SK50572006U1 - Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms - 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

Prolonged-release oral dosage form

Technical field

The invention relates to oral opioid sustained release dosage forms such as, but not limited to, 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 can be a serious problem in patients receiving such oral dosage forms.

Sustained opioid release dosage forms are intended to deliver opioids over a prolonged period of time to the patient. Replacement for multiple immediate release opioid oral dosage forms is often prescribed one oral opioid sustained release dosage form. For example, there is a great demand for oral opioid sustained release dosage forms intended to be administered once a day (qd) or twice a day (bid) to provide the patient with day-long relief.

Thus, the amount of opioid in such dosage forms, especially oral sustained release dosage forms of opioids 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 to induce rapid dose release (e.g., immediate dose release) is to accelerate delivery by administering oral opioid sustained release dosage forms together with an aqueous alcohol, especially aqueous ethanol. Various alcohols may induce an undesirable increase in the opioid release rate from the oral opioid sustained release dosage forms, which may even be close to the 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 drawbacks of the prior art solution of rapid alcohol-induced dose release, particularly ethanol-induced dose release. It would be even more desirable that these oral opioid sustained release dosage forms are oral opioid sustained release dosage forms intended to be administered once a day or twice a day, including the associated methods.

The essence of the solution

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

a once-per-day hydromorphone sustained release dosage form for administration to a patient together with an 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 the single dose administration achieved when the once-per-day hydromorphone sustained release dosage form is administered to a patient together with aqueous alcohol to the mean maximum concentration of hydromorphone in the single dose application achieved when For example, the once-per-day hydromorphone sustained release dosage form is administered to a patient without concurrent 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 extended release delivery structure; administering the once-per-day hydromorphone sustained release dosage form to the patient 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% or greater by volume; and wherein the plasma administration form is administered with an aqueous ratio of the maximum concentration of hydromorphone in an individual patient at. one-time achieved when a once daily prolonged-release hydromorphone is administered to a patient · to the maximum concentration of individual hydromorphone in a single patient's plasma when the once-per-day hydromorphone sustained-release dosage form is administered to a patient, without co-administration of aqueous alcohol, it is about 5: 1 or less.

According to a further aspect, the invention provides a method comprising: obtaining a once daily hydromorphone sustained release dosage form comprising hydromorphone and a once daily sustained release delivery structure, administering the once daily hydromorphone sustained release dosage form to the patient in conjunction 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 by (a) using an in vitro test method comprising test medium and (b) ) about 2 hours after the start of the in vitro test method; and wherein the assay medium comprises an aqueous alcohol that contains alcohol at concentrations of about 20% or greater by volume.

According to another aspect, the invention provides a method comprising: obtaining 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 mean maximum concentration of hydromorphone in a single dose administration achieved when the sustained release dosage form of hydromorphone is administered to a patient together with aqueous alcohol to the mean maximum concentration of hydromorphone in a single dose application achieved when the dosage form is sustained release of hydromorphone 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 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 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 co-administered with aqueous alcohol to the maximum concentration of the hydromorphone in the individual patient's plasma achieved in a single application the sustained release hydromorphone dosage form administered to a patient without concurrent administration of aqueous alcohol is about 5: 1 or less.

According to another aspect, the invention provides a method comprising: obtaining 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 hydromorphone sustained release dosage form releases less than about 80% (

a mass dose of hydromorphone from the hydromorphone sustained release dosage form, measured (a) using an in vitro test method comprising the test medium, and (b) within a period of about 2 hours after the start of the in vitro test method; and wherein the assay medium comprises an aqueous alcohol that contains alcohol at concentrations of about 20% or greater by volume.

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 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 once-per-day opioid 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 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 the mean maximum opioid plasma concentration in a single administration achieved when For example, the once-per-day opioid sustained release dosage form is administered to a patient without concurrent 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 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 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% or greater by volume; and wherein the ratio of the maximum opioid plasma concentration of a single patient in a single application 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 application wherein the once-per-day opioid sustained release dosage form is administered to the patient without concurrent administration of aqueous alcohol is about 5: 1 or less.

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 the aqueous alcohol; releasing the opioid from the once-per-day opioid sustained release dosage form; wherein the once daily opioid sustained release dosage form releases about 80% or less by weight of the opioid dose from the once daily opioid sustained release dosage form, measured by (a) using an in vitro test method comprising a test medium and (b) ) about 2 hours after the start of the in vitro test method; and wherein the test medium comprises aqueous alcohol which contains alcohol at concentrations that are about vol% or greater.

According to another aspect, the invention provides a method comprising: obtaining a sustained release dosage form comprising an opioid and an extended release delivery structure; administering the opioid sustained release dosage form to the patient together with the aqueous alcohol; releasing the opioid from the sustained-release opioid release form; wherein the aqueous alcohol comprises alcohol at concentrations of about 20% or greater by volume; and wherein the ratio of the mean maximum plasma opioid concentration in a single dose achieved when the sustained release opioid release form is administered to a patient together with aqueous alcohol to the mean maximum plasma opioid concentration in a single dose achieved when the dosage form is the sustained release opioid administered to the 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 sustained release dosage form comprising an opioid and an extended release delivery structure; administering the opioid sustained release dosage form to the patient together with the aqueous alcohol; releasing the opioid from the sustained-release opioid release 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 a patient together with aqueous alcohol to the maximum plasma opioid concentration of a single patient achieved in a single dose application The sustained release form of opioid 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 a sustained release dosage form comprising an opioid and an extended release delivery structure; administering the opioid sustained release dosage form to the patient together with the aqueous alcohol; releasing a dose of opioid from a sustained-release opioid dosage form wherein the sustained-release opioid dosage form releases less than about 80% by weight of the opioid dose from the opioid sustained release dosage form, measured (a) using an in vitro test method comprising a test medium; (b) within about 2 hours of initiation of the in vitro test method; and wherein the assay medium comprises an aqueous alcohol that contains alcohol at concentrations of about 20% or greater by volume.

In yet another aspect, the invention provides a method comprising: obtaining a once daily hydromorphone sustained release dosage form comprising hydromorphone and a once daily sustained release delivery structure; administering the once-per-day hydromorphone sustained release dosage form to the patient 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% or greater by volume; and wherein the ratio of the median time of onset of maximum plasma concentration in a single application 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 hydromorphone release form is once-daily administration to a patient without concomitant administration of aqueous alcohol ranges from about 0.5 to about 1.0.

In yet another aspect, the invention provides a method comprising: obtaining 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 median, the time of onset of maximum plasma concentration in a single application 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 hydromorphone release form administered to a patient without concomitant administration of aqueous alcohol is in the range of about 0.5 to about 1.0.

In yet 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 once-per-day opioid 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 application 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 opioid sustained release dosage form is once-daily administration to a patient without concomitant administration of aqueous alcohol ranges from about 0.5 to about 1.0.

According to yet another aspect, the invention provides a method comprising: obtaining an opioid sustained release dosage form comprising the opioid and the sustained release dosing structure, administering the opioid sustained release dosage form to the patient together with the aqueous alcohol; releasing the opioid from the sustained-release opioid release 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 application when the dosage form is co-administered with aqueous alcohol to the median of the time of onset of maximum plasma concentration in a single application when the opioid sustained release dosage form is administered to the patient administered without co-administration of aqueous alcohol is in the range of about 0.5 to about 1.0.

UNTIL

The following is a more detailed description of the solution.

I. Oral sustained release opioid 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 concentrated to solve the problems of rapid dose-induced alcohol, especially ethanol-induced use, using methods and corresponding sustained release forms. Dosage 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 these rapid response problems. dose-induced alcohol, especially ethanol. For example, in US Patent Application Publication No. 2005163856, 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 of the form which could potentially be abused! performed. Maloney et al. however, they do not provide any knowledge or guidance to suggest that this feature could be useful in solving the problem of rapid in vivo dose-induction caused by aqueous alcohol, especially aqueous ethanol, to which the present inventors have focused. The authors of this solution provided such knowledge and instructions.

Further evidence that this problem has not been underestimated in the prior art is the fact that others in the art have developed sustained-release opioid dosage forms that are in fact prone to rapid alcohol-induced dose release, especially ethanol. For example, Palladone ⁸ prolonged release hydromorphone (Purdue Pharma LP), Kadian® (Alpharma US Pharms) and Avinza® (Ligand Pharmaceuticals) have been reported to have problems with rapid dose-induced alcohol, particularly ethanol. The fact that these products are on the market despite the current risk of rapid release of alcohol-induced doses, in particular 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, it is possible to use coatings of the dosage form which act to limit or prevent the rapid release of the dose induced by the alcohol. In other embodiments, certain hydrophobic and / or hydrophilic components may be selected to limit or prevent the rapid dose-induced 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 may be resistant to swelling or dissolution in alcohol, such as semipermeable membrane coatings or certain non-enteric coatings.

