazone, etazocine, esomephenzine, ethidine, ethylmorphine, etonixine, etorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypatidine, isometholone, ketonide, levorphanol, nalorphine, allylfentanyl, pethidine, meptazinol, metazocine, methadone, metolone, morphine, mupirorphine, buprenorphine, nemorphine, methamphetamine, nicotinic, levorphanol, normorphine, morphine, normorphine, levorphanol, normorphine, morphine, normorphine, levorphanol, normorphine, morphine, normorphine, morphine, levorphanol, morphine, Nopiperidone, opium, oxycodone, oxymorphone, opiate alkaloids, pentazocine, phenoxepin, phenazocine, fenorphanol, phentermine, piminodine, pimonitine, pranopaline, meperidine, propiperidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof. Preferably, the opioid agonist is selected from hydrocodone, hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof. Most preferably, the opioid agonist is morphine, hydromorphone, oxycodone or hydrocodone. Equivalent analgesic doses (equiangelsic dose) of these opioids compared to hydrocodone at 15mg dose were as follows: oxycodone (13.5mg), codeine (90.0mg), hydrocodone (15.0mg), hydromorphone (3.375mg), levorphanol (1.8mg), meperidine (135.0mg), methadone (9.0mg) and morphine (27.0 mg).

Oxycodone, chemically known as 4, 5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioid agonist whose primary therapeutic effect is analgesia. Other therapeutic effects of oxycodone include anxiolytic (anxiolysis), euphoric and relaxing sensations. The exact mechanism of its analgesic effect is not known, but specific CNS opioid receptors for endogenous compounds with opioid activity have been identified throughout the brain and spinal cord and play a role in the analgesic effect of this drug. Oxycodone is commercially available in the united states, for example: oxycotin from Purdue Pharma L.P. (Stamford, Conn.)It is a controlled release tablet for oral administration comprising 10mg, 20mg, 40mg or 80mg oxycodone hydrochloride; and OxyIR, e.g. from Purdue Pharma L.P^TMIt is an immediate release capsule containing 5mg oxycodone hydrochloride. The invention includes all formulations comprising an opioid antagonist and/or an antagonist in sequestered form as part of a subunit comprising an opioid agonist.

Oral hydromorphone is commercially available in the United states, for example, Dilaudi from Abbott Laboratories (Chicago, Ill.)Oral morphine is commercially available in the United states, for example, Kadian by Faulding Laboratories (Piscataway, N.J.)

In embodiments where the opioid agonist comprises hydrocodone, the sustained release oral dosage form may comprise an analgesic dose of about 8mg to about 50mg hydrocodone per dosage unit. In a sustained release oral dosage form in which hydromorphone is a therapeutically active opioid, the hydromorphone is included in an amount from about 2mg to about 64mg of hydromorphone hydrochloride. In another embodiment, the opioid agonist comprises morphine and the sustained release oral dosage form described herein may comprise from about 2.5mg to about 800mg by weight of morphine. In yet another embodiment, the opioid agonist comprises oxycodone and the extended release oral dosage form described herein may comprise oxycodone in an amount from about 2.5mg to about 800 mg. In certain preferred embodiments, the extended release oral dosage form comprises from about 5mg to about 200mg oxycodone. Preferred embodiments of the dosage form may comprise oxycodone or a pharmaceutically acceptable salt thereof in an amount of 10mg, 20mg, 40mg, 60mg, 80mg, 100mg, and 120 mg. Controlled release oxycodone formulations are known in the art. The following references describe various controlled release oxycodone formulations suitable for use as described herein and methods for their preparation: such as U.S. Pat. No. 5,266,331; 5,549,912; 5,508,042; and U.S. Pat. No. 5,656,295, which is incorporated herein by reference. The opioid agonist may comprise tramadol, and the sustained release oral dosage form may comprise from about 25 to 800mg of tramadol per dosage unit.

In certain embodiments, another active agent included in the composition may be an opioid receptor antagonist. In certain embodiments, the agonist and antagonist are administered together separately or as a single pharmaceutical unit. In the example when the therapeutic agent is an opioid agonist, the antagonist is preferably an opioid antagonist, such as naltrexone, naloxone, nalmefene, cyclazocine (cyclazacine), levorphanol, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof. More preferably, the opioid antagonist is naloxone or naltrexone. "opioid antagonist" is meant to include one or more opioid antagonists, alone or in combination, and is also meant to include partial antagonists, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and combinations thereof. In a preferred embodiment, when the antagonist is naltrexone, preferably the complete dosage form releases less than 0.125mg or less of naltrexone over a 24 hour period, and when the dosage form is crushed or chewed, releases 0.25mg or more of naltrexone after 1 hour.

In a preferred embodiment, the opioid antagonist comprises naltrexone. In previous treatments for opioid addicted patients, naltrexone has been used in large oral doses (over 100mg) to prevent the euphoric effect of opioid agonists. Naltrexone has been reported to exert a strong preferential blocking effect on the μ site relative to the δ site. Naltrexone is considered a synthetic homologue of oxymorphone without opioid agonist properties and differs structurally from oxymorphone by the replacement of the methyl group located on the nitrogen atom of oxymorphone by a cyclopropylmethyl group. The hydrochloride salt of naltrexone is soluble in water, up to about 100 mg/cc. Naltrexone is evaluated for its pharmacological and pharmacokinetic properties in a variety of animal and clinical studies. See, e.g., Gonzalez et al, Drugs 35: 192-. Upon oral administration, naltrexone is rapidly absorbed (within 1 hour) and has an oral bioavailability of 5-40%. The protein of naltrexone bound to about 21% and the volume of distribution after single dose administration was 16.1L/kg.

Tablet forms of naltrexone are commercially available (Revia)DuPont (Wilmington, Del.)) for the treatment of alcohol dependence and the blocking of exogenously administered opioids. See, for example, Revia (naltrexone hydrochloride tablets), the Physician's Desk Reference, version 51, Montvale, N.J., and medical Economics51: 957-. Revia at a dose of 50mgBlocks the pharmacological effect of 25mg of heroin administered by intravenous injection for up to 24 hours. Known to be chronically associated with morphine, heroin or other opioidsUpon co-administration, naltrexone blocks the body-dependent formation of opioids. It is believed that the method by which naltrexone blocks the heroin effect is by competitive binding at the opioid receptors. Naltrexone has been used to treat narcotic addiction by completely blocking the effects of opioids. The most successful use of naltrexone for addiction to narcotics has been found to be in narcotic addicts with good prognosis, as part of comprehensive occupational or return projects including behavioral control or other compliance-increasing approaches. For narcotic-dependent treatment with naltrexone, it is desirable that the patient not take opioids for at least 7-10 days. For this purpose, the initial dose of naltrexone is usually about 25mg, and if no withdrawal signs are present, the dose may be increased to 50mg per day. A daily dose of 50mg is believed to produce a sufficient clinical block of the effects of parenterally administered opioids. Naltrexone is also used to treat alcoholism, aiding social and psychiatric treatment.

Other preferred opioid antagonists include, for example, cyclazocine and naltrexone, both of which have a cyclopropylmethyl substituent on the nitrogen, retain most of their efficacy by the oral route and persist for longer, reaching 24 hours after oral administration.

In one embodiment, a sequestering subunit comprising an opioid antagonist and a blocking agent is provided, wherein the blocking agent substantially prevents release of the opioid antagonist from the sequestering subunit in the gastrointestinal tract for a period of time greater than 24 hours. The sequestering subunit is incorporated into a single pharmaceutical unit that also comprises an opioid agonist. The drug unit thus comprises a core moiety to which the opioid antagonist is applied. A seal coat is then optionally applied over the antagonist. The composition comprising the pharmaceutically active agent is then applied over the seal coat. An additional layer comprising the same or a different blocking agent may then be applied, whereby the opioid agonist is released over time (i.e., controlled release) in the digestive tract. Thus, both the opioid antagonist and the opioid agonist are contained within a single pharmaceutical unit, typically in the form of a pellet.

As used herein, the term "sequestering subunit" refers to any means for containing an antagonist and preventing or substantially preventing, when intact (i.e., when undamaged), release of the antagonist in the gastrointestinal tract. As used herein, the term "blocking agent" refers to a means by which the sequestering subunit is able to substantially prevent the release of the antagonist. The blocking agent may be a sequestering polymer, as described in detail below.

As used herein, the term "substantially prevent", "prevent", or any word derived therefrom means that the antagonist is not substantially released from the sequestering subunit in the gastrointestinal tract. By "substantially not released" is meant that when the dosage form is orally administered to a host, such as a mammal (e.g., a human) as intended, the antagonist may be released in small amounts, but the amount released does not affect or does not significantly affect analgesic efficacy. As used herein, the terms "substantially prevent," "prevent," or any word derived therefrom do not necessarily imply complete or 100% prevention. Rather, there are varying degrees of prevention that one skilled in the art would consider to be of potential benefit. In this regard, the blocking agent substantially prevents or prevents the release of the antagonist to the extent that: preventing at least about 80% of the antagonist from being released from the sequestering subunit in the gastrointestinal tract over a period of more than 24 hours. Preferably, the blocking agent prevents at least about 90% of the antagonist from being released from the sequestering subunit in the gastrointestinal tract for a period of time greater than 24 hours. More preferably, the blocking agent prevents at least about 95% of the antagonist from being released from the sequestering subunit. Most preferably, the blocking agent prevents at least about 99% of the antagonist from being released from the sequestering subunit in the gastrointestinal tract for a period of more than 24 hours.

For the purposes of the present invention, the amount of antagonist released after oral administration can be measured in vitro by the dissolution test described in the United states pharmacopoeia (USP26) chapter <711> dissolution. For example, the release from the dosage unit at different times is measured at 37 ℃ using 900mL of 0.1N HCl, device 2 (paddle), 75 rpm. Other methods for determining the release of an antagonist from a sequestering subunit over a given period of time are known in the art (see, e.g., USP 26).

