CZ19137U1 - Oral dosage form with sustained opioids release - Google Patents

Abstract

Disclosed are methods of sustained release administration of opioids, including but not limited to hydromorphone and oxycodone, that exhibit improved properties with respect to coadministration with aqueous alcohol.

Description

Technical field

The solution sc relates to oral opioid sustained release dosage forms such as hydromorphone and oxycodone. These dosage forms exhibit improved properties when co-administered with an alcohol.

BACKGROUND OF THE INVENTION

Rapid release of the opioid dose from ethanol-induced prolonged-release oral dosage forms may present a serious problem in patients receiving such oral dosage forms.

The oral opioid sustained release dosage forms are intended to deliver the opioids to the patient for extended periods of time. In replacement for multiple oral opioid immediate release dosage forms, a single opioid sustained release oral dosage form is often prescribed. For example, there is a great demand for oral opioid sustained release dosage forms intended for once-a-day (qd) or twice-a-day (mis) delivery, which provide the patient with day-long relief,

Thus, the amount of opioid in such dosage forms, especially oral sustained release opioid dosage forms to be administered once daily, is significantly greater than the amount traditionally present in immediate release opioid dosage forms. Any factor that causes rapid release of such an opioid sustained release oral dosage form may result in an opioid drug overdose leading to respiratory depression and potentially death.

We have found that one way of inducing rapid dose release (e.g., immediate dose release) is the accelerated delivery induced by the administration of oral opioid sustained release dosage forms together with an aqueous alcohol, especially aqueous ethanol.

Various alcohols may induce an undesirable increase in the rate of opioid release from oral opioid sustained release dosage forms, which may even approach immediate dose release.

Thus, it would be desirable to develop an oral opioid sustained release dosage form and related methods that do not have the disadvantages of the prior art solution of rapid alcohol-induced dose release, especially ethanol-induced dose release. It would be even more desirable if these oral opioid sustained release dosage forms were both oral and opioid sustained release dosage forms intended to be administered once a day or twice a day, including the associated routes,

The essence of the solution

In one aspect, the present invention provides a method comprising: providing a once-per-day hydromorphone sustained release dosage form comprising hydromorphone and a once-per-day extended release delivery structure; administering the once-per-day hydromorphone sustained release dosage form

4 days a patient together with aqueous alcohol; releasing hydromorphone from the once-per-day hydromorphone sustained release dosage form; wherein the aqueous alcohol comprises alcohol at concentrations of about 20% or greater by volume; and wherein the ratio of the mean maximum concentration of hydromorphone in a single dose administration achieved when the once-per-day hydromorphone sustained release dosage form is administered to a patient together with aqueous alcohol,

The mean maximum plasma concentration of hydromorphone in a single dose achieved when the once-per-day hydromorphone sustained release dosage form is administered to a patient without concomitant administration of aqueous alcohol is about 1.8: 1 or less.

According to another aspect, the invention provides a method comprising: obtaining a once-per-day hydromorphone sustained release dosage form comprising hydromorphone and a once-per-day sustained release delivery structure; administering the once-per-day hydromorphone sustained release dosage form to the patient together with aqueous alcohol; releasing hydromorphone from the once-per-day hydromorphone sustained release dosage form; wherein the aqueous alcohol comprises alcohol at concentrations of about 20% or greater by volume; and wherein the ratio of the maximum concentration of hydromorphone in the individual patient's single-dose plasma achieved when the once-per-day hydromorphone sustained release dosage form is administered to a patient together with aqueous alcohol to the maximum concentration of individual hydromorphone in the single-dose when the once-per-day hydromorphone sustained release dosage form is administered to a patient without concurrent administration of aqueous alcohol, it is about 5: 1 or less.

According to a further aspect of the invention there is provided a method comprising: providing a dosage form for: o a sustained release of hydromorphone for once-daily administration comprising hydromorphone and a sustained release delivery structure allowing once-daily administration; administering the once-per-day hydromorphone sustained release dosage form to the patient together with aqueous alcohol; releasing hydromorphone from the once-per-day hydromorphone sustained release dosage form; wherein the once-per-day hydromorphone sustained release dosage form releases about 80% by weight or less of the hydromorphone dose of the once-per-day hydromorphone sustained release dosage form. measured (a) using an in vitro test method that includes a test medium, and (b) about 2 hours after the start of the in vitro test method; and wherein the test medium comprises an aqueous alcohol which comprises alcohol at concentrations of about 20 vol% or greater.

According to a further aspect of the invention there is provided a method comprising: providing a hydromorphone sustained release dosage form comprising hydromorphone and a sustained release delivery structure; administering the hydromorphone sustained release dosage form to the patient together with the aqueous alcohol; releasing hydromorphone from the hydromorphone sustained release dosage form; wherein the aqueous alcohol comprises alcohol at concentrations of about 20% or greater by volume; and wherein the ratio of the mean maximum concentration of hydromorphone in the single dose administration achieved when the sc-sustained release form of hydromorphone is administered to the patient together with the aqueous alcohol to the mean maximum concentration of hydromorphone in the single dose administration when the administration form is sustained release of hydromorphone administered to a patient without concomitant administration of aqueous alcohol is about 1.8: 1 or less.

In another aspect, the invention provides a method comprising: providing a hydromorphone sustained release dosage form comprising hydromorphone and a sustained release delivery structure; administering the hydromorphone sustained release dosage form to the patient together with the aqueous alcohol; releasing hydromorphone from the dosage form with elongation

Underated release of hydromorphone; wherein the aqueous alcohol comprises alcohol at concentrations of about 20% or greater by volume; and wherein the ratio of the maximum concentration of hydromorphone in the individual patient's plasma in a single application achieved when the sustained-release dosage form of the hydromorphone is administered to the patient together with aqueous alcohol to the maximum concentration of individual hydromorphone in the single application achieved when the the sustained release form of hydromorphone is administered to the patient without concomitant administration of aqueous alcohol, being about 5: 1 or less.

According to a further aspect of the invention there is provided a method comprising: providing a hydromorphone sustained release dosage form comprising hydromorphone and a sustained release delivery structure; administering the hydromorphone sustained release dosage form to the patient together with the aqueous alcohol; releasing hydromorphone from the hydromorphone sustained release dosage form, wherein the hyd15 morphor sustained release dosage form releases less than about 80% by weight of the hydromorphone dose from the hydromorphone sustained release dosage form, measured using an in vitro test method comprising a test medium, and (b) within about 2 hours of initiation of the in vitro test method; and wherein the test medium comprises an aqueous alcohol that contains alcohol at concentrations of about 20 vol% or greater.

According to another aspect, the invention provides a method comprising: obtaining a once-per-day opioid sustained release dosage form comprising an opioid and a once-per-day sustained release delivery structure; administering the once-per-day opioid sustained release dosage form to the patient together with aqueous alcohol; releasing the opioid from the sustained release opioid dosage form for administration once a day; wherein the aqueous alcohol comprises alcohol at concentrations of about 20% or greater by volume; and wherein the ratio of the mean maximum opioid plasma concentration in a single administration achieved when the once-per-day opioid sustained release dosage form is administered to a patient together with aqueous alcohol to 30 the mean maximum opioid plasma concentration in a single administration when the once-per-day opioid sustained release dosage form is administered to a patient without concurrent administration of aqueous alcohol, it is about 1.8: 1 or less.

According to another aspect, the solution provides a method comprising; obtaining a once-per-day opioid sustained release dosage form comprising an opioid and a sustained release delivery structure allowing once-per-day administration; administering the once-per-day opioid sustained release dosage form to the patient together with the aqueous alcohol; releasing the opioid from the once-per-day opioid sustained release dosage form: wherein the aqueous alcohol comprises alcohol at concentrations of about 20% v / v or greater; and wherein the ratio of the maximum opioid plasma concentration of a single patient in a single dose achieved when the once-per-day opioid sustained release dosage form is administered to a patient together with aqueous alcohol to the maximum plasma opioid concentration of a single patient achieved in a single dose when the once-per-day opioid sustained release dosage form is administered to a patient without concomitant administration of aqueous alcohol, it is about 5: t or less.

CZ 19137 Ul

According to another aspect, the invention provides a method comprising: obtaining a once-per-day opioid sustained release dosage form comprising an opioid and a once-per-day sustained release delivery structure; administering the once-per-day opioid sustained release dosage form to a patient along with an aqueous alcohol; releasing the opioid from the sustained release opioid dosage form for administration once a day; wherein the once-per-day opioid sustained release dosage form releases about 80% or less by weight of the opioid dose from the once-per-day opioid sustained release dosage form, measured (a) using an in vitro test method comprising a test medium and (b) within a period of about 2 hours after initiation of the in vitro test method: and wherein the test medium comprises aqueous alcohol that contains alcohol at concentrations of about 20% v / v or greater.

According to a further aspect of the invention there is provided a method comprising: providing an opioid sustained release dosage form comprising an opioid and a sustained release delivery structure; administering to the patient a sustained release opioid dosage form together with an aqueous alcohol; releasing the opioid from the sustained release opioid dosage form; wherein the aqueous alcohol comprises alcohol at concentrations of about 20% or greater by volume; and wherein the ratio of the mean maximum opioid plasma concentration in a single administration achieved when the sustained release form of the opioid is administered to a patient together with aqueous alcohol to the mean maximum opioid plasma concentration in a single administration achieved when the The sustained release opioid is administered to the patient without concomitant administration of aqueous alcohol is about 1.8: 1 or less.

According to a further aspect of the invention there is provided a method comprising: providing an opioid sustained release dosage form comprising an opioid and a sustained release delivery structure; administering to the patient a sustained release opioid dosage form together with an aqueous alcohol; releasing the opioid from the sustained release opioid dosage form; wherein the aqueous alcohol comprises alcohol at concentrations of about 20% or greater by volume; and wherein the ratio of the maximum opioid plasma concentration of a single patient in a single dose achieved when the sustained release opioid dosage form is administered to the patient together with aqueous alcohol to the maximum plasma opioid concentration of a single patient achieved in a single dose The sustained release opioid dosage form is administered to the patient without concomitant administration of aqueous alcohol is about 5: 1 or less.

According to another aspect, the invention provides a method comprising: obtaining an opioid sustained release dosage form comprising an opioid and a sustained release dosing delivery structure; administering to the patient a sustained release opioid dosage form together with an aqueous alcohol; releasing an opioid dose from an opioid sustained release dosage form wherein the opioid sustained release dosage form releases less than about a weight of opioid dose from the opioid sustained release dosage form, measured (a) using an in vitro test method that includes a test medium and (b) ) about 2 hours after the start of the in vitro test method; and wherein the test medium comprises an aqueous alcohol that contains alcohol at concentrations of about 20 vol% or greater.

In yet another aspect, the invention provides a method comprising: obtaining a sustained release hydromorphone dosage form for administration once a day. which comprises hydromorphone and a sustained release delivery structure allowing once-per-day administration; administration

The administration of the once-per-day hydromorphone sustained release dosage form together with the aqueous alcohol; releasing hydromorphone from the once-per-day hydromorphone sustained release dosage form; wherein the aqueous alcohol comprises alcohol at concentrations of about 20 vol% or greater; and wherein the median time to onset of peak plasma concentration in a single application in the event of. wherein the dosage form is administered to the patient together with aqueous alcohol, to the median time of peak plasma concentration on single use when the once-per-day hydromorphone sustained release dosage form is administered to the patient without concomitant administration of aqueous alcohol, e.g. is in the range of about 0.5 to about 1.0.

In yet another aspect, the invention provides a method comprising: providing a hydromorphone sustained release dosage form comprising hydromorphone and an extended release delivery structure; administering the hydromorphone sustained release dosage form to the patient together with the aqueous alcohol; releasing hydromorphone from the hydromorphone sustained release dosage form; wherein the aqueous alcohol comprises alcohol at concentrations of about 20% or greater by volume; and wherein the ratio of the median time of onset of maximum plasma concentration in a single administration when the dosage form is administered to a patient together with aqueous alcohol to the median of the time of onset of maximum plasma concentration in a single administration

The sustained release hydromorphone dosage form administered to a patient without concurrent administration of aqueous alcohol ranges from about 0.5 to about 1.0.

In yet another aspect, the invention provides a method comprising: providing a once-per-day opioid sustained release dosage form comprising an opioid and a once-per-day sustained release delivery structure; administering the once-per-day opioid sustained release dosage form to the patient together with aqueous alcohol; releasing the opioid from the sustained release opioid dosage form for administration once a day; wherein the aqueous alcohol comprises alcohol at concentrations of about 20% or greater by volume; and wherein the ratio of the median time of onset of maximum plasma concentration in a single dose when the dosage form is administered to a patient together with aqueous alcohol to the median of the time of onset of maximum plasma concentration in a single application when the sustained release opioid release form for administration once a day to a patient without concomitant administration of aqueous alcohol, ranging from about 0.5 to about 1.0.

According to yet another aspect, the invention provides a method comprising: providing an opioid sustained release dosage form comprising an opioid and a sustained release delivery structure; administering to the patient a sustained release opioid dosage form together with an aqueous alcohol; releasing the opioid from the sustained release opioid dosage form;

wherein the aqueous alcohol comprises alcohol at concentrations of about 20% or greater by volume; and wherein the ratio of the median time of peak plasma concentration on single use when administered to a patient in combination with aqueous alcohol to the median of time of peak plasma concentration on single use when the opioid sustained release dosage form is administered to the patient lodges. without co-administration of the aqueous alcohol, it is in the range of about 0.5 to about 1.0.

CZ 19137 Ul

Summary of the drawings

Fig. 1 shows an application form based on the principle of an elemental osmotic pump according to this solution.

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

FIG. 3 shows another example of a dosage form.

FIG. 4 shows another example of a dosage form.

5A to 5C show another example of a dosage form.

Figure 6 shows the cumulative liberation profiles of 16 mg tablets containing hydromoronone HCl according to this solution in ethanol solutions.

Giant. 7 shows a comparison of dissolution profiles of 16 mg forms containing hydromorphone HCl according to the present invention and Palladone XL 32 mg in the presence of aqueous alcohol.

Figure 8 shows the mean plasma concentration (and SD) profile of hydromorphone.

Figure 9c shows the mean plasma concentration (and SD) profile of hydromorphone.

Figure 10 shows the individual ratios of Cmax: Group 1, alcohol versus repeat study.

Figure 11 shows the individual ratios of Cmax: Group 2, alcohol versus repeat study.

Figure 12 shows the release of oxycodone hydrochloride from stearyl alcohol and formulations

2 (> without stearyl alcohol).

Figure 13 shows the release of hydromorphone hydrochloride from formulations with and without stearyl alcohol.

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

Figure 15 shows the effect of Eudragit ^K RS PO on hydromorphone hydrochloride drug release.

Figure 16 shows the relative effects of stearyl alcohol, kamauba wax and hydrogenated polyoxyl 60 castor oil on the release of oxycodone hydrochloride.

Figure 17 shows the in vitro dispersal profiles of OxyContin tablets.

and. Opioid sustained release oral dosage forms

After the problems described above have been identified in the prior art, the inventors have unexpectedly found a possible creative solution to the problem of rapid dose-induced alcohol, in particular rapid dose-induced ethanol.

In contrast to this solution, the prior art has not focused on solving the problems of rapid dose-induced alcohol, especially ethanol-induced use, using methods and corresponding sustained release forms. Application forms similar to those of the present invention are used because of their ability to discourage abuse, but no prior art or guidance can be found in the prior art to address such rapid release problems. alcohol-induced doses, especially ethanol-induced doses. For example, in U.S. Pat.

- 6 CZ 19137 Ul

156,850 Maloney et al. disclose a cation exchange resin with small particle size, the presence of which in the use forms of oxycodone improves the in vitro extraction properties that a potential abuser could perform. Maloney et al. however, they do not provide any evidence or guideline to suggest that this property could be useful in solving the problem of rapid in vivo dose release caused by the aqueous alcohol, especially the aqueous ethanol, to which the present inventors have focused. lacquer knowledge and clues provided by the authors of this solution.

Further evidence that this prior art problem has not been underestimated is the fact that others in the art have developed sustained release opioid dosage forms that, in fact, are susceptible to rapid alcohol-induced dose release, especially ethanol. For example, Palladone sustained release of hydromontone (Purdue Pharma) is reported to have problems with rapid dose-induced alcohol, especially ethanol

LP), Kadian ® (Alpharma US Pharms) and Avinza ® (Ligand Pharmaceuticals). The fact that these products are on the market, despite the current risk of rapid release of the alcohol-induced dose, especially ethanol, is evidence that this problem and its solution have been underestimated in the prior art.

After identifying this problem and its solution, the inventors considered a number of embodiments of the solution. In some embodiments, coatings of the dosage form may be employed which act to limit or prevent the rapid release of the alcohol-induced dose. In other embodiments, certain hydrophobic and / or hydrophilic components may be selected to limit or prevent the rapid release of the alcohol-induced dose. In embodiments with protective coatings of the dosage forms, the coatings may serve to modify the release time, such as enteric coatings, or be resistant to swelling or dissolution in alcohol, such as semipermeable membrane coatings or certain non-solvent coated coatings.

In embodiments in which the hydrophobic component is chosen to reduce the rapid release of the dose induced by the aqueous alcohol or to prevent it, it is advantageous to select substances which are relatively insoluble in water and swell at least in aqueous alcohol. For example, hydrophobic polymers can be selected which are at least swellable and are relatively insoluble in water and exhibit the same or lower swelling and / or solubility in aqueous alcohol. In embodiments that include non-polymeric hydrophobic components (such as, but not limited to, waxes or alcohols derived from fatty acids such as stearyl alcohol), components having lower solubility / swellability in aqueous alcohol than in water are preferred. In embodiments in which hydrophilic components are selected to reduce or prevent the rapid release of the aqueous alcohol-induced dose, substances that are less soluble and tend to swell in the aqueous alcohol than in water are preferably selected. For example, hydrophilic polymers may be selected which exhibit the same or lower swelling and / or solubility in aqueous alcohol as compared to water. In embodiments containing non-polymeric hydrophilic components, those that exhibit lower solubility in aqueous alcohol than in water are preferred.

In one process that can determine the desired coatings and the hydrophobic and hydrophilic components that are useful in carrying out this solution, films are prepared from the materials by casting and tested for swellability in the presence of aqueous alcohol. Bulk testing techniques can be used to produce a wide variety of suitable materials. Similar procedures can be used to assess the solubility of materials that are desirable in the practice of the present invention. Examples of materials that have been found to be useful in carrying out this solution are set forth herein.