In embodiments in which hydrophobic ingredients are selected to limit the rapid release of the dose induced by the aqueous alcohol or to prevent it, it is preferable to select substances that are relatively insoluble in water and minimally swellable in aqueous alcohol. For example, it is possible to select hydrophobic polymers that are at least swellable and relatively water insoluble and exhibit the same or lower swelling and / or solubility in aqueous alcohol. In embodiments that contain non-polymeric hydrophobic components (such as, but not limited to, waxes or alcohols derived from fatty acids such as stearyl alcohol), components that have lower solubility / swelling in aqueous alcohol than water are preferred. In embodiments in which hydrophilic ingredients are selected to limit the rapid release of the dose induced by the aqueous alcohol or to prevent it, the substances which are less soluble and tend to swell in aqueous alcohol than in water are preferably selected. For example, it is possible to select hydrophilic polymers that exhibit the same or lower swelling and / or solubility in aqueous alcohol as compared to water. In embodiments that contain non-polymeric hydrophilic components, those that exhibit lower solubility / swelling in aqueous alcohol than water are preferred.

In one method for determining the desired coatings and hydrophobic and hydrophilic components useful in carrying out this solution, casting films are prepared from the substances and tested for swelling in the presence of aqueous alcohol. It is possible to use bulk testing procedures to obtain a wide range 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 found to be useful in carrying out this solution are set forth in this description.

As the embodiments of this solution described in the examples, in particular Example 5, show, the amount of opioid released from oral opioid sustained release dosage forms can be controlled when co-administered with alcohol. In the embodiments described below, the 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, Example 5 exhibits an increase in hydromorphone release rate as a function of ethanol concentration, resulting in a slight increase in Cmax and a decrease in median Tmax when administered in the fasting state (minimum Tmax was 4 hours with alcohol versus 6 hours with 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 concentrations (in this case hydromorphone) at the first time after application (2 hours) are close to the limit of determination; then plasma concentrations increase slowly in all four applications in both groups, i.e. postprandially and fasting. Median T _ma x is 12 to 16 hours and Tmax range is in various types of applications similar between groups. These data suggest 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 sustained release characteristics, is consistent with the result found in vitro in the embodiments of the present invention described in Examples 1 and 2, 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 with those reported with a conventional hydromorphone formulation known as Palladone (available from Purdue Pharma). For this product, rapid dose release was observed to a large extent both 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, the maximum increase in Cmax for 4%, 20% and 40% ethanol relative to 0% alcohol corresponding to about 2.0, 5.7, and 15.7 times, respectively, is reported for an individual subject, and the mean maximum increase in Cmax for subjects is 4. %, 20% and 40% ethanol relative to 0% 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 1-3 and 7-7

11. Various materials that are useful in carrying out this solution are described. Interestingly, OxyContin, a sustained release product of oxycodone from Purdue Pharma LP, 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 the OxyContin ⁸ formulation to rapid dose-induced alcohol. This finding demonstrates the unexpected nature of this solution. OxyContin ”has been available for many years, but the nature of its resistance to fast induced alcohol-induced dose and the potential mechanism of this resistance has so far remained unclear. In addition to the incorporation of stearyl alcohol, 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.

II. 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.

Administration or administration means administration of a medicament to a patient in a manner that is pharmacologically useful.

The term alcohol refers to an organic compound having 1 to 5 carbon atoms in which the hydroxy (-OH) group is bonded to a carbon atom which is further bonded to another hydrogen and / or carbon atom. In a preferred embodiment, the alcohol comprises ethanol.

The apparent terminal half-life (6¼) is calculated as 0.693 / k, where k is the apparent rate elimination constant, which is calculated by linear regression of the logarithms of plasma concentration during the terminal log-linear elimination phase.

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

The area under the curve or AUC is the area under the plasma concentration of the drug. AUC is often specified by a time interval at which the curve of the plasma concentration integrated, e.g., _the AUC ₀ -48 čiatokkoníec- AUC AUC is thus obtained by integrating the plasma concentration curve in the interval of 0-48 hours, where 0 is the standard time of administration of the drug or a dosage form comprising a medicament to a patient. The term AUC _t is the area under the plasma concentration curve in the range 0 to t, where t is the time of the last detectable concentration, calculated according to the trapezoidal rule. AUCinf denotes the AUC value extrapolated to infinity, calculated as the sum, .AUC _t and the areas extrapolated to infinity, calculated as the concentration at time t (Ct) divided by k. (If it is not possible for the subject to estimate! T%, the mean values of tH are used to calculate AUCinf.) The mean area under the plasma concentration-time curve of AUCinf in a single dose is the mean AUCi _nf in a patient population or mean AUCinf achieved in one patient who received the drug several times at different times with sufficient elimination intervals between applications so that the drug levels after a single application could decrease in each patient! pre-application levels.

The abbreviation C stands for the concentration of the drug in the subject's blood plasma or blood serum, which is usually expressed as weight! per unit volume, typically in nanograms per milliliter. This concentration can also be in the text! referred to as drug concentration in plasma or plasma concentration. Plasma drug concentration at any time following drug administration is referred to as Cg _as, for example, such as C ₉ or C 4 H ₂ etc. The maximum plasma concentration after administration of the dosage form, which is obtained directly from the experimental data without interpolation, is referred to as' C _max . The mean or mean plasma concentration of the drug reached during the period of interest is referred to as C _avg or C _mea n. The mean maximum plasma concentration after single administration is the mean C _raax determined for a set of several patients. or in one patient to whom the drug has been administered several times at different times with elimination intervals between administrations so that the drug levels after a single administration may decrease to pre-administration levels for each patient. The maximum plasma concentration after a single administration to a single patient is defined as the C _max determined in a single patient after single administrations, including sufficient elimination intervals to allow the drug levels to drop to pre-administration levels in the patient.

In one embodiment, the solution comprises releasing an opioid (such as, but not limited to, hydromorphone or oxycodone) from an opioid sustained release dosage form, preferably from an opioid sustained release dosage form for once-daily or twice-daily administration, wherein the ratio of the mean maximum plasma opioid concentration for a single administration when the opioid sustained release dosage form is administered to a patient together with aqueous alcohol, to the mean maximum plasma opioid concentration in a single application achieved when the opioid sustained release dosage form is administered to a patient without concurrently administered with an 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, hydromorphone or oxycodone) from an opioid sustained release dosage form wherein the ratio of the maximum opioid plasma concentration of a single patient in a single administration achieved when the opioid sustained release dosage form is preferably for administration once or twice daily to a patient together with aqueous alcohol, to the maximum plasma opioid concentration of a single patient achieved by a single dose administration when the opioid sustained release dosage form is administered to the patient without concurrent administration of 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 with and the like is meant that two or more agents are administered to a patient for a limited period of time, preferably 180 minutes, more preferably during. 60 minutes, even more preferably 45 minutes, even more preferably 30 minutes, and even more preferably 15 minutes.

Dosage form refers to an opioid in a medium, carrier, vehicle or device suitable for oral administration. By oral dosage form is meant a dosage form suitable for oral administration. In one embodiment, the dosage forms of the 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.

Dosage refers to a unit of drug. Usually, the dosage is provided as a dosage form. Dosages can be administered to patients in different dosing regimens. Typical dosing regimens include once daily (qd), twice daily (bid) and three times daily (tid). The opioid dosages 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 1000 mg. 5 to about 500 mg, more preferably from about 0.5 to about 250 mg, even more preferably from about 1 to about

100 mg, most preferably from about 1 to about 50 mg.

An 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 twice daily application according to once a day ¹¹ (i.e. qd) or (i.e. bid) means the frequency of this solution. For example, once daily administration means once every 24 hours, i.e. qd.

Opioid refers to an agent that binds to opioid receptors that predominantly occur 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 include diamorphine (heroin), oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone and nicomorphine. Examples of fully synthetic opioids include methadone, levometadyl acetate hydrochloride (LAAM), petidine (meperidine), ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine and phenazocine. Other opioids are known to those skilled in the art. In this solution, opioids with oral bioavailability are 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, the oral opioid sustained release dosage forms of the present invention comprise about 0.01 to about 1000 mg of opioid, preferably about 0.1 to about 500 mg of opioid, more preferably about 0.25 to about 300 mg of opioid, even more preferably about 1 mg. up to about 100 mg of 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 solubility; the opioid in aqueous alcohol may have; a positive or negative effect on how the rapid release of the dose in aqueous alcohol from the sustained release dosage forms of the present invention and / or associated methods overcomes. In some cases, for example, large amounts of opioid and / or opioid forms that are highly soluble in aqueous alcohol may increase; the likelihood of rapid release of the aqueous alcohol dose. Conversely, in some embodiments, a high amount of opioid and / or a form that is highly insoluble in aqueous alcohol may reduce the likelihood of rapid release of the aqueous alcohol-induced dose.