Without being bound by any particular theory, it is believed that the sequestering subunit described herein overcomes the limitations of the sequestered forms of antagonists known in the art because the sequestering subunit described herein reduces osmotically driven release of the antagonist from the sequestering subunit. Furthermore, it is believed that the sequestering subunits of the invention reduce the release of the antagonist for a longer period of time (e.g., over 24 hours) as compared to the sequestered forms of antagonists known in the art. The fact that the sequestering subunit described herein provides a longer period of time to prevent release of the antagonist is particularly important because prohibitive withdrawal can occur after the time that the therapeutic agent is released and is acting. It is well known that the gastrointestinal transit times of individuals vary greatly within a population. Thus, the residue of the dosage form may remain in the gastrointestinal tract for more than 24 hours, and in some cases more than 48 hours. It is also well known that opioid analgesics cause reduced intestinal motility, further prolonging gastrointestinal transit time. Currently, the food and drug administration has approved a slow release form that is effective over a 24 hour period. In this regard, when undamaged, the sequestering subunits of the present invention prevent antagonist release for a period of time exceeding 24 hours.

The sequestering subunits described herein are designed to substantially prevent release of the antagonist when intact. By "intact" is meant that the dosage form has not experienced damage. The term "damage" means any treatment, including mechanical, thermal and/or chemical means, that alters the physical properties of the dosage form. The damage may be, for example, crushing, shearing, grinding, chewing, dissolving in a solvent, heating (e.g., above 45 ℃), or any combination thereof. When a sequestering subunit described herein is damaged, the antagonist may be released immediately from the sequestering subunit.

"subunit" is meant to include compositions, mixtures, granules, and the like, which when combined with another subunit are capable of providing a dosage form (e.g., an oral dosage form). The subunits may be in the form of beads, pellets, granules, spheres, etc., and may be combined with additional subunits, which may be the same or different, in the form of capsules, tablets, etc., to provide a dosage form, e.g., an oral dosage form. The sub-unit may also be part of a larger single unit, forming part of the unit, such as a layer. For example, the subunit may be a core coated with the antagonist and a seal coat; the subunit may then be coated with an additional composition comprising a pharmaceutically active agent, such as an opioid agonist.

The blocking agent prevents or substantially prevents release of the antagonist in the gastrointestinal tract for a period of time greater than 24 hours, e.g., 24 hours to 25 hours, 30 hours, 35 hours, 40 hours, 45 hours, 48 hours, 50 hours, 55 hours, 60 hours, 65 hours, 70 hours, 72 hours, 75 hours, 80 hours, 85 hours, 90 hours, 95 hours, or 100 hours, etc. Preferably, the release of the antagonist in the gastrointestinal tract is prevented or substantially prevented for a period of time of at least about 48 hours. More preferably, the period of time for which the blocking agent prevents or substantially prevents release is at least about 72 hours.

The blocking agent of the sequestering subunit of the invention can be a system comprising a first antagonist-impermeable material and a core. By "antagonist-impermeable material" is meant any material that is substantially impermeable to the antagonist such that the antagonist is not substantially released from the sequestering subunit. As used herein, the term "substantially impermeable" does not necessarily mean complete or 100% impermeability. Instead, there are varying degrees of impermeability that one skilled in the art would consider to be of potential benefit. In this regard, the antagonist-impermeable material substantially prevents or prevents the release of the antagonist to the extent that: preventing at least about 80% of the antagonist from being released from the sequestering subunit in the gastrointestinal tract over a period of more than 24 hours. Preferably, the antagonist-impermeable material prevents release of at least about 90% of the antagonist from the sequestering subunit in the gastrointestinal tract for a period of time that exceeds 24 hours. More preferably, the antagonist-impermeable material prevents at least about 95% of the antagonist from being released from the sequestering subunit. Most preferably, the antagonist-impermeable material prevents release of at least about 99% of the antagonist from the sequestering subunit in the gastrointestinal tract for a period of time that exceeds 24 hours. The antagonist-impermeable material prevents or substantially prevents release of the antagonist in the gastrointestinal tract for a period of time that exceeds 24 hours (desirably at least about 48 hours). More desirably, the antagonist-impermeable material prevents or substantially prevents release of the reverse acting agent (the additive agent) from the sequestering subunit for a period of at least about 72 hours.

Preferably, the first antagonist-impermeable material comprises a hydrophobic material such that, in the undamaged case, when intended for oral administration, the antagonist is not released or substantially not released during its transport through the gastrointestinal tract. Suitable hydrophobic materials for use as described herein may include those described below. The hydrophobic material is preferably a pharmaceutically acceptable hydrophobic material. Preferably, the pharmaceutically acceptable hydrophobic material comprises a cellulosic polymer.

Preferably, the first antagonist-impermeable material comprises a polymer that is insoluble in the gastrointestinal tract. One skilled in the art recognizes that upon digestion of the sequestering subunit, polymers that are insoluble in the gastrointestinal tract prevent release of the antagonist. The polymer may be a cellulosic polymer or an acrylic polymer. Desirably, the cellulose is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, and combinations thereof. The ethylcellulose includes, for example, ethylcellulose having an ethoxy content of from about 44% to about 55%. The ethylcellulose can be used in the form of an aqueous dispersion, an alcoholic solution or a solution in other suitable solvents. The cellulose may have a degree of substitution (d.s.) on anhydroglucose units of greater than 0 and up to 3, including 3. "degree of substitution" means the average number of hydroxyl groups on the anhydroglucose units of the cellulosic polymer that are replaced by a substituent. Representative materials include polymers selected from the group consisting of: cellulose acylate (cellulose acetate), cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, alkylated mono-cellulose (monoocellulose alkanate), alkylated di-cellulose, alkylated tri-cellulose, alkenylated mono-cellulose, alkenylated di-cellulose, alkenylated tri-cellulose, arylated mono-cellulose (monoocellulose aroylate), arylated di-cellulose, and arylated tri-cellulose.

More particular celluloses include: a cellulose propionate having 1.8 s, a propyl content of 39.2% to 45% and a hydroxyl content of 2.8% to 5.4%; a cellulose acetate butyrate having 1.8 d.s., an acetyl content of 13% to 15% and a butyryl content of 34% to 39%; a cellulose acetate butyrate having an acetyl content of 2% to 29%, a butyryl content of 17% to 53%, and a hydroxyl content of 0.5% to 4.7%; triacylated celluloses having a s. of 2.9 to 3, such as cellulose triacetate, cellulose tripentanate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, and cellulose trioctylate; cellulose diacylates having a d.s. of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctoate, cellulose dipentanate, and copolyesters of cellulose (coester), such as cellulose acetate butyrate, cellulose acetate octanoate butyrate and cellulose acetate propionate.

Other cellulosic polymers that may be used to prepare the sequestering subunits described herein may include acetaldehyde dimethylcellulose acetate (acetaldehyde), cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, and cellulose acetate dimethylcellulose acetate (acetaldehyde cellulose acetate).

The acrylic polymer is preferably selected from the group consisting of methacrylic polymers, copolymers of acrylic acid with methacrylic acid, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), alkylamide methacrylate copolymers, poly (methyl methacrylate), polymethacrylates, poly (methyl methacrylate) copolymers, polyacrylamides, aminoalkyl methacrylate copolymers, poly (methacrylic anhydride), glycidyl methacrylate copolymers, and combinations thereof. Acrylic polymers useful for preparing the sequestering subunits described herein can include acrylic resins comprising copolymers synthesized from acrylates and methacrylates (e.g., copolymers of lower alkyl acrylates and lower alkyl methacrylates) with acrylic monomers and methyl methacrylate used per moleThe acrylic monomer contains from about 0.02 moles to about 0.03 moles of tri (lower alkyl) ammonium groups. An example of a suitable acrylic resin is ammonium methacrylate copolymer NF21, i.e., made by Rohm Pharma GmbH, Darmstadt, Germany and available as EudragitPolymers sold under the trademark bazooka. Eudragit RS30D is preferred. EudragitIs a water soluble copolymer of Ethyl Acrylate (EA), Methyl Methacrylate (MM) and trimethyl ammonium methacrylate chloride (TAM) in a molar ratio of TAM to the remaining components (EA and MM) of 1: 40. Acrylic resins such as EudragitIt can be used in the form of an aqueous dispersion or a solution in a suitable solvent.

In another preferred embodiment, the antagonist impermeable material is selected from the group consisting of polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, and combinations thereof. In certain other embodiments, the hydrophobic material comprises a biodegradable polymer comprising poly (lactic/glycolic acid) ("PLGA"), polylactide, polyglycolide, polyanhydride, polyorthoester, polycaprolactone, polyphosphazene, polysaccharide, protein polymer, polyester, polydioxanone, polygluconate, polylactic acid-polyethylene oxide copolymer, poly (hydroxy propionate), polyphosphoester, or a combination thereof.

Preferably, the biodegradable polymer comprises poly (lactic/glycolic acid), i.e., a copolymer of lactic and glycolic acid, having a molecular weight of about 2,000 daltons to about 500,000 daltons. The ratio of lactic acid to glycolic acid is preferably from about 100:1 to about 25:75, more preferably the ratio of lactic acid to glycolic acid is about 65: 35.

Poly (lactic/glycolic acid) can be prepared by the procedures described in U.S. Pat. No. 4,293,539 (Ludwig et al), which is incorporated herein by reference. Briefly, Ludwig produces the copolymer by condensing lactic acid and glycolic acid in the presence of an easily removable polymerization catalyst (e.g., a strong ion exchange resin such as Dowex HCR-W2-H). The amount of catalyst is not critical to the polymerization, but is generally from about 0.01 to about 20 parts by weight relative to the total weight of the combination of lactic acid and glycolic acid. The polymerization reaction can be carried out without solvent at a temperature of about 100 ℃ to about 250 ℃, preferably under reduced pressure, for about 48 hours to about 95 hours, to facilitate removal of water and by-products. The poly (lactic/glycolic acid) is then recovered by filtering the molten reaction mixture in an organic solvent such as dichloromethane or acetone, and then filtering off the catalyst.

Suitable plasticizers, such as acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, diethyl phthalate, dibutyl phthalate or dibutyl sebacate, may also be mixed with the polymer used to prepare the sequestering subunits. Additives such as colorants, talc and/or magnesium stearate, among others, may also be used to prepare sequestering subunits of the present invention.

