Tamper-resistant products for opioid delivery

A pharmaceutical product containing an isolated agent

Pharmaceutical product comprising a sequestered agent

Full description

Background of the invention

Pharmaceutical products are sometimes subject to abuse. For example, a given dose of analgesic may be more effective when administered non-enterally than when compared to the same dose given orally. Some formulations can be manipulated to provide an analgesic containing a controlled release analgesic, sometimes crushed by bad operators to provide an anesthetic that is available for subsequent release for oral or non-oral use.

Intestinal parenteral administration.

Opioid antagonists have been combined with certain opioid-resistant drugs to prevent non-intestinal abuse of opioid-resistant compounds in prior action. The combination of pentazocine and naloxone has been used in tablets available in the United States, commercially available as Talwin7Nx from Sanofi-Winthrop. Talwin7Nx contains a direct-release pentazocine hydrochloride J equivalent to 50 mg base and naloxone hydrochloride equivalent to 0.5 mg base. The fixed treatment compound is equal to (0.5 mg) and

Naloxone (4 mg) has been available in Germany to deal with pain since 1978 (Valoron7N,

Goedecke The specific combination of naloxone and buprenoqhine was introduced in 1991 in New Zealand (Temgesic7Nx, Reckitt & Colman) for the treatment of pain.

Purdue Pharma LP currently markets sustained release oxycodone in dosage forms containing 10, 20, 40, and 80 mg oxycodone hydrochloride under the trade name

OxyContin 0

US Patent Nos. 502660331, 505080042, 505490912 and 506560295 for enhanced release formulations of oxycodone.

US Patent No. 504,720,943 for Crane describes methods for enhancing the analgesic efficacy of an effective analgesic agent by treating drug resistance with anti-analgesic compounds.

U.S. Patent Nos. 62770384, 494.H6047 and 7H9.E637 for Kaiko and 6228.863 for Coloxy are directed to reduce abuse of the efficacy of opioid antagonist dosage forms.

RCT publication No. 15485/01: Oral opioid agonist anti-tampering compounds: directed at reducing abuse related to opioid analgesic dosage forms by including anti-tamper compounds in opioid analgesic dosage forms.

opioid analgesic dosage.

There continues to be a need in the industry for oral dosage forms containing analgesic opioids

Which reduces abuse of effectiveness.

All references mentioned here contain the following, and are incorporated by reference in their entirety.

General description of the invention

It is an object of the present invention to provide an oral dose containing an opioid antagonist that significantly inhibits the removal of an analgesic opioid antagonist.

It is an object of some embodiments of the invention to provide an oral dosage form comprising a compound of an opioid antagonist that is useful for reducing the chance of analgesic abuse. opioid agonist

It is an object of some embodiments of the invention to provide an oral dosage form comprising a pain-resistant opioid agonist compound useful in reducing abuse without affecting the sedative effects of the opioid agonist compound.

Some embodiments of the invention include configuring a dosage form that provides an effective dose of the analgesic opioid and a dose of an antagonist opioid that does not alter or does not significantly alter the analgesic efficacy of the analgesic opioid when the dosage form is administered orally. However, if the dosage form is manipulated, the opioid's analgesic component is significantly released and abuse can be prevented by interfering with the opioid's analgesic effect.

It is an object of some forms of the invention to provide an oral dosage form that contains an effective dose of the opioid agonist in a controlled form and that contains an effective dose of the opioid agonist in a controlled form that does not release all available analgesics in direct dissemination when the dosage form is manipulated.

It is an object of some forms of this invention to provide a dosage form containing analgesic opioid molecules and isolated analgesic molecules wherein the analgesic molecules and antagonist analgesic molecules are similar, for example: in appearance, texture, odor, taste, hardness, shape, size and composition and therefore the mixture cannot They are effectively distinguished from each other by one or more of these characteristics.

It is an object of some forms of this invention to provide a method of preventing misuse of an oral dosage form consisting of an opioid agonist, including the dosage form of an opioid antagonist and an analgesic which are separated, for example, not bioavailable when the dose is manipulated, but bioavailable when the dosage form is manipulated. Dosage (eg in an attempt to misuse a dose

Analgesic opioid agonist.

It is an object of some embodiments of the invention to provide a method for managing pain in human patients including an oral dose of an opioid agonist that has reduced nasal, non-intestinal, or oral abuse.

The above objectives are achieved by the present invention which is directed in part to a dosage form consisting of a majority of the particles, each of the particles consisting of the antigenic analgesic dispersed in a tissue, and a layer removed around each of the particles, wherein the tissue and layer - to isolate (prevent High prevalence) opioid analgesic in dosage form for exposure to an environmental liquid.

In some embodiments of the drug, the fabric is composed of a hydrophobic material. In certain other forms, the layer is made of hydrophobic material.

In some types of embodiments, the invention is directed to a pharmaceutical dosage form consisting of:

(a) Partial Example: an emergent particle, consisting of an antidote dipped in a primary substance

of hydrophobic 0

(b) A layer consisting of a second hydrophobic material spread around the particle, the second material consisting of from about 2% to about 30% by weight of the particle and alternatively the second material consisting of from about 5% to about 25% from about 10% to about 20%. /, from about 22% to

About 28% From about 5% to about 15% by weight of particles. In some pharmaceutical forms, the invention is directed to an oral dosage form consisting of: (a) a majority of the particles, for example the extruded particles consisting of an analgesic and antagonist dispersed in a primary hydrophobic substance and a layer consisting of a second hydrophobic substance extruded around each particle, the substance The second hydrophobic material is deposited around each particle. The second hydrophobic material consists of about 2% to about 30% of the weight of the particles. (b) A group of substances consisting of an opioid agonist spread in a third substance

hydrophobic.

(c) A capsule containing a group of opioid agonist particles and a group of two opioid antagonist molecules. Alternatively, the second hydrophobic material consists of from about 5% to about 25%, from about 10% to about 20%, from about 10% to about 25%, from around

From about 15% to about 25%, from about 22% to about 28% to about 28% or from about 5% to about 15%

of particle weight.

In some pharmaceutical embodiments, the invention is directed to a dosage form consisting of a plurality of particles constituting a first matrix of an opioid, a plurality of molecules (released molecules) constituting a second matrix of an opioid and an antagonist, and a layer arranged around the particles constituting the antagonist component of an opioid analgesic. From exposure to environmental liquid. In certain forms, the template of the opioid antibody particle is hydrophobic. In other forms, the layer of the opioid antagonist is formed to be a hydrophobic substance. In some forms, the structure of the template and layer is hydrophobic.

In certain foods, a layer around an opioid agonist containing molecules organizes to create similar-looking opioid agonist particles to actually indistinguishably form opioid agonist particles, thus, reducing the ability for a bad user to physically separate the antagonist containing the molecules from the resistant complex containing the molecules. The resistive housing layer can be a functional layer to provide controlled release or to increase controlled diffusion. Alternatively, the resistive layer can be a non-functional layer, for example a cover layer, which provides capabilities to not Uncontrolled release or spread.

In some forms the invention is directed to an oral dosage consisting of:

(a) A group of molecules form an opioid-resistant layer in a releasable form.

(b) An array of particles, for example: an extruded particle forming a matrix of hydrophobic material and an opioid analgesic dispersed in the matrix, and a layer consisting of a hydrophobic material matrix around the particles such that the tissue and layer substantially prevent the diffusion of the analgesic and the opioid analgesic when the correct dosage form is administered to the patient.

In some forms of the invention, the ratio of the amount of antibody released from the tampered dosage form to the amount of antibody released from the intact dosage form is based on the dissolution per hour of the dosage form in 7,000 mg in simulated basal fluid (SGF) using USP Type II A stirrer with a speed of 0 5 rpm at temperatures of 37°C is about 20:1 or greater, about 0 5:1 or greater, about 100:1 or greater, about 150:1 or greater, about 0 0 0 1:1 or greater.

In some forms of the invention, the percentage weight of the antigen released from the intact dosage form is based on the dissolution in 1 hour of the dosage form in 70 ml of simulated gastric fluid using a USP Type II stirrer at 0.5 rpm at 37°C. It is less than 1.0%, less than 0.5%, less than 0.2, or less than 0.1% by weight. In some embodiments of the invention, the weight percentage of the counter factor released from the intact dose is based on the dissolution in 2 hours of the dosage form in 7.00 mL of SGF similar gastric fluid using a USP Type II stirrer with a capacity of 5.0 rpm at a temperature of 37 Celsius for the highest hour, followed by a conversion to 0.09 ml SIF thereafter, is less than 0.2%, less than 0.1%, less than 5.0% or less than 5.2.0%.

In some embodiments of the invention, the percentage by weight of the antibiotic drug released from the virgin dosage form is based on dissolving in 4 hours the dosage form in 7,00,0 ml of similar gastric fluid using a USP type II stirrer with a capacity of 5,000 rpm at 37°C for the first hour, followed by Converting to 0.90 ml is then less than 2.2%, less than 5. 1% Less than 1.0% or less than 0.75%

In some forms of the invention, the percentage of antigenicity released from the virgin (intact) dosage form is based on dissolution in 1 2 hours of the dosage form in 7 0 0 gastric fluid recombinant using USP Type II at 5 0 rpm at 37 °C for the first hour. , then converted into 0 0 9 ml of gastric fluid, is: less than 3.0% less than 8. 1%, less than 1.25% or less than 0.3%.

In some variations of the invention, the weight percentage of the counterfactual of the drug released from the intact dosage form is based on dissolving in 4 2 hours of the dosage form in 7 0 0 ml of gastric fluid using a USP Type II stirrer with a 5 0 revolutions (rpm) ) at 37°C for the first hour, followed by a transition to 900 ml of SIF thereafter, which is less than 8. 4%, less than 2.5%, less than 8. 1% or less than 4. 0%

In some embodiments of the invention, the percent weight of the counteractive agent released from the intact dosage form is based on the 36-hour dissolution of the dosage form in 700 mL of similar gastric fluid using a USP Type II stirrer with a capacity of 0.5 revolutions per second at 37°C for the first hour followed by Divert 0 0 9 ml of gastric fluid after that, and the percentage is less than 7.0%, less than 6.5%, less than 3.0% or less than 1.5%.

In certain cases of the invention, the proper dosage form releases 0.1% or less of the antigen in 1 hour 2.0% or less of the antigen in 2 hours 2.2% or less of the antigen in 4 hours 3.0% or less of the antigen in 2 1 hour-8. 4% or less in 24 hours, 0.7, or less in 36 hours is based on dissolving the dosage form in 7.00 ml of gastric fluid using a USP Type II stirrer at 5.0 rpm and at 37°C per hour. The first, followed by a transition to 0 * 9 ml of liquid afterwards. In some forms of the invention the proper dosage form releases 5% or less of the antigen in 1 hour, 1.0% or less in 2 hours, 1.5% or less in 4 hours, 1.8% or less in 1 hour, 2.5% or less in 24 hours, 6.5 % or less in 36 hours. Allow the dosage form to be dissolved in 0.70 ml of gastric fluid using a type 2 stirrer at 0.5 rpm for the first hour followed by transfer to 900 ml of liquid thereafter. In some embodiments of the invention, the intact dosage form releases, 0.4 02 or so of the antigen in one hour, 0.5% or less in 2 hours. 1.0% or less in 4 hours, 1.25% or less in 12 hours, 1.8% or less in 24 hours, 3.0% or less in 36 hours is based on dissolution of the dose form in 700 mL of gastric fluid aspirated using a USP Type II device. Stir at 0.5 rpm at 37°C for the first hour, followed by transfer to 900 ml of gastric fluid thereafter.

In some forms of the invention, the virgin dosage form is released as 1. 0% or less of the counter coefficient in 1 hour, 0.25% or less in 2 hours, 0.75% or less in 4 hours 0.3% or less 2 1 hour 4. 0% or less in 24 hours, 1.5% or less in 36 hours based on dissolving form

Dose in 0 0 7 ml of gastric fluid using a USP Form II rapid stirrer

5.0 rpm at 37°C for the first hour, followed by a switch to 9.00 ml of gastric fluid thereafter.

In some embodiments of the invention, the weight percent rate of the counteractive agent released from the dosage form after manipulation based on the dissolution per hour of the dosage form in 700 ml of gastric fluid of the equivalent using a USP Type II stirrer at 0.5 rpm at a temperature of 237°C is less than 50%. , less than 40%, or less than 35%. In some embodiments of the invention, the average Cmax of the antigen supplied after administering a single dose of the incorrect dosage form to a group of patients, for the normal rate of antigen supplied after administering a single dose of the invalid dosage form to a group of patients is about 20:

1 or greater, about 50:1 or greater, about 75:1 or greater, about 1:00 or greater, about 125:1 or greater, about 150:1 or greater, or about 0 0 0 1:1 or greater These values are preferably in the steady state.

In some embodiments of the invention, the maximum antigen coefficient produced after administering a single dose of the incorrect dose to a group of patients, and the normal maximum antigen coefficient released after a single dose of an intact dosage form for patients. This rate is about 0 2:1, to about 1000 : 1, from about 1:20 to about 150:1, from about 20:1 to about 125:1, from about 20:1 to about 10:1, from about 20:1 to about 75:1, or from about 2:1 to about 50:1, in other variations, the range is from about 50:1 to about 1000:1, from about 75: 1 to about 1000:1, from about 10:1 to about

2 1:1000, from about 125:1 to about 1000:1, or from about 150:1 to about

0 0 0 1:1. These values are preferably in the steady state.

In certain embodiments of the invention the ratio of the AUC of the antibody supplied after administering a single dose of the invalid dosage form to a section of patients, to the ratio of the antibody supplied after administering a single dose of the intact drug to a section of patients is of about 20:

1 to about 1000:1, from about 20:1 to about 150:1, from about 20:1 to about 125:1, from about 20:1 to about 100:1, from about 20:1 to about 75:1 or from about 20:1 to about 50:1 In other forms, the range is from about 50:1 to about

0 0 0 1:1, from about 75:1 to about 1:1000, or from about 150:1, to about 1000:1. These values are preferably in the steady state.

In certain embodiments of the invention, the normalized Auc of the antagonist provided after administering a single dose of the manipulated dosage form to a patient population; The Auc given after administering a single dose of the correct dosage form to a patient population is about 5:1 or greater, about 25:1 or greater, about 75:1 or greater, about 0 0 1:1 or greater, about

0 5 1:1 or greater, about 0 0 2:1 or greater or about .25:1 or greater.

In some forms of the invention, the normal rate of AUC of antigen released after administering a single dose of the manipulated drug to a section of patients, while the normal rate of AUC of antigen released after administering a single dose to a section of patients with healthy bereavement was a rate of about 5: 1 to about 250:1 from about 5:1 to about

0 0 2:1 From about 5:1 to about 150:1 From about 5:1 to about 0 0 1:1 Z

|about 5:1 to about 75:1, or from about 5:1 to about 25:1, in other cases, the range extends from about 215:1 to about 25:1 from about 70:1 to about 250:1, From about 100:1, about 250:1, from about 150:1 to about 0 0 0 1:1 or from about 200:1 to about 250:1. These values are preferably in the steady state. In certain cases the invention is directed to methods of preventing analgesic abuse of the opioid agonist using certain dosage forms, whereby if the dosage is subject to tampering and is administered orally, or non-gastrointestinally, the analgesic effects of the opioid agonist are largely or completely blocked by the release of the antagonist.

In certain cases, the invention is directed to methods for treating pain by, for example, oral administration, any of the embodiments of the drug described herein constitute a pain reliever for the patient in need thereof.

In figures where the sum of the molecules of the opioid-resistant form and the group of particles that make up the opioid antagonist drug are similar, or actually difficult to distinguish from each other, the similarity and actual indistinguishability of the molecules may be due to: (1) functional or non-functional classes. functional layers. (2) Similar methods of preparation which must be layered. (3) Different methods of preparation that produce similar or virtually indistinguishable end products.

(4) Different preparation methods result in different final products which are then subject to additional working steps (eg layering).

(5) Or any other method that results in the desired characteristics (for example, appearance, texture, smell, taste, hardness, shape, size, etc.).

