DK200600189U3 - Long-term oral dosage form containing an opioid and use thereof - Google Patents

Description

1GB 2006 00189 U3

FIELD OF THE INVENTION

The invention relates to methods for the administration of opioids, including but not limited to hydromorphone and oxycodone, for sustained release, which exhibit improved administration properties with aqueous alcohol.

BACKGROUND OF THE INVENTION

Ethanol-induced dose dumping of sustained-release oral dosage forms may be a serious problem for patients taking such oral dosage forms.

Oral dosage forms of sustained release opioids are designed to deliver opioids to a patient for a prolonged period of time. Often, one oral dosage form of sustained-release opioid is prescribed instead of many immediate-release oral dosage forms. For example, oral dosage forms of sustained-release opioids are needed for once daily administration (qd) and twice daily (bite), giving a patient full-day pain relief.

Accordingly, the amount of opioid contained in such dosage forms, especially oral dosage forms of once-daily oral administration, is significantly greater than that usually included in immediate-release opioid dosage forms. Anything that causes dose dumping from such oral dosage forms of sustained-release opioids can cause an opioid drug overdose, leading to respiratory depression and possibly even death.

The inventors have recognized that a modality for causing dose dumping (i.e., immediate release) is increased release rates caused by administration of the oral dosage forms of sustained release opioids with aqueous alcohol, especially aqueous ethanol. Various alcohols may increase the release of the opioid from the oral dosage forms of sustained-release opioids to undesirably high rates even approaching dose dumping / immediate release.

Accordingly, it would be desirable to develop oral dosage forms of sustained-release opioids and related methods that do not have prior art problems with respect to alcohol-induced dose dumping, especially ethanol-induced dose dumping.

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It would be even more desirable if these oral dosage forms of sustained release opioids and related methods were oral dosage forms of opioids and sustained release for once or twice daily or related methods.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a method comprising: providing a sustained release dosage form of hydromorphone for once daily administration comprising hydromorphone and a sustained release dosage structure providing once daily dosing; administration of the sustained release dosage form of hydromorphone for once-daily administration to a patient with aqueous alcohol; release of hydromorphone from the sustained release dosage form of hydromorphone for once daily administration; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater than ca. 20% by volume; and wherein the ratio of the average single plasma hydromorphone concentration achieved with a single dose when the sustained release dosage form of once-daily hydromorphone is administered to the patient with the aqueous alcohol, and an average maximum single plasma dose obtained when the sustained release dosage form of hydromorphone for once-daily administration to a patient without administration together with the aqueous alcohol is equal to or less than ca. 1.8: 1st

In another aspect, the invention relates to a method comprising: providing a sustained release dosage form of hydromorphone for once daily comprising hydromorphone and a prolonged release dosage structure providing once daily dosing; administration of the sustained release dosage form of hydromorphone for once-daily administration to a patient with aqueous alcohol; release of hydromorphone from the sustained release dosage form of hydromorphone for once daily administration; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater than 20% by volume; and wherein the ratio of the single-dose maximum plasma hydromorphone concentration obtained in an individual patient when the sustained-release once-daily dosage form of the hydromorphone is administered to the patient with the aqueous alcohol, and a maximum single-dose plasma hydromorphone concentration for an individual patient obtained when the sustained-release dosage form of hydromorphone for once daily administration to a patient without administration in combination with the aqueous alcohol is equal to or less than ca. 5: 1.

In yet another aspect, the invention relates to a method comprising: providing a sustained release dosage form of hydromorphone for once daily comprising hydromorphone and a sustained release dosage structure providing once daily dosing; administration of the sustained release dosage form of hydromorphone for once-daily administration to a patient with aqueous alcohol; release of hydromorphone from the sustained release dosage form of hydromorphone for once daily administration; in which the sustained-release dosage form of once-daily hydromorphone release less than or equal to ca. 80% by weight of the dose of hydromorphone from the sustained release dosage form of hydromorphone for once-daily administration as measured (a) using an in vitro experimental method comprising experimental media; and (b) for a period of approx. 2 hours after starting the in vitro test method; and wherein the test medium comprises aqueous alcohol which comprises alcohol at concentrations equal to or greater than ca. 20% by volume.

In another aspect, the invention relates to a method comprising: providing a sustained release dosage form of hydromorphone comprising hydromorphone and a sustained release dosage structure; administering the sustained release dosage form of hydromorphone to a patient with aqueous alcohol; release of hydromorphone from the slow release dosage form of hydromorphone; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater than 20% by volume; and wherein the ratio of an average maximum plasma hydromorphone concentration after a single dose obtained when the dosage form is administered to the patient with the aqueous alcohol, and an average maximum plasma hydromorphone concentration of a single dose obtained when the dosage form is administered to a patient without administration with the aqueous alcohol is equal to or less than approx. 1.8: 1st

In yet another aspect, the invention relates to a method comprising: providing a sustained release dosage form of hydromorphone comprising hydromorphone and a sustained release dosage structure; administering the sustained release dosage form of hydromorphone to a patient with aqueous alcohol; release of hydromorphone from the slow-release dosage form of hydromorphone 4 DK 2006 00189 U3 morphon; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater than 20% by volume; and wherein the ratio of a maximum plasma hydromorphone concentration following a single dose obtained for a single patient when the dosage form is administered to the patient together with the aqueous alcohol, and a maximum single plasma dose obtained for a single patient when the dosage form is administered to the patient. a patient without administration together with the aqueous alcohol is equal to or less than ca. 5: 1.

In yet another aspect, the invention relates to a method comprising: providing a sustained-release dosage form of hydromorphone comprising a hydro-morphone dose and a sustained-release dosage structure; administering the sustained release dosage form of hydromorphone to a patient with aqueous alcohol; releasing the hydromorphone dose from the sustained release dosage form of the hydromorphone; wherein the sustained release dosage form of hydromorphone releases less than ca. 80% by weight of the hydromorphone dose from the sustained release dosage form of the hydromorphone as measured (a) using an in vitro experimental method comprising experimental media; and (b) for a period of about 10 minutes. 2 hours after starting the in vitro test method; and wherein the test medium comprises aqueous alcohol comprising alcohol at concentrations equal to or greater than ca. 20% by volume.

In one aspect, the invention relates to a method comprising: providing a sustained release dosage form of once daily opioid comprising and a sustained release dosage structure providing once daily dosing; administration of the sustained-release opioid once daily dosage form to a patient with aqueous alcohol; release of opioid from the sustained release dosage form once daily; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater than about 20% by volume; and wherein the ratio of a maximum single-dose plasma opioid concentration obtained for a single patient when the sustained-release opioid dosage form is administered daily to the patient with the aqueous alcohol, and a single-dose maximum plasma opioid concentration obtained for a single patient, when the dosage form for prolonged release of opioid once daily is administered to a patient without administration together with the aqueous alcohol is less than or equal to approx. 1.8: 1st

In another aspect, the invention relates to a method comprising: providing a sustained release dosage form of opioid comprising an opioid and a sustained release dosage structure providing once daily dosing; administration of the sustained release dosage form of opioid once daily to a patient 5 with aqueous alcohol; release of opioid from the sustained release dosage form once daily; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater than about 20% by volume; and wherein the ratio of a maximum plasma opioid concentration of a single dose obtained for a single patient when the sustained release dosage form once daily is administered to the patient with the aqueous alcohol, and a maximum plasma opioid concentration of a single dose obtained for a single patient when the dosage form for prolonged release of opioid once daily is administered to a patient without administration together with the aqueous alcohol is less than or equal to approx. 5: 1, 15 In yet another aspect, the invention relates to a method comprising: providing a once-daily prolonged-release opioid dosage form comprising an opioid dosage and a sustained-release opioid dosage structure; administration of the sustained-release opioid once daily dosage form to a patient with aqueous alcohol; releasing the opioid dose from the sustained release dosage form once daily; wherein the sustained release dosage form of once daily opioid releases less than about 80 wt% of the opioid doses from the sustained release dosage form of opioid once daily as measured (a) using an in vitro experimental method comprising experimental media; and (b) for a period of about 10 minutes. 2 hours after initiation of the experimental method in vitro; and wherein the test media comprise aqueous alcohol comprising alcohol at concentrations equal to or greater than ca. 20% by volume.

In one aspect, the invention relates to a method comprising: providing a sustained release dosage form of opioid and a sustained release dosage structure; Administration of the sustained release dosage form of opioid to a patient with aqueous alcohol; release of opioid from the sustained release dosage form of opioid; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater than about 20% by volume; and wherein the ratio of an average maximum plasma opioid concentration of a single dose obtained when the dosage form is administered to the patient with the aqueous alcohol, and an average maximum plasma opioid concentration of a single dose obtained when the dosage form is administered to a patient without administration. together with the aqueous alcohol, is less than or equal to approx. 1.8: 1st

In another aspect, the invention relates to a method comprising: providing a sustained release dosage form of opioid comprising opioid and a sustained release dosage structure; administration of the sustained release dosage form of opioid to a patient along with aqueous alcohol; release of opioid from the sustained release dosage form of opioid; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater than about 20% by volume; and wherein the ratio of a maximum plasma opioid concentration of a single dose obtained for a single patient when the dosage form is administered to the patient with the aqueous alcohol, and a maximum plasma opioid concentration of a single dose obtained for a single patient when the dosage form is administered to a patient without administration. together with the aqueous alcohol, is less than or equal to approx. 5: 1.

In another aspect, the invention relates to a method comprising: providing a sustained release dosage form of opioid comprising an opioid dose and a sustained release dosage structure; administration of the sustained release dosage form of opioid to a patient along with aqueous alcohol; release of the opioid dose from the sustained release dosage form of opioid; in which the sustained release dosage form of opioid releases less than ca. 80% by weight of the opioid dose from the sustained release dosage form of the opioid as measured (a) using an in vitro experimental method comprising test media; and (b) for a period of about 10 minutes. 2 hours after starting the in vitro test method; and wherein the test medium comprises aqueous alcohol comprising alcohol at concentrations equal to or greater than about 20% by volume.

In yet another aspect, the invention relates to a method comprising: providing a sustained release dosage form of hydromorphone once daily comprising hydromorphone and a sustained release dosage structure providing once daily dosing; administering the once-daily release form of hydromorphone to a patient with aqueous alcohol; release of hydromorphone from the sustained release dosage form once daily; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater than about 20% by volume; and wherein the ratio of the average time to maximum plasma concentration of a single dose obtained when the dosage form is administered to the patient with aqueous alcohol, and the average time to maximum plasma concentration of a single dose obtained when the sustained release dosage form is administered. hydromorphone once daily administered to a patient without administration together with the aqueous alcohol, ranges from approx. 0.5 to approx. 1,0, 5 In another aspect, the invention relates to a method comprising: providing a dosage form for sustained release hydromorphone comprising hydromorphone and a sustained release dosage structure; administering the sustained release dosage form of hydromorphone to a patient with aqueous alcohol; Release of hydromorphone from the sustained release dosage form of hydromorphone; wherein the aqueous alcohol comprises alcohol at concentrations greater than or equal to about 20% by volume; and wherein the ratio of the average time to maximal plasma concentration of a single dose obtained when the dosage form is administered to the patient with the aqueous alcohol, and the average time to maximum plasma concentration of a single dose obtained when the sustained release dosage form of hydromorphone is administered to the patient. the patient without administration together with the aqueous alcohol, ranges from approx. 0.5 to approx. 1.0.

In another aspect, the invention relates to a method comprising: providing a sustained release dosage form of an opioid comprising an opioid and a sustained release dosage structure which provides once daily release; administration of the sustained release dosage form of opioid to a patient along with aqueous alcohol; release of opioid from the sustained release dosage form once daily; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater than about 20% by volume; and wherein the ratio of the average time to maximum single-dose plasma concentration obtained when the dosage form is administered to the patient with the aqueous alcohol, and the average time to maximum single-dose peak plasma concentration achieved when the once-daily prolonged release opioid dosage form administered to a patient without administration together with the aqueous alcohol, ranges from approx. 0.5 to approx. 1.0.

In another aspect, the invention relates to a method comprising: providing a dosage form for sustained release opioid comprising opioid and a sustained release dosage structure; administration of the sustained release dosage form of opioid to a patient along with aqueous alcohol; release of opioid from the dosage form 8 8DG 2006 00189 U3 the sustained release form of opioid; wherein the aqueous alcohol comprises alcohol at concentrations greater than or equal to about 20% by volume; and wherein the ratio of the average time to maximal plasma concentration of a single dose obtained when the dosage form is administered to the patient with the aqueous alcohol, and the average time to maximum plasma concentration of a single dose obtained when the dosage form of sustained release opioid is administered to the patient without administration with the aqueous alcohol, ranges from approx. 0.5 to approx. 1.0.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 shows a dosage form according to the invention as an elemental osmotic pump.

Figure 2 shows some embodiments of the invention of sustained release dosage forms.

Figure 3 shows another example of a dosage form.

Figure 4 shows another example of a dosage form.

Figures 5A-5C show another example of a dosage form.

Figure 6 shows in vitro cumulative release profiles of 16 mg hydromorphone HCl tablets of the invention in ethanol solutions.

Figure 7 shows a comparison of solution profiles between hydromorphone HCl tablets of 16 mg according to the invention and Palladone XL of 32 mg in the presence of aqueous alcohol.

Figure 8 shows an average plasma concentration profile of hydromorphone and standard deviation.

Figure 9 shows an average plasma concentration profile of hydromorphone and standard deviation.

Figure 10 shows individual Cmax preventions: study on group 1 alcohol versus repeated dosing study.

9 DK 2006 00189 U3

Figure 11 shows individual Cmax levels: Group 2 alcohol study versus repeated dosing study.

Figure 12 shows the release of oxycodone HCl from preparations with and without stearyl alcohol.

Figure 13 shows release of hydromorphone HCl from preparations with and without stearyl alcohol.

Figure 14 shows the effect of Eudragit® RS PO on the release of oxycodone HCl drug.

Figure 15 shows the effect of Eudragit® RS PO on the release of hydromorphone HCl drug.

Figure 16 shows relative effects of stearyl alcohol, carnauba wax, and hydrogenated polyoxyl-60 castor oil on oxycodone HCl release functionality.

Figure 17 shows in vitro solubility profiles of OxyContin® tablets.

DETAILED DESCRIPTION

I. Listed oral dosage forms with long-term release of opioid

Recognizing the problems of the prior art noted, the inventors unexpectedly discovered the embodiments of the invention that can provide solutions for alcohol-induced dose dumping, especially ethanol-enhanced dose dumping.

In the invention, the lack of a prior art understanding of the applicability of the methods of the invention and associated sustained release dosage forms to solve the alcohol-induced problems, especially ethanol-induced dose dumping, is remarkable. Similar dosage forms such as those mentioned have been used because of their abusive properties, but there is no mention or hint in the prior art that these structures can be used to solve the alcohol-induced, especially ethanol-induced, dose dumping problems . For example, U.S. Patent Application No. 2005163856 discloses to Maloney et al. a fine particle size cation exchange resin whose incorporation in a dosage form of oxycodone improves the performance of the dosage form with respect to in vitro extractions that may be made by a potential addict. However, Maloney et al. no mention or suggestion that this property could be useful in solving the in vivo dose dumping problem caused by aqueous alcohol, especially aqueous ethanol, which the inventors treat. The mention or implication provided by the inventors.

Further evidence that the present invention was not understood in the prior art prior to the present invention is the fact that other sustained-release dosage forms of opioids are in fact susceptible to alcohol-induced, particularly ethanol-induced, dose dumping. For example, Palladone® extended release hydromorphone (Purdue Pharma LP), Kadian® (Alpharma US Pharms) and Avinza® (Ligand Pharmaceuticais) are all reported to have alcohol-induced problems, especially ethanol-induced, dose dumping. The fact that these products were commercialized regardless of the associated hazards of alcohol-induced, especially ethanol-induced, dose dumping is evidence that the problem and the solutions provided herein were not understood in the prior art of the present invention.

After recognizing the problem and its solution, the inventors considered a number of embodiments of the present invention. In certain embodiments, it may be possible to provide dosage form coatings which serve to reduce or prevent dose dumping induced by aqueous alcohol. In further embodiments, certain hydrophobic or hydrophilic components may be selected which serve to reduce or prevent dose dumping induced by aqueous alcohol. In dosage protective coating embodiments, the selected coatings may serve to alter the release time, such as enteric coatings, or may be resistant to choking or dissolving in alcohol, such as semi-permeable membrane coatings or certain non-enteric coatings.

In embodiments where hydrophobic components are developed to reduce or prevent dose dumping induced by aqueous alcohol, materials which are relatively insoluble in water and swell minimally in aqueous alcohol may advantageously be selected. For example, hydrophobic polymers which are minimally quenched and relatively insoluble in water may be selected and exhibit equal or less quenching and / or solubility in aqueous alcohol. In embodiments comprising nonpolymeric hydrophobic components, (including but not limited to waxes or fatty acid alcohols such as stearyl alcohol), those with less solubility / swelling in aqueous alcohol are preferred than in water. In embodiments where hydrophilic components are selected to reduce or prevent dose dumping induced by aqueous alcohol, materials which are less soluble and less likely to swell in aqueous alcohol as compared to water may advantageously be selected. For example, hydrophilic polymers may be selected which exhibit equal or less swelling and / or solubility in aqueous alcohol as compared to water. In embodiments comprising non-polymeric hydrophilic components, those with less solubility / swelling are preferred in aqueous alcohol than in water.

One technique for creating desirable coatings and hydrophobic and hydrophobic components which can be used in the practice of this invention consists in casting films of the materials concerned and testing these materials for swelling in the presence of aqueous ethanol. Mass screening techniques can be used with this film analysis to provide a wide array of suitable materials. Similar techniques can be used to assess the solubility of materials desired to be used in the practice of this invention. Embodiments of materials which have been found useful in the practice of the invention are found elsewhere herein.

As shown in the embodiments of the invention mentioned in the Examples below, especially Example 5, it is possible to control the amount of opioid released from oral dosage forms with sustained release opioid when administered with aqueous alcohol. In the embodiments described below, aqueous alcohol (e.g., aqueous ethanol) does not lead to uncontrolled, immediate release of opioid from the embodiments of the dosage forms practiced by the methods of the invention. For example, in Example 5 ethyl alcohol concentration-dependent increases in hydromorphone release rates are observed leading to a slight increase in Cmax and decrease in average Tmax when the treatments are administered in the fasted state (the maximum Tmax value was 4 hours with alcohol compared to 6 hours with 0% ethanol and the maximum increase in C ™ observed with any individual was 2.5-fold when treated with 40% ethanol as compared to 0% ethanol). However, severe dose dumping, which would have led to a possible life-threatening event, did not occur.