In certain embodiments, additives may be included in the composition to improve the barrier properties of the barrier subunits. As described below, the ratio of additives or components relative to other additives or components may be adjusted to enhance or delay improving the segregation of the agents contained within the subunits. Various amounts of functional additives (i.e., charge neutralizing additives) may be included to modify the release of the antagonist, particularly where a water-soluble core (i.e., sugar sphere) is used. For example, it has been determined that inclusion of a small amount of charge neutralizing additive (by weight) relative to the sequestering polymer can result in reduced release of the antagonist.

In certain embodiments, surfactants may be used as charge neutralizing additives. In certain embodiments, such neutralization reduces swelling of the sequestering polymer by hydrating positively charged groups contained therein. Surfactants (ionic or non-ionic) may also be used to prepare the sequestering subunit. Preferably, the surfactant is ionic. Suitable exemplary materials include, for example, alkyl aryl sulfonates, alcohols of sulfuric acid, sulfosuccinates, sulfosuccinamates, sarcosinates or taurates, and the like. Additional examples include, but are not limited to, ethoxylated castor oil, benzalkonium chloride, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, docusate sodium, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, sodium lauryl sarcosinate and sodium methylcocoyl taurate, magnesium lauryl sulfate, triethanolamine, cetrimide, sucrose laurate and other sucrose esters, glucose (dextrose) esters, dimethicone, octoxynol (octoxynol), dioctyl sodium sulfosuccinate, polyglycolyglycerides, sodium dodecylbenzenesulfonate, sodium dialkyl sulfosuccinate, fatty alcohols (such as lauryl, cetyl and stearyl alcohols), Glycerides, cholic acid or derivatives thereof, lecithin and phospholipids. These materials are generally characterized as ionic (i.e., anionic or cationic) or nonionic. In certain embodiments described herein, it is preferred to use Anionic Surfactants such as Sodium Lauryl Sulfate (SLS) (U.S. Pat. No. 5,725,883; U.S. Pat. No. 7,201,920; EP502642A 1; Shokiri et al, phase. Sci.2003, The Effect of Sodium Lauryl Sulfate on The Release of cellulose from cellulose prepared by sizing technique; Wells et al, Effect of inorganic Surfactants on The Release of cellulose major ingredient insert, heterogenesis Matrix, Drug Development and industry 18(2) (1992 175-; Rao et al, "Effect of cellulose Sulfate and index of cellulose preparation of cellulose, viscosity of cellulose, cellulose of cellulose, cellulose of cellulose, cellulose of. Other suitable surfactants are known in the art.

As shown herein, the combination of SLS with Eudragit RS is particularly useful when the sequestering subunits are formed on a sugar sphere matrix. The inclusion of less than about 6.3% by weight of SLS relative to the sequestering polymer (i.e., Eudragit RS) can provide a charge neutralization function (theoretically 20% and 41% neutralization, respectively) that significantly slows the release of the active agent (i.e., the antagonist naltrexone) encapsulated thereby. SLS comprising more than about 6.3% relative to the sequestering polymer appears to increase the release of the antagonist from the sequestering subunit. For andSLS combined with RS, preferably, with respect to the sequestering polymer (i.e., RS)RS) there is about 1%, 2%, 3%, 4% or 5% SLS, and typically less than 6% SLS, on a w/w basis. In a preferred embodiment, there may be about 1.6% or about 3.3% SLS relative to the sequestering polymer. As discussed above, a number of substances (i.e., surfactants) may be substituted for SLS in the compositions disclosed herein.

Other useful substances include those that can physically block the migration of the antagonist from the subunit and/or enhance the hydrophobicity of the barrier. An exemplary material is Talc, which is commonly used in pharmaceutical compositions (Pawar et al, agglutination of Ibuprofen With Talc by NovelCrystallo-Co-agglutination Technique, AAPS PharmSciTech.2004; 5(4): article 55). As shown in the examples, talc is particularly useful in cases where the sequestering subunits are formed on a sugar sphere core. Any form of talc may be used as long as it does not adversely affect the function of the composition. Most talcs consist of Silica (SiO) dissolved in excess₂) In the presence of (C) dolomite (CaMg (CO)₃)₂) Or magnesite (MgO), or by modification of serpentine or quartzite. The talc may include minerals, such as tremolite (CaMg)₃(SiO₃)₄) Serpentine (3 MgO. multidot.2SiO)₂·2H₂O), directly amphibole (Mg)₇·(OH)₂·(Si₄O₁₁)₂) Magnesite, mica, chlorite, dolomite, calcium carbonate (CaCO)₃) Calcite form, iron oxide, carbon, quartz and/or magnesium oxide. In the compositions described herein, the presence of such impurities is acceptable as long as the function of the talc is maintained. Preferably, the talc is USP grade. As noted above, the talc described herein functions to enhance hydrophobicity, thereby enhancing the functionality of the sequestering polymer. Many talc substitutes may be used in the compositions described herein as can be determined by one skilled in the art.

It has been determined that the ratio of talc to sequestering polymer can produce significant differences in the functionality of the compositions described herein. For example, the following examples demonstrate that the ratio (w/w) of talc to sequestering polymer is important for compositions designed to prevent release of naltrexone therefrom. It has also been demonstrated that it comprises talc and talc in approximately equal amounts (by weight)RS results in a very low naltrexone release profile. In contrast, significantly lower or higher (69% w/w low and 151% w/w high) talc withThe ratio of RS results in an increase in naltrexone release. Thus, when talc andRS, preferably, relative toRS, talc present in any percentage of about 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, 142%, or 150% w/w. As mentioned above, the most beneficial ratios for the other additives or componentsThe rate will vary and can be determined using standard experimental procedures.

In certain embodiments, such as where a water-soluble core is used, it is useful to include a substance that can affect the osmotic pressure of the composition (i.e., an osmotic pressure regulator) (see generally and with reference toRelated WO 2005/046561 a2 and WO 2005/046649 a 2). The use of an osmolality adjusting agent may depend on the choice of agonist or antagonist and the form (salt) of the agonist and antagonist selected. To the extent that the osmolyte regulator is selected for a particular composition, it is preferred that the substance be applied toOn the RS/talc layer. In drug units comprising a sequestering subunit covered by an active agent (i.e., a controlled release agonist formulation), the tonicity modifier is preferably located directly beneath the active agent layer. Suitable tonicity adjusting agents may include, for example, Hydroxypropylmethylcellulose (HPMC) or chloride ion (i.e., from NaCl), or a combination of HPMC and chloride ion (i.e., from NaCl). Other ions that may be used include bromide or iodide. For example, the combination of sodium chloride and HPMC may be prepared in water or in a mixture of ethanol and water. HPMC is commonly used in pharmaceutical compositions (see, e.g., U.S. patent nos. 7,226,620 and 7,229,982). In certain embodiments, HPMC may have a molecular weight of about 10000 to about 1500000, typically about 5000 to about 10000 (low molecular weight HPMC). HPMC typically has a specific gravity of about 1.19 to about 1.31, an average specific gravity of about 1.26, and a viscosity of about 3600 to 5600. HPMC may be a water-soluble synthetic polymer. Examples of suitable commercially available hydroxypropyl methylcellulose polymers include Methocel K100 LV and Methocel K4M (Dow). Other HPMC additives are known in the art and may be suitable for preparing the compositions described herein. In certain embodiments, preferably, the charge neutralizing additive (i.e., NaCl) is included at less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of the composition. In other preferred embodimentsThe charge neutralizing additive is present at about 4% by weight of the composition.

Thus, in one embodiment, a sequestering subunit formed on a sugar sphere matrix is provided, the sequestering subunit comprising a sequestering polymer (i.e., an optimizing agent) in combination with several optimizing agents (optimizing agents)RS) comprising Sodium Lauryl Sulfate (SLS) as a charge neutralizing species that reduces membrane swelling by hydrating positively charged groups on the polymer; talc for creating a solid impermeable barrier to naltrexone transport across the membrane and as a hydrophobicity-enhancing substance; and chloride ions (i.e., NaCl form) as a permeate pressure reducing substance. It has surprisingly been found that the ratio of each additional component relative to the sequestering polymer is important for the function of the sequestering subunit. For example, embodiments provide a sequestering subunit comprising a sequestering polymer; and less than 6%, preferably 1-4%, even more preferably 1.6% or 3.3% in w/w of the optimizer SLS relative to the Eudragit RS; in an amount equal to aboutTalc of RS (in w/w); and NaCl present at about 4% w/w.

The therapeutic agent may be an opioid agonist. "opioid" is meant to include natural or synthetic drugs, hormones or other chemical or biological substances that have sedative, anesthetic or other similar effects to those of an opioid or natural or synthetic derivative thereof. An "opioid agonist" is sometimes used interchangeably herein with the terms "opioid" and "opioid analgesic" to mean an opioid agonist comprising one or more opioid agonists alone or in combination, and further to mean an agonist-antagonist comprising a base, mixture or combination of opioids, a partial agonist, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and combinations thereof.

Opioid agonists include, for example: alfentanil, allylmorphine, alfalidine, anileridine, benzylmorphine, bezilimide, buprenorphine, butorphanol, lonicerazine, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, dinolamine, dihydrocodeine, dihydroetorphine, dihydromorphine, dextromethorphan, dimemethadol, demewhat, dimethylthiodine, morelbutyl ester, dipiperazone, etazocine, esomephenzine, ethidine, ethylmorphine, etonixine, etorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypatidine, isometholone, ketonide, levorphanol, nalorphine, allylfentanyl, pethidine, meptazinol, metazocine, methadone, metolone, morphine, mupirorphine, buprenorphine, nemorphine, methamphetamine, nicotinic, levorphanol, normorphine, morphine, normorphine, levorphanol, normorphine, morphine, normorphine, levorphanol, normorphine, morphine, normorphine, morphine, levorphanol, morphine, Nopiperidone, opium, oxycodone, oxymorphone, opiate alkaloids, pentazocine, phenoxepin, phenazocine, fenorphanol, phentermine, piminodine, pimonitine, pranopaline, meperidine, propiperidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof. Preferably, the opioid agonist is selected from hydrocodone, hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof. Most preferably, the opioid agonist is morphine, hydromorphone, oxycodone or hydrocodone. In a preferred embodiment, the opioid agonist comprises oxycodone or hydrocodone and is present in the dosage form in an amount of about 15mg to about 45mg, and the opioid antagonist comprises naltrexone and is present in the dosage form in an amount of about 0.5mg to about 5 mg.