In some preferred embodiments, the typical diameter of the particles is from about 1.0 to about

2 1 mm, and from about 1 . 0 to about 2.5 mm, from about 0.2 to about 6 mm, from about 0.5 mm to about 3 mm, from about 0.5 mm to about 2 mm or from about 1 mm to about 2 mm.

This amount of opioid release, if found in the correct dosage form, is such that the dosage form would remain effective for pain relief.

In some instances of the present invention, the ratio of the opioid-resistant sedative to the isolated opioid antagonist compound is from about 1:1 to about 50:1 by weight preferably from about 1:1 to about 1:20 by weight; Or from about 5 1:1 to about 30:1 by weight weight ratio of

The sedative resistance to the antagonist sedative is due to the weight of the active ingredients. For example, the weight of the opioid antagonist exceeds the weight of the coating and matrix, which together serve to isolate the antagonist compound from the opioid. In certain preferred forms, the weight ratio of the moderator to the isolated counteractant is about 1:1 to about 10:1 by weight.

Oral dosage forms of the present invention comprise tablets and capsules. Oral dosage forms of the present invention may include any desired drug excipients. It is well known to those skilled in this craft. Oral dosage forms We may provide direct release of an opioid agonist and/or controlled release of a resistant opioid agonist.

Abuse-resistant dosage forms of the present invention are useful in conjunction with controlled-release forms that constitute a dose of an opioid intended to be released over a prolonged period of time. Abusive abusers may take such products and crush, grind, extract, or otherwise disintegrate the product with the intent to release the entire contents of the dosage form. For Direct Absorption Since manipulation of the dosage form of the invention results in the antagonist opioid compound becoming available for absorption, the present invention provides a means of thwarting such abuse. The invention also refers to a method of treating pain in the form of a dosage set forth herein. A method could be to provide an oral dosage form containing a resistant opioid in a releasable form and the isolated antagonist compound as described herein and administer the correct oral dosage via oral route to a mammal (eg, a human) in need of such treatment.

In certain embodiments, the invention directs to methods for preparing oral dosage forms as set forth herein. In certain embodiments, the invention constitutes a method for preparing an oral dosage form preparing to project a plurality of particles comprising an opioid antagonist dispersed into a matrix consisting of a hydrophobic material, and exposing a layer of hydrophobic material around the ejected particles. , where the layer and template serve to isolate

Antagonistic analgesic when the given dosage form is virgin. The method may consist of mixing the isolated analgesic in a releasable form (e.g., controlled release) with the opioid sedative in such a way as to achieve complementarity of the isolated analgesic. In all embodiments of the invention, the hydrophobic material of the mold may or may not be the same as the layer material

hydrophobic material layer.

Although the preferred embodiments of the invention are the opioid antagonist analgesic in a form that completely prevents release of the opioid antagonist, the invention also includes an antagonist in a form that cannot be widely released. The terms "non-extensibly" or "non-extensively releasable" refer to the analgesic, which It may be released in a small amount, as long as the amount removed does not affect, or does not significantly affect, the effectiveness of the analgesic when the dosage form is given orally to people as intended.

In isolated analgesic particles there are several possibilities according to the present invention. First, the mold is able to somewhat insulate the dwelling without the layer and the layer enhances the insulation. Secondly, the layer is able to somewhat insulate the counter housing below the mold and the mold enhances the insulation. Third, the template is capable of isolating the analgesic without the layer, the layer is unable to isolate the analgesic without the template, and the template and layer together are capable of providing a controlled release of the antagonist individually, but the template and layer together in the same dosage form isolate the antagonist). In the first and second possibilities, the mold and/or layer enhance the insulation as they are able to provide individually controlled removal of the analgesic.

In some preferred forms of the invention, a substantially ineluctable form of the analgesic is resistant to laxatives (e.g., mineral oil) used to deal with obstructed colonic passage and resistant to achlorhydric conditions. In the preferred cases of the forms of the present invention, the form that cannot be substantially released from the antagonistic opioid is attributable to thermomechanical manipulation (e.g., manipulation by crushing, shearing, stabbing, pinching and dissolving in a solution by working with heating (e.g. greater than 45°C)) of the form Oral dosage. When manipulated, the integrity of the non-releasable form of the opioid antagonist will be compromised, and the opioid antagonist will be made available for immediate elimination, thus at least partially and preferably blocking the effects of the opioid-resistant Mahdi. Thus, when the oral dosage form of the opioid antagonist is Opioids and opioid antagonists are chewed, crushed, dissolved, or heated in a solution, and given orally, nasally, or intra-intestinally, so that the analgesic and euphoric effects of the opioid are reduced or eliminated.

The present invention directs a method of reducing the potential for abuse of a muscle controlled by another muscle in an oral dosage form. The method consists of administering the drug in an oral dosage form as described herein.

The term “analgesic effectiveness” is defined for the purposes of the present invention as a satisfactory reduction or elimination of pain, with a tolerance level for side effects, as determined by the patient.

The expression "Anot blocks the analgesic effect of this muscle" for the purposes of the present invention means that the resisting muscle does not block the effects of the controlled muscle in a sufficient manner to shift the dosage form therapeutically and be less effective for the analgesic given.

The term “tampering” means manipulation by mechanical, thermal, or chemical means that alters the physical properties of the proper dosage form in order to release at least part of the muscle for more rapid or immediate release, or to make that muscle available for inappropriate administration (i.e., non-enteral parenteral administration). The dosage form can be tampered with. Sound means, by crushing, shearing, grinding, chewing, dissolving in a solvent or heating (meaning, more than 45 degrees Celsius) and any bonding from that source which accomplishes this purpose.

In certain inclusions, tampering of the dosage form may be by crushing the powder with a mortar hand. In other inclusions, tampering may be by means of an auger crusher or by using two steel spoons.

In specific applications of the mortar hand, crushing can simulate chewing. For example, 3 strokes of the mortar hand can create a smooth chew, 6 strokes give a medium chew, and 12 give a complete chew. The mortar hand can be used to crush the powder dosage form. With, that is, 24, 500, 50, or 600 strokes of the hand. In specific aspects of using a screw crusher, place the dosage form in the crusher and the screw cap rotates to crush the dosage form, then the cap is removed, the crusher is screwed onto a hard surface and the crushing is repeated.

twice.

In specific implications for the use of steel tablespoons, the dosage form is placed on one spoon, the second spoon is placed on top of the first and the dosage form is crushed between spoons using hand pressure.

The term muscle-free layer means that the layer contains no muscle other than small amounts that may migrate from the ejected element. A greater AAT that partially blocks the effect of the opioid, is defined for the purposes of the present invention to mean that the opioid blocks at least as significantly an active effect of the muscle.

The expression controlled release as used for a muscle is defined for the purposes of the present invention as a release of the drug from a formulation that will give a longer survival event than a single dose of the regular formulation (meaning, immediate release), for example, over a period of one hour, as compared to the oral formulation of controlled release and controlled release that may be released Medication, for example, a period between 4 and 2 hours. For the purposes of the present invention, the expression analgesic opioid may be replaced by the expression opioid or analgesic opioid and includes a muscle or groups of more than one muscle and also includes the use of partial muscles, pharmaceutically acceptable salts from that source, chemical compounds from that source, ethers from that source, organic salts from that source, and a mixture of any Previous matters. For purposes of the present invention, the term analgesic antagonist will include a single muscle and groups of more than one muscle and also include the use of a base, pharmaceutically acceptable salts from that source, chemical compounds from that source, ether from that source, organic salts from that source, and a combination of any of the foregoing.

The invention disclosed herein is intended to include the use of all pharmaceutically acceptable salts from that source for muscles controlled by other exposed muscles and other resistant muscles. Pharmaceutical acceptable salts include, but are not limited to, iron salts such as sodium salt, potassium salt, and cesium salt. And the like, alkaline earth minerals such as calcium salt, magnesium salt and the like, organic amine salts such as alkaline salt Triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, N,N'-dibenzylethylenediamine saltj dicyclohexylamine salt and the like, and inorgairic acid salts such as:

hydrochloride, hydrobromide, sulfate, phosphate and the like, organic acid salts such as:

formate, acetate, trifluoroacetate, maleate, tartrate and the like, sulfonates such as: methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like, amino acid salts such as arginate, asparginate, glutamate and the like.

Some controlled muscles Other muscles and other resistant muscles used according to the present invention may contain one or more asymmetric centers and may cause or cause enanbhomersdiastereomers or other forms of steraisomeric The ones described here contain double olefinic bonds

olefinic double bonds or other centers of geometric asymmetry are meant to contain both geometric components Z and E. All tautohers are intended to be covered by the present invention as well.

The expression “layer” means a material arranged around an atom (which may include itself or one or more layers such as a seal coat) which may be used, for example, as a covering. Laying down layers may be performed by procedures known in the art, e.g. Cover, dip, or cover feathers.

The term 'disposed about' means that the material arranged around the atom covers at least part of the material with or without a layer or layers between the material and the atom; in certain inclusions, the material covers the atom entirely.

As used herein, the term 'solid chemical compounds' is a general term for all individual molecular compounds that differ only in the orientation of their nitrate. It is to the point that it includes enontiomers and chemical compounds for compounds with more than one chimt that are not mirror images of other diastereomers.

The term “China center” refers to the carbon atom to which we connect 4 groups. The term “enantiomer” or “enantiomeric” refers to a molecule that does not have a mirror image and is therefore optically active, as the enantiomers rotate around the plane of polarized light in one direction and its mirror image rotates around the plane of polarized light in the opposite direction.

The term “analysis” refers to the separation, concentration, or depletion of one of the two enantiomeric forms in a molecule.

The term For example, 100 mg of unlayered atoms, later coated to gain 10% weight, will have 100 mg of hydrophobic in the layer. The term “diameter” refers to the diameter of the cross-section of the atoms, which depends on the diameter of the hole used in the extrusion process.

The term 'length' means the length of the ejected atoms, which is largely dependent on the separator cut of the ejected wire.

The term “pharmaceutical product” means that the dosage form is suitable for administration or a component of the dosage form.

Brief explanation of the drawings

Figure 1 is a graphical representation of the plasma concentration time 5 for intact naltrexone HCI MEMs (whole), ground naltrexone HCI MEMs (ground) and immediate-release naltrexone tablet HCI dosage form (IRNTX) in Example 1.

Figure 2 is a graphical representation of naltrexone concentration (pg/ml) versus time curve data for the example

No. 5.

Figure 3 is a graphical representation of naltrexone concentration (pg/ml) versus time curve data for Example No.

13a.

It is a graphical representation of naltrexone concentration (pg/ml) versus time curve data for Example 13b.

Detailed description

The present invention is based on the observation that the nitrate of a muscle resistant to other opioids can be treated by covering the nitrate of this muscle with a lid, which reduces the consumption of the muscle from proper exposure to the environmental liquid. With the present invention, when this muscle combines an opioid preferentially with a muscle controlled by another muscle, only a trivial amount of the opioid-controlled muscle (that is, an amount that does not affect the analgesics given by the muscle controlled by another muscle) is released under the conditions described for use preferentially. More than a measured quantity or quantity cannot be released into the resistant muscle under the prescribed conditions of use. In specific inclusions, the present invention includes an oral dosage form consisting of assembling atoms comprising a therapeutically and orally effective amount of an opioid muscle by attaching and uniting with separate and extruded atoms comprising a muscle resistant to another opioid in the amount to block the effects of a controlled muscle if the dosage form is tampered with. Preferably the group of pharmaceutically acceptable atoms that includes the opioid-resistant muscle and the group of pharmaceutically acceptable atoms that include the muscle controlling another muscle are similar and preferentially indistinguishable.

In specific implications, the ratio of the muscle controlled by another opioid to the muscle resisting another is such that when the oral dosage form is manipulated to equal the integrity and integrity of the atoms that

Including the opioid-resistant muscle, the amount of opioid-resistant muscle will be released as it reduces or eliminates the active effect of the opioid-controlled muscle when administered to a person orally, intranasally, or/and sublingually.

For example in specific and preferred inclusions of the invention, the effect of drug activity will be reduced or eliminated by the opioid drug when the dosage form is administered non-enterically or/and sublingually. In specific inclusions, when the dosage form is chewed, crushed, dissolved or heated in a solvent and administered Oral, intranasal, non-gastric, or sublingual, the analgesic effect of the opioid is reduced or eliminated due to the release of the opioid in certain inclusions. The effect of the opioid is essentially blocked by the opioid. Because the proper oral dosage form of the present invention, when administered as intended, does not release the antagonist drug, the amount of the antagonist drug varies more widely than if the opioid drug were present for release in the Gl system at the oral administration level. The opioid drug in the discrete form includes an ejected polyatom consisting of the opioid drug dispersed in a matrix with a layer arranged around each of the atoms, such that the template and layer convert the opioid into something that cannot be released. In one inclusion, the layer is composed of a pharmaceutically acceptable hydrophobic material. In another inclusion, the die is composed of a pharmaceutically acceptable hydrophobic material. The hydrophobic substance of the matrix may be the same as, or different from, the hydrophobic substance of the coating. The hydrophobic substance is such that the antigen is not released, released, or substantially not released from the coated matrix, and is therefore not available or substantially unavailable for absorption during transport of the dosage form. Oral through the Gl system.

In certain preferred embodiments of the present invention, the antibody is diffused into the matrix by melt extrusion, the matrix being composed of one or more pharmaceutically acceptable hydrophobic materials. In certain inclusions of the invention, the opioid drug containing nitrate is a multi-minute controlled release extruded matrix. It is found in certain inclusions that when a controlled-release extruded multi-minute matrix is tampered with in order to make the opioid drug available for immediate release, only a portion of the drug is Released for immediate release In other inclusions, the percentage of drug released from the ejected dosage form after tampering is based on a one-hour analysis of the dosage form at 0.0.7 mm SGF using a USP Type II device (stirr) at 0.5 rpm. At 37 degrees Celsius, they cough out less than 50%, less than 0.4%, or less than 35%. Because the opioid portion can be released for immediate release from multiple minutes of the template when manipulated or tampered with, the antagonist drug can include a higher load to ensure that the amount necessary for the relevant opportunities of the invention can be released when tampered with. For example, if the inclusion of the invention releases 50% of the antibody upon tampering, the dosage form may be formulated to contain 4 mg of the antibody if a release of 2 mg of the antibody is required to be released upon tampering because the oral dosage forms of the present invention do not provide Release or essentially no release of the antagonist drug When administering the proper dosage form, a high load of the antagonist drug will not result in release of the proper dosage form for the amount of antagonist drug as it interferes with the efficacy of the antagonist drug.

Materials used in the extruded molds of the present invention include, by way of example and without limitation, hydrophilic or/and hydrophobic materials, such as gum, cellulose ethers, and gum.

acrylic resins and protein-derived materials; And digestible, long chain - C8 C50 especially [C12-C40] and variable or unchanged hydrocarbons such as fatty acids, fatty alcohols, organic glyceryl salts of fatty acids, glyceryl esters of fatty acids, vegetable and mineral oils, natural and artificial waxes, and converted stearyl alcohol and polyalkylene glycols. The molds may contain between 1% and 80% (by weight) of at least one hydrophilic or preferentially at least one hydrophilic material.

hydrophobic.

When the extruded matrix is composed of a hydrophilic, hydrophobic substance, any hydrophobic substance useful for this purpose is preferentially selected from the group of alkylcelluloses, acrylic and methacrylic acid polymers 0, copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof in preferred and specified inclusions. In the present invention, the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including But it is not limited to any of:

acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic) acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

The acrylic polymers involved in the present invention include, but are not limited to, acrylic resins containing copolymers made from: copolymer of acrylic acid lower alkyl ester and methacrylic acid lower alkyl ester which

It contains about 2 0.0 to 3 0.0 molecular weight of ammonium (lower alkyl) per molecular weight of acrylic and methacrylic monomers used. A suitable example of acrylic resin is the polymer manufactured by Rohm Pharma GmbH and sold under the H, Eudragit7 RS trademark. . Eudragit7 RS30D is preferred. Or Eudragit7 RS is a copolymer dissolved in water:

ethyl actylate (EA), methyl methacrylate (MM) and trimethylammoniumethyl

methacrylate chloride (TAM)

As the mass ratio of (TAM) to the remaining elements (EA and MM) is 1:40 Acrylic resins such as Eudragit7 RS or grades may be used in the form of a water suspension mixture. In other inclusions, the hydrophobic material is selected from materials such as one or more of

Hydroxyalkylcelluloses such as hydroxypropylmethylcellulose.

