KR20090065543A

KR20090065543A - Robust sustained release formulations of oxymorphone and methods of use thereof

Info

Publication number: KR20090065543A
Application number: KR1020097008717A
Authority: KR
Inventors: 케빈 피츠머라이스; 애넌드 알 바이춸; 스티브 라부드진스키; 스파크스 마이클 하워드; 앨런 라이치트맨; 윌리엄 하인
Original assignee: 펜웨스트 파머슈티칼즈 컴파니
Priority date: 2009-04-28
Filing date: 2006-10-10
Publication date: 2009-06-22

Abstract

Robust sustained release formulations, solid dosage forms comprising robust sustained release formulations, and methods of making and using these formulations and solid dosage forms are provided. The robustness of the sustained release formulation is related to the particle size of the hydrophilic gum. Sustained release formulations are resistant to dose dumping when ingested with alcohol. The formulations are useful for the treatment of patients suffering from conditions such as pain. The formulation comprises one or more drugs. In one embodiment, the drug is an opinoid, such as oxymorphone.

Description

Robust Sustained-Release Formulation of Oxymorphone and its Preparation and Use

The present invention provides robust sustained release pharmaceutical preparations and methods for their preparation and use. Formulations of the present invention include one or more drugs and a sustained release delivery system.

Sustained release drug formulations often contain higher amounts than drugs of immediate release formulations. The function and safety of sustained release formulations are based on known controlled rates of drug release from the formulation over a prolonged period of time, such as 8 to 24 hours. The drug release profile of the formulation often depends on the chemical environment of the sustained release formulation, such as pH, ionic strength and the presence of a solvent such as ethanol.

When the agent releases the drug at a rate faster than the intended controlled release rate, the relatively high amount of drug present in the sustained release formulation harms the patient in some cases. If the agent releases the drug at a rate slower than the intended controlled release rate, the therapeutic efficacy of the drug may be reduced.

In most cases, if a sustained release formulation fails, the drug is released quickly into the bloodstream. This rapid release is generally faster than the intended slow release of the drug from the formulation, so it is often referred to as “dose dumping”.

Dose dumping can have serious consequences for patients, including permanent harm and even death. Examples of drugs that can be fatal, for example when doses that are beneficial for treatment are exceeded, such as by dose dumping, include analgesics such as opioids.

Oral formulations are typically taken with commercially available beverages such as water, juice, carbonated beverages or often ethanol containing beverages. Ethanol containing beverages are commonly referred to as beverages capable of drinking ethanol, alcohol or simply drinkable ethanol. As used herein, the term "drinkable ethanol" refers to ethanol, or ethanol-containing ("drinkable ethanol") beverages, such as beer, wine and hard liquor, such as vodka, rum or whiskey. Dose dumping in the presence of ethanol raises safety issues because the patient is similar to ingesting the formulation with a beverage capable of drinking ethanol. This can be exacerbated if the drug can interact with being able to drink ethanol. A further safety issue is that the patient can drink alcoholic beverages while being treated with the drug in the formulation even if the patient has not taken the formulation simultaneously with the beverage that can drink ethanol.

A patient who wishes to abuse a drug, such as a drug that produces a euphoric effect, may want to intentionally induce dose dumping to enhance the drug's pleasant effect. In addition, individuals who desire drug abuse may already be abusing alcohol, which increases the similarity of sustained release formulations of drugs taken or taken concurrently with alcoholic beverages.

In 2005, some drugs were withdrawn from the market or labeled with warnings due to the effects of ethanol on the sustained release formulation of the drug.

For example, the U.S. Food and Drug Administration (FDA) has asked Purdue Parma to collect Palladone® (hydromorphone hydrochloride) long-term release capsules on the market, which will damage long-term release formulations when taken with Palladone alcohol, resulting in dose dumping. This can happen because studies have shown (see FDA Press Release on July 13, 2005). The FDA further warned that taking Palladone® with a single alcoholic beverage could be fatal for patients.

Alfama has issued a press release reporting that the FDA has required increased labeling for KADIAN® warnings on alcohol (see the July 22, 2005 Alpharma press release). The enhanced warning was the result of in vitro studies demonstrating that the long-term release properties of KADIAN® are compensated in the presence of alcohol.

AVINZA® (morphine sulfate long-term release capsule) has been shown to increase the risk of dose dumping when taken with ethanol. In an in vitro study conducted by the FDA, when mixing 30 mg of AVINZA with 900 ml of ethanol (20% and 40%) buffer, the dose of morphine released was alcohol concentration dependent, leading to more rapid release of morphine, The FDA said this could result in the absorption of potentially lethal doses of morphine in vivo. As a result, during or around October 2005, Ligand Pharmaceuticals Incorporated, Inc., added some of the AVINZA® prescription information to highlight and reinforce the warning that patients should not drink alcohol while taking AVINZA®. The dog section has been revised. In addition, patients were warned not to use alcohol-containing prescriptions or over-the-counter medications with AVINZA® treatment.

The FDA also noted that in vitro testing of sustained-release alcohol-induced undermining on additional sustained release products may be advisable as routine characterization testing. It is also the FDA's position that for certain drugs (such as those with a high C _max or a low C _min scary outcome or a narrow therapeutic index), alcohol sensitive sustained release formulations should not be approved. Rather than simply confirm that dose dumping does not occur through in vivo studies, FDA prefers to manufacture the formulation to be ethanol-resistant by design (at the Pharmaceutical Sciences Advisory Committee Meeting, October 26, 2005). See FDA's positional clearance on alcohol-induced dose dumping as presented).

According to the FDA, in vivo alcohol resistance testing is not a preferred approach because the test may plague human subjects due to potential harm. A preferred approach according to the FDA is an in vitro dissolution test in the presence of 40% ethanol. This approach may be desirable because the strength of the most common "strong" liquor is about 80 standard proof or about 40% ethanol. The FDA proposes to classify agents into three groups, rugged, vulnerable, and indeterminate. At the Pharmaceutical Sciences Advisory Committee Meeting of October 26, 2005, the Office of Pharmaceutical Sciences (OPS) staff at the Center for Drug Evaluation and Research (CDER) found that ethanol had a higher concentration (eg 40%) in vulnerable formulations. Data were presented demonstrating that drug release may be induced faster than at lower concentrations (eg 20% or 4%). In the FDA's example of a rugged formulation, drug release from the formulation dissolved in 40% ethanol was substantially slightly slower (although similar) compared to the control formulation dissolved in the medium without ethanol (Pharmaceutical, 26 October 2005). Presentation at the Sciences Advisory Committee Meeting.

Changing the product labeling (ie, adding a warning about the dangers of taking the drug with alcohol) is only limited in effect and does not seem to discourage patients trying to abuse the drug.

Pain is the most commonly reported symptom and a common clinical problem facing clinicians. Tens of millions of people in the United States suffer from chronic undertreatment or inadequately administered severe pain. The clinical utility of opioid analgesic properties has been recognized for centuries, and morphine and its derivatives have been widely used for analgesic action in various clinical pain states for centuries.

Oxymorphone HCl (14-hydroxydihydromorphinone hydrochloride) is a semisynthetic phenanthrene derivative opioid agonist used in the treatment of acute and chronic pain with analgesic efficacy similar to other opioid analgesics. Oxymorphone is currently marketed as an injection (1 mg / ml in 1 ml ampoule) for intramuscular, subcutaneous and intravenous administration. At one time, a 10 mg oral immediate release formulation of oxymorphone HCl was sold. Oxymorphone HCl is basically metabolized in the liver to form a conjugate with glucuronic acid and reduced to 6-alpha and 6-beta hydroxy epimers.

The main purpose of analgesic therapy is to achieve continuous relief of chronic pain. Regular analgesic administration is generally necessary to ensure the delivery of the next dose before the effects of the previous dose have vanished. Compliance with opioids increases as the frequency of administration required decreases. Non-compliance results in sub-optimal pain control and poor quality of life. Guidelines for use in the treatment of chronic non-malignant pain currently recommend deliberate administration of opioids rather than "as needed." Unfortunately, evidence from previous clinical trials and clinical experience suggests that the short duration of action of immediate release oxymorphone should be administered every four hours in order to maintain optimal levels of analgesic action in patients with chronic pain. Suggests need. Immediate release oxymorphone also exhibits low oral bioavailability because oxymorphone is widely metabolized in the liver.

Many drugs, such as opioids such as oxymorphone, can lead to serious adverse effects or even death in patients if the sustained release formulation fails, making them more robust or lug safer than currently available sustained release formulations. Is needed in the art.

Several sustained release formulations are disclosed in US Pat. No. 5,399,358, the disclosure of which is incorporated herein by reference in its entirety. It has now been unexpectedly found that the particle size of hydrophilic gums, such as xanthan gum, affects the robustness and dissolution properties of sustained release formulations.

Although references are cited in the Background section of this application, references are not admitted to be prior art.

Summary of the Invention

The present invention provides a sustained release pharmaceutical formulation, and a solid dosage form comprising a sustained release formulation. The invention also provides a method of treating a patient using a sustained release formulation, and a method for preventing dose dumping, such as by providing a patient with a therapeutically effective amount of a sustained release drug formulation. The pharmaceutical formulations described herein may result in less dose dumping than conventional sustained release formulations, thereby making them more lug, safer and applicable to a wide variety of drugs.

The invention further provides ethanol resistant pharmaceutical agents and methods of increasing drug safety and reducing the likelihood of drug abuse. This can be accomplished by providing, prescribing and / or administering an effective amount of an ethanol resistant drug formulation to the patient. Ethanol resistant drug formulations are safer and less abuseable than commercially available formulations because their sustained dissolution profiles are substantially the same in aqueous or ethanol containing solutions. In one embodiment, the drug in the ethanol resistant formulation comprises an opioid compound or derivative thereof.

The invention also provides an ethanol resistant pharmaceutical agent, and a method for preventing dose dumping. This can be accomplished by providing, prescribing and / or administering an effective amount of an ethanol resistant drug formulation to the patient. Ethanol resistant pharmaceutical formulations described herein do not cause dose dumping in the presence of beverage-strength ethanol. In one embodiment, the drug in the ethanol resistant formulation comprises an opioid compound, a pharmaceutically acceptable salt of the opioid compound, or a derivative thereof.

In one aspect, the invention is a drug; And a sustained release delivery system comprising a hydrophilic gum, a homopolysaccharide gum, and a pharmaceutical diluent, wherein at least about 30% of the hydrophilic gum used to prepare the sustained release formulation is a # 270 mesh. It can pass through a sieve and the sustained release formulation releases less than about 70% of the drug within 2 hours after ingestion with an ethanol-free or ethanol containing beverage.

In another aspect, the invention is a drug; And hydrophilic gums; Cationic crosslinking compounds selected from monovalent cations, polyvalent cations and salts; And a sustained release delivery system comprising a pharmaceutical diluent, wherein at least about 30% of the hydrophilic gums used in the manufacture of the sustained release formulation can pass through a # 270 mesh sieve, the sustained release formulation Releases less than about 70% of the drug within 2 hours after ingestion with an ethanol-free or ethanol containing beverage.

In some embodiments, the hydrophilic gum is a heterologous polysaccharide gum. In some embodiments, the hydrophilic gum is xanthan gum.

In one embodiment, the sustained release delivery system further comprises a cationic crosslinking compound selected from monovalent cations, polyvalent cations and salts. In one embodiment, the cationic crosslinker is a sodium salt.

In another aspect, the invention is a drug; And a sustained release delivery system comprising a hydrophilic gum, a homologous polysaccharide gum, and a pharmaceutical diluent, wherein at least about 30% of the hydrophilic gum particles used in the preparation of the sustained release formulation are about 53 microns in diameter. Smaller, sustained release formulations release less than 70% of the drug within 2 hours after ingestion with an ethanol-free or ethanol containing beverage.

In another aspect, the invention is a drug; And hydrophilic gums; Cationic crosslinking compounds selected from monovalent cations, polyvalent cations and salts; And a sustained release delivery system comprising a pharmaceutical diluent, wherein at least about 30% of the hydrophilic gum particles used to prepare the sustained release formulations are less than about 53 microns in diameter, and the sustained release formulations Less than 70% of the drug is released within 2 hours after ingestion with an ethanol free or ethanol containing beverage. In some embodiments, the sustained release delivery system further comprises a hydrophobic polymer.

In some embodiments, the sustained release formulation further comprises an outer coating. In some embodiments, the outer coating comprises a hydrophobic polymer and / or a plasticizer.

In some embodiments, the drug is a water soluble drug. In some embodiments, the drug is a drug used for the treatment of antidepressants, bipolar disorder, panic disorder, epilepsy, migraine and / or attention deficit hyperactivity disorder. In some embodiments, the drug is a neutral sulphate of dextroseamphetamine and amphetamine with dextrome isomers of alprazolam, lithium carbonate, divalproex sodium, amphetamine saccharide and d, l-amphetamine aspartate monohydrate. Salts, tramadol hydrochloride, and other pharmaceutically acceptable salts of the active pharmaceutical ingredients thereof.