Oral sustained release delivery structure means 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). Osmotic oral sustained release delivery structure is understood to mean an oral sustained release delivery structure that provides sustained release of the osmosis drug (s).

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

Pharmaceutically acceptable salt means any salt whose anion 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, 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. fumarate, gluceptate, gluconate, glutamate, glycolylarzanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isotionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrite, methylnitrite ammonium salt of N-methylglucamine, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

The plasma drug concentration curve or plasma drug concentration curve or plasma concentration curve or plasma concentration profile or plasma concentration profile is a curve obtained by plotting the plasma drug concentration or plasma concentration over 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.

By extended time is meant 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 a greater time such as about 14 hours and a maximum of about 24 hours.

Release rate means the amount of drug released from the dosage form per unit of time, e.g., milligrams of drug released per hour (mg / h). The rate of drug release from the dosage forms can be measured as the rate of drug release in vitro, i.e., the amount of 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 basket sample holders attached to the USP Type 7 bath disc in deionized water at a constant water bath temperature of 37 ° C. Aliquots of solutions to measure release rate are collected at predetermined intervals and injected 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, e.g.

Premiere ”5100.

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

In one embodiment, the assay medium comprises an aqueous alcohol that comprises an alcohol. In a preferred embodiment, the test medium comprises an aqueous alcohol comprising 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% or greater.

Sustained release refers to 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 the drug or drug dose.

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

The median time of onset of maximum plasma concentration T _max after a single administration is the median of the time elapsed from administration of the drug-containing dosage form to the patient until reaching the C _max of the drug after a single administration of the dosage form obtained directly from experimental data without interpolation. wherein the median is determined for a plurality of patients or determined for multiple drug administrations to a single patient who has been administered the drug at different times with sufficient elimination intervals between administrations to allow drug levels to decrease to pre-administration levels in the patient after single administration. In one embodiment, the ratio of the median time of onset of maximum plasma concentration in a single application 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 dosage form is The opioid is administered to the patient without concurrent 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 about 0.7 to about 1.0, most preferably from about 0.75 to about 1.0.

A therapeutically effective amount is an amount of drug that elicits a biological or therapeutic response in the animal or human tissue system that the researcher, veterinarian, physician, or other clinic seeks, and which includes alleviating the symptoms of the disease or disorder being treated.

III. Application forms

In embodiments of this solution, the sustained release dosage forms are formulated as the 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 only examples.

Various sustained release dosage forms are suitable for use in the present invention. In some embodiments, the dosage form can be administered orally, and the dosage form has the size and shape of a conventional tablet or capsule. Dosage forms for oral administration can be manufactured in one of a number of different ways. For example, the dosage form can be prepared as a diffusion system, 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 Pharmaceutical Sciences, Remington, 18th edition, p. 1676-1686 (1990); Mack Publishing Co .; The Pharmaceutical and Clinical Pharmacokinetics, 3rd Edition, p. 1-28 (1984), Lea and Febreger, Philadelphia.

Osmotic dosage forms generally utilize osmotic pressure to generate a force by which a liquid is soaked 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 work independently of pH, and the rate given by osmosis persists over an extended period of time, although the dosage form passes through the gastrointestinal tract and encounters different types of microenvironment whose pH varies considerably. An overview of 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 its entirety. U.S. Pat. 3,845,770, 3,916,899,

995 631, 4 008 719, 4 111 202, 4 160 020, 4 327 725,

Nos. 578,075, 4,681,583, 5,019,397 and 5,156,850 disclose osmotic devices for continuous drug delivery.

Sustained-release osmotic dosage forms by which the drug composition is released as a suspension or solution from a small exit orifice by the expanding layer are described in U.S. Pat. 5,633,011, 5,190,765, 5,252,338,

620,705, 4,931,285, 5,006,346, 5,024,842, and 5,160,743, all of 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 which allows for 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 could be achieved by applying an enteric coating, preferably a coating that is insoluble in aqueous alcohol and does not swell in aqueous alcohol and at gastric pH, on an osmotic sustained release dosage form. The semipermeable membrane may 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.

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 shows an application form based on the principle of an elementary osmotic pump according to this solution.

In FIG. 2, some embodiments of sustained release dosage forms of the present invention are shown.

In FIG. 3 shows another example of a dosage form.

In FIG. 4 shows another example of a dosage form.

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

In FIG. 6 shows the cumulative liberation profiles of 16mg tablets containing hydromorphone HCl, according to this solution in ethanol solutions.

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

&

In FIG. 8 shows the mean concentration profile (a

SD) of hydromorphone in plasma.

In FIG. 9 shows the mean plasma concentration (and SD) profile of hydromorphone.

In FIG . 10 They are illustrated individually condition Cmax: Group 1, study with alcohol versus study with repetitive application. In FIG . 11 They are illustrated individually condition Cmax: Group 2, study with alcohol versus study with repetitive application.

In FIG. 12 shows the release of oxycodone hydrochloride from formulations with stearyl alcohol and without stearyl alcohol.

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

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

In FIG. 15 shows the effect of Eudragit® RS PO on the release of the drug hydromorphone hydrochloride.

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

33 ^

In FIG. 17 shows the in vitro dissolution profiles of OxyContin ⁰ tablets.

EXAMPLES

An example of a dosage form, referred to in the art as an elemental osmotic pump based dosage form, is shown in FIG. A dosage form 20, shown in a spatial section, is also referred to as an elemental osmotic pump (EOP), comprising a semipermeable membrane 22 that surrounds and encapsulates the inner compartment.

24. The inner compartment comprises a one-component layer, referred to herein as a drug layer 26, which comprises a compound 28 of the invention in admixture with selected excipients. The excipients are adapted to achieve the osmotic activity gradient required to bring the 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. description of this application.

The semipermeable membrane 22 of the osmotic dosage form is permeable to the outer liquid, such as water and biological fluids, but substantially non-permeable to the components of the inner compartment. The materials useful in forming the membrane are substantially throughout the life of the dosage form

non-erodible and substantially insoluble in biological fluids. Representative polymers that can be used to form the semipermeable membrane include homopolymers and copolymers such as cellulose esters, cellulose ethers and cellulose ester-ethers. The liquid permeability of the membrane can be adjusted using flow control agents which are mixed with the membrane-forming material. 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, polyalkylene diols, polyesters of alkylene glycols and the like.

During operation, the osmotic gradient on the membrane 22 due to the presence of osmotic active agents causes the gastric fluid to be drawn through the membrane, the drug layer swells and a transportable complex formulation (for example, a solution, suspension or other liquid composition) is formed in the inner compartment. The transportable formulation of a compound of the invention is released by the exit 38 as the liquid formulation enters the interior compartment, as the drug formulation is already released, the fluid still permeates into the interior compartment, which is a continuous release drive mechanism. In this way, the substance of the invention is released steady and continuously over an extended period of time.

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

In 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 as the liquid is sucked in such a way 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 outside through the membrane 20, and upon aspiration of the liquid to form a transportable complex formulation. Excipients include, but are not limited to, a suitable suspending agent (also referred to herein as a drug carrier), but not an osmotically active agent, an osmagent, such as a salt, sodium chloride. It has been found that by releasing the salt from the second drug layer, which contains the major part of the drug fully present in the dosage form, in combination with the salt in the first drug layer, an increase in the release rate is achieved and the rate increase is maintained for longer.

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, to achieve the desired substantially increasing release rate.

O c

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 polymeric carrier. The hydrophilic polymer is involved in the controlled opioid transport. Representative 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 polymeric alkaline salt of carboxymethylcellulose, polymeric sodium salt of carboxymethylcellulose, polymeric potassium salt of carboxymethylcellulose, and polymeric lithium salt of carboxymethylcellulose. The drug layer 40 may further comprise hydroxypropylalkylcellulose with a number average molecular weight of 9,200 to 125,000 which can improve the transport properties of the dosage form, for example, hydroxypropylethylcellulose, hydroxypropylmethylcellulose, hydroxypropylbutylcellulose and hydroxypropylpentylcellulose; and polyvinylpyrrolidone with an average molecular weight of 7,000 to 75,000 which can improve the flow properties of the dosage form. Of these polymers, poly (ethylene oxide) having a number average molecular weight of 100,000 to 300,000 is preferred. Carriers which are subject to erosion in the stomach environment, i.e. a biologically erodible carrier, are particularly preferred.

The drug layer 40 and / or the drug layer 30 may also contain carriers other than carbohydrates, which are osmotically active enough. they could be used alone or with other eight-millers. Examples of such carbohydrates include monosaccharides, 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. Preference is given to maltodextrins having a dextrose equivalent (DE) value of 20 or less, preferably DE in the range of about 4 to about 20, and often from 9 to 20. Maltodextrins with a DE of 9 to 12 have been found to be useful.