Pharmaceutically acceptable salts of the antagonists or agonists discussed herein include alkali metal salts, e.g., sodium, potassium, cesium and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; amino acid salts such as arginine salt, aspartic acid salt, glutamic acid salt and the like.

In embodiments where the opioid agonist comprises hydrocodone, the sustained release oral dosage form may comprise an analgesic dose of about 8mg to about 50mg hydrocodone per dosage unit. In a sustained release oral dosage form in which hydromorphone is a therapeutically active opioid, the hydromorphone is included in an amount from about 2mg to about 64mg of hydromorphone hydrochloride. In another embodiment, the opioid agonist comprises morphine and the sustained release oral dosage form described herein may comprise from about 2.5mg to about 800mg by weight of morphine. In yet another embodiment, the opioid agonist comprises oxycodone and the sustained release oral dosage forms described herein may comprise oxycodone in an amount of about 2.5mg to about 800mg by weight. In certain preferred embodiments, the extended release oral dosage form comprises from about 20mg to about 30mg oxycodone. Controlled release oxycodone formulations are known in the art. The following references describe various controlled release oxycodone formulations suitable for use as described herein and methods for their preparation: such as U.S. Pat. No. 5,266,331; 5,549,912; 5,508,042; and U.S. Pat. No. 5,656,295, which is incorporated herein by reference. The opioid agonist may comprise tramadol, and the sustained release oral dosage form may comprise from about 25 to 800mg of tramadol per dosage unit.

In embodiments where the opioid agonist comprises hydrocodone, the sustained release oral dosage form may comprise an analgesic dose of about 8mg to about 50mg hydrocodone per dosage unit. In a sustained release oral dosage form in which hydromorphone is a therapeutically active opioid, the hydromorphone is included in an amount from about 2mg to about 64mg of hydromorphone hydrochloride. In another embodiment, the opioid agonist comprises morphine and the sustained release oral dosage form may comprise from about 2.5mg to about 800mg by weight of morphine. In yet another embodiment, the opioid agonist comprises oxycodone and the extended release oral dosage form comprises oxycodone in an amount from about 2.5mg to about 800 mg. In certain preferred embodiments, the extended release oral dosage form comprises from about 20mg to about 30mg oxycodone. Controlled release oxycodone formulations are known in the art. The following references describe various controlled release oxycodone formulations suitable for use as described herein and methods for their preparation: such as U.S. Pat. No. 5,266,331; 5,549,912; 5,508,042; and U.S. Pat. No. 5,656,295, which is incorporated herein by reference. The opioid agonist may comprise tramadol, and the sustained release oral dosage form may comprise from about 25 to 800mg of tramadol per dosage unit.

In a preferred embodiment, the oral dosage form may be formulated to provide an increased duration of therapeutic action that allows for once daily administration. Typically, delayed-release (release-retaining) materials are used to provide increased duration of therapeutic action. Preferably, once-a-day administration is provided by the dosage form. In certain embodiments, the blood level of the agonist reaches its maximum concentration (T) about 8-24 hours after administration_max). In a preferred embodiment, T is achieved from about 10 hours to about 16 hours after administration_max. In certain embodiments, C₂₄(concentration of agonist in 24 hours blood) with C_max(maximum concentration of agonist in blood) ratio of about 0.2 to 0.8.

Preferred delayed release materials include acrylic polymers, alkyl celluloses, shellacs, zeins, hydrogenated vegetable oils, hydrogenated castor oils, and combinations thereof. In certain preferred embodiments, the delayed release material is a pharmaceutically acceptable acrylic polymer, including acrylic and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), alkylamide methacrylate copolymers, poly (methyl methacrylate), poly (methacrylic anhydride), methyl methacrylate, polymethacrylate, poly (methyl methacrylate) copolymers, polyacrylamide, aminoalkyl methacrylate copolymers, and glycidyl methacrylate copolymers. In certain preferred embodiments, the acrylic polymer comprises one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers are well known in the art and are described in NF21, 21 nd edition National Formulary, published by United states pharmaceutical Convention Inc. In other preferred embodiments, the delayed release material is an alkyl cellulose material, such as ethyl cellulose. One skilled in the art will recognize that other cellulose polymers, including other alkyl cellulose polymers, may partially or fully replace ethyl cellulose.

Release-modifying agents that affect the release properties of the delayed release material may also be used. In a preferred embodiment, the release modifier is used as a porogen. Porogens may be organic or inorganic and include materials that may be dissolved, extracted or leached from the coating in the environment of use. The porogens may comprise one or more hydrophilic polymers, such as hydroxypropyl methylcellulose. In certain preferred embodiments, the release modifier is selected from the group consisting of hydroxypropylmethylcellulose, lactose, metal stearates, and combinations thereof.

The delayed release material may also include an erosion-promoting agent, such as starches and gums; release modifiers for forming microporous lamellae in a use environment, such as polycarbonates of linear polyesters containing carbonic acid (in which the carbonate groups are re-present in the polymer chain); and/or a semi-permeable polymer.

For the compositions of the present invention, the compositions are preferably in oral dosage form. An "oral dosage form" is meant to include unit dosage forms comprising subunits that are prescribed or intended for oral administration. Desirably, the composition comprises a sequestering subunit coated with a therapeutic agent in releasable form, thereby forming a complex subunit comprising the sequestering subunit and the therapeutic agent. Accordingly, the present invention also provides a capsule suitable for oral administration comprising a plurality of such composite subunits.

Alternatively, the oral dosage form may comprise any of the sequestering subunits disclosed herein in combination with a therapeutic subunit, wherein the therapeutic subunit comprises a therapeutic agent in releasable form. In this regard, there is provided a capsule suitable for oral administration comprising a plurality of the sequestering subunits of the invention and a plurality of therapeutic subunits, each of which comprises a therapeutic agent in releasable form. For the compositions disclosed herein, the compositions may preferably be in oral dosage forms. An "oral dosage form" is meant to include unit dosage forms comprising subunits that are prescribed or intended for oral administration. Desirably, the composition comprises a sequestering subunit coated with a therapeutic agent in releasable form, thereby forming a complex subunit comprising the sequestering subunit and the therapeutic agent. Accordingly, there is also provided a capsule suitable for oral administration comprising a plurality of such composite subunits.

Alternatively, the oral dosage form may comprise any sequestering subunit in combination with a therapeutic agent subunit, wherein the therapeutic agent subunit comprises the therapeutic agent in releasable form. In this regard, there is provided a capsule suitable for oral administration comprising a plurality of the sequestering subunits of the invention and a plurality of therapeutic subunits, each of which comprises a therapeutic agent in releasable form.

When the blocking agent is a system comprising a first antagonist-impermeable material and a core, the sequestering subunit can be in one of a number of different forms. For example, the system can further comprise a second antagonist-impermeable material, in which case the sequestering unit comprises an antagonist, a first antagonist-impermeable material, a second antagonist-impermeable material, and a core. In this example, the core is coated with a first antagonist-impermeable material, which in turn is coated with an antagonist, which in turn is coated with a second antagonist-impermeable material. The first antagonist-impermeable material and the second antagonist-impermeable material substantially prevent release of the antagonist from the sequestering subunit in the gastrointestinal tract for a period of time that exceeds 24 hours. In some examples, preferably, the first antagonist-impermeable material is the same as the second antagonist-impermeable material. In other examples, the first antagonist-impermeable material is different from the second antagonist-impermeable material. One skilled in the art will be able to determine whether the first and second antagonist-impermeable materials should be the same or different. Factors that influence the determination of whether the first and second antagonist-impermeable materials should be the same or different may include: whether a layer to be placed on the antagonist-impermeable material requires some property to prevent dissolution of some or all of the antagonist-impermeable layer when the next layer is applied, or to promote adhesion of the layer to be applied on the antagonist-impermeable layer.

Alternatively, the antagonist may be incorporated into the core, and the core may be coated with the first antagonist-impermeable material. In this case, a sequestering subunit comprising an antagonist, a core, and a first antagonist-impermeable material can be provided, wherein the antagonist is incorporated into the core and the core is coated with the first antagonist-impermeable material, and wherein the first antagonist-impermeable material substantially prevents release of the antagonist from the sequestering subunit in the gastrointestinal tract for a period of time that exceeds 24 hours. As used herein, "incorporation" and words derived therefrom are meant to include any means of incorporation, such as uniform dispersion of the antagonist throughout the core, a monolayer of the antagonist coated on top of the core, or a multilayer system comprising the antagonist of the core.

In another alternative embodiment, the core comprises a water-insoluble material and the core is coated with the antagonist, which in turn is coated with a first antagonist-impermeable material. In this case, a sequestering subunit comprising an antagonist, a first antagonist-impermeable material, and a core comprising a water-insoluble material is provided, wherein the core is coated with the antagonist, which is in turn coated with the first antagonist-impermeable material, and wherein the first antagonist-impermeable material substantially prevents release of the antagonist from the sequestering subunit in the gastrointestinal tract for a period of time that exceeds 24 hours. As used herein, the term "water-insoluble material" means any material that is substantially insoluble in water. The term "substantially water insoluble" does not necessarily mean completely or 100% water insoluble. Instead, there are varying degrees of water insolubility that one of skill in the art would consider to be of potential benefit. Preferred water-soluble materials include, for example, microcrystalline cellulose, calcium salts, and waxes. Calcium salts include, but are not limited to, calcium phosphates (e.g., hydroxyapatite, apatite, etc.), calcium carbonate, calcium sulfate, calcium stearate, and the like. Waxes include, for example, carnauba wax, beeswax, petroleum wax, candelilla wax, and the like.