In Example 5, the concentrations of plasma opioid (hydromorphone in this case) were close to the limit of quantification at the first time after dosing at 2 hours; then plasma concentrations increased slowly in all 4 treatments in both fed and fasting groups. Mean Tmax was between 12 and 16 hours, and the range of Tmax was similar for treatments in the 2 groups. These data suggest that the controlled release property of the enumerated dosage forms is maintained in the presence of ethanol and that there is no "dose dumping". The maintenance of the controlled release properties was consistent with the in vitro results of embodiments of the invention disclosed in Examples 1 and 2, which also did not exhibit dose dumping even with sustained exposure to ethanol for 24 hours.

This data with dosage forms of hydromorphone according to the invention contrasts with results reported for a common form of hydromorphone known as Palladone® (available from Purdue Pharma). For that product, a significant amount of "dose dumping" was seen both in vitro and in vivo. As shown in Example 2, approx. 90% of the drug within 1 hour in ethanol in vitro. In vivo, the maximum increase in Cmax for 4%, 20% and 40% ethanol relative to 0% alcohol was reported to be approx. 2.0, 5.7 and 15.7 for an individual, and for average increase across individuals, the maximum increase in Cmax was reported for 4%, 20% and 40% ethano! compared to 0% alcohol to be approx. 1,1,2,1 and 5.8 times.

Materials which may be used in the practice of this invention are set forth in the present specification and in particular in Examples 1 to 3 and 7 to 11. Various materials useful in the practice of the present invention are disclosed. An interesting point is that OxyContin®, an extended release oxycodone product available from Purdue Pharma LP and tested below in Example 12, shows minimal signs of dose dumping in the presence of aqueous alcohol. As part of the present invention, it has been discovered that excipient stearyl alcohol may be responsible for OxyContin®'s resistance to alcohol-induced dose dumping. This discovery is evidence of the unexpected nature of the present invention. OxyContin® has been available for many years, but the nature of its resistance to alcohol-induced dose dumping and the discovery of a possible mechanism for that resistance have been unknown until the discovery herein, Other formulation strategies besides including stearyl alcohol which can be used in the development of dosage forms. with sustained release, and related methods which provide resistance to dose dumping induced by aqueous alcohol can be found elsewhere herein. Some such embodiments are exemplified in Examples 7 to 11.

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The invention will now be described in more detail below.

II. Definitions 5 All percentages are by weight unless otherwise noted.

All of the scriptures cited herein are incorporated herein in their entirety by reference and for all purposes as if they were fully reproduced herein.

The present invention is best understood by reference to the following definitions, the drawings and the examples provided herein.

"Administration" means supplying a patient with a drug in a pharmacologically useful manner.

"Alcohol" means an organic compound having from 1 to about 5 carbon atoms in which a hydroxyl group (-OH) is bonded to a carbon atom which is again bonded to other hydrogen and / or carbon atoms. In a preferred embodiment, alcohol comprises ethanol.

"Apparent terminal half-life" (Γ / 2) is calculated as 0.693 / k, wherein "k" means the apparent rate of elimination rate estimated by linear regression of the logarithmically transformed plasma concentration during the terminal logarithmic linear elimination phase.

"Aqueous alcohol" means a combination comprising water and alcohol. Varying amounts of alcohol can be found in aqueous alcohol. Preferably, the aqueous alcohol comprises from 1% by volume (i.e., volume of alcohol / total volume of aqueous alcohol, expressed as%) to ca. 100% by volume of alcohol in aqueous alcohol, in particular, the aqueous alcohol comprises 30 alcohol at concentrations equal to or greater than ca. 20, more preferably, the aqueous alcohol comprises alcohol at concentrations equal to or greater than ca. 25% by volume, and even more preferably, the aqueous alcohol comprises alcohol at concentrations equal to or greater than ca. 40% by volume.

"Area under the curve" or "AUC" is the area measured under a plasma drug concentration curve. Most often, AUC is expressed in time interval over 14 14DK 2006 00189 U3, which integrates the piasma drug concentration curve, e.g. AUCstart-end. Thus, AUCO-48 denotes AUC obtained by integrating the plasma concentration curve for a period from 0 to 48 hours, where 0 is conventionally the time of administration of the drug or dosage form comprising the drug to a patient. The AUCt denotes the area under the plasma concentration curve from hour 0 to the last detectable concentration at time t, calculated by the trapezoidal rule. AUCinf denotes the AUC value extrapolated to infinity, calculated as the sum of AUCt and the area extrapolated to infinity, calculated using the concentration at time t (Ct) divided by k. (If the value of VA could not be estimated for an individual, the mean t / 4 value in for the treatment for calculating AUCinf). "Average area under a plasma concentration-time curve for a single dose of AUCinf means the average AUCinf obtained over several patients or multiple administrations to the same patient on different occasions with sufficient washout between dosages to allow drug levels to drop to pre-dosing levels after a single administration. of a dosage form for each patient.

"C" means the concentration of drug in an individual's blood plasma or serum, usually expressed as mass per unit dose. volume unit, typically nanograms per unit volume. milliliter. This concentration is conveniently referred to herein as "drug plasma concentration", "plasma drug concentration" or "plasma concentration". The plasma drug concentration at any time after drug administration is referred to as C time as in C9t or C24t, etc. A maximum plasma concentration obtained after administration of a dosage form obtained directly from the experimental data without interpolation is referred to as Cmax. The mean plasma concentration obtained for a period of interest is referred to as Cgns. "Average maximum single-dose plasma concentration" means the average Cmax obtained over several patients or multiple administrations to the same patient with sufficient washout between dosages to allow drug levels to drop to pre-dosing levels followed by a single administration of a dosage form for each patient. "Maximum single-dose plasma concentration for an individual patient" means the Cmax obtained for a single patient after a single administration with sufficient leaching between dosages to allow drug levels to drop to dosage levels followed by a single administration of a dosage form for each patient.

In one embodiment, the method of the invention comprises releasing opioid (such as, but not limited to hydromorphone or oxycodone) from the sustained release dosage form of opioid, preferably a sustained release opioid dosage form for once daily administration. 2 times daily, at which the ratio of an average maximum single-dose plasma opioid concentration obtained when the sustained-release opioid dosage form is administered to the patient with the aqueous alcohol, and an average maximum single-dose plasma opioid concentration achieved when the sustained-release dosage form of opioid administered to a patient without administration together with the aqueous alcohol is equal to or less than ca. 1.8: 1, preferably equal to or less than ca. 1.6: 1 and even more preferably equal to or less than ca. 1.4: 1st

In one embodiment, the method of the invention comprises release of opioid (such as, but not limited to hydromorphone or oxycodone) from the sustained-release opioid dosage form, wherein the ratio of an individual patient's maximum single-dose plasma opioid concentration achieved when the sustained-release opioid dosage form , preferably a sustained release dosage form of opioid for once or twice daily administration, is administered to the patient along with the aqueous alcohol, and an individual patient's maximum plasma opioid concentration after a single dose obtained when the sustained release dosage form is administered to a patient. patient without administration together with the aqueous alcohol is equal to or less than ca. 5: 1, preferably equal to or less than ca. 4: 1 and in particular equal to or less than approx. 3: 1.

"Administration with" means dosage of two or more substances to a patient within a limited period of time, preferably within 180 minutes, more preferably within 60 minutes, even more preferably within 45 minutes, still more preferably within 30 minutes, and especially within 15 minutes.

"Dosage form" means an opioid in a medium, carrier or device suitable for administration to a patient. "Oral dosage form" means a dosage form suitable for oral administration. In one embodiment, the dosage forms of the invention may comprise a sustained release dosage structure for the sustained release of the opioid and optionally an instant release component for immediate release of the opioid. In one embodiment, dosage forms of the invention may contain or exclude opioid antagonists such as naltrexone, naloxone or other common opioid antagonists.

16 DK 2006 00189 U3 "Dose" means a unit of drug. Usually a dose is provided as a dosage form. Doses can be administered to patients according to different dosing regimens. Common dosing regimens include once daily (qd), twice daily (bite) and three times daily (time). Opioid dosages useful in the practice of the invention are in the range of from ca. 0.001 mg to approx. 5000 mg, preferably from ca. 0.01 to approx. 1000 mg, more preferably from ca. 0.1 to approx. 750 mg, still more preferably from ca. 0.5 to approx. 500 mg, even more preferably from ca. 0.5 to approx. 250 mg, especially from approx. 1 to approx. 100 mg and most preferably from ca. 1 to approx. 50 mg.

"Immediate Release Dosage Form" means a dosage form which releases more than or equal to approx. 75% of the drug in less than or about 45 minutes after administration of the dosage form to a patient.

"Once daily" or "twice daily" means dosing frequency according to the methods of the invention. For example, once daily means that dosing usually takes place once every 24 hours.

Opioid "means an agent that binds to opioid receptors found mainly in the central nervous system and the gastrointestinal tract and is selected from opium alkaloids and semi-synthetic or fully synthetic opioids. Examples of opium alkaloids include morphine, codeine and thebain. Examples of semi-synthetic opioids include diamorphine, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone and nico-morphine Examples of fully synthetic opioids include methadone, levomethadyl acetate hydrochloride (LAAM), pethidine (meperidine), ketobemidone, propoxyphene, dextropene Other opioids are known to those of skill in the art. Preferred opioids in the practice of this invention include orally bioavailable opioids More preferred opioids include morphine, hydromorphone, hydrocodone, oxymorphone and oxycodone Opioids include pharmaceutically acceptable salts and free bases or free acids. the opioids of the invention period. In embodiments, sustained-release oral dosage forms of opioids of the present invention comprise from ca. 0.01 mg to approx. 1000 mg of opioid, preferably from ca. 0.1 mg to approx. 500 mg of opioid, more preferably from ca. 0.25 mg to approx. 300 mg of opioid and even more preferably from ca. 1 mg to approx. 100 mg of opioid. It should be noted that the solubility in water and / or aqueous alcohol of opioids according to the invention can vary considerably. In embodiments, the amount of opioid in a sustained release dosage form and / or the solubility of the opioid in aqueous alcohol can positively or negatively affect dose dumping in aqueous alcohol of sustained release dosage forms and / or related methods of the invention. For example, large amounts of aqueous alcohol of easily soluble opioid and / or opioid form in certain embodiments may increase the likelihood of dose dumping induced by aqueous alcohol. Conversely, large amounts of aqueous alcohol can greatly insoluble opioid and / or opioid form reduce the likelihood of dose dumping induced by aqueous alcohol.

"Long-release oral dosage structure" means a structure suitable for oral administration to a patient and comprising one or more drugs, which structure serves for long-term release of the drug (s). "Long-release oral osmotic dosage structure" means a sustained-release oral dosage structure which operates by an osmotic long-release drug or drug release mechanism.

"Patient" means an animal, preferably a mammal, and in particular a human in need of therapeutic intervention.

"Pharmaceutically acceptable salt" means any salt whose anion does not contribute significantly to the toxicity or pharmacological action of the salt and as such are the pharmacological equivalents of the drug base. Suitable pharmaceutically acceptable salts include acid addition salts, such as e.g. may be formed by reacting the drug compound with a suitable pharmaceutically acceptable acid such as hydrochloric, sulfuric, fumaric, maleic, succinic, acetic, benzoic, citric, tartaric, carbonic or phosphoric acids.

Thus, representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate , estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxy-naphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, malinate, malinate, malinate , methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartate, tartrate triethiodide and valerate.

18 DK 2006 00189 U3 "Plasma drug concentration curve" or drug plasma concentration curve "or" plasma concentration curve "or" plasma profile "or" plasma concentration profile "usually means the curve obtained by depicting the plasma drug concentration or drug concentration or drug concentration concentration or drug concentration that the zero point on the time scale (traditionally on the x-axis) is the time of administration of the drug or dosage form comprising the drug to a patient.

"Elongated period" means a continuous period longer than approx. 2 hours, preferably longer than approx. 4 hours, more preferably longer than approx. 8 hours, even more preferably longer than approx. 10 hours, still more preferably longer than approx. 14 hours and most preferably longer than approx. 14 hours and up to approx. 24 hours.

"Release rate" means the amount of drug released from a dosage form per day. unit of time, e.g. milligrams of drug released per day. hour (mg / hour). Drug release rates for dosage forms can be measured as the in vitro rate of drug release, i.e. an amount of drug released from the dosage form per unit of time measured under appropriate conditions and in a suitable test medium.

In a preferred embodiment, the release rates set forth herein may be determined by placing a dosage form to be tested in demineralized water in metal coil or metal cage sample holders connected to a USP type VII bath recorder in a constant temperature water bath of 37 ° C. Samples of the release rate solutions collected at predetermined intervals are then injected into a chromatographic system equipped with an ultraviolet detector or refractive index detector to quantify the amount of drug released in the trial intervals. In other embodiments, other commonly known and used release rate experiments in vitro may also be used in the practice of this invention, such as the use of a USP type II apparatus, e.g. Distek Premiere® 5100.

In one embodiment, the sustained release dosage form of the opioid of the invention releases less than or equal to approx. 80% by weight, preferably less than or equal to approx. 70% by weight, more preferably less than or equal to approx. 60% by weight, even more preferably less than or equal to approx. 50% by weight, still more preferably less than or equal to approx. 40% by weight and most preferably less than or equal to approx. 25% by weight of the opioid dose from the sustained release dosage form of opioid 19 as measured using a test method in vitro. In a preferred embodiment, the in vitro assay method, such as the aforementioned assay methods in vitro or other conventional in vitro assay methods, comprises assay media in which the sustained release dosage form of opioid is placed in the trial period. In one embodiment, the amount of opioid released from the sustained-release opioid dosage form of the invention is measured for a set period of time, preferably for a period of about 10 minutes. 24 hours after initiation of the experimental method in vitro, more preferably for a period of approx. 12 hours after initiation of the experimental method in vitro and even more preferably for a period of approx. 2 hours after initiation of the experimental method in vitro.

In one embodiment, the test medium comprises aqueous alcohol which comprises alcohol. In a preferred embodiment, the test medium comprises aqueous alcohol which comprises alcohol at concentrations equal to or greater than ca. 20% by volume (volume of alcohol / total volume of test medium), preferably equal to or greater than ca. 25% by volume, more preferably equal to or greater than ca. 30% by volume, still more preferably equal to or greater than approx. 35% by volume and most preferably equal to or greater than approx. 40% by volume.

"Prolonged release" means sustained release of a drug or dose of a drug for an extended period of time.

"Long-release release dosage structure" means one or more physical elements providing long-term release of a drug or dose of a drug.

"Long-release dosage form" means a type of dosage form which provides for long-term release of a drug or dose of a drug.

"Average Time to Maximum Plasma Concentration Tmax after a Single Dose" is the average of several patients or many administrations to the same patient with sufficient washout between dosages to allow drug levels to drop to levels prior to dosing the elapsed time from administration to a patient of a dosage form. comprising a drug at the time at which the Tmax of that drug is obtained, followed by a single administration of the dosage form to each patient and obtained directly from the experimental data without interpolation. In one embodiment, the ratio of the average time to maximum plasma concentration of a single dose obtained when the dosage form is administered to the patient along with the aqueous alcohol, and the average time to maximum plasma concentration after a single dose, obtained when the dosage form is obtained with sustained release of opioid administered to a patient without concomitant administration of the aqueous alcohol, ranges from approx. 0.5 to approx. 1.0, preferably from ca. 0.6 to approx. 1.0, more preferably from ca. 0.7 to approx. 1.0 and most preferably from ca. 0.75 to approx. 1.0.

"Therapeutically effective amount" means the amount of drug that induces the biological or medical response in a tissue system, animal or human being sought by a researcher, veterinarian, medical doctor or other physician and which includes relief of the symptoms of the disease or disorder. that is being processed.

III. Dosage Forms In embodiments, the sustained release dosage forms of the invention are formulated into dosage forms which can be administered to patients in need thereof. The sustained release dosage forms and treatment methods using the sustained release dosage forms will now be described. It is to be understood that the sustained release dosage forms described below are merely examples.

Various sustained release dosage forms are suitable for use in the present invention. In certain embodiments, the dosage form can be administered orally and has the size and shape of a conventional tablet or capsule. Orally administered dosage forms can be prepared by one of several different methods. For example, the dosage form can be prepared as a diffusion system, such as a storage device or matrix device, a solution system such as encapsulated solution systems (including, for example, "tiny time pills" and beads), and matrix solution systems and combined diffusion / dissolution systems and ion exchange resin systems, such as , ed., pp. 1676-1686 (1990), Mack Publishing Co.; and The Pharmaceutical and Clinical Pharmacokinetics, 3rd ed., pp. 1-28 (1984). Lea and Febreger, Philadelphia.

Osmotic dosage forms usually employ osmotic pressure to create a driving force to absorb fluid in a compartment at least partially formed by a semipermeable membrane which allows free diffusion of fluid but not drug or osmotic agents if present. . A significant advantage of osmotic systems is that they act pH-independent and thus continue with the osmotic determined rate for an extended period of time, although the dosage form passes through the gastrointestinal tract encounters different microenvironments with significantly different pH values. An overview of such dosage forms is found in Santus and Baker, "Osmotic drug delivery; a review of the patent literature", Journal of Controlled Release 35 (1995) 1-21, which is incorporated herein by reference. U.S. Patent Nos. 3,845,770, 3,916,899, 3,995,631, 4,008,719, 4,111,202, 4,160,020, 4,327,725, 4,578,075, 4,681,583, 5,019,397 and 5,156,850 disclose osmotic devices for sustained release of active substance.

Long-release osmotic dosage forms in which a drug composition is delivered as a slurry, suspension or solution from a small mouth by the action of an expandable layer are disclosed in U.S. Patent Nos. 5,633,011, 5,190,765, 5,252,338, 5,620. 705, 4,931,285, 5,006,346, 5,024,842 and 5,160,743 which are incorporated herein by reference. Typical devices include an expandable pressure layer and a drug layer surrounded by a semipermeable membrane. In some cases, the drug layer is provided with an undercoat to delay release of the drug composition into the application environment or to form a cured coating in conjunction with the semipermeable membrane. In one embodiment, further protection against dose dumping can be obtained by applying an enteric coating, preferably one which is insoluble in aqueous alcohol and not swelling in aqueous alcohol and gastric pH, to the sustained release osmotic dosage form. To protect the semipermeable membrane, a film of hydrophilic (such as vinyl alcohol) or hydrophobic material may be coated on the semipermeable membrane. If the team allows less ethano! To contact the semipermeable membrane, swelling of the semipermeable membrane can be avoided or minimized.

An example of a dosage form, which in the art is referred to as an elemental dosage array form with osmotic pump, is shown in Figure 1. The dosage form 20, seen as cut, is also referred to as an elemental osmotic pump (EOP) and consists of a semipermeable membrane 22 which surrounds and encloses an inner compartment 24. The inner compartment contains a single component layer, herein referred to as drug layer 26, comprising a substance of the invention 28 in admixture with selected excipients. The excipients are adapted to provide a gradient of osmotic activity to attract liquid from an external environment through the membrane 22 and form a releasably complex composition after fluid suction. The excipients may contain a suitable suspending agent, also referred to herein as drug carrier 30, a binder 32, a lubricant 34, and an osmotically active agent referred to as an osmagic 36. Examples of materials useful for these components can be found throughout the present application.