In certain inclusions, the hydrophobic materials of the invention have a melting point of approx

30 E.C. to about 200 E.C., or from about 45 E.C. to about 0.9 E.C.

In certain inclusions, the hydrophobic material consists of synthetic or natural waxes and fatty alcohols

(such as lauryl, myristyl, stearyl, cetyl or cetostearyl alcohol), and fatty acids which include, but are not limited to organic fatty acid salts, fatty acid

Mono-, di-, and tri-glycerides (glycerides), hydrogen lipids, hydrocarbons, regular wax, stearic aid, stearyl alcohol, hydrophobic and hydrophilic substances that contain the hydrocarbon backbones. Suitable waxes include, for example: beeswax, glycowax, castor wax, and carnauba wax. For the purposes of the present invention, a wax-like substance is defined as any substance that is naturally solid at room temperature and has a melting point from about 30 EC to about 100 EC.

In specific inclusions, the hydrophobic material of cellulose polymer selected from the group consisting of:

ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate and cellulose triacetate

Maybe used. Ethoxy is one that contains 4% to 55% of hydrophobic ethylcellulose in the form of an alcoholic solution. In certain other inclusions, ethylcellulose

: Containing

polylactic acid, polyglycolic acid or a co-polymer of polylactic and polyglycolic acid.

In certain inclusions, the hydrophobic material is composed of cellulose polymer which is classified from the group containing:

cellulose ether, cellulose ester, cellulose ester ether, and cellulose. In certain inclusions, the cellulosic polymers have a degree of change, DS, on the anhydroglucose unit, of higher than

Zero up to 3 inclusive by the degree of change means that the average number of hydroxyl groups is ahead of the anhydroglucose unit that includes the cellulose polymer that replaces the variable group.

Representative materials include a polymer named from the group consisting of:

Cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono, di, and tricellulose alkanylates, mono, di, and tricellulose aroylates, and mono, di, and tricellulose alkenylates.

Typical polymers include up to 1 acetyl and DS content containing cellulose acetate, up to 32 to 39.8% cellulose containing cellulose acetate, and 21 to 35% acetyl content for one or two cellulose acetates and DS content containing acetate.

From 35 to 24.8% acetyl 2 to 3 and the DS content contains

DS containing cellulose propionate specified includes cellulosic polymers cellulose acetate from 2.8 to 5.4%, hydroxyl content from 39.2 to 45%, propyl content butyryl content from 3 to 15% and acetyl content to 1 08%, DS containing butyrate. From 2 to 429 acetyl containing cellulose acetate butyrate content, from 34 to 39%, from 0.5 to 4.7% cellulose, from 7 1 to 35%, and butyrate content

From 2.9 to 3, such as: DS contains triacylate

cellulose triacetate, cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, and cellulose trioctanoate; Cellulose diacylates having a DS

202 to 2.6 such as:

cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulose

: Such as cellulose and common organic salts

cellulose acetate butyrate, cellulose acetate octanoate butyrate and cellulose acetate propionate

:- cellulose polymers

acetaldehyde dimethyl cellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, and cellulose acetate dimethylaminocellulose acetate, pharmaceutically accepted hydrophobic containing in certain inclusions, a substance

Which consists of: polymer

Copolymer of lactic and glycolic acid (“PLGA”), polylactide, polyglycolide, polyanhydride, polyorthoester, polycaprolactone, polyphosphazene, polysaccharide, proteinaceous polymer, polyester, polydioxanone, polygluconate, polylactic-acid-polyethylene oxide copolymers, poly(hydroxybutyrate), polyphosphoesther

Or a combination of any of the above.

In certain inclusions, the biodegradable polymer consists of PLGA, having a molecular weight of about 2,000 to about 500,000 daltons. The ratio of lactic acid to glycolic acid is about 5:

100 To about 75:25, with a lactic acid to glycolic acid ratio of about 35:65 considered preferable.

PLGA can be prepared by a procedure described in U.S. Patent No. 4,293,539 (Ludwig & Co.), the disclosure of which is comprehensive in its comprehensiveness. Briefly, a Ludwig copolymer is prepared by condensing lactic acid and glycolic acid in the presence of a displacable polymerization catalyst ( For example, with ion-exchange resin for a strong acid such as Dowex HCR-W2-H, the amount of catalyst is not dangerous for the polymerization, but it is from about 1.0.0 to about 2.0 parts by weight relative to the total weight of lactic acid, glycolic acid, and the aggregate. . The polymerization reaction may take place without solvents at a temperature of about 100°C to about 250°C for about 48 to about 96 hours, at low pressure to facilitate the removal of water and to obtain a byproduct that coats the PLGA by filtering the reaction mixture in the organic solvent. Such as dichloromethane or acetone and then filtered to remove the catalyst.

In specific and preferred inclusions, the association of two or more hydrophobic substances included in the extruded matrix If two or more inclusions are made, at least one of the hydrophobic substances shall be selected from natural and synthetic waxes, fatty alcohols, fatty acids, and mixtures thereof. Examples include; But not specified, beeswax, stearic acid, carnauba, and stearyl alcohol. When a hydrocarbon is hydrophobic, the hydrocarbon has a melting point between 25°C and 90°C. Of the long-chain hydrocarbons, aliphatic (fatty alcohols)

Preferably the matrix may contain at least 60% (by weight) of an indigestible long-chain hydrocarbon.

In certain preferred inclusions, the extruded matrix contains at least one 60% (by weight) polyalkylene glycol.

One suitable extruded matrix consists of at least one hydrolytic hydroxyalkyl cellulose, at least one C12-C36, preferably a C14-C22, aliphatic alcohol and, furthermore, one of: one polyalkylene glycol that is a hydroxy (C1 to C6) alkyl cellulose, such as hydroxypropylcellulose or hydroxypropyhnethylcellulose. Or hydroxyethylcellulose

The amount of hydroxyalkyl cellulose in the oral dosage form will be determined by the exact percentage of release of the active agent required. Aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol, or stearyl alcohol. However, in particularly favorable inclusions, aliphatic alcohol is myristyl alcohol 0.4 stearyl alcohol, the amount of aliphatic alcohol.

Alcohol in the oral dosage form will be determined by the exact ratio of release and release

The required active ingredient. It will also vary depending on whether polyalkylene glycol is present in the oral dosage form. In the absence of polyalkylene glycol, the oral dosage form will contain between about 20% and about 50% (by weight) of aliphatic alcohol. When at least one polyalkylene glycol is present in the oral dosage form, the combined weight of the aliphatic alcohol polyalkylene glycol constitutes between 20% and 50% (by weight) of the total dosage form in one inclusion, the proportion of hydroxyalkyl cellulose or acrylic resins to the polyalkylene glycol/aliphatic alcohol is determined. , to a large extent, the release rate of the active ingredient from

The equation. A ratio of hydroxyalkyl cellulose to polyalkylene glycol /aliphatic alcohol between 2:1 and 4:1 is preferred, with a ratio between 3:1 and 4:1 being particularly preferable. Polyalkylene may, for example, be polypropylene glycol or polyethylene glycol. The average atomic weight of polyalkylene glycol is between about 0 1,000 and about 15,000, specifically between 1,500 and about 12,000.

Other suitable extruded matrix includes alkylcellulose (particularly ethylcellulose), C12 to C36 of aliphatic alcohol and, optionally, polyalkylene glycol. Other suitable extruded matrix includes acrylic polymer (particularly C12 or RSPO) to C36 of aliphatic alcohol and, optionally, polyalkylene glycol. In specified preferred inclusions , the mold includes a combination of at least two pharmaceutically acceptable hydrophobies.

As previously described, a plurality of extruded atoms consisting of a pharmaceutically acceptable matrix containing the antigen are layered with one or more hydrophobies that, in addition to the matrix, can provide action to the antagonist. The hydrophobic material for the cover can be chosen from one of the above. In preferred and specified inclusions, the hydrophobie material is a cellulose, polymer, or acrylic polymer material, or the combination from that source. The terms first, second, and third hydrophobie materials, each intended to include one or more hydrophobie materials, at least partially diffusive or laminar, in the first hydrophobie materials. The second and third can be the same or different in inclusions

Specifically, the first and second hydrophobie substances can be the same thing, the second and third hydrophobie substances can be the same thing or the first, second and third hydrophobie substances can be the same thing.

In inclusions with more than one hydrophobie in the layer, the hydrophobies can be interspersed or partially interspersed. Alternatively, the hydrophobies can be in laminar order. For example, a layer in the amount of 25% by weight of the atoms can contain On 15% of the ethylcellulose layer by arranging the atoms and 10% of the acrylic polymer layer by arranging the atoms arranged around the ethylcellulose layer. The coating compound may be applied by spraying it onto multiple projected particles using any suitable spraying equipment known to the art. For example, a Worster liquid system may be used where a pneumatic tube enters from the bottom and the liquid material covers the paint and affects the dryness during the process of spraying the paint onto it. The thickness of the coating will depend on the characteristics of the composition used.

Hydrophilic materials suitable for forming the extruded atom layers of the present invention include cellulosic materials and polymers, which include alkylcelluloses. One of the preferred polymers is ethylcellulose; Although other cellulose and/or alkylcellulose polymers may be employed singly or in combination, as all or part of the hydrophobic coating according to the invention. One commercially available aqueous diffusion of ethylcellulose is aqueous coating (FMC Corp., Philadelphia, Pennsylvania, USA), which is prepared by dissolving ethylcellulose in an organic solvent that is immiscible with water and then by emulsification.

The same is true in the presence of surfactant. After homogenization to produce secondary micronized droplets, the solvent

The organic evaporates under vacuum to form a false juice. Surelease7 (Colorcon, Inc., West is another commercially available ethylcellulose aqueous diffusion for this product prepared by a molder incorporated into the diffusion through Point, Pennsylvania, USA). The stabilizer (dibutyl sebacate) plasticizer and the milk polymer manufacturing process. Hot melting to obtain alkaline is prepared with a homogeneous mixture which is expanded with oleic acid solution.

Aqueous diffusion which is applied directly onto the acrylic polycarbonate of the layer is hydrophobic. In another preferred designation of the present invention, a material

Pharmaceutically acceptable, but not specified, for: polymer acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), Polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate copolymers.

The collection is from that source.

In certain preferred inclusions, an acrylic polymer composed of one or more of:

Ammonio methacrylate copolymers are well known in the art and are described in NF XVII fully polymerized copolymers of acrylic and methacrylic acid esters with low group content. quaternary ammonium

In specific inclusions, it may be necessary to combine two or more ammonio methactylate copolymers that have different physical properties, such as gram molecular weight ratios of quaternary ammonium groups and neutral (meth)acrylic esters.

In certain inclusions, the acrylic layer consists of a mixture of acrylic resin commercially available from Rohm Pharma (Darmstadt, Germany) under the trade names:

RL30D and 7Rohm Pharma (Darmstadt, Germany) under the Tradenames Eudragit7 RS30D 7 and Eudragit 7, respectively. Eudragit 7Eudragit are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups. The ratio of the molecular weight in grams of ammonium groups to the remaining salts of meth (acrylic esters) is 20:1 in Eudragit7 RL30D and 40:1 in Eudragit7 RS30D. The atomic weight is about 150,000 names. The codes RL (high permeability) and RL (low permeability) refer to the permeability characteristics of these agents in specific inclusions. The Eudragit7 RS in the present invention is selected from the group consisting of: RS12.5 RSIOO, Eudragit7 RSPO, Eudragit7 RSPM, Eudragit7 Eudragit7 and mixtures from thereof, RSPM Eudragit7 represents general unground powders RS Eudragit7 represents

Eudragit7 RSPO finely ground powder Eudragit7 RS and Eudragit7 RSIOO represent granulated Eudragit7 RS, while Eudragit7 RS12.5 Eudragit7 RS represents a solution product wherein Eudragit7 RS is dissolved in an organic solvent in specified inclusions, Eudragit7 RL for use in the present invention is made up of a combination consisting of Eudragit7 RLPM The Eudragit7 RLPO, Eudragit7 RL100, Eudragit7 RL12.5 and the blends from that source for the punches “PM&, &PO', &100&, and &12.5& are defined as before with respect to the Eudragit7 RS mixture of the Eudragit7 RS in the RS series and the Eudragit7 RS series in any ratio The ammonio methacrylate copolymer of the present invention is used.

The RL/RS spread of the present invention is mixed together in any desired proportion in order to obtain the separated dye or equation containing the desired analyte. For example, the desired equations, for example, may be obtained from students derived from

100% Eudragit7 RL, 50% Eudragit7 RL, 50% Eudragit RS, 10% Eudragit7 RL

Eudragit7 RS 90% Of course, those who are skilled in this trait will distinguish other acrylic polymers that may also be used, such as Eudragit, for example.

The layer may be used in the form of an aqueous or organic solution, or in a diffusive form. The layer is used to obtain a weight gain from about 2% to about 25% of a pharmaceutically acceptable polyatom. It is protected from the opioid drug to obtain a desired separation. Radioactive coatings from aqueous diffusions are described. Basil, for example, in an American patent with numbers

502730760 and 5,286,493 are other examples of covers that may be used according to the present invention.

Includes US patent numbers 5,324,351, 5,356,467, and 5,472,712.

In certain inclusions, where the plurality of extruded atoms comprising the antibody are layered with an aqueous diffusion of the hydrophobie, the aqueous diffusion of the hydrophobie includes an effective amount of the colorant.

In implications of the present invention, since the layer is an aqueous diffusion of a hydrophobie, the effective amount of colorant in the aqueous diffusion will improve the physical properties of the layer. For example, because ethylcellulose has a relatively high transfer temperature through glass and does not form a flexible film under normal covering conditions, it is preferable to incorporate Colorant in the coating solution ethylcellulose In general, the amount of colorant included in the solution depends on the concentration of the film former, for example, from about 1% to about 50% by weight of the film former. Examples of suitable colorants for ethylcellulose include water-soluble colorants such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although other water-soluble colorants (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used. Triethyl citrate is a preferred colorant for water-based diffusions

ethylcellulose 0

Examples of suitable colorants are acrylic polymers of the present invention containing, but not specified,: citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and

propylene glycol

Other colorants that have been shown to be suitable for enhancing the film flexibility of acrylic films such as Adrogate RL/RS for lacquer solutions include:

Polyethylene glycols, diethyl phthalate, castor oil, and triacetin is a preferred colorant especially for the aqueous diffusion of... acrylic polymers

The colored hydrophobic material is applied to the pharmaceutically acceptable polyatoms that make up the opioid drug by spray, using any suitable spray tool known in the industry. In the preferred method, the fluid spray system is used as a pneumatic tube; It is inserted from the bottom, sprays the main material and affects the drying while spraying the cover.

The cover analyzes of the present invention may consist in addition to a hydrophobic substance to the colorant, a solvent system (for example, water) and a colorant to give elegance and distinction to the product. The appropriate coloring agents include alcohol or propylene glycol which establishes the dispersion of the colors. And crushed aluminum opacifiers such as titanium dioxide and iron oxide pigments. Color agents are added to the diffusion of the hydrophobic material during the coating process. Alternatively, any other suitable color imparting method with the equations of the present invention may be used. For example, a color coating such as Opadry may be applied to pharmaceutically acceptable coated atoms. In certain inclusions, a small amount of talc can be used to reduce aqueous diffusion tendencies to settle during the process, or/and to act as a polishing agent.

Several pharmaceutically acceptable atoms can consist of the drug opioid disseminated in a controlled release matrix that slowly releases the drug in a controlled manner over a period of time.