In one embodiment, the sequestering subunit comprises an antagonist and a seal coating, wherein the seal coating forms a layer that physically separates the antagonist within the sequestering subunit from the agonist layered (layer) on the sequestering subunit. In one embodiment, the seal coat comprises one or more of an osmotic pressure modulator, a charge neutralizing additive, a sequestering polymer hydrophobicity-enhancing additive, and a first sequestering polymer (each described above). In such embodiments, preferably, the tonicity modifier, charge neutralizing additive and/or sequestering polymer hydrophobicity-enhancing additive (if present separately) is present in proportion to the first sequestering polymer such that no more than 10% of the antagonist is released from the complete dosage form. When an opioid antagonist is used for the sequestering subunit and the intact dosage form comprises an opioid agonist, preferably, the ratio of the tonicity modifier, charge-neutralizing additive and/or sequestering polymer hydrophobicity-enhancing additive (if present separately) relative to the first sequestering polymer is such that the physiological effect of the opioid agonist is not impaired when the composition is in its intact dosage form or during normal digestion by the patient. Release may be determined using the USP paddle method (optionally using a buffer comprising a surfactant such as Triton X-100) as described above, or measured from plasma following administration to a patient in a fed or non-fed state. In one embodiment, plasma naltrexone levels are determined; in other embodiments, plasma 6-beta naltrexone levels are determined. Standard tests can be used to determine the effect of an antagonist on agonist function (i.e., pain reduction).

In one embodiment, the sequestering subunit comprises an antagonist and a seal coating, wherein the seal coating forms a layer that physically separates the antagonist within the sequestering subunit from the agonist layered on the sequestering subunit. In one embodiment, the seal coat comprises one or more of an osmotic pressure regulator, a charge neutralizing additive, a sequestering polymer hydrophobicity-enhancing additive, and a first sequestering polymer (each described above). In such embodiments, preferably, the tonicity modifier, charge neutralizing additive and/or sequestering polymer hydrophobicity-enhancing additive (if present separately) is present in proportion to the first sequestering polymer such that no more than 10% of the antagonist is released from the complete dosage form. When an opioid antagonist is used for the sequestering subunit and the intact dosage form comprises an opioid agonist, preferably, the ratio of the tonicity modifier, charge-neutralizing additive and/or sequestering polymer hydrophobicity-enhancing additive (if present separately) relative to the first sequestering polymer is such that the physiological effect of the opioid agonist is not impaired when the composition is in its intact dosage form or during normal digestion by the patient. Release may be determined using the USP paddle method (optionally using a buffer comprising a surfactant such as Triton X-100) as described above, or measured from plasma following administration to a patient in a fed or non-fed state. In one embodiment, plasma naltrexone levels are determined; in other embodiments, plasma 6-beta naltrexone levels are determined. Standard tests can be used to determine the effect of an antagonist on agonist function (i.e., pain reduction).

In certain embodiments, the release of the antagonist of the sequestering subunit or composition is expressed based on the ratio of the release achieved after damage (e.g., by crushing or chewing) relative to the amount released from the intact formulation. Thus, the ratio is expressed as [ crushed ]: total ], and desirably, the ratio has a numerical range of at least about 4:1 or greater (e.g., crushed release over 1 hour/intact release over 24 hours). In certain embodiments, the therapeutic agent and antagonist are present in the sequestering subunit in a ratio of about 1:1 to about 50:1 (by weight), preferably about 1:1 to about 20:1 (by weight) or 15:1 to about 30:1 (by weight). The weight ratio of therapeutic agent to antagonist is relative to the weight of the active ingredient. Thus, for example, the weight of the therapeutic agent does not include the weight of the coating, matrix, or other component that isolates the antagonist, or other possible excipients associated with the antagonist particles. In certain preferred embodiments, the ratio is from about 1:1 to about 10:1 (by weight). Because the antagonist is in sequestered form in certain embodiments, the amount of such antagonist within the dosage form can vary more than a therapeutic/antagonist combination dosage form, both of which can be released upon administration, because the formulation does not rely on differential metabolism (hepatic metabolism) or liver clearance to function properly. For safety reasons, the amount of antagonist present in the substantially non-releasable form is selected so as to be harmless to humans (even if fully released under damaging conditions).

The present invention provides a composition comprising a plurality of multilayer pellets comprising: a water-soluble core; an antagonist-containing layer comprising naltrexone hydrochloride coating the core; a sequestering polymer layer coating the antagonist-containing layer; an agonist layer comprising an opioid agonist coating the sequestering polymer layer; and a controlled release layer coating the agonist layer; wherein the weight of the naltrexone hydrochloride comprises at least 5% of the combined weight of the water-soluble core, the antagonist-containing layer, and the sequestering polymer layer, and wherein, when administered to a human, the agonist is substantially released and the naltrexone hydrochloride is substantially sequestered. In certain embodiments, the naltrexone hydrochloride comprises from about 5% to about 30% of the combined weight of the water-soluble core, the antagonist-containing layer, and the sequestering polymer layer. In other embodiments, the naltrexone hydrochloride comprises from about 5% to about 20% of the combined weight of the water-soluble core, the antagonist-containing layer, and the sequestering polymer layer. In a preferred embodiment, the naltrexone hydrochloride comprises from about 5% to about 10% of the combined weight of the water-soluble core, the antagonist-containing layer, and the sequestering polymer layer. In other preferred embodiments, the naltrexone hydrochloride comprises from about 6% to about 10% or from about 7% to about 10% or from about 8% to about 10% of the combined weight of the water-soluble core, the antagonist-containing layer, and the sequestering polymer layer.

The compositions of the present invention are particularly useful for preventing abuse of therapeutic agents. In this regard, the present invention provides a method of preventing abuse of a therapeutic agent in a human. The method comprises incorporating the therapeutic agent into any of the compositions described herein. When the compositions described herein are administered to a human, release of the antagonist in the gastrointestinal tract is substantially prevented for a period of time exceeding 24 hours. However, if a person damages the composition, the mechanically fragile sequestering subunit will break and thereby release the antagonist. Because the mechanical fragility of the sequestering subunit is the same as the therapeutic agent in releasable form, the antagonist will be mixed with the therapeutic agent, making it almost impossible to separate the two components.

The effectiveness of treatment of chronic moderate to severe pain (osteoarthritis concentrated in the hip or knee) is typically measured by: diary concise Pain (BPI) score mean change (mean daily score of mean Pain averaged over 7 days; clinical BPI and/or daily diary BPI (most severe, lowest and current Pain)), WOMAC osteoarthritis index, Medical Outcome Study (MOS) sleep score, Beck Depression scale (Beck Depression Inventory), and patient global change impression (PGIC). Two measurements of Adverse Events (AEs), clinical experimental data, vital signs, and opioid withdrawal were used: subjective Opioid Withdrawal Score (SOWS) and Clinical Opioid Withdrawal Score (COWS), comparing the safety and tolerability of opioid drugs such as Kadian NT to placebo.

The compositions described herein may comprise a plurality of multilayer pellets comprising: a water-soluble core; an antagonist-containing layer comprising naltrexone hydrochloride coating the core; a sequestering polymer layer coating the antagonist-containing layer; an agonist layer comprising an opioid agonist coating the sequestering polymer layer; and a controlled release layer coating the agonist layer; wherein the weight of the naltrexone hydrochloride comprises at least 5% of the combined weight of the water-soluble core, the antagonist-containing layer, and the sequestering polymer layer, and wherein, when administered to a human, the agonist is substantially released and the naltrexone hydrochloride is substantially sequestered.

All documents cited herein are incorporated by reference in their entirety. The following non-limiting examples describe specific embodiments of the compositions and methods described herein.

Examples

Example 1

20% oxycodone formulation

Sifted sugar ball

Prior to seal coating, the sugar spheres were sieved to remove undersized spheres. Sugar spheres of acceptable size were collected and used in the seal coating process.

Hermetically coated sugar spheres

Load(s)

600-710 mu m-mesh sugar sphere

Seal coat dispersion	Solutions of	Solid body	Application of
				SD3A ethanol	80.00%	---	4532.8g
Dibutyl sebacate NF	0.50%	2.50%	28.3g
				Ethyl cellulose 50NF	5.00%	25.00%	283.3g
Magnesium stearate	2.00%	10.00%	113.3g
				Talc USP	12.50%	62.50%	708.3g
Total of	100.00%	100.00%	5666.0g

The preparation of the seal coated sugar spheres comprises preparing a seal coated dispersion and spraying the dispersion onto the sieved sugar spheres.

The seal coat dispersion was prepared by first dissolving dibutyl sebacate and ethyl cellulose in ethanol. Then, talc and magnesium stearate were added and uniformly dispersed in the solution prior to the seal coating operation. Mixing was continued until all dispersion was applied.

The seal coat dispersion was sprayed onto the sieved sugar spheres in a fluidized bed using a Wurster insert. Coating (coat application) is performed under predetermined process parameter settings. After all the seal coat dispersion had been sprayed, ethanol was sprayed on the product to flush the pump tubing and the nozzle. Once the flushing is complete, the product pellets are dried, discharged, weighed and sieved. The oversized and undersized pellets are then discarded. The pellets of acceptable size are further processed to the next step.

Overview of naltrexone hydrochloride pellets

Naltrexone hydrochloride pellets were prepared by starting with the layering of naltrexone hydrochloride (NT) drug on the seal-coated sugar spheres to form a naltrexone core (the NT drug layering represents about an 18.5% increase in total weight). These naltrexone cores were then subjected to a two-step coating of a barrier film (also referred to as a barrier coat), which showed a total weight gain of about 122.6%. All drug layering and coating was done in a fluidized bed equipped with a Wurster insert. After each step of barrier coating, curing is carried out in an oven and the final cured finished pellets are sieved.

NT nucleus

Load(s)

Hermetically coated sugar spheres (-18/+30 mesh): 1700g

Naltrexone hydrochloride dispersion	Solutions of	Solid body	Application of
				SD3A ethanol	63.07%	----	956.7g
Purified water USP	16.22%	---	246g
				Ascorbic acid USP	1.16%	5.60%	17.6g
HPC NF(75-150cps)	2.24%	10.82%	34.0g
				Naltrexone hydrochloride USP	11.81%	57.02%	179.2g
Talc USP	5.50%	26.57%	83.5g
				Total of	100.00%	100.00%	1517.0g

Naltrexone nucleus

Naltrexone dispersions were first prepared by dissolving ascorbic acid and hydroxypropyl cellulose in ethanol and purified water. Naltrexone hydrochloride and talc were then added and dispersed evenly in the solution. Mixing was continued until all dispersion was applied.