The semipermeable membrane 22 of the osmotic dosage form is permeable to the passage of an outer fluid such as water and biological fluids, but is substantially impermeable to the passage of components within the inner compartment. Applicable materials for forming the membrane are substantially non-erodible and are essentially insoluble in biological fluids in the dosage form lifetime. Representative polymeric ten! formation of the semipermeable membrane comprises homopolymers and copolymers such as e.g. cellulose esters, cellulose ethers and cellulose esters. Flow regulating agents can be mixed with the membrane forming material to modulate the fluid permeability of the membrane. For example, agents which produce a marked increase in fluid permeability such as water are often substantially hydrophilic, while those which produce a marked water permeability decrease are substantially hydrophobic. Examples of flow regulators include polyhydric alcohols, polyalkylene glycols, polyalkylene diols, polyester alkylene glycols, and the like.

In use, the osmotic gradient across the membrane 22, due to the presence of osmotically active agents, entails the absorption of gastric fluid through the membrane, swelling of the drug layer, and formation of a releasably complex preparation (e.g., a solution, suspension, slurry or other liquid composition). in the internal department. The release composition of the substance of the invention is released through an outlet 38 as fluid continues to enter the inner compartment. Even when drug preparation is released from the dosage form, fluid continues to be sucked into the inner compartment, thereby driving continued release. In this way, the substance of the invention is released prolonged and sustained over an extended period of time.

Figure 2 illustrates certain embodiments of sustained release dosage forms of the invention. Dosage forms of this type are described in detail in U.S. Patent Nos. 4,612,008, 5,082,668 and 5,091,190 and are further described below.

Figure 2 shows an embodiment of one type of sustained release dosage form, namely the sustained release osmotic dosage form. A first drug layer 30 comprises osmotically active components and a lower amount of opioid into a second drug layer 40. The osmotically active component (s) of the first component drug layer comprises an osmagent such as salt and one or more osmopolymers having small molar weights which exhibit swelling as fluid is absorbed so that release of these osmopolymers through an exit 60 is similar to that of drug layer 40. Additional excipients such as binders, lubricants, antioxidants and dyes may also be included in the first drug layer 30 .

The second drug layer 40 comprises opioid in admixture with selected excipients intended to provide a gradient of osmotic activity to drive fluid from an external environment through the membrane 20 and form a drug composition that can be delivered after fluid aspiration. The excipients may contain a suitable suspending agent, herein also referred to as drug carrier, but no osmotically active agent, "osmagens," such as salt or sodium chloride. It has been discovered that omission of salt from this second drug layer, which contains a higher proportion of the total drug in the dosage form, in combination with the salt of the first drug layer, provides an improved increasing rate of release, creating longer duration of increasing rate.

The drug layer 40 has a higher concentration of opioid than the drug layer 30. The ratio between the concentration of opioid in the first drug layer 30 and the concentration of opioid in the second drug layer 40 is preferably kept less than 1 and preferably less than or equal to approx. 0.43 to provide the desired substantially increasing release rate.

The drug layer 40 may also comprise other excipients such as lubricants, binders, etc.

Both the drug layer 40 and the drug layer 30 further comprise a hydrophilic polymer as a carrier. The hydrophilic polymer contributes to the regulated delivery of the opioid. Representative examples of these polymers are poly (alkylene oxide) having a number average molecular weight of 10,000 to 750,000, including poly (ethylene oxide), poly (methylene oxide), poly (butylene oxide) and poly (hexylene oxide) and a polyfcarboxymethyl cellulose having a number average 40,000 to 400,000, represented by poly (alkali metal carboxymethyl cellulose), poly (sodium carboxymethyl cellulose), poly (potassium carboxymethyl cellulose) and poly (lithium carboxymethyl cellulose). The medicament layer 40 may further comprise a hydroxypropylalkyl cellulose (hydroxypropylmethylcellulose) hydroxypropylmethylcellulose and hydroxypropylmethylcyllucyl) ethylcellulose and hydroxypropyl butylcyclose the flow properties of the dosage form. Of these polymers, poly (ethylene oxide) having number average molecular weight 100,000 to 300,000 is preferred. Carriers that are eroded in the gastric environment, ie. bioerodible carriers are particularly preferred.

10

Other carriers which may be incorporated into drug layer 40 and / or drug layer 30 include carbohydrates which exhibit sufficient osmotic activity to be used alone or in combination with other osmagens. Such carbohydrates include monosaccharides, disaccharides and polysaccharides. Representative examples include maltodextrins (i.e., glucose polymers prepared by hydrolysis of corn starch) and the sugars comprising lactose, glucose, raffinose, sucrose, mannitol, sorbitol and the like. Preferred maltodextrins are those having a detraction equivalent (DA) of 20 or less, preferably with a DA in the range of about 10 4 to approx. 20 and often 9 to 20. Maltodextrin with a DA of 9 to 12 has proven useful.

20

The drug layer 40 and drug layer 30 will typically be a substantially dry composition having a water content less than 1% by weight formed by compressing the carrier, opioid and other excipients as a layer.

The drug layer 40 can be formed by particles by comminution which produce the size of the drug and the size of the accompanying polymer used in the preparation of the drug layer, typically as a core containing the compound according to the invention. Methods for producing particles include granulation, spray drying, sieving, freeze drying, crushing, grinding, jet milling, grinding and chopping to produce the intended micrometer particle size.

The method can be carried out with size reduction equipment such as a micro-pulverizer mill, a liquid energy grinding mill, a grinding mill, a rolling mill, a hammer mill, a grinding mill, a work-up mill, a ball mill, a vibrating ball mill, a grinding mill mill, a grinding mill mill, a grinding mill mill, crush. The particle size can be controlled by screening, including with a heavy sorting grate, a flat screen, a vibrating screen, a sorting drum, a shaking screen, an oscillating screen and a reciprocating screen. The methods and equipment for preparing drug and carrier particles are disclosed in Pharmaceutical Sciences, Remington, 17th ed., Pp. 1585-1594 (1985), Chemical Engineers Handbook, Perry, 6th ed., Pp. 21-13 to 21 -19 (1984), Journal of Pharmaceutical Sciences, Parrot, Vol. 61, No. 6, pp. 813-829 (1974) and Chemical Engineer, Hixon, pp. 94-103 (1990).

The first drug layer 30 comprises active substance in admixture with selected excipients intended to provide a gradient of osmotic activity to drive fluid from an external environment through the membrane 20 and to form a releasable drug preparation after fluid aspiration. The excipients may contain a suitable suspending agent, also referred to herein as a drug carrier, and an osmotically active agent, i.e. an "osmagic" such as salt. Other excipients such as lubricants, binders, etc. may also be included. Surprisingly, it has been found that when the first component drug layer 30 comprises an osmotically active component and a lower amount of active substance than in the second component drug layer 40, an improved increasing release rate can be created which provides longer duration of the increasing rate.

The osmotically active component of the first drug layer typically comprises a relatively small molecular weight osmopolymer and one or more osmopolymers which exhibit swelling as fluid is aspirated so that release of these osmopolymers through the outlet 60 is similar to that of drug layer 40.

The ratio of opioid concentration in the first drug layer to the second drug layer changes the release rate profile. The release rate profile is calculated as the difference between the maximum release rate and the release rate obtained at the first time after start (eg at 6 hours) divided by the average release rate between the two data points.

The drug layer 30 and drug layer 40 may optionally contain surfactants and disintegrants in both drug layers. Examples of the surfactants are those with a FILB value of approx. 10 to 25 such as polyethylene glycol 400 monostearate, polyoxyethylene-4-sorbitan monolaurate, polyoxyethylene-20-sorbitan monolaurate, polyoxyethylene-20-sorbiatane monopalmitate, polyoxyethylene-20-monolaurate, polyoxyethylene-40-stearate, sodium oleate and the like.

26 DK 2006 00189 U3

Disintegrants can be selected from starch species, clays, cellulose species, alginates and gums as well as cross-linked starch species, cellulose species and polymers. Representative disintegrants include corn starch, potato starch, croscarmellose, crospovidone, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum and the like.

The membrane 20 is made so that it is permeable to passage of an outer fluid, such as water and biological fluids, and is substantially impervious to passage of paliperidone, osmagogue, osmopolymer and the like. As such, it is semipermeable. The selectively semipermeable compositions used to prepare the membrane 20 are substantially non-erodible and substantially insoluble in biological fluids during the life of the dosage form.

Representative polymers for the preparation of membrane 20 include semipermeable 15 homopolymers, semipermeable copolymers and the like. In a presently preferred embodiment, the compositions may comprise cellulose esters, cellulose ethers and cellulose ester ethers. The cellulose polymers typically have a degree of substitution, "SG", on their anhydroglucose unit from greater than 0 up to and including 3. Degree of substitution is understood as the average number of hydroxyl groups initially found on the anhydroglucose unit which is replaced by a substituting group or converted to another group. The anhydroglucose moiety may be replaced in whole or in part by such groups as acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy, halogen, carboalkyl, alkylcarbamate, alkylcarbonate, alkylsulfonate, alkylsulphamate, groups forming semipermeable polymers and the like. The semi-permeable compositions typically contain an element selected from cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose triacetate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tri-cellulose alcanylates, mono-, di-, di-, , di- and tri-aroylates and the like.

Examples of polymers may e.g. include cellulose acetate having an SG of 1.8 to 2.3 and an acetyl content of 32 to 39.9%, cellulose diacetate having an SG of 1 to 2 and an acetyl content of 21 to 35%, cellulose triacetate having an SG of 2 to 3, and an acetyl content of 34 to 44.8% and the like. More specific cellulosic polymers include cellulose propionate having a SG of 1.8 and a propionyl content of 38.5%; ceilulose acetate propionate having an acetyl content of 1.5 to 7% and an acetyl content of 39 to 42%; cellulose acetate propionate having an acetyl content of 2.5 to 3%, an average propylene content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having a SG of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylates with an SG of 2.6 to 3, such as cellulose trivalent, cellulose trilamate, cellulose tripalmitate, cellulose trioctanoate, and cellulose tripropionate; mixed cellulose esters such as cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate; cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate heptonate and the like. Semipermeable polymers are known from U.S. Patent No. 4,077,407 and can be synthesized by methods described in Encyclopedia of Polymer Science and Technology, Vol. 3, pp. 325 to 354, 1964, published by Interscience Publishers, Inc. , New York.

Additional semi-permeable polymers for preparing the semi-permeable membrane may include, for example, cellulose acetaldehyde dimethyl acetate; celluloseacetatethylcar carbamate; cellulose acetate methylcarbamate; cellulose dimethylaminoacetate; semipermeable polyamide; semi-permeable polyurethanes; semipermeable sulfonated polystyrenes; crosslinked selectively semipermeable polymers prepared by precipitating a polyanion and a polycation together as disclosed in U.S. Patent Nos. 3,173,876, 3,276,586, 3,541,005, 3,541,006, and 3,546,142 semipermeable polymers as disclosed in U.S. Pat. 3,133,132; semipermeable polystyrene derivatives, semipermeable poly (sodium styrene sulfonate); semipermeable poly (vinylbenzyl trimethyl ammonium chloride); semipermeable polymers which exhibit a fluid permeability from 10'5 to 10'2 (cc. mil / cm hr.atm) expressed as per atmosphere hydrostatic or osmotic pressure difference across a semipermeable membrane. The polymers are known from U.S. Patent Nos. 3,845,770, 3,916,899 and 4,160,020 and from the Handbook of Common Polymers by J.R. Scott and W.J. Roff, 1971, published by CRC Press, Cleveland, Ohio.

The diaphragm 20 may also comprise a flow regulator. The flow regulator is a compound added to assist in regulating the fluid permeability or flow through the membrane 20. The flow regulator may be a flow enhancer or a flow reducing agent. The agent may be selected in advance to increase or decrease the fluid flow. Agents which produce a marked increase in the permeability of fluids such as water are often substantially hydrophilic, while those which produce a marked decrease in the permeability of fluids such as water are substantially hydrophobic. The amount of regulator in the membrane 20, when incorporated therein, is usually from ca. 0.01% to 20% by weight or more. The flow control agents in one embodiment which increase the flow include, for example, polyhydric alcohols, polyalkylene glycols, polyalkylene diols, polyesters of alkylene glycols and the like. Typical flow enhancers include polyethylene glycol 300, 400, 600, 1500, 4000, 6000, poly (ethylene glycol co-propylene glycol) and the like; low molecular weight glycols such as polypropylene glycol, polybutylene glycol and polyamylene glycol; the polyalkylene diols such as poly (1,3-propanediol), poly (1,4-butanediol), poly (1,6-hexanediol) and the like; aliphatic diols such as 1,3-butylene glycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol and the like; alkyl triols such as glycerol, 1,2,3-butanetriol, 1,2,4-hexanetriol, 1,3,6-hexanetriol and the like; esters such as ethylene glycol dipropionate, ethylene glyco butyrate, butylene glycol dipropionate, glycerol acetate esters and the like. Representative flow reducing agents include, for example, phthalates substituted with an alkyl or alkoxy group or with both an alkyl and an alkoxy group such as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate and [di (2-ethylhexyl) phthalate], aryl phthalate, aryl phthalate, ; insoluble salts such as calcium sulfate, barium sulfate, calcium phosphate and the like; insoluble oxides such as titanium oxide; powders, granules and the like, such as polystyrene, polymethyl methacrylate, polycarbonate and polysulfone; esters such as citric acid esters esterified with long chain alkyl groups; inert and substantially water impermeable fillers; resins compatible with cellulose-based membrane forming materials and the like.

Other materials which can be used to make the membrane 20 to impart the flexibility and elongation properties to the wall, to make the membrane less brittle or not at all brittle and provide tear strength, e.g. phthalate plasticizers such as dibenzyl phthalate, dihexyl phthalate, butyloctyl phthalate, straight chain 6 to 11 carbon atoms, diisodecyl phthalate, diisononyl phthalate and the like. The plasticizers include non-phthalates such as triacetin, dioctyllazate, epoxidized tallate, triisoctyltrimellilate, triisononyltrimellite, sucrose acetate isobutyrate, epoxidized soybean oil and the like. When softener is incorporated into a membrane, the amount thereof is approx. 0.01% to 20% by weight or more.

The pressure layer 50 comprises an expandable layer disposed in contact with the second layer 40 as shown in Figure 2. The pressure layer 50 comprises a polymer which absorbs an aqueous or biological fluid and swells to express the drug composition through the device. outlet opening.

The expandable layer comprises, in one embodiment, a hydro-activated composition which swells in the presence of water, e.g. is found in stomach fluids. Conveniently, it may comprise an osmotic composition comprising an osmotic solute which exhibits an osmotic pressure gradient across the semipermeable membrane towards an outer fluid present in the application environment. In another embodiment, the hydroactivated layer comprises a hydrogel which absorbs and / or absorbs fluid in the layer through the outer semipermeable membrane. The semipermeable membrane is non-toxic. It maintains its physical and chemical integrity during operation and is essentially free of interaction with the expandable layer.

The expandable layer comprises, in a preferred embodiment, a hydroactive layer comprising a hydrophilic polymer, also known as osmopolymers. The osmopolymers exhibit fluid suction properties. The osmopolymers are swellable, hydrophilic polymers, and they interact with water and aqueous biological fluids and swell or expand to an equilibrium state. The osmopolymers exhibit the property of swelling in water and biological fluids and retaining a significant portion of the absorbed fluid in the polymer structure. The osmopolymers swell or expand to a very high degree and usually exhibit 2 to 50 fold volume increase. The osmopolymers may be non-crosslinked or crosslinked. The swellable hydrophilic polymers are in one embodiment slightly cross-linked, such cross-linking being formed by covalent bonds or ionic bonds or remaining crystalline regions after swelling. The osmopolymers may be of vegetable, animal or synthetic origin.

The osmopolymers are hydrophilic polymers. Hydrophilic polymers suitable for the present purpose include poly (hydroxyalkyl methacrylate) having a molecular weight of from 30,000 to 5,000,000; poly (vinylpyrrolidone) having a molecular weight of 10,000 to 360,000; anionic and cationic hydrogels; complex polyelectrolytes; low residual acetate poly (vinyl alcohol), cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization from 200 to 30,000; a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose; a mixture of hydroxypropyl methylcellulose and sodium carboxymethylcellulose; a mixture of hydroxypropyl-ethylcellulose and sodium carboxymethylcellulose; a mixture of sodium carboxymethyl cellulose and methyl cellulose, sodium carboxymethyl cellulose; potassium carboxylic acid methylcellulose; a water-insoluble, water-swellable copolymer formed from a dispersion of finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene crosslinked with from 0.001 to about 0.5 mole saturated crosslinking agent per moles of maleic anhydride per copolymer; water-swellable polymers of N-vinyl lactams; polyoxyethylene-polyoxypropylene gel; locust bean gum; polyacrylic acid; polystergel; polyurinstofgel; polyether gel; polyamide gel; polycellulosic gel; poly-rubber gel; initially dry hydrogels, which absorb and absorb water, which permeate the vitreous hydrogel and lower its glass temperature; and the like.

Representatives of other osmopolymers are polymers which form hydrogels such as carbopol ™, acidic carboxy polymer, an acrylic acid polymer crosslinked with polyallyl sucrose, also known as carboxypolymethylene, and carboxyvinyl polymer having a molecular weight of 250,000 to 4,000,000; Cyanamer ™ polyacrylamides; crosslinked water-swellable internal maleic anhydride polymers; Good-rite ™ polyacrylic acid with a molecular weight of 80,000 to 200,000; Polyox ™ polyethylene oxide polymer having a molecular weight of 100,000 to 5,000,000 and above; starch seed copolymers; Aqua-Keeps ™ acrylate polymer polysaccharides composed of condensed glucose units, such as diesters of cross-linked polyglurane; and the like. Representative polymers forming hydrogels are known from U.S. Patent Nos. 3,865,108, 4,002,173, and 4,207,893; and Handbook of Common Polymers by Scott and Roff, published by Chemical Rubber C., Cleveland, Ohio. The amount of osmopolymer constituting a hydroactivated layer can be from ca. 5% to 100%.