The drug layer 40 and the drug layer 30 are typically a substantially dry (with water content < 1 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 a drug particle size and an accompanying polymer particle size that is used in the manufacture of the drug layer, typically as a core containing compound, according to the mode and method of the present invention. Methods for preparing particles include granulation, spray drying, sieving, lyophilization, crushing, grinding, jet milling, micronization, and chopping to achieve the intended micrometer particle size.

The method can be carried out using a crushing device such as a micropulverizer mill, jet mill, wheel mill, roller mill, hammer mill, disc mill, wheel mill, ball mill, vibratory ball mill, impact pulverizer mill, coarse mill and fine mill. The particle size can be ensured by sieving, such as sieving using a sieve screen, flat screen, vibrating screen, rotary screen, shaker screen, oscillating screen and weaving screen. Methods and devices for preparing drug particles and carriers are described in Pharmaceutical Sciences, Remington,

17th edition, p. 1585-1594 (1985); Chemical Engineers Handbook, Perry, 6th Edition, p. 21-13-21-19 (1984); Journal of Pharmaceutical Sciences, Parrot, Vol. 61, no. 6, p. 813-829 (1974) and Chemical Engineer, Hixon, p. 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, such 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 can be achieved and the rate increase is maintained for a longer period of time.

The osmotically active ingredient in the first drug layer comprises an osmagent and one or more osmopolymers. with a relatively low molecular weight, which swell as the liquid is sucked in such a way that the release of these osmopolymers occurs via the outlet 60 similar to the drug layer 40.

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

Optionally, the drug layer 30 and the drug layer 40 may comprise surfactants and disintegrants. Examples of surfactants include surfactants having an HLB (hydrophilic-lipophilic balance) 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.

Disintegrants may be selected from starches, clays, celluloses, algines and gums, and cross-linked starches, celluloses and polymers. Representative disintegrants include corn starch, potato starch, croscarmellose, crospovidone, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum, and the like.

The membrane 20 is formed to be permeable to an external liquid, such as water and biological fluids, and substantially non-permeable 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 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 ether ethers. Cellulose polymers have a degree of substitution 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 hydroxy groups that were originally present on the anhydroglucose unit and were replaced by or substituted for the substitution 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, alkylsulfamate groups, semipermeable polymer forming groups and the like. The semipermeable compositions typically comprise a member selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose triacetate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and trialkanylates, mono, di- and trialkenylates, mono-, di- and cellulose triaroylates, and the like.

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 3 9.9%; cellulose diacetate with D.S. 1 to 2 and an acetyl content of 21 to 35%, cellulose triacetate with D.S. 2 to 3 and an acetyl content of 34 to 44.8% and the like.

More specifically, cellulose polymers include cellulose propionate with D.S. 1.8 and propionyl groups

38.5%; cellulose acetate propionate having an acetyl content of 1.5 to 7% and an acetyl content of 39 to 42%; cellulose acetate propionate having an acetyl content of 2.5 to 3% and an average propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose 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 with an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylates with D.S. 2.6 to 3, such as cellulose trivalerate, cellulose trilamate, cellulose tripalmitate, cellulose trioctanoate and cellulose tripropionate; cellulose diesters with 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 acetate valerate, cellulose acetate succinate, cellulose propionate, cellulose acetate octanoate, cellulose valmitate, cellulose acetate heptanoate and the like. Semi-permeable polymers are known from U.S. Pat. No. 4,077,407 and can be synthesized according to the methods described in Encyclopedia of Polymer Science and Technology, Vol. 3, p. 325 to 354. 1964, vyd. Interscience Publishers, Inc., New York.

polyamide; sulfonated

Other semipermeable polymers that can be used to form the semipermeable membrane include, for example, cellulose acetaldehyde dimethyl acetate; cellulose acetate ethylcarbamate; cellulose acetate methylcarbamate; cellulose dimethylaminoacetate; semipermeable semipermeable polyurethanes; semipermeable polystyrenes; cross-linked selective semipermeable polymers formed by coprecipitation of polyanion and polycation according to U.S. Pat. 3,173,876, 3,276,586, 3,541,005; 3,541,006 and 3,546,142; semipermeable polymers described in U.S. Pat. 3,133,132; semipermeable polystyrene derivatives; semipermeable poly (sodium styrene sulfonate); semipermeable poly (vinylbenzyltrimethylammonium chloride);

polymers with liquid permeability (cc. mil / cm hr.atm) expressed per atmosphere of hydrostatic or osmotic pressure difference across the semipermeable membrane. Such polymers are known in the art of semipermeable 10-5 to 10-2 and are described in U.S. Pat. 3,845,770, 3,916,899 and 4,160,020 and in the Handbook of Common Polymers, Scott, J. R., and

Roff, W.J., 1971, eds. 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 assist in controlling liquid permeability or flow through the membrane 20. The flow control agent may be a flow enhancing agent or a flow reducing agent. The reagent may be preselected to increase or decrease the flow of liquid. Agents that cause a marked increase in liquid permeability, such as water, are often substantially hydrophilic, while agents that cause a marked decrease in liquid permeability, such as water, are substantially hydrophobic. The amount of regulatory agent in the membrane 20, if any, is usually from about 0.01% to 20% by weight or greater. Flux control agents in one embodiment in which the flow increases are, 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 copropylene glycol) and the like; low molecular weight glycols such as polypropylene glycol, polybutylene glycol and polyamylene glycol; polyalkylenediols such as poly (1,3-propanediol), poly (1,4-butanediol), poly (1,1-hexanediol) and the like; aliphatic diols such as 1,3-butylene glycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol and the like; alkylenetriols such as glycerol, 1,2,3-butanetriol, 1,2,4-hexanetriol, 1,3, β-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 phthalates λ ~>

aryl phthalates, such as insoluble salts, substituted with an alkyl or alkoxy group, or substituted with both alkyl and alkoxy groups such as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate and [di (2-ethylhexyl) phthalate], triphenyl phthalate and butyl benzyl phthalate;

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 esters of citric acid esterified with long chain alkyl groups; inert and substantially water impervious fillers; resins which are compatible with cellulosic substances forming a membrane and the like.

Other materials that can be used in forming a membrane 20 to impart flexibility and elongation to the wall to render the membrane less brittle to non-brittle and to achieve structural strength include, for example, phthalate plasticizers such as dibenzyl phthalate, dihexyl phthalate, butyloctyl phthalate, six to eleven straight chain carbon atoms, diisononyl phthalate, diisodecyl phthalate, and the like. Further, non-phthalate plasticizers such as triacetin, dioctyl alate, epoxidized talc, triisoctyl trimellitate, triisononyltrimelitate, sucrose isobutyrate acetate, epoxidized soybean oil and the like can also be mentioned. The amount of plasticizer in the membrane, if present in the membrane, is about 0.01% to 20% by weight. or higher.

The extrusion layer 50 includes an expandable layer that is arranged to contact the second drug layer 40 as shown in FIG. 2. The extrusion layer 50 comprises a polymer that absorbs an aqueous or biological fluid and swells to expel the drug composition from the outlet of the device.

In one embodiment, the expandable layer 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 on the semipermeable membrane exhibits an osmotic pressure gradient over the external liquid present in the delivery environment. In another embodiment, the water-activated layer comprises a hydrogel that sucks and / or adsorbs liquid into the layer through an 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. Osmopolymers are swellable, hydrophilic polymers that interact with water and aqueous biological fluids and swell or increase their volume until equilibrium is reached. The osmopolymers exhibit the ability to swell in water and biological fluids and retain a substantial portion of the absorbed liquid in their polymeric structure. The osmopolymers swell or expand 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 donon bonds or residual crystalline regions after swelling. The osmopolymers may be of vegetable, animal or synthetic origin.

Gly Λ low glyoxal, carboxymethylcellulose; an anhydride-forming copolymer

Osmopolymers are hydrophilic polymers. Suitable hydrophilic polymers for this purpose include poly (hydroxyalkyl methacrylate) having a molecular weight of from 30,000 to 30,000.

000 000; poly (vinylpyrrolidone) having a molecular weight of

000 to 360 000; anionic and cationic hydrogels;

polyelectrolyte complexes; a poly (vinyl alcohol) fraction of acetate groups, cross-linked with formaldehyde or glutaraldehyde and having a degree of polymerization of from 200 to 30,000; a mixture of methylcellulose, cross-linked agar and carboxymethylcellulose; a mixture of hydroxypropyl methylcellulose and sodium carboxymethylcellulose; a mixture of hydroxypropylethylcellulose and sodium carboxymethylcellulose; a mixture of sodium carboxymethylcellulose and methylcellulose, sodium sodium carboxymethylcellulose;

which is water-insoluble but swellable when dispersed the finely divided maleic acid copolymer with styrene, ethylene, propylene, butylene or isobutylene crosslinked 0.001 to about 0.5 moles of saturated crosslinking agent per mole of maleic anhydride per copolymer; water-swellable polymers of N-vinyl lactams; polyoxyethylene polyoxypropylene gel; carob rubber; polyacrylic gel; polyester gel; polyurea gel; polyether gel, polyamide gel; polycellulose gel; gel polygum; hydrogels / which are initially dry and soak up and absorb water which penetrates the glassy hydrogel and lowers its glass temperature and the like.