Naltrexone dispersions were sprayed onto the seal coated sugar spheres in a fluidized bed using a Wurster insert. The drug coating is performed under predetermined process parameter settings. After all the naltrexone dispersion had been sprayed, ethanol was sprayed on the product to flush the pump lines and nozzles. Once the rinsing is complete, the product cores are dried and discharged.

NT intermediate pellets

Naltrexone hydrochloride nuclei (-18/+30 mesh): 1700g

Intermediate dispersions	Solutions of	Solid body	Application of
				SD3A ethanol	62.34%	---	3249.8g
Purified water USP	17.67%	---	921g
				SLS NF	0.64%	3.20%	33.4g
Dibutyl sebacate NF	0.96%	4.79%	49.9g
				Eudragit RS	7.59%	37.99%	395.9g
Talc USP	10.80%	54.02%	563.0g
				Talc USP (Chalk)	---	---	11.6g
Total of	100.00%	100.00%	5213.0g

NT finished product pellet

Load(s)

Naltrexone hydrochloride intermediate pellets (-16/+25 mesh): 1700.0g

Naltrexone pellets (intermediates and finished products)

The barrier coating process was carried out in two steps, i.e. the first step to make naltrexone intermediate pellets (61.3% weight gain based on the naltrexone core) and the second step to make finished pellets (a total of 122.6% weight gain based on the naltrexone core).

Barrier coating dispersions for both intermediate pellets and finished pellets were prepared in the same manner. Firstly, copolymer B type (Eudragit) of sodium dodecyl sulfate, dibutyl sebacate and ammonium methacrylate is preparedRS) was dissolved in ethanol and purified water. Talc was dispersed in the solution and barrier coating was then initiated. Mixing was continued until all dispersion was applied.

For the naltrexone intermediate pellets, the barrier coating dispersion was sprayed onto the naltrexone core in a fluidized bed using a Wurster insert. The coating is performed under predetermined process parameter settings. After all the barrier coating dispersion had been sprayed, ethanol was sprayed on the product to flush the pump tubing and the nozzle. Once the flushing is complete, the product pellets are dried and powdered with talc. The intermediate pellets were then transferred to an oven tray for curing. After curing, the intermediate pellets were weighed and sieved. The oversized and undersized pellets are then discarded. The naltrexone intermediate pellets of acceptable size are further processed into finished naltrexone pellets.

For the finished naltrexone pellets, the barrier coating dispersion was sprayed onto the cured naltrexone intermediate pellets using a Wurster insert in a fluidized bed. The same operations as for the intermediate pellets were carried out (spraying, ethanol rinsing, drying, powdering, curing and sieving). The oversized and undersized pellets are then discarded. The finished naltrexone pellets, which are acceptable in size, are further processed to the next step.

ALO-02 nucleus

Load(s)

Naltrexone hydrochloride pellets (-14/+25 mesh): 2000g

Oxycodone hydrochloride dispersion	Solutions of	Solid body	Application of
				SD3A ethanol	80.35%	---	2408.7g
HPC NF(75-150cps)	2.69%	13.70%	80.7g
				Oxycodone hydrochloride USP	11.31%	57.54%	339.0g
Talc USP	5.65%	28.77%	169.5g

Oxycodone hydrochloride core with isolated naltrexone hydrochloride

Preparation of the oxycodone hydrochloride core with isolated naltrexone hydrochloride involved preparing an oxycodone hydrochloride drug dispersion and spraying the dispersion onto naltrexone hydrochloride pellets.

Oxycodone hydrochloride drug dispersions were prepared by first dissolving hydroxypropyl cellulose in ethanol. Oxycodone hydrochloride was added and dispersed evenly in the solution prior to drug lamination. Mixing was continued until all dispersion was applied.

Oxycodone hydrochloride drug dispersions were sprayed on naltrexone hydrochloride pellets using a Wurster insert in a fluidized bed. The drug layer application is performed under predetermined process parameter settings. After all of the drug dispersion has been sprayed, ethanol is sprayed on the product to flush the pump tubing and the nozzle. Once the flushing is complete, the product pellets are dried and discharged. The cores were then weighed and sieved. Oversized and undersized cores are discarded. The final dimensionally acceptable core is further processed to the next step.

ALO-02 pellet

Load(s)

Oxycodone hydrochloride core: 2250.0g

Top coat dispersion	Solutions of	Solid body	Application of
				SD ethanol	85.71%	---	2762.3g
Phthalic acid diethyl ester NF	1.05%	7.34%	33.8g
				PEG6000	1.84%	12.85%	59.2g
Eudragit L100-55	0.74%	5.19%	23.9g
				Ethyl cellulose 50NF	5.90%	41.24%	190.0g
Talc USP	4.77%	33.38%	153.8g
				Talc USP (Chalk)	---	---	11.6g
Total of	100.00%	100.00%	3223.0g

End product pellets-oxycodone hydrochloride extended release formulation with sequestered naltrexone hydrochloride

Preparation of an oxycodone hydrochloride extended release formulation with isolated naltrexone hydrochloride involves preparing a coating dispersion and spraying the dispersion onto an oxycodone hydrochloride core with isolated naltrexone.

By first mixing diethyl phthalate, polyethylene glycol (PEG) and methacrylic acid copolymer C type (Eudragit)L100-55) and ethyl cellulose in ethanol to prepare a coating dispersion. Then, talc was added and uniformly dispersed in the coating solution. Mixing was continued until all the dispersion was completely sprayed.

The coated dispersion was sprayed onto oxycodone hydrochloride cores with isolated naltrexone using a Wurster insert in a fluidized bed. The coating is performed under predetermined process parameter settings. After all of the coating dispersion had been sprayed, ethanol was sprayed on the product to flush the pump lines and nozzles. Once the flushing is complete, the product pellets are dried and powdered with talc. The pellets were then weighed and sieved. Oversized and undersized pellets are discarded. The final acceptably sized pellets are further processed to the next step.

Oxycodone hydrochloride and naltrexone hydrochloride extended release capsule

The target fill weight of an individual capsule was calculated based on the fractional potency (fractional potency) and capsule strength of the oxycodone hydrochloride of the final product pellets. An acceptable weight limit is calculated which must be ± 5% of the target fill weight. The specified capsule shells and pellets were dispensed. The capsules are filled with pellets either manually or by an automatic encapsulation machine.

The total amount of each component (in weight and percentage) and the weight of each component per capsule in the batch are shown in the following table:

oxycodone hydrochloride and naltrexone hydrochloride composition extended release capsule, 40mg/8mg

¹The amount loaded to the batch can be corrected for efficacy and/or moisture.

²Although naltrexone hydrochloride is the active ingredient, the formulation is designed to sequester naltrexone hydrochloride so that it does not release.

³A treating agent used in the preparation.

Example 2

Oxycodone dissolution profile of 20% oxycodone

The in vitro dissolution of the capsules was tested by placing six sample capsules of oxycodone/naltrexone pellets prepared as described in example 1 in 0.1N HCl for 1 hour and then in 0.05M phosphate ph7.5 for 72 hours. The results are shown in the table below.

Example 3

Naltrexone dissolution profile for 20% oxycodone

The in vitro dissolution of the capsules was tested by placing six sample capsules of oxycodone/naltrexone pellets prepared as described in example 1 in 0.1N HCl for one hour and then in 0.05M phosphate ph7.5 for 72 hours. The results are shown in the table below.

Example 4

Oxycodone dissolution profile of 20% oxycodone in ethanol

Example 5

In vivo single dose study of 20% oxycodone formulation

The study was a non-blind (open-label), single dose, randomized, 2-cycle crossover study in healthy volunteers. Twenty-four (24) subjects were enrolled and randomly assigned to one of two treatment orders. Each subject received both treatments throughout the study. Twenty-two (22) subjects completed these two dosing sessions, including all post-dose Pharmacokinetic (PK) assessments.

Treatment a =4 × 5mg oxycodone hydrochloride IR tablets (total oxycodone hydrochloride dose =20mg) (reference)

Treatment B =1 × oxycodone hydrochloride (40mg) and naltrexone hydrochloride (8mg) ER capsule i.e. (ALO-02) (test)

The subjects completed the screening phase, the treatment phase consisting of two dosing periods, and the study termination phase. The screening session was performed on an outpatient basis within 30 days prior to the start of the treatment session.

During each dosing period, subjects were admitted to a Clinical Research Unit (CRU) the evening prior to dosing (day 1). Subjects were dosed and confined in CRU for 48 hours on day 1 of each dosing period (released on day 3).

Venous blood was continuously sampled from hospitalized patients for the first 48 hours after dosing, and from here on to outpatients for 120 hours after dosing. Vital signs, Adverse Event (AE) assessment, clinical trial assessment, and pulse oximetry were performed at prescribed times. Subjects were released from CRUs on day 3, samples were obtained 48 hours post-dose, and all clinical assessments were fully satisfied by the investigator. Subjects returned to the CRU for blood sampling of the outpatient 120 hours after dosing. Then, after a washout period of at least 7 days, the patients were clinically examined at dosing period 2. At the end of dosing period 2 (end of study), a final safety assessment was performed.

A total of 24 healthy adult male and female subjects (30% -60% female) were enrolled to ensure that a minimum of 18 subjects was completed. Twenty-four (24) subjects were enrolled and 22 subjects completed both dosing sessions. For Pharmacokinetic (PK) analysis, data obtained from 24 patients who completed at least 1 dosing session was included in PK population lists and profiles, statistical analysis of treatment comparisons, and plots of oxycodone, dose normalized oxycodone, and noroxycodone. Subject #1 and subject #21 received both treatments, but experienced vomiting in less than 2 hours after dosing with the IR tablet (reference) in period 1 and period 2, respectively. Subject #21 stopped dosing session 2, while subject #1 was dosed at session 2. For affected treatments, these data were excluded from the summary statistics. Subjects #2, #10, and #21 experienced emesis during dosing period 1 after receiving ER capsules (test), and these data were excluded from the summary statistics for the affected treatments. Subject #1 returned to phase 2 and dosed as per the protocol, who vomited after dosing with ER capsules (test). The pharmacokinetic data for this subject (period 2) was included in the summary statistics, as the time to emesis occurred within one minute of the end of dosing at 12 hour intervals. All 24 subjects were included in the safety analysis.