The expandable layer may comprise, in another make, an osmotically effective compound comprising inorganic and organic compounds exhibiting an osmotic pressure gradient across a semipermeable membrane toward an outer fluid. The osmotically efficient compounds, like the osmopolymeric fluid, absorb in an osmotic system thereby making fluid available to press against the inner wall, i.e. in some embodiments, the barrier layer and / or membrane of the soft or hard capsule to express active agent from the dosage form. The osmotically effective compounds are also known as osmotically effective solvents and as osmagens. Useful osmotically active solvents include magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, acidic potassium phosphate, mannitol, inositol, magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose, glucose, lactose, sorbitol and mixtures. The amount of osmagogue may be from 5% to 100% of the weight of the layer. The expandable layer may optionally comprise an osmopolymer and an osmagogue with a total amount of osmopolymer and the osmagal equal to 100%. Osmotically effective solvents are known, e.g. from U.S. Patent No. 4,783,337.

A protective undercoat, the inner wall 90, is permeable to passage of fluid entering the compartment defined by the membrane 20. The wall 90 provides a lubricating function which facilitates the movement of the first drug layer 30, the second drug layer 40 and the pressure layer 50 towards the outlet 60. The wall 90 can be formed of hydrophilic materials and excipients. The wall 90 promotes the release of the drug composition from the ward and reduces the amount of remaining drug composition remaining in the ward at the end of the delivery period, especially when the slurry, suspension or solution of the drug composition being delivered is highly viscous during the period of delivery. In dosage forms with hydrophobic agents and no inner wall, it has been observed that significant residual amounts of drug may remain in the device after the end of the delivery period. In some cases, amounts of 20% or more may remain in the dosage form at the end of a 24 hour period when tested in a release rate analysis. Especially in the case of costly active compounds, such an improvement offers significant economic benefits, since it is not necessary to fill the drug layer with excess drug to ensure that a minimal amount of drug will be delivered. The inner membrane 90 can be made as a coating applied to the compressed core.

The wall 90 may typically be 0.01 to 5 mm thick, more typically 0.5 to 5 mm thick, and it comprises an element selected from hydrogels, gelatin, low molecular weight polyethylene oxides, e.g. less than 100,000 hydroxyalkyl celluloses, e.g. hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyisopropyl cellulose, hydroxybutyl cellulose and hydroxyphenyl cellulose and hydroxyalkylalkylcelluloses, e.g. hydroxypropylmethyl cellulose, and mixtures thereof. The hydroxyalkyl celluloses comprise polymers having a number average molecular weight of 9,500 tonnes. 1,250,000. For example, hydroxypropyl cellulose with number average molecular weights is 80,000 tons. 850,000 usable. The wall 90 can be prepared from conventional solutions or suspensions of the above materials in aqueous solvents or inert organic solvents.

32 DK 2006 00189 U3

Preferred materials for wall 90 include hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, povidone [poly (vinylpyrrolidone)], polyethylene glycol and mixtures thereof.

Particularly preferred are mixtures of hydroxypropyl cellulose and povidone prepared in organic solvents, especially polar organic solvents such as lower alkanols of 1-8 carbon atoms, preferably ethanol, mixtures of hydroxyethyl cellulose and hydroxypropyl methyl cellulose prepared in aqueous solution and mixtures of hydroxy resolution. In particular, it is preferred that wall 90 comprises a mixture of hydroxypropyl cellulose and povidone prepared in ethanol.

It is preferred that wall 90 comprises between ca. 50% and approx. 90% hydroxypropyl cellulose identified as EC with an average molecular weight of approx. 80,000 to 15 between approx. 10% and about 50% polyvinylpyrrolidone identified as K29-32.

Conveniently, the weight of wall 90 applied to the pressed core may be correlated with the thickness of wall 90 and residual drug remaining in a dosage form in a release rate assay as described herein. As such, the thickness of the wall 90 during manufacture can be controlled by controlling the weight of the wall 90 absorbed in the coating step.

When wall 90 is formed as an undercoat, i.e. by coating on the tableted composition containing one or all of the first drug layer, the second drug layer and the pressure layer, the wall 90 can fill the surface irregularities formed on the core during the tableting process. The resulting smooth outer surface facilitates sliding between the coated composite core and the semipermeable membrane upon delivery of the drug, resulting in a lower amount of residual drug composition remaining in the device at the end of the dosing period. When wall 90 is made of gelling material, contact with water in the ambient environment facilitates formation of the gel or gel-like inner coating with a viscosity that can promote and enhance sliding between membrane 20 and drug layer 30 and drug layer 40.

Convenient brow coating can conveniently be used to provide the complete dosage form, except for the outlet opening. In the pan coating system 33, the wall-forming composition is deposited to the wall or membrane, as the case may be, by successively spraying the appropriate membrane composition onto the pressed three-layer or multi-layer cores comprising the drug layers, optionally barrier layers and pressure layers, accompanied by tumbling in a rotating pan. . A brow coating is used because of its availability on a commercial scale. Other techniques can be used to coat the pressed core. Once the core is coated, the membrane is dried in a hot air oven or in a controlled temperature and humidity furnace to release the dosage form of solvents used in the preparation. Drying conditions are conveniently selected on the basis of available equipment, ambient conditions, solvents, coatings, coating thicknesses and the like.

Other coating techniques may also be used. For example, the diaphragm or walls of the dosage form can be designed in a technique using the air suspension method. This method consists in suspending and tumbling the pressed core into an air stream and the composition forming the semipermeable membrane until the membrane is applied to the core. The air suspension method is well suited to independently form the dosage form membrane. The air suspension method is disclosed in U.S. Patent No. 2,799,241; in J. Am Pharm. Assoc., Vol. 48, pp. 451-459 (1959); and ibid., 49, pp. 82-84 (1960). The dosage form can also be coated with a Wurster® air suspension coating, e.g. using methylene chloride / methanol as an auxiliary solvent for the membrane forming material. An Aeromatic® air suspension coating can be used using an auxiliary solvent.

In one embodiment, the sustained-release dosage form of the invention is provided with at least one output 60 as shown in Figure 2. The output 60 cooperates with the pressed core for uniform release of drug from the dosage form. The output may be provided during the preparation of the dosage form or during the delivery of the dosage form drug in a liquid application environment.

One or more exit openings are drilled into the drug layer of the dosage form, and any water-soluble coatings which may be colored (e.g., Opadry colored coatings) or clear (e.g., Opadry Clear) may be coated on the dosage form to provide the finished dosage form.

34 DK 2006 00189 U3

The outlet 60 may contain an opening formed or formed by a substance or polymer which is eroded, dissolved or leached from the outer membrane, thereby forming the exit opening. The substance or polymer may e.g. contain an erodible polyglycolic acid or polylactic acid in the semipermeable wall; a gelatinous filament; a water-removable polyvinyl alcohol; a leachable compound such as a fluid-irreversible pore former selected from the group consisting of inorganic and organic salt, oxide and carbohydrate.

One or more exits can be formed by leaching an element selected from sorbitol, lactose, fructose, glucose, mannose, galactose, tallose, sodium chloride, potassium chloride, sodium citrate and mannitol to provide an exit aperture as uniformly sized pore.

The output may be of any shape, such as round, triangular, square, elliptical, and the like, for uniformly metered dose release of a drug from the dosage form. The sustained release dosage form can be constructed with one or more spaced outputs or one or more surfaces of the sustained release dosage form.

Drilling, including mechanical drilling and laser drilling, through the semipermeable membrane can be used to form the exit aperture. Such outputs and equipment ten! formation of such outputs is disclosed in United States Patent No. 3,916,899 to Theeuwes and Higuchi and in U.S. Patent No. 4,088,864 to Theeuwes et al. At present, it is preferred to use two outlets of equal diameter. In a preferred embodiment, the output 60 penetrates the undercoating 90, if present, to the drug layer 30.

Dosage forms according to the embodiments depicted in Figure 1 are prepared by standard techniques. For example, the dosage form can be prepared by wet granulation technique. In the wet granulation technique, the drug and carrier are formed using an organic solvent, such as denatured anhydrous ethanol, as the granulation fluid. The other ingredients can be dissolved in a portion of the granulation fluid, such as the solvent described above, and this latter wet mixture prepared is added slowly to the drug mixture during continuous mixing in the mixer. The granulating fluid is added until a wet mixture is prepared and it is then driven through a predetermined sieve onto oven plates.

35 DK 2006 00189 U3

The mixture is dried for 18 to 24 hours at 24 ° C to 35 ° C in a hot air oven. The dried granules are then sorted by size.

Then, magnesium stearate or other suitable lubricant is added to the drug granulate and the granulate is placed in grinding containers and mixed on a grating mill for 10 minutes. The composition pressed into a layer, e.g. in a Manesty® press or a Korsch LCT press. To a three-layer core, granules or powders of the drug layer compositions and the pressure layer composition are sequentially placed in a nozzle of appropriate size, intermediate compression steps being transferred to each of the first two layers, followed by a final compression step after the last layer is added to the three-layer core nozzle. . The intermediate compression typically takes place under a pressure of approx. 50 to 100 newtons. The pressing in the final step typically takes place at a force of 3,500 newtons or more, often 3,500 to 5,000 newtons. The pressed core is applied to a dry coating press, e.g. a Kilian® Dry Coater press, and then coated with the membrane materials as described above.

In another embodiment, the drug and other constituent constituents are mixed and pressed into a solid layer. The layer has dimensions corresponding to the inner dimensions of the area that the layer is to occupy in the dosage form, and it also has dimensions corresponding to the pressure layer, if included, to form a contact arrangement therewith. The drug and other ingredients may also be mixed with a solvent and mixed into a solid or semi-solid form by conventional methods such as ball milling, calendering, stirring or rolling milling, and then pressed to a preselected form. If a layer of the osmopolymer composition is included, it is then placed in contact with the drug layer in a similar manner. The aggregation of the drug preparation and the osmopolymer layer can be prepared by conventional two-layer pressing techniques. A similar method can be followed for the preparation of the three-layer core. The pressed cores can then be coated with the wall material and the semipermeable membrane material as described above.

Another method of preparation which can be used involves mixing the powdered components to each layer in a fluid bed bed granulator. After dry mixing the powdered components in the granulator, a granulating fluid is sprayed, e.g. polyvinylporrolidone in water, on the powders. The coated powders are then dried in the granulator. In this method, all of the constituents present therein are granulated with the addition of granulation fluid. After drying the granulate, a lubricant such as stearic acid or magnesium stearate is mixed in the granulate using a mixer, e.g. a V-mixer or a carrier mixer. The granulate is then pressed in the manner described above.

Examples of solvents suitable for preparing the dosage form components include aqueous or inert organic solvents which do not adversely affect the materials used in the system. The solvents broadly comprise elements selected from aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic and heterocyclic solvents and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl ether , carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, aqueous solvents containing inorganic salts, such as sodium chloride and calcium, calcium thereof, such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene chloride and methanol and ethylene chloride and methanol.

An important consideration in practicing the invention is the physical state of the opioid to be delivered by the dosage form. In certain embodiments, the opioids may be in paste or liquid state. In such cases, solid dosage forms may be unsuitable for use in the practice of this invention. Instead, dosage forms should be used to dispense substances in a paste-like or liquid state.

The present invention provides a liquid composition of substances for use with oral osmotic devices. Oral osmotic devices for dispensing liquid preparations and methods for using them are known, e.g. as described and subject to claims in the following United States patents owned by ALZA Corporation: 6,419,952, 6,174,547, 6,551,613, 5,324,280, 4,111,201 and 6,174,547. Methods for using oral osmotic devices for delivering therapeutic agents with increasing release rate can be found in International Patent Applications Nos. WO 98/06380, WO 98/23263 and WO 99/62496.

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Examples of liquid carriers for the present invention include lipophilic solvents (e.g. oils and lipids), surfactants and hydrophilic solvents. Examples of lipophilic solvents include, but are not limited to, Capmul PG-8, Caprol MPGO, Capryol 90, Plurol Oleique CC 497, Capmul MCM, Labrafac PG, n-decyl alcohol, Caprol 10G10O, oleic acid, vitamin E, Maisine 35-1, Gelucire 33/01, Gelucire 44/14, lauryl alcohol, Captex 355EP, Captex 500, ca p ry I / ca pri nsy retri g I yce ri d Peceol, Caprol ET, Labrafil M2125 CS, Labrafac CC, Labrafil M 1944 CS, Captex 8277, Myvacet 9-45, isopropyl myristate, Caprol PGE 860, olive oil, Plurol Oleique, peanut oil, Captex 300 Low C6 and capric acid,

Examples of surfactants include, but are not limited to, vitamin E, TPGS, cremophor (quality EL, EL-P and RH40), Labrasol, Tween (quality 20, 60, 80), Pluronic (quality L-31, L-35 , L-42, L-64 and L-121), Acconon S-35, Solutol HS-15 and Chip (grades 20 and 80). Examples of hydrophilic solvents include, but are not limited to, isosorbide dimethyl ether, polyethylene glycol (PEG grades 300, 400, 600, 3000, 4000, 6000 and 8000) and propylene glycol (PG).

Those skilled in the art will appreciate that any composition comprising a sufficient dose of opioid solubilized in a liquid carrier suitable for administration to the individual and for use in an osmotic device may be used in the present invention. In one example of an embodiment of the present invention, the liquid carrier is PG, solutol, cremophor EL or a combination thereof.

For example, the liquid composition of the present invention may also comprise additional excipients such as an antioxidant, a permeation enhancer and the like. Antioxidants may be provided to slow down or effectively stop the rate of any auto-oxidizable material present in the capsule. Representative antioxidants may comprise an element selected from ascorbic acid; alpha-tocopherol; ascorbyl palmitate; ascorbates; isoascorbates; butylated hydroxyanisole; butylated hydroxytoluene; nordihydroguaiaretic acid; esters of gallic acid comprising at least 3 carbon atoms comprising an element selected from propyl gallate, octyl gallate, decyl gallate, decyl gallate; 6-ethoxy-2,2,4-trimethyl-1,2-dihydro-quinoline; N-acetyl-2,6-di-tert-butyl-p-aminophenol; butyltyrosine; 3-tert-butyl-4-hydroxyanisole; 2-tert-butyl-4-hydroxyanisole; 4-chloro-2,6-di-tert-butylphenol; 2,6-di-tert-butyl-p-methoxyphenol; 2,6-di-tert-butyl-p-cre sol; polymeric antioxidants; trihydroxybutyrophenone; physiologically acceptable salts of ascorbic acid, erythorbic acid and ascorbyl acetate; calcium ascorbate; sodium ascorbate; 38 DK 2006 00189 U3 sodium bisulfite and the like. For example, the amount of antioxidant used for the present purposes may be from 0.001% to 25% of the weight amount present in the cavity. Antioxidants are known in the prior art from U.S. Patent Nos. 2,707,154, 3,572,936, 3,637,772, 4,038,434, 4,186,465, and 4,559,237, each incorporated herein by reference in its entirety for all purposes.

The liquid composition of the invention may comprise permeation enhancers which facilitate absorption of the drug into the application environment. Such amplifiers can e.g. open the so-called "tight joints" of the gastrointestinal tract or alter the action of cellular components such as a β-glycoprotein and the like. Suitable enhancers may include alkali metal salts of salicylic acid such as sodium salicylate, caprylic acid or capric acid such as sodium caprylate or sodium caprate, and the like. For example, enhancers may contain bile salts such as sodium deoxycholate. Various β-glyco protein modulators are disclosed in U.S. Patent Nos. 5,112,817 and 5,643,909. Various other absorption enhancing compounds and materials are described in U.S. Patent No. 5,824,638. Amplifiers can be used either alone or as mixtures in combination with other amplifiers.

In certain embodiments, the substances of the invention are administered as a self-emulsifying preparation. Like the other liquid carriers, the surfactant serves to prevent aggregation, reduce the interfacial tension through constituents, enhance the free flow of the constituents, and reduce the occurrence of retention of constituents in the dosage form. The emulsion composition of this invention comprises a surfactant which provides emulsification. Examples of surfactants may include, in addition to the surfactants listed above, an element selected from polyoxyethylene castor oil comprising ethylene oxide at a concentration of 9 to 15 moles, polyoxyethylene sorbitan monopalmitate, mono- and tristearates comprising 20 moles of ethylene oxide, polyoxyethylene sorbitan monostene, sorbitan trioleate comprising 20 moles of ethylene oxide, polyoxyethylene lauryl ether, polyoxyethylenated stearic acid comprising 40 to 50 moles of ethylene oxide, polyoxyethylenated stearyl alcohol comprising 2 moles of ethylene oxide, and polyoxyethylene oleyl alcohol comprising 2 moles of ethylene oxide. The surfactants are available from Atlas Chemical Industries.

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The emulsified medicament compositions of the present invention may initially comprise an oil and a nonionic surfactant. The oil phase of the emulsion includes any pharmaceutically acceptable oil that is not immiscible with water. The oil may be an edible liquid such as an unpolar ester of an unsaturated fatty acid, derivatives of such esters or mixtures of such esters. The oil can be of vegetable, mineral, animal or marine origin. Examples of non-toxic oils may include, in addition to the surfactants listed above, an element selected from peanut oil, cottonseed oil, sesame oil, corn oil, almond oil, mineral oil, castor oil, coconut oil, palm oil, cocoa butter, colourant butter, color tint -18 carbon atoms, unsaturated fatty acids, fractionated triglycerides derived from coconut oil, fractionated liquid triglycerides derived from short-chain fatty acids with 10-15 carbon atoms, acetylated monoglycerides, acetylated diglycerides, acetylated triglycerides, olein, also known as glyceryl , also known as glycerol tristearate, lauric acid hexyl ester, oleic acid oleic ester, glycolysed ethoxylated glycerides of natural oils, branched fatty acids with 13 molecules of ethylene oxide and oleic acid decyl ester. The concentration of oil or oil derivative in the emulsion formulation can be from ca. 1% by weight to approx. 40% by weight, all components of the emulsion composition together being 100% by weight. The oils are disclosed in Pharmaceutical Sciences by Remington, 17th ed., Pp. 403 to 405 (1985) published by Mark Publishing Co., in Encyclopedia of Chemistry by Van Nostrand Reinhold, 4th ed., Pp. 644-645, (1984). ) published by Van Nostrand Reinhold Co.; and in U.S. Patent No. 4,259,323.

The amount of opioid incorporated into the dosage forms of the present invention is usually from about 1 10% by weight to approx. 90% by weight of the composition depending on the therapeutic indication and the desired administration time, e.g. every 12 hours, every 24 hours and the like. Depending on the dose of opioid desired to be administered, one or more of the dosage forms may be administered.

The osmotic dosage forms of the present invention may have two different forms, a soft capsule form (shown in Figure 3) and a hard capsule form (shown in Figure 4). The soft capsule used in the present invention, preferably in its final form, comprises a piece. The one-piece capsule is of sealed construction encapsulating the drug composition therein. The capsule can be prepared by various methods, including the plate method, the rotary nozzle method, the reciprocating nozzle method, and the continuous process. An example of the plate method is the following. In the plate method, a set of molds is used. A hot sheet made of capsule lamina forming material is laid over the lower mold and poured onto the composition. Another sheet of the lamina forming material is placed over the composition followed by the top mold. The mold set is placed under pressure and a pressure is applied with or without heat to produce a unit capsule. The capsules are washed with solvent to remove excess preparation from the outside of the capsule and the air-dried capsule is encapsulated with a semi-permeable wall. The rotary nozzle method uses two continuous films of capsule lamina forming material which converge between a pair of rotary nozzles and an injector wedge. The process fills and seals the capsule in two concurrent operations. In this method, the sheets of capsule laminating material are passed over guide rollers and then down between the wedge injector and the nozzle rollers.