In some embodiments, the drug is an opioid, such as alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, buprenor Buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diopramide diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepeheptanol, dimethyltiambutene, dioxaphetyl butyrate, dipippa Dipipanone, Eptazocine, Ethoheptazine, Ethheptazine, Ethylmethylthiambutene, Ethylmorphine, Etoninitazine, Fentanyl, Heroin, Hydrocodone, Hydromorphone, Hydroxypetidine (hydroxypethidine), isome Isomethadone, ketobemidone, levalorphan, levophanol, levophenacylmorphan, lofentanil, meperidine, meptazinol , Metazocine, methadone, methopone, morphine, myropine (myrophine), nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone (normetorphanol) normethadone, nalorphine, normorphine, norpipanone, opiate, oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretum, pentazosin , Phenadoxone, phenomorphan, phenazocine, phenoperidine, phenoperidine, piminodine, pyritramide, propheptazine, promethol (promedol), properidine, propiram, propoxyphene, sufenta (Sufentanil), tramadol, Tilly Dean (tilidine), is its stereoisomers, metabolites thereof, ethers thereof, esters thereof, derivatives thereof and pharmaceutically acceptable salts thereof.

In addition, the present invention provides a method for preparing a sustained release pharmaceutical formulation, and a solid dosage form comprising the sustained release formulation.

In one aspect, the invention is a drug; And a sustained release delivery system comprising a hydrophilic gum, a homopolysaccharide gum, and a pharmaceutical diluent, the method providing a hydrophilic gum with particles having at least a portion of a diameter less than about 53 microns. step; Granulating the hydrophilic gum, the homopolysaccharide gum, and the pharmaceutical diluent to form granules; Mixing the granules with the drug to form a granulation composition; And applying pressure to the granulation composition to prepare the formulation.

In another aspect, the invention is a drug; And hydrophilic gums; Cationic crosslinking compounds selected from monovalent cations, polyvalent cations and salts; And a sustained release delivery system comprising a pharmaceutical diluent, the method comprising the steps of providing a hydrophilic gum with particles having a portion of less than about 53 microns in diameter; Granulating the hydrophilic gum, the homopolysaccharide gum, and the pharmaceutical diluent to form granules; Mixing the granules with the drug to form a granulation composition; And applying pressure to the granulation composition to prepare the formulation.

In some embodiments, the providing step comprises receiving, preparing and / or processing the hydrophilic gum. In some embodiments, the processing step includes measuring the size of at least some hydrophilic gum particles and / or passing at least some hydrophilic gums through a sieve. In some embodiments, the sieve is a # 270 mesh sieve.

In some embodiments, the method of making the sustained release formulation and the solid dosage form further comprises applying an outer coating to at least a portion of the sustained release formulation.

In some embodiments, the granulating step comprises mixing the component with a water comprising solution. In another embodiment, granulation comprises mixing the component with an alcohol solution, such as an ethanol containing solution.

In one aspect, the invention is a drug; And a sustained release delivery system comprising a hydrophilic gum, a homologous polysaccharide gum, and a pharmaceutical diluent, wherein the method has an average and / or mean particle size in diameter. Mixing hydrophilic gums, homopolysaccharide gums, and pharmaceutical diluents greater than about 53 microns with a solution comprising water to form granules; Mixing the granules with the drug to form a granulation composition; And applying pressure to the granulation composition to prepare the formulation.

In another aspect, the invention is a drug; And hydrophilic gums; Cationic crosslinking compounds selected from monovalent cations, polyvalent cations and salts; And a sustained release delivery system comprising a pharmaceutical diluent, said method comprising a hydrophilic gum, a cationic crosslinking compound having an average and / or median particle size greater than about 53 microns in diameter, and Mixing the pharmaceutical diluent with a solution comprising water to form granules; Mixing the granules with the drug to form a granulation composition; And applying pressure to the granulation composition to prepare the formulation.

In one embodiment, the method of making the sustained release formulation further comprises recording a dissolution profile of the sustained release formulation, or a solid dosage form comprising the sustained release formulation, in an ethanol containing solution.

In one embodiment, the present invention provides a method for alleviating pain, comprising administering to a patient a therapeutically effective amount of a sustained release formulation described herein or a solid dosage form comprising the sustained release formulation.

In another embodiment, the present invention provides a method of treating a patient with a condition comprising administering to the patient a therapeutically effective amount of a sustained release formulation described herein, or a solid dosage form comprising a sustained release formulation.

In another aspect, the present invention provides a method of reducing dose dumping of a sustained release drug formulation, comprising providing the patient with a sustained release formulation described herein.

In another aspect, the present invention provides a solid dosage form comprising the sustained release formulation described herein. In some embodiments, the solid dosage form is a powder, granule, tablet or capsule.

In one aspect, the sustained release formulation comprises about 5 to about 80 mg of oxymorphone hydrochloride and about 80 to about 360 mg of the sustained release delivery system, wherein the sustained release delivery system contains about 8.3 to about 41.7 weight percent of the locust bean. Gum, about 8.3 to about 41.7 weight percent xanthan gum (at least about 30% of the xanthan gum particles can pass through a # 270 mesh sieve), about 20 to about 55 weight percent dextrose, about 5 to Comprising about 20% calcium sulfate dihydrate and about 2 to about 10% ethyl cellulose, wherein the sustained release formulation releases less than 70% of the drug within 2 hours after ingestion with an ethanol-free or ethanol-containing beverage .

In another aspect, the sustained release formulation comprises about 5 to about 80 mg of oxymorphone hydrochloride and about 300 to about 420 mg of a sustained release delivery system, wherein the sustained release delivery system comprises about 8.3 to about 41.7 weight percent of locust bean. Gum, about 8.3 to about 41.7 weight percent, xanthan gum having at least about 30% particle diameter less than about 53 microns, about 20 to about 55 weight percent dextrose, about 5 to about 20 weight percent sulfuric acid Comprising calcium dihydrate and about 2 to about 10 weight percent ethyl cellulose, the sustained release formulation releases less than 70% of the drug within 2 hours after ingestion with an ethanol-free or ethanol containing beverage.

In one embodiment, the sustained release formulation comprises about 20 mg of oxymorphone hydrochloride. In another embodiment, the sustained release formulation comprises about 160 mg of a sustained release delivery system. In another embodiment, the sustained release formulation comprises about 360 mg of a sustained release delivery system. In another embodiment, the sustained release delivery system includes about 25% locust bean gum, about 25% xanthan gum, about 35% dextrose, about 10% calcium sulfate dihydrate and about 5% ethyl cellulose It includes.

In another aspect, the present invention provides a pharmaceutical composition comprising a drug to a patient who can drink ethanol while being treated with the drug; And providing an effective amount of the drug in the form of an ethanol resistant sustained release formulation comprising a sustained release delivery system comprising at least one hydrophilic gum, at least one homopolysaccharide gum, and at least one pharmaceutical diluent. A method for preventing dose dumping of a formulation, wherein at least about 30% of the hydrophilic gums used in the preparation of sustained release formulations can pass through a # 270 mesh sieve, and the sustained release formulations are combined with ethanol-free or ethanol-containing beverages. Less than about 70% of the drug is released within 2 hours after ingestion.

In one aspect, the invention provides a drug to a patient capable of drinking ethanol while being treated with the drug; And at least one hydrophilic gum; At least one cationic crosslinking compound selected from monovalent metal cations, polyvalent metal cations and salts; And providing an effective amount of the drug in the form of an ethanol resistant sustained release formulation comprising a sustained release delivery system comprising one or more pharmaceutical diluents, the method comprising: At least about 30% of the hydrophilic gums used in the manufacture of sustained release formulations can pass through a # 270 mesh sieve, and the sustained release formulations are less than about 70% of the drug within 2 hours of ingestion with ethanol-free or ethanol-containing beverages. Emits.

In another aspect, the present invention provides a pharmaceutical composition comprising a drug to a patient who can drink ethanol while being treated with the drug; And providing an effective amount of drug in the form of an ethanol resistant sustained release formulation comprising a sustained release delivery system comprising at least one hydrophilic gum, at least one homopolysaccharide gum, and at least one pharmaceutical diluent. A method of improvement is provided, wherein the improvement in safety is a result of controlled hydrophilic gum particle size and ethanol resistant sustained release properties of the formulation.

In another aspect, the invention provides a drug to a patient who can drink ethanol while being treated with the drug; And at least one hydrophilic gum; At least one cationic crosslinking compound selected from monovalent metal cations, polyvalent metal cations and salts; And providing an effective amount of the drug in the form of an ethanol resistant sustained release formulation comprising a sustained release delivery system comprising one or more pharmaceutical diluents, wherein the improvement in safety is Results of controlled hydrophilic gum particle size and ethanol resistant sustained release properties of the formulation.

In one aspect, the present invention provides a sustained release oxymorphone formulation comprising a sustained release delivery system and about 5 to about 80 mg of oxymorphone, comprising about 4 to about 40% ethanol with about 200 to 300 ml of a patient After oral administration of a single dose to a patient, the formulation provides a secondary peak of oxymorphone concentration in the blood about 12 hours after administration and provides analgesic to the patient for at least about 12 hours after administration.

In some embodiments, the formulation comprises about 20 to about 60 mg of oxymorphone or about 40 mg of oxymorphone. In one embodiment, the formulation is a solid dosage form, such as a tablet, granules, capsule or powder.

In another aspect, the present invention provides a sustained release delivery system and a sustained release oxymorphone formulation comprising about 5 to about 80 mg of oxymorphone, wherein after oral administration of a single dose to a patient, the formulation is ingested without ethanol. With a maximum blood concentration of oxymorphone of less than about 5 times when ingested with about 200 to about 300 ml of ethanol up to about 40% compared to hour, and the formulation is analgesic to the patient for at least about 12 hours after administration To provide.

In one embodiment, the maximum blood concentration of oxymorphone is less than about 2.5 times higher when ingested with about 200% to about 300 ml of ethanol up to about 40% compared to when ingested without ethanol.

In another aspect, the present invention provides a sustained release delivery system and a sustained release oxymorphone formulation comprising about 5 to about 80 mg of oxymorphone, wherein after oral administration of a single dose to the patient, the formulation provides about 40% The ratio of the maximum blood concentration of oxymorphone when ingested with about 200 to 300 ml of ethanol versus the maximum blood concentration of oxymorphone when ingested after high-fat without ethanol is about 0.5 to about 2, and the formulation is administered for at least 12 hours after administration. Provides pain relief for the patient.

In one embodiment, the ratio of the maximum blood concentration of oxymorphone when ingested with about 200% to 300 ml of the formulation with about 40% ethanol to the maximum blood concentration of oxymorphone when ingested after high-fat diet without ethanol is about 0.8 to About 1.5.

In one aspect, the present invention provides a sustained release oxymorphone formulation comprising a sustained release delivery system and about 5 to about 80 mg of oxymorphone, wherein the patient has about 4 to about 40% ethanol about 200 to about 300 ml After oral administration of a single dose together, the formulation provides a maximum blood concentration of oxymorphone of about 0.1 to about 15 ng / ml, and the formulation provides analgesic action to the patient for at least about 12 hours after administration.

In some embodiments, the formulation provides a maximum blood concentration of oxymorphone of about 0.5 to about 7.5 ng / ml, or about 1 to about 4 ng / ml.

In one embodiment, the formulation comprises about 10 to about 20 mg of oxymorphone and the formulation provides a maximum blood concentration of about 0.3 to about 3.2 ng / ml, or about 0.4 to about 2.8 ng / ml of oxymorphone. to provide.

In some embodiments, the formulation comprises about 10 mg of oxymorphone and the formulation provides a maximum blood concentration of about 0.3 to about 1.8 ng / ml, or about 0.5 to about 1.5 ng / ml of oxymorphone.

In another embodiment, the formulation comprises about 20 to about 40 mg of oxymorphone and the formulation has a maximum blood concentration of about 0.5 to about 7 ng / ml, or about 0.9 to about 6 ng / ml of oxymorphone. to provide.

In another embodiment, the formulation comprises about 20 mg of oxymorphone and the formulation provides a maximum blood concentration of about 0.5 to about 3.2 ng / ml, or about 0.75 to about 2.8 ng / ml of oxymorphone. .

In one embodiment, the formulation comprises about 40 to about 80 mg of oxymorphone and the formulation provides a maximum blood concentration of about 1 to about 15 ng / ml, or about 1.9 to about 12 ng / ml of oxymorphone. to provide.

In another embodiment, the formulation comprises about 40 mg of oxymorphone and the formulation provides a maximum blood concentration of oxymorphone of about 1 to about 7 ng / ml, or about 1.4 to about 5 ng / ml.

In another embodiment, the formulation comprises about 80 mg of oxymorphone and the formulation provides a maximum blood concentration of about 3.5 to about 15 ng / ml, or about 4 to about 13 ng / ml of oxymorphone. .

In one aspect, the present invention provides a sustained release oxymorphone formulation comprising a sustained release delivery system and about 5 to about 80 mg of oxymorphone, wherein the formulation provides a patient with about 4 to about 40% ethanol about 200 to about A single dose with 300 ml provides a minimum blood concentration of at least about 0.013 ng / ml oxymorphone at 12 hours after oral administration, and the formulation provides analgesic action to the patient for at least about 12 hours after administration.

In one embodiment, the formulation comprises about 5 mg of oxymorphone and provides a minimum blood concentration of oxymorphone of at least about 0.07 ng / ml.