PK parameters for oxycodone and noroxycodone include maximum observed plasma concentration (C)_max) Area under plasma concentration-time curve (AUC)_lastAnd AUC_inf) First moment area under curve (AUMC)_lastAnd AUMC_inf) Time to maximum observed plasma concentration (T)_max) Half life (T)_1/2) An apparent termination cancellation rate constant (λ)_z) And Mean Transit Time (MTT). There were no calculable PK parameters for naltrexone, as only two subjects showed any measurable naltrexone level, and only 4 subjects testedThose with PK parameters evaluated for 6-beta-naltrexone (C only)_max、AUC_lastAnd AUC_inf)。

Descriptive statistics of oxycodone, noroxycodone, and 6-beta-naltrexone concentrations and PK parameters are provided. Dose-normalized ln-transformed (ln-transformed) plasma oxycodone PK parameters AUC_last、AUC_infAnd C_maxAnalysis of variance (ANOVA) was performed. Will be provided withProcmized (version 9.1.3) was used with sequence, treatment and period as a fixed effect and subjects nested within the sequence as a random effect. Geometric Least Squares Means (LSM), mean ratios, and 90% Confidence Intervals (CI) are provided. The target ratio was tested for ER capsules (ER 1X 40mg oxycodone hydrochloride and naltrexone hydrochloride capsules) versus reference IR tablets (IR 4X 5mg oxycodone hydrochloride tablets, dose standardized to 40mg oxycodone hydrochloride).

Safety assessments included morbidity, intensity, relationship to study drug and AE severity, as well as changes in vital signs, 12-lead Electrocardiogram (ECG), clinical laboratory test values (chemistry, hematology, urinalysis), and physical examination.

Using the 12.1 th edition supervision Activity Medical Dictionary (Medical Dictionary for regulatory Activities)To encode the adverse event. The incidence of Treatment Emergent Adverse Events (TEAEs) was tabulated and compared between treatments. A descriptive summary of clinical trials, vital signs and ECG results is provided.

Plasma oxycodone

Descriptive statistics of the PK parameters of oxycodone in plasma are shown in the table below.

Pharmacokinetic parameters of plasma oxycodone

Oxycodone C_maxAnd T_maxMean values of (a) indicate that the absorption rate of oxycodone in ER capsules is substantially lower than the absorption rate of oxycodone in IR tablets, e.g. lower mean C compared to the dose normalized PK data for the tablets_maxValues (22.6 ng/mL vs 77.8 ng/mL) and extended median T_max(14.0 hours vs. 1.0 hour). In terms of AUC_lastAnd AUC_infThere was no evidence of reduced oxycodone bioavailability for ER capsules. The AUC of ER capsules was on average slightly higher than that of IR tablets. Given the different doses used, the mean bioavailability results indicate that the overall delivery of oxycodone in ER capsules is at least comparable to the commercial IR tablets.

The elimination phase for each treatment showed a well characterized mean half-life value for ER capsules and IR tablets of 12.0 hours and 3.7 hours, respectively. Also, the mean oxycodone transport time (MTT) of ER capsules was longer (25.6 hours versus 6.2 hours) compared to IR tablets.

Statistical analysis of oxycodone in plasma (dose-normalized PK parameters)

ANOVA was performed to compare PK parameter C for treatment B (40mg ER capsules, test) and treatment A (20mg IR tablets, reference, values dose-normalized to 40mg)_max、AUC_lastAnd AUC_inf. The results of the statistical comparison are shown in the table below.

Statistical analysis of oxycodone PK parameters (dose normalized)

Results of statistical analysis based on geometric LSM ratio evaluation indicate C for ER capsules_maxOnly IR sheet27.8% of the agent, indicating that the peak concentration of oxycodone has been blunted by the extended release technique by about 72%. There is no evidence of reduced bioavailability of the ER test capsules compared to the commercial IR reference tablets. In fact, AUC of ER capsules_lastAUC of ER capsule higher than IR tablet by 9.56%_inf19.04% higher than the IR tablets. These slight differences in total bioavailability (i.e., AUC) were not considered clinically significant given the number of subjects and the different doses used in this study.

Plasma noroxycodone

A statistical summary of the PK parameters of noroxycodone in plasma is shown in the table below.

Pharmacokinetic parameters of plasma noroxycodone

ER capsules (test) showed lower noroxycodone C than IR tablets (reference)_max(although given at twice as high a dose of oxycodone) and longer T_max(14 hours vs. 1 hour). Noroxycodone exposure (AUC) for 40mg ER capsules (tested)_inf) The overall degree of (a) is about 1.8 times the noroxycodone exposure of the oxycodone dose of the 20mg IR tablet (reference).

The elimination phase appeared well characterized with half-life values of 14.5 hours and 6.51 hours for ER capsules (test) and IR tablets (reference), respectively. The IR tablet (reference) had a noroxycodone MTT of 10 hours compared to 30 hours for the ER capsule (test). The mean time to peak for ER capsules (test) was 14 hours post-dose versus 1 hour post-dose for IR tablets (reference).

Plasma naltrexone and 6-beta-naltrexone

Blood samples of plasma naltrexone and 6-beta-naltrexone were collected up to 120 hours after administration of ER capsules (8mg naltrexone). Of the 288 naltrexone plasma samples collected, only 2 subjects had a quantifiable plasma naltrexone concentration above the lower limit of quantification (LLOQ) of the assay (4 pg/mL). Subject #2 had a naltrexone concentration of 4.59pg/mL 120 hours post-dosing, while subject #17 had a naltrexone concentration of 5.13pg/mL 72 hours post-dosing. 286 (99.3%) of the 288 naltrexone samples were reported below the limit of quantitative determination, including subjects removed from statistical analysis due to vomiting.

In contrast to naltrexone, plasma concentrations of 6- β -naltrexone were quantified in 15 subjects. Typically, low levels of metabolites occur within 48-120 hours of administration, and no levels are detectable in any subject within the first 24 hours of administration. For 6- β -naltrexone, 4 of 24 subjects (subjects 1, 4, 17 and 23) had more than 2 measurable concentrations, and PK parameters were calculated for only those subjects.

Descriptive statistics of PK parameters of 6- β -naltrexone in plasma are shown in the table below.

Descriptive statistics of 6-beta-naltrexone

The highest observed plasma concentration of 6- β -naltrexone was 161pg/mL, occurring 72 hours after dosing in subject #17 (table 14.2.4.1). However, the mean 6- β -naltrexone concentration at 72 hours post-administration was 12.52pg/mL, and the median concentration at all time points (except 96 hours post-administration (2.16pg/mL)) was 0 pg/mL. In general, the low levels of 6- β -naltrexone combined with only trace concentrations of naltrexone indicate that naltrexone remains largely intact within the core throughout gastrointestinal transit of the product, which is a desirable result for product performance.

No serious ae (sae) was reported during this study. One (1) subject was discontinued due to an AE believed to be drug-related emesis. A total of 210 AEs were reported by 24(100%) subjects, with slightly higher AE incidence for the IR tablets (reference) compared to the ER capsules (test). Headache is the most common AE, reported by 15(63%) subjects, followed by dizziness (54%), nausea (50%) and tiredness (50%). All AEs resolved without sequelae. Of 210 AEs, 205 were mild in intensity and 5 were moderate. The investigator considered 187 AEs related to study drug. No clinically relevant or treatment-related differences were observed in clinical trials, vital signs or ECG parameters.

Conclusion

The overall degree of oxycodone exposure for 1 × 40mg oxycodone hydrochloride and naltrexone hydrochloride ER capsules (test) was about 19% higher than the reference IR formulation (4 × 5mg dose normalized to 40mg oxycodone hydrochloride tablets). ER capsules (test) C compared to IR tablets (reference)_maxAbout 72% lower.

The median time to peak oxycodone and noroxycodone concentrations for the ER capsules (test) was 14 hours post-dose versus 1 hour post-dose for the IR tablets (reference).

The half-life values (oxycodone at 12.0 hours and noroxycodone at 14.5 hours) of the ER capsules (test) were found to be higher than the reference IR tablets (oxycodone at 3.74 hours and noroxycodone at 6.51 hours).

Following administration of oxycodone hydrochloride ER capsules (test) containing naltrexone hydrochloride in its core, the plasma concentrations of naltrexone were below the limit of quantification (except for two subjects each with a measurable value (4.00pg/mL) just above the limit of quantification). The majority of 6- β -naltrexone plasma concentrations were below the limit of quantification and in 15 subjects, low 6- β -naltrexone levels were observed 48-120 hours post-dose.

Overall, the PK results of this study indicate that ALO-02 can deliver therapeutic amounts of oxycodone and that systemic exposure levels of naltrexone are low compared to commercially available oxycodone IR formulations.

Single doses of both oxycodone hydrochloride IR tablets (reference) and oxycodone hydrochloride and naltrexone hydrochloride ER capsules (test) administered in this study generally appeared safe and were equally well tolerated by these healthy male and female subjects. The most frequent AEs are those commonly associated with opioid administration, including headache, dizziness, nausea, and tiredness. Despite the higher oxycodone dose of ER, the distribution of these AEs was similar to or sometimes larger than the IR formulation, suggesting that some AEs such as euphoria may correlate with the peak concentration of oxycodone (C)_max) Rather than its overall exposure level (AUC). No clinically relevant or treatment-related differences were observed in clinical trials, vital signs or ECG parameters.

Example 6

12% oxycodone formulation

Sieved sugar pills

Hermetically coated sugar spheres

Load(s)

600 to 710 μm mesh sugar spheres (about 30 mesh) 1700g

Seal coat dispersion	Solutions of	Solid body	Administration of
				SD3A ethanol	80.00%	---	4533.3g
Dibutyl sebacate NF	0.50%	2.50%	28.3g
				Ethyl cellulose 50NF	5.00%	25.00%	283.3g
Magnesium stearate	2.00%	10.00%	113.3g
				Talc USP	12.50%	62.50%	708.3g
Total of	100.00%	100.00%	5666.7g

The seal coat dispersion was sprayed onto the sieved sugar spheres in a fluidized bed using a Wurster insert. The coating is performed under predetermined process parameter settings. After all the seal coat dispersion had been sprayed, ethanol was sprayed on the product to flush the pump tubing and the nozzle. Once the rinsing is complete, the product pellets are dried, drained, weighed and sieved. Oversized and undersized balls are then discarded. The balls of acceptable size are further processed into the next step.