As the embodiments of this solution described in the examples, in particular Example 5, show, the amount of opioid released from the sustained release opioid dosage forms when co-administered with alcohol can be controlled. In the embodiments described below, an aqueous alcohol (e.g., aqueous ethanol) does not result in the uncontrolled immediate release of the opioid from the dosage forms of the embodiments of the methods of the present invention. For example, in Example 5, the hydromorphone release rate increased as a function of the concentration of ethanol, resulting in a slight increase in Cmax and a decrease in median Tmax when administered on an empty stomach (minimum Tmax was 4 hours with alcohol versus 6 hours with alcohol). 0% ethanol and the maximum increase in Cmax observed in any individual was 2.5-fold compared to 0% ethanol when administered with 40% ethanol). However, there was no serious rapid dose release that could have potentially fatal consequences.

In Example 5, the plasma opioid concentration (in this case hydromorphone) at the first time after application (2 hours) approaches the limit of determination; thereafter, plasma concentrations of all four applications in both groups, both postprandially and fasted, slowly increase. The median Tmax is 12 to 16 hours and the range of Tmax is similar for each type of application in both groups. These data suggest that. that the dosage forms retain the controlled-release capability in the presence of alcohol and do not rapidly release the dose. This result, maintaining the controlled release characteristics, is consistent with the in vitro result of the embodiments of the present invention described in Examples 1 and 2, and which also do not exhibit rapid dose release even with sustained exposure to ethanol for 24 hours.

These data from the hydromorphone dosage forms of the present invention are in contradiction to those reported with a conventional hydromorphone formulation known as Palladone ® (available from Purdue Pharma). For this product, rapid dose release has been observed to a large extent in vitro and in vivo. In vitro, as shown in Example 2, about 90% of the drug is released in ethanol over 1 hour. In vivo, a maximum increase in C max of 4% is reported. 20% and 40% ethanol relative to 0% alcohol corresponding to about 2.0, 5.7, and 15.7 times, respectively, for an individual subject, and the mean maximum increase in subjects Cmax for 4%, 20% and 40% ethanol relative to 0%, respectively. of alcohol corresponding to about 1.1, 2.1 and 5.8 times, respectively.

Materials useful in carrying out the present invention are set forth in this description, and in particular in Examples 1 to 3 and 7 to 11. Various materials that are useful in carrying out the present invention are described. Interestingly, the OxyContin extended release product of oxycodone from Purdue Pharma TP, as tested in Example 12, exhibits minimal signs of rapid dose release in the presence of aqueous alcohol. In developing this solution, it has been found that the stearyl alcohol excipient may be responsible for the resistance of OxyContin ® to rapid dose-induced alcohol. the photo finding demonstrates the unexpectedness of this solution. OxyContin ”has been available for many years, but the nature of its resistance to alcohol-induced rapid release and its potential mechanism of resistance has not yet been elucidated.

In addition to stearyl alcohol incorporation, other formulation strategies useful in the development of sustained release dosage forms and associated methods that result in resistance to rapid alcohol-induced dose release can be found below. Some such embodiments are described in Examples 7-11.

The following is a more detailed description of the solution.

11. Definitions

All percentages are by weight unless otherwise indicated.

All publications are cited as a substitute for transferring their content to this text.

The solution is best understood on the basis of the following definitions, figures and exemplary embodiments.

By "administering" or "administering" or "administering" is meant providing a medicament to a patient in a manner. which is useful to pharmacologists.

The term "alcohol" refers to an organic compound of 1 to 5 carbon atoms in which the hydroxy 45 group (-OH) is bonded to a carbon atom which is further bonded to other hydrogen and / or carbon atoms.

In a preferred embodiment, the alcohol comprises ethanol.

The apparent terminal half-life ( ¹⁵⁰ °) is calculated as 0.693 / k, where k represents the apparent rate elimination constant, which is calculated by linear regression of the log concentration of plasma concentration during the terminal logarithmic-linear elimination phase.

The term "aqueous alcohol" refers to a mixture containing water and alcohol. Different amounts of alcohol may be present in the aqueous alcohol. The aqueous alcohol preferably comprises about 1% (v / v) (i.e., the volume of alcohol / total volume of the aqueous alcohol in percent) to about 100% alcohol in the aqueous alcohol. More preferably, the aqueous alcohol comprises alcohol at a concentration of about 20% or greater by volume. Even more preferably, the aqueous alcohol comprises alcohol at a concentration of about 25% vol or higher, and even more preferably the aqueous alcohol contains alcohol at a concentration of about 40% vol or higher.

The term "area under the curve" or "AUC" refers to the area under the plasma drug concentration curve. AUC is often specified by the time interval in which the curve of drug plasma concentrations integrated, as AUC _POC átck terminus · AUCius therefore represents the AUC obtained by integration of the curve of the plasma concentration in the range 0-48 hours, where 0 is the default i5 time of administration of the drug or dosage forms containing the medicament to the patient. By AUC, is meant the area under the plasma concentration curve in the interval 0 to t, where t is the time of the last detectable concentration, calculated according to the trapezoidal rule. AUC _INR denotes AUC value extrapolated to infinity, calculated as the sum of AUC, and the area extrapolated to infinity, calculated as the concentration at time t (Ct) divided by k. (If the entity can not estimate the t '/ ₂ to calculate AUC _MF "mean area under the plasma concentration-time curve for single-dose AUC _ini " means the mean AUCj _tt f in a set of patients or the mean AUCi _nt achieved in a single patient given multiple times in different doses. times with sufficient elimination spacing between administrations so that drug levels after single administration may decrease to pre-administration levels for each patient.

The abbreviation "C" refers to the concentration of a drug in the subject's plasma or blood serum, which is usually expressed as weight per unit volume, typically in nanograms per milliliter. This concentration can also be referred to herein as "drug concentration in plasma" or "plasma concentration". Plasma drug concentration at any time after drug administration is reported as

C _IAS, such as C ₂ or 4h etc. Maximum plasma concentration after administration of a dosage form obtained directly from the experimental data without interpolation is referred to as C, _MX. The mean or mean plasma concentration of the drug reached during the period of interest is referred to as _Cvvg or (? "." Mean maximum plasma concentration after single administration "means the mean _CIIiax determined for the set several patients, or one patient who has been administered multiple times at different times, with elimination intervals between applications, so that drug levels after a single administration can decrease to pre-administration levels for each patient. is understood the _IR "specified in one patient after single administrations, among which are the elimination sufficient distances that the drug level may drop to a patient the levels before application,

In one embodiment, the solution comprises releasing the opioid (such as, but not limited to, hydromorphone or oxycodone) from the opioid sustained release dosage form, preferably from the opioid sustained release dosage form for administration once a day or twice a day. wherein the ratio of the mean maximum plasma opioid concentration in a single application when the sustained release form of the opioid is administered to the patient together with aqueous alcohol to the mean maximum plasma opioid concentration in a single application achieved when the sustained release dosage form is the opioid is administered to a patient without concurrent administration of aqueous alcohol is about 1.8: 1 or less, more preferably about 1.6: 1 or less, and even more preferably about 1.4: 1 or less.

In one embodiment, the solution comprises releasing an opioid (such as, but not limited to, hydromoronone or oxycodone) from a sustained release opioid dosage form wherein, after a single administration, the concentration of the opioid is measured in a single patient. prolonged-release opioid release, preferably for once or twice daily administration to a patient, co-administered with aqueous alcohol, to the maximum plasma opioid concentration of a single patient in a single administration achieved when the opioid sustained release dosage form is administered to the patient. concurrently administered with an aqueous alcohol is about 5: 1 or less, preferably about 4: 1 or less, more preferably about 3: 1 or less.

By "co-administration" or "co-administration" and the like is meant that two or more agents are administered to a patient for a limited period of time, preferably within 180 minutes, more preferably within 60 minutes, even more preferably within 45 minutes, even more preferably within minutes and more preferably within 15 minutes.

The term "dosage form" refers to an opioid in a medium, carrier, vehicle or device suitable for oral administration. The term "oral dosage form" refers to a dosage form suitable for oral administration. In one embodiment, the dosage forms of the present invention may comprise a sustained release structure for sustained release of the opioid and optionally an immediate release component for immediate release of the opioid. In one embodiment, the dosage forms of the present invention may or may not include opioid antagonists, such as naltrexone, naloxone or other conventional opioid antagonists.

The term "dose" refers to a unit of medicament. Usually, the dosage is provided as a dosage form. Dosages can be administered to patients in a variety of dosing regimens. Typical administration regimens include once per day (qd), twice per day (bid), and three times per day (tid).

Dosages of the opioid useful in practicing the present invention range from about 0.001 mg to about 5000 mg, preferably from about 0.01 to about 1000 mg, more preferably from about 0.1 to about 750 mg, even more preferably from about 0, to about 0 mg. 5 to about 500 mg, more preferably from about 0.5 to about 250 mg, even more preferably from about 0.5 to about 250 mg

2? about 1 to about 100 mg, most preferably about 1 to about 50 mg.

The term "immediate release dosage form" refers to a dosage form that releases about 75% or more of the drug within 45 minutes or less of time after administration to the patient.

The term "once per day" (ie qd) or "twice per day" (ie misery) refers to the frequency of application according to this solution. For example, "once-daily application" refers to total once every 24 hours, ie qd.

The term "opioid" refers to an agent that binds to opioid receptors that are predominantly found in the central nervous system and gastrointestinal tract, and is selected from opium alkaloids and semisynthetic or fully synthetic opioids. Examples of opium alkaloids include morphine, codeine and thebaine. Examples of semisynthetic opioids are diamine 35 (heroin), oxycodone, hydrocodone. dihydrocodeine, hydromorphone, oxymorphone and nicomorphine.

Examples of fully synthetic opioids include methadone, levomethadyl acetate hydrochloride (LAAM), pethidine (meperidine), ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine and thenazocine. Other opioids are known to those skilled in the art. In this embodiment, an opioid with oral bioavailability is preferred. More preferred opioids include morphine, hydromorphone, hydrocodone, oxymorphone and oxycodone. The term includes pharmaceutically acceptable salts and opioids in free base or free acid form. In embodiments of the opioid sustained release oral dosage forms of the present invention comprise about 0.01 to about 1000 mg opioid, preferably about 0.1 to about 500 mg opioid, more preferably about 0.25 to about 300 mg opioid, even more preferably about 1 mg to about 1 mg. 100 mg opioid. It should be noted that the solubility in water and / or aqueous alcohol of the opioids according to the present invention may vary considerably. The amount of opioid in embodiments of the sustained release dosage form of the present invention and / or the solubility of the opioid in aqueous alcohol may have a positive or negative effect. how the rapid release of the aqueous alcohol dose from the sustained release dosage forms of the present invention and / or the associated methods occurs. In some cases, for example, large amounts of opioid and / or opioid form that are highly soluble in aqueous alcohol may increase the likelihood of rapid release

-1037 19137 Ul of an alcohol-induced dose. Conversely, in some embodiments, high amounts of opioid and / or form that are highly insoluble in aqueous alcohol may reduce the likelihood of rapid release of the aqueous alcohol-induced dose.

The term "sustained release oral delivery structure" refers to a structure that is suitable for oral administration to a patient and comprises one or more drugs, which structure provides for sustained release of the drug (s). The term "osmotic oral sustained release delivery structure" refers to an oral sustained release delivery structure that provides sustained release of the osmosis-based drug (s).

The term "patient" refers to an animal, preferably a mammal, more preferably a human in need of therapeutic intervention.

The term "pharmaceutically acceptable salt" refers to any salt whose ammonium has no significant contribution to the toxicity or pharmacological activity of the salt, and as such is the pharmacological equivalent of the drug base. Pharmaceutically acceptable salts include acid addition salts, which may be prepared, for example, by reacting the compound with a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

Thus, non-limiting examples of representative pharmaceutically acceptable salts include acetate, benzenesulfonate, bezoate, bicarbonate, hydrogensulfate, hydrogen tartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, esylate, esylate. , fumarate, gluceptate, gluconate, glutamate, glycolysanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapholate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl bromide, methyl bromide, nitrate, ammonium salt of N-methylglucamine, oleate, pamoate (emhonate), palmitate, pantothenate, fos25 phate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subaeetate, succinate, tannate, tartrate, theoclate, tosylate, triethojodide and valetate.

The term "plasma drug concentration curve" or "plasma drug concentration curve" or "plasma concentration curve" or "plasma profile" or "plasma concentration profile" refers to a curve that sc is obtained by plotting the concentration plasma drug or plasma concentration versus time. The zero point on the timeline (default x-axis) is usually the time of administration of the drug or dosage form containing the drug to the patient.

The term "extended time" refers to a continuous time of greater than about 2 hours, preferably greater than about 4 hours, more preferably greater than about 8 hours, more preferably greater than about 10 hours, even more preferably greater than about 14 hours, and most preferably is longer than about 14 hours and maxi35 is about 24 hours.

By "release rate" is meant the amount of drug released from the dosage form per unit of time, for example milligrams of drug released per hour (mg / h) The rate of drug release from the dosage forms can be measured as the in vitro release rate of the drug. released from the dosage form per unit of time under appropriate conditions and in a suitable test medium.

In a preferred embodiment, said release rate can be determined by placing the dosage forms in metal spiral or cup sample holders attached to the disc of a USP type 7 bath device in deionized water at a constant water bath temperature of 37 ° C. Aliquots of the solutions used to measure the release rate are collected at predetermined intervals and injection) into a chromatographic system equipped with a UV or refractive index detector to determine the amount of drug released during the test intervals. In another embodiment, other in vitro release rate assays that are generally known and used, such as a Type 2 USP device, such as the Distek Premiere 5100, can also be used in the practice of this invention.

CZ 19137 Ul

In one embodiment, the opioid sustained release dosage form of the present invention releases about 80% or less, preferably about 70% or less, more preferably about 60% or less, even more preferably about 50% or less, even more preferably about 40% by weight or less, and most preferably about 25% or less by weight of the opioid dose from the opioid sustained release dosage form, as measured by the in vitro test. Preferably, the in vitro test, such as the in vitro test procedures described above or other conventional in in vitro, comprises a test medium into which the opioid sustained release dosage form is placed during testing. In one embodiment, the amount of opioid released from the opioid sustained release dosage form of the present invention is measured for a particular period, preferably for a period of about 24 hours after initiation of the in vitro test, more preferably for a period of about 12 hours after the in vitro test. even more preferably for a period of about 2 hours after initiation of the in vitro assay.

In one embodiment, the test medium comprises an aqueous alcohol that comprises alcohol. In a preferred embodiment, the test medium comprises an aqueous alcohol that contains alcohol at concentrations of about 20 vol% or higher (alcohol volume / total test medium volume), preferably about 25 vol% or higher, more preferably about 30 vol% or higher, even more preferably about 35 vol% or greater, and most preferably about 40 vol% or greater.

The term "sustained release" refers to the sustained release of a drug or dose of drug over an extended period of time.

The term "sustained release delivery structure" refers to one or more physical elements that enable sustained release of a drug or drug dose.

The term "sustained release dosage form" refers to a type of dosage form that allows sustained release of a drug or drug dose.

The "median time to onset of maximum plasma concentration T" _m after a single-shot application "refers to the median of the time elapsed from administration of a dosage form containing a drug to a patient until reaching the C _{r11Lx of} this drug after a single administration of the dosage form obtained directly from non-interpolation experimental data, the median being determined for multiple patients or for multiple drug administrations to a single patient receiving the drug at different times with sufficient elimination spacing between applications to allow drug levels to decrease to a single patient levels before application. In one embodiment, the ratio of the median time of onset of maximum plasma concentration in a single dose when the dosage form is administered to a patient together with aqueous alcohol is to the median of the time of onset of maximum plasma concentration in a single dose when the sustained release dosage form is the opioid is administered to the patient without concomitant administration of aqueous alcohol in the range of about 0.5 to about 1.0, preferably about 0.6 to about 1.0, more preferably from about 0.7 to about 1.0, most preferably from about 0.75 to about 1.0.

The term "therapeutically effective amount" refers to the amount of drug that elicits a biological or therapeutic response in the animal or human tissue system sought by a researcher, veterinarian, physician or other clinic, which includes alleviating the symptoms of the disease or disorder being treated.

III. Application forms

In embodiments of this embodiment, the sustained release dosage forms are formulated as dosage forms that can be administered to patients in need of such administration. Further described are sustained release dosage forms and methods of treatment using sustained release dosage forms. However, the forms described below are merely examples.

Various sustained release dosage forms are suitable for use herein. In some embodiments, the dosage form can be administered orally, and the dosage form has a size of a conventional tablet or capsule. Oral dosage forms can be manufactured in one of a number of different ways. For example, the dosage form may be prepared as a diffusion system, such as a reservoir or matrix device, a dissolution system such as encapsulated dissolution systems (such as micropellets and microcapsules) and matrix dissolution systems and combined diffusion / dissolution systems and ion exchange resin systems which are described in Pharmaccutical Sciences, Remington, 18th edition, pp. 1676-1686 (1990), Mack Publishing Co .; The Pharmaceutical and Clinical Pharmacokmetics, 3rd Edition, pp. 1-28 (1984), I.ea and Tebreger, Philadelphia.

Osmotic dosage forms generally utilize osmotic pressure to generate the force by which the liquid is sucked into a compartment that is at least partially formed by a semipermeable membrane that allows free diffusion of the liquid but not the drug or osmagent (s) if present. An important advantage of osmotic systems is that they operate independently of pH, and the rate given by the osmosis will last for extended periods of time. although the dosage form passes through the gastrointestinal tract and encounters different types of microenvironment whose pH varies greatly. Overview i? such dosage forms can be 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. In U.S. Patent Nos. 3,845,770,

Nos. 916 899, 3 995 631, 4008 719, 4 111 202, 4 160020, 4 327 725, 4 578 075, 4 681 583, 5 019 397 and 5 156 850 disclose osmotic devices for the continuous transport of the active ingredient.

Sustained-release osmotic dosage forms by which the drug composition is released as a suspension or solution from a small orifice through the expansion layer are described 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 that is surrounded by a semipermeable membrane. In some cases, the drug layer is provided with an auxiliary layer that allows the delayed release of the drug composition into the delivery environment or forms a bonded layer together with the semipermeable membrane. In one embodiment, additional protection against rapid dose release may be achieved by applying an enteric coating, preferably a coating which is insoluble in aqueous alcohol and non-swellable in aqueous alcohol and at the pH of the stomach, to an osmotic sustained release dosage form. The semipermeable membrane can be protected by applying a thin layer of a hydrophilic material (such as polyvinyl alcohol) or a hydrophobic material. If such a layer reduces ethanol contact with the semipermeable membrane, swelling of the semipermeable membrane can be prevented or minimized.

An example of a dosage form, referred to herein as an elemental osmotic pump based dosage form, is shown in FIG. 1. The application form 20, shown in a spatial section, is also referred to as an elemental osmotic pump (EOP), containing a semipermeable membrane. 22 that surrounds and encapsulates the inner compartment 24. The inner compartment comprises a one-component layer, referred to herein as the drug layer 26. which comprises substance 28 according to the solution in admixture with selected excipients. The excipients are adapted to achieve a gradient of osmotic activity required to bring liquid from the outside through the membrane 22, and upon aspiration of the liquid to form a transportable complex formulation. Excipients which may be mentioned are suitable suspending agents, also referred to herein as drug carrier 30, binder 32, lubricant 34, and osmotic active agent, referred to as osmagent, 36. Examples of materials useful for these components can be found throughout the description. of this application.