When absorbed, it is exposed to gastric fluid and then to intestinal fluid. The atomized template provides a controlled release of the drug for a period of from about 8 to about 24 hours, preferentially from about 12 to about 24 hours. The controlled release template for use in the atoms that forms on the opioid drug may include those substances previously described in connection with substances. Hydrophobic or/and hydrophobic materials (such as gums, cellulose ethers, acrylic resins and protein-derived hydrocarbons, Easily digestible, long chain (especially C8-C50 - C12 C40) variable and non-variable substances such as fatty alcohols, fatty acids, salts of fatty alcohols, glyceryl esters, vegetable and mineral oils, and waxes (natural and synthetic),

polyalkylene glycols

In specific inclusions, the atoms that make up the opioid may consist of an immediate release template with a controlled release layer arranged on its surface. The controlled release layer probably includes one or more of the previously described hydrophobies.

In certain inclusions, a pharmaceutically acceptable polycarbonate containing an opioid drug layered with one or more substances suitable for

(1) Regulating the release of opioid drugs.

(2) In order to protect the equation or.

(3) Giving the cover an indistinguishable shape from those given atoms and making up the drug

Antagonist or binding to 1, 2, 3 For example, in one inclusion, the cap is given to allow either pH-dependent or pH-independent release, for example when exposed to liquid G2.

The approved PH cap serves to release the opioid into desirable areas of the GI tract, for example the stomach or small intestine. This absorption is given and is able to provide at least 8 hours and preferably about 2 1 to 4 2 hours of analgesia to the patient. When a pH-independent layer is desired, the layer is designed to achieve opioid release regardless of pH changes in the environmental fluid, eg, the GI tract, the stomach, and release the remainder of the dose into another area of the GI tract, eg, the small intestine.

In certain inclusions, a pharmaceutically acceptable polypeptide containing an opioid drug and an opioid antagonist is processed. The atoms are processed until an endpoint is reached such that the pharmaceutically acceptable polymorphism yields a stable solution (or no solution). The endpoint of treatment may be determined by comparing the dissolution curve. For the dosage form immediately after treatment For the dissolution curve for the dosage form after exposure to accelerated storage conditions for at least, for example, one month at 40°C and 75% relative humidity Therapeutic equations and formulas are described in detail, for example in a patent. US Patent Nos. 5,2730760, 5,286,493, 5,500,227, and 5,580,578 Controls and covers that may be used in accordance with the present invention include those described in US Patent Nos. 5,032,403,51, 5,3560467, and 5,472,712. In specified inclusions, the plurality of pharmaceutically acceptable atoms containing an opioid or/and pharmaceutically acceptable atoms containing an opioid antagonist are considered to be membrane coatings with material that does not affect the release of the opioid or/and opioid antagonist from the pharmaceutically acceptable atoms in specified inclusions; A film coating, such as Opadry, is applied to a pharmaceutically acceptable multiplicity of atoms. A film coating is given in order to reduce the atomization of atoms or to help make the drug

An antidrug containing molecules that are difficult to distinguish from one another, the membrane coating of the present invention shall be capable of producing a continuous, strong membrane that is smooth, neat, capable of supporting granules and other coating substances, non-toxic, inert, and free of debris. In addition to the previous elements or ingredients, either or both of the atoms that contain the opioid drug and the atoms that make up the antibiotic drug may also contain appropriate amounts of other substances,

For example:

diluents, lubricants, binders, granulating aids, spheronizing agents, colorants, flavorants and glidants

Who are natures in the pharmaceutical art. The quantities of these additional materials will be in it to give the desired effect to the desired formula. Examples of candles or oils include, but are not specified:

magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid, sodium stearyl fumarate, and magnesium palmitate.

Suitable cohesive materials, such as low viscosity, well-known water-soluble polymers such as hydroxy propyl cellulose, would be preferred.

Colorants may contain dioxide and/or food dyes such as known dyes 42 FD & C and natural coloring agents such as grape skin extract and red beetroot powder, beta carotene, annato, carmine, turmeric, paprika, and any combination of the above.

The flavors contained in the compound are selected from synthetic flavor oils, fragrance flavors or/and natural oils, extracts from plants, leaves, flowers and fruits and combine any of the above.

Specific examples of pharmaceutically acceptable carriers, diluentes, granular acids, quintic acids, and other excipients that may be used to formulate oral dosage forms are described in the American Pharmaceutical Association's Pharmaceutical Excipients Textbook (1986).

A number of processes can be used to prepare the dosage forms of the present invention as long as the techniques do not destroy the integrity of the separated antibody (for example, when combining the nitrate of the antibody with the nitrate of the drug). Destruction of the integrity of the separated drug atoms results in an amount of opioid drug being released upon administration of the correct dosage form that normalizes the drug's effectiveness.

The preferred process for preparing atoms for the present invention is through granule melting or solute bombardment techniques. In general, the techniques for dissolving granules involve dissolving or softening the solid hydrophobic material, e.g., wax and incorporating the ground drug into specific inclusions. Additional hydrophobic material, e.g., ethylcellulose or acrylic polymer not dissolved in water, may be added to the dissolved and fine hydrophobic material.

Additional hydrophobic material may consist of one or more wax-like thermoplastic materials. In certain inclusions, the individual wax-like materials in the equation must be highly insoluble in Gl liquids during the initial release periods. Useful wax-like materials can be soluble and less than approx. 5,000:1 (w/w). In specific inclusions, preparations for a suitable extruded and dissolved matrix of the present invention can include the steps of mixing the drug or antidrug, with at least one or more hydrophobic substances to obtain a homogeneous mixture. Then heat the homogeneous mixture to a temperature sufficient to soften the mixture enough to extrude the same. The resulting homogeneous mixture is extruded, for example to form extended filaments. The extruded material is cooled and cut into multiple particles (i.e. multiple atoms) by known means. The melted material has a diameter from about 1.0 to about 1.2 metres, from about 0.1 to about 205 metres, or about 2. 0 to about 6 metres, or 0.5 to about 3 metres, or about 1 meter. Suitable hydrophobic materials useful in preparing the melted extruded mold include: acrylic polymers, cellulosic polymers and aliphatic alcohols as previously described. The optional process for preparing the melted projectiles of the present invention includes direct measurement of the hydrophobic substance, the therapeutic active agent and the optional cohesive substance, mixing and heating the constituents to form a homogeneous mixture, extruding the homogeneous mixture to form an extended filament, and cooling the filament containing

On a homogeneous mixture, cut polynitrate threads whose size ranges from about 1.0 meters to about

12 Like a meter. In connection with this invention, a relatively continuous manufacturing procedure is achieved.

The diameter of the extruded hole or outer hole can be adjusted to vary the thickness of the extruded filaments. Moreover, the outer opening of the ejector must not be circular; It can be rectangular, etc. Extruded threads can be reduced to atoms using a hot thread cutter, guillotine, etc. The melted projectiles can be in the form of pellets, for example, or squidroids, depending on the external finish of the projectile. For the purposes of the present invention, the terms melted projectile templates, melted projectile template systems, melted projectile multiparticles, and dissolved projectile atoms all refer to a multiplicity of units preferentially of similar size and/or shape and containing one or more active agents and more than one excipient, including a hydrophobic substance as It is described by Hanna. In relation to this, the melted projectile molds will have a size ranging from about 0.1 to about 1.2 mm m, from

About 1.0 to about 2.5 mm m, from about 2. 0 to about 6 mm m, from about 5. 0 to about 3 mm m, from about 05. mm m to about 2 mm m, or from about 1 mm m to about 2 mm m diagonally or/and longitudinally. In addition, it is understood that the melted projectile templates can be of geometric shape, so from this range in size in certain estimates the projectile can be It cuts the desired length and divides doses of the opioid drug or opioid drug without requiring a spheronizahion step.

In other inclusions of the invention, the dissolved extruded substance can be prepared without the guesswork of an opioid drug and/or opioid antagonist as it is added to the extruded substance. These formulations will contain drugs mixed with the extruded template material and the mixture will then be formed in several minutes by means known in the art such formulations. It can be positive, for example, when the drug opioid

Or the opioid drug included in the formulation is sensitive to the temperatures necessary to soften one or more hydrophobic substances.

In specific inclusions, the process of manufacturing pharmaceutically acceptable atoms is the ejection process. For this process, the opioid drug or the opioid antidote is a bulk liquid with the substance that helps it bond together. It is extruded through a perforated plate and placed on a rotating disk. The ejected material is divided into parts that are circular and into semi-spheres or spheroids or Circular chopsticks on a rotating plate The preferred process and compounding for this method involves using water to agglomerate a mixture that contains about 20% to 75% of the cellulose derived from the mixture, for example about 80% to 25% of the opioid or drug. Opioid antagonist.

In specific inclusions, the process of manufacturing a number of pharmaceutically acceptable atoms involves the use of an organic solvent to assist in mixing the opioid or drug with the template material. This technique may be used when it is desirable to use a template material with an unsuitable high melting point where, if The substance used is in a melting state, causing the drug or matrix to decompose or producing an unacceptable melt viscosity, thereby preventing the drug (e.g., an opioid) or an opioid antagonist from mixing with the matrix.

The matrix material and drug can be combined with a small amount of solvent to form a paste and then forced through the screen to form granules that the solvent removes. Optionally, the drug and template material may be taken with a solvent sufficient enough to dissolve the template material and sprayed and the resulting solution (which may contain solid drug atoms) dried to form a number of pharmaceutically acceptable atoms.

This technique is preferred when the mold material is a synthetic polymer with a high molecular weight, such as Cellulose ether or Cellulose ester. The solvents used for the process include: acetone, ethanol, isopropanol, ethyl acetate and mixtures from that source. As mentioned previously, the multiplicity of projected atoms that contain the opioid contain a layer that forms a hydrophobic substance, and are arranged around each atom. The nitrates of the layer containing the opioid reduce or significantly prevent the release or release of the opioid, during the accepted process Pharmaceutical drugs that contain an opioid provide a controlled release of the opioid over a period of time of about 8 to about 4 hours or more.

Preferably for a period of time from about 2 1 to about 4 2 hours. In preferred embodiments, the layer arranged around the matrix containing the antagonist drug is impermeable to water or substantially impermeable to the antagonist drug and cannot be dissolved or substantially cannot be dissolved in the GI system when the correct dosage form of the present invention is administered to the human race orally, The opioid drug is not released or absorbed into the body.

This opioid antagonist drug, although present in the dosage form, does not counteract the analgesic action of the opioid drug. However, if the oral dosage form of the present invention is tampered with, the antagonist drug contained herein will be released to at least partially block the analgesic effect of the opioid drug. This aspect of the invention reduces The potential for misuse or diversion of an opioid drug in the oral dosage form. For example, if a person attempts to misuse the drug in the oral dosage form of the present invention by, for example, manufacturing, crushing, grinding, or dissolving it in a solvent with heat (above

5 °C to about 50), both the matrix and the layer will be destroyed, and the opioid drug will no longer separate. When a tampered dosage form is administered, the opioid drug will enhance or release and block the active effect of the opioid drug.

The multiplicity of pharmaceutically acceptable atoms (that is, the atoms ejected by the opioid in the layer

tp&e

The opioid drug atoms of the present invention are combined in the oral dosage form, and optionally with...

Excipients known in the art.

In one preferential inclusion, oral dosage forms are prepared to include the effective amount of opioid-containing atoms and opioid-containing atoms within the capsule. For example, the total pharmaceutically acceptable atoms are placed in a gelatin capsule in sufficient quantity to provide an effective release of the dose upon ingestion. The capsule can first be sealed by sealing the atoms. In another implication, the appropriate amount of atoms containing the drug antagonist in the layer unite with the atoms containing the opioid drug and press into the opportunities of my mouth without disrupting the integrity of the total of pharmaceutically acceptable atoms.

In another inclusion, the appropriate amount of antidrug-containing atoms in the layer are bound to the opioid formulation (e.g., stabilized release beads) and pressed into the tablet, such that the antidrug-containing atoms are embedded in the drug matrix without disrupting the integrity of the pharmaceutically acceptable aggregate.

Techniques and compounds for making tablets (compressed and soft gelatin), capsules (hard and soft gelatin), and pills are described in Remington's Pharmaceutical Sciences (Arthur Osol, editor) 1553-1593 (1980).

In certain inclusions, oral dosage forms may also include an amount of the release or release opioid drug for immediate therapeutic effect. In certain inclusions, the immediate-release opioid drug may be packaged, for example, as separate pills within a gelatin capsule or may be coated on the surface of the container containing the drug in a number of dosage forms.

The controlled release or controlled release formulas of the present invention release or release the opioid drug slowly, for example, upon digestion and successive exposure to gastric fluids, and then to intestinal fluids. The controlled release form of the formulas in the invention can be varied, for example, by changing the amount of inhibitor, i.e., Hydrophobie material, by changing the amount of colorant attached to the hydrophobic material, by including additional ingredients or justifications, by changing the manufacturing method, etc.

In preferred inclusions, the beneficial opioid drugs of the present invention include, but are not limited to:

alfentanil, allylprodine, alphaprodine, anileridine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dipipanone, eptazocine, ,dimepheptanol, dimethylthiambutene

eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine,

dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nal buphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol

The pharmaceutically acceptable salts from that source and mixtures of any of the above in including the specified amount of the opioid drug in the dosage form are approximately 75 ng to 750 mg. In preferred embodiments, the opioid antagonist drug of the present invention is selected from: naltrexone, naloxone, nalmefene, cyclazacine, levallorphan and pharmaceutically acceptable salts from that source and mixtures of any of the foregoing in specified preferred inclusions, the opioid antagonist drug is Naltrexone or the pharmaceutically acceptable salt from that source (for example, (HCI Naltrexone) in specified inclusions, the amount of the opioid antagonist drug, present in non It can be released, it can be from about 0.0 milligrams to about 0.5 grams, or from about 1 milligram to about 25 milligrams, or from about 2 milligrams to about 20 milligrams, or from about 5 milligrams to about 5 milligrams. 1 milligram or about 2 milligrams to about 1 milligram (or from about 4 milligrams to about 1 milligram) or from about 6 milligrams to

About 8 ml grams.

Naloxone is an opioid antagonist drug, as it is free of the effects of opioids. Subcutaneous doses of up to 12 mg of naloxone do not produce discernible effects, and 24 mg of naloxone causes mild drowsiness. Only small doses (0.4-8.0 mg) of naloxone are given. Intramuscularly or intravenously in humans, it blocks the effects of the morphine-like opioid drug. One gram of naloxone intravenously can completely block the effect of 25 milligrams of heroin. The effects of naloxone can be seen immediately after intravenous administration. The drug is absorbed after use. It is administered orally, but it is said to be metabolized in an inactive form quickly in its prime through the liver, so it is said to have a lower efficacy than when administered without the esophagus or intestinal route. An oral dose of more than one gram is said to be completely metabolized in less than 4 2 hours. It is also said that 25% of naloxone taken sublingually is absorbed Weinberg and Associates, Sublingual Absorption of Selected Opioid Analgesics, but Clin Pharmacol Ther (1988) 335-340 :44.

(71 1) Other opioid antagonist drugs, such as cyclazocine and naltrexone, both of which have cyclopropylmethyl changes to the nitrogen, maintain their effectiveness by the oral route and have a longer duration of action, up to 24 hours after oral dosing. In a preferred inclusion of the invention, the opioid drug consists of:

oxycodone, hydrocodone, hydromorphone, morphine, oxymorphone, codeine or the pharmaceutically acceptable salt from that source. The opioid antagonist drug consists of naltrexone or the pharmaceutically acceptable salt from that source and is present in quantity from about 2 grams to about

15 milligrams or in the form of a quantity from about 5 milligrams to about 10 milligrams or from about 6 milligrams to about 8 milligrams.

In inclusions where the opioid drug consists of hydromorphone or a pharmaceutically acceptable salt from that source, the steady-release oral dosage forms include analgesic doses from about 8 mg to about 0.5 mg of hydrocodone or the salt from that source.

In each dose unit.