The composition of the agent to be encapsulated gravitates down into a positive displacement pump. The pump measures the composition of the agent through the wedge injector and into the sheets between the rollers. The bottom of the wedge contains small mouths, aligned with the pockets of the nozzle rollers. The capsule is approximately half-sealed as the pressure of the pumped-agent composition drives the sheets into the nozzle pockets in which the capsules are simultaneously filled, shaped, hermetically sealed and cut from the sheets of laminating materials. The capsule is sealed by mechanical pressure on the die rolls and by heating the sheets of lamina-forming materials with the wedge. After preparation, they are dried with medium-sized capsules in the presence of forced air and a semipermeable lamina is encapsulated thereto.

The reciprocating nozzle method produces capsules by passing two films of capsule lamina forming material between a set of vertical nozzles. As the nozzles close, open and close, they behave like a continuous vertical plate forming row after row of pockets across the film. The pockets are filled with compositions according to the invention, and as the pockets move through the nozzles, they are sealed, shaped and cut from the moving film as capsules filled with medium composition. A semi-permeable enclosure lamina is then coated to provide the capsule. The continuous process is a manufacturing system which also uses rotating nozzles, with the added feature that the process can successfully fill active agent in the form of dry powder in a soft capsule in addition to encapsulating fluids. The filled capsule from the continuous process is encapsulated with a semi-permeable polymeric material to provide the capsule. Methods for making soft capsules are disclosed in U.S. Patent Nos. 4,627,850 and 6,419,952.

The dosage forms of the present invention may also be prepared from an injection molding composition by an injection molding technique. Injection molding compositions provided for injection molding in the semipermeable membrane comprise a thermoplastic polymer or the compositions comprise a mixture of thermoplastic polymers and optional injection molding components. The thermoplastic polymer which can be used for the present purpose comprises low-softening point polymers, e.g. below 200 ° C, preferably in the range of 40 ° C to 180 ° C. The polymers are preferably synthetic resins, addition polymerized resins such as polyamides, resins obtained from deep oxides and primary alkanolamines, glycerol and phthalic anhydride resins, polymethane, polyvinyl resins, free resin or esterified carboxyl polymer resins, acrylic acid, acrylamide or acrylic acid esters, polycaprolactone and its copolymers with dilactide, diglycolide, valerolactone and decalactone, a resin composition comprising polycaprolactone and polyalkylene oxide and a resin composition including polycaprolactone, poly (hydroxypropyicellulose). The membrane forming composition may comprise any membrane forming components such as polyethylene glycol, talc, polyvinyl alcohol, lactose or polyvinylpyrrolidone. The compositions for forming a polymer composition for injection molding may comprise 100% thermoplastic polymer. In another embodiment, the composition comprises 10% to 99% of a thermoplastic polymer and 1% to 90% of a second polymer which is 100% in total. The invention also provides a thermoplastic polymer composition comprising 1% to 98% of a first thermoplastic polymer, 1% to 90% of a different second polymer therefrom and 1% to 90% of a third polymer therefrom, all polymers constituting 100%.

Representative compositions include 20% to 90% thermoplastic polycaprolactone and 10% to 80% polyalkylene oxide; a composition comprising 20% to 90% polycaprolactone and 10% to 60% polyethylene oxide, the constituents being 100%; a composition comprising 10% to 97% of polycaprolactone, 10% to 97% of polyalkylene oxide, and 1% to 97% of polyethylene glycol, all components constituting 100%; a composition comprising 20% to 90% polycaprolactone and 10% to 80% poly (hydroxypropylcellulose), all of which constituting 100%; and a composition comprising 1% to 90% of polycaprolactone, 1% to 90% of polyethylene oxide, 1% to 90% of poly (hydroxypropylcellulose) and 1% to 90% of polyethylene glycol, all components constituting 100%. The percentages are expressed in% by weight.

In another embodiment of the invention, an injection molding composition to provide a membrane can be prepared by blending a composition comprising 63% by weight polycaprolactone, 27% by weight polyethylene oxide and 10% by weight polyethylene glycol, in a conventional mixer such as in a Moriyama ™ Mixer at 65 ° C to 95 ° C, the ingredients being added to the mixer in the following order of addition: polycaprolactone, polyethylene oxide and polyethylene glycol. In one example, all the ingredients are mixed for 135 minutes at a rotor speed of 10 to 20 rpm. Then, the mixture is applied to a Baker Perkins Kneader ™ extruder at 80 ° C to 90 ° C at a pump speed of 10 rpm and a worm speed of 22 rpm and then cooled to 10 ° C to 12 ° C to reach a uniform temperature. Then, the cooled extruded composition is applied to an Albe Pelletizer and converted into pills 5 mm in length at 250 ° C. The pellets are then applied to an injection molding machine, an Arburg Allrounder ™ at 93 ° C to 177 ° C, heated to a melt polymer composition, and the liquid polymer composition is driven into a high pressure and high speed mold cavity until the mold is filled and the composition comprising the polymers solidify in a preselected form. The parameters of the injection molding consist of a belt temperature through zone 1 to zone 5 in the drum of 91 ° C to 191 ° C, an injection molding pressure of 1818 bar, a speed of 55 cm3 per unit. second and a casting temperature of 75 ° C. The injection molding compositions and injection molding methods are disclosed in U.S. Patent No. 5,614,578.

Alternatively, the capsule can be conveniently made in two parts, one part of which (the "cap") slides over and closes the other part ("the body") as long as the capsule can be deformed under the forces exerted by the expandable layer and sealed to prevent leakage of the fluid, preparation of active substance from between the interposable parts of the body and the cap. The two parts completely surround and encapsulate the inner cavity containing the liquid active ingredient composition which may contain useful additives. The two parts can be brought together after the body is filled with a preselected preparation. The assembly may be made by sliding or displacing the cap portion over the body portion and sealing the cap and body, thereby completely enclosing and encapsulating the active substance preparation.

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Soft capsules typically have a wall thickness greater than the wall thickness of hard capsules. For example, soft capsules may have a wall thickness of the order of 0.25 to 1 mm, with approx. 0.5 mm is typical, while hard capsules may, for example, have a wall thickness of the order of 0.05 to 0.15 mm, with about 0.1 mm is typical.

In one embodiment of the dosing system, a soft capsule may be a single-unit structure and may be surrounded by an asymmetric hydro-activated layer such as the expandable layer. This expandable layer will usually be asymmetrical and have a thicker portion distant from the exit aperture. As the hydroactivated layer absorbs and / or absorbs outer fluid, it expands and applies pressure to the wall of the capsule and any barrier layers and drives active agent preparation through the exit aperture. The presence of an asymmetric layer serves to ensure that the maximum dose of agent is dispensed from the dosage form as the thickest portion of the layer distant from the passage swells and moves toward the mouth.

In yet another embodiment, the expandable layer may be formed into separate sections that do not completely comprise any barrier layer-coated capsule. The expandable layer may be a single element formed to fit the shape of the capsule at the contact area. The expandable layer can be conveniently made by tabletting to form a concave surface complementary to the outer surface of the barrier-coated capsule.

Suitable tools, such as a convex piston in a conventional tablet press, can provide the necessary complementary shape of the expandable layer. In this case, the expandable layer is granulated and pressed rather than formed as a coating. The methods of preparing an expandable layer by tabletting are well known and are described, for example, in U.S. Patent Nos. 4,915,949, 5,126,142, 5,660,861, 5,633,011, 5,190,765, 5,252,338, 5,620,705, 4,931. .285, 5,006,346, 5,024,842, and 5,160,743.

In some embodiments, a barrier layer may first be coated on the capsule, and then the tabulated, expandable layer may be bonded to the barrier-coated capsule with a biologically compatible adhesive. Suitable adhesives include, for example, starch paste, aqueous gelatin solution, aqueous gelatin / glycerol solution, acrylate-vinyl acetate-based adhesives such as Duro-Tak adhesives (National Starch and Chemical Company), aqueous solutions of water-soluble hydrophilic polymers, such as hydroxy propyl methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and the like. The intermediate dosage form can then be coated with a semi-permeable layer. The outlet opening is formed in the side or end of the capsule opposite the expandable layer section. When the expandable layer absorbs fluid, it will swell. As it is blocked by the semipermeable layer, as it expands, it will press the barrier-coated capsule and squeeze the liquid active ingredient composition out of the capsule's interior into the application environment.

Typically, the hard capsules are composed of two parts, a cap and a body, which are put together after the larger body is filled with a preselected appropriate composition. This can be done by sliding or sliding the hood section over the body section so that the composition of the useful agent is completely surrounded and encapsulated. For example, hard capsules can be made by dipping stainless steel molds in a bath containing a solution of a capsule lamina forming material to coat the mold with the material. The molds are then withdrawn, cooled and dried in an air stream. The capsule is removed from the mold and trimmed to provide a lamina element with an inner cavity. The sheath which can be displaced over the body containing the composition is prepared in a similar manner. Then, the closed and filled capsule can be encapsulated with a semi-permeable lamina. The semi-permeable lamina can be applied to the capsule portions before 20 or after the portions are assembled to the finished capsule. In another embodiment, the hard capsules can be made such that each part has adapted locking rings near their opened end which allows assembly and interlocking of overlapping cap and body after filling with preparation. In this embodiment, a pair of fitted locking rings are formed in the cap portion and the body portion, and these rings provide locking means for securely holding the capsule, the capsule may be manually filled with the preparation, or it may be filled with the preparation on machine. In the finished composition, the hard capsule is encapsulated by a semipermeable lamina which is permeable to passage of fluid and substantially impervious to passage of the useful agent. Methods for preparing hard capsule dosage forms are disclosed in U.S. Patent Nos. 6,174,547, 6,596,314, 6,419,952 and 6,174,547.

For example, the hard and soft capsules may comprise gelatin; gelatin with a viscosity of 15 to 30 millipoise and a bloom value of up to 150 g; gelatin with a bloom value of 160 to 2500 g, a composition comprising gelatin, glycerol, water and titanium dioxide; a composition comprising gelatin, erythrosine, iron oxide and titanium dioxide; a composition comprising gelatin, glycerol, sorbitol, potassium sorbate and titanium dioxide; A composition comprising gelatin, acacia, glycerol and water; and the like. Materials which can be used to make capsule membranes are known from U.S. Patent Nos. 4,627,850 and 4,663,148. Alternatively, the capsules may be made from materials other than gelatin (see, for example, products made from BioProgres pie.).

The capsules can typically be provided in sizes e.g. from approx. 3 to approx. 22 minim (with 1 minim equal to 0.0616 ml) and in oval, oblong or other forms. They can be provided in standard form and various standard sizes, usually referred to as (000), (00), (0), (1), (2), (3), (4) and (5). The largest number corresponds to the smallest form. Non-standard forms can also be used. Both in the case of soft capsule and hard capsule, unusual shapes and sizes can be used if needed for a particular application.

The osmotic devices of the present invention may comprise a semi-permeable membrane which is permeable to passage of an external biological fluid and substantially impervious to passage of opioid composition. The selectively permeable compositions used to prepare the membrane are substantially non-erodible and are insoluble in biological fluids during the life of the osmotic system. The semipermeable membrane comprises a composition which does not adversely affect the host, the opioid preparation, an osmopolymer, an osmagogue and the like. Materials useful for the preparation of a semi-permeable membrane are disclosed elsewhere herein.

The semipermeable membrane may also comprise a flow regulating agent. Materials which can be used as flow regulating agents are disclosed elsewhere herein. Other materials which can be used to prepare the semi-permeable membrane to impart flexibility and extensibility to the semi-permeable membrane are also discussed elsewhere herein.

The semipermeable membrane surrounds and forms a compartment containing one or more layers, one of which is an expandable layer which in some embodiments may contain osmotic agents. The composition of such extensible layers is discussed elsewhere herein.

In some solid and liquid embodiments, the dosage forms may further comprise a barrier layer. The barrier layer in certain embodiments is deformable under the pressure exerted by the expandable layer, and will be impermeable (or less permeable) to fluids and materials which can be found in the expandable layer, the liquid active ingredient composition. and in the application environment, during the release of the active substance preparation. Some permeability of the barrier layer may be allowed if the rate of release of the active substance preparation is not adversely affected. however, it is preferred that the barrier layer does not completely transport fluids and materials in the dosage form and the application environment therethrough during the period of delivery of the active substance. The barrier layer may be deformable under forces applied by the expandable layer to allow compression of the capsule to drive the liquid active composition out of the exit aperture. In some embodiments, the barrier layer will be deformable to such an extent that it forms a seal between the expandable layer and the semi-permeable layer in the region where the exit opening is formed. In this way, the barrier layer will deform or flow to a limited extent, closing the initially exposed areas of the expandable layer and the semi-permeable layer as the exit opening is formed, such as by drilling or the like or during the initial operating steps. When sealed, the only path for fluid penetration into the expandable layer is through the semipermeable layer, and there is no backflow of fluid to the expandable layer through the outlet opening.

Suitable materials for preparing the barrier layer may include, for example, polyethylene, polystyrene, ethylene vinyl acetate copolymers, polycaprolactone and Hytrel ™ polyester elastomers (DuPont), cellulose acetate, (such as Surelease ™ provided by 10 Colorcon, West Point, Pa or Aquacoat ™ provided by FMC Corporation, Philadelphia, Pa.), nitrocellulose, polylactic acid, polyglycolic acid, polylactide glycolide copolymers, collagen, polyvinyl alcohol, polyvinyl acetate, polyethylene vinyl acetate, polyethylene acetate, polyethylene -butadiene styrene, polyisobutylene, polyisobutylene-isoprene copolymer, polyvinyl chloride, polyvinylidene chloride-vinyl chloride copolymer, copolymers of acrylic acid and methacrylic acid esters, copolymers of methyl methacrylate and ethyl acrylate, p olypropylen, copolymers of propylene oxide and ethylene oxide, propylene oxide ethylene oxide block copolymers, ethylene vinyl alcohol copolymer, polysulfone, ethylene vinyl alcohol copolymer vinylalcohol copolymer, polyxylylenes, polyalkoxysilanes, polydimethyl siloxane, polyethylene glycol-silicone elastomers, electromagnetic irradiation crosslinked acrylforbindeiser, silicones, or polyesters, 47 47GB 2006 00189 U3 thermally crosslinked acrylics , silicones or polyesters, butadiene-styrene rubber and mixtures of the above.

Preferred materials may include cellulose acetate, copolymers of acrylic acid and methacrylic acid esters, copolymers of methyl methacrylate and ethyl acrylate, and latex of acrylate esters. Preferred copolymers may include poly (butyl methacrylate), (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1: 2: 1, 150,000, sold under the trademark EUDRAGIT E; poly (ethyl lacry I at, methyl methacrylate) 2: 1, 800,000, sold under the trademark EUDRAGIT NE 30 D; poly (methacrylic acid, methyl methacrylate), 1: 1, 135,000, sold under the trademark EUDRAGIT L; poly (methacrylic acid, ethyl acrylate) 1: 1, 250,000, sold under the trademark EUDRAGIT L; poly (methacrylic acid, methyl methacrylate) 1: 1, 135,000, sold under the trademark EUDRAGIT S; poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1: 2: 0.2, 150,000, sold under the trademark EUDRAGIT RL; poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1: 2: 0.1, 150,000, sold as EUDRAGIT RS. In each case, the ratio x: y: z indicates the molar ratios of the monomeric units, and the last number is the number average molecular weight of the polymer. Particularly preferred are cellulose acetate containing plasticizers such as acetyl tributyl citrate and ethyl acrylate-methyl-methacrylate copolymers such as EUDRAGIT NE.

The above materials for use as barrier layers can be formulated with plasticizers to make the barrier layer suitably deformable, so that the force exerted by the expandable layer will collapse the compartment formed by the barrier layer to dispense the liquid composition of active substance. . Examples of typical plasticizers are the following: polyhydric alcohols, triacetin, polyethylene glycol, glycerol, propylene glycol, acetate esters, glycerol triacetate, triethyl citrate, acetyl triethyl citrate, glycerides, acetylated monoglycerides, oils, mineral oil, castor oil and the like. The plasticizers can be blended into the material in amounts of 10 to 50% by weight relative to the weight of the material.

The various layers constituting the barrier layer, the expandable layer and the semi-permeable layer can be applied by conventional coating methods such as described in U.S. Patent No. 5,324,280. Although, for convenience, the barrier layer, the expandable layer and the semipermeable membrane have been illustrated and described as single layers, each of the layers may be composed of several layers. For example, for particular applications, it may be desirable to coat the capsule with a first layer of a material which facilitates coating with a second layer having the permeability properties of the barrier layer. In that case, the first and second layers form the barrier layer. Similar considerations will apply to the semipermeable layer and the expandable layer.

The exit orifice may be formed by mechanical drilling, laser drilling, erosion of an erodible element, extraction, dissolution, blasting, or leaching of a passageway from the composition wall. The outlet opening may be a pore formed by leaching of sorbitol, lactose or the like from a membrane or layer as disclosed in U.S. Patent No. 4,200,098. This patent discloses pores of controlled size formed by dissolving, extracting or leaching a material from a wall such as sorbitol from cellulose acetate. A preferred form of laser drilling is the use of a pulsed laser which eventually removes material from the membrane of the composition to the desired depth to form the exit aperture.

Figures 5A to 5C illustrate another example of an embodiment known and described in U.S. Patent Nos. 5,534,263, 5,667,804, and 6,020,000. Briefly, a cross-section of a dosage form 80 is shown prior to ingestion in the gastrointestinal tract of Figure 5A. The dosage form is a cylindrical shaped matrix 82 comprising a fabric according to the invention. Ends 84, 86 of die 82 are preferably rounded and convex in shape to ensure easy ingestion. Bands 88, 90 and 92 concentrically surround the cylindrical matrix and are formed of a material which is relatively insoluble in an aqueous environment. Suitable materials are set forth in the aforementioned patents and elsewhere herein.

After taking the dosage form 80, regions of the matrix 82 between the bands 88, 90, 92 begin to erode as illustrated in Figure 5B. Erosion of the matrix initiates release of the substance of the invention into the fluid environment of the gastrointestinal tract. As the dosage form continues passage through the gastrointestinal tract, the matrix continues to erode as illustrated in Figure 5C. Here, erosion of the matrix has proceeded to such an extent that the dosage form breaks into three pieces 94, 96, 98. The erosion will continue until the matrix parts in each of the pieces are completely eroded. The bands 94, 96, 98 will then be ejected from the gastrointestinal tract.