In another embodiment, the formulation comprises about 10 mg of oxymorphone and provides a minimum blood concentration of oxymorphone of at least about 0.15 ng / ml.

In another embodiment, the formulation comprises about 20 mg of oxymorphone and provides a minimum blood concentration of oxymorphone of at least about 0.3 ng / ml.

In one embodiment, the formulation comprises about 40 mg of oxymorphone and provides a minimum blood concentration of oxymorphone of about 0.6 ng / ml or more.

In another embodiment, the formulation comprises about 80 mg of oxymorphone and provides a minimum blood concentration of oxymorphone of at least about 1.2 ng / ml.

In some embodiments, the formulation is a solid dosage form, such as a tablet, capsule, granule or powder.

In one aspect, the invention provides a method for alleviating pain, comprising administering to a patient a sustained release delivery system and a sustained release oxymorphone formulation comprising about 5 to about 80 mg of oxymorphone. After oral administration of a single dose with about 200 to about 300 ml of about 4 to about 40% ethanol, the formulation provides a secondary peak of oxymorphone concentration in the blood about 12 hours after administration, and the formulation is at least about 12 hours after administration Gives the patient analgesic action.

In another aspect, the present invention provides a method of alleviating pain, comprising administering to a patient a sustained release delivery system and a sustained release oxymorphone formulation comprising about 5 to about 80 mg of oxymorphone. After oral administration of a single dose, the formulation provides a maximum blood concentration of oxymorphone of about 40% or less of about 200% less than about 5% ethanol uptake when compared to ingestion without ethanol, and the formulation is administered after Provide analgesic action to the patient for at least about 12 hours.

In one embodiment, the maximum blood concentration of oxymorphone is less than about 2.5 times higher than intake of about 200% to 300 ml of ethanol of up to about 40% compared to intake without ethanol.

In another aspect, the invention provides a method of alleviating pain, comprising administering to a patient a sustained release delivery system and a sustained release oxymorphone formulation comprising about 5 to about 80 mg of oxymorphone. After oral administration of a single dose to a patient, the formulation is a ratio of the maximum blood concentration of oxymorphone when ingested with about 200-300 ml of about 40% ethanol to the maximum blood concentration of oxymorphone when ingested after high-fat diet without ethanol. About 2 and the formulation provides analgesic action to the patient for at least about 12 hours after administration.

In one aspect, the invention provides a method for alleviating pain, comprising administering to a patient a sustained release delivery system and a sustained release oxymorphone formulation comprising about 5 to about 80 mg of oxymorphone. After oral administration of a single dose with about 200 to about 300 ml of about 4 to about 40% ethanol, the formulation provides a maximum blood concentration of oxymorphone of about 0.1 to about 15 ng / ml, and the formulation is about 12 Provide analgesic action to the patient for more than a time.

In another aspect, the present invention provides a method for alleviating pain, comprising administering a sustained release delivery system and a sustained release oxymorphone formulation comprising about 5 to about 80 mg of oxymorphone to the patient, The patient is provided with a minimum blood concentration of at least about 0.013 ng / ml oxymorphone at about 12 hours after oral administration of a single dose with about 4 to about 40% ethanol about 200 to about 300 ml, and the formulation is about 12 Provide analgesic action to the patient for more than a time.

In another embodiment, the formulation comprises about 80 mg of oxymorphone and provides a minimum blood concentration of oxymorphone of at least about 1.2 ng / ml. Sustained release formulations described herein can be used in therapy. In addition, the sustained release formulations described herein can be used in the manufacture of a medicament for the treatment of a condition. In one embodiment, the sustained release formulations described herein can be used in the manufacture of a medicament for pain relief.

These and other aspects and embodiments of the invention are described in detail herein.

Detailed description of the invention

1. Definition

Unless otherwise specified, the conjunction "or" as used herein is used in the sense including "and / or" but is not used in the sense of excluding "any one or".

As used herein, the term "strong" refers to a property of a sustained release formulation that is less likely to have a dissolution profile that is substantially altered, damaged, or failed. An example of a failure in sustained release formulations is dose dumping. "Strong" and "rug" mean synonyms.

As used herein, the term "fine" refers to the particle size of a polymer having a diameter of less than 53 microns, or alternatively having particles that can pass through a # 270 mesh sieve.

As used herein, the term "dose dumping" refers to the rapid release of a drug or active ingredient from the sustained release formulation into the bloodstream. This rapid release is generally faster than the sustained release of the drug from the formulation. Dose dumping also refers to a release having a maximum concentration of drug in plasma that is higher than the intended maximum concentration of drug in the West. Dose dumping can cause dangerous overdose, which in some cases can have fatal consequences.

As used herein, the term "sustained release" means that the drug is released from the formulation at a controlled rate to maintain the blood concentration (but below toxic concentration) of the drug for the treatment over a long period of time.

As used herein, the terms "sustained release", "extended release" and "controlled release" are synonymous. In other words, it has the same meaning.

As used herein, the term “immediate release” means that the drug is released from the formulation in a short time, such as within about 4 hours after administration of the formulation.

The term "AUC" as used herein refers to the area under the concentration-time curve.

The term “C _max ” as used herein refers to the maximum observed concentration.

The term "RSD" as used herein refers to relative standard deviation.

The term "CI" as used herein refers to a confidence interval.

As used herein, the term “high fat diet” refers to a meal wherein about 50% of the total calorie content of the meal is derived from fat. Examples of high-fat diets are two buttered eggs, two bacon strips, two pieces of buttered toast, 4 ounces of hash brown potatoes and 8 ounces of whole milk.

The term "liquid" as used herein includes, for example, gastrointestinal fluids, aqueous solutions (such as those used in in vitro dissolution testing) and mucus (such as mucus such as mouth, nose, lungs, esophagus, etc.).

As used herein, the term “ethanol resistance” refers to releasing less than 50% of the active ingredient (eg drug) within 1 hour in dissolution profile determination by USP Procedure Drug Release USP 23 in 0.1N HCl and 40% ethanol solution. Refers to.

As used herein, the term "drug" includes any pharmaceutically active chemical or biological compound and any pharmaceutically acceptable salt thereof used for alleviating symptoms, treating or preventing a condition.

Suitable drugs for the robust sustained release formulations described herein include alprazolam (XANAX XR®), lithium carbonate (LITHOBID®), divalproex sodium (DEPAKOTE®), amphetamine saccharide and d, l-amphetamine aspartate monohydrate. Dextromeamphetamine and neutral salt salts of amphetamine (ADDERALL XR®), tramadol hydrochloride (TRAMADOL ER®) and opioids such as morphine (AVINZA® and KADIAN®) and oxycodone (OXYCONTIN®) It is not limited to this.

The term “opioid” as used herein includes its stereoisomers, metabolites thereof, salts thereof, ethers thereof, esters thereof and / or derivatives thereof (such as pharmaceutically acceptable salts thereof). The opioid may be a mu-antagonist and / or a mu-agonist / antagonist mixture. Exemplary opioids include alfentanil, allylprodine, alphaprodine, anilridine, benzylmorphine, benzitramide, buprenorphine, butophanol, clonitogen, codeine, cyclazosin, desormorphine, dextromemora Amide, dezosin, diopromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimefetanol, dimethyl thiambutene, dioxafetyl butyrate, dipipanone, eptazinine, etoheptazine, ethylmethyl thi Ambutene, ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypettidine, isometadon, ketobemidone, revalorphan, levophanol, levofenacylmorphan, lofentanil, memeth Ferridine, meptazinol, metazosin, methadone, methopone, morphine, myropine, nalbuphine, narcane, nicomorphine, norrebopanol, normethadon, nallopine, normorphine, norfipanone, opium, oxycodone, oxy Morfon, 6-hydroxyoxy Lepon, papaveretum, pentazosin, phenadoxone, phenomorphan, phenazosin, phenoferidine, piminodine, pyritramide, propeptazine, promedol, properidine, propyram, propoxyphene, susu Fentanyl, tramadol, tilidine, stereoisomers thereof, metabolites thereof, salts thereof, ethers thereof, esters thereof and / or derivatives thereof. In some embodiments, the opioid is morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, 6-hydroxyoxymorphone (6-α-hydroxyoxymorphone and And / or 6-β-hydroxyoxymorphone) or tramadol.

The term "oxymorphone" as used herein includes oxymorphone, metabolites thereof and derivatives thereof. Metabolites of oxymorphone include, for example, 6-hydroxyoxymorphone (such as 6-α-hydroxyoxymorphone and / or 6-β-hydroxyoxymorphone).

The term "condition" as used herein includes any set of diseases or conditions that require treatment with a drug. Exemplary conditions include panic disorder (with or without plaque), bipolar disorder (manic illness), acute manic or mixed episodes associated with bipolar disorder, epilepsy, migraine, attention deficit hyperactivity disorder (ADHD), depression and pain Include.

The pain can be mild to moderate, or moderate to severe. The pain can be acute or chronic. Pain can also be persistent and may require continuous 24-hour relief for long periods of time. Pain can be associated with cancer, autoimmune disease, infection, surgical trauma or accident trauma, for example. The patient can be an animal, a mammal or a human.

The drug may be in the form of any pharmaceutically acceptable salt known in the art. Exemplary pharmaceutically acceptable salts include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, maleic acid, malic acid, ascorbic acid, citric acid, tartaric acid, palmic acid, lauric acid, stearic acid, palmitic acid, oleic acid, myristic acid Salts such as lauryl sulfate, naphthalinsulphonic acid, linoleic acid and linolenic acid.

Robust sustained release formulations of the drug are administered in an amount sufficient to alleviate the symptoms, treat or prevent the condition for a long period of time, such as for about 8 to about 24 hours, or for a period of about 12 to about 24 hours. The robust sustained release oral solid dosage forms described herein can be administered four times a day, three times a day, twice a day or only once a day.

Sustained release formulations of opioids are administered in an amount sufficient to relieve pain for a long period of time, such as for about 8 to about 24 hours, or for a period of about 12 to about 24 hours. The opioid sustained release oral solid dosage forms described herein may be administered four times a day, three times a day, twice a day or only once a day.

The therapeutically effective amount of the drug is an amount sufficient to eliminate or alleviate the symptoms of the condition (eg, reduce pain as compared to pain seen before administration of the opioid sustained release formulation).

The drug may be present in the composition in an amount of about 0.5 to 1000 mg, in an amount of about 1 to about 800 mg, in an amount of about 1 to about 200 mg, or in an amount of about 1 to about 100 mg.

2. Effect of Particle Size on the Robustness of Sustained-Release Formulations

It has been unexpectedly found that the particle size of hydrophilic gums, such as xanthan gum, affects the dissolution properties of sustained release formulations, and solid dosage forms comprising sustained release formulations, affecting their robustness. It is not known until now to discover the quality-by-design principle and to understand how it applies to the dissolution profile of long-term release formulations of drugs (such as opioids).

In particular, the particle size of the hydrophilic gum has been found to affect the robustness of the ethanol / ethylcellulose granulation formulation. For example, ethanol / ethylcellulose granulation formulations comprising xanthan gum as hydrophilic gums are robust when at least about 30% of the particles have a diameter smaller than 53 microns. For different hydrophilic gums, some of these may be less or larger, for example about 20 to 80%, about 40 to 60% or about 50%. In addition, when hydrophilic gum particles are screened through different mesh filters, the size distribution of the hydrophilic gums required to produce robust sustained release formulations may be different. The robustness of the sustained release formulations described herein is likely due to the combination of particle size distribution and selection of hydrophilic gums. In general, the coarser the hydrophilic gum, the larger some small particles are needed for the robust formulation. Similarly, the finer the hydrophilic gum, the smaller some of the small particles are needed for the robust formulation. In some cases, a formulation may be desired that comprises more than% of hydrophilic gums in an amount that makes the formulation robust. If the hydrophilic gum is xanthan gum, the formulation may comprise more than 30% xanthan gum particles smaller than 53 microns, such as about 40%, about 50% or about 60%.

Without wishing to be bound by any theory, the hydrophilic properties of certain hydrophilic gums (such as xanthan gum) are due to the initial hydration of the sustained release formulation and the solid dosage form, in one embodiment they are drug, one or more heteropolysaccharide gums, and one or more. Homologous polysaccharide gums, and in other embodiments includes one or more crosslinking compounds selected from drugs, one or more heterologous polysaccharide gums and monovalent cations, polyvalent cations and salts.

The integrity of sustained release formulations and solid form formulations, including hydrophilic gums such as xanthan gum, has also been found to be sensitive to the method used to granulate formulations comprising xanthan gum particles.

When the granulation method chosen is granulation using non-aqueous solvents such as alcohols, glycerol, propylene glycol or other non-aqueous solvents, the particle size of xanthan gum is substantial to the hydration and integrity of the granulated sustained release formulation and the solid dosage form. Will work.

Rapid hydration of xanthan gum in cold water is due to the integrity of the non-water granulated sustained release formulations and finished solid formulations described herein. The rate of hydration of xanthan gum was found to depend on the particle size of the xanthan gum. Small diameter xanthan gum particles will hydrate, for example, faster than larger diameter xanthan gum particles. Thus, non-aqueous granulated sustained release formulations and solid dosage forms comprising xanthan gum particles with small average and / or medium diameters are granulated sustained release formulations and solid phase comprising xanthan gum particles with large average and / or medium diameters. It will hydrate faster and be more robust than formulation.