In sustained-release oral dosage forms where the hydromorphone or pharmaceutically acceptable salt from that source is a therapeutically active opioid, there are included in an amount from about 2 ml g to about 4 6 ml g of hydromorphone or the salt from that source and the controlled oral dosage form of the present invention. It includes from about 2 mg to about 0.80 mg of morphine or salt from that source. In another inclusion, an opioid drug consisting of oxycodone or the pharmaceutically acceptable salt from that source and including a controlled oral dosage form from about 2 mg to about 0.80 mg of oxycodone or the pharmaceutically acceptable salt from that source in certain preferred inclusions, including the dosage form. Oral for sustained release: approximately 5 mg, 1.0 mg, 2 mg, 4.0 mg, 6.0 mg, 80 mg, 8.0 mg, or 32.0 mg of oxycodone hydrochloride. Formulas of oxycodone in controlled release are known in the art. In certain inclusions, an opioid drug consisting of tramadol or a pharmaceutically acceptable salt from that source and controlled-release oral dosage forms comprising from approximately 5 2 mg to 800 mg of tramadol per unit dose, the dosage form containing more than one opioid drug. To give a therapeutic effect

Synonym As a comparison with the therapeutic effect achieved by a single drug product Bilea, the opioid dosage form of the invention contains mass equivalent amounts of salts of other drugs

Present.

In opioids in specific inclusions, the stabilizer is included in the dosage form to prevent dissolution of the antagonist drug. Certain inclusions, stabilizers for use in the dosage form include, in a separate and unlimited manner, acids, for example: organic amino acids, carboxylic acids, and acidic salts of amino acids.

cysteine, L-cysteine, cysteine hydrochloride, glycine hydrochloride or cystine dihydrochloride), sodium metabisulphite, ascorbic acid and its derivatives, malic acid, isoascorbic acid, citric acid, tartaric acid, palmitic acid, sodium carbonate, sodium hydrogen carbonate, calcium carbonate, Calcium hydrogen phosphate, sulfur dioxide, sodium sulphite, sodium bisulphate, tocopherol, as well as its water- and fat-soluble derivatives, such as eg, tocofersolan or tocopherol acetate, sulphites, bisulphites and hydrogen sulphites or alkali metal, alkaline earth metal and other metals, PHB esters, gallates, butylated hydroxyanisol (BHA) or butylated hydroxytoluene (BHT), and 2,6-di-t-butyl-.alpha.-dimethylamino-p -cresol, t-butylhydroquinone, di-t-butylhydroquinone, butylhydroxytoluene, butylhydroxyanisole, pyrocatechol, pyrogallol, propyl/gallate, and nordihydroguaiaretic acid, as well as lower fatty acids, fruit acids, phosphoric acids, sorbic and benzoic acids as well as their salts, esters, derivatives and isomeric compounds, ascorbyl palmitate, lecithins, mono- and polyhydroxylated benzene derivatives, ethylenediamine-tetraacetic acid and its salts.

citraconic acid, conidendrine, diethyl carbonate, methylenedioxyphenols

P,P'-dithiopropionic acid, biphenyl

Other phenyl derivatives and pharmaceutically acceptable salts from that source and mixtures from that source. The oral dosage form of the present invention includes the addition of an opioid drug and an antagonist drug, one or more drugs which may or may not act synergistically so that, in certain inclusions, a connection of two opioid drugs may be included in the dosage form, in addition to the opioid antagonist drug for example including two drugs. Opioids have different properties, such as half-life, solubility, and potency. Any of the above are present in additional inclusions. One or more opioid drugs are included and a non-opioid drug is also included. In addition to the opioid antagonist drug, non-opioid drugs provide sedation. Additionally, it includes, for example:

aspirin, acetaminophen; non-steroidal anti-inflammatory drugs(''NSAID''), eg,

ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate (NMDA) receptor antagonists, eg, a moiphinan such as dextromethoiphan or dextrorphan, or ketamine; cycooxygenase-II

;(@inhibitors (ACOX-II inhibitors

The additional agent can be contained in the same atoms of the prodrug or in different atoms. In a specific and preferred implication of the present invention, the invention allows for the use of low doses of an opioid analgesic to include an additional non-opioid drug, such as an NSAID or an antibiotic.

2-Cox, by using low amounts of either or both drugs the side effects associated with effective pain management in humans may be reduced. Suitable anti-inflammatory and non-steroidal agents include:

ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmet in, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam

Pharmaceutical accepted salts from that source, mixtures from that source, and the like. The beneficial doses of these drugs are known to those skilled in the art.

The recipient of N-methyl-D-aspartate (IDA) antagonist drugs is known in the art and includes, for example, morphinans such as dextromethorphan or dextrorphan, ketamine, d-methadone, or pharmaceutically acceptable salts in that source. For the purposes of the present invention, the term ANMDA antagonist drug includes drugs that A consequence located within a protoplasmic cell blocks the activity of the recipient ANMDA antagonist@'For example: ganglioside such as:

GM1 or GT1b a phenothiazine such as trifluoperazine or a naphthalenesulfonamide such

as N-(6-aminothexyl)-5-chloro-lnaphthalenesulfonamide

These drugs are understood to prevent the development of tolerance or/and are based on addictive drugs, for example, analgesics, etc., in an American patent bearing numbers morphine, codeine, such as narcotic, and for the treatment of chronic hopelessness, in patents (and others both by Mayer) 5,556,838 and 5,321,120.

and others (Mayer, US Patent No. 5,502,058. Treatment of chronic pain through the use of anti-glycine receptor drugs and the definition of these drugs.) Weber) is described in US patent No. 5,514,680. It is known in the production of Cox-2 antibiotics in several chemical structures. It is said that antibiotics are described, for example, in US patents Cox-2 cyclooxygenase-2 antibiotics.

: with numbers

50,616,601, 604,260 AH, 5,593,994, 5,550,142, 5,536,752, 5,521,213, 5,475,995, 5,639,780, 0604,253 AH, 5,552,422 and 368. 5,510,368 and 5,436,26.5 Preferred and specified include: Cox-2 5,130,311 and 5,409,944 Antibiotics celecoxib (SC-58635), DW-697, flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid (6-MNA), MK-966 (also known as Vioxx), nabumetone (prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614;

Under Cox-2 pharmaceutically acceptable salts and their units from that source, dose levels for the R-order are about 5 0 0. 0 milligrams to about 0.4 1 milligrams per kilogram of body weight. Alternatively, about 0.25 milliliters of morphine per day. It is therapeutically effective in combination with the analgesic. An opioid is taken in combination with the Cox-2 analgesic. About 7 grams per morphine per day of the drug.

Conjugates of opioids and 2-Cox antibiotics are disclosed in international application No. 99/13799.

In additional inclusions, a non-opioid drug cannot be included insofar as it gives a desired effect other than analgesics, for example, antitussive, expectorant, anti-emetic, decongestant antihistamine drugs, local anesthetics, and the like.

The present invention also refers to the dosage forms described herein using links to the different antidrug/active agent (i.e., non-opioid) in order to prevent misuse of the active agent. For example, when a benzodiazepine is used as the active agent in the dosage form of the present invention, the benzodiazepine antagonist drug can The separated salt is formulated in dosage form When used as an active agent in the reversible form of the present invention, the antagonist drug of this separated salt is formulated in dosage form. When used as an active agent in a dosage form of the present invention, the vitamin antagonist drug can be formulated into a dosage form.

The term benzodiazepines refers to benzodiazepines and drugs as derivatives of benzodiazepines as they are able to remove stress on the main nervous system. Benzodiazepines include, but are not limited to

alprazolam, bromazepam, chlordiazepoxied, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam,

quazepam, temazepam, triazolam, methylphenidate

And the moods are from that source.

Benzodiazepine antagonist drugs that may be used in the present invention include, but they are

Flumazenil is not limited to the analgesics derived from: hypnotic drugs referring to barbituric acid salts that include salts (but they are not barbituric acid (2, 4, 6,-trioxohexahydropyrimidine).

: limited) on

amobarbital,aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital

And the moods are from that source.

Babiturate drugs that may be used in the present invention include, but are not limited to, amphetamines as described herein.

Stimulants refer to drugs that stimulate the central nervous system. Stimulants include, but are not limited to, amphetamines, such as:

amphetamine, dextroamphetamine resin complex, dextroamphetamine,

Methamphetamine, methylphenidate

And the moods are from that source.

The stimulant drugs that may be used in the present invention include benzodiazepines as described herein.

The present invention also directs the dosage form described herein to use counteracting agents and not antidrugs in order to prevent misuse of the active agent. The term "adverse agent" indicates that any agent that can create an unfavorable effect can be administered in an unadulterated form. Examples of adverse agents, not drugs, include emetics, irritants, and bittering agents.

emetics include, but are not limited to, . ipecac and apomorphine Irritants include, but are not limited to, capsaicin and capsaicin analogues and mixtures from that source capsaicin analogues include:

resiniferatoxin, tinyatoxin, heptanoylisobutylamide, heptanoyl guaiacylamide, other isobutylamides or guaiacylamides, dihydrocapsaicin, homovanillyl octylester, nonanoyl

vanillilamide

And the moods are from that source.

Bittering agents include, but are not limited to, flavor oils, flavoring aromatics, oleoresins, and extracts derived from plants and leaves.

Flowers, fruit flavours, sucrose derivatives, chlorosucrose derivatives and quinine sulphate.

and denatonium benzoate and fusions from that source.

The present invention will be fully described by accompanying examples, however, it should be understood that the following description is illustrative and should not be taken in any way as a limitation of the invention.

Example (1)

2 mg Naltrexone HCl Capsules:

This is a comparative example of the opioid antagonist naltrexone HCl which is formulated as multiple soluble excreted molecules (MEMs) to produce an isolated product. Depending on the polymers and excipients added and selected, these MEM pellets release very little naltrexone when the intact pellets are analyzed but release a significant amount of naltrexone when they are tampered with (crushed). This example is included as a reference to demonstrate how the coatings in the examples that follow can enhance these isolated properties. The HCI Naltrexone composition equation for Example (1) is listed in the table below:

IA PI composition equation table

<img file="SA2189B1_D0001.tif" />

The HCI naltrexone compound of Example 1 was prepared using the following process:

the operation:

1. Grinding: Pass Stearyl Alcohol flakes through a 6-mesh grinder to obtain an easily mixable powder.

2. Mixing: Mix Naltrexone HCl, Stearyl Alcohol, ground Eudragit RSPO, and Stearic Acid GHT in a double lid blender.

03 Subtraction/Extrusion: Continuously feed the mixed material from step (2) into a twin foam ejector and collect the projectile from (27-Leistritz ZSE) at a rate ranging from 1.7 kg/hour to 2.6 kg/hour. Pour the mixture at a barrel temperature ranging from 75% to 100°C in containers approximately 1 mm in diameter. Collect the material placed on a conductor.

4. Cooling: Allow the parts to cool on the connector.

5. Making small pellets: Cut the excreted material into small pellets approximately 1 mm in length using a Pelletizer.

6. Purpose: Display the pellets through a vibrating isolator using a mesh screen 6 1 TBC and 26 TBC Collect the remaining material on the screen 26 TBC as a desired product.

7. Capsule Filling: Fill the presented pellets into 121 mg hard gelatin capsules.

Vitro Dissolution

Compounds prepared according to Example 1 gave the following results listed in Table 1B when subjected to the Vitro dissolution test method: Method:

1. Tool: USP type 2 (stirrer), 75 rpm.

2. Sample making time: 1, 2, 4, 8, 12, 24, 36 hours.

3. Method: 700 liters of young liquid and in the stomach for an hour, with a change to 900 ml of

The resulting gastric fluid is then removed. 4. Analytical method: High performance liquid chromatography. Results:

<img file="SA2189B1_D0002.tif" />

The process of imitation manipulation and melting

Compounds prepared according to Example 1 were subjected to a simulated tampering process and then subjected to the following Vitro dissolution test method:

* The results of the 1-hour dissolution are listed in Table IC. In the manipulation process, the naltrexone pellets were ground with a mortar and pestle (600 strokes) into powder in order to study the dissolution. This is the dissolution method: Same as above.

Results:

<img file="SA2189B1_D0003.tif" />

● Crushing: the rate of intact material

The crushing to intact material rate is the ratio of the percentage dissolution of crushed pellets in one hour to the percentage dissolution of intact pellets in 36 hours. Crushing results for intact pellet ratio: 33.5%/6.2% = 5.4:1 MEMs manufactured using the above process and formulation were used in a clinical study to determine the pharmacokinetic/biosimilar capabilities compared to the immediate release of Natrexone tablets. Human subjects were administered either HCI. naltrexone MEMs (whole), or powdered naltrexone HCI MEMs (ground), or immediate-release naltrexone HCI tablets The results are shown in the graph representation in Figure 1. The adjusted dose (to 1 mg tablet

<img file="SA2189B1_D0004.tif" />

Adjusted Dosage: Plasma concentration indicates that there is less release of naltrexone from the MEM dosage form when taken in its original form. The level of naltrexone increases when crushed MEMs are taken based on the Cmax of crushed (intact) MEMs, the Cmax of MEMs capsules is about 8, and similarly to the Auct, powder, MEMs capsules rate of about 4.4. This indicates that the total and peak exposure rates increase significantly after crushing. Example (2)

Ethylcellulose coated granules Naltrexone HCl 2 mg

In Example 2, Naltrexone MEMs were prepared similarly to Example 1 and were then coated with Ethylcellulose to multiple levels (5%, 10%, 15%, and 20% weight gain). And a compound

'

The unencapsulated HCI Naltrexone for Example 2 is listed in Table 2a below:

.

<img file="SA2189B1_D0005.tif" />

The unencapsulated naltrexone HCl formula of Example 2 was prepared using the following process: Process:

1. Grinding: Pass the stearyl alcohol flakes through a stir mill equipped with a mesh sieve to obtain an easily mixable powder.

2. Mixing: To mix Naltrexone HCl, Eudragit RSPO, milled Stearyl, naltrexone Alcohol, Stearic Acid and BHT in a double-sealed blender.

3. Subtraction: Continuously feed the mixed material from step 2 into the double action screw extruder at a rate of 9. 2 kg to 8. 4 kg/hour. Throw the mixture at a drum temperature ranging between 95 and 150°C into strands with a diameter of approximately 1 mm. Collect the thrown strands on a conveyor.

4. Cooling: Cut the cooled strands into approximately 1 mm grains using a grain cutter.

5. Separation by sieving: Screening of the granules through a vibrating separator using 6 1 TBC and 26 TBC mesh sieves The retained material was collected on a 26 TBC mesh sieve as desired for the product. In dissolving Vitro

The unencapsulated composition prepared according to Example 2 gave the results listed in Table 2/B when subjected to the Vitro dissolution test method. Method:

1. Tools: USP type (stirrer), 50 rpm, 37 m.

2. Sample making time:

<img file="SA2189B1_D0006.tif" />

The process of imitation manipulation and melting

Compounds prepared according to Example 2 were subjected to a simulated tampering process and then subjected to the following dissolution screening method. The 45-minute dissolution results are listed in Table 2. In the tampering process, the naltrexone granules were then ground with a mortar and pestle (24 strokes) into a powder for this dissolution study. Melting method:

1. USP tools, type 2 (stirrer), 50 rpm, 37 m.

2. Sample time: 45 minutes.

3. Method: 700 ml of similar gastric fluid.

4. Analytical Method: High Performance Liquid Chromatography (LLC).

Results:

<img file="SA2189B1_D0007.tif" />

Crushing: the correct rate

The crushing to intact material rate is the ratio of the percentage dissolution of crushed granules in 5 2 minutes to the percentage of intact granules in 36 hours. Crushing results: 31% 5.3% = 1:5.8

The naltrexone beads prepared according to Example 2 and listed in Table 2A are further coated with a hydrophobic coating. The beads are coated with a 5%, 10%, 15% and 20% color gain and a 2% hydrophobic coating and a color coating. Example of a composition that has 20% weight gain and a color coating. My colors are listed in the following table:

Table 2D

20% weight gain with color packaging

<img file="SA2189B1_D0008.tif" />

The encapsulated HCI naltrexone formulations of Example 2 were prepared using the following process:

1 0 Dip Functional Packaging Extract the 15% w/w Surelease solution of solids by mixing with water.