49 DK 2006 00189 U3

Other methods for achieving sustained release of drugs from oral dosage forms are known. For example, diffusion systems such as storage devices and matrix devices, solution systems such as encapsulated solution systems (including, for example, "tiny time pills"), and matrix solution systems, combined diffusion / solution systems, and ion exchange resin systems, are known and discussed in the Remington's Pharmaceuticals, 1990, 1682-1685. Dosage forms operating in accordance with these other methods are included to the extent herein described to such an extent that the drug release and / or blood plasma concentration properties as cited herein and in the claims disclose embodiments either literally or equivalent.

In other embodiments of the methods of the invention, said sustained release dosage forms can be protected from the effects of ethanol in the gastrointestinal tract using an enteric coating. Alcohol, especially ethanol, tends to be absorbed in the upper gastrointestinal tract, especially the stomach. Accordingly, use of an enteric coating can attenuate the effects of co-administered alcohol on a sustained release dosage form of the invention by delaying the initial release of drug into the upper gastrointestinal tract.

In a preferred embodiment, the enteric coating comprises an enteric polymer. Preferably, the enteric polymer should not dissolve rapidly in ethanol but may swell or dissolve very slowly. Other polymers or materials can be mixed with the enteric polymer as long as their addition does not impair the performance of the enteric coating in ethanol. In certain embodiments, the polymer or material which may be admixed with the enteric polymer may be selected to enhance the performance of the enteric polymer in aqueous alcohol. For example, a polymer or material having little or no swellability / solubility in aqueous alcohol can advantageously be mixed with the enteric polymer in one embodiment. An emollient such as PEG 6000 may be needed at a level of 1 to 20% to prevent brittleness. Enteric polymers suitable for use in the invention include cellulose acetate phthalates such as those produced by Eastman Chemical. In certain embodiments, enteric polymers can be applied from solvent systems such as acetone or acetone / ethanol mixtures, or from aqueous dispersions. In some cases, the enteric coatings can be applied using pressure molding techniques.

In other embodiments of the present invention, non-enteric polymers can be used to coat the sustained release dosage forms and thus reduce susceptibility to alcohol-induced dose dumping, especially ethanol-induced dose dumping. In one embodiment, the Eudragit® RS100 and Eudragit® RL100 can be used. These polymers are reported to be insoluble in water and slowly dissolve in ethanol / water mixtures. It is reported that they present low and moderate water permeability, respectively. If applied to a sustained release tablet matrix, they would be reasonably effective rate limiting films in water and in ethanol / water mixtures. Such structures could behave according to principles of diffusion-regulated release. These films are typically applied from aqueous dispersions and formulated with a plasticizer such as triethyl citrate and an anti-adhesive such as talc. In another embodiment, cellulose acetate having an acetyl content of 24 to 28% can be used. This material is reported to be soluble in water and less soluble in ethanol / water mixtures, thus reducing the likelihood of dose dumping when a dosage form is administered with alcohol, especially with ethanol. The non-enteric polymers can be coated in solution or applied using compression molding techniques.

In one embodiment, the sustained release dosage form of the invention may be a matrix dosage form. A matrix dosage form typically contains a gelling component, a hydrophobic excipient to regulate initial blasting, drug, and diluent. Typically, the gelling component is 20 to 60% by weight and the hydrophobic excipient 5 to 20% by weight relative to the total dry weight of the dosage form. These dosage forms can be prepared by granulation or dry mixing and pressing into tablets. Alternatively, the compositions may be heat-melt extruded into strands which are chopped and filled into capsules, thus providing dosage forms of the present invention.

Suitable gelling components include: 1. Mixtures of various grades of HPMC (K4M, K100, E5) to obtain the desired swelling and viscosity. HPMC is insoluble in ethanol and is therefore expected to release more slowly in alcohol / water than in water. HPC (Klucel® from Hercules-Aqualon) can be added to reduce the rate of hydration.

2. Mixtures of various grades of polyethylene oxide (Polyox® available from Dow Chemical). Polyox quenches much less in ethanol / water than in Water, Suggested 51 DK 2006 00189 U3 grades are POLYOX WSR-205 NF, WSR-1105 NF, WSR N-12K NF, WSR N-60K NF, WSR-301 NF, WSR- 303 NF, WSR Coagulant NF. These usually constitute 20 to 55% of the composition.

3. NaCMC (sodium carboxymethylcelluse) is insoluble in ethanol and is likely to be less susceptible to dose dumping in ethanol / water mixtures.

4. Alginic acid is insoluble in ethanol, swells in water and is therefore expected to swell less in ethanol / water.

5. Xanthan gum and guar gum matrices.

6. Polyvinyl alcohol is reported to be soluble in water but insoluble in ethanol.

The following hydrophobic excipients for explosion control should be equally effective or more effective in ethanol / water mixtures due to low ethanol solubility: 1. MC (methylcellulose, Methocel-A-Premium® from Dow Chemical) 2. Glycerol palmito stearate (Precirol® ATO-5, Gattefosse) 3. Glycerol behenate (Compritol® 888-ATO, Gattefosse) 4. Calcium stearate 5. Waxes 6. Vegetable and mineral oils 7. Aliphatic alcohols 8. Polycaprolactone

9. PLGA

10. rosin In one embodiment, the hydrophobic excipients include hydrophobic excipients having melting points above or equal to ca. 55 ° C. Such hydrophobic excipients include, but are not limited to, white paraffin wax, stearyl alcohol, beeswax, Lubritab® (vegetable oil), rosin, carnauba wax and hydrogenated castor oil.

Diluents or fillers used in matrix compositions typically do not significantly affect the release profile. However, care should be taken in selecting these excipients, as the diluents in the presence of alcohol may significantly affect the onset and release profile of the controlled release matrices. In one embodiment, a diluent may conveniently be selected to have lower solubility in aqueous alcohol than in water, so that core hydration and consequently drug dissolution can be limited in environments of aqueous alcohol. In a preferred embodiment, a useful diluent comprises mannitol.

The following hydrophobic excipients are to a lesser extent used in the present invention: 1. EC (Dow Chemical ethyl cellulose) is typically used but is soluble in ethanol.

2. Hydrogenated polyoxyl-60 castor oil.

U.S. Patent Nos. 5,871,778 and 5,656,299 disclose nearly zero-order active ingredient microsphere preparations when administered to a patient. U.S. Patent Nos. 5,654,008, 5,650,173, 5,770,231, 6,077,843, 6,368,632, and 5,965,168 disclose sustained-release microparticle compositions and their use. regulated release of active agents.

In another embodiment, osmotic beads may be used in the practice of the present invention. The opioid can be Wurster coated on nonpareil beads or other materials with sufficient osmotic activity. Then a semipermeable film is deposited by another Wurster coating process. For the latter, the product is removed at different times or coating degrees so as to obtain a wide distribution of coating thicknesses. After hydration, the system sucks water due to osmosis and bursts to release the drug. The burst time should be proportional to the membrane thickness of each bead. These beads, including optionally any without any semi-permeable coating to serve as the instant release component, can be filled into capsules and constitute an embodiment of the sustained release dosage forms of the invention.

If the drug loading with osmotic beads is too limiting, then beads can be made using extrusion spheronization techniques. An advantage of this method is that more of the drug can be incorporated into the bead and there is a coating process less. Preferred carriers for extrusion spheronization techniques may include, but are not limited to, PLGA R208, rosin and other high molecular weight materials. Other bead-making techniques, such as coating of cores without drug, may also be used. Alternatively, the drug-containing beads may be coated with films that are not semi-permeable to water and release will be controlled by a combination of diffusion and osmosis. In embodiments, stiffening agents and / or hydrophobic materials may be incorporated into the sustained release dosage structure to prevent alcohol induced dose dumping. Preferred stiffening agents and / or hydrophobic materials include, but are not limited to, fatty alcohols, waxes, oils and biodegradable materials; in particular, such materials include, but are not limited to, stearyl alcohol, carnauba wax, castor wax and rosin.

In embodiments, gastric retention systems may also be used. Conventional gastrointestinal retention systems achieve gastric retention by virtue of their size (i.e., larger than the pyloric opening) and density (lighter than gastrointestinal tract contents, which allows flow). The systems can use polymers, including but not limited to polyethylene oxide (Polyox), HPC, HPMC, Cross-povidone, Sodium CMC, Ethyl cellulose and the like. Addition of hydrophobic materials or waxes can improve the performance of such materials (which tend to form weaker gels in aqueous alcohol and thus may give unsatisfactory performance). However, hydrophobic materials can significantly increase the risk of spreading such a gastroretentive system further downstream from the stomach.

Other types of gastrorentative systems include rigid frames with associated and / or interconnected controlled release portions. These controlled release frameworks and / or portions are preferably comprised of materials which are relatively insensitive to aqueous alcohol to maintain gastric retention properties and controlled release.

It is to be understood that the dosage forms and formulation strategies described herein are merely examples of various dosage forms intended to obtain administration of the substance (s) of the invention. Those of skill in the pharmaceutical art may identify other formulation strategies that would be suitable, especially since not all formulation strategies will necessarily work for all opioids. Optimization in the ordinary art can be useful in the practice of the present invention.

54 DK 2006 00189 U3 IV. examples

Example 1 - Hydromorphone tablet, double layer 16 mg system

A sustained release dosage form of hydromorphone of the invention adapted, designed and shaped as osmotic drug delivery device was prepared as follows: First, a drug composition was prepared. 8.98 kg of hydromorphone hydrochloride, 2.2 kg of povidone (polyvinylpyrrolidone) identified as K29-32 and 67.06 kg of polyethylene oxide having an average molecular weight of 200,000 were placed in a fluidized bed granulator bowl. Then 6.0 kg of povidone (polyvinylpyrrolidone) identified as K29-32 and with an average molecular weight of 40,000 was dissolved in 54.0 kg of water to prepare the binder solution. The dry materials were granulated in fluidized bed by spraying with 18.0 kg of binder solution. Then, the wet granules in the granulator were dried to an acceptable moisture content and sorted using a mill equipped with a 7 mesh screen. The granulate was then transferred to a mixer and mixed with 16 g of butylated hydroxytoluene as antioxidant and lubricated with 0.20 kg of magnesium stearate.

Then, a pressure composition was prepared as follows: 24.0 kg of sodium chloride and 0.32 kg of black iron oxide were sorted using a 21 mesh screen Qadro Comil, The screened materials, 1.6 kg of hydroxypropyl methylcellulose identified as 2910 and 51.44 kg of polyethylene oxide with an average molecular weight of approx. 7,000,000, was added to the fluidized bed granulator bowl. A binder solution was then prepared. Then 6.0 kg of hydroxypropylmethylcellulose, identified as 2910, was dissolved with an average viscosity of 5 cps in 54.0 kg of water to prepare the binder solution. The dry materials were granulated in fluidized bed by spraying 24.0 kg of binder solution. Then, the wet granules in the granulator were dried to an acceptable moisture content and sorted using a mill equipped with a 0.094 inch screen. The granulate was then transferred to a mixer and mixed with 40 g of butylated hydroxytoluene and lubricated with 0.20 kg of magnesium stearate.

Thereafter, the hydromorphone drug composition and the pressure layer composition were pressed into double layer cores. First, 150 mg of the hydromorphone medium composition was placed in the plunger cavity and extruded, then 130 mg of the pressure layer composition was added and the layers were pressed into standard 11/32 "diameter concave double layer arrangements.

55 DK 2006 00189 U3

The double-layer arrangements were coated with a semi-permeable wall. The wall-forming composition comprised 99% cellulose acetate identified as 398-10 and having an average acetyl content of 39.8% and 1% polyethylene glycol identified as 3350 and having an average molecular weight of 3350. The wall-forming composition was dissolved in a mixture of 96% acetone and 4 % water to prepare a solution with 6% solids content. The wall-forming composition was sprayed onto and around the bilayer arrangements in a pan coating until approx. 30 mg of membrane was applied to each tablet.

An 0.64 mm exit passage was laser drilled through the semipermeable wall to connect the drug layer to the exterior of the dosing system. The residual solvent was removed by drying for 72 hours at 45 ° C and 45% relative humidity. After drying humidity, the tablets are dried for 4 hours at 45 ° C and ambient humidity.

Example 2 - In vitro release study -16 mg hydromorphone

A number of dissolution experiments were performed using the hydromorphone tablets of Example 1 to assess the effect of alcohol on the in vitro release properties of sustained release dosage forms of the hydromorphone of the invention comprising 16 mg of hydromorphone as hydromorphone HCl. Hydromorphone hydrochloride release was measured for 24 hours in aqueous solutions containing 0, 4, 20 and 40% by volume of ethanol using a Type VII solution bath.

Tablets with 16 mg of hydromorphone HCl of Example 1 were used. to determine the release rate and cumulative release profiles in 0%, 4%, 20% and 40% ethanol. Results of release rate from the 0 month stability point were used as 0% ethanol condition (water). The results for the 4%, 20% and 40% ethanol conditions were obtained using additional samples from the 0 month stability draw point. The release rate conditions were as follows: apparatus: USP type VII; medium: aqueous solutions containing 0%, 4%, 20% and 40% ethanol by volume; volume: 50 ml; temperature: 37 ± 0.5 ° C; times: 2, 4, 6, 8, 10, 12, 14, 16, 18 and 24 hours.

Note: Care must be taken to minimize evaporation of release rate medium. In the first 6 intervals and the last interval (2 to 12 hours and 24 hours), release rate media were added approx. 30 minutes before each interval, and the release slides were taken out of the release rate bath immediately after each interval was made. For the intervals 14, 16 and 18, media were placed in the bath simultaneously, so that the release rate slides were in the bath for approx. 6½ hours.

The medium was prepared as follows: 4% by volume ethanol: 140 ml of pure ethanol (Sigma-Aldrich, 200 proof) was added to 3,360 ml of water and mixed well.

20% by volume ethanol: 700 ml of pure ethanol was added to 2,800 ml of water and mixed well.

40% by volume of ethanol: 1400 ml of pure ethanol was added to 2,100 ml of water and mixed well.

Samples were prepared as follows: Sample solutions in 4% and 20% ethanol were injected as they are after mixing. A quick study was conducted to prove the validity of this method. Two standards prepared in water at different concentrations were diluted using 20% and 40% ethanol and analyzed by HPLC, the percent recovery and tip shape assessed. Since the splitting of the tip is observed for samples in the presence of 40% ethanol, but not in the other sample solutions, and the sample solutions in 40% ethanol must be further treated, while the sample solutions in 4% and 20% ethanol are injected as they are.

To avoid fragmentation of peak values, sample solutions in 40% ethanol were prepared as follows: after cooling to room temperature, solutions in the release rate slides were reset to 50 ml with 40% ethanol solution and mixed well. 2 ml of sample solution was then added to a scintillation vial. Sample solution was evaporated to dryness using an evaporator at 45 ° C (SPD SpeedVac, SPD131DDA, RVT4104 chilled vapor trap, OFP-400, Thermo Savant). 2 ml of water was added back to the scintillation vial and mixed well. The sample solution was then injected onto HPLC.

57 DK 2006 00189 U3 HPLC conditions Column: Mobile phase: Flow rate: Temperature: Injection volume: Wavelength: Running time:

Varian Inertsil Phenyl-3.5 mm, 4.6 x 150 mm 35% methanol, 65% buffer (0.1% sodium phosphate, 0.2% sodium octane sulfonate, pH 2.2) 1.5 ml / minute 45 ° C 50 ml 280 nm 7 minutes

The results of this test are shown in Figure 6. For sustained release dosage forms of hydromorphone of the invention, the various ethanol solutions did not cause dose dumping or uncontrolled release. However, a tendency for increased release rate is observed as the ethanol concentration of the dissolution media increases. The average release rate was greatest (about 10% of stated content per hour) in the media with 40% ethanol and was unaffected (about 6% of stated content per hour) 10 in the media with 4% ethanol relative to the control of 0% (6% of stated content per hour). Similarly, the time to deliver 90% of the drug (T90) was unaffected in the 4% medium relative to the control and most affected in the 40% medium as shown in Table 1. Even for the 40% ethanol condition, T90 was 12 hours. In addition, there was minimal effect of the 2 hour cumulative release time interval (start time) for the tablet, reflecting the absence of dose dumping across all ethanol concentrations assessed.

Table 1: Summary of release properties in vitro in ethanol solutions for 16 mg hydromorphone tablets (from Example 1)

Hydromorphone Composition of ethanol / water solution in volume% 0% (control) 4% 20% 40% T90 (hours) 18 18 15 12 Cumulative% released after 2 hours (% of stated content) <1 <1 <1 4 Average release rate (% of stated content per hour) 6 6 7 10 Average release rate relative to 0% ethanol (%) Reference 100 116 160 58 58GB 2006 00189 U3

Example 3 - Comparative study of in vitro release

In comparison, the release of hydromorphone hydrochloride from capsules was evaluated with 32 mg Palladone XL® in vodka (27% by volume ethanol) and water using a Type II solution bath compared to the hydromorphone tablets of Example 1.

The resolution parameters are as follows: resolution apparatus: Varian VK7010 resolution unit and VK8000 automatic sampler; medium: water and vodka respectively (Pavlova, 40% alcohol by volume); volume: 900 ml; about stirring speed: 50 rpm; volume withdrawn: 5 ml; temperature: 37 + 0.5 ° C; times: T = 1, 2.4, 6.10, 14.18 and 24 hours. Note: Experimental results showed that the alcohol content of Pavlova is only 27% Due to vodka chromatographic interference, sample solutions in vodka were evaporated prior to analysis; the detailed methods were as follows: 5 ml of sample solution was taken by automatic sampler in a test tube. After cooling to room temperature, 2 ml of sample solution was added to a scintillation vial. The sample solution was evaporated to dryness with an evaporator at 45 ° C (SPD SpeedVac, SPD131DDA, RVT4104 cooled steam trap, OFP-400, Thermo Savant). 2 ml of water was again added to the scintillation vial and mixed gently. The sample solution was then injected on HPLC. Sample solutions were cooled in water to room temperature and injected on HPLC.

As sample solutions in water were injected as they are, while sample solutions in vodka were evaporated and reconstituted with water as part of the sample preparation. A brief confirmation study was conducted to show that there was no difference between two sample preparations. For sample solutions in water, two standards of 100.04 and 180.07 mg per vapor were evaporated. To dryness, 2 ml of water was again added separately and mixed well followed by HPLC analysis. For sample solutions in vodka, a standard of 250.13 mg per ml was diluted. to 50.03 mg per ml. ml of vodka in triplo and evaporated to dryness, 2 ml of water was added again and mixed well followed by HPLC analysis. The recovery was judged for the equivalence of two sample preparations.