In some embodiments, granulation using a non-aqueous solvent may be used in an amount effective to slow hydration of the formulation when exposed to environmental fluids (eg, copolymers of alkylcellulose, acrylic acid and methacrylic acid esters, waxes, Shellac, zein, hydrogenated vegetable oil and mixtures of any of the foregoing).

For example, when the granulation method chosen is granulation using ethanol and ethylcellulose, the size of the xanthan gum particles affects the hydration properties and integrity of the granulated sustained release formulation and the solid dosage form.

If the granulation method chosen is wet granulation with water or any other aqueous solution, the water can be used to perform hydration from the aqueous solution, and the xanthan gum particle size is less or negligible for the hydration of the solid dosage form. It can have only beneficial or even nonexistent effects. Based on poor cold water solubility, certain homopolysaccharide gums, such as locust bean gum, are not expected to affect the initial hydration of sustained release formulations and solid dosage forms. Thus, the average and / or median particle size of these homopolysaccharide gums does not affect the hydration properties and integrity of sustained release formulations and solid dosage forms.

Particle size can be measured using any suitable method used in the art. Perhaps the most common method of measuring particle size involves particle screening through a sieve. Other exemplary methods include optical methods such as laser diffraction measurements, light microscopy, surface area measurements (eg mercury porosimetry, nitrogen gas adsorption, krypton gas adsorption). Other physical measurements can also be used to calculate particle size.

The robustness and integrity of solid dosage forms such as tablets, capsules, granules and powders can be measured using several techniques, such as dissolution profile measurements. Exemplary dissolution profile measurements include drug release measurements using USP type I, type II, III or IV dissolution devices.

3. Ethanol Effect on the Robustness of Sustained-Release Formulations

It has been found that the sustained release formulations described herein retain their sustained solubility properties in the presence of ethanol.

Without wishing to be bound by any theory, the physicochemical properties of hydrophilic compounds (such as xanthan gum) crosslinked by crosslinking agents (such as locust bean gum) are gum or gum-like matrices in which they together are insoluble or substantially insoluble in ethanol. To form. Such dissolution properties of the formulation may be attributed to the hydrophilic nature of the sustained release delivery system, which in one embodiment comprises at least one hydrophilic gum and at least one homopolysaccharide gum, and in other embodiments at least one hydrophilicity Gums, and one or more monovalent cations, polyvalent cations and / or salts. Small amounts of hydrophobicizing agents (such as hydrophobic polymers such as ethylcellulose) do not substantially alter the dissolution properties of the formulation in ethanol, probably because the sustained release delivery system maintains its hydrophilic properties. The properties of the drug do not seem to affect the gum or gum-like properties of the matrix so that the formulations described herein are appropriate and / or applicable to a wide range of drugs.

Several factors are believed to affect the release of the drug from the formulation in the presence of ethanol: the solubility of the drug in ethanol, the substance containing the formulation (eg, hydrophilic compounds are more resistant to ethanol than hydrophobic compounds). ), And formulations of formulations (eg tablets are more resistant to ethanol than capsules).

Additional factors that are believed to affect the release of the drug from the formulation in the presence of ethanol include the compressibility of the formulation (eg, harder tablets are more resistant to ethanol than softer tablets), tablet compositions [eg, monolithic ( monolithic) tablet compositions are less resistant to ethanol than multiparticulate particle unit formulations sealed in gelatin capsules], and the presence of a gel-like coating that is resistant to dissolution in ethanol (such as certain celluloses).

Thus, the sustained release formulations described herein can be used to prevent or substantially reduce the effect of any unwanted ethanol on the release of the drug from the formulation. Exemplary undesirable effects include dose dumping and slow release dissolution profile changes.

Alteration of the sustained-release profile can be seen in the bioavailability profile of the drug, such as, for example, an altered plasma concentration time curve after administration of the drug with or without ethanol-containing beverages. Typical variables measured are high maximum drug concentration (C _max ), an increase that can increase the safety risk of the drug, drug concentration (C _min ) at the end of the treatment period, and a decrease that can decrease the efficacy of the drug. Sustained release formulation described herein shows an increase of about 1.7 times the average C _max when taken together with 0% to 40% alcohol in comparison with alcohol. This is considered acceptable because the C _max ratio of fasted individuals to individuals who have taken the drug (with standard high-fat diets) can change from about 0.7 to about 3.5 (average C _max ratio is about 1.5). being). Therefore, taking the drug with 40% ethanol has a similar effect to taking the drug after high fat diet. Taking the drug with 20% or 4% ethanol has less effect on C _max than the high fat diet, as indicated by the average C _max ratio of about 1.2 and about 1.1, respectively.

In an exemplary scenario, an agent whose sustained profile has been altered by ethanol may release a large amount of drug, eg immediately after administration (eg, within 0-6 hours), resulting in higher C _max than intended. If the drug is toxic, higher C _max than intended can cause adverse side effects, including death. As a result of this rapid release, fewer drugs are needed for subsequent release, resulting in lower C _min than intended at the end of the treatment period (ie, immediately before administration of the subsequent dose). Lower C _min than intended may result in drug efficacy that may lead to decreased drug efficacy, or even relapse of the patient's condition.

The maximum drug concentration C _max higher than intended may be, for example, a concentration four times higher than the intended C _max . Lower C _min than intended may be, for example, a concentration less than 1/3 of the intended C _min .

At the Pharmaceutical Sciences Advisory Committee Meeting of October 26, 2005, FDA staff presented the results of pre-approval in vivo studies of known drugs. Studies have shown that taking a drug with a beverage containing 40% alcohol increases the C _max by five times and that C _max doubles when taking the same drug with a beverage containing 20% alcohol. Taking the drug with a beverage containing 5% alcohol had a lower average effect, but one or more individuals doubled C _max .

Thus, the sustained release formulations described herein can be used to increase the safety of drugs that have potentially harmful effects at high concentrations and to reduce the abuse of drugs that produce pleasure effects such as opioids. The formulations described herein can also be used to reduce or prevent harm to a patient in situations where reduced levels of the drug (such as lower than therapeutically beneficial levels) can adversely affect the patient's health. The formulations described herein may be useful for formulations of narrow therapeutic range drugs, often referred to as narrow therapeutic index drugs.

If a patient described herein is taken with an alcoholic beverage, or if the patient ingests before or after drinking an alcoholic beverage, the formulation will substantially retain its sustained release properties and will slowly release the drug from the resulting hydrophilic gel matrix. .

Since the formulations described herein do not cause dose dumping in the presence of ethanol, it is used in preparations of drugs that are at risk of being taken with ethanol, such as abuse potential drugs and drugs prescribed to alcohol and / or drug abusers, or when overdose It can be used in the preparation of drugs which cause harmful or fatal side effects. Examples of such drugs include opioids.

In addition, panic disorder (with or without accompany phobia), bipolar disorder (manic depression), acute manic or mixed episodes associated with bipolar disorder, epilepsy, migraine, attention deficit hyperactivity disorder (ADHD), depression and / or pain Patients who are treated for the same condition may be more likely to drink alcohol than regular individuals. This may be the result of a patient's desire to experience a pleasant effect in a drunken state and / or to eliminate or alleviate the symptoms of their condition, such as pain.

Because of the slow release of drugs from the formulations described herein, patients (eg drug addicts) may be readily available by abuse of conventional formulations (eg opioid formulations) by oral inhalation / ingestion or oral intake with alcoholic beverages. You may not be able to experience that pleasure. Thus, the drug formulations described herein may not be abused by the patient, or the likelihood of abuse by the patient may be significantly reduced (such as compared to conventional opioid formulations).

For example, the sustained release formulations described herein can be used to grind the solid formulation into powder, pour into 95% ethanol, dilute the resulting solution with beverage strength ethanol with water, and cope with filtration through coffee or other paper filters. Removing the substance prevents the drug from being extracted from the formulation. Ethanol content of strong liquor typically ranges from 40 to 45%. This extraction method is believed to be used by drug addicts who wish to abuse drugs from sustained release formulations such as opioids by injecting drugs extracted from the formulation.

In addition, many sustained release formulations contain relatively large amounts of drug because the drug is slowly released from the sustained release formulation over a long period of time. Sustained release formulations containing a large amount of drug are generally more harmful to the patient upon failure than immediate release formulations containing a small amount of drug. Thus, the drug formulations described herein may increase the safety of drugs that may be harmful and / or fatal at levels above the level advantageous for treatment.

4. Sustained release delivery system

Sustained release delivery systems include one or more hydrophilic compounds. In some embodiments, the hydrophilic compound is a gum, such as a heterologous polysaccharide gum, and forms a gel matrix that releases the drug at a constant rate upon exposure to liquid.

The rate of drug release from the gel matrix depends on the drug partition coefficient between the components of the gel matrix and the aqueous phase in the gastrointestinal tract. In the compositions described herein, the weight ratio of drug to hydrophilic compound is generally in the range from about 1: 0.5 to about 1:25, or from about 1: 0.5 to about 1:20. Sustained release delivery systems generally comprise a hydrophilic compound in an amount of about 20 to about 80 weight percent, in an amount of about 20 to about 60 weight percent, in an amount of about 40 to about 60 weight percent, or in an amount of about 50 weight percent Include as.

The hydrophilic compound can be any known in the art. Exemplary hydrophilic compounds include gums, cellulose ethers, acrylic resins, polyvinyl pyrrolidones, protein derived compounds, and mixtures thereof. Exemplary black heteropolysaccharide gums and homopolysaccharide gums such as xanthan, tragacanth, pectin, acacia, karaya, alginate, agar, guar, hydroxypropyl guar, carrageenan, locust bean gum and gellan gum Include. Exemplary cellulose ethers include hydroxyalkyl celluloses and carboxyalkyl celluloses such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl-cellulose, carboxy methylcellulose and mixtures thereof. Exemplary acrylic resins include polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate and methyl methacrylate. In some embodiments, the hydrophilic compound is a gum, such as a heterologous polysaccharide gum, such as xanthan gum or a derivative thereof. Derivatives of xanthan gum include, for example, diacylated xanthan gum, carboxymethyl esters of xanthan gum and propylene glycol esters of xanthan gum.

In another embodiment, the sustained release delivery system further includes one or more crosslinkers. The crosslinker may be a compound capable of crosslinking the hydrophilic compound to form a gel matrix in the presence of a liquid. Sustained release delivery systems generally comprise a crosslinker in an amount of about 0.5 to about 80 weight percent, in an amount of about 2 to about 54 weight percent, in an amount of about 20 to about 30 weight percent, or in an amount of about 25 weight percent Include.

Exemplary crosslinkers include homopolysaccharides. Exemplary homopolysaccharides include galactomannan gums such as guar gum, hydroxypropyl guar gum and locust bean gum. In some embodiments, the crosslinking agent is locust bean gum, guar gum or derivatives thereof. In another embodiment, the crosslinker is an alginic acid derivative or hydrocolloid.

When the sustained release delivery system includes at least one hydrophilic compound and at least one crosslinker, the ratio of hydrophilic compound to crosslinker is generally about 1: 9 to about 9: 1, or about 1: 3 to about 3: 1.

In some embodiments, the sustained release delivery system includes one or more cationic crosslinking compounds. In some embodiments, cationic crosslinking compounds may be used in place of or in addition to crosslinking agents. The cationic crosslinking compound can be used in an amount sufficient to crosslink the hydrophilic compound to form a gel matrix in the presence of a liquid. The cationic crosslinking compound is present in the sustained release delivery system in an amount of about 0.5 to about 30 weight percent, or about 5 to about 20 weight percent.

Exemplary cationic crosslinking compounds include monovalent metal cations, polyvalent metal cations, and inorganic salts including alkali metal and / or alkaline earth metal sulfates, chlorides, borates, bromides, citrate, acetates, lactates and mixtures thereof. For example, cationic crosslinking compounds include calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, At least one of magnesium sulfate, sodium fluoride or a mixture thereof.

When the sustained release delivery system includes at least one hydrophilic compound and at least one cationic crosslinking compound, the ratio of hydrophilic compound to cationic crosslinking compound is generally about 1: 9 to about 9: 1, or about 1: 3 to about 3: 1.

Two properties of a compound that forms a gel matrix upon exposure to a liquid (such as at least one hydrophilic compound and at least one crosslinking agent; or at least one hydrophilic compound and at least one cationic crosslinking compound) may result in rapid hydration of the compound / formulation and gel strength. High gel matrix. These two properties necessary to slow the release of the gel matrix are maximized by certain combinations of compounds (such as at least one hydrophilic compound and at least one crosslinking agent; or at least one hydrophilic compound and at least one cationic crosslinking compound). For example, hydrophilic compounds (such as xanthan gum) have good water-wicking properties that provide fast hydration. Thereby the combination of materials capable of crosslinking the rigid helical structure of the hydrophilic compound with the hydrophilic compound (such as a crosslinking agent and / or cationic crosslinking compound) synergistically results in a higher viscosity (ie higher gel strength than expected) of the gel matrix. ).