The semipermeable membrane 22 of the osmotic dosage form is permeable to an external liquid, such as water and biological fluids, but substantially impermeable to the interior compartment components. Materials useful in forming the membrane are substantially non-erodible and substantially insoluble in biological fluids over the life of the dosage form. Representative polymers that can be used to form the semipermeable membrane include homopolyinery and copolymers such as cellulose esters, cellulose ethers and cellulose ester ethers. The permeability of the membrane to the liquids can be adjusted using flow control agents. which are mixed with

The material which forms the membrane. For example, agents that cause a significant increase in liquid permeability, such as water, are often substantially hydrophilic, while agents that cause a significant decrease in water permeability are substantially hydrophobic. Examples of flow control agents include polyhydric alcohols, polyalkylene glycols, polyalkylenediols, poly5 alkylene glycol esters and the like.

During operation, the osmotic gradient on the membrane 22 due to the presence of osmotically active agents causes aspiration of gastric fluid across the membrane, the drug layer swells, and a transportable complex formulation (e.g., solution, suspension or other liquid composition) is formed in the inner compartment. The transportable formulation of a substance of the invention is released as liquid 38 enters the inner compartment through the outlet 38.1 when the drug formulation is already released, the liquid still enters the inner compartment, which is the driving mechanism for continuous release. In this way, the substance of the invention is released sustainably and continuously over an extended period of time.

FIG. 2 shows some embodiments of the sustained release dosage forms of the present invention. Application forms of this type are described in detail in U.S. Patent Nos. 4,612,008, 5,082,668 and 5,091,190, and hereinafter.

FIG. 2 shows an embodiment of one type of sustained release dosage form, namely an osmotic sustained release dosage form. The first drug layer 30 contains osmotically active ingredients and less opioid than the second drug layer 40. The osmotically active ingredient (s) in the first drug component layer comprises an osmagent, such as a salt, and one or more relatively low molecular weight osmopolymers which swell with suction of the liquid so that release of the osmopolymers occurs through the outlet 60 similar to the drug layer 40. The first drug layer 30 may also contain other excipients such as binders, lubricants, antioxidants, and coloring agents.

The second drug layer 40 comprises the opioid in admixture with selected excipients which are adapted to achieve the osmotic activity gradient required to bring the liquid from the external environment through the membrane 20, and upon aspiration of the liquid to form a transportable complex formulation. Excipients which may be mentioned are suitable suspending agents (also referred to herein as drug carriers), but not the osmotically active agent, "osmagent", such as salt, sodium chloride. It was discovered. that is, by discharging the salt from the second drug layer, which contains the majority of the drug in the total dosage form present, in combination with the salt in the first drug layer, an increase in the release rate is achieved and the increase in rate is maintained for a longer period.

The drug layer 40 has a higher opioid concentration than the drug layer 30. The ratio of the opioid concentration in the first drug layer 30 to the opioid concentration in the second drug layer 40 is preferably kept below 1, and preferably about 0.43 or less, thereby achieving the desired substantially increasing release rate.

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

The drug layer 40, as well as the drug layer 30, further comprises a hydrophilic polymer carrier. The hydrophilic polymer is involved in the controlled transport of the opioid. Representative examples of such polymers include poly (alkylene oxide) having a number average molecular weight of 100,000 to 750,000 such as poly (ethylene oxide), poly (methylene oxide), poly (butylene oxide) and poly (hexylene oxide); and poly (carboxymethylcellulose) having a number average molecular weight of 40,000 to 400,000 such as a polymeric carboxymethylcellulose alkaline salt, a polymeric sodium carboxymethylcellulose, a polymeric potassium carboxymethylcellulose, and a polymeric carboxymethylcellulose lithium salt.

The drug layer 40 may further comprise hydroxypropyl alkylcellulose having a number average molecular weight of 9,200 to 125,000 which can be used to improve the transport properties of the dosage form, for example hydroxypropyl ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbutylcellulose and hydroxypropyipentylcellulose; and polyvinylpyrrolidone having a number average molecular weight of 7,000 to 75,000 which can improve the flow properties of the dosage form. Of these polymers, preference is given to poly (ethylene oxide) having a number average molecular weight of 100,000 to 300,000.

- 14GB 19137 U1, carriers that are subject to erosion in the stomach environment, i.e., biodegradable carriers, are preferred.

The drug layer 40 or the drug layer 30 may also contain other carriers, such as carbohydrates, that are osmotically active enough to be used alone or by other osmagents. Examples of such carbohydrates include monosaeharides. disaccharides and polysaccharides. Representative examples include maltodextrins (i.e., glucose polymers obtainable by hydrolysis of corn starch) and sugars such as lactose, glucose, raffinose, sucrose, mannitol, sorbitol, and the like. Maltodextrins having a dextrose equivalent value (DE) are preferred. 20 or lower, preferably a DE in the range of about 4 to about 20, and often from 9 to 20, has been found to be useful with maltodextrins with a DE of 9 to 12.

The drug layer 40 and the drug layer 30 are typically a substantially dry (water content < 1 2 > wt%) composition formed by compressing the carrier, opioid and other excipients to form a single layer.

The drug layer 40 may be formed from particles by comminution to achieve the particle size of the drug and the particle size of the accompanying polymer used in the manufacture of the drug layer, blowing the furnace as the core containing the compound, according to the mode and method of the invention. Methods for preparing the particles include granulation, spray drying, sieving, lyophilization, crushing, grinding, jet grinding, micronization, and chopping to achieve the intended micrometer particle size.

The method can be carried out using a comminution apparatus such as a micropulverizer mill, a stream mill, a wheel mill, a roller mill, a hammer mill, a disc mill, a wheel mill, a ball mill, a vibrating ball mill, a pulverizing mill, a coarse crusher and a fine crusher. . The particle size can be ensured by sieving, such as sieving using a sieve screen, flat screen, vibratory screen, rotary screen, shirring screen, oscillating screen, and weaving screen. Methods and devices for preparing drug particles and carriers are described in Pharmaceutical Sciences, Remington, 17th ed., Pp. 1585-1594 (1985); Chemical Engineers Handbook, Perry, 6th Edition, pp. 21-13-21-19 (1984); Journal of Pharmaceutical Sciences, Parrot, Vol. 61, No. 6, pp. 813-829 (1974) and Chemical Engmeer, Hixon, pp. 94-103 (1990).

The first drug layer 30 contains the active ingredient in admixture with selected excipients which are adapted to achieve the osmotic activity gradient required to bring the liquid from the outside through the membrane 20, and upon aspiration of the liquid to form a transportable drug formulation. The excipients include a suitable suspending agent, also referred to herein as a drug carrier, and an osmotically active agent, "osmagent", as a salt. Other excipients such as lubricants, binders, etc. may also be present. Surprisingly, it has been found that when the first drug component layer 30 contains an osmotically active ingredient and a lower amount of active ingredient than in the second drug component layer 40, an improvement in the release rate , and the speed increase is maintained for a longer period of time.

The osmotically active component in the first drug layer comprises an osmagent and one or more relatively low molecular weight osmopolymers which swell as they soak up the liquid. The release of these osmomers occurs via an outlet 60 similar to the drug layer 40.

4o The ratio of opioid concentration in the first drug layer and 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 at the first moment after initiation (e.g., at 6 hours) divided by the average release rate between the two reference points.

The drug layer 30 and the drug layer 40 may optionally contain surfactants and a disintegrant. Examples of surfactants include surfactants having an HLB (hydrophilic-lipophile equilibrium) value of about 10 to 25, such as polyethylene glycol 400 monostearate. polyoxyethylene-4-sorbitan monolaurate, polyoxyethylene-20-sorbitan monooleate, polyoxyethylene-20-sorbitan monopalmitate, polyoxyethylene-20-monolaurate. polyoxyethylene-40 stearate, sodium oleate and the like.

- 15 CZ 19137 Ul

The disintegrants may be selected from starches, clays, eeluloses, algins and gums and crosslinked starches, eeluloses and polymers. Representative disintegrants include corn starch, potato starch, croscarmellose, crospovidone, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethyl-cellulose, alginic acid, guar gum and the like.

The membrane 20 is designed to be permeable to an external liquid, such as water and biological fluids, and substantially impermeable to paliperidone, osmagent, osmopolymer, and the like. As such, it is semipermeable. The selectively semipermeable compositions used to form the membrane 20 are substantially non-erodible and substantially insoluble in biological fluids over the life of the dosage form.

Representative polymers that can be used to form the membrane 20 include semipermeable homopolymers, semipermeable copolymers, and the like. In one currently preferred embodiment, the compositions may comprise cellulose esters, cellulose ethers, and cellulose ester ethers. Cellulose polymers have a degree of substitution of "D.S" on their anhydroglucose unit of more than 0 to 3 inclusive. The degree of substitution is understood to mean the average number of hydro15 groups that were originally present on the anhydroglucose unit and have been replaced or converted to another group. The anhydroglucose unit may be partially or fully substituted by groups such as acyl, alkanoyl, alkenoyl, aroyl, alkyl, alkoxy, halogen, alkylcarbonyl, alkylcarbamate, alkylcarbonate, alkylsulfonate, alkylsulfainate groups, typically forming semipermeable polymers and semipermeable polymers. a group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose triacetate, cellulose acetate, cellulose diacetate, cellulose acetate, mono-, di- and trialkanylates, mono-, di- and trialkenylates, mono-, di- and triaroylates, cellulose .

Examples of polymers that may be included are cellulose acetate with D.S. 1.8 to 2.3 and an acetyl content of 32 to 39.9%; cellulose diacetate with D.S. 1 to 2 and an acetyl content of 21 to 35%, cellulose triacetate with D.S. More specifically, cellulose polymers include cellulose propionate with D.S. 1.8 and a propionyl content of 38.5%: cellulose acetate propionate with an acetyl content of 1.5 to 7% and an acetyl content of 39 to 42%; cellulose acetate propionate with an acetyl content of 2.5 to 3% and an average propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; Eelulose acetate butyrate with D, S. 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%, a cellulose acetate butyrate having an acetyl content of 2 to 29 To, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylates with D.S. 2.6 to 3, such as cellulose trivalerate. cellulose trilamate, cellulose tripalmitate, cellulose trioctanoate, and cellulose tripropionate; diestery eelulosa s

D.S. 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicycrylate and the like; mixed cellulose esters such as cellulose valerate acetate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate, cellulose heptanoate acetate, and the like. of Polymer Science and Technology, Vol. 3, pp. 325 to

354, 1964, edited by Interscience Publishers, Inc., New York.

Other semi-permeable polymers that can be used to form the semi-permeable membrane include, for example, cellulose acetaldehyde dimethyl acetate; cellulose acetate ethylcarbamate; cellulose acetate methylcarbamate; cellulose dimethylaminoacetate; semipermeable polyamide; semipermeable polvurethanes; semipermeable sulfonated polystyrenes; crosslinked selectively semipermeable polymers formed by coprecipitation of polyanion and polycation according to U.S. Patent Nos. 3,173,876, 3,276,586, 3,541,005; 3,541,006 and 3,546,142; semipermeable polymers disclosed in US Patent No. 3,133,132; semipermeable polystyrene derivatives; semipermeable poly (sodium styrene sulfonate); semipermeable poly (vinylbenzyltrimethylammonium chloride); semipermeable polymers having a liquid permeability of 10-5 to 10-2 (cc. mil / em hr.atm) expressed per atmosphere of hydrostatic or osmotic pressure difference across the semipenable membrane. Such polymers are known in the art and are described in U.S. Patent Nos. 3,845,770.

- 16GB 19137 Ul

916,899 and 4,160,020 and in the Handbook of Common Polymers, Scott, J.R. and Roff, W.J., 1971, edited by CRC Press, Cleveland Ohio.

The membrane 20 may also comprise a flow control agent. A flow control agent is a compound that is added to help control liquid permeability or membrane flow

20, The flow controlling agent may be a flow enhancing agent or a flow reducing agent. The agent may be pre-selected to increase or decrease the flow of liquid. Agents that cause a significant increase in permeability to liquids such as water are often substantially hydrophilic, while agents that cause a significant decrease in permeability to liquids such as water are substantially hydrophobic. The amount of the regulating agent in the membrane 20, if any, is typically from about 0.01% to 20% by weight or greater. As flow control agents in one embodiment. 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 polyamyl glycol; polyalkylenediols 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; alkylene 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 glycol butyrate, butylene glycol dipropionate, glycerol acetate esters and the like. Representative examples of flow reducing agents include alkyl- or alkoxy-substituted phthalates or alkyl- and alkoxy-substituted phthalates such as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate, and dimethyl phthalate. such as triphenyl phthalate and butyl benzyl phthalate; insoluble salts such as calcium sulfate, barium sulfate, calcium phosphate and the like; insoluble oxides such as titanium dioxide; polymers in the form of powder, 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 which are compatible with cellulosic substances forming a membrane and the like;

Other materials which can be used in forming the membrane 20 to impart flexibility and elongation to the wall so that the membrane is less brittle to non-brittle and to achieve structural strength include, for example, phthalate plasticizers, such as dibenzyl phthalate, dihexyl phthalate, butyloctyl phthalate, eleven carbon atoms and straight chain, diisononyl phthalate. diisodecyl phthalate and the like. Non-phthalate plasticizers, such as triacetin, dioctyl alate, epoxidized talc, triisoctyltrinellitate, triisononyltrinellitate, sucrose isobutyrate acetate, epoxidized soybean oil and the like can also be mentioned.

3? from about 0.01% to about 20% by weight of a plasticizer; or higher.

The extrusion layer 50 includes an expandable layer that is arranged to contact the second medicament layer 40 as shown in Figure 2. The extrusion layer 50 comprises a polymer that absorbs an aqueous or biological liquid and a swellable, thereby expelling the drug composition from the outlet of the device. .

The expandable layer in one embodiment comprises a water-activated composition that swells in the presence of water, such as water that is present in the gastric fluid. Suitably, it may comprise an osmotic composition comprising an osmotic solute which exhibits an osmotic pressure gradient over the external fluid that is present on the semipermeable membrane. present in the application environment. In another embodiment, the water-activated layer comprises a hydrogel that sucks and / or adsorbs ka45 palm into the layer through the outer semipermeable membrane. The semipermeable membrane is non-toxic. During the process, it retains physical and chemical integrity and essentially has no interaction with the expanding layer.

In one preferred embodiment, the expandable layer comprises a hydroactive layer comprising a hydrophilic polymer, also known as an osmopolymer. Osmopolymers have the ability to absorb liquids.

The osmopolymers are swellable. hydrophilic polymers that interact with water and aqueous biological liquids and swell to increase their volume until equilibrium is reached.

- 17 C7. 19137 Ul

The osmopolymers exhibit the ability to swell in water and biological fluids and to retain a significant portion of the aspirated fluid in their polymeric structure. Osmopolymers swell or increase their volume to a very high degree; they usually show a 2- to 50-fold increase in volume. The osmopolymers may be uncrosslinked or crosslinked. The swellable hydrophilic polymers are in one embodiment weakly crosslinked, wherein such crosslinking occurs through covalent or ionic bonds or residues of the crystalline regions upon swelling. The osmopolymers may be of vegetable, animal or synthetic origin.

Osmopolymers are hydrophilic polymers. Suitable hydrophilic polymers for this purpose include poly (hydroxyalkyl methacrylate) having a molecular weight of from 30,000 to 5,000,000; in poly (vinylpyrrolidone) having a molecular weight of from 10,000 to 360,000; anionic and cationic hydrogels; polyelectrolyte complexes; poly (vinyl alcohol) with a low proportion of acetate groups, crosslinked with glyoxal, formaldehyde or glutaraldehyde and with a degree of polymerization from

200 to 30,000; a mixture of methylcellulose, cross-linked agar and carboxymethylcellulose; a mixture of hydroxypropylmethylcellulose and sodium carboxymethylcellulose; a mixture of hydroxypropylethylcellulose and sodium carboxymethylcellulose; a mixture of sodium carboxymethylcellulose and methylcellulose, sodium carboxymethylcellulose; potassium carboxymethylcellulose; a water-insoluble but swellable copolymer formed by dispersing the finely divided malic acid anhydride copolymer with styrene, ethylene, propylene, butylene or isobutyllene crosslinked 0.001 to about 0.5 moles of saturated crosslinking agent per mole of malic acid anhydride per copolymer; water swellable polymers of N-vinyl lactams; a polyoxyethylene-polyoxypropylene gel; carob rubber; polyacrylic gel; polyester gel; polyurea gel; a polyether gel, a polyamide gel; a polyeelulose gel; gel polygum; hydrogels, which are initially dry and absorb and absorb water, which penetrates the glassy hydrogel and lowers the glass temperature, etc.

Representative of other osmopolymers include polymers that form hydrogels such as ^{Carbopol! M} karboxypolynier acid. an acrylic acid polymer cross-linked with polyallyl sucrose, also known as carboxypolymethylene, and a carboxyvinyl polymer having a molecular weight of 250,000 to 4,000,000; Cyanamer ^IM Polycarylamides; cross-linked indenmaleic anhydride polymers that swell in water; Good-rite ^IM polyacrylic acids having a molecular weight of 80,000 to 200,000; Polyox polyethylene oxide polymer having a molecular weight ^COMES from 100 000 to 5,000,000 and higher; starch graft copolymers; AquaK.eep ^1M acrylate polymers, condensed glucose unit polysaccharides, such as a diester crosslinked polyglucan, and the like. Representative hydrogel-forming polymers are known from U.S. Patent No. 3,865,108; U.S. Pat. 4,002,173; U.S. Patent No. 4,207,893 and the Handbook of Common Polymers, Scott and Roff, eds., Chemical Rubber Co., Cleveland, Ohio. The amount of osmopolymers contained in the hydroactivated layer may be from about 5% to about 100%.

In another embodiment, the expandable layer may comprise an osmotically active compound that includes inorganic and organic compounds that exhibit an osmotic pressure gradient on the semi-permeable membrane against the external liquid. Osmotically active compounds, such as osmopolymers, suck the liquid into the osmotic system, and the liquid available thus pushes the inner wall, i. in some embodiments, onto a barrier layer or membrane of a soft or hard capsule to expel the active agent from the dosage form. Osmotically active compounds are also known as osmotically active solutes and also as osmagents. As osmotically active solutes, magnesium sulphate, magnesium chloride, potassium sulphate, sodium sulphate, lithium sulphate, potassium hydrogen phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates such as raffinos can be used. sucrose, glucose, lactose, sorbitol and mixtures thereof. The amount of osmagent present may be from about 5% to 100% by weight of the layer. The expandable layer optionally comprises an osmopolymer and an osmagent. wherein the total amount of osmopolymers and osmagent is 100%. Osmotically active solutes are known in the art as described in U.S. Patent No. 4,783,337.