The sample solution volume for both water and vodka was measured after 24 hours and the evaporation rate was calculated according to the following formula on the basis of linear evaporation: evaporation rate = (900 - final volume - 8 x 5) / 24 hours 8 x 5 = 5 ml per ml.

59 DK 2006 00189 U3 removal for 8 times. Evaporation was corrected in the solution profile calculations. Sampled volume was confirmed as a separate test in both water and vodka by triplicate measurements.

The HPLC conditions were as follows: Column: Mobile phase: Flow rate: Temperature: Injection volume: Wavelength: Run time:

Varian Inertsil Phenyl-3, 5 mm, 4.6 x 150 mm 35% methanol, 65% buffer (0.1% sodium phosphate, 0.2% sodium octane sulfonate, pH 2.2)

1.5 ml / min 45 ° C

100 ml 280 nm 6.5 minutes

The volume of injection was increased to 100 ml due to the low concentration of the sample solutions at earlier times.

When exposed to 27% ethanol, Palladone XL released 100% of the indicated content within 2 hours compared to 21% of the indicated water content as shown in Table 2 and shown in Figure 7.

15

Table 2: Summary of in vitro release properties in ethanol-based solutions for 32 mg Palladone XL capsules

Palladone XL Composition of ethanol / water solutions by volume 0% (control) 27% T90 (hours)> 24 1 Cumulative% released after 2 hours (% of stated content) 21 100 60 DK 2006 00189 U3

Example 4 - Hydromorphone tablet 16 mg double layer system

A sustained release dosage form of hydromorphone of the invention adapted, designed and shaped as osmotic drug delivery device was prepared as follows: First, a drug composition was prepared. 8.98 kg of hydromorphone hydrochloride, 2.2 kg of povidone (polyvinylpyrrolidone) identified as K29-32 and 67.06 kg of polyethylene oxide having an average molecular weight of 200,000 were placed in a fluidized bed granulator bowl. Then 6.0 kg of povidone (polyvinylpyrrolidone) identified as K29-32 and with an average molecular weight of 40,000 was dissolved in 54.0 kg of water to prepare the binder solution. The dry materials were granulated in fluidized bed by spraying with 18.0 kg of binder solution. Then, the wet granules in the granulator were dried to an acceptable moisture content and sorted using a mill equipped with a 7 mesh screen. The granulate is then transferred to a mixer and mixed with 16 g of butylated hydroxytoluene as antioxidant and lubricated with 0.20 kg of magnesium stearate.

Then, a pressure composition was prepared as follows: 24.0 kg of sodium chloride and 0.32 kg of black iron oxide were sorted using a Quadro Comil with a 21 mesh screen, The screened materials, 1.6 kg of hydroxypropyl methylcellulose identified as 2910 and 51.44 kg of polyethylene oxide with an average molecular weight of approx. 7,000,000 were added to the fluidized bed granulator bowl. A binder solution was then prepared. Then 6.0 kg of hydroxypropylmethylcellulose, identified as 2910, was dissolved with an average viscosity of 5 cps in 54.0 kg of water to prepare the binder solution. The dry materials were granulated in fluidized bed by spraying 24.0 kg of binder solution. Then the wet granules in the granulator were dried to an acceptable moisture content and sorted using a mill equipped with a 0.094 inch screen. The granulate is then transferred to a mixer and mixed with 40 g of butylated hydroxytoluene and lubricated with 0.20 kg of magnesium stearate. Then, the hydromorphone drug composition and the pressure layer composition were pressed into double layer cores. First, 150 mg of the hydromorphone drug composition was placed in the plunger cavity and extruded, then 130 mg of the pressure layer composition was added and the layers pressed into concave standard 11/32 "diameter double layer arrangements.

The double-layer arrangements were coated with a semi-permeable wall. The wall forming composition comprised 99% cellulose acetate identified as 398-10 and 61 DK 2006 00189 U3 having an average acetyl content of 39.8% and 1% polyethylene glycol identified as 3350 and having an average molecular weight of 3350. The wall forming composition was dissolved in a mixture of 96% acetone and 4% water to prepare a solution with 6% solids content. The wall-forming composition was sprayed onto and around the bilayer arrangements in a pan coating until approx. 33 mg of membrane was applied to each tablet.

An 0.64 mm exit passageway was pierced through the semipermeable wall to connect the drug layer to the exterior of the dosing system. The residual solvent was removed by drying for 72 hours at 45 ° C and 45% relative humidity. After drying humidity, the tablets are dried for 4 hours at 45 ° C and ambient humidity.

The dried tablets were then coated with a colored and clear coating. The yellow color coating Opadry II was identified as Y-30-12863-A. 14.4 kg of the yellow Opadry II color was mixed with 105.6 kg of water for a colored suspension. The Color SUS pension was sprayed on and around the dried tablets in a pan coat until approx. 18 mg was applied to each tablet. Then a clear coating solution was prepared by mixing 2.4 kg of clear Opadry identified as YS-1-19025 in 45.6 kg of water. The clear solution was sprayed onto and around the dried tablets in a pan coat until approx. 1.5 mg was applied to each tablet.

After colored and clear coatings, HM 16 was printed on each tablet with an Opacode water-based black ink identified as NS-78-17715. Printing was done on a ramp printer.

Example 5 - In vivo study

A phase I study was conducted to assess the effect of alcohol on the pharmacokinetics of hydromorphone tablets of Example 3 in healthy subjects in the fasted and in the fed state.

Two groups of 24 healthy adult men and women aged 21 to 45 years, including weighing at least 70 kg and within 25% of normal height and body weight, participated in the study. The study was an intersection study in two groups of individuals with a single center, a single dose, an open label, 4 treatments, 4 periods and 4 sequences.

62 DK 2006 00189 U3 In group 1, each individual received the following fasting treatments:

Treatment A - 16 mg hydromorphone tablets of Example 3 with 240 ml of orange juice

Treatment B - 16 mg hydromorphone tablets of Example 3 with 240 ml of 4% alcohol in orange juice

Treatment C - 16 mg hydromorphone tablets of Example 3 with 240 ml 20% alcohol by volume in orange juice

Treatment D - 16 mg hydromorphone tablets of Example 3 with 240 ml of 40% alcohol by volume in orange juice In group 2, each subject received the following treatments after a normal ripe meal:

Treatment E - 16 mg hydromorphone tablets of Example 3 with 240 ml of orange juice

Treatment F - 16 mg hydromorphone tablets of Example 3 with 240 ml of 4% alcohol in orange juice

Treatment G - 16 mg hydromorphone tablets of Example 3 with 240 ml 20% alcohol by volume in orange juice

Treatment H - 16 mg hydromorphone tablets of Example 3 with 240 ml of 40% alcohol by volume in orange juice

The alcohols in treatments B, C, D, F, G and H were diluted with orange juice and consumed over approx. 30 minutes, usually without sinking. For each treatment, the individual received approx. 50 mg of naltrexone as an opioid antagonist starting approximately 14 hours before dosing and twice daily during dosing and for approx. 48 hours after dosing. There was a washout period of approx. 6 to 14 days between treatment periods, with the wash-out period beginning approx. 24 hours after dosing.

63 DK 2006 00189 U3

During each treatment, blood samples were collected from each subject to measure the plasma hydromorphone concentration at ca. 0 (before dosing), 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42 and 48 hours after dosing.

Plasma samples were analyzed by a confirmed liquid chromatography-tandem mass spectrometry method (LC / MS / MS) developed at CEDRA Corporation. Human plasma containing hydromorphone and the internal standard hydromorphone D3 were extracted with an ethyl acetate / hexane solution and the organic layer was removed and back-extracted before evaporating to dryness. The extract was reconstituted and a portion was injected onto a SCIEX API 4000 LC / MS / MS equipped with an HPLC column. Positive ions were monitored in "multiple reaction monitoring (MRM) mode".

This method was confirmed with a minimal quantifiable hydromorphone concentration of 0.05 ng per minute. ml. During the confirmation, calibration curves for the analyte were constructed by plotting the ratio of analyte to internal standard against known analyte concentrations. A calibration curve was constructed using peak area ratio (PAR) of the calibration standards by applying a linearly weighted regression algorithm of 1 / concentration2. The hydromorphone calibration curve was linear in the range of 0.05 to 10.0 ng per second. ml.

The following pharmacokinetic parameters were determined on the basis of plasma concentrations of hydromorphone:

Cmax - maximum observed plasma concentrations

Tmax - time to maximum concentration k - apparent elimination rate constant was determined by linear regression of the log-transformed plasma concentrations during the terminal log-linear decline phase.

tV2 values for apparent half-life were calculated as 0.693 / k.

The AUCt area under the plasma concentration time profile from hour 0 to the last detectable concentration at time t was determined by the linear trapezoid method.

AUCinf - The AUC value extrapolated to infinity was calculated as the sum of AUCt and the area extrapolated to infinity, calculated by the concentration at time t (Ct) divided by k.

In both fed and fasted groups, plasma concentrations were close to the limit of quantification at the first time after dosing at 2 hours. Thereafter, plasma concentration increased slowly in all 4 treatments. Each group had some individuals with no concentration values for some treatments (outcome) or low 5 values without any clinical explanation; these individuals with low values were excluded from the analysis. Average Tmax was between 12 and 16 hours. Cmax values for the three fasting alcohol treatments were slightly higher compared to the value for the 0% alcohol treatment with ratios of 117, 131 and 128%, respectively, than in the treatments with 4, 20 and 40% alcohol, respectively. In the consumed condition, the plasma 10 hydromorphone concentration profiles were similar for the four treatments and led to lower (W ratios compared with the fasted state. Cmax ratios showed no relationship to the alcohol percentage {114, 114 and 110% in the 4 treatments, respectively). 20 and 40% alcohol relative to the 0% alcohol treatment).

15 AUC values for the three alcohol treatments versus 0% alcohol treatment met 80 to 125% bioequivalence criteria for reliability interval in both the eaten and the fasted state. Figure 8 shows the mean concentration profile after the four fasting treatments (group 1). Table 3 summarizes the pharmacokinetic parameters. Figure 9 depicts the average 20 concentration profile after the four treatments in group 2, in which all treatments were administered after a normal breakfast. Table 4 summarizes the PK parameters.

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Table 3 Average (SA) pharmacokinetic parameters for hydromorphone group 1 fasting 0% alcohol 4% alcohol 20% alcohol 40% alcohol Cmax (ncj / rnl) 1.37 (0.32) 1.56 (0.39) 1, 90 (0.66) 1.89 (0.85) Tmax (t) [average (range)] 16 (6-27) 12 (6-27) 12 (4-16) 12 (6-24) Ty, (t) 12.4 (5.1) 12.6 (6.5) 12.4 (7.2) 11.1 (3.0) AUCirif 40.6 (11.0) 39.9 (14, 1) 43.7 (12.1) 42.2 (13.2) Ratio - arithmetic mean (range) Cmax Ref 1.19 (0.8-1.7) 1.35 (0.7-2.4 ) 1.37 (0.7-2.5) Ratio -% geometric mean (90% CI) Cmax Ref 116.70 (104.48-130.36) 131.16 (117.01-147.02) 128 , 31 (114.18-144.17) AUCjnf Ref 96.83 (87.48-107.19) 103.21 (92.93-114.62) 101.65 (91.32-113.13) 5 Table 4 Average (SA) Pharmacokinetic Parameters for Hydromorphone Group 2 Eaten 0% Alcohol 4% Alcohol 20% Alcohol 40% Alcohol Cm «(ng / ml) 1.42 (0.50) 1.64 (0.60) 1 , 52 (0.32) 1.56 (0.56) Tmax (t) [average (range)] 16 (6-27) 12 (8-24) 16 (6-27) 12 (6-24) T * (t) 11.6 (5.1) 11.6 (6.5) 10.4 (3.9) 10.8 (4.8) AUCi nf 37.1 (8.6) 36.7 (10.5) 36.6 (9.7) 34.8 (11.9) Ratio - arithmetic mean (range) Cmax Ref 1.20 (0.7- 1.8 - 1.20 (0.8-1.9) 1.14 (0.6-2.0) Ratio -% geometric mean (90% CI) Cmax Ref 113.72 (99.97-126, 36) 114.36 (100.14-130.61) 110.34 (97.08-125.41) AUCjnf Ref 94.72 (96.44-103.79) 106.21 (96.63-116, 73) 94.09 (85.91-103.04) 66 DK 2006 00189 U3

Example 6: Comparison of individual conditions: Alcohol study versus repeated dose study

A study was conducted to assess the bioequivalence of batches prepared in two different locations (batch A versus batch B). This was a repeat trial design for four periods in which each of the two batches was administered on two separate occasions with leaching between treatments to characterize the variability between individuals and for a subject of pharmacological variability of dosing in healthy individuals.

Medication supplies for Lot A and Lot B were prepared as sustained release oral osmotic dosage forms according to the invention, usually in accordance with the methods and techniques described in Examples 1 and 2. Each individual received each of the following treatments twice in four consecutive sequences determined on a random schedule: 15

Treatment A: Lot A with 50 mg of naltrexone HCl

Treatment B: Lot B with 50 mg of naltrexone HCl.

20 mg of naltrexone was administered 12 hours before and at the time the dosage forms of hydromorphone of the invention were administered. An additional 50 mg doses of naltrexone were administered 12 and 24 hours after hydromorphone administration as needed. There was a washout period of at least 7 days between doses.

Plasma from the matched blood samples collected after drug administration was analyzed for hydromorphone concentrations from which Cmax, Tmax, terminal half-life (tK) and area under the concentration-time curve (AUC0-72 and AUCO-inf) were determined.

30 Samples of 10 ml of venous blood were taken in test tubes containing anticoagulants at each sample time. The samples were centrifuged within 1 hour of collection and stored at -40 ° C until analyzed. Blood samples should be taken during each dosing period 0 (before dosing), 2, 4, 6, 8, 10, 12, 16, 20, 24, 36, 42, 48, 56, 64 and 72 hours after each dosing of hydromorphone dosage forms according to invention. 35 Plasma samples were analyzed by a confirmed liquid chromatography-tandem mass spectrometry method (LC / MS / MS) developed at CEDRA Corporation.

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The Cmax ratio from this repeated administration represents variability within an individual. From this study, the ratio of C C values (high value / low value) for each subject was estimated and compared to the ratio of Cmax values (treatment with alcohol / without alcohol) from the previous example. Figures 10 and 11 5 show this comparison for groups 1 and 2 of Example 5. As shown in these figures, the observed range of Cmax ratios with alcohol and without alcohol is in the same range as ratios representing variability within an individual.

Example 7: Study of the effect of stiffening agents and 10 acrylic resin on oxycodone release in water and in ethanol / water 40:60 (% by volume) 10 g of each of the preparations with and without stearyl alcohol were prepared by wet granulation technique. The required amount of oxucodone hydrochloride, lactose and Eudragit® RS PO were combined in a suitable container and mixed for 5 minutes. The powder mixture 15 was granulated with water until a moist mass appeared. The wet mass was then passed through a 16 mesh screen and allowed to dry overnight under ambient conditions. In a small container, the required amount of stearyl alcohol was melted in a water bath. While the molten stearyl alcohol was kept in the water bath, the desired amount of dry granulate was added and mixed until the granulate was sufficiently coated with the molten stearyl alcohol. The mixture was removed from the water bath and allowed to cool under ambient conditions before sorting through a 16 mesh screen. Talc and magnesium stearate were added to the coated granules and mixed with a suitable mixer. The granulate was then pressed to 375 mg tablets using a suitable tableting machine such as a Carver 25 press. Granules that were not coated with stearyl alcohol were pressed into 300 mg tablets.

30 68 DK 2006 00189 U3

Table 5: Formulation of 30 mg oxycodone HCl tablets with stearyl alcohol: Dose = 30 mg per tablet; tablet = 375 mg each. Substance Weight% Oxycodone HCl 8.02 Lactose 56.72 Eudragit RS PO 11.97 Stearyl Alcohol 20.29 Talc 1.99 Mg Stearate 1.00

Table 6: Formulation of 30 mg oxycodone HCl tablets without stearyl alcohol Dose = 30 mg per tablet; tablet - 300 mg each. ; Substance: Weight% Oxycodone HCl 10.09 Lactose 71.13 Eudragit RS PO 14.99 Talc 2.49 Mg stearate 1.30

Example 8: Hydromorphone HCl Preparations with and without Stearyl Alcohol

The same preparation method as in Example 7 was used, replacing oxycodone HCl with hydromorphone HCl.

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Table 7: Formulation of 30 mg hydromorphone HCl tablets with stearyl alcohol Dose = 30 mg per tablet; tablet = 375 mg each. Substance: Weight% Hydromorphone HCl 8.02 Lactose 56.72 Eudragit RS PO 11.97 Stearyl Alcohol 20.29 Talc 1.99 Mg Stearate 1.00

Table 8: Formulation of 30 mg hydromorphone HCl tablets without stearyl alcohol r; Dose = 30 mg per day tablet; tablet = 300 mg each; æ:: .. Fabric ..; Weight% e, =. Hydromorphone HCl 10.09 Lactose 71.13 Eudragit RS PO 14.99 Talc 2.49 Mg stearate 1.30 Example 9: Release properties of opioids from and without stearyl alcohol

Samples for this experiment came from Examples 7 and 8. The release of the tablets was tested according to USP type VII. The release media used were the following: ethanol data: ethanol 10 = 40% EtOH / water = 0 to 4 hours and then water = 4 to 24 hours; water data: water was used as medium for all intervals. Drug analysis was performed in the analysis laboratory by HPLC methods (LAR 007411, AAM1,773v1, AAM1,585v50).

Result: Stearyl alcohol suppressed ethanol action on opioid function, as shown in Figures 12 and 13.

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Example 10: Effect of Eudragit® RS PO on Opioid Function

The same wet granulation method as detailed in Example 7 was followed to prepare the granules. However, Eudragit RS PO is excluded from the powder-5 mixtures. The tablet weight was adjusted so that 30 mg of opioids were obtained in each tablet. The preparations are as shown in Tables 9 and 10.

Table 9: Formulation of 25 mg oxycodone HCl tablets without Eudragit RS Dose = 25 mg per day. tablet; tablet = 300 mg each. Substance · .....:% Weight% Hydromorphone HCl 7.99 Lactose 69.03 Eudragit RS PO 19.98 Talc 2.00 Mg Stearate 1.00 · - · Table 10: Formulation of 25 mg hydromorphone HCl tablets without Eudragit RS Dose = 30 mg per day tablet; tablet = 300 mg each. Substance: ώίΞ Weight% Oxycodone HCl 7.99 Lactose 69.03 Eudragit RS PO 19.98 Talc 2.00 Mg stearate 1.00

Results: As shown in Figure 14, the absence of Eudragit® RS PO in the preparation had no effect on oxycodone-HCl function, neither in water nor water / ethanol medium. As shown in Figure 15, the absence of Eudragit® RS PO in the composition had no effect on hydromorphone HCl function in either water or water / ethanol medium.