In some embodiments, the sustained release delivery system further comprises one or more pharmaceutical diluents known in the art. Exemplary pharmaceutical diluents include monosaccharides, disaccharides, polyhydric alcohols and mixtures thereof such as starch, lactose, dextrose, sucrose, microcrystalline cellulose, sorbitol, xylitol, fructose and mixtures thereof. In another embodiment, the pharmaceutical diluent is water soluble, such as lactose, dextrose, sucrose or mixtures thereof. The ratio of pharmaceutical diluent to hydrophilic compound is generally about 1: 8 to about 8: 1, or about 1: 3 to about 3: 1. Sustained release delivery systems generally include one or more pharmaceutical diluents in an amount of about 20 to about 80 weight percent, such as about 35 weight percent. In another embodiment, the sustained release delivery system includes one or more pharmaceutical diluents in an amount of about 40 to about 80 weight percent.

In some embodiments, the sustained release delivery system further includes one or more hydrophobic polymers. The hydrophobic polymer can be used in an amount sufficient to slow the hydration of the hydrophilic compound without grinding the hydrophilic compound. For example, the hydrophobic polymer may be present in the sustained release delivery system in an amount of about 0.5 to about 20 weight percent, in an amount of about 2 to about 10 weight percent, in an amount of about 3 to about 7 weight percent, or in an amount of about 5 weight percent May exist.

Exemplary hydrophobic polymers include alkyl cellulose (such as C _1-6 alkyl cellulose, carboxymethylcellulose), other hydrophobic cellulose materials or compounds (such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate), polyvinyl acetate polymers (such as polyvinyl acetate Phthalates), polymers or copolymers derived from acrylic acid and / or methacrylic acid esters, zein, waxes, shellac, hydrogenated vegetable oils and mixtures thereof. The hydrophobic polymer can be for example methyl cellulose, ethyl cellulose or propyl cellulose.

The composition described herein comprises at least one wetting agent (such as polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acid from castor oil, polyethoxylated fatty acid from hydrogenated castor oil), It may further be mixed with a lubricant (such as magnesium stearate), one or more buffers, one or more colorants and / or other conventional ingredients.

In some embodiments, the robust sustained release preparations comprising the drug are solid dosage forms, such as orally administrable solid dosage forms, such as tablets, capsules comprising a plurality of granules, sublingual tablets, powders or granules. In some embodiments, the orally administrable solid dosage form is a tablet. Tablets optionally include enteric coatings or hydrophobic coatings.

5. Robust Sustained Release Formulations Containing Oxymorphone

In one embodiment, the robust sustained release formulations described herein comprise an analgesic effective amount of oxymorphone or a pharmaceutically acceptable salt thereof.

The administration of oxymorphone is often hindered by the very low bioavailability of the oral immediate release preparation of oxymorphone, which requires an administration frequency every four hours. The bioavailability of the robust sustained release formulations described herein is sufficiently high that the robust sustained release formulations can be used to treat patients suffering from pain with only one or two administrations per day.

Robust sustained release formulations of oxymorphone are administered in an amount sufficient to relieve pain for a long period of time, such as for a period of 8 to about 24 hours, or for a period of about 12 to about 24 hours.

The oxymorphone sustained release oral solid dosage forms described herein may be administered four times a day, three times a day, twice a day or once a day.

In certain embodiments, upon oral ingestion of a robust sustained release formulation comprising oxymorphone and contact with the gastrointestinal fluid, the robust sustained release formulation swells and gels to form a hydrophilic gel matrix from which oxymorphone is released. Swelling of the gel matrix results in a decrease in the bulk density of the formulation and provides the buoyancy needed to float the gel matrix over the stomach contents, thus delivering oxymorphone slowly. Hydrophilic matrices whose size depends on the size of the original formulation can swell significantly and occlude near the pyloric opening. Since oxymorphone is dispersed throughout the formulation (and consequently throughout the gel matrix), an amount of oxymorphone is released per unit time in vivo by dispersion or erosion outside the hydrophilic gel matrix. The process continues until substantially all of the oxymorphone is released while the gel matrix remains suspended in the stomach.

In certain embodiments, the chemistry of certain of the components of the formulation, such as hydrophilic compounds (such as xanthan gum), is believed to be a magnetic buffer in which the components are not substantially sensitive to the solubility of oxymorphone and, depending on the length of the gastrointestinal tract, Is such a chemistry to change. In addition, the chemistry of the components is believed to be similar to certain known muco-adhesive materials such as polycarbophil. Mucoadhesive properties are desirable for ball delivery systems. Thus, robust sustained release formulations may weakly interact with mucin in the gastrointestinal tract, providing another mode in which a constant rate of delivery of oxymorphone is achieved.

In one embodiment, the robust sustained release formulations described herein, as measured by USP Procedure Drug Release USP 23 (incorporated herein by reference in its entirety), contain about 15% to about 50% by weight of oxymor In vitro dissolution rates of the phone, about 45 to about 80 weight percent oxymorphone after 4 hours, and at least about 80 weight percent oxymorphone after 10 hours. The in vitro and in vivo release properties of the robust sustained release formulations described herein can be altered using different plasticizers and using a mixture of one or more different water insoluble and / or water soluble compounds, providing a release modifying compound for the coating. And / or vary the thickness of the sustained release film, such as by providing a passage through the coating.

Some embodiments include about 1 to about 200 mg of oxymorphone hydrochloride, or about 5 to about 80 mg oxymorphone hydrochloride; And a sustained release solid dosage form comprising about 80 to about 200 mg of a sustained release delivery system, or about 120 to about 200 mg of a sustained release delivery system, or about 160 mg of a sustained release delivery system. The system comprises about 8.3 to about 41.7% locust bean gum, or about 25% locust bean gum; From about 8.3 to about 41.7% xanthan gum having at least about 30% of particles less than about 53 microns in diameter, or about 25% of xanthan gum having a diameter of at least about 30% of the particles less than about 53 microns; About 20 to about 55% dextrose, or about 35% dextrose; About 5 to about 20% calcium sulfate dihydrate, or about 10% calcium sulfate dihydrate; And about 2-10% ethyl cellulose or about 5% ethyl cellulose.

Other embodiments include about 1 to about 200 mg of oxymorphone hydrochloride, or about 5 to about 80 mg oxymorphone hydrochloride; And a sustained release solid dosage form comprising about 80 to about 200 mg of a sustained release delivery system, or about 120 to about 200 mg of a sustained release delivery system, or about 160 mg of a sustained release delivery system. The system comprises about 8.3 to about 41.7% locust bean gum, or about 25% locust bean gum; From about 8.3 to about 41.7% xanthan gum (at least about 30% of the xanthan gum particles can pass through a # 270 mesh sieve), or about 25% of xanthan gum (at least 30% of its particles are # 270 Can pass through a mesh sieve); About 20 to about 55% dextrose, or about 35% dextrose; About 5 to about 20% calcium sulfate dihydrate, or about 10% calcium sulfate dihydrate; And about 2 to about 10% ethyl cellulose, or about 5% ethyl cellulose.

Some embodiments include about 1 to about 200 mg of oxymorphone hydrochloride, or about 5 to about 80 mg oxymorphone hydrochloride; And a sustained release solid dosage form comprising about 200 to about 420 mg of a sustained release delivery system, or about 300 to about 420 mg of a sustained release delivery system, or about 360 mg of a sustained release delivery system. The system comprises about 8.3 to about 41.7% locust bean gum, or about 25% locust bean gum; From about 8.3 to about 41.7% xanthan gum having at least about 30% of particles less than about 53 microns in diameter, or about 25% of xanthan gum having a diameter of at least 30% of the particles less than about 53 microns; About 20 to about 55% dextrose, or about 35% dextrose; About 5 to about 20% calcium sulfate dihydrate, or about 10% calcium sulfate dihydrate; And about 2-10% ethyl cellulose, or about 5% ethyl cellulose.

Other embodiments include about 1 to about 200 mg of oxymorphone hydrochloride, or about 5 to about 80 mg oxymorphone hydrochloride; And a sustained release solid dosage form comprising about 200 to about 420 mg of a sustained release delivery system, or about 300 to about 420 mg of a sustained release delivery system, or about 360 mg of a sustained release delivery system. The system comprises about 8.3 to about 41.7% locust bean gum, or about 25% locust bean gum; From about 8.3 to about 41.7% xanthan gum (at least about 30% of the xanthan gum particles can pass through a # 270 mesh sieve), or about 25% of xanthan gum (at least 30% of its particles are # 270 Can pass through a mesh sieve); About 20 to about 55% dextrose, or about 35% dextrose; About 5 to about 20% calcium sulfate dihydrate, or about 10% calcium sulfate dihydrate; And about 2-10% ethyl cellulose, or about 5% ethyl cellulose.

Upon oral administration to a patient, the robust sustained release formulations described herein exhibit the following in vivo properties: (a) the maximum plasma level of oxymorphone occurs within about 2 to about 6 hours after administration; (b) the duration of the oxymorphone analgesic effect is from about 8 to about 24 hours; (c) The relative oxymorphone bioavailability is about 0.5 to about 1.5 compared to the aqueous solution of oral administration of oxymorphone.

The oxymorphone composition described herein can be administered as the sole active pharmaceutical compound by the methods described herein, but it can also be used with one or more compounds known to be therapeutically effective for pain.

In one embodiment, there is provided a pharmaceutical kit comprising one or more containers filled with one or more of the robust sustained release oxymorphone formulations described herein. The kit may further comprise instructions for use and other pharmaceutical compounds known in the art to be therapeutically effective for pain.

6. Preparation of Robust Sustained-Release Formulations

The robust sustained release formulations described herein can be prepared by wet granulation methods. Solid dosage forms described herein can be prepared by direct compression of the formulation or by wet granulation of the formulation.

In some embodiments, sustained release formulations are prepared by wet granulation techniques. Wet granulation techniques, components (such as hydrophilic compounds such as xanthan gum, crosslinkers, pharmaceutical diluents, cationic crosslinking compounds, hydrophobic polymers, etc.) are mixed together and then one or more liquids (such as water, propylene glycol, glycerol, alcohols) Wet) to form a wetted mass, which is then dried. The dried mass is then ground into granules of a sustained release delivery system using conventional equipment. The sustained release delivery system is then mixed with a predetermined amount of drug and optionally one or more wetting agents, one or more lubricants, one or more buffers, one or more colorants, or other conventional ingredients to produce the granulation composition. Sustained release delivery systems and drugs can, for example, be blended with a high shear mixer. The drug may be finely and uniformly dispersed in the sustained release delivery system. An amount of granulation composition sufficient to produce a uniform batch of tablets is usually purified at compression pressure, ie, at a tablet press of a typical production scale at about 2,000 to 16,000 psi. The mixture should then not be compressed to the point where it is difficult to hydrate upon exposure to liquid. Exemplary methods for making sustained release delivery systems are disclosed in US Pat. Nos. 4,994,276, 5,128,143, 5,135,757, 5,455,046, 5,512,297, and 5,554,387, the disclosures of which are disclosed herein. Cite the entirety by reference.

When the sustained release delivery system is a non-aqueous solution such as an ethanol / ethylcellulose suspension, it was unexpectedly found that the particle size of the hydrophilic compound (such as xanthan gum) affects the robustness and integrity of the formulation and the solid dosage form.

In particular, small particles of some hydrophilic compounds (such as xanthan gum) (such as less than 53 microns in diameter) affect the robustness and integrity of sustained release formulations and solid dosage forms prepared by wet granulation with a non-aqueous solvent. . For example, when the xanthan gum used to prepare the formulation contains less than a certain portion (eg about 30%) xanthan gum small particles, the sustained release formulation has been found to be a failure. If some of the xanthan gum small particles used in the preparation of the formulation meet or exceed a certain threshold, the formulation has been found to be robust and not to fail. For example, if a critical portion of about 30% of xanthan gum particles smaller than 53 microns in diameter are met or exceeded, no change is observed in the robustness and integrity of the formulation and solid formulation (see Table 4 below).

It will be apparent to those skilled in the art that other combinations of xanthan gum particle sizes and some critical thresholds may also be used in the preparation of the robust sustained release formulations described herein. For example, if the critical portion is less than about 30%, such as from about 5 to 25%, or from about 10 to 20%, formulations comprising xanthan gum particles smaller than 45, 38, 32, 25 or 20 microns in diameter will be robust. Can be. When the critical portion is greater than about 30%, such as from about 30 to 100%, or from about 50 to 90%, formulations comprising xanthan gum particles smaller than 63, 75, 90, 106, 125 or 150 microns in diameter are robust. can do. The robustness and integrity of sustained-release formulations and solid dosage forms granulated with non-aqueous solutions can be improved by controlling the particle size distribution of hydrophilic compounds (such as xanthan gum). Control of the particle size distribution of the hydrophilic compound can be achieved by screening the hydrophilic compound (eg xanthan gum) particles, for example, through a sieve (eg # 270 mesh sieve) that allows particles smaller than a particular size (eg 53 microns in diameter) to pass through. have. Thereafter, batches, lots and combinations thereof having some of the particles having a certain size may be used with other ingredients for the production of robust sustained release formulations.

Alternatively, hydrophilic compounds (such as xanthan gum) can be prepared to have a desired particle distribution, in which case no screening or other processing is required. In addition, hydrophilic compounds having a predetermined particle size distribution (eg, average particle size, median particle size, minimum particle size, maximum particle size, or a combination thereof) can be received from external sources such as commercial manufacturers or vendors.