- 18 Cl 19137 Ul

The protective backing layer, the inner wall 90, is permeable to liquid that enters the compartment defined by the membrane 20. The wall 90 has a sliding function that facilitates the movement of the first medicament layer 30, the second medicament layer 40 and the extrusion layer 50 towards the outlet 60. be formed from hydrophilic substances and excipients. The wall 90 promotes the release of the drug composition from the compartment and reduces the amount of residual drug composition remaining in the compartment at the end of the transport period, especially if the transported suspension or solution of the drug composition is highly viscous at the time of transport. For dosage forms that contain hydrophobic agents and do not contain an inner wall, it has been found that considerable residual amounts of drug may remain in the device after the transport time. In some cases at the end of the 24-hour period, amounts of 20% or greater may remain in the dosage form in the release rate tests. Especially in the case of very expensive active compounds, such an improvement presents considerable economic advantages since the drug layer does not need to contain excess drug in order to ensure that a minimum amount of drug is transported.

The inner membrane 90 may be formed as a coating applied to the molded core.

and? The wall 90 may have a thickness of typically 0.01 to 5 mm, more typically a thickness of 0.5 to 5 mm, and comprises a member selected from hydrogel, gelatin, low molecular weight polyethylene oxides such as less than 100,000 molecular weight, hydroxyalkyl cellulose such as hydroxyethyl cellulose, hydroxypropyl cellulose; hydroxyisopropylcellulose, hydroxybutylcellulose and hydroxyphenylcellulose, and hydroxyalkylalkylcellulose, such as hydroxypropylmethylcellulose, and mixtures thereof. Hydroxyalkylcelluloses include polymers with an average molecular weight of 9,500 to 1,250,000. For example, hydroxypropylcellulose with an average molecular weight of 80,000 to 850,000 may be useful. The wall 90 may be prepared from conventional solutions or suspensions of the above in aqueous solvents; inert organic solvents.

Preferred wall materials include hydroxypropylcellulose, hydroxyethylcellulose 25, hydroxypropylmethylcellulose, povidone, [poly (vinylpyrrolidone)], polyethylene glycol, and mixtures thereof.

Highly preferred are mixtures of hydroxypropylcellulose and povidone prepared in organic solvents, especially organic polar solvents such as lower alkanols having 1 to 8 carbon atoms, preferably ethanol, mixtures of hydroxyethyl cellulose and hydroxypropyl methylcellulose prepared in aqueous solution and mixtures of hydroxyethyl cellulose and polyethylene glycols. The wall 90 most preferably comprises a mixture of hydroxypropylcellulose and povidone prepared in ethanol.

In a preferred embodiment, the wall 90 comprises about 50% to about 90% of the hydroxypropylcellulose designated as EF with an average molecular weight of about 80,000 and about 10% to about 50% of the polyvinyl 35 pyrrolidone designated as K.29-32.

Advantageously, the weight of the wall 90 applied to the molded core can correlate with the wall thickness 90 and the residual drug that remains in the dosage form in the release rate test described herein. The thickness of the wall 90 per se can be controlled during manufacturing operations by controlling the weight of the wall 90 during coating.

If the wall 90 is formed as a backing, i.e. by coating a tableted composite comprising one or all of the following layers: a first drug layer, a second drug layer and an extrusion layer, then the wall 90 can fill the core surface irregularities during tabletting. The resulting smooth outer surface facilitates sliding between the coated composite core and the semipermeable membrane during drug delivery, resulting in less residual drug composition remaining in the device at the end of the administration period. When the wall 90 is formed of a gel-forming material, contact with water in the application environment facilitates the formation of a gel or gel-like inner coating with a viscosity that can promote and increase slippage between membrane 20 and drug layer 30 and drug layer 40.

In the preparation of the final dosage form, it is advantageous to use a drum coating, except for the outlet opening. In the drum coating system, the press triple layer or multilayer

(u) CZ 19137 U1, a core comprising drug layers, an optional barrier layer and an extrusion layer, applies a wall-forming composition for the wall or, optionally, a membrane by successively spraying a suitable membrane composition while rolling in a rotating drum. The auction drum is used because of its availability on an industrial scale. Other methods can be used to coat the compressed core. After coating, the membrane is dried in a forced air dryer or in a temperature and humidity controlled oven, thereby releasing the dosage form (s) used in manufacture. Suitably, the drying conditions are selected according to the available equipment, ambient conditions, solvents, coating, coating thickness and the like.

Other coating processes may also be used. For example, the membrane or walls of the dosage form may be formed in one embodiment using a fluidized bed process. In this procedure, the compressed core is suspended and rolled in an air stream and the semipermeable membrane forming composition until the membrane is deposited on the core. The fluid process is suitable for independent membrane formation of the dosage form. The fluid process is described in US Patent No. 2,799,241; J.

Am. Pharm. Assoc., Vol. 48, pp. 451-459 (1959) and ibid. 49, sir. 82-84 (1960). The application form can also be coated with a Wuster® fluidized-bed apparatus, for example using dichloromethane and methanol as a co-solvent for the membrane-forming material. It can also be coated in an Aeromatic ^Hj fluid coating device using a co-solvent.

In one embodiment, the sustained release dosage form of the present invention comprises at least one outlet 60 shown in Figure 2. The outlet 60 cooperates with the molded core to uniformly release the drug from the dosage form. The output may be produced during manufacture of the dosage form, or may be generated during drug delivery in the delivery environment.

At the end of the drug-coated dosage form, one or more exit holes are drilled and the dosage form may be provided with optional water-soluble spiral coatings which may be colored (e.g., colored Opadry coatings) or clear (e.g., clear Opadry coating) to provide a final coating. application form.

The outlet 60 may include an orifice that is or may be formed from a substance or polymer that erodes, dissolves, or is leached from the outer membrane to form an orifice.

For example, the substance or polymer may be an erodible poly (glycolic) acid or poly (lactic) acid in a semipermeable wall; gelatinous fiber; water-removable poly (vinyl alcohol); an extractable compound, such as a porous substance, which is removable by a liquid selected from the group consisting of an inorganic and organic salt, an oxide and a carbohydrate.

The outlet or multiple outlets may be produced by leaching a member selected from the group consisting of sorbitol, lactose, fructose, glucose, mannose, galactose, talose, sodium chloride, potassium chloride, sodium citrate, and mannitol to provide a pore outlet opening sized for even release.

The outlet may have any shape, such as circular, triangular, square, elliptical, and the like, to uniformly release a metered dose of drug from the dosage form. The sustained release dosage form may be formed with one or more spaced outlets or one or more surfaces of the sustained release dosage form.

The outlet may be formed by drilling, such as by mechanical or laser drilling of the semipermeable membrane. Such outlets and devices for generating such outlets are described in US Patent Nos. 3,916,899 (Theeuwes and Higuchi) and 4,088,864 (Theeuwes et al.). Currently, two outlets of the same diameter are preferably used. In a preferred embodiment, the outlet 60 passes through the backing layer 90, if present, to the drug layer 30.

The dosage forms of the embodiments shown in Fig. 1 are manufactured by standard procedures. For example, the dosage form can be manufactured by a wet granulation process. In the wet granulation process, the drug and the carrier are mixed using an organic solvent such as denatured anhydrous ethanol as the granulating liquid. The remaining ingredients can be dissolved in a portion of the granulation liquid such as the solvent described above, and the latter wet mixture is added slowly to the drug-containing mixture with continuous mixing in the mixer. The granulation liquid is added until a wet mixture is formed, and the wet mass is then passed through a predetermined sieve to dryers. The mixture is dried in a forced-air oven at 24-35 ^° C for 18-35 ^° C

24 hours. The dried granules are then processed to a suitable size.

Magnesium stearate or other suitable lubricant is then added to the drug granulate and the granulation mixture is placed in grinding drums and blended in a ball mill for 10 minutes. The composition is compressed to form a layer, for example, in a Manesty® or Korsch LCT press. In the case of a three-layered core, a granular or powdered medicament layer composition and a granular or powdered extrusion layer composition are successively placed in a suitable size die matrix, with the intermediate intermediate step being added after the addition of the composition of each of the first two layers. the composition of the last layer into the matrix is subjected to final compression to give a triple layer core. Typically, a compression force of about 50 to 100 N is applied in the intermediate stage. Final compression is performed with a force of 3500 N or more, often 3500 to 5000 N. The compressed cores are introduced into a dry coating press, such as Kilian, and subsequently coated with the membrane materials described above. .

In another embodiment, the drug and other ingredients contained in the drug layer are mixed together and compressed to form a solid layer. The layers have dimensions that correspond to the internal dimensions of the area that the layer in the application layer should occupy, and also have dimensions that correspond to the extrusion layer, if present, so as to form a contact arrangement. The drug and other ingredients may also be mixed with the solvent and mixed to form a solid or semi-solid form by conventional techniques such as ball milling, calendering, mixing or roller milling, and then compressed to a preselected shape. Then, optionally in a similar manner, a layer of osmopolymic composition is placed in contact with the drug layer. The drug formulation layers and the osmopolymer layer can be formed using conventional two-layer compression techniques. A similar procedure can be used to prepare a three-layer core. The molded cores can then be coated with the wall-forming material and the semipermeable membrane material described above.

It is also possible to use another manufacturing process in which the components of each powdered layer are mixed in a fluidized bed. After mixing the powder components in the granulator dry, the powder mixture is sprinkled with a granulating liquid such as poly (vinylpyrrolidone) in water. The coated powders are then dried in the granulator. In this way, all the ingredients present are granulated by the addition of a granulating liquid. After drying the granules, a lubricant such as stearic acid or magnesium stearate is mixed into the granulate using a mixer, for example a V-mixer or a container mixer. The granules are then compressed as described above,

Examples of solvents suitable for the preparation of the components of the dosage form include aqueous or inert organic solvents which do not damage the materials used in the system. Solvents in the broadest sense include members selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic agents, aromatics, heterocyclic solvents, and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone. methyl propyl octone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate. dichloromethane, dichloroethane, dichloropropane, carbon tetrachloride, nitroethane, nitropropane, carbon tetrachloride, diethyl ether, isopropyl ether, cyclohexane. cyclooctane, benzene, toluene, naphthalene, 1,445 dioxane, tetrahydrofuran, diglyme, water, aqueous solvents containing inorganic salts. such as sodium chloride, calcium chloride and the like, and mixtures thereof, such as mixtures of acetone and water, acetone and methanol, acetone and ethanol, dichloromethane and methanol, and dichloroethane and methanol.

Of particular importance in this solution is the physical state of the opioid to be delivered by the dosage form. In some embodiments, the opioids may be semi-solid (paste) or liquid. In such cases, solid dosage forms may not be suitable for use in the practice of this invention. Instead, dosage forms that are capable of delivering the substances in a solid or liquid state should be used.

The subject of the solution is a liquid formulation of substances for use with oral osmotic devices. Oral osmotic devices for delivering liquid formulations and methods of use are? known in the art; for example, they are described and claimed in US patents owned by ALZA. 6,419,952; 6,174,547; 6,551,613; 5,324,280; Methods of using oral osmotic devices to deliver therapeutic agents with increasing release rates can be found in International Patent Applications WO 98/06380, WO 98/23263 and WO 99/62496.

Examples of liquid carriers useful in the present invention include lipophilic solvents (e.g., oils and lipids), surfactants, and hydrophilic solvents. Non-limiting examples of lipophilic solvents include Capmul PG-8, Caprol MPGO, Capryol 90, Plurol Oleique CC 497, Capmul MCM, Labralac PG, n-decanol, Caprol 10G100, oleic acid, vitamin E, Maisine 35-1, Gelucire 33 / 01, Gelucire 44/14, lauryl alcohol, Captex 355EP, Captex

500, caprylic / capric acid triglyceride, 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.

Non-limiting examples of surfactants include Vitamin E TPGS, Cremophor (type EL, EL-P and RH40), Labrasol, Tween (type 20,60,80), Pluromc (type L-31, L-35, L42, L -64 and L20 121), Acconon S-35, Solutol HS-15 and Span (Types 20 and 80). Non-limiting examples of hydrophilic solvents include isosorbide dimethyl ether, polyethylene glycol (PEG types 300, 400, 600, 3000, 4000, 6000 and 8000) and propylene glycol (PG).

It will be apparent to one skilled in the art that any formulation that contains a sufficient dose of an opioid solubilised in a liquid carrier suitable for administration to a subject and for use in an osmotic device may be utilized in the present invention. In one exemplary embodiment of the present invention, the liquid carrier is PG, Solutol, Cremophor EL, or a combination thereof.

The liquid formulations of the present invention may also contain, for example, other excipients such as an antioxidant, a permeation enhancer, and the like. Anti-oxidants may be used to slow or effectively stop the autooxidation of any auto-oxidizable substance that is present in the capsule. Representative anti-oxidants include members selected from the group consisting of ascorbic acid; alpha-tocopherol; ascorbate palmitate: ascorbate; isoascorbates; butylated hydroxyanisole; butylated hydroxytoluene; nordihydroguayaretic acids; gallic acid esters of at least 3 carbon atoms comprising a member selected from the group consisting of propyl gallate, octyl gallate, decyl gallate, decyl gallate; 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline;

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-tert-butyl-p-cresol; polymeric antioxidants; hydroxybutyrophenone, physiologically acceptable salts of ascorbic acid, erythorbic acid and ascorbylacetate; calcium ascorbates; sodium ascorbates; sodium sulfite and the like. The amount of antioxidants used for this purpose may be, for example, about 0.001% to 25% of the total weight of the composition present in the cavity. Prior art antioxidants are known from US Patent Nos. 2,707,154; 3,573,936; 3,637,772; 4,038,434; Nos. 4,186,465 and 4,559,237, which are incorporated herein by reference in their entirety.

The liquid formulation of the present invention may contain a permeation enhancer that facilitates drug absorption in the delivery environment. Such permeation enhancers may, for example, open the zonula occludens in the gastrointestinal tract or modify the effect of cellular components such as p-glycoprotein and the like. Suitable permeation enhancers include salts of salicylic acid, caprylic acid or capric acid with alkali metals such as sodium salicylate, sodium caprylate or sodium caprate, and the like. Permeation enhancers include, for example, bile salts such as sodium deoxycholate. Various modulators of the glycoprotein are described in U.S. Patent Nos. 5,112,817 and 5,643,909.

Absorbency enhancing materials are described in US Patent No. 5,824,638. The permeation enhancers may be used alone or in the form of a mixture with other permeation enhancers.

In some embodiments, the agents of the invention are administered as a self-emulsifying formulation.

As with other liquid carriers, the function of the surfactant is to prevent aggregation, reduce interfacial tension, improve the flow properties of the components, and reduce the incidence of component retention in the dosage form. The emulsion formulation of the present invention comprises a surfactant which permits emulsification. Examples of surfactants include, in addition to the above surfactants, a member selected from the group consisting of polyoxyethylenated castor oil containing 9 to 15 moles ethylene oxide, polyoxyethylenated sorbitan monopalmitate, mono- and tristearate containing 20 moles ethylene oxide, polyoxyethylenated sorbitan monostearate containing 4 mole of ethylene oxide, polyoxyethylenated sorbitan trioleate containing 20 moles of ethylene oxide, polyoxyethylene lauryl ether, polyoxyethylenated stearic acid containing 40 to 50 moles of ethylene oxide, polyoxyethylenated stearic alcohol containing 2 moles of ethylene oxide and polyoxyethylenated oleyl alcohol containing 2 moles of ethylene oxide. Surfactants can be obtained from Atlas Chemical Industries.

The emulsion formulations of the present invention may initially comprise an oil and a nonionic surfactant. The oily phase of the emulsion includes any pharmaceutically acceptable oil that is not miscible with water. The oil may be an edible liquid, such as a non-polar unsaturated fatty acid ester, selines, derivatives of such esters or mixtures of such esters. The oil may be of vegetable, mineral, animal or marine origin. Examples of nontoxic oils include, in addition to the above-mentioned surfactants, peanut oil, cottonseed oil, sesame oil, corn oil, almond oil, mineral oil, castor oil, coconut oil, palm oil, cocoa butter, safflower oil, mono- and diglycine mixtures 16 to 18 carbon atoms, unsaturated fatty acids, fractionated coconut-derived triglycerides, fractionated liquid short-chain fatty acids of 10 to 15 carbon atoms, acetylated monoglycends, acetylated diglycerides, acetylated triglycerides, olein, also known as tololeoleate glycerol, palmitine, also known as glyceryl tripalmitate, stearin, also known as glytyeryl tristearate, lauric hexyl ester, oleic acid oleyl ester, glycolyzed ethoxylated carbohydrates of natural oils, branched fatty acids with 13 molecules of ethylene oxide and ducyl ester of oleic acid. The concentration of the oil or oil derivative in the emulsion formulation may be about 1% by weight to about 40% by weight, the weight of all components in the emulsion formulation being 100% by weight. Oils are described in Pharmaceutical Sciences, Remington, 17th Edition, pp. 403-405 (1985), Maek Publishing Co., Encyclopedia of Chemists 55, Van Nostrand Reinhold, 4th Edition, pp. 644-645 (1984), eds Van Nostrand Reinhold Co, and US Patent No. 4,259,323.

The amount of opioid incorporated in the dosage forms of the present invention is generally about 10% to about 90% by weight based on the weight of the composition, depending on the therapeutic indication and the desired time of administration, e.g. every 12 hours, every 24 hours and the like. One or more dosage forms to be administered may be administered.

The osmotic dosage forms of the present invention may be in two different forms, a soft capsule (shown in Figure 3) and a hard capsule (shown in Figure 4). The soft capsule as used in the present invention is in its final form a single piece. The one-piece capsule has a closed construction and the drug composition is encapsulated therein. The capsule can be prepared in a variety of ways, such as by surface compression, rotary compression, reversible dies and a continuous process. By way of example, a surface compression process is described below. The flat-molding process uses mold sets. The warm sheet of the prepared sheet-forming capsule material is applied over the lower mold and the formulation is poured onto it. A second sheet of prepared sheet-forming capsule material is placed over the formulation. The upper mold is then placed on it. On the set

The molds are subjected to pressure, optionally with heating, to form an integral capsule. The capsules are washed with solvent to remove excess drug-containing formulation from the outer surface of the capsule and the encapsulated semipermeable wall is encapsulated from the dried capsule. When rotating

Two continuous films of sheet-forming capsule material are used which converge between a pair of compression rollers and an injection wedge. The capsule is filled and sealed in two parallel steps. In this method, the sheets of the capsule-forming material are guided through the guide rolls and then down between the wedge injection nozzle and the press rolls.