Representative examples of other osmopolymers include hydrogel-forming polymers such as Carbopol ™, an acidic carboxypolymer, a polyallyl sucrose crosslinked acrylic acid polymer, also known as a carboxypolymethylene, and a carboxyvinyl polymer having a molecular weight of 250,000 to 4,000,000; Cyanamer ™ Polycarylamides; cross-linked indenmaleic anhydride polymers that swell in water;

Good-rite ™ polyacrylic acids with molecular weight

000 to 200 000; Polyox ™ polyethylene oxide polymer having a molecular weight of 100,000 to 5,000,000 and higher; starch graft copolymers; AquaKeep ™ acrylate polymers, polysaccharides formed by condensed glucose units, such as a cross-linked polyglucan to form a diester and the like. Representative hydrogel-forming polymers are known in the art from U.S. Pat. 3,865,108;

U.S. Pat. 4,002,173; U.S. Pat. 4,207,893 and the Handbook of Common Polymers, Scott and Roff, eds. Chemical Rubber Co., Cleveland, Ohio. The amount of osmopolymer contained in the hydroactivated layer may be from about 5% to about 100%.

In another embodiment, the expandable layer may comprise an osmotic active compound that includes inorganic and organic compounds that exhibit an osmotic pressure gradient on the semipermeable membrane against the external liquid. Osmotic active compounds, such as osmopolymers, suck the liquid into the osmotic system, and the liquid available thus presses on the inner wall, i.e., in some embodiments, on the barrier layer and / or membrane of the soft or hard capsule to expel the active agent from the delivery device. forms. Osmotic active compounds are also known as osmotic active solutes and also as osmagents. As osmotic active solutes, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium hydrogen phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose, glucose, lactose, sorbitol, and sorbitol can be used. mixtures thereof. The amount of osmagent contained may be from about 5% to 100% by weight, based on. layer. The expandable layer optionally comprises an osmopolymer and an osmagent, wherein the total amount x / r of the osmopolymer and osmagent is equal to 100%. Osmotically active solutes are known in the art as described in U.S. Pat. 4,783,337.

The protective backing layer, the inner wall 90, is permeable to the liquid entering the compartment defined by the membrane 20. The wall 90 has a sliding function that facilitates the movement of the first drug layer 30, the second drug layer 40 and the extrusion layer 50 towards the outlet 60. a flat. 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 when suspensions or solution of the drug composition are transported highly viscous at the time of transport. In dosage forms that contain hydrophobic agents and do not contain an inner wall, it has been found that significant 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. Particularly in the case of very expensive active compounds, such an improvement presents considerable economic advantages, since the drug layer need not contain excess drug 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.

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 includes a member selected from hydrogels, gelatin, low molecular weight polyethylene oxides, e.g., less than 100,000 molecular weight, hydroxyalkylcelluloses such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxyisopropylcelluloses, hydroxybutylcelluloses and hydroxyphenylcelluloses, and hydroxyalkylalkylcelluloses, such as hydroxypropylmethylcelluloses, 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 or inert organic solvents. solvents.

Preferred wall 90 materials include hydroxypropylcellulose, hydroxyethylcellulose, 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 hydroxyethylcellulose and hydroxypropylmethylcellulose prepared in aqueous solution and mixtures of hydroxyethylcellulose and polyethylene glycol. 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 polyvinylpyrrolidone designated as K29-32.

Preferably, the weight of the wall 90 applied to the molded core can correlate with the thickness of the wall 90 and the residual drug,

9 which remains in the dosage form in the release rate test described herein. As such, the thickness of the wall 90 as such may be controlled during manufacturing operations by controlling the weight of the wall 90 during coating.

When the wall 90 is formed as a backing, i.e. by stretching a tablet 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 may fill the surface irregularities formed on the core 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 gelling 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 slip between the membrane 20 and the drug layer 30 and the drug layer 40.

In the preparation of the final dosage form, it is advantageous to use a drum coating, with the exception of the outlet opening. In a drum coating system, a molded three-layer or multi-layer core comprising drug layers, an optional barrier layer, and an extrusion layer is applied to a wall-forming composition for a wall or, optionally, a membrane by successively spraying a suitable membrane composition while rolling in a rotating drum. The auction drum is used due to 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 oven or in a controlled oven

temperature and humidity, thereby releasing the dosage form of the solvent (s) used in the manufacture. Suitably, the drying conditions are selected according to the equipment available, ambient conditions, solvents, coatings, 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 a stream of air and a 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 U.S. Pat. 2,799,241; J. Am. Pharm. Assoc., Vol. 48, p. 451-459 (1959) and also there, Vol. 49, p. 82-84 (1960). The dosage form can also be coated with a Wuster ¹ ”fluidic coating apparatus, for example using dichloromethane and methanol as a co-solvent for the membrane forming material. It is also possible to coat in an Aeromatic fluidized-bed coater using a co-solvent.

In one embodiment, the sustained release dosage form of the present invention comprises at least one outlet 60 shown in FIG. The outlet 60 cooperates with the compressed core to uniformly release the drug from the dosage form. The outlet 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 apertures are drilled and the dosage form may be provided with optional water-soluble topcoats that may be colored (e.g., colored Opadry coatings) or clear (e.g., a clear Opadry coating) to give a final 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; gelatin fiber; water-removable poly (vinyl alcohol); extractable compound, such as a pore-forming substance, which is removable by a liquid selected from the group consisting of inorganic

and organic salt, oxide and carbohydrate. Output, whose a larger number of outputs may arise leaching member selected from the file consisting of sorbitol, lactose, fructose, glucose, mannose, galactose,

talc, sodium chloride, potassium chloride, sodium citrate and mannitol, by means of which it is possible to achieve an outlet opening - pore sized evenly. release.

The outlet may have any shape, such as circular, triangular, square, elliptical, and the like, for uniformly delivering 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 U.S. Pat. No. 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, into the drug layer 30.

The dosage forms according to the embodiments shown in FIG. 1 are produced 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 a granulating liquid. The remaining ingredients can be dissolved in a portion of the granulating liquid, such as the solvent described above, and this later prepared wet mixture is slowly added to the drug containing mixture during 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 screen onto the scaffolding. The mixture is dried in a forced-air oven at 24-35 ° C for 18-24 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® press or Korsch LCT. In the case of a three-layer core, granular or powder formulations are successively placed in a suitable size die matrix and granular or powder embossed layer formulations are added successively, after the composition of each of the first two layers is added, a compression intermediate is added and the composition is added. of the last layer into the matrix, a final compression is performed to obtain a three-layer core. Typically, a compression force of about 50 to 100 N is applied in the compression intermediate. 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 a Kilian® press and subsequently coated with the above described membrane. materials

In another embodiment, the drug and other ingredients contained in the drug layer are mixed together and compressed to form a solid layer. The layer has dimensions that correspond to the internal dimensions of the area that the layer in the application layer should occupy, and also has dimensions that correspond to the extrusion layer, if included, so as to form a contact arrangement. The drug and other ingredients may also be mixed with a solvent and mixed to form a solid or semi-solid form by conventional techniques such as ball milling, calendering, blending or roller milling, and then compressed to a preselected shape. Then, optionally, in a similar manner, a layer of the osmopolymer composition is placed in contact with the drug layer. The drug formulation layers and the osmopolymer layer are. can be formed by conventional two-layer molding processes. Similarly, it is possible to prepare a three-layer core. The molded cores can then be coated with a wall-forming material and a semipermeable membrane material, which are wrapped 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 the 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 tank 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 substances, 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, methylpropyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, monoethyl acetate ethylene, carbon tetrachloride, carbon tetrachloride, diethyl ether, cyclooctane, benzene, toluene, naphthalene, 1,4-dioxane, tetrahydrofuran, diglyme, water, aqueous solvents containing inorganic salts such as sodium chloride, calcium chloride and the like, and mixtures thereof such as acetone / water mixtures , acetone and methanol, acetone and ethanol, dichloromethane and methanol, and dichloroethane and methanol.

dichloromethane, nitroethane, isopropyl ether, dichloroethane, nitropropane, cyclohexane,

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 practicing this solution.

</ 1

Instead, dosage forms that are capable of delivering the substances in a semi-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 using them are known in the art; for example, they are described and claimed in U.S. Pat. 6,419,952; 6,174,547;

551 613; 5,324,280; Methods of using oral osmotic devices to deliver therapeutic agents with increased 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, Labrafac 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), Pluronic (type L-31, L-35, L42, L-64 and L-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 those skilled in the art that any formulation comprising a sufficient dose of the opioid solubilized in a liquid carrier suitable for administration to a subject and for use in an osmotic device may be employed in the present invention. In one exemplary embodiment of the present invention, the liquid carrier is PG, Solutol, Cremophor EL. or combinations thereof.