When the sustained release delivery system is wet granulated with water or any other aqueous solution, the particle size of the hydrophilic compound (such as xanthan gum) does not appear to affect the robustness and integrity of the sustained release formulation and the solid dosage form. (See Table 5 below).

The average particle size of the pharmaceutical formulation before tableting is about 50 to about 400 microns, or about 185 to about 265 microns. The average density of the pharmaceutical formulation is about 0.3 to about 0.8 g / ml, or about 0.5 to about 0.7 g / ml. Tablets formed from pharmaceutical formulations generally have a hardness of about 6 to about 8 kg.

When the tableting step in the preparation of a solid dosage form is carried out using wet granulation instead of direct compression, the particle size of the hydrophilic compound (such as xanthan gum) does not affect the robustness and dissolution properties of the solid dosage form.

In some embodiments, the sustained release coating on the inner core comprises one or more drugs. For example, the inner core containing the drug may be coated with a sustained release film that releases the drug at a constant rate upon exposure to the liquid.

In one embodiment, the sustained release coating comprises one or more water insoluble compounds. The water insoluble compound may be a hydrophobic polymer. The hydrophobic polymer may be the same or different from the hydrophobic polymer used in the sustained release delivery system. Exemplary hydrophobic polymers include alkyl cellulose (such as C _1-6 alkyl cellulose, carboxymethylcellulose), other hydrophobic cellulose materials or compounds (such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate), polyvinyl acetate polymers (such as polyvinyl acetate Phthalates), polymers or copolymers derived from acrylic acid and / or methacrylic acid esters, zein, waxes (alone or mixtures with fatty alcohols), shellac, hydrogenated vegetable oils and mixtures thereof. The hydrophobic polymer can be for example methyl cellulose, ethyl cellulose or propyl cellulose. Robust sustained release formulations may be coated with a water insoluble compound such that the weight gain is between about 1 and about 20 weight percent.

The sustained release coating may further comprise one or more plasticizers, such as triethyl citrate, dibutyl phthalate, propylene glycol, polyethylene glycol or mixtures thereof.

Sustained release coatings may also contain one or more water soluble compounds such as polyvinylpyrrolidone, hydroxypropylmethylcellulose or mixtures thereof. Sustained release coatings may include one or more water soluble compounds in an amount of about 1 to about 6 weight percent, such as in an amount of about 3 weight percent.

Sustained release coatings may be applied to the drug core by spraying an aqueous dispersion of the water insoluble compound onto the drug core. The drug core can be, for example, by dry or wet granulation of a mixed powder of drug and one or more binders; By coating inert beads with the drug and one or more binders; Or a granulation composition prepared by spheroidizing a mixed powder of drug and one or more spheroonizing agents. Exemplary binders include hydroxypropylmethylcellulose. Exemplary spurizing agents include microcrystalline cellulose. The inner core may be a tablet made by compressing the granules or by compressing the drug containing powder.

In another embodiment, a composition comprising one or more drugs and a sustained release delivery system as described herein is coated with a sustained release coating as described herein. In another embodiment, a composition comprising one or more drugs and a sustained release delivery system, as described herein, is coated with a hydrophobic polymer as described herein. In another embodiment, a composition comprising one or more drugs and a sustained release delivery system, as described herein, is prepared by enteric coatings such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid aerials. Coating with coalescing, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimelliate or mixtures thereof. In another embodiment, a composition comprising one or more drugs and a sustained release delivery system as described herein is coated with a hydrophobic polymer as described herein and further coated with an enteric coating as described herein. . In any of the embodiments described herein, a composition comprising a drug and a sustained release delivery system, as described herein, may be on or under a sustained release film, on or under a hydrophobic coating, and / or on an enteric coating or It can optionally be coated with a hydrophilic coating which can be applied below. Exemplary hydrophilic coatings include hydroxypropylmethylcellulose.

While not wishing to be bound by any theory, the sustained release formulation swells and gels to form a hydrophilic gel matrix from which the drug is released, when orally ingesting the drug sustained release formulation and bringing the formulation into contact with the gastrointestinal fluid. Swelling of the gel matrix results in a decrease in the bulk density of the formulation and provides the buoyancy needed to float the gel matrix onto the stomach contents, resulting in slow drug delivery. Hydrophilic matrices whose size depends on the size of the original formulation can swell significantly and occlude near the pyloric opening. Since the drug is dispersed throughout the formulation (and consequently throughout the gel matrix), an amount of drug can be released per unit time in vivo by dispersion or erosion outside the hydrophilic gel matrix. This phenomenon is referred to as zero order emission profile or zero order kinetics. The process continues until the gel matrix remains suspended in the stomach and substantially all of the drug is released.

While not wishing to be bound by any theory, the chemistry of certain of the components of the formulation, such as hydrophilic compounds (such as xanthan gum), is considered a magnetic buffer in which the components are not substantially sensitive to the solubility of the drug, and the gastrointestinal tract It is such a chemical that the pH changes over the length of the. In addition, the chemistry of the components is believed to be similar to certain known mucoadhesive materials such as polycarbophil. Mucoadhesive properties are desirable for ball delivery systems. Thus, robust sustained release formulations may potentially interact weakly with mucin in the gastrointestinal tract, providing another mode in which a constant rate of delivery of the drug is achieved.

The two phenomena discussed above (hydrophilic gel matrix and mucoadhesive properties) are possible mechanisms by which the robust sustained release formulations described herein can interact with odorless and gastrointestinal fluids and deliver drugs at a constant rate.

7. Usefulness of Robust Sustained Release Formulations

The robust sustained release formulations and solid dosage forms described herein are useful in the formulation of drugs that pose a risk to the patient in case of formulation failure. Solid formulations comprising the formulations and formulations described herein are useful for the provision (eg, prescription, administration) of drugs that pose a risk to the patient in case of formulation failure. Examples of such drugs include, for example, opioids such as oxymorphone.

The robust sustained release formulations and solid dosage forms described herein may be formulated and / or administered by a therapeutically effective amount of a robust sustained release formulation of the drug (eg, an opioid such as oxymorphone) to a patient capable of drinking ethanol while being treated with the drug. It is useful for treating conditions (such as pain). The therapeutically effective amount is an amount sufficient to eliminate the condition or to reduce the condition (ie, to reduce the symptoms compared to those present before the administration of the robust sustained release formulation).

The formulations and solid dosage forms described herein may be administered as the sole active pharmaceutical composition by the methods described herein, but they may also be used with one or more compounds and / or compositions known to be therapeutically effective for the condition.

There is provided a pharmaceutical kit comprising one or more of the drug formulations described herein. The pharmaceutical kit may, for example, comprise one or more containers filled with one or more of the robust sustained release formulations and / or solid dosage forms described herein. The kit may further comprise other pharmaceutical compounds known in the art as therapeutically effective for the condition, and instructions for use.

The following examples are for illustrative purposes only and are not intended to limit the claims.

Some experiments were performed using albuterol sulfate, which is similar in capacity, solubility and other physicochemical properties to opioids such as oxymorphone and oxycodone.

Example 1

Preparation of TIMERx-N® Sustained Release Delivery System Using Ethanol / Ethylcellulose Granulation

Lots of TIMERx-N® sustained release delivery systems were prepared following procedures associated with those disclosed in US Pat. Nos. 4,994,276, 5,128,143, and 5,554,387, which are incorporated herein by reference in their entirety.

A series of mesh sieves were used for particle size testing on lots of xanthan gum (a fraction zlauer from Perhoven, Austria or Cfi Kelco, Chicago, Illinois, USA). These sieves included a # 270 mesh sieve that allowed the passage of particles (fine particles) smaller than 53 microns in diameter. The weight fraction of the xanthan gum particles passing through the sieve (ie, the fraction of the fine xanthan gum) was measured. A batch with a fraction of the known fine xanthan gum particles was then prepared. TIMERx-N® was prepared by dry blending a predetermined amount of xanthan gum, locust bean gum, calcium sulfate and dextrose in a high speed mixer / granulator for 3 minutes. Ethyl cellulose was dissolved in ethyl alcohol to prepare a slurry of hydrophobic polymer (ethylcellulose). The slurry was added to the dry blended mixture, and then the material was granulated for 4 minutes while running the chopper / impeller. The granules were then dried in a fluid bed dryer so that the LOD (loss on drying) was less than 9% by weight (eg conventional LOD was ˜3-5%). The granules were then ground using a 1.0 mm (0.040 ") screen. The components of the sustained release excipients are described in Table 1 below.

TIMERx-N® Composition ingredient % Xanthan gum 2. Locust Bean Sword 3. Calcium sulfate 4. Dextrose 5. Ethyl cellulose 6. Ethyl alcohol 252510355-20 ^* * Removed during machining

Example 2

Water granulation Used TIMERx - M50A ® Sustained Release Delivery System

Lots of TIMERx-M50A® sustained release delivery systems were prepared according to procedures associated with those disclosed in US Pat. No. 5,399,358, which is hereby incorporated by reference in its entirety.

Xanthan gum batches with known fractions of fine particles were prepared according to Example 1. TIMERx-M50A® was prepared by dry blending an amount of xanthan gum, locust bean gum, calcium sulfate and mannitol in a high speed mixer / granulator for 3 minutes. Water was added to the dry blended mixture with the chopper / impeller running and the mixture was granulated for an additional 3 minutes. The granules were then dried so that the loss on drying (LOD) in the fluid bed dryer was less than about 6% by weight. Typical LOD was-3-5%. The granules were then ground using a 0.065 "screen. The components of the sustained release delivery system are described in Table 2 below.

TIMERx-M50A® Composition ingredient % Xanthan gum locus bean gum mannitol calcium sulfate 20304010-30-40 ^* * Removed during machining

Example 3

Preparation of sustained release formulations and solid dosage forms comprising varying amounts of fine xanthan gum

Sustained-release formulations were screened by # 20 mesh sieves of albuterol sulphate, ProSolv SMCC® 90 (silicated microcrystalline cellulose, JALS Parma Elphi, Paterson, NY) and TIMERx-N® or TIMERx-M50A®, respectively, through a # 20 mesh sieve Prepared. Albuterol sulfate, ProSolv SMCC® 90 and TIMERx-N® or TIMERx-M50A®, prepared according to Examples 1 and 2, respectively, were blended for 11 minutes in Patterson-Kelley P / K Blendmaster V-Blender. Pruv ™ (sodium stearyl fumarate, JRS Parma Elphi, Paterson, NY) was added to this mixture and the mixture was blended for 5 minutes. The blended granules were compressed to 224.0 mg and ˜11 Kp on a tablet press using 5/16 "round standard concave beveled edge tooling. The final tablet composition is listed in Table 3 below.

Tablet composition ingredient % Mg / tablet Albuterol sulfate TIMERx-N® or TIMERx-M50A® ProSolv SMCC® 90Pruv ™ 17.971.48.91.8 40.0160.020.04.0

Example 4

Determination of Dissolution Profile of Solid Forms Containing Various Amounts of Fine Xanthan Gum

An albuterol sulphate tablet comprising a TIMERx-N® and TIMERx-M50A® sustained release delivery system was prepared as described in Example 3. The dissolution profile of the tablets was evaluated using a USP Apparatus 2 dissolution tester in 900 mL of 5 mM potassium phosphate buffer, pH 4.5. The solution was stirred at 50 r.p.m. A series of about 1.5 ml samples were discharged at predetermined intervals for a period of up to 14 hours.

Drug release of all tablets was monitored by RP-HPLC using a Phenomenex® SecurityGuard ™ C18 (4 × 3.0 mm) guard column followed by a Water Symmetry® C18 column (4.6 × 25 mm) (or equivalent). The monitoring wavelength was set to 226 nm. The mobile phase consisted of a buffer: acetonitrile: methanol in an 85: 10: 5 v / v ratio. The buffer consisted of 1 ml of triethylamine and 1 ml of trifluoroacetic acid in 1 L of H ₂ O. The column temperature was 30 ° C. and the flow rate was set to 1.5 ml / min. To determine the percentage of drug released at each time point, the concentration of the sample taken at that time point was compared with that of the standard solution. Standard solution by dissolving 45 mg of albuterol sulphate in 100 ml of 50 mM potassium phosphate buffer (pH 4.5) followed by 5 ml of this solution and diluting it to 50 ml with additional 50 mM potassium phosphate buffer (pH 4.5). Was prepared.

The results of dissolution experiments using tablets made with alcohol / ethylcellulose granulation TIMERx-N® comprising xanthan gum with different particle size distributions are shown in Table 4 below.

Tablets containing 13.7% and 27.9% fine xanthan gum in ethanol / ethylcellulose granulation TIMERx-N® almost immediately released almost the entire amount of drug. This is an example of unwanted dose dumping. Tablets containing at least 31.6% fine xanthan gum were dissolved in the expected sustained manner. The data in Table 4 above suggests that there appears to be no substantial difference in dissolution profiles of formulations containing from about 31.6 to about 88.8% of fine xanthan gum particles.

The results of dissolution experiments using tablets made with water granulation TIMERx-M50A® containing xanthan gum with different particle size distributions are shown in Table 5 below.