2. Dip color coating: To mix the color apoi powder with water to obtain 10% W/W of diffusion.

3. Functional encapsulation: Spray Surelease solution onto the prepared naltrexone granules and above 700 grams of the scale using a liquid base processor using the following parametric working steps:

- Air speed: 71 to 900 meters/second

- Air temperature inlet: 40-50 m

- Spray rate: 8-11 grams/minute.

Samples were taken when a theoretical solution amount of approximately: 5%, 10%, 15%, and 20% was sprayed by weight.

4. Color packaging: Upon completion of functional packaging, spray colored Opadry on the coated beans using the following working methods:

- Air speed: 7.0/meter per second.

- Air temperature inlet: 50°C.

- Solution spray rate: 8.5 grams/minute.

05 Sifting: Sift the kernels through a US 4 1 mesh sieve and a US 2 0 mesh sieve. Collect the reserved material on a US 2 0 mesh sieve according to the desired product.

6. Processing: Keep the filtered beans and samples in a 45°C oven for 24 hours.

The tablets are coated with 5%, 10% and 15% by weight of the mixture prepared according to the 20% composition and procedure using 6.05, 12.1 and 18.15 mg of Surelease per unit respectively. In dissolving Vitro

The coated compounds according to the second example gave the following results listed in Table E2 when they were subjected to the Vitro melting test method: 1. Tools: USP Type II (stirr), 50 rpm, 37 m. 20 Sample time: 1, 2, 4, 8, 12, 18, 24, 36 hours.

3. Medium: 700 mm of gastric fluid equivalent to 1 hour with conversion to 900 mm of fluid

after that.

4. Analytical method: High performance liquid chromatography

<img file="SA2189B1_D0009.tif" />

As can be seen from the dissolution results, the dissolution of naltrexone pills generally decreases with...

Increasing levels of polymer encapsulation.

The compositions prepared according to Example 2 were subjected to a compaction process and then subjected to the following dissolution test method:

The 5-4 minute dissolution results are listed in Table 2F 2F in the packing process Coated and uncoated naltrexone beads were ground separately with a mortar and pestle (24 strokes) into a powder for this dissolution study. Melting method:

1. Tools: USP type 2 (stirr), 0-5 rpm, at a temperature of 37°C. Sample time: 45 minutes.

3. Method: 700 ml of similar gastric fluid.

4. Analytical method: High performance liquid chromatography

Results:

<img file="SA2189B1_D0010.tif" />

Extracting the percentage of intact material The crushing to virgin material rate is the ratio of the percentage of dissolution of the crushed granules in 45 minutes to the percentage dissolution of the virgin granules in 36 hours. The results are listed in Table 2G below: Crushing to the percentage of intact material

<img file="SA2189B1_D0011.tif" />

As can be seen from the dissolution results, as the level of encapsulation increases: the rate of the material

Sound increases.

Results of the second example, compared to the second example:

Thus, by over-encapsulating the drug MEml, the second example, which is the same composition as the unencapsulated MEMs in Example 1, the diffusion of the drug in 36 hours decreased from above 5% to approximately 2%. As a result, the leakage of the antagonistic analgesic component from the unencapsulated MEM in Example 1 is also reduced. Obviously using a functional shell the extraction rate of the intact material can be increased from approximately 5:1 to 10:1. Example (3)

8 mg naltrexone ethylcellulose coated tablets

In Example 3, beads containing 8 mg of naltrexone were prepared and then coated with Surelease (Ethylcellulose) at multiple levels (5%, 10%, 15%, 20%, 25%, 30% gain weights).

The non-HCI encapsulated naltrexone composition in Example 3 is listed in the table below.

<img file="SA2189B1_D0012.tif" />

The unencapsulated HCI naltrexone formulations of Example 3 were prepared using the following process:

1 Composer: Pass the stearyl alcohol flakes through a stir mill fitted with a 6-clip sieve to obtain a powder that can be easily mixed.

2. Mixing: To mix stearyl alcohol, Eudragit RSPO, ground HCI naltrexone, BHT and Stearic Acid in a double jacket blender.

3. Extraction: Continuously feed the mixture from step 2 to the twin extruder at a rate of 3.9 kg/h. Extract the mixture at a drum temperature of 95°C and 100°C in strands of approximately 1 mm diameter. Collect the extracted strands on a conveyor. 4. Cooling: Allow the strands to cool on the conveyor.

5. Converting into beads: Cut the cold strands into small beads approximately 1 mm in length using a special cutter.

6. Screening: Screening the grains through a vibrating buffer using a 6 1 TBC and 26 TBC screening sieve. Collect the remaining material on 26 TBC sieves depending on the desired product. In Vitro Thaw

The unencapsulated composition prepared according to Example 3 gave the following results listed in Table 3B when subjected to the Vitro dissolution test method. Method: 1. Tools: USP type 2 (stirrer), 50 cycles at 37°C.

2. Sample time: 1, 6, 2, 1, 4, 36 hours.

3. Method: 700 ml of similar gastric fluid for an hour with dusting to 900 ml of

Questioner later.

4. Analytical method: High performance liquid chromatography. Results:

<img file="SA2189B1_D0013.tif" />

The compositions prepared according to the example were subjected to a compaction process and then subjected to the subsequent dissolution screening method. The results for 45 minutes are listed in Table 23. In the compaction process, uncoated naltrexone tablets were ground using a mortar and pestle (24 strokes) into a powder for this study.

soluble.

Dissolution method

1. Tools: USP Type II (stirrer) 0-5 rpm at a temperature of 37 degrees Celsius.

2. Sample making time: 45 minutes. 3. Method: 700 ml of similar gastric fluid.

4. Analytical method: High performance liquid chromatography. Results:

<img file="SA2189B1_D0014.tif" />

Crushing (extraction) rate of sound material

The extraction from intact material rate is the ratio of the percentage dissolution of crushed granules in 4.5 minutes to the percentage dissolution of intact granules in 36 hours. Crushing the rate of sound material gives the result: 57%-18.7% = 0.3. The naltrexone beads prepared according to Example 3 and listed in Table 3A are further coated with a hydrophobic coating. The grains were coated with excess weights of 5%, 10%, 15%, 20% and 25% with Surelease hydrophobic coating and 30% with Surelease hydrophobic coating and color coating (Opadry). An example of a combination that has 30% of the weights gained from hydrophobic packaging and color packaging is listed in the following table:

<img file="SA2189B1_D0015.tif" />

The HCI-encapsulated naltrexone formulations of Example 3 were prepared using the following process:1. Deployment of functional encapsulation: Surelease was extracted with 15% w/w solids mixed with water.

2. Functional encapsulation: Spray Siolase solution onto prepared naltrexone granules above 0.70 mg using a liquid handler using the following measuring steps:

- Air speed: 8.6 to 9.6 meters/second

- Inlet air temperature: 40-50 degrees Celsius.

- Spray rate: 9-4.8 1g/minute.

Samples were taken when the theoretical amount of spread and spraying was approximately 5%, 10%, 15%, 20%, 25%, and 30% weight gain (6.05, 12.1, 18.15, 24.2, and 30.25 mg Surelease/per unit respectively).

4. Color Encapsulation: When functional encapsulation is completed: Spray Opadry solution onto the encapsulated beads using the following steps:

- Air speed: 8.6-9.0 meters/second.

- Inlet air temperature: 47 degrees Celsius.

- Spray spreading rate: 9.0 grams/minute

5. Sifting: Sift the grains through a US 4 1 mesh sieve and a US 2 0 mesh sieve. Collect the sediment on a US 2 0 mesh sieve according to the desired product.

Compounds coated with a hydrophobic coating (Searles) and Opadry color coating prepared according to Example 3 gave the following results listed in Table 3E when subjected to the Vitro dissolution test method. Method:

1. Tools: USP Type II (stirrer) 0 5 rpm at a temperature of 37 degrees Celsius.

2. Sample making time: 1, 6, 12, 24, 36 hours.

3. Method: 700 ml of similar gastric fluid for an hour, with a change to 900 ml of liquid after that.

4. Analytical method: High performance liquid chromatography. Results:

<img file="SA2189B1_D0016.tif" />

As can be seen from the dissolution results, the dissolution of naltrexone beads generally decreases with increasing levels of polymer coating.

The compositions prepared according to Example 3 were subjected to a tampering or compaction process and then subjected to the following dissolution test method. The results of the 5-4 minute dissolution are listed in Table 3F. In the process of compacting both types of coated and uncoated naltrexone beads and then grinding them separately with a mortar and pestle (24 strokes) into a powder for this dissolution study. Melting method:

1. Tools: USP Type II (stirrer) with a capacity of 0.5 revolutions per minute and a temperature of 37 degrees Celsius.

2. The time to make your samples is 45 minutes.

3. The method is 700 ml of similar gastric fluid.

4. Analytical method: High performance liquid chromatography. Results:

<img file="SA2189B1_D0017.tif" />

Crushing: the rate of sound material.

The crushing to intact material rate is the rate of percentage dissolution of crushed grains in 45 minutes to the percentage dissolution of intact grains in 36 hours. The results are listed in Table 3G below.

Crushing results for bulk material rate

<img file="SA2189B1_D0018.tif" />

As can be seen from the dissolution results listed above, as the level of encapsulation increases, the amount of naltrexone released from the intact pellets decreases (from approximately 18% to less than 20% in 36 hours), however, when crushed, approximately 50% of the antagonist analgesic varies and the intact rate varies. It increases dramatically.

After encapsulation, the intact 8 mg beads showed a significant decrease in naltrexone extraction when compared to the uncoated intact beads. However, the extraction from the crushed coated 8 mg beads was higher when compared to the uncoated 2 mg beads.

Example 4

The 8 mg naltrexone beads coated with Methacrylic Polymer in Example 4. The beads containing 8 mg of naltrexone were prepared as in Example 3, but were coated with Eudragit RS 30D (Methacrylic copolymer) to multiple levels (5%, 10%, 15%, 20%, 25% excess weights) The unencapsulated naltrexone formulation of Example 4 is listed in Table 4A below.

<img file="SA2189B1_D0019.tif" />

the operation:

1. Grinding: Pass the stearyl alcohol flakes through a stir mill fitted with a 16-mesh sieve to obtain an easily mixable powder.

2. Blending: To mix Naltrexone HCl, Eudragit RSPO, milled Stearyl Alcohol, Stearic Acid and BHT in a double lid blender.

3. Extraction and extraction: Continuously feed the mixed material from step 2 into the extruder at a rate of 3.9 kg/hour. Extract the mixture at a temperature between 95°C and 100°C into strands approximately 1 mm in diameter. Collect the extracted material in these strands onto a conveyor.

4. Allow the strands to cool on the conveyor.

5. Converting into beads: Cut the cooled strands into approximately beads. 1 mm in length using a grain clip.

6. Screening: Sift the grains through a vibrating isolator using a 16 TBC and 26 TBC mesh sieve. Collect the reserved material on a 226 TBC mesh sieve according to the desired product.

In Vitro melting: Vitro

Unencapsulated compositions prepared in accordance with Example 4 gave the following results listed in Table 4B when subjected to the Vitro Selection method of dissolution.

Method:

1. Tools: USP Type II (stirrer) at a speed of 50 rpm and a temperature of 37 degrees Celsius.

2. Sample time: 1, 6, 12, 24, 36 hours.

3. Method: 700 ml of asymptomatic gastric fluid for 1 hour with transition to 900 ml thereafter.

4. Analytical method: High performance liquid chromatography. Results

<img file="SA2189B1_D0020.tif" />

Compaction and melting process:

The compositions prepared according to Example 4 were subjected to a certain compaction process and then subjected to the following dissolution test method: The 5-4 minute dissolution results are listed in Table 2.4. In the process of compacting the uncoated naltrexone pills, they were ground with a mortar and pestle (24 strokes) to accompany this study of dissolution. Melting method:

1. Tools: USP Type II (stirrer) at a speed of 0.5 rpm at a temperature of 37 degrees Celsius. 2. Sample time: 45 minutes. 3. Method: 700 ml of similar gastric fluid. 4. Analytical method: High performance liquid chromatography.

Results:

<img file="SA2189B1_D0021.tif" />

Crushing: the rate of sound material

The crushing to intact material rate is the rate of dissolution of crushed grains in 45 minutes to dissolution of intact grains in 36 hours.

Crushing results for intact material rate: 57% / 18.7% = 3.0.

The naltrexone beads prepared according to Example 4 and listed in Table 4A were coated with a hydrophobic coating. The beads were coated with a weight gain of 5%, 10%, 15%, 20% with a hydrophobic coating (based on Eudragit) and 25% with a hydrophobic coating (based on Eudragit and an Opadry color coating). An example of a composition that has 25% by weight of the hydrophobic coating and the color coating is listed in the table below.

Table 4D

Coated pill formula for 25% of weight gain

<img file="SA2189B1_D0022.tif" />

The naltrexone encapsulated formulations of Example 4 were prepared using the following process:

1. Functional Packaging Dispensing: To mix Eudragit RS 30D with triethyl citrate to agitate for 15 minutes Disperse Cab-O-Sil in sufficient water to obtain 20% w/w to disperse solids. Add Cab-O-Sil to the Eudragit mixture.

02 Color Packaging Dispersion: To mix Opadty with water to obtain a spread of 10% w/w

3. Functional Packaging: Spray Opadry onto the Naltrexone pills prepared above with a 0.70 titer

grams using a liquid bottom processor by following the following working steps:

- Air speed: 8.5 to 9.5 meters/second.

- Inlet temperature: 35 degrees Celsius.

- Iridescence spray rate: 14 grams/minute.

4. Color packaging: Upon completion of functional packaging, spray Opadry spray on the packaged tablets using the following standard instructions:

- Air speed: 8.5 meters/second

- Inlet temperature: 35-45 degrees Celsius.

- Sunflower spray rate: 8.5 g/minute.

5. Sifting: Sift the snakes through a US 4 1 mesh sieve and a US 20 mesh sieve. Collect the reserved material on a US 2 0 mesh sieve according to the desired product.

6. Processing: Place the screened beans and samples in an oven at 45°C for 24 hours.

In vitro thawing

Compositions coated with a hydrophobic coating prepared according to Example 4 gave the following results listed in Table 4E when subjected to the following in vitro dissolution test method:

1. Tools: USP Type II (stirring device) 0 5 revolutions/min 37°C.

2. Sample time: 1, 6, 12, 24, 36 hours.

3. Method: 700 ml of gastric fluid for an hour, switching to 900 ml after that. 4. Analytical method: high performance liquid chromatography. Results

<img file="SA2189B1_D0023.tif" />

As can be seen from the dissolution results, the solubility of naltrexone beads generally decreases with increasing levels of polymer coating.

Compositions prepared according to Example 4 were subjected to a specific tampering process and then subjected to the following dissolution check method. The results of dissolution for 5 4 minutes are listed in Table 4F in the bead tampering process.

Encapsulated and unencapsulated naltrexone were ground separately by mortar and pestle (24 strokes) into a solubility powder for this study. Dissolving method:

1. Tools: USP type 2 (stirrer) at a speed of 50 rpm and a temperature of 37 degrees Celsius.

2. Sample time: 45 minutes. 3. Method: 700 ml of simulated gastric fluid. 4. Analytical method: High performance liquid chromatography. Results:

<img file="SA2189B1_D0024.tif" />

Crushing rate of intact material, percentage of dissolution of powder proof in 5 4 minutes, percentage of dissolution of intact grains in 36 hours. The results are listed in Table 4G below:

<img file="SA2189B1_D0025.tif" />

As can be seen from the analysis results above, as the level of encapsulation increases, the amount of naltrexone released from intact beads decreases significantly (from over 18% to approximately 1% or less in 36 hours), however, when crushed, approximately 50% of the analgesic The antigen is still released and the extraction rate of the intact substance is increasing.

The product shows that the addition of encapsulation results in a significant decrease in the release of naltrexone from intact pills, while retaining the ability to release large amounts of the antagonist from crushed pills.

Example (5)

(231) In Example 5 the example composition was replicated on a pilot balance under GMP conditions and used for in-vivo evaluation.