71 DK 2006 00189 U3

Example 11: Relative effects of stearyl alcohol, hydrogenated polyoxyl-60 castor oil and carnauba wax on oxycodone HCl functionality

The same wet granulation method as detailed in Example 7 was followed to prepare the granules. However, stearyl alcohol was replaced with either hydrogenated polyoxyl-60 castor oil or carnauba wax. The tablet weight was maintained at 375 mg to obtain 30 mg of opioids in each tablet. The preparations are as shown in Table 11. The tablets are released in the following media; ethanol data: 40% EtOH / water = 0 to 4 hours, water = 4 to 24 hours, water data: water was used as medium for all intervals.

10

Table 11: Formulation of Tablets with 30 mg Oxycodone HCl Weight% Substance Stearyl Alcohol Hydrogenated Polymeric Oil Carnauba Wax Oxycodone HCl 8.02 8.06 8.08 Lactose 56.72 57.00 57.13 Eudragit RS PO 11.97 12.03 12.06 Stearyl alcohol 20.29 19.92 19.76 Talc 1.99 1.98 1.98 Mg stearate 1.00 0.99 0.99

Result: as shown in Figure 16, carnauba wax could be used as a substitute for stearyl alcohol but not hydrogenated polyoxyl castor oil.

Example 12: Testing dosage forms of OxyContin®

Experiments with dissolution of dosage forms of OxyContin® in vitro were performed essentially under the following conditions: 20 25 72 DK 2006 00189 U3

Apparatus: Stirring speed: Volume: Bath temperature: Sample volume:

Solution conditions: USP type II 50 rpm 900 ml 37 ± 0.5 ° C 5 ml

Solution media: Water and 40% ethanol, both of analytical grade (n = 6 tablets per medium) Sampling interval: T = 0.5, 1, 2.4, 6, 8.10 and 12 hours. Sample solutions were analyzed with a Cm column under UV detection at a wavelength of 286 nm. Quantity determination was performed by linearity curve in the range of 1.05 to 100.53 pg / ml to adjust to sample concentrations. The detailed HPLC conditions for this particular analysis were essentially as follows.

Column: Mobile phase: HPLC conditions: Zorbax Extended C18, 5 µm, 50 x 4.6 mm THF / acetonitrile / 34 mM phosphate buffer (3:25:72 by volume)

Flow rate: 1.2ml / minute Detector wavelength: 286 nm Injection volume: 30 µl Column temperature: 50 ° C

Running time: 4 minutes

The results are shown in Figure 17.

Claims (70)

73 DK 2006 00189 U3 A sustained release oral dosage form comprising an opioid and a sustained release dosage structure, wherein the sustained release dosage structure releases the opioid from the sustained release dosage form in the presence of aqueous alcohol comprising alcohol at concentrations equal to or greater than ca. 20% by volume, the ratio of an average maximum plasma opioid concentration obtained when the sustained release dosage form of opioid is administered to a patient with the aqueous alcohol to an average maximum single-dose plasma opioid concentration obtained when the dosage form is reached. long-term release of opioid is administered to a patient without administration together with the aqueous alcohol, equal to or less than ca. 1.8: 1st The sustained release oral dosage form according to claim 1, wherein the ratio is equal to or less than about 1.6: 1, preferably equal to or less than about. 1.4: 1st A sustained release oral dosage form comprising an opioid and a sustained release dosage structure, wherein the sustained release dosage structure releases the opioid from the sustained release dosage form in the presence of aqueous alcohol comprising alcohol at concentrations equal to or greater than ca. 20% by volume, the ratio of a maximum single-dose plasma opioid concentration obtained for a single patient when the sustained-release opioid dosage form is administered to the patient with aqueous alcohol, and a maximum single-dose plasma concentration obtained for a single patient, when the sustained release dosage form of opioid is administered to a patient without administration together with the aqueous alcohol is equal to or less than ca. 5: 1. The sustained-release oral dosage form according to claim 3, wherein the ratio is equal to or less than about 10%. 4: 1, preferably equal to or less than ca. 3: 1. A sustained release oral dosage form comprising an opioid and a sustained release dosage structure, wherein the sustained release dosage structure releases the opioid from the sustained release dosage form in the presence of aqueous alcohol comprising alcohol at concentrations equal to or greater than ca. 20% by volume, with the sustained release dosage form of opioid releasing less than or equal to approx. 80% by weight of the opioid dose from the sustained release dosage form of opioid as measured (a) using an in vitro experimental method comprising experimental media; and (b) for a period of about 30 minutes. 2 hours after starting the in vitro test method; and wherein the test media comprise aqueous alcohol at concentrations equal to or greater than ca. 20% by volume. 5 The oral dosage form of claim 5, wherein the release is less than or equal to approx. 50% by weight of the opioid dose, preferably less than or equal to approx. 25% by weight of the opioid dose. A sustained release oral dosage form comprising an opioid and a sustained release dosage structure, wherein the sustained release dosage structure releases the opioid from the sustained release dosage form in the presence of aqueous alcohol comprising alcohol at concentrations equal to or greater than ca. 20% by volume, the ratio of average time to maximum plasma concentration of a single dose obtained when the sustained release dosage form is administered to the patient with the aqueous alcohol, and the average time to maximum plasma concentration of a single dose obtained when the dosage form is long-term release is administered to a patient without administration along with the aqueous alcohol, ranges from about. 0.5 to approx. 1.0. 20 The sustained-release oral dosage form according to any one of claims 1 to 7, which provides once or twice daily dosing. The sustained release oral dosage form according to any one of claims 1 to 8, wherein the opioid is selected from morphine, codeine, thebain, diamorphine, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, nicomorphine, methadone, levomethadylacetate hydrochloride, ketobemidone, propoxyphene, dextro-propoxyphene, dextromoramide, bezitramide, piritramide, pentazocin and phenazocin, The sustained-release oral dosage form according to any one of claims 1 to 9, wherein the aqueous alcohol is equal to or greater than about 10%. 25% by volume, preferably equal to or more than approx. 30% by volume, in particular equal to or greater than approx. 35% by volume, and most preferably equal to or more than ca. 40% by volume. The sustained release oral dosage form of any one of claims 1 to 10, further comprising an opioid antagonist such as naltrexone, levallorphan, naloxone, naltrexone, buprenorphine, nalbuphine, nalophin, nalmefene, diprenorphine, etazocin, metazocin or naloxone. The sustained-release oral dosage form according to any one of claims 1 to 11, wherein the oral dosage form comprises the opioid in an amount in the range of from about 10 to about 10. 0.001 mg to approx. 5,000 mg, preferably from ca. 0.01 to approx. 1,000 mg, especially from approx. 0.1 to approx. 750 mg, more preferably from ca. 0.5 to approx. 500 mg, even more preferably from ca. 0.5 to approx. 250 mg, even more preferably from about 1 to approx. 100 mg and most preferably from ca. 1 to approx. 50 mg. The sustained release oral dosage form according to any one of claims 1 to 12, wherein the oral dosage form is selected from a diffusion system, a solution system, a combined diffusion / solution system, an ion exchange resin system, an osmotic system, a gastric dosage form. retention, prolonged microspheres, and a sustained release osmotic dosage form. The sustained release oral dosage form of claim 13, wherein the diffusion system is selected from a storage device or a matrix device. The sustained release oral dosage form of claim 13, wherein the solution system is selected from an encapsulated solution system such as tiny time pills, beads and a matrix solution system. The sustained release oral dosage form of claim 13, wherein the osmotic dosage form comprises a compartment at least partially formed by a semipermeable membrane. The sustained release oral dosage form of claim 16, wherein the semipermeable membrane is coated with a polyvinyl alcohol film. The sustained release oral dosage form according to claim 16 or 17 comprising a drug composition in the form of a slurry, suspension or solution, a small exit opening and an expandable layer. 76 DK 2006 00189 U3 The sustained release oral dosage form of claim 18, wherein the medicament layer is provided with an undercoat or cured coating in conjunction with the semipermeable membrane. The sustained release oral dosage form according to any one of claims 16 to 19, wherein the osmotic dosage form comprises sustained release an enteric coating or a non-enteric coating. The sustained release oral dosage form of claim 20, wherein the enteric coating comprises a material selected from CAP, HMPCP and PVAP. The sustained release oral dosage form of claim 13 in the form of an elemental osmotic pump comprising a semipermeable membrane surrounding and enclosing an inner compartment containing a medicament layer comprising the medicament in admixture with one or more excipients intended for to provide an osmotic activity gradient and to form a releasably complex composition after fluid aspiration. The sustained release oral dosage form of claim 22, wherein the excipient comprises a suitable drug carrier, binder, lubricant and osmagant. The sustained release oral dosage form of claim 22 or 23, wherein the semipermeable membrane comprises a polymer selected from homopolymers and copolymers such as cellulose esters, cellulose ethers and cellulose ester ethers. The sustained release oral dosage form according to any one of claims 22 to 24, further comprising a flow regulator, particularly selected from polyhydric alcohols, polyalkylene glycols, polyalkylene diols, polyester of alkylene glycols and the like. The sustained-release oral dosage form of claim 13 in the form of a sustained-release osmotic dosage form comprising a first drug layer comprising osmotically active ingredients and a second drug layer comprising more drug than the first layer and optionally an expandable layer. 77 DK 2006 00189 U3 The sustained release oral dosage form of claim 26, wherein the osmotically active components are selected from an osmagin such as a salt and one or more relatively low molecular weight osmopolymers exhibiting swelling when fluid is aspirated. The sustained release oral dosage form according to claim 26 or 27, wherein the first drug layer further contains excipients such as binders, lubricants, antioxidants and dyes. The sustained-release oral dosage form according to any one of claims 26 to 28, wherein the second drug layer comprises the opioid in admixture with selected excipients adapted to provide a gradient of osmotic activity, such as a suitable drug carrier. The sustained release oral dosage form of claim 29, wherein the second layer is free of osmotically active agents. The sustained release oral dosage form according to any one of claims 26 to 30, further comprising an exit opening. The sustained release oral dosage form according to any of claims 26 to 31, wherein the first and second drug layers further comprise a hydrophilic polymer carrier, in particular a carrier that is eroded in the gastric environment. The sustained release oral dosage form of any one of claims 26 to 32, further comprising a semi-permeable membrane, in particular comprising cellulose esters, cellulose ethers and cellulose ester ethers. The sustained release oral dosage form according to any one of claims 26 to 33, further comprising a flow regulator, in particular a flow enhancer or flow reducing agent selected from polyhydric alcohols, polyalkylene glycols, polyalkylene diols, polyesters of alkylene glycols and the like. The sustained release oral dosage form according to any one of claims 26 to 34, wherein the expandable layer comprises a hydroactive layer comprising osmopolymers or osmagens. 78 DK 2006 00189 U3 The sustained release oral dosage form of claim 13 in the form of a soft capsule or hard capsule. The sustained-release oral dosage form of claim 36 in the form of a soft capsule 5 in a sealed construction piece encapsulating the drug composition therein. The sustained-release oral dosage form of claim 36 or 37, wherein the soft capsule is surrounded by an asymmetrical hydro-activated layer as expandable layer and an outlet port. 10 The sustained release oral dosage form according to any of claims 36 to 38, wherein the soft capsule further comprises a barrier layer. The sustained release oral dosage form according to any one of claims 15 36 to 39, wherein the expandable layer is formed in separate sections that do not completely comprise the barrier-coated capsule. The sustained-release oral dosage form of claim 36 in the form of a two-piece hard capsule composed of two parts, a cap and a body. 20 The sustained release oral dosage form of claim 41, wherein the capsule is encapsulated with a semi-permeable lamina. 43. The sustained release oral dosage form according to claim 41 or 42, wherein the hard 25 capsule is made so that each portion has adapted locking rings near their open end which permit assembly and interlocking of the overlapping cap and body after filling with preparation. The sustained release oral dosage form according to any one of claims 30 36 to 43, wherein the capsule further comprises a semi-permeable membrane. The sustained release oral dosage form of claim 44, wherein the semipermeable membrane comprises a flow regulator. 79 DK 2006 00189 U3 The sustained release oral dosage form of claims 43 to 45, wherein the semipermeable membrane surrounds and forms a compartment containing one or more layers, one of which is an expandable layer which preferably contains an osmotic agent. The sustained release oral dosage form according to any one of claims 36 to 46, further comprising a barrier layer, preferably formulated with plasticizers. The sustained release oral dosage form of claim 13 in the form of a cylindrical shaped matrix comprising the opioid with the ends of the matrix rounded and convex in shape, and bands concentrically surrounding the cylindrical matrix and formed of a material which is relatively insoluble in a aqueous environment. The sustained release oral dosage form of claim 13, in the form of a gastric retention dosage form comprising a tablet or capsule comprising several particles of a dispersion of a drug of limited solubility in a hydrophilic, water-swellable, crosslinked polymer which maintains its physical integrity over the life of the dosage, but then rapidly dissolves. The sustained release oral dosage form according to claim 13 in the form of a matrix dosage form containing a gelling component, a hydrophobic excipient, a drug and a diluent. The sustained-release oral dosage form of claim 13 in the form of osmotic beads comprising nonpareil grains or other materials of sufficient osmotic activity coated with a semi-permeable film of wide coating thickness or a non-semi-permeable film of water. The sustained release oral dosage form of claim 51, wherein the osmotic beads are contained in a capsule. The sustained release oral dosage form according to any one of claims 1 to 52 for use in medicine, 54. Use of a sustained-release oral dosage form comprising an opioid and a sustained-release dosage structure providing sustained-release dosage; for the manufacture of a medicament for the treatment of pain when the oral dosage form for prolonged release of opioid is administered to a patient together with aqueous alcohol; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater or ca. 20% by volume; and release of opioid from the oral dosage form with sustained release of opioid; wherein the ratio of an average maximum plasma opioid concentration obtained with a single dose when the oral sustained release form of opioid is administered to the patient with the aqueous alcohol, and an average maximum plasma opioid concentration obtained for a single dose when the oral dosage form with the sustained release of opioid is administered to a patient without administration together with the aqueous alcohol, equal to or less than approx. 1.8: 1st Use of a sustained-release oral dosage form of opioid according to claim 54, wherein the ratio is equal to or less than ca. 1.6: 1, preferably 1.4: 1. Use of a sustained release oral dosage form comprising an opioid and a sustained release dosage structure providing sustained release dosage; for the manufacture of a medicament for the treatment of pain when the oral dosage form for prolonged release of opioid is administered to a patient together with aqueous alcohol; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater or ca. 20% by volume; and release of opioid from the oral dosage form with sustained release of opioid; wherein the ratio of a maximum plasma opioid concentration of a single dose obtained for a single patient when the sustained release dosage form of the opioid is administered to the patient with the aqueous alcohol, and a maximum plasma opioid concentration of a single dose obtained for a single patient when the dosage form with long-term release of opioid is administered to a patient without administration together with the aqueous alcohol, is less than or equal to approx. 5: 1. Use of a sustained-release oral dosage form of opioid according to claim 56, wherein the ratio is equal to or less than ca. 4: 1, preferably 3: 1. Use of a sustained release oral dosage form comprising an opioid and a sustained release dosage structure providing sustained release dosage; for the manufacture of a medicament for the treatment of pain when the oral dosage form for prolonged release of opioid is administered to a patient together with aqueous alcohol; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater or ca. 20% by volume; and release of opioid from the oral dosage form with sustained release of opioid; the sustained release dosage form of opioid releases less than or equal to about 80% by weight of the opioid dose from the sustained release dosage form of the opioid as measured (a) using an in vitro experimental method comprising test media; and (b) for a period of about 10 minutes. 2 hours after starting the in vitro test method; and wherein the test medium comprises aqueous alcohol at concentrations equal to or greater than ca. 20% by volume. The sustained-release oral dosage form of claim 58, wherein the release is less than or equal to ca. 50% by weight of the opioid dose, preferably less than or equal to approx. 25% of the opioid dose. Use of a sustained release oral dosage form comprising an opioid and a sustained release dosage structure providing sustained release dosage; for the manufacture of a medicament for the treatment of pain when the oral dosage form for prolonged release of opioid is administered to a patient together with aqueous alcohol; wherein the aqueous alcohol comprises alcohol at concentrations equal to or greater or ca. 20% by volume; and release of opioid from the oral dosage form with sustained release of opioid; the ratio of the average time to maximum plasma concentration of a single dose obtained when the sustained release dosage form is administered to the patient with the aqueous alcohol, and the average time to maximum plasma concentration of a single dose obtained when the sustained release dosage form is administered to a patient. patient without administration together with the aqueous alcohol, ranges from approx. 0.5 to approx. 1.0. Use of an oral dosage form according to any one of claims 54 to 60, which provides dosing once daily or twice daily. The use of a sustained release oral dosage form according to any one of claims 54 to 61, wherein the sustained release dosage structure comprises an osmotic oral sustained release dosage structure. 82 DK 2006 00189 U3 Use according to any one of claims 54 to 62, wherein the alcohol comprises ethanol. Use according to any one of claims 54 to 63, wherein the aqueous alcohol is equal to or greater than ca. 25% by volume, preferably equal to or more than approx. 30% by volume, in particular equal to or greater than approx. 35% by volume, and most preferably equal to or more than ca. 40% by volume. Use according to any one of claims 54 to 64, wherein the oral dosage form comprises the opioid in an amount in the range of from about. 0.001 mg to approx. 5,000 mg, preferably from ca. 0.01 to approx. 1,000 mg, especially from approx. 0.1 to approx. 750 mg, more preferably from ca. 0.5 to approx. 500 mg, even more preferably from ca. 0.5 to approx. 250 mg, even more preferably from about 1 to approx. 100 mg and most preferably from ca. 1 to approx. 50 mg. Use according to any one of claims 54 to 64, wherein the oral sustained release form of opioid further comprises an immediate release component for immediate release of the opioid. Use according to any one of claims 54 to 66, wherein the opioid is selected from morphine, codeine, thebain, diamorphine, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, nicomorphine, methadone, levomethadylacetate hydrochloride, pethidine, pethidine. , dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocin and phenazocin. Use according to any one of claims 54 to 67, wherein the oral sustained release formulation of opioid further comprises an opioid antagonist such as naltrexone, levallorphan, naloxone, naltrexone, buprenorphine, nal-buphin, nalophin, nalmefene, diprenorphine , cyclazocin, etazocin, metazocin or naloxone. Use according to any one of claims 54 to 68, wherein the administration together is carried out simultaneously or separately from the aqueous alcohol. Use according to any one of claims 54 to 69, wherein the oral dosage form is selected from a diffusion system, a solution system, a combined diffusion / solution system, an ion exchange resin system, an osmotic system, a dosage form. gastric retention, prolonged microspheres, and a sustained release osmotic dosage form.