The formulation containing the active ingredient to be filled is delivered to the positive displacement pump by gravity. The pump dispenses the formulation containing the active ingredient through the wedge injector and into the leaves between the rollers. The wedge base comprises small holes aligned with the recesses of the cylindrical die. The capsule is half-closed when the pressure of the pumped formulation with the agent pushes the sheet into the die recess where the capsules are simultaneously filled, shaped, hermetically sealed and cut off from the sheets of the sheet-forming material. The capsule is closed by mechanical pressure on the press rolls and by heating the sheets of the sheet-forming material with a wedge. Upon completion of the manufacturing process, the capsules filled with the active ingredient formulation are dried in the presence of forced air circulation and encapsulated with a semipermeable membrane layer.

Using return dies, capsules are prepared by passing two films of the capsule-forming material between a set of vertical dies. By their gripping, zooming out and re-gripping, the dies create, as a continuous flat forming, line by line of pocket throughout the film. The pockets are filled with the formulation according to the solution and are closed, shaped and cut off from the moving film as capsules filled with the active ingredient formulation as they pass through the rollers. After application of the semipermeable encapsulation layer, a capsule is obtained. The continuous process uses a manufacturing system that also includes a rotary molded. An additional feature of this procedure is that they can be gradually filled with the soft capsule in addition to the active ingredient encapsulated in the form of a dry powder. The filled capsules obtained by the continuous process are encapsulated with a semipermeable polymeric material to form the resulting capsule. Methods for making soft capsules are described in U.S. Patent No. 4,627,850 and U.S. Patent No. 6,067,144. 6,419,952.

The dosage forms of the present invention can also be prepared from injectable compositions by injection molding. Injectable compositions for injection into the semipennial membrane comprise a thermoplastic polymer, or the compositions comprise a mixture of thermoplastic polymers and optional injection additives. A thermoplastic polymer which can be used for this purpose is polymers having a low softening point, for example less than 200 ° C. preferably from about 40 ^° C to about 180 ^° C. The polymers are preferably synthetic resins, addition polymerized resins such as polyamides, diepoxide-based and primary alkanolamines, glycerin-based resins and phthalic anhydrides, polymethane, polyvinyl resin, polymeric resins whose terminal the positions are free or esterified with carboxyl or carboxamide groups, for example by reaction with acrylic acid, acrylamide or acrylic acid esters, polycaprolactone and its copolymers with dilactide, diglycolide, valerolactone and decalactone, a polycaprolactone-containing resin composition and a polyalkylene oxide-containing resin composition, polyethylene oxide, poly (cellulose), such as poly (hydroxypropylmethylcellulose), poly (hydroxyethylmethylcellulose) and polv (hydroxypropylcellulose). The membrane-forming composition may include optional diaphragm-forming components such as polyethylene glycol, talc, polyvinyl alcohol. lactose or polyvinylpyrrolidone. The compositions for preparing the injectable polymer composition may comprise 100% thermoplastic polymer. In another embodiment, the composition comprises 10% to 99% thermoplastic polymer and 1% to 90% different polymer, wherein the sum of the proportions of the individual polymers is 100%. The invention also encompasses a thermoplastic polymer composition comprising from about 1% to about 98% of the first thermoplastic polymer. 1% to 90% of the different second polymer and 1% to 90% of the different third polymer, the sum of the proportions in all polymers being! () ()%,

Representative compositions include 20% to 90% thermoplastic polycaprolactone and 10% to 80% poly (alkylene oxide); a composition comprising 20% to 90% polycaprolactone and 10 to 60% poly (ethylene oxide), wherein the sum of all components is 100%; a composition comprising 10% to 97% polycaprolactone. 10 to 97% poly (alkylene oxide) and 1% to 97% poly (ethylene glycol), the sum of all components being 100%; a composition comprising 20% to 90% polycaprolactone and 10 to 80 To poly (hydroxypropylcellulose), the sum of the proportions of all components being

- 24GB 19137 Ul

100% and a composition comprising 1% to 90% polycaprolactone, 1% to 90% poly (ethylene oxide),% to 90% poly (hydroxypropylcellulose) and 1% to 90% poly (ethylene glycol), the sum of all components being 100%. The percentages given are percentages by weight.

In another embodiment, an injection molding composition to form a membrane can be prepared by mixing compositions comprising polycaprolactone (63 wt%), polvethylene oxide (27 wt%) and polyethylene glycol (10 wt%) in a conventional mixer such as in a Moriyama ^IM Mixer, at 65-95 ° C, the ingredients being added to the mixer in the following order: polycaprolactone, polyethylene oxide and polyethylene glycol. In one example, all the ingredients are mixed for 135 minutes at a rotational speed of 10 to 20 minutes ^first The mixture is then processed in an Baker Perkins Kneader ^1M extender at 80-90 ° C at a pump speed of 10 min ^-1 and a rotation speed of min ^-1 and then cooled to 10-12 ° C to achieve a uniform temperature. The cooled extruded composition is introduced into an Albe Pelletizer, where it is pelleted at 250 ° C to pellets of 5 mm in length. The pellets were fed to an Arburg Allrounder ^IM at 93-177 ° C. wherein heating results in a molten polymer composition. The liquid polymer composition is blown into the mold cavity at high pressure and high speed until the mold is filled. Then, the polymer-containing composition is allowed to solidify to a predetermined shape. The injection parameters consist of a temperature in zones 1 to 5 of the cylinder of 91 to 191 ° C, an injection pressure of 181.8 MPa, a speed of 55 cmVs and a temperature of 75 ° C. Injection compositions and injection techniques are described in U.S. Patent No. 5,614,578.

Alternatively, the capsules may conveniently be prepared as two-part, one portion (the "cap") being slid onto the other part (the "body") which covers when the capsule is deformable under the forces exerted by the expanding layer and tightly closes to prevent leakage; containing the active substance, between the protruding parts of the body and the lid. These two parts completely encapsulate and encapsulate the inner cavity which contains the liquid, a formulation containing the active ingredient that may contain useful additives. The cap and body can be joined after the body is filled with the selected formulation. The capsule can be assembled by sliding the cap on the body, and the cap and body are tightly closed so that they completely surround and encapsulate the active ingredient formulation.

For soft capsules, the wall thickness is typically greater than the wall thickness of the hard capsules. For example, soft capsules may have a wall thickness of the order of 254 to 1016 µm, typically 508 µm, while hard capsules may have a wall thickness of, for example, 51 to 152 µm, typically 102 µm.

In one embodiment of the delivery system, the soft capsule may be in one piece and surrounded by an asymmetric hydroactive layer as an expandable layer. The expandable layer will usually be asymmetric and a portion of greater thickness will be spaced from the exit orifice. When the hydro-active layer sucks and / or absorbs the external liquid, it expands and pushes against the capsule wall and any barrier layer and expels the active substance-containing formulation through the outlet. The asymmetry of the layer ensures that the maximum dose of the active ingredient will be transported from the dosage form as the portion of the layer of greater thickness spaced from the passageway is swellable and moves toward the opening.

In yet another embodiment, the expandable layer may be formed in discrete sections that do not surround the entire capsule, optionally with a coated barrier layer. The expandable layer may be a single panel that is configured to fit the capsule shape in the area of contact. Conveniently, the expandable layer may be prepared by tabletting to form a concave surface that is flush with the outer surface of the barrier-coated capsule.

The required complementary shape of the expandable layer can be achieved using a suitable machine, such as a convex punch in a conventional tablet press. In this case, the expansion layer is not formed as a coating, but is granulated and compressed. Methods for forming the expandable layer by tabletting are well known and are described, for example, in US Patent Nos. 4,915,949; 5,126,142; 5,660,861; 5,633,011; 5,190,765; 5,252,338: 5,620,705; 4 931285; 5,006,346; 5,024,842 and 5,160,743.

CZ 19137 Ul

In some embodiments, the barrier layer is first coated onto the capsule, and then the barrier coated capsule is combined with the tableted expandable layer using a biocompatible adhesive. Suitable adhesives include, for example, starch grease, aqueous gelatin solution, aqueous gelatin / glycrol solution, acrylate-vinyl acetate adhesives such as Duro-Tak adhesives (National Starch and Chemical Company), aqueous solutions of water-soluble hydrophilic polymers such as xypropyl methyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose and the like. The intermediate dosage form can then be coated with a semipermeable layer. The outlet opening is formed on the side or end of the capsule that is opposite the expansible layer panels. As the expanding layer absorbs liquid, swellable. Because it is limited by the seed permeable layer, when expanded, it compresses the capsule with the coated barrier layer and forces the liquid containing the active ingredient formulation out of the interior of the capsule into the delivery environment.

Hard capsules typically consist of two parts, a cap and a body, which are joined together after filling a larger body with a preselected corresponding formulation. This is done by placing the cap on or not on the body, so that a useful formulation containing the active ingredient is completely surrounded and encapsulated. For example, hard capsules can be prepared by dipping the stainless steel molds into a bath containing a solution of a layer-forming material that forms a coating on the lorm. The molds are then removed, cooled and dried in a stream of air. The capsule is withdrawn from the mold and trimmed to obtain a layer member having an internal cavity. In a similar manner, a slip-on cap is prepared which slips on the body containing the formulation. The sealed and filled capsule can then be encapsulated in a semipermeable layer. The semi-permeable layer may be applied to the capsule parts before or after joining them into the final capsule. In another embodiment, hard capsules can be prepared whose parts near the open end contain rings that engage with each other and, after the formulations have been filled, allow the capsules to be joined and fixed to each other. In this embodiment, rings are formed on the cap and body that engage each other to form a lock that securely holds the capsule together. The capsule can be filled by formulation manually or by machine. In the final manufacture, the hard capsule is encapsulated by a semipermeable layer which is liquid pervious and substantially impermeable to the active ingredient. Methods for preparing dosage forms such as hard capsules are described in US Patent No. 6,174,547, US Patent No. 6,596,314,

6,419,952 and 6,174,547.

For example, hard and soft capsules may contain gelatin; gelatin with a viscosity of 1.5 to 3 mPa · s and a bloom value of up to 150 g; gelatin with a block value of 160 to 250; 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 35; a composition comprising gelatin, acacia, glycerol and water; and the like. Materials useful in the preparation of capsule membranes are known from U.S. Patent Nos. 4,627,850 and 4,663,148. Alternatively, capsules may be prepared from materials other than gelatin (see, for example, BioProgres plc products).

The capsules may typically have a size of from about 0.1848 ml (3 minima) to about 1.3552 ml (22 minima) and may be oval, elongated or otherwise. They may have a standard shape and various standard sizes, which are usually referred to as (000), (00), (0). (1), (2), (3), (4) and (5). The highest number corresponds to the smallest size. However, non-standard shapes can also be used. If required in a particular case, both soft and hard capsules may be in unusual shapes and sizes.

The osmotic devices of the present invention may comprise a semipermeable membrane that is permeable to an external biological liquid and substantially impermeable to the opioid formulation. The selectively permeable compositions used to prepare the membrane are substantially non-erodible and insoluble in biological fluids for the life of the osmotic system. The semipermeable membrane comprises a composition that does not harm the host, an opioid formulation 50i, an osmopolymer, an osmagent, and the like. Materials that are useful in forming the semipermeable membrane are described elsewhere herein.

-26GB 19137 Ul

The semipermeable membrane may also contain a flow control agent. Materials useful as flow control agents are described elsewhere herein. Other materials that can be used to form a semi-permeable membrane impart flexibility and elongability are also described elsewhere herein.

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

In some solid and liquid embodiments, the dosage forms may further comprise a barrier layer. The barrier layer, in some embodiments, is deformable by the pressure exerted by the reinforced layer, and is impermeable (or less permeable) to liquids and materials that are present in the expandable layer, the liquid formulation containing the active ingredient during transport. substance and application environment. A certain degree of permeability of the barrier layer can be admitted unless the rate of transport of the drug-containing formulation is adversely affected. However, a barrier layer that does not transport liquids and materials that are in the dosage form and the delivery environment during full release is preferred. The barrier layer may be deformable by the forces exerted by the expandable layer so as to allow the capsule to be compressed and the liquid containing the active substance to be expelled from the outlet. In some embodiments, the barrier layer will be deformable to the extent that it forms an insulation between the expandable layer and the semipermeable layer in the region where it is formed.

2o outlet hole. In this method, the barrier layer will deform or will flow to a limited extent and isolate regions of the expandable layer and the semipermeable layer that were initially exposed when forming the exit orifice, for example, by drilling or the like, or in the initial stages of the operation. After the isolation, the only access path for the liquid to pass into the expandable layer through the semipermeable layer is to prevent liquid from flowing back into the expandable layer through the exit orifice.

Suitable barrier layer materials include, for example, polyethylene, polystyrene, ethylene-vinyl acetate copolymers, polycaprolactone and polyester elastomers, Hytrel ^rM (Du Pont), cellulose acetate, eelulose acetate pseudolatex (such as the pseudolatex described in U.S. Patent No. 5,024,842). ), ac. cellulose propionate, cellulose acetate butyrate, ethylcellulose, ethylcellulose-based pseudolatex (such as Surelease supplied by 10 Colorcon, West Point, PA, or Aquacoat ^1M supplied by FMC Corporation, Philadelphia, PA), nitrocellulose, polylactic acid, polyglycolic acid, polyglycolic acid glycolide copolymers, collagen, polyvinyl alcohol, polyvinyl acetate, polyethylene vinyl acetate, polyethylene terephthalate, polybutadiene-styrene, polyisobutylene, polyisobutylene-isoprene copolymer, polyvinyl chloride, polyvinyl35 idenchloride-vinyl chloride copolymer, acrylic acid copolymer acrylic acid and methacrylate esters copolymers (such as Eudragit ^IM supplied by RohmPharma, Darmstadt, Germany), polypropylene, propylene oxide / ethylene oxide copolymers, propylene oxide / ethylene oxide block copolymers, ethylene / vinyl alcohol copolymer, polysulfone, ethylene copolymer and vinyl alcohol. polyxylylenes, polylakoxysiates, polydimethylsiloxane, elastomers based on polyethylene glycol and silicone, acrylates, silicones or polyesters crosslinked by electromagnetic radiation, thermally crosslinked acrylates, silicones or polyesters, butadiene-styrene rubber, and mixtures of the above.

Preferred materials include cellulose acetate, copolymers of acrylic acid and methacrylic acid esters, copolymers of methyl methacrylate and ethyl acrylate, and a latex based on acrvlate esters. Preferred copolymers are nols (butyl methacrylate). (2-dimethylaminoethyl) methacrylate. methyl methacrylate) 1: 2: 1, 150,000, which is marketed under the trademark EUDRAGIT E; poly (ethyl acrylate, methyl methacrylate) 2: 1, 800,000, which is marketed under the trademark EUDRAGIT NE 30 D; poly (methacrylic acid, methyl methacrylate) 1: 1, 135 000, which is marketed under the trademark EUDRAGIT L; yo poly (methacrylic acid, ethyl acrylate) 1: 1, 250,000, which is marketed under the trademark EUDRAGIT E; poly (methacrylic acid, methyl methacrylate) 1: 2, 135 000, marketed under the trademark EUDRAGIT S: poly (ethyl acrylate, methyl methacrylate, trimethylamo-> 7).

CZ 19137 Ulium ethyl methacrylate chloride) 1: 2: 0,2, 150 000, which is marketed under the trademark EUDRAGIT RL; poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1: 2: 0.1, 150,000, marketed as EUDRAGIT RS. In each case, the ratio x: y: z denotes the molar ratio of the monomer units, and the number which is always mentioned last indicates the number average molecular weight of the polymer. Particular preference is given to eelulose acetate containing plasticizers such as acetyltributyl nitrate and copolymers of ethyl acrylate and methyl methacrylate such as Eudragit NE,

The aforementioned materials for use as a barrier layer can be formulated with plasticizers to prepare such a suitably deformable barrier layer such that the force exerted by the granular layer will collapse the compartment formed by the barrier layer, thereby transporting the liquid containing the active ingredient formulation. Examples of typical emollients include: polyhydric alcohols, triacetin, polyethylene glycol, glycerol, propylene glycol, acetate esters, glycerol triacetate, triethyl citrate, acetyl triethyl citrate, glycerides, acetylated monoglycerides, oils, mineral oils, castor oil and the like. Plasticizers can be incorporated into the material in amounts of 10 to 50% by weight based on the weight of the material.

The various layers forming the barrier layer, the expandable layer and the semipermeable layer can be applied by conventional coating methods, such as those described in US Patent No. 5,324,280. Although the barrier layer, expandable layer and semipermeable membrane have been effectively illustrated and described as monolayers, each it may consist of several layers. For a particular application, for example, it may be desirable to coat the capsule with a first layer of material that facilitates coating with a second layer having a barrier layer permeation profile. In this case, the barrier layer comprises the first and second layers. For semipermeable layers and expandable layers, this is similar.

The outlet may be formed by mechanical drilling, laser drilling, erosion of the erosion member, extraction, dissolution, rupture, or leaching of the material that forms a channel in the composite wall. The outlet orifice may be a pore formed by leaching sorbitol, sucrose and the like from a membrane or layer as described in U.S. Pat. This patent discloses porosity-controlled pores that are formed by dissolving, extracting or leaching a wall material such as sorbitol from eelulose acetate. In laser drilling, it is preferable to use a pulsed laser, which gradually removes material from the composite membrane until the desired depth is achieved and thus an outlet opening is obtained.

FIGS. 5A-5C show another example of a dosage form known in the art and described in U.S. Patent Nos. 5,534,263; This form can be briefly described as follows: FIG. 5A is a cross-sectional view of the dosage form 80 prior to admission to the gastrointestinal tract. The dosage form comprises a cylinder-shaped matrix 82 which contains the active ingredient. The ends 84, 86 of the die 82 preferably have a round and convex shape for ease of ingestion. The bands 88, 90 and 92 concentrically surround the cylindrical matrix and are formed of a material that is relatively insoluble in an aqueous environment. Suitable materials are disclosed in patents cited elsewhere herein.

4 »After ingestion of dosage form 80, the die region 82 between the webs 88, 90, 92 begins to erode. as shown in FIG. 5. Matrix erosion initiates the release of the active ingredient into the liquid environment of the GI tract. As the GI dosage form passes through the tract, matrix erosion continues as shown in FIG. 5C. Here, the matrix was eroded to such an extent that the dosage form disintegrated into three pieces. 94, 96, 98. Erosion will continue until the die parts of each of these pieces are completely ero45 imported. The bands 94, 96, 98 will then be excluded from the GI tract.

Other methods are known in the art to provide sustained release of drugs from oral dosage forms. For example, diffusion systems such as storage devices and matrix devices, dissolution systems, such as encapsulated dissolution systems such as dark time pills and matrix dissolution systems are known. systems, combining dilution / dissolution systems, and ion exchange systems as described in Remington's Pharmaceutical Sciences, 1990. pp. 1682-1685. Application forms that function according to these other

The methods of the invention fall within the scope of this solution to the extent that the drug liberation profile and / or blood plasma concentration profile as set forth herein and the claims describe these dosage forms literally or on an equivalent basis.