Overview of naltrexone hydrochloride pellets

Naltrexone hydrochloride pellets were prepared by layering a naltrexone hydrochloride (NT) drug over the seal-coated sugar spheres to form a naltrexone core. These naltrexone cores are then subjected to a two-step coating of a barrier film (also known as a barrier coat). All drug layering and coating was done in a fluidized bed equipped with a Wurster insert. After each step of barrier coating, curing is carried out in an oven and the final cured finished pellets are sieved.

NT nucleus

Load(s)

Hermetically coated sugar spheres (-18/+30 mesh): 1700g

Naltrexone hydrochloride dispersion	Solutions of	Solid body	Administration of
				SD3A ethanol	63.07%	----	534.5g
Purified water USP	16.21%	---	137.4g
				Ascorbic acid USP	1.16%	5.61%	9.8g
HPC NF(75-150cps)	2.24%	10.81%	19.0g
				Naltrexone hydrochloride USP	11.81%	57.01%	100.1g
Talc USP	5.50%	26.57%	46.7g
				Total of	100.00%	100.00%	847.5g

Naltrexone nucleus

NT intermediate pellets

Naltrexone hydrochloride nuclei (-18/+30 mesh): 1700g

Intermediate dispersions	Solutions of	Solid body	Application of
				SD3A ethanol	62.34%	---	3249.8g
Purified water USP	17.67%	---	921g
				SLS NF	0.64%	3.20%	33.4g
Dibutyl sebacate NF	0.96%	4.79%	49.9g
				Eudragit RS	7.60%	37.99%	395.9g
Talc USP	10.80%	54.02%	563.0g
				Talc USP (Chalk)	---	---	---
Total of	100.00%	100.00%	5212.9g

NT finished product pellet

Load(s)

Naltrexone hydrochloride intermediate pellets (-16/+25 mesh) 2000.0g

Intermediate dispersions	Solutions of	Solid body	Application of
				SD ethanol	62.34%	---	3823.3g
Purified water USP	17.67%	---	1083.5g
				SLS NF	0.64%	3.20%	39.2g
Dibutyl sebacate NF	0.96%	4.79%	58.7g
				Eudragit RS	7.60%	37.99%	465.8g
Talc USP	10.80%	54.02%	662.3g
				Talc USP (Chalk)	---	---	---
Total of	100.00%	100.00%	6132.8g

Naltrexone pellets (intermediates and finished products)

The barrier coating process is carried out in a two-step process, i.e. the first step to make naltrexone intermediate pellets and the second step to make finished pellets.

For the finished naltrexone pellets, the barrier coating dispersion was sprayed onto the cured naltrexone intermediate pellets using a Wurster insert in a fluidized bed. Spraying, ethanol rinsing, drying, powdering, solidifying and sieving were performed in the same operation as the intermediate pellets). The oversized and undersized pellets are then discarded. The finished naltrexone pellets, which are acceptable in size, are further processed to the next step.

ALO-02 nucleus

Load(s)

Naltrexone hydrochloride pellets (-14/+25 mesh): 2250g

Oxycodone hydrochloride dispersion	Solutions of	Solid body	Application of
				SD ethanol	80.05%	---	2680.6g
HPC NF(75-150cps)	2.73%	13.69%	91.5g
				Oxycodone hydrochloride USP	11.48%	57.54%	384.4g
Talc USP	5.74%	28.77%	192.2g

Oxycodone hydrochloride core with isolated naltrexone hydrochloride

ALO-02 pellet

Load(s)

Oxycodone hydrochloride core: 2000.0g

Top coat dispersion	Solutions of	Solid body	Application of
				SD ethanol	85.71%	---	2454.5g
Phthalic acid diethyl ester NF	1.05%	7.33%	30.0g
				PEG6000	1.84%	12.86%	59.6g
Eudragit L100-55	0.74%	5.20%	21.3g
				Ethyl cellulose 50NF	5.89%	41.24%	168.8g
Talc USP	4.77%	33.38%	136.6g
				Talc USP (Chalk)	---	---	11.6g
Total of	100.00%	100.00%	2863.9g

End product pellets-extended release formulation of oxycodone hydrochloride with sequestering naltrexone hydrochloride

Oxycodone hydrochloride and naltrexone hydrochloride extended release capsule

The target fill weight of an individual capsule was calculated based on the oxycodone hydrochloride partial efficacy and capsule strength of the end product pellets. An acceptable weight limit is calculated which must be ± 5% of the target fill weight. The specified capsule shells and pellets were dispensed. The capsules are filled with pellets either manually or by an automatic encapsulation machine.

oxycodone hydrochloride and naltrexone hydrochloride composition extended release capsule, 40mg/4.8mg

¹The amount loaded to the batch can be corrected for efficacy and/or moisture.

Claims

1. A composition comprising a plurality of multi-layered pellets, said multi-layered pellets comprising:

a. a water-soluble core;

b. an antagonist-containing layer comprising naltrexone hydrochloride coating the core;

c. a sequestering polymer layer coating the antagonist-containing layer;

d. an agonist layer comprising an opioid agonist coating the sequestering polymer layer; and

e. a controlled release layer coating the agonist layer;

wherein the naltrexone hydrochloride comprises at least 10% by weight of the opioid agonist, and wherein, when administered to a human, the agonist is substantially released and the naltrexone hydrochloride is substantially sequestered.

2. The composition of claim 1, wherein the naltrexone hydrochloride comprises from about 10% to about 30% by weight of the opioid agonist.

3. The composition of claim 1, wherein the naltrexone hydrochloride comprises from about 10% to about 25% by weight of the opioid agonist.

4. The composition of claim 1, wherein the naltrexone hydrochloride comprises from about 10% to about 20% by weight of the opioid agonist.

5. The composition of claim 1, wherein the opioid agonist is oxycodone.

6. A composition comprising a plurality of multi-layered pellets, said multi-layered pellets comprising:

a. a water-soluble core;

c. a sequestering polymer layer coating the antagonist-containing layer;

e. a controlled release layer coating the agonist layer;

wherein the weight of the naltrexone hydrochloride comprises at least 5% of the combined weight of the water-soluble core, the antagonist-containing layer, and the sequestering polymer layer, and wherein, when administered to a human, the agonist is substantially released and the naltrexone hydrochloride is substantially sequestered.

7. The composition of claim 6, wherein the weight of said naltrexone hydrochloride comprises from about 5% to about 30% of the combined weight of said water-soluble core, said antagonist-containing layer, and said sequestering polymer layer.

8. The composition of claim 6, wherein the weight of said naltrexone hydrochloride comprises from about 6% to about 25% of the combined weight of said water-soluble core, said antagonist-containing layer, and said sequestering polymer layer.

9. The composition of claim 6, wherein the weight of said naltrexone hydrochloride comprises from about 7% to about 15% of the combined weight of said water-soluble core, said antagonist-containing layer, and said sequestering polymer layer.

10. The composition of claim 6, wherein the weight of said naltrexone hydrochloride comprises from about 8% to about 10% of the combined weight of said water-soluble core, said antagonist-containing layer, and said sequestering polymer layer.

11. The composition of claim 6, wherein the opioid agonist is oxycodone.

12. A dosage form comprising oxycodone hydrochloride and sequestered naltrexone hydrochloride, wherein the naltrexone hydrochloride is present in an amount by weight that is from about 10% to about 30% of the amount of oxycodone hydrochloride, wherein the dosage form sequesters 100% of the naltrexone hydrochloride as determined by the method comprising: first, the composition was placed in 500mL of 0.1N HCl solution at 37 ℃ for 1 hour using the USP paddle method at 100 rpm, and then in 500mL of 0.05M phosphate buffer pH7.5 at 37 ℃ for 72 hours using the USP paddle method at 100 rpm, followed by measurement of the amount of sequestered naltrexone hydrochloride at 73 hours.

13. The dosage form of claim 12, wherein the naltrexone hydrochloride is present in an amount by weight that is about 12% of the amount of oxycodone hydrochloride.

14. The dosage form of claim 12, wherein the naltrexone hydrochloride is present in an amount by weight that is about 12% of the amount of oxycodone hydrochloride.

15. A composition comprising a plurality of multi-layered pellets, said multi-layered pellets comprising:

a. a water-soluble core;

c. a sequestering polymer layer coating the antagonist-containing layer;

e. a controlled release layer coating the agonist layer;

wherein the naltrexone hydrochloride comprises at least 10% by weight of the opioid agonist, and wherein, when administered to a human, the agonist is substantially released and reaches a time to maximum observed plasma concentration (Tmax)_max) Over about 10 hours, while the naltrexone hydrochloride is substantially sequestered.

16. The composition of claim 15, wherein said T is_maxOver about 12 hours.

17. The composition of claim 15, wherein said T is_maxOver about 14 hours.

18. The composition of claim 15, wherein said T is_maxFrom about 10 hours to about 16 hours.

19. The composition of claim 15, wherein said T is_maxFrom about 12 hours to about 16 hours.

20. A method of treating moderate to severe chronic pain in a patient in need thereof, comprising administering to the patient a multi-layered pharmaceutical composition comprising:

a. a water-soluble core;

c. a sequestering polymer layer coating the antagonist-containing layer;

e. a controlled release layer coating the agonist layer;

21. A method of treating moderate to severe chronic pain in a patient in need thereof, comprising administering to the patient a multi-layered pharmaceutical composition comprising:

a. a water-soluble core;

c. a sequestering polymer layer coating the antagonist-containing layer;

e. a controlled release layer coating the agonist layer;

wherein the naltrexone hydrochloride comprises at least 10% by weight of the opioid agonist, and wherein the agonist is substantially released, the plasma concentration (Cx) of the agonist 24 hours after administration₂₄) And maximum observed plasma concentration (C)_max) Is from about 0.2 to about 0.8.