Tablets made by direct compression of water granulation TIMERx-M50A® formulations comprising xanthan gum are not sensitive to xanthan gum particle size. The data in Table 5 above shows a substantial difference between the dissolution profiles of tablets made with xanthan gum with a particle size less than 180 microns and tablets made with xanthan gum with less than 75 microns when the xanthan gum is granulated with water in the formulation preparation process. Implies that there seems to be no.

Table 6 below shows the dissolution profiles of tablets prepared by direct compression and granulation of ethanol / ethylcellulose granulated sustained release formulations comprising different fractions of # 270 (fine) mesh xanthan gum particles.

A comparison of the dissolution profiles of TIMERx-N® containing tablets made using direct compression or wet granulation in the tableting step, if the tablets were prepared by direct compression, but not by wet granulation, Robustness seems to be sensitive to xanthan gum particle size. Ethanol / Ethylcellulose Granulation with 27.9% Fine Particles Tablets comprising TIMERx-N® had a predetermined dissolution profile when tableted using wet granulation, but not tableted using direct compression. . If the fraction of fine xanthan gum exceeds about 30%, a tablet with the desired dissolution profile was prepared by direct compression of the ethanol / ethylcellulose granulation formulation.

Example 5

Ethanol Resistance of Solid Forms Containing Various Amounts of Fine Xanthan Gum

Tablets of TIMERx-N® formulations of albuterol sulphate were prepared as described in Example 3. The dissolution profile of each formulation was measured as described in Example 4. A medium of 40% ethanol and 60% 0.1M HCl in the presence of alcohol was used as the dissolution model. 0.1 M HCl was chosen to mimic the biological environment of the upper gastrointestinal tract / stomach area where the sustained release formulations first initiate drug release.

Dissolution experiments were performed using a USP Type II dissolution apparatus according to the method described above. The results of dissolution experiments using tablets made with alcohol / ethylcellulose granulation TIMERx-N® comprising xanthan gum with different particle size distributions are shown in Table 7 below.

Tablets containing 28% fine xanthan gum in ethanol / ethylcellulose granulation TIMERx-N® almost immediately released almost all of the drug. This is an example of unwanted dose dumping. Tablets containing at least 35% fine xanthan gum were dissolved in the expected sustained manner. The data in Table 7 shows that from about 35% to about 86% fine xanthan gum particles, although formulations containing about 86% fine xanthan gum particles dissolve slightly slower in 40% ethanol solution than standard buffer It appears that there is no substantial difference in the dissolution profile of the containing formulation.

Thus, formulations containing at least about 30% fine xanthan gum exhibit robust dissolution properties and dissolve in a sustained manner in the presence and absence of beverage strength ethanol.

Example 6

Preparation of Robust Sustained Release Oxymorphone Formulations and Solid Forms

A controlled release delivery system was prepared by dry blending xanthan gum, locust bean gum, calcium sulfate dihydrate and dextrose for several minutes in a high speed mixer / granulator. Ethyl cellulose was mixed with alcohol to prepare a slurry. The slurry was added to the dry blended mixture with the chopper / impeller running and granulated for several minutes. The granules were then dried so that the LOD (loss on drying) was less than about 10% by weight. The granules were then ground using the screen. The relative amounts of the components used to make the sustained release delivery system are listed in Table 8A below.

Excipient % Of formulation Locust bean gum, FCC 25.0 Xanthan Gum, NF 25.0 Dextrose, USP 35.0 Calcium Sulfate Dihydrate, NF 10.0 Ethyl Cellulose, NF 5.0 Alcohol, SD3A (anhydrous) 10 gun 100.0

Tablets containing 40 mg of oxymorphone hydrochloride were prepared using the controlled release delivery system shown in Table 8A above. The amount of refined sugar component is shown in Table 8B below.

ingredient Refined sugar amount (mg) Oxymorphone HCl, USP (mg) 40 TIMERx-N® sustained release delivery system 160 Silicified microcrystalline cellulose, N.F. 20 Sodium stearyl fumarate, N.F. 2 Total theoretical weight of uncoated drug product 222 Methylparaben 0.08140 Opadry (colored) 8.88 Opadray (transparent) 1.11 Total theoretical weight of final drug product (coated) 232.07

Example 7

Extraction Resistance of Powdered Sustained Release Oxymorphone Tablets

Tablets of TIMERx-N® sustained release formulations containing 40 mg of oxymorphone were tested for abuse by the intravenous route of administration. Humans, such as drug addicts who want to abuse the agent, may attempt to inject the resulting solution by extracting the opioid from the tablet.

Tablets of TIMERx-N® sustained release formulations containing 40 mg of oxymorphone were prepared according to the procedure of Example 6 and ground to a powder. In the water extraction test, the resulting powder was dispersed in 30 ml of water and stirred for 5 seconds. In the 95% ethanol / water extraction test, the resulting powder was dispersed in 15 mL of 95% ethanol, stirred for 5 seconds and then diluted with an additional 15 mL of water. In a 95% ethanol extraction test, the resulting powder was dispersed in 30 ml of 95% ethanol and stirred for 5 seconds. In each test, the resulting solution was left for 15 minutes before filtering through a paper filter. Oxymorphone recovery from the filtered solution was measured using HPLC at 40 ° C. using a Zorbax® XDB-C18 column and a UV detector set to 230 nm. The recovery of oxymorphone from each test is shown in Table 9 below.

refine Volume recovered after extraction in% water 95% ethanol / water 95% ethanol 123 3.33.83.3 14.813.311.3 87.385.382.5 Average 3.5 13.0 85.0

Sustained-release formulations containing 40 mg of oxymorphone formulated with TIMERx-N® made of xanthan gum, wherein at least 30% of the particles could pass through a # 270 mesh sieve, were powdered and extracted with water, 15 After 3 minutes, about 3-4% of oxymorphone was released into water. To mimic abuse by dropping tablets into 95% ethanol and diluting them to edible concentrations, the powdered tablets were first suspended in 95% ethanol for 5 seconds and then diluted with water to provide a 47.5% ethanol solution. . In this experiment, about 11-15% of oxymorphone was released in water / ethanol solution after 15 minutes. Accordingly, powdered 40 mg oxymorphone tablets formulated with TIMERx-N® made with xanthan gum, which can pass through # 270 mesh sieve, where at least 30% of the particles can pass through, extract in one or more possible abuse scenarios. Was resistant to.

Example 8

Dissolution Profile of Sustained-Release Oxymorphone Tablets in the Presence of Drink Strength Ethanol

Sustained release 40 mg oxymorphone tablets were prepared as described in Example 6. Dissolution testing was performed on a set of 12 tablets in 500 ml of 0.1N HCl and ethanol / 0.1N HCl solution at 4%, 20% and 40% ethanol concentrations. Oxymorphone release was measured by HPLC as described above.

The tablets remained intact after dissolution testing in all media. The average concentration of oxymorphone released is shown in Table 10A below. Similarity factor (f ₂ ) for ethanol dissolution media for 0.1 N HCl media was calculated using standard methods, suggesting that the drug release rate is inversely correlated with the amount of ethanol in the dissolution medium. Increasing the ethanol content of the dissolution medium moderately reduced the rate of drug release.

The results of the dissolution test are summarized in Table 10A below.

The presence of up to 40% ethanol did not significantly affect the dissolution profile of the sustained release 40 mg oxymorphone tablets. The presence of 4% ethanol had a non-significant effect on the dissolution profile of the 40 mg sustained release oxymorphone tablets compared to its dissolution profile in the absence of ethanol. Oxymorphone release was inversely correlated with the amount of ethanol in the dissolution medium. The presence of 20% and 40% ethanol in the dissolution medium slowed the release of oxymorphone, while oxymorphone was still released in a controlled manner. No dose dumping was observed at ethanol concentrations between 0% and 40%. Thus, tablets comprising sustained release formulations described herein released oxymorphone in a controlled manner in the presence of at least 40% or less ethanol.

Similarity Factor (f ₂ ) for Dissolution Profile of 40 mg Oxymorphone Sustained-Release Formulation in 0.1N HCl and Ethanol Solution medium 4% ethanol 20% ethanol 40% ethanol Figures relative to 0.1 N HCl 97 60 45

Similarity factors for ethanol containing media relative to 0.1 N HCl media (0% ethanol) were 97, 60 and 45 for 4%, 20% and 40% ethanol solutions, respectively. Thus, oxymorphone tablets are resistant to beverage strength concentrations of ethanol and do not cause dose dumping in the presence of at least 40% or less ethanol.

Example 9

Sustained release Oxymorphone From tablets Oxymorphone Effect of Ethanol on Bioavailability

Healthy volunteers were used in the study to evaluate the pharmacokinetics of oxymorphone 40 mg sustained-release tablet when co-administered with 240 ml of 40%, 20%, 4% and 0% (water) ethanol.

The study design was performed on 28 subjects with randomization, open label, single dose, 4 cycle crossover. To block the opioid effect of oxymorphone, naltrexone HCl (50 mg) was administered about 12 and 2 hours prior to each oxymorphone administration and again 12 hours after administration. Subjects were fasted overnight for at least 8 hours prior to dosing. Unlimited water was provided except 1 hour before dosing and 1 hour after dosing. Standard meals were given 4 and 10 hours after dosing.

Oxymorphone 40 mg sustained-release tablets were administered for each of the four cases with 240 ml of A) 40% ethanol, B) 20% ethanol, C) 4% ethanol or D) 0% ethanol. Continuous blood samples were obtained 0-48 hours after administration. Oxymorphone was assayed for plasma samples. Pharmacokinetic parameters for oxymorphone were defined using non-differential methods for data evaluation. Point estimates and natural 90% confidence intervals (CI) for the natural logarithmic strains C _max , AUC ₀ _-t and AUC ₀ _- _inf were calculated using the least square method (LSMean). Any treatment in which the subject vomited during the dosing interval (0-12 hours) was excluded from the primary pharmacokinetic analysis.

Thirty subjects were enrolled in the study. Twenty-five subjects completed the study, which means that they received all four treatments. Subjects vomiting within the dosing interval (0-12 hours) had to exclude treatment from pharmacokinetic analysis. There were 10 individuals vomiting between 0 and 12 hours for Treatment A (40% ethanol) and 5 individuals vomiting between 0 and 12 hours for Treatment B (20% ethanol). No subjects vomited for Treatment C (4% ethanol) or D (0% ethanol). Mean plasma concentration-time data for each treatment except individual data from the treatment when the subject vomited was shown in Table 11 below.

Statistical analysis of pharmacokinetic parameters is presented in Table 12 below.

The geometric mean ratio (GMR) and 90% CI for these treatments in which the subject completed the study without vomiting between 0 and 12 hours are shown in Table 13 below.

Average plasma concentration-time data in Table 11 shows that 40% and 20% ethanol treatment produced higher plasma concentrations during the first 4-6 hours compared to 0% ethanol treatment. 4% ethanol treatment Average plasma concentrations were similar to those for 0% ethanol treatment. All data were similar to 16-48 hours after dosing. Secondary peaks were observed at 5 hours for 4% and 0% ethanol treatment and at 12 hours for all 4 treatments. 40% ethanol treatment mean plasma concentrations were higher than 0%, 4% or 20% at 0.5-6 hours, but then the concentrations were decreased and lower than the other three treatments at 8-12 hours. C _max was the only pharmacokinetic variable that appeared to be directly related to ethanol treatment (Table 12). From the ratios shown in Table 13, it can be seen that the increase in C _max is 70%, 31% and 7% for 40% ethanol, 20% ethanol and 4% ethanol treatment, respectively, compared to 0% ethanol treatment. Changes in AUC _0-t and AUC _0-inf ranged from 1 to 13% for ethanol treatment compared to 0% ethanol (Table 13). In addition to C _max , no significant differences in pharmacokinetic variables were observed between the various treatments.

Analysis of all individuals with or without vomiting is presented in Tables 14 and 15 below. Mean plasma concentration-time data for each treatment without vomit are shown in Table 14 below.

The mean plasma concentration-time profile (Table 14), which did not exclude the vomiting treatment (n = 25), showed 40% ethanol treatment with a second peak at 5 hours, which is shown in Table 11 showing only 15 individuals. It wasn't obvious. 20% ethanol treatment (n = 25) appeared similar to Table 11 showing 20 individuals. 4% and 0% ethanol treatment represented the same sample of the subject as in Table 11. As already pointed out in Table 12, C _max was only a pharmacokinetic variable that appears to be directly related to ethanol treatment (Table 15).

The GMR data shown in Table 16 show that the C _max increase compared to 0% ethanol treatment is 62%, 15% and 8% for 40% ethanol, 20% ethanol and 4% ethanol treatment, respectively. Changes in the AUC ₀ _-t and AUC _0-inf was -10 to 7% range for ethanol treatment compared to the 0% ethanol. 40% and 20% C _max , AUC ₀ _-t and AUC ₀ _- _inf increases were lower than when including the vomiting subjects.