(232) Pills containing 8 mg of naltrexone were prepared as in Example 4 and coated with a hydrophobic coating to a weight gain of 15%. These pills were packaged in size #2 capsules. The non-coated Naltrexone formulation for Example 5 is listed in Table. The uncoated granules of Example 5 were prepared using the following process: 1. Milling: Pass the Stearyl Alcohol flakes through a stir mill equipped with a 6-mesh screen.

To obtain an easily mixable powder.

2. Mixing: To mix Eudragit, naltrexone, ground stearyl alcohol, stearic acid, BHT and in a double lid blender.

3. Discharge: Continuously feed the mixed material from step 2 into a dual extruder at a rate from 4 kg/h to about 4.8 kg/h. Discharge the mixture at the drum temperature in the range of 80°C to 10.0°C in strands of Its diameter is between 8. 0 mm to 2. 1 mm. Collect the strands laid out on a conveyor.

4. Cooling: Allow the strands to cool on the conveyor.

5. Conversion to grains: Sift the grains through a vibrating separator using a 6 1 TBC sieve and a 26 TBC sieve. Collect the reserved material on a 26 TBC sieve according to the desired product. (233) The naltrexone beads prepared according to Example 5 and listed in Table 5A were subsequently coated with a hydrophobic coating. The beads were coated to a weight gain of 5.1% with a hydrophobic coating. The beads coated with a degree in the table below:

Table 5A

Capsule-encapsulated formula for 15% weight gain

<img file="SA2189B1_D0026.tif" />

the operation:

1. Functional coating dispersion: To mix Eudragit RS 30D with triethyl citrate to aerate for 15 minutes Cab-O-Sil in sufficient water to obtain a total of 20% solids for dispersion Add Cab-O-Sil dispersion to the Eudragit mixture.

2. Color Packaging Dispersion: To mix Opadry with water to obtain 10% spread. 3. Functional Packaging: Spray Eudragit on the above prepared 9 kg naltrexone beads using a liquid processor with the following instructions: Airflow: 700 to 780 CFM

- Inlet air temperature: 35 degrees Celsius.

- Spray rate of 5 1 1 to 135 grams/minute.

4. Color coating: When color coating is complete, spray Opadry spray on the coated pills using the following instructions:

Air flow: 0.75 to 760 CFM.

- Inlet temperature: 35-45 degrees Celsius.

- Sunflower spray rate: 75 to 95 grams per minute.

5. Screening: Screen the kernels through a vibrating isolator using a 4 1 TBC sieve and a sieve.

26 TBC Collect the reserved material on a 26 TBC sieve according to the desired product.

6. Preparing capsules: Fill the sifted grains into hard gelatin capsules at the intended weight

Preparation of capsules: Fill the sifted grains into hard gelatin capsules at intended weight

149.7 mg. In vitro thawing (untainted kernels).

(234) The hydrophobic-coated compositions in Example 5 in the form of swollen beads and encapsulated beads gave the following results listed in Table 5C when subjected to the following in vitro dissolution method:

Melting method:

1. Tools: USP type 2 stirrer / 50 revolutions per minute at a temperature of 37 degrees Celsius.

2. Sample time: 1, 2, 4, 8, 12, 24, 36 hours.

3. Method: 700 ml of simulated gastric fluid for 1 hour with transfer to 900 ml of

The questioner then.

4. Analytical method: High performance liquid chromatography. Results:

<img file="SA2189B1_D0027.tif" />

(35 2) The compositions prepared according to Example 5 were subjected to a simulated tampering process and then subjected to the following dissolution test method: In the process of packing the coated tablets, they were ground with a mortar and pestle (24 strokes) into a powder specific for dissolution in this study. Thawing method:

1. Equipment: USP, the second type of stirring device, 50 revolutions per minute, at a temperature of 37 degrees Celsius.

2. Sample time: 45 minutes. 3. Method: 700 ml of simulated gastric fluid. 4. Analytical method: High performance liquid chromatography. Results:

<img file="SA2189B1_D0028.tif" />

Plasma concentrations show that there is a very small amount of naltrexone release when intact naltrexone pills are taken when intact naltrexone pills are taken. The naltrexone concentration versus time curve data is shown in Figure 2. Plasma levels of naltrexone increased significantly when the tablets were taken orally in powdered or ground form in the steady state.

The in-vitro and in-vivo comparison of the uncoated MEMs of Example 1 and the coated MEMs of Example 5 is provided in Tables 5E and 5F below:

<img file="SA2189B1_D0029.tif" />

Form 6

MEM HCI naltrexone 2 mg encapsulated Methacrylic copolymer.

The non-encapsulated HCI naltrexone composition of Example 6 is listed in Table 6A below:

Table 6a

Pill composition

<img file="SA2189B1_D0030.tif" />

The naltrexone HCl composition of Example 6 was prepared using the following process:

the operation:

1. Grinding: Pass the steryl alcohol flakes through a stir mill equipped with a mesh sieve to obtain an easily mixable powder.

2. Mixing: To mix ground Stearyl Alcohol, RSPO Eudragit, HCI naltrexone,

HHT Stearic Acid in double blender.

3. Extraction: Continuously feed the mixed material from step 2 into a dual extruder at a rate of 2.9 kg/hour to 4.8 kg/hour Extract the mixture at a temperature between 95°C and 105°C into strands approximately 1 mm in diameter. Collect Strands on a vector.

40 Cooling: Allow the strands to cool on the conveyor.

5. Converting to beads: Cut the cooled strands into beads approximately 1 mm long using a grain cutter.

6. Screening: Sift the grains through a vibrating separator using a 1 TBC 6 mesh sieve and a 26 TBC mesh sieve depending on the desired product. Thawing In Vitro (intact granules)

Compositions prepared according to Example 6 gave the following dissolution results listed in Table 6B when subjected to the following Vitro dissolution test method: 1. Instruments: USP Type II (stirr) 50 rpm at 37°C.

2. Sample time: 1, 2, 4, 8, 12, 18, 24, 36.

30 Method: 700 ml of simulated gastric fluid one hour/900 ml of fluid later. 4. Analytical method: High performance liquid chromatography.

<img file="SA2189B1_D0031.tif" />

Compositions prepared according to Example 6 were subjected to a simulated manipulation and subjected to the following Vitro dissolution test. The 1-hour dissolution results are listed in Table 6C. In the manipulation, naltrexone was ground with a mortar and pestle (24 strokes) into a powder for this dissolution study.

Melting method:

1. Tools: USP Type II/stirrer, 50 rpm, temperature 37 degrees Celsius. 2. Sample time: 45 minutes. 3. Method: 700 ml of simulated gastric fluid. 4. Analytical method: High performance liquid chromatography.

<img file="SA2189B1_D0032.tif" />

Crushing: the percentage of intact material.

The crush-to-material ratio is the ratio of the percentage of dissolution of crushed beads in 4.5 minutes to the percentage of dissolution of intact beads in 36 hours. Powder to original material ratio: 31%, 5.3%=5.8:1

The naltrexone beads prepared in accordance with Example 6 and listed in Table 6A were coated with a hydrophobic coating. The beads with an additional 15% weight were coated with a hydrophobic coating (based on RS30D Eudragit). The composition that has 15% additional weight is listed in the following table:

Table 6D

The composition of the coated grains is 15% by weight

<img file="SA2189B1_D0033.tif" />

Encapsulated naltrexone formulations are prepared using the following process: Process: Dispersing Functional Encapsulation: Mix Eudragit RS 30D with triethyl citrate to infuse for 15 minutes. Cab-O-Sil in enough water to obtain a total of 20% solid moth. Add Cab-O-Sil to the Eudragit mixture. a

2. Functional packaging: Spray Eudragit on the above prepared naltrexone tablets in 700 gm standard using liquid primer (GPCGI) with the following instructions:

- Air speed: 9.0 m/s

- Inlet temperature: 35 degrees Celsius

- Sunflower spray rate: 8.8 grams/minute

3. Sifting: Sift the grains through a 4 1 us mesh sieve and a 2 0 mesh sieve. Collect the collected material on a 20 us sieve according to the desired product. In vitro thawing (intact kernels)

The hydr.ph.blc-coated compositions prepared according to Example 6 gave the following results listed in Table 6E when subjected to the Vitro dissolution test method. Method:

1. Tools: USP Type II (stirrer) 0-5 rpm at 37 degrees

percentage.

2. Sample time: 1, 2, 4, 8, 12, 24, 36 hours.

3. Method: 700 ml of simulated gastric fluid for 1 hour with transition to 900 ml of fluid later.

4. Analytical method: High performance liquid chromatography. Results:

<img file="SA2189B1_D0034.tif" />

Counterfeit tampering process and dissolution process (crushed tablets). The encapsulated formulations prepared according to Example 6 were subjected to a simulated manipulation and then subjected to the following dissolution test. The results of the 1-hour dissolution are listed in Table 6F. In the manipulation the naltrexone beads were ground with a mortar and pestle (24 strokes) into a powder for this dissolution study.

Dissolution method: Same as above. Results:

<img file="SA2189B1_D0035.tif" />

Crushing: the percentage of intact material.

The crushed to intact material ratio is the ratio of the percentage dissolution of crushed grains in one hour to the percentage dissolution of intact grains in 36 hours.

Ratio of crushed to intact material: 7%-6% = 12

(Note that since Naltrexone was not detected from intact pills, the crushed/intact ratio could be more than (12). I do not understand. Example (7)

Methacrylic copolymer then naltrexone coated Surelease 8 mg In Example 7, a two-stage sequential encapsulation of MEMs first with RS 30D Eudragit to a weight gain of 15%, then followed by Surlyz to an additional weight gain of 10% (based on uncoated extruded beads) was prepared. Pills containing 8 mg Naltrexone were prepared, as in Example 5, and were coated with methacrylic copolymer (Eudragit RS 30D) to a 15% weight gain, followed by ethylcellulose (Surelease) to a 10% weight gain. This product shows a significant decrease in the release of naltrexone from the intact pills, while Promotes higher release than crushed pills The unencapsulated naltrexone composition of Example 7 is listed in Table 7A below.

<img file="SA2189B1_D0036.tif" />

The unencapsulated HCI naltrexone formulation of Example 7 was prepared using the following process: 1. Grinding: Pass the stearyl alcohol flakes through a stir mill equipped with a 6-mesh grinder to obtain an easily mixable powder.

2. Mixing: To mix Naltrexone HCI, Eudragit RSPO, milled Stearyl Alcohol, Stearic

BHT and Acid in a double lid blender.

3. Discharge: Continuously feed the mixed material from step 2 into a twin-screw extruder at a rate ranging from 4.0 kg/hour to 8. 4 kg/h. Roll out the mixture at a temperature between 85°C and 0.9°C into strands with a diameter ranging from 0.8mm to 1.2mm.

Collect the strands laid out on a conveyor.

4. Cooling: Allow the strands to cool on the conveyor.

5. Conversion into beads: Cut the cooled strands into beads 0.8 to 1.4 mm long using a grain cutter.

6. Screening: Sift the grains through a vibrating isolator using a 6 1 TBC mesh sieve and a 26 TBC sieve. Collect the reserved material on the 26 TBC sieve according to the desired product. The HCI naltrexone beads prepared according to Example 7 and listed in Table 7A were then coated with a hydrophobic coating and the beads were coated with an additional 5% 1% methacrylic copolymer thereafter.

10% additional weight (based on uncoated kernels) with ethylcellulose for coated kernels is listed in the table below.

Table 7b

Pill composition coated for 15% of the gained weight Methacrylic Copolymer followed by 10% of the weight

Plus Ethylcellulose.

<img file="SA2189B1_D0037.tif" />

The encapsulated formulation of HCI naltrexone was prepared using the following process: 1. Dispersing Methacrylic Packaging: To mix RS30D Eudragit with triethyl citrate to quench for 15 minutes Cab-O-Sil in sufficient water to obtain a total 20% solid dispersion. Add Cab-O-Sil dispersion to the Eudragit mixture.

2. Ethylcellulose Encapsulation Dispersal: To mix Surelease with sufficient water to obtain a total of 15% solid dispersion.

3. Color Packaging Dispersion: To mix Opadry with water to get 10% spread. 4. -Methacrylic spray coating spread Eudragit on the above prepared 0.0 7 ml naltrexone beads using a liquid base treatment following the following instructions:

- Air speed: 8.8 to 9.0 meters/second

- Inlet temperature: 35 degrees Celsius.

- Spray rate of dispersed material: 9.6 grams/minute.

6. Color Coating: When functional coating is complete, spray Opadry colored spray on the coated areas using the following instructions:

- Air speed: 9.0 m/s.

- Inlet temperature: 0.4°C to 45°C.

- Spray rate of dispersed material: 9.2 to 9.6/minute.

7. Sifting: Sift the grains through a 1 US 4 mesh sieve and a 2 US 0 mesh sieve. Collect the remaining material on a 2 US 0 mesh sieve according to the desired product. Thaw in Vitro (correct kernels

Hydrophobic coating-coated compositions (methacrylic copolymer coating and ethylcellulose coating) prepared according to Example 7 gave the following results listed in Table 7C when subjected to the following in vitro thawing method:

Method:

1. Tools: USP Type II (stirrer) 0-5 rpm at 37°C.

2. Sample time: 1, 2, 4, 8, 12, 24, 36 hours.

3. Method: 700 ml of simulated gastric fluid.

4. Analytical method: High performance liquid chromatography. Results

<img file="SA2189B1_D0038.tif" />

Compositions prepared according to Example 7 were subjected to a simulated tampering process and then subjected to the following dissolution testing method. In the tampering process, the coated naltrexone beads were ground by a mortar and pestle (24 strokes) into a powder for this dissolution study. Melting method:

1. Tools: USP type 2 (stirrer), 50 rpm, at a temperature of 37 degrees

percentage.

20 Sample time: 45 minutes. 3. Method: 700 ml of simulated gastric fluid. Results:

<img file="SA2189B1_D0039.tif" />

Crushing: the rate of correct material.

The ratio of crushed to intact material is the percentage of dissolution of crushed pills in 4.5 minutes to the percentage of dissolution of intact pills in 36 hours. Ratio of crushed to intact material = 9205.

Naltrexone - HCI-MEMs 8 mg suspension with Sureleas then methacrylic copolymer:

Pills containing 8 mg of naltrexone were prepared as in Example 5 and were coated with ethylcellulose (Surelease) to 10% weight gain followed by Eudragit RS 30D (methacrylic copolymer) to 15% weight gain (based on uncoated pills). This product shows a significant decrease in naltrexone release from intact pellets while promoting a higher release from crushed pellets. The non-encapsulated HCI naltrexone composition of Example 8 is listed in Table 8A below:

Table 8a - Pill composition

<img file="SA2189B1_D0040.tif" />

The non-encapsulated HCI naltrexone formulation was prepared using the following process: 1. Grinding: Pass the stearyl alcohol flakes through a stir mill equipped with a 6-mesh sieve to obtain an easily mixable powder.

2. Mixing: To mix stearyl alcohol, RSPO Eudragit, ground HCI naltrexone, BHT and Stearic Acid in a double lid blender.

3. Subtraction: Feed the material into the mixture continuously from step 2. To a double screw extruder at a rate ranging from 0.4 kg/hour to 8. 4 kg/hour. Extract the mixture at a temperature between 85°C and 95°C into strands with a diameter ranging from 8 mm to 1.2 mm. Collect the strands on a conveyor.

4 Cooling: Allow the strands to cool on the conveyor.

5. Cutting into beads: Cut the cooled strands into beads of length ranging from 8. 0 mm to 4. 1 mm using a grain clip.

6. Screening: Sift the grains through a vibrating isolator using a 6-1 TBC sieve and a 26 TBC mesh sieve. Collect the reserved material on the 26 TBC sieve mesh according to the desired product. The naltrexone beads prepared according to Example 8 and listed in Table 8A are then coated with a hydrophobic coating. The beads are sealed to 10% weight gain with ethylcellulose followed by 15% weight gain with methacrylic copolymer (based on the uncoated beads). The coated beads are listed in the table below. Table 8b

The formula of the coated tablet is 0.1% gained ethylcellulose followed by 15% gained weight of...

methactylic copolymer

<img file="SA2189B1_D0041.tif" />

The Naltrexone encapsulated HCI formulation of Example 8 was prepared using the following process: 1. Dispersing Ethylcellulose Packaging: To mix Surelease with enough water to obtain a total of 15% of the solid fractions of the dispersed material.