In other embodiments, the sustained release dosage forms can be protected from the action of ethanol in the gastrointestinal tract by enteric coatings.

Alcohol, especially ethanol, is predominantly absorbed in the upper gastrointestinal tract, especially the stomach. Thus, the use of an enteric coating may alleviate the effects of co-administered alcohol on a sustained release dosage form by delaying the initial release of the drug in the upper GI tract.

In a preferred embodiment, the enteric coating comprises an enteric polymer. The enteric polymer should preferably not dissolve rapidly in ethanol, but may swell or dissolve very slowly. Other polymers or materials may be mixed with the enteric coating provided that their addition does not compromise the functioning of the enteric coating in ethanol. In some embodiments, the polymer or material that may be mixed with the enteric coating may be selected to improve the functioning of the enteric coating in the aqueous alcohol. For example, in one embodiment, the polymer or material that swellable in the aqueous alcohol may be mixed with the enteric coating. it dissolves little or no. Prevention of breakage may require the use of a plasticizer such as PEG 6000 in an amount of 1 to 20%. Enteric polymers suitable for use in the present invention include cellulose acetate phthalates, e.g.

2u products from Eastman Chemical. In some embodiments, the enteric polymers can be applied from solvent systems such as acetone or mixtures of acetone and ethanol, or from aqueous dispersions. In some cases, enteric coatings may be applied by compression techniques.

In other embodiments of the present invention, the sustained release dosage forms can be coated with non-enteric polymers, thereby reducing the susceptibility to rapid alcohol-induced dose release, especially ethanol-induced dose release. In one embodiment, Eudragit ^κ RS100 and Eudragit '* ¹ ' RL100 can be used. These polymers are reported to be insoluble in water and slowly soluble in mixtures of ethanol and water. They are believed to exhibit low or moderate water permeability, respectively. If applied to the matrix of sustained release tablets, these substances could form a moderate speed limiting film in water and ethanol-water mixtures. Such structures may function on the principles of the release controlled by the network. These films are typically deposited from aqueous dispersions and are formulated using a plasticizer such as triethyl citrate and an antiadherent such as talc. In another embodiment, cellulose acetal containing 24 to 28% acetyl groups may be used. This material is said to be water soluble and less soluble in ethanol-water mixtures. thus reducing the likelihood of rapid dose release when the dosage form is co-administered with an alcohol, especially ethanol. Non-enteric polymers can be solutions or can be applied by compression techniques.

In one embodiment, the sustained release dosage form of the present invention may be a matrix dosage form. Matrix dosage forms typically comprise a gelling agent, a hyd40 starch excipient controlling initial rupture, a drug, and a diluent. The gelling component typically constitutes 20 to 60% by weight and the hydrophobic excipient typically constitutes 5 to 20% by weight, based on the total dry weight of the dosage form. These dosage forms may be prepared by dry granulation or mixing and compression into tablets. Alternatively, the formulations may be melt extruded into strips which are chopped and filled into capsules to obtain dosage forms of the present invention.

Suitable gelling agents include:

1. Mixtures of different types of HPMC (K4M, K100, E5) to achieve the desired swelling and viscosity. The HPMC is insoluble in ethanol and hence a slower release in the alcohol / water mixture is expected than in water. The speed of the hydrataee can be slowed by the addition of HPC (KluceU from Hercules-Aqualon).

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2. Mixtures of various types of polyethylene oxide (Polyox® available from Dow Chemical). Polyox in a mixture of ethanol and water swells significantly less than in water. Suitable types are the POLYOX WSR-205 NF, the WSR-1105 NF, the WSR N-12K NF, the WSR N-60K NF, the WSR-301 NF, the WSR-303 NF, the WSR Coagulant NF. These materials typically make up 20-55% of the formulation.

3. NaCMC (sodium carboxymethylcellulose) is insoluble in ethanol, making it less likely to be rapidly released in ethanol-water mixtures.

4. Alginic acid is insoluble in ethanol, swellable in water, and is therefore expected to swell less in ethanol-water mixtures.

5. Matrices with xanthan gum and guar gum.

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

The following hydrophobic crack control excipients in ethanol / water mixtures should be equally effective or more effective due to the low solubility in ethanol;

1. MC (methylcellulose. Methocel-A Premium from Dow Chemical)

2. Glycerol palmitostearate (Prccirol * ATO-5, Gattefosse)

3. Glycerol behenate (CompntoU 888-ATO, Gattefosse)

4. Magnesium stearate

5. waxes

6. vegetable and mineral oils

7. aliphatic alcohols

8. polycaprolactone

9. PLGA

10. Natural resin.

In one embodiment, the hydrophobic excipients include hydrophobic excipients having a melting point of 55 ° C or higher. Non-limiting examples of such excipients include paraffin wax.

stearyl alcohol, beeswax, Lubritab '(vegetable oil), natural resin, Kamauba wax and hydrogenated castor oil.

Diluents and fillers used in matrix formulations typically do not significantly affect the liberation profile. However, care should be taken in selecting these excipients as diluents in the presence of alcohol can greatly affect the initiation and release profile of controlled-release matrices. In one embodiment, the diluent may conveniently be selected to have a lower solubility in aqueous alcohol than in water, and thus, in the aqueous-alcoholic environment, the hydration of the core and thus dissolution of the drug may be limited. In a preferred embodiment, the useful diluent is mannitol. In this solution, the following hydrophilic excipients are less preferred;

1. EC (ethyl cellulose from Dow Chemical), which is used typically but is soluble in ethanol35;

2. Hydrogenated polyoxyl 60 castor oil.

U.S. Pat. Nos. 5,887,778 and 5,656,299 disclose microspheric formulations with an almost zero order release rate of the active ingredient when administered to a patient. U.S. Patent Nos. 5,654,008; 5,650,173; 5,770,231; 6,077,843; US Patent Nos. 6,368,632 and 5,965,168 disclose sustained release microparticle compositions and their use for the controlled delivery of drugs.

In another embodiment, osmotic beads may be used. The opioid can be applied to nonpareil beads or other substrates with sufficient osmotic activity by the Wurster process. Subsequently, a semi-permeable film is applied by another Wurster m coating process. In this further coating, the product is withdrawn to varying extents at different times so as to achieve a broad distribution of coating thickness. After hydration, the systems in the water are deformed by osmosis and burst, releasing the drug. The rupture time should be proportional to the thickness of the membrane on each bead. These pearls, among which pearls without semipermeable coating may be represented, which in turn act as an immediate release component,

C'Z 19137 U1 can be filled into capsules to form the sustained release dosage form of the present invention.

If drug loading using osmotic beads is too restrictive, beads may be prepared by extrusion-spheronization procedures. The advantage of this approach is that more drugs can be incorporated into the beads and less one coating is performed. Non-limiting examples of preferred carriers for extrusion-spheronization processes include PLGA R208, natural resin and other high molecular weight materials. Other techniques for preparing beads, such as coating drug-free cores, may also be used. Alternatively, drug-containing beads can be coated with non-semipermeable water films and the release is controlled by a combination of di fuse and osmosis. In some formulations, stiffening agents and / or hydrophobic agents can be incorporated into the sustained release delivery structure to prevent rapid dose release. substances. Non-limiting examples of preferred reinforcing and / or hydrophobic materials include aliphatic alcohols, waxes, oils and biodegradable materials. Non-limiting examples of these preferred materials include stearyl alcohol, carnauba wax, hydrogenated castor oil and natural resin.

In some embodiments, gastroretentional systems may also be utilized. In conventional gastroretentive systems, gastric retention occurs on the basis of their size (i.e., greater than the pylorus channel) and density (density lower than that of GI content permits floatation). Systems may employ polymers, including, but not limited to, polyethylene oxide (Polyox), HPC, HPMC, crospovidone, CMC sodium, ethylcellulose, etc. Adding hydrophobic materials or waxes may improve the functionality of such materials (which tend to form weaker gels in aqueous alcohol) their properties may not be satisfactory). However, hydrophobic materials can significantly increase the risk of such gastroretentive systems being distributed from the stomach to the lower sections of the GI tract.

Other types of gastroretentive systems include rigid frames with attached and / or incorporated controlled release portions. These frames or incorporated controlled release portions preferably comprise materials that are relatively insensitive to aqueous alcohol so that they retain their gastroretentive and controlled release profiles.

The dosage forms and formulation strategies described herein are merely exemplary of a number of different dosage forms that can be used to administer the active agent (s). Other formulation strategies will be able to be identified by those skilled in the pharmaceutical arts, especially since not all formulation strategies may work for all opioids. When implementing this solution, it may be useful to perform optimization that will fall within the scope of the routine. Examples

Example 1: Hydromorphone tablet, bilayer fracture system

The dosage form according to the hydromorphone sustained release solution is prepared as follows, which is processed, formulated and shaped as an osmotic drug delivery device: First, a drug composition is prepared. Weigh 8.98 kg of hydromorphone hydrochloride, 2.2 kg of povidone (polyvinylpyrrolidone), labeled as

K.29-32 and 67.06 kg of polyethylene oxides with an average molecular weight of 200,000. Then 6.0 kg of povidone (polyvinylpyrrolidone) designated K29-32 with an average molecular weight of 40,000 were dissolved in 54.0 kg of water to obtain a binder solution. . The dry materials are granulated in a fluidized bed using a binder solution spray (18.0 kg). Then, the wet granulate in the granulator is dried to an acceptable moisture content and comminuted using a 1.38 mm (7 mesh) sieve attached to a mill, then transferred to a blender where it is mixed with 16 g of butylated hydroxytoluene as an antioxidant and lubricated with 0.20 kg of stearate. magnesium.

The extrusion composition is then prepared as follows: 24.0 kg of sodium chloride and 0.32 kg of pure iron oxide are comminuted using a Quadro Comil with a 21 mesh screen.

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The sieved material, 1.6 kg of hydroxypropylmethylcellulose, designated 2910, and 51.44 kg of polyethylene oxide having an average molecular weight of about 7,000,000 are weighed into a fluid granulator tank. A binder solution is then prepared. 6.0 kg of hydroxypropylmethylcellulose designated 2910 with a mean viscosity of 5 mPa.s was dissolved in 54.0 kg of water to obtain a binder solution. The dry materials are granulated in a fluid bed, spraying 24.0 kg of binder solution. The wet granulate is dried to an acceptable moisture content in the granulator and comminuted using a comminution apparatus equipped with a 2.3876mm screen. The granulate is then transferred to a blender and mixed with 40 g of butylated hydroxytoluene and lubricated with 0.20 kg of magnesium stearate.

Thereafter, two-layer cores are compressed from the drug composition comprising hydromorphone and the extrusion composition. 150 mg of the hydromorphone-containing drug composition is first added to the matrix cavity and pre-compression is performed. After addition of 130 mg of extrusion composition, the layers are compressed to standard concave bilayer structures with a diameter of 8.5 mm (11/32).

The bilayer structures sc cover the semipermeable wall. The wall-forming composition comprises 99% cellulose acetate designated 398-10 with an average acetyl content of 39.8%, and a 1% poly15 ethylene glycol designated 3350 with an average molecular weight of 3350. The wall-forming composition is dissolved in a mixture of 96% acetone and 4% water. gives a solution of 6% solids concentration. The wall-forming composition is sprayed onto the bilayer structure in a coating pan so that about 30 mg of membrane is applied to each tablet.

By drilling the semipermeable membrane with a laser, one 0.64mm exit channel is formed so that the drug layer is bonded to the exterior of the delivery system. The residual solvent is removed by drying at 45 ° C and 45% relative humidity for 72 hours. After drying at the indicated humidity, the tablets are dried for 4 hours at 45 ° C and ambient humidity.

Example 2: In vitro release study - 16 mg hydromorphone

In order to evaluate the effect of alcohol on the in vitro liberation profile of hydromorphone sustained release dosage forms of this solution containing 16 mg of hydromorphone as hydromorphone hydrochloride, a series of dissolution experiments were performed using the hydromorphone tablets of Example 1. Hydromorphone hydrochloride release was measured during 24 hours in aqueous solutions containing 0, 4, 20 and 40% ethanol by volume using a Vil type dissolution bath.

To determine the release rate and cumulative liberation profiles in 0%, 4%, 20% and 40% ethanol, 16 mg tablets containing hydromorphone hydrochloride according to Example 1 were used. For 0% ethanol (water) the results obtained in the time stability test were used 0 months. Results for 4%, 20% and 40% ethanol were obtained using special samples from the stability test at 0 months. The conditions under which the release rate was determined are as follows: USP Type VII apparatus; medium: aqueous solutions containing 0%, 4%, 20% and 40% ethanol by volume; volume: 50 ml; temperature: 37 ± 0.5 ° C; time points: 2, 4, 6, 8, 10, 12, 14, 16. 18 and 24 hours.

Note: Measures have been taken to minimize evaporation of media in which release rate was tested. For the first 6 intervals and the last interval (2 to 12 hours and

24 hours), the media was added approximately 30 minutes before each interval and the tubes used in the release rate test were removed from the test bath immediately after that interval. At intervals of 14, 16 and 18, the media was loaded into the bath at the same time, so that the tubes in the bath were approximately for 6 and a half hours.

The media was prepared as follows:

+5 4% (v / v) ethanol: pure ethanol (140 ml volume) (Sigma Aldrich, 200 proot) is added to

3360 ml of water and mix well.

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20% (v / v) ethanol: pure ethanol (700 ml volume) is added to 2800 ml water and mixed well.

40% (v / v) ethanol: pure ethanol (1400 ml volume) is added to 2100 ml water and mixed well.

The samples were prepared as follows: Sample solutions in 4% and 20% ethanol are called as they are after mixing. A rapid study shall be conducted to demonstrate the validity of this procedure. Two standards prepared in water at different concentrations are diluted using 20% and 40% ethanol, analyzed by HPLC and evaluated for% recovery and peak shape. Since sample cleavage is observed in samples in the presence of 40% ethanol but not in other sample solutions, sample solutions in 40% ethanol are further processed, while sample solutions in 4% and 20% ethanol are injected as they are.

To avoid cleavage of the peak, sample solutions in 40% ethanol are prepared as follows: After cooling to room temperature, the solutions are made up to 50 ml with 40% ethanol solution to test the rate of release and thoroughly mixed. 2 ml solution i? The sample is then added to the scintillation cuvette. Sample solution using evaporator (SPC SpeecVac, SPD131DDA, RVT4104 freeze trap, QFP-400, Thermo

Savant) is evaporated to dryness at 45 ° C. 2 ml of water is again added to the scintillation vial. After thorough mixing, the sample solution is sprayed on HPLC.

HPLC conditions;

Column: Varian Inertsil Phenyl-3, 5 mm, 4.6> 150 mm

Mobile phase: 35% methanol, 65% buffer (0.1% sodium phosphate, 0.2% octanesulfonic acid, sodium salt. PH ~ 2.2)

Flow rate: 1.5ml / min

Temperature: 45 ° C

Injection volume: 50 ml

Wine length: 280 nm

Cycle time: 7 min.

The results of this testing are shown in Figure 6. In the hydromorphone sustained release dosage forms of the present invention, various ethanol solutions did not induce rapid dose or uncontrolled release. However, as the concentration of ethanol in the dissolution medium increased, a trend to increase the release rate was observed. The average release rate compared to the 0% control (6% declared content per hour) was the highest (about 10% declared content per hour) in 40% ethanolic medium and the same (about 6% declared content per hour) in 4% ethanolic medium . Also, the time to release 90% of drug (T90) in 4% ethanol medium was not changed compared to the control and the biggest change occurred in 40% medium, see Table 1. Even under 40% ethanol conditions, the T90 was 12 hours. In addition, there was minimal effect on the 2 hour cumulative release (initial time) of the tablet, reflecting the absence of rapid dose release for all ethanol concentrations evaluated.

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Table 1: Summary of In vitro Liberation Properties of a 16mg Hydromorphone Tablet (Example 1) in Ethanol Solutions

Hydromorphone Ethanol / water solution composition (% v / v) 0% (control) 4% 20% 40% T90 (h) 18 18 15 Dec 12 Cumulative% released at 2 hours <1 , -1 4 (% of declared content) ^; 1 1 The average release rate ¹ 6 6 7 10 (% of declared content) Average release rate compared to i comparative 100 ALIGN! 116 1 160 with 0% ethanol

Example 3: Comparative in vitro release study

The release of hydromorphone hydrochloride from Palladone XL ^A 32 mg capsules in vodka (27% v / v ethanol) and water was compared using a type II dissolution bath with the hydromorone tablets of Example 1.

The dissolution parameters are given below; Equipment; dissolution unit Varian VK.7010 and autosampler VK8000; medium: water and vodka (Pavlova, 40% (v / v) alcohol); volume: 900 ml; Io blade rotation speed: 50 ^min-1; 5 ml collection volume; temperature 37 ± 0.5 ^° C; time points; T =

1, 2, 4, 6, 10, 14, 18 and 24 hours. Note; the results of the test showed that the alcohol content of Pavlova is only 27%.

Due to the electrochemical interference of vodka, the sample solutions in the vodka are evaporated before analysis. Using an automatic sample feeder, 5 ml of the sample solution is withdrawn into the tube.

After cooling to room temperature, 2 ml of the sample solution is added to the scintillation cuvette. The sample solution is evaporated to dryness at 45 ° C using an evaporator (SPC SpeeeVac, SPD131DDA, RVT4104, OFP-400, Thermo Savant). 2 ml of water is again added to the scintillation vial. After thorough mixing, the sample solution is sprayed on HPLC. Sample solutions in water were cooled to room temperature and injected on HPLC.

2o Inject sample solutions in water as they are, while sample solutions in vodka are evaporated and reconstituted using water to prepare the sample. A short validation study shall be performed to demonstrate that there is no difference between the two types of sample preparation. In the case of sample solutions in water, two standards of 100,04 and 180,07 mg / ml are evaporated to dryness, 2 ml of water are separately added to the evaporators again and mixed thoroughly by HPLC analysis,

For vodka sample solutions, dilute the standard of 250.13 mg / ml in triplicate to 50.03 mg / ml in triplicate, evaporate the diluted samples to dryness, add 2 ml of water to the residue and mix thoroughly. analysis by HPLC. The equivalence between the two types of sample preparation is evaluated on the basis of recovery.

After 24 hours for both water and vodka, the volume of the sample solution is determined and the evaporation rate is calculated using the following linear evaporation formula:

Evaporation rate ~ (900 - final volume -8x5) / 24 hours where 8> 5 - 5 ml collection at 8 time points.

On the basis of evaporation the correction of the calculation of the discharge profile is carried out. For both water and vodka, the sample volume collected shall be verified as an independent experiment in triplicate.