The liquid formulations of the present invention may also contain, for example, other excipients such as an antioxidant, a penetration enhancer and the like. The antioxidants may be used to retard or effectively stop the autooxidation of any auto-oxidizable substance present in the capsule. Representative antioxidants include members selected from the group consisting of ascorbic acid; alpha-tocopherol; ascorbyl; of vitamin C; izoaskorbátov; butylated hydroxyanisole; butylated hydroxytoluene; Nordihydroguayaretic acid; 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-paminofenolu; butyltyrozínu; 3-tert-butyl-4-hydroxyanisole; 2-tert-butyl-4-hydroxyanisole; 4-chloro-2,6-di-tert-butyl phenol;

2,6-di-tert-butyl-p-methoxyphenol; 2,6-di-tert-butyl-p-cresol; polymeric antioxidants; trihydroxy-butyrophenone, physiologically acceptable salts of ascorbic acid, erytorbic acid and ascorbylacetate; calcium ascorbate; sodium ascorbate; sodium bisulfite and the like. The amount of antioxidant 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 U.S. Pat. 2,707,154; 3,573,936; 3,637,772;

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 comprise a penetration enhancing agent that facilitates drug absorption in the delivery environment. Such penetration enhancers may, for example, open so-called &quot; zonula 'occludens in the gastrointestinal tract or modify the effect of cellular components such as p-glycoprotein and the like. Suitable penetration enhancers include alkali metal salts of salicylic acid, caprylic acid or capric acid, such as sodium salicylate, sodium caprylate or sodium caprate, and the like. Penetration enhancers include, for example, bile acid salts such as sodium deoxycholate. Various modulators of p-glycoprotein are described in U.S. Pat. Nos. 5,112,817 and 5,643,909. Various other compounds and materials promoting absorption are described in U.S. Pat.

824 638. The penetration enhancers may be used alone or in admixture with other penetration enhancers.

In some embodiments, the agents of the invention are administered as self-emulsifying formulations. As with other liquid carriers, the function of the surfactant is to prevent aggregation, reduce interfacial tension, also improve the 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 are possible

in addition to the aforementioned surfactants, a member selected from the group consisting of polyoxyethylene castor oil containing 9 to 15 moles of ethylene oxide, polyoxyethylene sorbitan monopalmitate, mono- and tristearate containing 20 moles of ethylene oxide, polyoxyethylene sorbitan monostearate oxide containing 4 moles of ethylene oxide, sorbitan monostearate, polyoxyethylene sorbitan monostearate 20 moles of ethylene oxide, polyoxyethylene lauryl ether, polyoxyethylenated stearic acid containing 40 to 50 moles of ethylene oxide, polyoxyethylene stearyl 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 this 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 ester of an unsaturated fatty acid, 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 oilmeat oil, almond oil, mineral oil, castor oil, coconut oil, palm oil, cocoa butter, yellow oil, a mixture of mono- and diglycerides with 16 to 18 carbon atoms, unsaturated fatty acids, fractionated with coconut-derived triglycerides, fractionated liquid triglycerides derived from short-chain fatty acids of 10 to 15 carbon atoms, acetylated monoglycerides, acetylated diglycerides, acetylated triglycerides, also oleate, also oleate , palmitine, also known as glyceryltripalmitate, stearin, also known as glyceryl tristearate, lauric hexyl ester, oleic acid oleyl ester, glycolyzed ethoxylated natural oil glycerides, branched fatty acids with 13 molecules of ethylene oxide and decyl ester of acid oil. 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, p. 403-405 (1985), Mack Publishing Co., Encyclopedia of Chemistry, Van Nostrand Reinhold, 4th edition, p. 644-645 (1984), eds. Van Nostrand Reinhold Co. and U.S. Pat. 4,259 323.

The amount of opioid incorporated in the dosage forms of the present invention is usually 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. Depending on the dose of opioid to be administered, one or more dosage forms may be administered.

The osmotic dosage forms of the present invention may be in two different forms, a soft capsule (shown in Fig. 3) and a hard capsule (shown in Fig. 4). The soft capsule, as used herein, 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 by a variety of methods such as flat-stamping, rotary-stamping, reversible stamping, and a continuous process. By way of example, the surface compression process is described below. The flat-molding process uses mold sets. The warm sheet of the prepared capsule former is placed over the bottom mold and the formulation is poured onto it. The second sheet of the prepared capsule former is placed over the formulation. The top mold is then placed thereon. The mold set is subjected to pressure and / or heating to obtain an integral capsule. The capsules are washed with solvent to remove excess drug-containing formulation from the outer surface of the capsule and the air-dried capsule is encapsulated by a semipermeable wall. Rotary molding uses two continuous films of the capsule-forming material, which converge between a pair of press rolls 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 nozzle and into the leaves between the rollers. The wedge base comprises small holes flush with the recesses of the roller compactor. The capsule is closed halfway when the pressure of the pumped formulation with the agent pushes the sheet into the recess of the die 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 sheeting 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 layer of semipermeable membrane.

Using reversible punches, capsules are prepared by passing two films of the capsule forming material between

system of vertical presses. With their gripping, zooming and re-gripping, the presses create, like a continuous flat forming, row by row pockets throughout the film. The pockets are filled with the formulation of the invention and are sealed, shaped and cut off from the moving film as the capsules are filled with the active ingredient formulation. A capsule is obtained after application of the semipermeable encapsulation layer. The continuous process uses a manufacturing system that also includes rotating presses. An additional feature of this process is that it is possible to gradually fill the soft capsule in addition to the encapsulated active ingredient in the form of a dry powder. The filled capsules obtained by the continuous process are encapsulated with a semi-permeable polymeric material to form the resulting capsule. Methods for making soft capsules are described in U.S. Pat. No. 4,627,850 and U.S. Pat. 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 a semipermeable membrane include a thermoplastic polymer, or the compositions comprise a mixture of thermoplastic polymers and optional injection additives. As a thermoplastic polymer which can be used for this purpose, polymers having a low softening point, for example less than 200 ° C, preferably in the range of 40 to 180 ° C can be mentioned. The polymers are preferably synthetic resins, addition polymerized resins such as polyamides, resins based on diepoxides and primary alkanolamines, resins based on glycerin and phthalic anhydrides, polymethane, polyvinyl resins, polymer resins whose terminal positions are free or esterified with carboxyl or carboxamide by reaction with acrylic acid, acrylamide or acrylic acid esters, polycaprolactone and its copolymers with dilactide, diglycolide, valerolactone and decalactone, a resin composition comprising a polycaprolactone and a polyalkylene oxide and a resin composition such as a polycaprolactone, a polycaprolactone, a polycaprolactone, ), poly (hydroxyethylmethylcellulose) and poly (hydroxypropylcellulose). The membrane-forming composition may comprise optional membrane-forming components such as polyethylene glycol, talc, polyvinyl alcohol, lactose or polyvinylpyrrolidone. Compositions for preparing an injectable polymer composition may include 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 1% to 98% of the first thermoplastic polymer, from% to 90% different, the second polymer, and from 1% to 90% different, the third polymer, wherein the sum of all polymers is 100%.

Representative compositions include 20% to 90% thermoplastic polycaprolactone and 10% to 80% poly (alkylene oxide); compositions comprising 20% to 90% polycaprolactone and 10% to 60% poly (ethylene oxide), wherein the sum of the proportions of all components is 100%; compositions comprising 10% to 97% polycaprolactone, 10 to 97% poly (alkylene oxide) and 1% to 97% poly (ethylene glycol), wherein the sum of the proportions of all components is 100%; compositions comprising 20% to 90% polycaprolactone and 10 to 80% poly (hydroxypropylcellulose), wherein the sum of all components is 100% and compositions comprising 1% to 90% polycaprolactone, 1% to 90% poly (ethylene oxide), 1% to 90 % poly (hydroxypropylcellulose) and 1% to 90% poly (ethylene glycol62 l), the sum of the proportions of all components being 100%. The percentages given are percentages by weight.

order: polycaprolactone,

According to one example,

In another embodiment, an injection composition to form a membrane can be prepared by mixing a composition comprising polycaprolactone (63% by weight), polyethylene oxide (27% by weight) and polyethylene glycol (10% by weight) in a conventional mixer, as in a Moriyama ™ Mixer, at 65-95 ° C, wherein the ingredients are added to the mixer in this polyethylene oxide and the polyethylene glycol all mix for 135 minutes at a rotation speed of 10 to 20 min ^-1 . The mixture is then processed in a Baker Perkins Kneader ™ extruder at 80 to 90 ° C at a pump speed of 10 min ^-1 and a rotation speed of 22 min ^-1 and then cooled to 60 ° C. 10 to 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 5 mm in length. The pellets are introduced into an Arburg Allrounder ™ injection apparatus at 93-177 ° C where heating to form 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 cm ³ / s and a temperature of 75 ° C. Injection compositions and injection techniques are described in U.S. Pat. 5,614,578.