Example 10

40 mg sustained release jade Cymorphone Tablets and 4 × 10 mg Oxymorphone Effect of food on bioavailability of rapid release

Studies were conducted in healthy volunteers to determine the effect of food on the bioavailability of sustained release 40 mg oxymorphone tablets and oxymorphone rapid release tablets (4 × 10 mg). The study design was performed on 28 subjects with randomization, open label, single dose, 4 cycle crossover. 40 mg oxymorphone sustained-release tablets and 4 × 10 mg oxymorphone rapid release tablets were evaluated under food fed and fasting conditions. To block the opioid effect of oxymorphone, naltrexone HCl (50 mg) was administered about 12 hours before each oxymorphone dose. Subjects fasted overnight at least 8 hours prior to dosing. For food intake treatment, subjects were given a high fat breakfast and administered 10 minutes after breakfast completion. Each dose was administered with 240 ml of water. Subjects were not allowed any other food until 4 hours after dosing. Continuous blood samples were obtained 0-72 hours after administration. Oxymorphone was assayed for plasma samples. Pharmacokinetic parameters for oxymorphone were determined using a non-differential method. Point estimates and 90% CI for the natural logarithmic strains C _max , AUC ₀ _-t and AUC ₀ _- _inf were calculated using LSMean.

25 individuals completed the study. Mean plasma concentration-time data for fasting and food intake treatment for sustained-release tablets are shown in Table 17 below.

As shown in Table 17 above, the food intake treatment produced higher plasma oxymorphone concentrations in the first 8 hours than the fasting treatment. Mean plasma concentrations for both treatments were similar 10 to 48 hours after administration. Secondary peaks were observed at 5 hours for fasting treatment and at 12 hours for both treatments. Mean plasma oxymorphone concentration-time data, or fasting or food intake treatment for immediate release, are shown in Table 18 below. Food intake treatment produced higher plasma concentrations in the first 10 hours than fasting therapy. Mean plasma concentrations for both treatments were similar after 12 to 48 hours of administration. Secondary peaks were seen at 12 hours for fasting and food intake treatment.

The mean plasma oxymorphone concentration-time profile for food intake and fasting treatment for immediate release oxymorphone tablets (4 × 10 mg) is shown in Table 18 below.

Food intake treatment with 4 × 10 mg immediate release oxymorphone tablets produced higher plasma oxymorphone concentrations in the first 10 hours than fasting therapy. Mean plasma oxymorphone concentrations for both treatments were similar after 12 to 48 hours of administration. Secondary peaks were observed at 12 hours for fasting and food intake treatment. C _max was increased for both sustained and rapid release in the presence of food, and AUC was increased by food treatment for rapid release (Table 19). From the GMR data (Table 20 below), it can be seen that the food increased C _max by 51% and 38% for slow release and rapid release, respectively, compared to administration under fasting conditions. Food increased AUC ₀ _-t and AUC ₀ _- _inf by 43% and 38%, respectively, for immediate release. For sustained-release tablets administered with food, the AUC _0- _t and AUC ₀ _- _inf increases were less than 10% and 90% CI was within 80-125%.

From the GMR data (Table 20), it can be seen that when compared to administration under fasting conditions, food increased C _max by 51% and 38% for slow- and slow-release tablets, respectively. Food increased AUC ₀ _-t and AUC ₀ _- _inf by 43% and 38%, respectively, for immediate release. For sustained-release tablets, the increase in AUC _0-t and AUC ₀ _- _inf was minimal with food intake, and 90% CI was 80-125%.

In vitro studies (Example 8) showed that 40% ethanol did not increase the dissolution rate of oxymorphone 40 mg sustained-release tablets. These data suggest that the formulation drug release matrix is not compensated by the beverage strength ethanol concentration and that immature release of oxymorphone does not occur when exposed to ethanol at a concentration of 40% or less. However, data from human ethanol studies showed that co-administration of 240 ml of 40% ethanol and less than 20% ethanol had no apparent effect on AUC, while increasing C _max of oxymorphone from 40 mg sustained-release tablets. Proved (Tables 12 and 13). In vitro and in vivo results suggest that beverage strength ethanol does not directly affect the integrity of the formulation, but may cause other effect (s) that may obviously increase the rate of absorption of oxymorphone.

Interestingly, an increase in the rate of absorption of oxymorphone was also observed when oxymorphone 40 mg sustained release tablets were administered after the high fat diet (Tables 19 and 20). The degree of increase and the plasma concentration-time course are similar to when oxymorphone tablets formulated with TIMERx-N® are administered after high fat diet or with ethanol (see Tables 11 and 16). This observation suggests that there may be a common mechanism between food and ethanol that increases C _max . The pharmacokinetic parameters measured after administration of oxymorphone rapid release and oral solution were also affected when taken after high fat diet (Tables 19 and 20). In addition to the increase in C _max , the AUC for rapid release also increased, unlike the results for slow-release tablets, where AUC did not change significantly after ethanol or food intake. This difference suggests that sustained-release tablets do not release oxymorphone at an accelerated rate in the presence of ethanol, but this is not just the level of oxymorphone dissolved in the gastrointestinal tract affected by food or ethanol.

In vitro results suggest no oxymorphone sustained release formulation-ethanol interaction. Results from the bioavailability studies demonstrated that pharmacokinetic interactions exist when 40 mg oxymorphone sustained-release tablets are ingested with 240 ml of 40% ethanol, indicating an excess intake of ethanol. The increase is similar to that observed with oxymorphone sustained release after standardized high fat diet. The underlying mechanism of this phenomenon is currently unclear.

Based on the evaluation of in vitro and initial in vivo data, the observed increase in C _max is not caused by premature release of oxymorphone due to disruption of the sustained release delivery system (ie, dose dumping), but instead with the formulation. Is believed to be caused by an independent apparent absorption rate increase.

Since the properties of the sustained-release system affect the dissolution properties of the formulation to a significantly greater extent than the properties of the drug in the formulation, similar results are expected to be obtained with other drugs. Ethanol dissolution testing is believed to be a standard procedure in the development of new sustained release products.

Patents, patent applications, and publications mentioned herein are hereby incorporated by reference in their entirety.

In addition to those described herein, it will be apparent to those skilled in the art from the above description that various modifications of the invention are possible. Such changes are intended to be included in the claims.

Claims

A method of alleviating pain, comprising administering to a patient a sustained release oxymorphone formulation comprising a sustained release delivery system and about 5 to about 80 mg of oxymorphone. After oral administration of a single dose to a patient with from about 200% to about 300 ml of about 40% ethanol, the formulation provides a secondary peak of blood oxymorphone concentration about 12 hours after administration, and the formulation is about 12 hours after administration A method of providing analgesic to a patient during an abnormality.

The method of claim 1, wherein the sustained release oxymorphone formulation comprises about 20 to about 60 mg of oxymorphone.

The method of claim 2, wherein the sustained release oxymorphone formulation comprises about 40 mg of oxymorphone.

The method of claim 1, wherein the sustained release oxymorphone formulation is a solid dosage form.

The method of claim 4, wherein the solid dosage form is selected from the group consisting of tablets, capsules, granules and powders.

The method of claim 5, wherein the solid dosage form is a tablet.

A method of alleviating pain, comprising administering a sustained release delivery system and a sustained release oxymorphone formulation comprising about 5 to about 80 mg of oxymorphone to a patient, wherein after oral administration of a single dose to the patient, It provides a maximum blood concentration of oxymorphone of less than about 5 times when ingested with about 200% to about 300 ml of ethanol up to about 40% compared to when ingested without ethanol, and the formulation is administered to the patient for at least 12 hours after administration. How to provide analgesic action.

8. The method of claim 7, wherein the maximum blood concentration of oxymorphone is less than about 2.5 times higher when ingested with about 200 to about 300 ml of ethanol of up to about 40% compared to when ingested without ethanol.

8. The method of claim 7, wherein the sustained release oxymorphone formulation comprises about 20 to about 60 mg of oxymorphone.

The method of claim 9, wherein the sustained release oxymorphone formulation comprises about 40 mg of oxymorphone.

A method of alleviating pain, comprising administering a sustained release delivery system and a sustained release oxymorphone formulation comprising about 5 to about 80 mg of oxymorphone to a patient, wherein the formulation is provided after oral administration of a single dose to the patient. Is a ratio of the maximum blood concentration of oxymorphone when ingested with about 200% to about 300 ml of ethanol, and the maximum blood concentration of oxymorphone when ingested after high-fat without ethanol, from about 0.5 to about 2. Providing analgesic action to the patient for at least about 12 hours.

The ratio of the maximum blood concentration of oxymorphone when ingested with about 200% to about 300 ml of the formulation with about 40% ethanol to about 0.8% of the maximum blood concentration of oxymorphone when ingested after high-fat diet without ethanol. To about 1.5.

The method of claim 11, wherein the sustained release oxymorphone formulation comprises about 20 to about 60 mg of oxymorphone.

The method of claim 13, wherein the sustained release oxymorphone formulation comprises about 40 mg of oxymorphone.

A method for alleviating pain, comprising administering a sustained release delivery system and a sustained release oxymorphone formulation comprising about 5 to about 80 mg of oxymorphone to about 4 to about 40% ethanol about 200 to about After oral administration of a single dose to a patient with 300 ml, the formulation provides a maximum blood concentration of oxymorphone of about 0.1 to about 15 ng / ml, and the formulation provides analgesic action to the patient for at least about 12 hours after administration. How to provide.

The method of claim 15, wherein the sustained release oxymorphone formulation provides a maximum blood concentration of oxymorphone of about 0.5 to about 7.5 ng / ml.

The method of claim 16, wherein the sustained release oxymorphone formulation provides a maximum blood concentration of oxymorphone of about 1 to about 4 ng / ml.

The method of claim 15, wherein the sustained release oxymorphone formulation comprises about 10 to about 20 mg of oxymorphone and the formulation provides a maximum blood concentration of oxymorphone of about 0.3 to about 3.2 ng / ml. Way.

The method of claim 18, wherein the formulation provides a maximum blood concentration of oxymorphone of about 0.4 to about 2.8 ng / ml.

The method of claim 18, wherein the formulation comprises about 10 mg of oxymorphone and the formulation provides a maximum blood concentration of oxymorphone of about 0.3 to about 1.8 ng / ml.

The method of claim 20, wherein the formulation provides a maximum blood concentration of oxymorphone of about 0.5 to about 1.5 ng / ml.

The method of claim 15, wherein the formulation comprises about 20 to about 40 mg of oxymorphone and the formulation provides a maximum blood concentration of oxymorphone of about 0.5 to about 7 ng / ml.

The method of claim 22, wherein the formulation provides a maximum blood concentration of oxymorphone of about 0.9 to about 6 ng / ml.

The method of claim 22, wherein the formulation comprises about 20 mg of oxymorphone and the formulation provides a maximum blood concentration of oxymorphone of about 0.5 to about 3.2 ng / ml.

The method of claim 24, wherein the formulation provides a maximum blood concentration of oxymorphone of about 0.75 to about 2.8 ng / ml.

The method of claim 15, wherein the formulation comprises about 40 to about 80 mg of oxymorphone and the formulation provides a maximum blood concentration of oxymorphone of about 1 to about 15 ng / ml.

The method of claim 26, wherein the formulation provides a maximum blood concentration of oxymorphone of about 1.9 to about 12 ng / ml.

The method of claim 26, wherein the formulation comprises about 40 mg of oxymorphone and the formulation provides a maximum blood concentration of oxymorphone of about 1 to about 7 ng / ml.

The method of claim 28, wherein the formulation provides a maximum blood concentration of oxymorphone of about 1.4 to about 5 ng / ml.

The method of claim 26, wherein the formulation comprises about 80 mg of oxymorphone and the formulation provides a maximum blood concentration of oxymorphone of about 3.5 to about 15 ng / ml.

The method of claim 30, wherein the formulation provides a maximum blood concentration of oxymorphone of about 4 to about 13 ng / ml.

A method for alleviating pain, comprising administering a sustained release delivery system and a sustained release oxymorphone formulation comprising about 5 to about 80 mg of oxymorphone, wherein the formulation is about 4 to about 40% ethanol Providing a minimum blood concentration of at least about 0.013 ng / ml of oxymorphone at least 12 hours after oral administration of a single dose to a patient with 200 to about 300 ml, and the formulation providing analgesic action to the patient for at least about 12 hours after administration. How to provide.

The method of claim 32, wherein the formulation comprises about 5 mg of oxymorphone.

The method of claim 32, wherein the formulation comprises about 10 mg of oxymorphone.

The method of claim 32, wherein the formulation comprises about 20 mg of oxymorphone.

The method of claim 32, wherein the formulation comprises about 40 mg of oxymorphone.

The method of claim 32, wherein the formulation comprises about 80 mg of oxymorphone.

The method of claim 33, wherein the minimum blood concentration of oxymorphone is at least about 0.07 ng / ml.

The method of claim 34, wherein the minimum blood concentration of oxymorphone is at least about 0.15 ng / ml.

The method of claim 35, wherein the minimum blood concentration of oxymorphone is at least about 0.3 ng / ml.

The method of claim 36, wherein the minimum blood concentration of oxymorphone is at least about 0.6 ng / ml.

The method of claim 37, wherein the minimum blood concentration of oxymorphone is at least about 1.2 ng / ml.

43. The method of any one of claims 7-42, wherein the sustained release oxymorphone formulation is a solid dosage form.

The method of claim 43, wherein the solid dosage form is selected from the group consisting of tablets, capsules, granules, and powders.

45. The method of claim 44, wherein the solid dosage form is a tablet.