-; 4_

CZ 19137 Ul

ÍIPLC Conditions:

Column: Varian Inersil Phenyl-3, 5 mm, 4.6 χ 150 µm

Mobile phase: 35% methanol, 65% talc (0.1% sodium phosphate, 0.2% octanesulfonic acid, sodium salt, pH = 2.2)

Flow rate: 1.5ml / mm

Temperature: 45 ° C

Injection volume: 100 ml

Wavelength: 280 nm

Cycle time: 6.5 min.

The injection volume was increased to 100 ml as the early concentrations of the sample solutions were low.

Upon exposure to 27% ethanol, Palladone XL releases 100% of the declared content over 2 hours versus 21% of the declared content that is released in water. These results are shown in Table 2 and shown in Figure 7.

Table 2: Summary of In vitro Liberation Properties of Palladone XT 32mg Capsules in Ethanol-based Solutions

Palladone XL Ethanol / water solution composition (% _obj) 0% (control) 27% | i 1 * 90 (h) > 24 1 Cumulative% released at 2 hours i ί1 ' i od (% of declared content) _ 1 1 Uv

Example 4: Ilydromorphone tablet, bilayer 16mg system

The hydromorphone sustained release dosage form of the present invention is prepared, formulated and shaped as an osmotic device in the following manner: o drug delivery: First, a drug composition is prepared. Weigh 8.98 kg of hydromorphone hydrochloride, 2.2 kg of povidone (polyvinylpyrrolidone) designated as K29-32 and 67.06 kg of polyethylene oxide having an average molecular weight of 200,000 and weighed into the fluidized bed granulator tank. Then 6.0 kg of povidone (polyvinylpyrrolidone) labeled as K.29-32 with an average molecular weight of 40,000 dissolved in 54.0 kg of water. to obtain a binder solution. The dry materials are granulated in a fluidized bed by spraying 18.0 kg of binder solution. Thereafter, the wet granulate in the granulator is dried to an acceptable moisture content and comminuted using a 7 mesh screen. The comminuted granulate is transferred to a blender where it is mixed with 16 g of butylated hydroxytoluene as an antioxidant and lubricated with 0.20 kg of magnesium stearate.

Thereafter, an extrusion composition is prepared as follows: 24.0 kg of sodium chloride a

0.32 kg of black iron oxide is comminuted using a Quadro Comil with a 21 mesh screen.

The sieved material, 1.6 kg of hydroxypropylmethylcellulose, designated 2910, and 51.44 kg of polyethylene oxide having an average molecular weight of about 7,000,000 are weighed into a fluid granulator tank. A binder solution is then prepared. 6.0 kg of hydroxypropylmethylcellulose designated 2910 with a mean viscosity of 5 mPa.s was dissolved in 54.0 kg of water to obtain a binder solution. The dry materials are granulated in a fluidized bed sprayed with 24.0 kg of binder solution. The wet granulate is dried to an acceptable moisture content in the granulator and comminuted using a comminution apparatus equipped with a 2.3876mm screen. The granulate sc is then transferred to a blender and mixed with 40 g of butylated hydroxytoluene and lubricated with 0.20 kg of magnesium stearate.

Thereafter, bilayer cores are compressed from the drug composition comprising hydromorphone and the extrusion composition. 150 mg of the hydromorphone-containing drug composition is first added to the matrix cavity and pre-compression is performed. After addition of 130 mg of extrusion composition, the sc layers are compressed to standard concave bilayer structures with a diameter of 8.5 mm.

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The two-layer structures are coated with a semi-permeable wall. The wall-forming composition comprises 99% cellulose acetate designated 398-10 with an average acetyl content of 39.8%, and 1% polyethylene glycol designated 3350 with an average molecular weight of 3350. The wall-forming composition is dissolved in a mixture of 96% acetone and 4% water to a solution having a 6% solids concentration. The wall-forming composition is sprayed onto the bilayer structures in a coating pan so that about 33 mg of membrane is applied to each tablet.

By drilling the semipermeable membrane with a laser, one 0.64mm exit channel is formed so that the drug layer is bonded to the exterior of the delivery system. The residual solvent was removed by drying at 45 ° C and 45% relative humidity for 72 hours. After drying under the indicated wet bone, the tablets are dried for 4 hours at 45 ° C and ambient humidity.

The dried tablets are then coated with a colored and clear coating. The Opadry II yellow colored coating is designated Y-3012863-A. 14.4 kg of a yellow Opadry II mixture are mixed with 105.6 kg of water to give a colored suspension. The color suspension is spray-coated in a coating pan onto the dried tablets until about 18 mg of coating is applied to each tablet. A clear coating solution 15 is then prepared by stirring 2.4 kg of the clear Opadry mixture designated YS-1-19025 in 45.6 kg of water. The clear solution is spray-coated onto the dried tablets in the coating pan until 1.5 mg of coating is applied to each tablet.

After applying a colored and clear coating, the text "HM 16" is printed on each tablet using black Opacode water based ink NS-78-17715. The printing is performed using a ramp printing device.

Example 5: In vivo studies

The purpose of the Phase I study is to evaluate the effect of alcohol on the pharmacokinetic properties of hydromorphone tablets according to Example 3 in the fasted state and postprandially in healthy subjects.

The study encompasses two groups of 24 healthy adult males and females aged 21 to 45 years (inclusive) weighing at least 70 kg and within 25% of normal weight relative to height and body build. The study is conducted as a single-dose, single-dose, open, four-treatment, four-period, four-sequence crossover study in two groups of subjects.

Each subject in Group 1 is fasted to the following treatments:

Treatment A - 16 mg hydromorphone tablets according to example 3 with 240 ml of orange juice

Treatment B - 16 mg hydromorphone tablet according to example 3 with 240 ml of 4% (v / v) alcohol in orange juice

Treatment of C-16mg hydromorphone tablet according to example 3 with 240 ml of 20% (v / v) alcohol in orange juice

Treatment of D-16mg hydromorphone tablet according to Example 3 with 240 ml of 40% (v / v) alcohol in orange juice.

Each subject in Group 2 is subjected to the following treatments after a standard breakfast:

Treatment of E-16mg hydromorphone tablet according to Example 3 with 240 ml of orange juice

Treatment of F-16mg hydromorphone tablet according to example 3 with 240 ml of 4% (v / v) alcohol in orange juice

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

Treatment of H-16mg hydromorphone tablet according to example 3 with 240 ml of 40% (v / v) alcohol in orange juice.

CZ 19137 Ul

The alcohol used in treatments B, C, D, F, G and II is diluted with orange juice and consumed within approximately 30 minutes without swallowing. About 50 mg of naltrexone is administered to the subject for each treatment. as an opioid antagonist, which is administered about 14 hours prior to administration and twice a day during administration and for the first approximately 48 hours after administration. Between treatment periods 5 mi, there is an approximately 6 to 14 day elimination period beginning approximately 24 hours after administration.

Blood samples are taken from all subjects at time 0 (before administration), 2, 4, 6, 8, 10, 12, 16, 20, 24, 27, 30, 36, 42, and 48 hours post-treatment.

Plasma samples are analyzed using a liquid-chromatography tandem mass spectrometry (LC / MS / MS) assay developed by CEDRA Corporation. Human plasma containing hydromorphone and hydromorphone-D; Extract with ethyl acetate / hexane as internal standard. The organic layer was separated, back extracted and evaporated to dryness. The extract is reconstituted and an aliquot is injected into a SC1EX API 4000 LC / MS / MS system equipped with

IIPLC column. Positive ions are monitored in multi-reaction monitoring (MRM) mode.

This method is validated with a minimum quantifiable concentration of hydromorphone at 0.05 ng / ml. During validation, the calibration curves for the analyte are plotted by plotting the ratio of analyte: internal standard against known analyte concentrations. A calibration curve is constructed using the peak area ratio of the calibration standards using the inverse of the square of the concentration, a linear-weighted regression algorithm. The hydromorphone calibration curve is linear between 0.05 and 10.0 ng / ml.

The following pharmacokinetic parameters are determined based on plasma hydromorphone concentrations:

Cmax - maximum observed plasma concentrations Tmax - time required to reach maximum concentration k - apparent rate elimination constant, which is calculated by linear regression of logarithms

2? plasma concentration during the terminal log-linear elimination phase t ¹ /? - apparent terminal half-life values calculated as 0,693 / k

AUC _t - area under the plasma concentration curve in the interval 0 to t, where t is the time of the last detectable concentration, calculated according to a linear trapezoidal rule

AUCjnf - the AUC value extrapolated to infinity, which is calculated as the sum of the AUC, and the areas extrapolated to infinity, calculated as the concentration at time t (Ct) divided by the constant k.

In the fasted and postprandially treated groups, plasma concentrations were close to the limit of quantitation at the first time point after administration, i.e. at 2 hours; thereafter, plasma concentrations increased slowly in all 4 treatments. In each group, there were some subjects for which no concentration values (dropouts) were determined for some treatments or low values were determined without clinical explanation; these low-value subjects were excluded from the analysis. The median Tmax was 12-16 hours. The C max values were slightly higher for the three treatments involving alcohol, compared to those involving 0% alcohol, at 117% for 4% alcohol. 131% for 20% alcohol and 128% for 40% fasting alcohol. IN

4 (even in the post-prandial application, the plasma hydromorphone concentration profiles were very similar in four treatments and resulted in lower Cmax ratios compared to fasting applications. No relationship of Cmax ratios to alcohol concentrations was demonstrated (114% for 4% alcohol. 114% v in the case of 20% alcohol and 110% in the case of 40% alcohol, based on the results of the treatment comprising 0% alcohol).

The AUC values of the three alcohol-containing treatments relative to the 0% alcohol-containing treatment met the 80-125% bioequivalence criterion for the fasting and postprandial confidence interval. Figure 8 shows the mean concentration profile after four fasting treatments (group 1). The pharmacokinetic parameters are summarized in Table 3. FIG. 9 is shown against 1

The mean concentration after four treatments in Group 2, in which all medications were performed after the standard breakfast, Pharmacokinetic parameters are summarized in Table 4.

Table 3: Mean (SD) pharmacokinetic parameters of hydromorphone - Group 1 (nalaeno)

0% alcohol ¹ 4% alcohol 20% alcohol 40% alcohol Cmax (ng / ml) 1.37 (0.32) 1 1.56 (0.39) 1.90 (0.66) 1.89 (0.85) T max (h) i 16 (6-7) ¹ 12 (6-27) 12 (5-16) 12 (6-7) [median (range)] 1 and ; TU (h) 12.4 (5.1) 12.6 (6.5) : 12.4 (7.2) 11.0 (3.0) ‘AUCinf 40.6 (11.0) i 39.9 (14.1) 43.7 (12.1) 42.2 (13.2) 1 Ratio  Arithmetic mean (range) Cmax comparative l 1.19 1.35 ” '1.37 1 (0.8-1.8) (0.7-2.4) ^! (0,7-2,5) Ratio -% Geometric Diameter (90% Cl) Cmax 'comparative I 116.70 131.16 , 128.31 ! (104.48-130.36) (117,01-147,02) i (114.18-144.17) AUCinf comparative 1 98.83 103.21 101 101.65 (87,48-107,19) (92.93-1 14.62) (91,32-113,13)

Table 4: Mean (SD) pharmacokinetic parameters of hydromorphone - group 2 (postprandial)

0% alcohol 4% alcohol ! 20% alcohol 40% alcohol Cmax (ng / ml) 1.42 (0.50) 1.64 (0.60) ! U52 (0.33) 1.56 (0.56) Imax (h) 16 (6-7) 12 (7-24) 12 (6-7) 16 (6-7) [median (range)] T% (h) ´ 11,6 (5,1) 11.6 (4.9) 10.4 (3.9) ^; 10.8 (4.8) AUCinf  37.1 (8.6) 36.7 (10.5) 36.6 (9.7) 34.8 (11.9) Ratio - Arithmetic mean (range) Cmax comparative 1.20 1.20 1.14 (0.7-1.8) (0,8-1,9) (0,6-2,0) Ratio - ° Á i Geometric diameter (90% CI) Cmax comparative 113.72 114.36 110.34 (99.97-129.36) (100.14-130.61) _; (97.08-125.41) AUCinf comparative 94.72 106,21 i 94.09 _: (88.44-103.70) (96.63-1 16.73) 1 (85,91-103,04)

Example 6: Comparison of Individual Ratios; Alcohol versus Repeat Study o The study is performed to assess bioequivalence between two batches prepared at two different sites (batch A versus batch B). This is a four-period and repeat study in which each of the two batches is administered on two different occasions and treatment periods include elimination periods. The aim is to characterize the variability of pharmacokinetics between subjects and one subject. Subjects are healthy.

The drug stock for batch A and batch B is prepared as the sustained release oral osmotic dosage forms of the present invention, generally using the methods and procedures described in Examples 1 and 2. Each subject is randomly subjected to each of two consecutive periods of 4 consecutive periods. following treatments:

Treatment A: Lot A, with Naltroxone hydrochloride, 50 mg

Treatment B: Lot B, with naltrexone hydrochloride, 50 mg.

Naltrexone 50 mg is administered 12 hours prior to administration and at the time of administration of the hydromorphone dosage forms of the present invention. An additional 50 mg dose of naltrexone is administered as needed 12 and 24 hours after hydromorphone administration. Allow at least seven days for elimination between applications.

Plasma from blood samples taken at given times after drug administration is analyzed for hydromorphone concentrations to determine Cmax, Tmax, terminal half-life (tCz) and area under the concentration-time curve (AUC0-72 and AUCO-inf).

At each collection time, 10 ml of venous blood samples are collected in tubes containing anticoagulants. Within 1 hour of collection, the samples are centrifuged and stored at -40 ° C until analysis. Blood samples should be taken during each administration period at time 0 (before administration) and 2, 4, 6, 8, 10, 12, 16, 20, 24, 36, 42, 48, 56, 64 and 72 hours after each administration. hydromorphone dosage forms of the present invention. Plasma samples are analyzed using validated liquid ehromatography-tandem mass spectrometry (LC / MS / MS) by a procedure developed by CEDRA Corporation.

The C max ratio of these repeated administrations represents individual variability. Based on this study, an estimate of the ratio of Cmax (high / low) for each individual is compared to the ratio of Cmax (with / without alcohol) from the previous example. Figures 10 and 11 show comparisons for Groups 1 and 2 of Example 5. From these figures, it is clear that the range of the C max ratio observed with alcohol treatment versus non-alcohol treatment is within the same range of ratios that represent individual variability.

Example 7: Study of the effect of reinforcing agents and acrylic resin on the release of oxycodone in water and 40/60 ethanol / water mixtures (v / v)

Using a wet granulation sc procedure, 10 g of each formulation with and without stearyl alcohol are prepared per bar. Mix the necessary amounts of oxycodone hydrochloride, lactose and Eudragi® RS PO in a suitable container and mix for 5 minutes. The powder mixture is granulated using water until a wet mass is formed. The wet mass was then passed through a 16-mesh sieve and allowed to dry overnight under ambient conditions. In a small vessel sc in a water bath melts the required amount of stearyl alcohol. The stearyl alcohol is kept molten in a water bath and the required amount is added

3o of dried granules. The resulting mixture is stirred until the granules are sufficiently coated with molten stearic alcohol. The water bath is removed, the mixture is allowed to cool to ambient conditions and milled using a 16 mesh screen. Talc and magnesium stearate are added to the coated granules and mixed in a suitable blender. The granules are then compressed into 375 mg tablets using a suitable tableting machine, such as a Carver press. 7. 300 mg tablets are compressed into granules which have not been coated with stearyl alcohol.

Table 5: Formulations of tablets containing oxycodone hydrochloride (30 mg) using stearyl alcohol dose - 30 mg / tablet; tablet = 375 mg each

Component % by weight Oxycodone IICl Lactose 8.02 j ”56.72 ^! Eudragit RS PO Stearyl alcohol 11.97 20.29 Talc 1.99 Magnesium stearate 1.00

- 9 CZ 19137 Ul

Table 6: Formulations of tablets containing oxycodone hydrochloride (30 mg) without stearyl alcohol dose - 30 mg / tablet; tablet - 300 mg each

Folder ¹ % by weight Oxycodone HCl 10.09 Lactose 71.13 Eudragit RS PO 14.99 ¹ Talc 2.49 Magnesium stearate 1.30

Example 8: Formulations containing hydromorphone hydrochloride with and without stearylal- koholu The same manufacturing process as hydromorphone hydrochloride was used. in Example 7, but instead of oxycodone hydrochloride was added Table 7; Formulation of tablets containing hydromorphone hydrochloride (30 mg) using stearyl- alcohol dose ~ 30 mg / tablet; tablet ^; = 375 mg each Component % by weight Hydromorphone HCl 8.02 Lactose ¹ 56.72 Eudragit RS PO 11.97 Stearyl alcohol 20.29 Talc 1.99 Magnesium stearate i L? 00 Table 8: Formulations of tablets containing hydromorphone hydrochloride (30 mg) without stearylal-

koholu dose ~ 30 mg / tablet; tablet - 300 mg each Component % by weight Hydromorphone HCl 10,09 1 Lactose 71.13 Eudragit RS PO 14.99 Talc 2.49 Magnesium stearate 1.30

Example 9; Opioid release profile from stearyl alcohol and stearyl alcohol-free formulations

Samples for this assay come from Examples 7 and 8. Release from tablets was tested in a USP Type VII apparatus. The following liberal media will be used:

i.) Ethanol: ethanol - 40% FtOH / water = 0 to 4 hours and then water to 4 to 24 hours Water: water is used as the medium at all time intervals.

Drug determination is performed in an analytical laboratory using HPLC methods (LAR 007411. AAM1,773vl, AAM1.585v50).

Conclusion: Stearyl alcohol suppresses the effect of ethanol on opioid release. 12 and 13.

- 40 CZ 19137 Ul

Example 10: Effect of Eudragium RS PO on Opioid Release

The granules are prepared by the wet granulation method described in detail in Example 7. However, Eudragit RS PO is omitted from the powder blends. The weight of the tablets is adjusted so that each tablet contains 30 mg of opioid. The composition of the formulations is shown in Tables 9 and 10.

s Table 9: Formulations of Eudragit-free Oxycodone Hydrochloride (25 mg) Tablets RS Dose = 25 mg / tablet; tablet = 310 mg each

Folder_% weight_

Hydromorphone HCl _________ 7.99

Laktosa 69.03 ___

Stearylalkohol___ 19,98__

Mastek____ j_2,00_

Magnesium stearate'1,00

Table 10: Formulations of tablets containing hydromorphone hydrochloride (25 mg) without inududit RS dose - 30 mg / tablet; tablet = 300 mg each

 Component % by weight Oxycodone HCl 7.99 Lactose 69.03 Stearyl alcohol 19.98 Talc 2.00 Magnesium stearate 1.00

Conclusions: As shown in Figure 14, the absence of Eudragit RS PO in the formulation had no effect on the release of oxycodone hydrochloride in water or in the water / ethanol mixture as a medium. As shown in Figure 15, the absence of Eudragit RS PO in the formulation had no effect on the release of hydromorphone hydrochloride in water or in the water / ethanol mixture as a medium.