Alternatively, the capsules may conveniently be prepared in two parts, one part (cap) being slid onto the other part (body), which covers when the capsule is deformable by the forces exerted by the expanding layer and tightly closes,

In order to prevent the liquid, the active substance-containing formulation, from leaking between the slide-out parts of the body and the cap. The two parts completely enclose and encapsulate the inner cavity which contains the liquid, a formulation containing the active ingredient, which 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 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, such as an expandable layer. The expandable layer will usually be asymmetric and a portion of greater thickness will be spaced from the outlet. When the hydroactive layer sucks and / or absorbs the external liquid, it expands and pushes against the wall of the capsule and the optional barrier layer and expels the formulation containing the active substance 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 remote from the passageway swells and moves toward the opening.

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

The complementary shape of the expandable layer is required. can be achieved using a suitable tool such as a convex punch in a conventional tablet press. In this case, the expandable 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 U.S. Pat. 4,915,949; 5,126,142; 5,660,861; 5,633,011; 5,190,765; 5,252,338; 5,620,705; 4,931,285; 5,006,346; 5,024,842 and 5,160,743.

In some embodiments, the barrier layer may first be 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 wax, gelatin aqueous solution, gelatin / glycerol aqueous solution, acrylate-vinyl acetate adhesives such as Duro-Tak adhesives (National Starch and Chemical Company), aqueous solutions of water-soluble hydrophilic polymers such as hydroxypropyl methylcellulose, hydroxymethylcelluloses, hydroxyethylcelluloses and the like. Such an intermediate dosage form can then be coated with a semipermeable layer. The outlet opening is formed at the side or end of the capsule that is opposite to the expansible layer portion. It absorbs the liquid as an expansion layer, swells. Because it is constrained by the semipermeable layer, as it expands, it compresses the capsule coated with the barrier layer and forces the liquid containing the active ingredient formulation from 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 putting the cap on or sliding over 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 stainless steel molds into a bath containing a solution of a layer-forming material that forms a coating on the mold. 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 sliding cap is prepared which, by sliding, closes the body containing the formulation. Then, the sealed and filled capsule can 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, it is possible to prepare hard capsules whose parts close to the open end contain rings which engage with each other and, after being filled with the formulations, allow to engage and fix the sliding cap together with the body. In this embodiment, rings are formed on the cap and body that engage with each other to form a lock that securely holds the capsule together. The capsule can be formulated manually or by machine. In the final manufacture, the hard capsule is encapsulated by a semipermeable layer which is liquid pervious and substantially impervious to the useful active ingredient. Methods for preparing dosage forms such as hard capsules are described in U.S. Pat. No. 6,174,547, U.S. Pat. 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; a composition comprising gelatin, a resin, glycerol and water; and so on. Materials useful in the preparation of capsule membranes are known from U.S. Pat. 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 in oval, oblong or other shapes. 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, it is also possible to use non-standard shapes. If necessary 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 sernipermeable membrane that is permeable to the external biological liquid and substantially non-permeable 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, an osmopolymer, an osmagent, and the like. Materials that are useful in forming the semipermeable membrane are described elsewhere herein.

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

The semipermeable membrane surrounds and forms a compartment comprising one or more layers, one of which in some embodiments is an expandable layer, and may comprise 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. In some embodiments, the barrier layer is deformable by the pressure exerted by the expansible layer and is impervious (or less pervious) to the liquids and materials that are present in the expansive layer, the active agent-containing liquid formulation, and the delivery environment during transport. A certain degree of permeability of the barrier layer can be accepted unless the rate of transport of the active substance-containing formulation is adversely affected. However, it is preferred that the barrier layer does not fully transport liquids and materials that are in the dosage form and the delivery environment during the release of the active agent. The barrier layer may be deformable by the forces exerted by the expandable layer so as to allow the capsule to be compressed, thereby expelling the liquid of the active substance-containing formulation from the outlet. In some embodiments, the barrier layer will be deformable to such an extent as to provide insulation between the expandable layer and the semipermeable layer in the region where the exit orifice is formed. In this method, the barrier layer will deform or will to a limited extent flow and isolate regions of the expanding 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 isolation, a single access path for the liquid to pass to the expandable layer through the semipermeable layer leads to no return of liquid to 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 ™ (Du Pont), cellulose acetate, cellulose acetate pseudolatex (such as the pseudolatex described in U.S. Pat.

024 842), cellulose acetate propionate, cellulose acetate butyrate, ethylcellulose, ethylcellulose-based pseudolatex (such as Surelease supplied by 10 Colorcon, West Point, PA, or Aquacoat ™ supplied by FMC Corporation, Philadelphia, PA), nitrocellulose, polylactic acid, acid polyglycolic, polylactide-glycolide copolymers, collagen, polyvinyl alcohol, polyvinyl acetate, polyethylene vinyl acetate, polyethylene terephthalate, polybutadiénstyrén, polyisobutylene, copolymers of polyisobutylene and isoprene, polyvinyl chloride, copolymer of polyvinylidene chloride and vinyl chloride, acrylic acid and methacrylic acid esters, copolymers of methylmethacrylate and ethylacrylate, latex of the acrylic esters (As Eudragit ™ 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, polylakoxysilanes, polydimethylsiloxane, polyethylene glycol and silicone elastomers, acrylates, silicones or polyesters crosslinked by electromagnetic radiation, thermally crosslinked acrylates, silicones or polyesters, butadiene-styrene mixtures of the foregoing.

Preferred materials include cellulose acetate, copolymers of acrylic acid and methacrylic acid esters, copolymers of methyl methacrylate and ethyl acrylate and latex based on acrylate esters. Preferred copolymers include poly (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; poly (methacrylic acid, ethyl acrylate) 1: 1, 250 000, marketed under the trademark EUDRAGIT L; poly (methacrylic acid, methyl methacrylate) 1: 2, 135 000, which is marketed under the trademark EUDRAGIT S; poly (ethyl acrylate, methyl methacrylate, trimethylammonium methyl methacrylate chloride) 1: 2: 0.2, 150,000, marketed under the trademark EUDRAGIT RL; poly (ethyl acrylate, methyl methacrylate, trimethylammonium methyl methacrylate chloride) 1: 2: 0,1, 150 000, marketed as

EUDRAGIT RS. In each of the above cases, the ratio x: y: z denotes the molar ratio of monomer units, and the number always mentioned last indicates the number average molecular weight of the polymer. Particularly preferred are cellulose acetate containing plasticizers such as acetyltributyl citrate and a copolymer of ethyl acrylate and methyl methacrylate such as Eudragit NE.

The above-mentioned materials for use as a barrier layer can be formulated with plasticizers to prepare them

a suitably deformable barrier layer such that the force exerted by the expandable layer breaks down the compartment formed by the barrier layer, thereby transporting the liquid of the active substance-containing formulation. Examples of typical plasticizers 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 oils, mineral oils, castor oils. Plasticizers can be blended 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. 5,201,549. Although the barrier layer, the expandable layer, and the semipermeable membrane have been expediently illustrated and described as monolayers, each may be formed by 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 penetration profile. In this case, the barrier layer comprises the first and second layers. This is similar for the semipermeable layer and the expandable layer.

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

In FIG. 5A to 5C, another example of a dosage form known in the art and described in U.S. Pat. 5,534,263; 5,667,804 and 6,020,000. This form can be briefly described as follows: FIG. 5A is a cross-sectional view of dosage form 80 prior to admission to the gastrointestinal tract. The dosage form consists of a roller-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 the aqueous environment. Suitable materials are disclosed in patents cited elsewhere herein.

Upon ingestion of the dosage form 80, the matrix regions 82 between the bands 88, 90, 92 begin to erode, as shown in FIG. 5B.

Matrix erosion is the initiated 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 erosion of the matrix occurred to such an extent that the dosage form disintegrated into three pieces, 94, 96, 98. The erosion would continue until the matrix pieces of each of these pieces were completely eroded. The bands 94, 96, 98 will then be excluded from the GI tract.

Other methods are known in the art to achieve sustained release of drugs from oral dosage forms. For example, diffusion systems such as storage devices and matrix devices are known, m

dissolution systems, such as encapsulated dissolution systems (such as tiny team pills) and matrix dissolution systems, combined diffusion / dissolution systems, and ion exchange systems, as described in Remington's Pharmaceutical Sciences, 1990, p. Dosage forms that function according to these other methods fall within the scope of the present invention 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 either verbatim or per se. base equivalents.