2. Methacrylic Coating: To mix RS30D Eudragit with Sterilized Eudragit for quenching for a period of time

15 minute. Sprinkle the cap oisk in enough water to obtain a total of 20% of the solid parts

For the dispersed material, add Cap Osil to the Eudragit mixture

3. Color packing dispersant: To mix Opadry with water to obtain 10% dispersion. 4. Ethylcellulose Packaging: Spray Surelease on coated 700g tablets using a liquid base treatment with the following instructions:

- Air speed: 9.0 to 9.2 meters/second

- Inlet temperature: 0-5°C.

- Airbrush spray rate: 0.1 grams/minute.

5. Methacrylic Coverage:

Once Surelease coating is complete, spray Eudragit Dispersion onto the naltrexone granules prepared above using a liquid coater using the following standard instructions:

- Air speed: m/s90

- Air inlet temperature: 35°C.

- Dispersion spray rate: g/min17.7

6. Color Coating

Once functional coating is completed, spray Opadry Dispersion onto the coated granules using the following standard instructions:

Air speed: 750 to 760 CFM.

- Air inlet temperature: 0-5°C.

- Dispersion spray rate: 9.2 g/min. 7. Screening:

Scan the grit through a 14 US mesh screen and a 20 US mesh screen. Collect the remaining material on a 20 US mesh screen. 08 Place the screened granules in an oven at 45 degrees. Remove the part in 24 hours. Coating compositions using hydrophobic coatings (ethylcellulose and methacrylic copolymer coatings) are prepared according to Example 8, giving the following dissolution results in Table 8C when the following dissolution method is applied to them:

Curriculum:

1. Apparatus: USP Type II stirrer, 0.5 turns at 37°C. Sample time: 8, 4, 1, 2, 12, 24, 36. hour

2. Average: 700 ml of SGF in one hour changing to 900 ml of SIF after that.

3. Analytical method: liquid chromatography with high performance and effectiveness.

Results:

<img file="SA2189B1_D0042.tif" />

Compaction and dissolution process (powdered granules).

The compositions prepared according to Example 8 are subjected to a compaction process and then the following dissolution test method is applied to them. In the compaction process, the covered naltrexone granules are ground using a mortar (4 pestle 2 strokes) to turn into a powder for this dissolution study. The list of results is presented in Table 8D. Thawing method:

1. Apparatus: USP Type II stirrer, 50 revolutions at 37°C.

2. Sample time: 4-5 minutes.

3. Medium: 0.70 ml of SGF.

4. Analytical method: high-potency liquid chromatography. Results:

<img file="SA2189B1_D0043.tif" />

Crushing-fixing ratio.

The crushing-stabilization ratio is the % dissolution of crushed granules in 45 minutes to the crushing-stabilization ratio: 42.9.

Compare the three covered 25% granules

In examples 4, 7 and 8. The MEm naltrexone granules were covered with a total of 25% coverage with different covering materials or the crushing and stabilization rate was compared as follows:

<img file="SA2189B1_D0044.tif" />

Based on the in-vitro dissolution information of the MEM stabilized grains, the 25% coverage of RS Eudragit appears slightly better than the composition coverage. The controlled-release Oxycodone Hydrochloride tablets (0.1 mg) in this prophetic example can be prepared as follows: Organic plant Oxycodone hydrochloride (1.0 mg/tablet) and dried lactose spray (71.25 mg/tablet) are converted to a suitable volumetric mixture. Mix it for 6 minutes and disperse the powder. RS PM 7 Eudragit in ethanol. While the powders are mixed, filtration is done with dispersion and mixing continues until a wet granular mass is formed. An additional amount of ethanol is added when needed to reach the final point of sieving. The granules are transferred to a liquid bed dryer and dried at 30°C and passed through Through a cross-linking scanner 2 1 RS PM 7Eudragit (9 mg/tablet) is dispersed in a solution of 90 parts ethanol and 10 parts filtered water. It is sprayed on the granules in a liquid layer dryer/sifter at a temperature of 30°C and then passes through a mesh scanner 21. Stearyl alcohol (25 mg/tablet) is dissolved

At a temperature of approximately (0 6-0 7) Celsius, the warm granules are returned to the mixture and during mixing, dissolved Stearyl alcohol is added. The covered granules are removed from the mixture and left to cool. After that, they are passed through a Shabika scanner 2 1. Particles are then mixed in Example 5.

Desirable pharmaceutical inactive additives such as talc and magnesium stearate are mixed in a suitable mixing device and compressed into tablets. Example (10)

Method of Treating Pain:

The oral dosage composition according to the present invention is administered to the patient

To relieve pain. The oral dosage formulation may contain an effective amount of the agent

Reactive opioid and non-extracted opioid antagonist The coating of antigen-containing molecules is intended to reduce the leakage of the antagonist from immobilized antigen-containing molecules.

When the dosage form is administered orally and reaches the GI tract of the patient requiring treatment, the interacting opioid agent is released from the dosage form through the normal process of digestion, providing the patient with relief, but the opioid antagonist, because it is extracted non-reductively, is not released through the transport process. Through the GI tract, it is preferable to use the non-released form of a laxative-resistant agent, such as mineral oil, to delay colonic transport or in cases of achlorhydria. For patients taking a combination dose (such as (mechanical agitation, heating, dissolution in solution) they will not have an adequate amount of anti-IBD agent absorbed during any time interval during the administration of the dosage combination and this will result in

To reduce the analgesic effectiveness of the opioid antagonist. In other words, the amount of the antagonist extracted from the fixed dose formulation (when taken orally) absorbed in the GI tract and combined in the patient’s body will not increase the level of the effective effect or change the analgesic effectiveness of the dose of the antagonist present in Dosage composition. Example (11)

How to prevent the use of the ipod-reactive agent.

The oral dosage composition according to the present invention may be used to prevent systemic misuse of the opioid interacting agent contained in the composition. The oral dosage composition includes the opioid interacting agent combined with the opioid antagonist agent, the opioid antagonist agent being in a virtually unreleased form. During the digestion process, therefore, when the dose formulation reaches the GI tract orally without agglutination, the antigen is prevented from being released into the GI system. However, if the oral dosage composition is agitated by mechanical agitation (e.g. crushing, grinding, shearing or heating) (temperatures higher than 45

percentage (preferably between 45 and 50) or dissolving the dosage formulation in a solution (with or without heating).

The opiod antagonist agent is available to the opiod effects and therefore when the dosage composition is calculated and the

When administered orally, nasally, esophagus, or sublingually, the effect of the ipod-reactive agent is partially blocked.

Through the antagonist agent opioid.

Example (12)

Hydromorphone HCI controlled release capsules can be prepared with naltrexone HCI granules through this prophetic example as follows: The composition is shown in Table 12A below:

<img file="SA2189B1_D0045.tif" />

The capsules in Example 5 are prepared using the following process:

the operation:

1. Milling: releasing thin layers of Stearyl Alcohol through an impact mill. 2. Blending: Mix Hydomorphone HCl, Eudragit, Ethycellulose and milled Stearyl Alcohol with a double-shell blender.

3. Extruding: Continuously feed the mixed material into a twin-screw extruder and collect the resulting strands in the conveyor. 4. Cooling: Let the strands cool on the conveyor.

5. Pelletizing: Cut the cold strands into pellets using a pellet making machine.

6. Wiping: Wipe the granules and collect the required sifted amount. 7. Clear coating: Sprinkle pink opioid dispersion water onto the opioid granules in a liquid dish.

8. Encapsulation: Fill perforated coated Hydromorphone HCl pellets (126 mg) and NatrexoneHCl pellets (from example). 49.7 1 mg in hard gelatin capsules. Variations of the present invention will be obvious to those skilled in the art within the perspective of the claims contained in this resource.

Example (13)

In Example 13a, HCI Naltrexone granules prepared in accordance with Example 5 and described in a list in Table 5a are subsequently coated with a hydrophobic coating. The granules are coated with a 2% weight gain hydrophobie coating (based on Eudragit RS 30D) showing the covered granules in the table below. Table 13a

Granules formula covered in capsules for 25% weight gain

<img file="SA2189B1_D0046.tif" />

The process used to prepare the granules in Example 3(a) is as follows: 1 0 Disperse the Eudragit RS 30D functional cover with triethyl citrate plasticize for 15 minutes. Dissolve Cab-O-Sil in enough water to obtain a total of 20% w/w solid slurry. Add the slurry of Cab-O-Sil to the Eudragit mixture.

2. Cover scattering: The line is replaced with water to obtain 10%/w/w scattering. 3. Functional coverage: Spray Eudragit onto the Naltrexone granules prepared above in a 9 kg scale using a liquid bed handler (15-Gpcg) with the following standard guidelines: Air flow: 400 to 450 CFM.

- Air inlet temperature: 0.4°C.

- Spraying rate: 75 to 0.9 g/min.

4. Color coverage: After completing functional coverage, spray Opadry on the coated granules using the following standard instructions: a.

- Air flow: 400 to 450 cfm.

- Air inlet temperature: 50-55 Celsius.

- Spraying rate: 0.6 to 0.7 g/min.

5. Wiping: Wipe the granules through a vibrating separator using a 4 TBC mesh sweeper and a 26 TBC mesh sweeper. Collect the remaining material on the 26 TBC mesh sweeper according to the desired product.

6. Encapsulation: Fill the cleared granules into hard gelatin capsules with a specific weight of 164086 mg.

Dissolution (stabilized granules)

The compositions covered with hydrophobic coating, as in Example 13(a), in the form of volumetric granules and granules in the form of capsules, gave the following results in Table 13b when the following method of dissolving stabilized granules was applied: Dissolution method:

1. Apparatus: USP Type II stirrer, 0.5 revolutions at 37°C.

2. Sample time: 1, 2, 4, 8, 12, 24, 36 hours.

3. Medium: 700 ml SGF in one hour changing to 0 0 9 ml SIF thereafter. 4. Analytical method: liquid chromatography with high performance and effectiveness.

Results:

<img file="SA2189B1_D0047.tif" />

Imitation compaction and melting process (powdered granules).

The compositions prepared according to Example 31 (a) are defined as a simulated compaction process and then the following dissolution test method is applied in the compaction process. The covered naltrexone granules are crushed with a mortar and pestle (24 strokes) to turn it into a powder and for this dissolution study. Thawing method:

1. Apparatus: USP Type II stirrer, 0.5 revolutions at 37°C.

2. Sample time: 4-5 minutes. 3. Medium: 700 ml of SGF.

4. Analytical method: liquid chromatography with high performance and effectiveness.

Results:

<img file="SA2189B1_D0048.tif" />

The crushing and stabilization rate is the % dissolution rate for crushed granules in 45 minutes and for granules stabilized in 36 hours. A list of results has been placed below.

Crushing-consolidation ratio: 27.0 /0.5 = 54 Example 13b

In Example 13b, HCI Naltrexone granules are prepared according to. For example 5, they were placed in a list in Table 5C and were later covered with a hydrophobic coating. The granules were covered for a 30% weight gain with a hydrophobic coating (based on 10901-7-Surelease E). A list of the covered granules is shown in the table below.

Table 13D

A formula of granules covered in capsule form for 30% weight gain

<img file="SA2189B1_D0049.tif" />

The process used to prepare the granules in Example 31(a) is as follows: 1. Functional Dispersion: To mix RS30D Eudragit with triethyl citrate for 15 minutes annealing with Cab-O-Sil in sufficient water to obtain a total of 20% ww solid dispersion. Add a sprinkle of Cab-O-Sil to the Eudragit mixture.

2. Chromatic dispersion Mix Opadry with water to obtain 10% ww dispersion. 3. Functional coverage: Spray Eudragit onto the above prepared naltrexone granules in a 9 kg scale using a liquid bed conditioner (15-GPCG) with the following standard guidelines: Air flow: 400 to 450 CFM.

- Air inlet temperature: 0.4°C.

- Spraying rate: 75 to 0.9 g/min.

4. Color coverage: After functional coverage is achieved, spray Opadry on the coated granules using the following standard instructions:

Air flow: 400 to 450 CFM.

- Air inlet temperature: 50-55°C.

- Spraying rate: 0.6 to 0.7 g/min.

5. Wiping: Wipe the granules through a vibrating separator using a 4 TBC mesh wiper and a 26 TBC mesh wiper. Collect the remaining material on the 26TBC mesh wiper according to the product.

Required.

6. Encapsulation: Fill the cleared granules into hard gelatin capsules with a specific weight of 164.86 mg. Dissolving stabilized granules

The compositions covered with hydrophobic coating, as in Example 13(b), in the form of bulk granules and granules in the form of capsules, gave the following results in Table E13 when the following method of dissolving stabilized granules was applied: Dissolution method:

1. Device: USP type 2 stirrer, 50 revolutions at 37 degrees Celsius.

2. Sample time: 1, 2, 4, 8, 12, 24, 36 hours.

3. Medium: 700 ml of SGF one hour changing to 900 ml of SIF after that.

4. Analytical method: High-performance liquid chromatography.

Results:

<img file="SA2189B1_D0050.tif" />

Imitation compaction and melting process (powdered granules)

The compositions prepared according to Example 31 (b) are defined for a simulated compaction process, and then the following dissolution test method is applied. In the compaction process, the covered naltrexone granules are crushed with a mortar and pestle (24 strokes) to turn it into a powder for the dissolution study. This is the dissolution method:

5. Equipment: stirrer for stirring and mixing, type 2, USP 0 5, rotated at 37 degrees Celsius. 6. Sample time: 45 minutes. 7. Medium: 0.70 ml of SGF. 8. Analytical method: High-performance liquid chromatography

<img file="SA2189B1_D0051.tif" />

The rate or ratio of crushing to cohesion is the percentage of dissolution of crushed granules in 45 minutes to the percentage of dissolution of cohesive granules in 36 hours. The list of results has been placed below.

Crushing to cohesive ratio result: 26.0 /1.6 = 16.3 In Vivo Hurman Pharmacokinetic/Bioavailability-Study

Capsules manufactured using the above process of Examples 13a and b were used in two separate clinical studies to determine the bioavailability and pharmacokinetics of MEMs tested under various conditions and were compared to the bioavailability/pharmacokinetics of Naltrexone immediate-release tablets. A group of people were given either powdered Naltrexone HCI MEMs (containing a powder capsule and sealed) or immediate-release Naltrexone HCI in the form of sealed tablets. Or a cohesive MEMs capsule when satiated. These studies were an open-label, single-dose, 5-way, cross-sectional study in healthy subjects. The treatment was generalized as follows: A. Naltrexone MEM Capsule 1

B. Naltrexone MEM 1 x 8 mg capsule with crushed capsule contents in a permeable state.

C. Naltrexone MEM 1 x 8 mg capsule is compact and ridged.

Dr.. Naltrexone MEM 8x5 mg (0.4 mg) capsule is held together in a stabilized state.

Dr.. Naltrexone Immediate-Release Tablets 1 The initial plasma concentrations given indicate that there is a negligible amount of naltrexone release when Naltrexone MEM granules are taken stabilized. The Naltrexone concentration (ml pg) correlates with the information on the time curve shown in Figures 3 and 4. Plasma Naltrexone levels were effectively increased when crushed oral naltrexone granules were taken in a stabilized state. The ratio of cohesive MEMs capsule/crushed MEMs Cmax for Fudiagit 25% layer and Suielease 30% layer is 187.91 and 71.98, respectively. Also, the ratio of coherent MEMs capsule/crushed MEMs AULT for Eudiagit 25% layer and Surelease 30% layer is 66.07 and 39.27. Respectively, the comparison of the in-vitro and in-vivo coated MEMs of Examples 13 or 13b is described in Table 13G as follows:

<img file="SA2189B1_D0052.tif" />

Information modified from 5*8 mg

<img file="SA2189B1_D0053.tif" />

While the invention here is limited to variations and applications from that source, very many variations and modifications can also be made by those skilled in the craft without abandoning the spirit and perspective of the present invention, and it can be understood that these modifications must be within the perspective of the attached claims.