Example 11: Relative effects of stearyl alcohol, hydrogenated polyoxyl 60 castor oil and Kamauba wax on the release of oxycodone hydrochloride

The wet granulation process described in detail in Example 7 provides granules. However, either hydrogenated polyoxyl 60 castor oil or carnauba wax is used instead of 20 stearyl alcohol. The tablets prepared will also have a weight of 375 mg and each tablet will contain 30 mg of opioid. The formulation of the formulations is shown in Table 11. The release test is performed in the following media:

Ethanol: 40% EtOH / water = 0 to 4 hours, water = 4 to 24 hours 25 Water: water is used as the medium at all intervals.

CZ 19137 Ul

Table 11: Oxycodone hydrochloride formulation, 30 mg, tablets

Ingredients (wt.%) Stearyl alcohol Hydrogenated poles castor oil Kamauba wax Oxycodone HCl 8.02 ¹ 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 Magnesium stearate 1.00 0.99 0.99

Conclusion: As can be seen in Figure 16, a substitute for stearyl alcohol can be used as a Kamauba wax, but not hydrogenated polyoxyl castor oil.

Example 12: Testing OxyContirU dosage forms

Hive

The dissolution tests of the OxyContin dosage forms are performed essentially under the following conditions:

Device: USP Type II

Paddle mixer speed 50 min ^-1

Volume:

Bath temperature:

Sample volume:

Dissolution media:

Sampling interval:

900 ml ± 0.5 ° C ml water of analytical purity and 40% ethanol (n = 6 tablets per medium)

T -0,5,1,2,4, 6, 8, 10 and 12 hours.

The collected solutions were analyzed on a CIS column with detection at a UV wavelength of 286 nm. Quantification is performed on a linear curve ranging from 1.05 to 100.53 pg / ml giving sample concentrations. A detailed description of the HPLC conditions in this particular analysis is given below. HPLC conditions:

Column: Zorbax ExtendedCIS, 5 µ, 50 x 4.6 mm

Mobile phase: TFIF: acetonitrile: 34mM Phosphorous Buffer (3: 25: 72, v / v)

Flow; 1.2ml / min

Detection at wavelength: 286 nm Injection volume; 30 μΐ

Column temperature: 50 ° C

Cycle time: 4 min.

The results are shown in Figure 17.

Claims (68)

PROTECTION REQUIREMENTS An oral sustained release dosage form comprising an opioid and a sustained release dosing structure, wherein the sustained release dosing structure of the sustained release dosage form is in the presence of an aqueous alcohol that contains alcohol at concentrations of about 20 vol. higher; it releases the opioid so that Cl 19137 U1 ratio of the mean maximum plasma opioid concentration in a single application achieved when the sustained release form of the opioid is administered to a patient together with aqueous alcohol to the mean maximum plasma opioid concentration in a single application achieved when 5, the sustained release opioid dosage form is administered to a patient without concomitant administration of aqueous alcohol of 1.8: 1 or less. The sustained release oral dosage form of claim 1, wherein the ratio is 1.6: 1 or less, preferably 1.4: 1 or less. ío An oral sustained release dosage form comprising an opioid and a sustained release dosing structure, wherein the sustained release dosing structure of the sustained release dosage form in the presence of an aqueous alcohol containing alcohol at concentrations of 20% by volume or higher, releases the opioid so that 15 is the ratio of the maximum opioid plasma concentration of a single patient in a single dose achieved when a sustained release opioid dosage form is administered to a patient together with aqueous alcohol to the maximum plasma opioid concentration of a single patient achieved in a single dose application with sustained release opioid administration to the patient without 20, the aqueous alcohol is co-administered, it is 5: 1 or less. The sustained release oral dosage form of claim 3, wherein the ratio is 4: 1 or less, preferably 3: 1 or less. 5. An oral sustained release dosage form comprising an opioid and a dosage form 25 is a sustained-release structure characterized in that the sustained-release dosing structure of the sustained-release dosage form in the presence of an aqueous alcohol containing alcohol at concentrations of 20% or greater by volume releases the opioid so as to release the opioid from the sustained-release dosage form. releasing the opioid releases 80% or less by weight of the opioid dose. measured (a) using an in vitro test method which: 30 comprises assay medium and (b) within 2 hours of initiation of the in vitro assay method; wherein the test medium comprises aqueous alcohol which contains alcohol at concentrations that are 20% or greater by volume. The sustained release oral dosage form of claim 5, wherein the release is 50% or less by weight of the opioid dose, preferably 25%. 35 opioid dose by weight or less. An oral sustained release dosage form comprising an opioid and a sustained release dosing structure, wherein the sustained release dosing structure of the sustained release dosage form in the presence of an aqueous alcohol containing alcohol at concentrations of 20% by volume or higher, it releases the opioid such that the ratio of the median time of onset of the maximum plasma concentration in a single application in the case of the opioid. that the dosage form is administered to the patient together with aqueous alcohol, to the median time of onset of the maximum plasma concentration in a single administration when the opioid sustained release dosage form is to be administered once a day to the patient 45 administered without concomitant administration of aqueous alcohol ranges from 0.5 to 1.0. -45 CZ 19137 Ul The sustained release oral dosage form of any one of claims 1 to 7, which allows once-per-day or twice-per-day administration. The sustained release oral dosage form of any one of claims 1 to 8, wherein the opioid is selected from morphine, codeine, thcbaine, diamorphine, a 5 oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, nicomorphine, methadone. levomethadylacetate hydrochloride, pethidine, ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine and phenazocine. The sustained release oral dosage form of any one of claims 1 to 9, wherein the aqueous alcohol has a concentration of 25 vol% or more, more preferably 30 vol% or more, even more preferably 35 vol% or more, and most preferably ] or 40% or more 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, buprcnorphin, nalbutin, nalorin, nalbten diprenortin, cyclazocine, elazoin tin, metazocin or metazocin. naxolone. The sustained release oral dosage form of any one of claims 1 to 11, wherein the opioid is present in an amount ranging from 0.001 to 5000 mg, preferably from 0.01 to 1000 mg, more preferably from 0.1 to 750 mg. more preferably from 0.5 to 500 mg, even more preferably from 0.5 to 250 mg, even more preferably from 1 to 100 mg, and most preferably from 1 to 50 mg. The sustained release oral dosage form of any one of claims 1 to 12, wherein said oral dosage form is sustained release. is selected from a diffusion system, a dissolution system, a combined dissolution / dissolution system, an ion-resin-based system, an osmotic system, a gastroretentive dosage form, and an extended particle microparticle formulation 25 release and sustained release dosage forms based on the osmosis principle; The sustained release oral dosage form of claim 13, wherein the diffusion system is selected from a reservoir device or a matrix command. The sustained release oral dosage form of claim 13, wherein the dissolution system is selected from an encapsulated dissolution system, such as micropellets and microcapsules, and a matrix dissolution system. 16. The extended release oral dosage form of claim 13, wherein the oral dosage form is as claimed in claim 13. wherein the osmotic dosage form comprises a reservoir that is at least partially formed by a semipermeable membrane. / 5 The oral extended release dosage form of claim 16, wherein the semipermeable membrane is coated with a polyvinyl alcohol film. The oral sustained release dosage form of claim 16 or 17, comprising a suspension or solution drug composition, a small outlet orifice, and an expandable layer. 4o The sustained release oral dosage form of claim 18, wherein the drug layer is provided with an auxiliary layer or the drug layer together with the semipermeable membrane forms a bonded coating. -44GB 19137 Cl The sustained release oral dosage form of any one of claims 16 to 19, wherein the osmosis sustained release dosage form comprises an enteric coating or a non-enteric coating. 21. The sustained release oral dosage form of claim 20, wherein the enteric coating comprises a material selected from cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, and polyvinyl acetate phthalate. The oral sustained release dosage form of claim 13, wherein the oral dosage form is an elemental osmotic pump and comprises a semipermeable membrane that surrounds and encapsulates an inner compartment comprising a layered drug in which the drug is in admixture with one or more excipients which are adapted to achieve a gradient of osmotic activity and upon suction of the liquid to form a transportable complex formulation. The sustained release oral dosage form of claim 22, wherein the excipient comprises a suitable drug carrier, binder, lubricant and osmagent. The sustained release oral dosage form of claim 22 or 23, wherein the semipermeable membrane comprises a polymer selected from homopolymer and copolymers such as cellulose esters, cellulose ethers and cellulose ester ethers. The sustained release oral dosage form of any one of claims 22 to 25 24. characterized in that it further comprises a flow control agent, in particular selected from 20 polyhydric alcohols, polyalkylene glycols, polyalkylenediols, polyesters of alkylene glycols and the like. 26. The extended release oral dosage form of claim 13, wherein the oral dosage form is an osmosis dosage form comprising a first drug layer comprising osmotic active ingredients and a second drug layer containing a greater amount of drug than the first layer. and optionally an expandable layer. The sustained release oral dosage form of claim 26, wherein the osmotic active ingredients are selected from an osmagent, such as a salt, and one or more relatively low molecular weight osmopolymers which are consumed by the suction of the shoe liquid. 28. The extended release oral dosage form of claim 26 or 27, wherein the first medicament layer further comprises excipients such as binders, lubricants, antioxidants, and coloring agents. The sustained release oral dosage form of any one of claims 26 to 28, wherein said oral dosage form is sustained release. wherein the second drug layer comprises an opioid in admixture with selected excipients. which are adapted to achieve a gradient of osmotic activity, such as 35 a suitable drug carrier. 30. The sustained release oral dosage form of claim 29, wherein the second drug layer is free of osmotic active agents. The sustained release oral dosage form of any one of claims 26 to 30 30 further comprising an opioid active ingredient exit opening. 4i) The sustained release oral dosage form of any one of claims 26 to 32 31. wherein the first and second drug layers further comprise a hydrophilic polymeric carrier, particularly a carrier that erodes in the stomach environment. CZ 19137 Ul The sustained release oral dosage form of any one of claims 26 to 32, further comprising a semipermeable membrane, in particular comprising cellulose esters, cellulose ethers and cellulose ester ethers. The sustained release oral dosage form of any one of claims 26 to 34 533 further comprising a flow control agent, in particular a flow enhancing agent or a flow reducing agent selected from polyhydric alcohols, polyalkylene glycols, polyalkylenediols, alkylene glycol polyesters and the like. The sustained release oral dosage form of any one of claims 26 to 34, wherein the expandable layer comprises a hydroactive layer comprising 10-osmopolymers or osmagents. The sustained release oral dosage form of claim 13, wherein the oral dosage form is a soft or hard capsule. The sustained release oral dosage form of claim 36, wherein the oral dosage form is a one-piece, closed-capped, soft capsule in which the medicament is 15 the composition is encapsulated. 38. The extended release oral dosage form of claim 36 or 37, wherein the soft capsule is surrounded by an asymmetric hydroactive layer as an expandable layer and comprises an outlet orifice. The sustained release oral dosage form of any one of claims 36 to 39 20 38, wherein the soft capsule further comprises a barrier layer. The sustained release oral dosage form of any one of claims 36 to 39, wherein the oral dosage form is as claimed in any one of claims 36 to 39. wherein the expandable layer is formed in discrete sections that do not surround the entire capsule coated with a barrier layer. 41. The extended release oral dosage form of claim 36, wherein the oral dosage form is in the form of a two-part hard capsule consisting of two parts, a cap and a body. 42. The sustained release oral dosage form of claim 41, wherein the capsule is encapsulated by a semipermeable coating. 43. The sustained release oral dosage form of claim 41 or 42, wherein each hard capsule portion near the open end comprises rings that engage with each other and, after the formulations have been filled, allow them to join and engage with each other. fix the sliding cap with the body. The sustained release oral dosage form of any one of claims 36 to 43, wherein the capsule further comprises a semipermeable membrane. 35. The sustained release oral dosage form of claim 44, wherein the semipermeable membrane comprises a flow control agent. The sustained release oral dosage form of any one of claims 43 to 46 45. characterized in that the semipermeable membrane surrounds and forms a container comprising one or more layers, one of which is an expandable layer preferably comprising 40 osmotic agent. - 46GB Ul The sustained release oral dosage form of any one of claims 43 to 46, further comprising a barrier layer, preferably formulated using plasticizers. 48. The sustained release oral dosage form of claim 13, wherein the oral dosage form is in the form of a cylindrical matrix, wherein the ends of the matrix have a round and convex shape. and strips formed of a material that is relatively insoluble in an aqueous environment are encircling the matrix concentrically. The oral sustained release dosage form of claim 13, wherein the oral dosage form is a gastroretentive dosage form comprising a tablet or capsule 10 containing a plurality of particles of a limited soluble drug dispersion in a hydrophilic water swellable crosslinking polymer that retains physical activity. integrity for the duration of drug release, but then dissolves rapidly. 50. The sustained release oral dosage form of claim 13, wherein the matrix dosage form comprising the gelling component is hydrophobic. 15 excipient, drug and diluent. 51. The extended release oral dosage form of claim 13, wherein the oral dosage form is in the form of osmotic beads comprising nonpareil sugar beads or other substrates having sufficient osmotic activity, coated with a semi-permeable film having a broad film thickness distribution or a non-semipermeable film. water. 20 May 52. The sustained release oral dosage form of claim 51, wherein the osmotic beads are present in a capsule. The oral sustained release dosage form of any one of claims 1 to 52 for use in medicine. 54. A sustained release oral dosage form comprising an opioid and a dosage form 25 is a sustained release structure that allows sustained release and release of the opioid from the opioid sustained release dosage form, wherein the ratio of the mean maximum plasma opioid concentration in a single administration achieved when the opioid sustained release dosage form is administered to a patient with aqueous alcohol, in addition, the mean maximum plasma opioid concentration in a single application achieved when the sc opioid sustained release dosage form is administered to a patient without concomitant administration of aqueous alcohol of 1.8: 1 or less for use in the treatment of pain in the case of that the oral opioid sustained release dosage form is administered to the patient together with an aqueous alcohol; whereas The aqueous alcohol comprises alcohol at concentrations that are 20% or greater by volume. The sustained release oral dosage form for use of claim 54, wherein the ratio is 1.6; 1 or less, preferably 1.4: 1 or less. 56. An extended release oral dosage form comprising an opioid and an extended release delivery structure that allows sustained release and release of the opioid from the opioid sustained release dosage form. wherein the ratio of the maximum opioid plasma concentration of an individual patient in a single administration achieved when the opioid sustained release dosage form is administered to the patient together with aqueous alcohol, to The maximum single opioid plasma concentration of a single application achieved when the opioid sustained release dosage form is administered to a patient without concomitant administration of aqueous alcohol is 5: 1 or less for use in the treatment of pain when the opioid sustained release oral dosage form is administered to the patient together with an aqueous alcohol; wherein the aqueous alcohol comprises alcohol at concentrations that are 20% or greater by volume. The sustained release oral dosage form for use according to claim 56, wherein the ratio is 4: 1 or less, preferably 3; 1 or less. 58. An oral sustained release dosage form comprising an opioid and an extended release delivery structure that allows sustained release and release of the opioid from the opioid sustained release dosage form, wherein the opioid is released by releasing the opioid sustained release dosage form. 80% or less by weight of the opioid dose, measured (a) using the in vitro test method, which includes the test medium, and (b) within 2 hours of the start of the in vitro test method; where the test medium includes i? an aqueous alcohol that contains alcohol at concentrations that are 20% or greater by volume; for use in the treatment of pain when the oral opioid sustained release dosage form is administered to a patient together with an aqueous alcohol; wherein the aqueous alcohol comprises alcohol at concentrations that are 20% or greater by volume. The sustained release oral dosage form for use according to claim 58, wherein the release is 50% by weight or less of the opioid dose, preferably 25% by weight of the opioid dose or less. 60. An oral sustained release dosage form comprising an opioid and a sustained release delivery structure that provides sustained release and release of the opioid from the opioid sustained release dosage form, wherein 25 the ratio of the median time of onset of the maximum plasma concentration in a single dose when administered to a patient with aqueous alcohol to the median of the time of onset of the maximum plasma concentration in a single application when the sustained release opioid dosage form is administered administered to the patient once a day without concomitant use of aqueous alcohol, 30 is in the range of 0.5 to 1.0; for use in the treatment of pain when the oral opioid sustained release dosage form is administered to a patient together with an aqueous alcohol; wherein the aqueous alcohol comprises alcohol at concentrations that are 20% or greater by volume. The sustained release oral dosage form for use according to any one of claims 54 to 60, which permits administration once a day or twice a day. 35 An oral sustained release dosage form for use according to any one of claims 54 to 61, wherein the sustained release delivery structure comprises an osmotic sustained release delivery structure. The sustained release oral dosage form for use according to any one of claims 54 to 62, wherein the alcohol comprises ethanol. 40 The sustained release oral dosage form for use according to any one of claims 54 to 63, wherein the aqueous alcohol has a concentration of 25 vol% or more, more preferably 30 vol% or more, even more preferably 35 vol% or more, and most preferably 40 vol% or more. more. -48 CZ 19137 Ul The sustained release oral dosage form for use according to any one of claims 54 to 64, wherein the oral dosage form comprises the opioid in an amount ranging from 0.001 to 5000 mg, preferably from 0.01 to 1000 mg, more preferably from 0.1 to 750 mg, more preferably from 0.5 to 500 mg, even more preferably from 0.5 to 250 mg, even more preferably from 1 to 100 mg, and most preferably from 5 to 50 mg. The sustained release oral dosage form for use according to any one of claims 54 to 65, wherein the opioid sustained release oral dosage form further comprises an immediate opioid release component for immediate opioid release. The sustained release oral dosage form for use according to any one of claims 54 to 66, wherein the opioid is selected from morphine, codeine, thebaine, diamorphine, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, nicomorphine, methadone, levethhadyine hydrochloride, . ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, pintramide, pentazocine and phenazocine. The sustained release oral dosage form for use according to any one of claims 54 to 67, wherein the oral dosage form further comprises an opioid antagonist such as naltrexone levallorte, naloxone, naltrcxone, buprenorphine, nalbuphine, nalorph, nalmefene diprenorphine, eyclazocine, etazocin, etazocin, etazocin, etazocin, etazocine or naxolone. The sustained release oral dosage form for use according to any one of claims 54 to 68, wherein the co-administration is carried out simultaneously with the aqueous alcohol or separately. 2 (also from aqueous alcohol. The sustained release oral dosage form for use according to any one of claims 54 to 69, wherein the oral dosage form is selected from a dissolution system, a dissolution system, a combined diffusion / dissolution system, an ion exchange resin based system. osmotic system, gastroretening of the dosage form, sustained release microparticle formulations, and osmosis sustained release dosage forms.