In other embodiments of these solutions, the sustained release dosage forms can be protected from the action of ethanol in the gastrointestinal. traction with 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 preferably should not dissolve rapidly in ethanol, but could swell or dissolve very slowly. Other polymers or materials may be mixed with the enteric coating, so long as their addition does not compromise the functioning of the enteric coating in ethanol. In some embodiments, the enteric coating polymer or material may be selected to operate the enteric coating in an aqueous alcohol. For example, in one embodiment, the polymer or material may be preferably mixed with the enteric polymer, which may improve or swell / dissolve the aqueous alcohol to be mixed with it. Avoiding brittleness may require the use of a plasticizer such as PEG 6000 in an amount of 1 to 20%. Enteric polymers suitable for use herein include cellulose acetate phthalates such as Eastman Chemical products. In some embodiments, the enteric polymers can be deposited 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 this solution, the sustained release dosage forms can be coated with non-enteric polymers and thus reduce the susceptibility to rapid alcohol-induced dose release, particularly ethanol-induced dose release. In one embodiment, Eudragit ® RS100 and Eudragit ® 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 diffusion-controlled release. 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 acetate 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.

ΊΛ

The non-enteric polymers may 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. The matrix dosage forms typically comprise a gelling agent, a hydrophobic excipient controlling the initial rupture, the drug, and a diluent. The gelling agent 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 ingredients include:

1. Mixtures of different types of HPMC (K4M, K100, E5) to achieve the desired swelling and viscosity. HPMC is insoluble in ethanol, and thus a slower release in the alcohol / water mixture than in water can be expected. The hydration rate can be slowed by the addition of HPC (Klucel ⁸ from Hercules-Aqualon).

2. Mixtures of various types of polyethylene oxide (Polyox ⁸ available from Dow Chemical). Polyox in the ethanol-water mixture swells significantly less than in water. Suitable types are POLYOX WSR-205 NF, WSR-1105 NF. WSR N-12K NF, WSR N-60K, WSR-301 NF, WSR-303 NF.,. WSR Coagulant NF. These materials usually 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 it is therefore expected that it will swell less in ethanol-water mixtures.

5. Matrix of xanthan gum and guar gum.

6. Polyvinyl alcohol is referred to as a substance that is soluble in water but insoluble in ethanol.

The following hydrophobic crack control excipients in ethanol-water mixtures should be equally effective or more effective due to their low solubility in ethanol:

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

2. Glycerol palmitostearate (Precirol® ATO-5, Gattefosse)

3. Glycerol behenate (Compritol® 888-ATO, Gattefosse)

4. Magnesium stearate

5. waxes

6. vegetable and mineral oils

7. aliphatic alcohols

8. polycaprolactone

9. PLGA

10. Natural resins

In one embodiment, 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, carnauba wax and hydrogenated castor oil.

The diluents and fillers used in matrix formulations typically do not significantly affect the liberation profile. However, care should be taken in selecting these excipients since 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 the hydration of the core and thus dissolution of the drug may be limited in the aqueous-alcoholic environment. In a preferred embodiment, the useful diluent is mannitol.

In this solution, the following hydrophobic excipients are less preferred:

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

2. Hydrogenated polyoxyl 60 castor oil.

U.S. Pat. Nos. 5,871,778 and 5,656,299 disclose microspheric formulations having an almost zero-order release rate of the active ingredient when administered to a patient. U.S. Pat. 5,654,008; 5,650,173; 5,770,231; 6,077,843; Nos. 6,368,632 and 5,965,168 disclose sustained release microparticle compositions and their use for the controlled delivery of active ingredients.

In another embodiment, osmotic beads can be used in this solution. The opioid can be applied to nonpareil beads or other substrates with sufficient

osmotic activity. Subsequently, a semipermeable film is applied by another Wurster coating process. In this further coating, the product is withdrawn to different 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 beads, among which pearls without semipermeable coating may be represented, which then act as an immediate release component, can be filled into capsules to form an extended release dosage form according to the present invention.

If drug loading using osmotic beads is too restrictive, beads can be prepared by extrusion-spheronization procedures. The advantage of this approach is that more drugs can be incorporated into the beads and one coat less. 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 non-drug cores, may also be used. Alternatively, drug-containing beads can be coated with films that are not semipermeable to water and release is controlled by a combination of diffusion and osmosis. In some embodiments, reinforcing agents and / or hydrophobic agents may be incorporated into the sustained release delivery structure to prevent rapid dose-induced alcohol delivery. Non-limiting examples of preferred reinforcing agents and / or hydrophobic materials include aliphatic alcohols, waxes, oils and biodegradable materials. Non-limiting examples of such preferred materials include, but are not limited to, stearyl alcohol, carnauba wax, hydrogenated castor oil, and natural resin.

In some embodiments, gastroretentive systems may also be utilized. In conventional gastroretention systems, gastric retention occurs based on their size (i.e., greater than the pylorus channel) and density (density lower than that of GI content permits drift). The systems may employ polymers, including, but not limited to, polyethylene oxide (Polyox), HPC, HPMC, crospovidone, sodium CMC, ethylcellulose, and the like. The addition of hydrophobic materials or waxes can improve the functionality of such materials (which tend to form weaker gels in aqueous alcohol and hence their properties may not be satisfactory). However, hydrophobic materials can significantly increase the risk that such gastroretentive systems will be 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 and / 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 to be considered only as examples of a number of different dosage forms that can be used for the administration of 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. In carrying out this solution, it may be useful to carry out an optimization that falls within the skill of the art.

Examples are m-enid.

Example 1: Hydromorphone tablet, bilayer 16mg system

The dosage form of the hydromorphone sustained release solution is prepared, formulated and shaped as an osmotic drug delivery device as follows: 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 K29-32 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 fluid bed using spray binder solution (18.0 kg). The wet granulate in the granulator is then dried to an acceptable moisture content and comminuted using a 7 mesh screen attached to the comminution apparatus, then transferred to a mixer where it is mixed with 16 g of butylated hydroxytoluene as an antioxidant and lubricated with 0.20 kg of magnesium stearate.

An extrusion composition is then prepared as follows: 24.0 kg of sodium chloride and 0.32 kg of black iron oxide are 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 with 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 so

a mean viscosity of 5 mPa.s is dissolved in 54.0 kg of water to give a binder solution. The dry materials are granulated in a fluid bed while 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.

The bilayer cores are then 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 the 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 are coated with a semipermeable 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 gives a solution with a 6% solids concentration. The wall-forming composition is sprayed onto the bilayer structure in the coating drum so that about 30 mg of membrane is applied to each tablet.

Drilling the semipermeable membrane with a laser creates one 0.64mm outlet channel 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 using hydromorphone tablets according to Example 1 are performed. hours in aqueous solutions containing 0, 4, 20 and 40% ethanol by volume using a type VII dissolution bath.

16mg tablets containing hydromorphone hydrochloride according to Example 1 were used to determine the release rate and cumulative liberation profiles in 0%, 4%, 20% and 40% ethanol. For 0% ethanol (water), the results obtained in the Time 0 stability test were used. 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 the media in which the release rate was tested. For the first 6 intervals and the last interval (2 to 12 hours and 24 hours), 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 the interval. At intervals of 14, 16 and 18, the media was loaded into the bath at the same time, so the tubes in the bath were approximately for 6 and a half hours.

The media was prepared as follows:

4% (v / v) ethanol: pure ethanol (140 ml volume) (Sigma Aldrich, 200 proof) is added to 3360 ml water and mixed well.

20% (v / v) ethanol: pure ethanol (v 700 ml) is added to 2800 ml of water and well mixed. 40% (v / v) ethanol: pure ethanol (v 1400 ml) is added to 2100 ml of water and well mixed. Samples were prepared following method: solutions

samples in 4% and 20% ethanol are injected as they are after mixing. A rapid study will be conducted to demonstrate the validity of this procedure. The 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 peak splitting 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 in the release rate test tubes are made up to 50 ml with 40% ethanol and mixed thoroughly. 2 ml of the sample solution is then added to the scintillation cuvette. The sample solution is evaporated to dryness at 45 ° C using an evaporator (SPC SpeecVac, SPD131DDA, RVT4104, OFP-400, Thermo Savant). 2 ml of water are again added to the scintillation vial.

After thorough mixing, the sample solution is injected on HPLC.

HPLC conditions:

Column: Mobile phase:

flow rate:

temperature:

Injection volume Wavelength:

Cycle time:

Varian Inertsil Phenyl-3, 5 mm, 4.6x150 mm 35% methanol, 65% buffer (0.1% sodium phosphate, 0.2% octanesulfonic acid, sodium salt, pH = 2.2)

1.5 ml / min

45 ° C ml

8 0 nm min

The results of this test are shown in FIG. 6. In the hydromorphone sustained release dosage forms of the present invention, various ethanol solutions did not induce rapid dose release 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 highest (about 10% declared content per hour) in 40% ethanol medium and the same (about 6% declared content per hour) in 4% ethanol medium. Also, the time to release 90% of drug (T90) in 4% ethanol medium was not changed compared to control and the biggest change occurred in 40% medium, see Table 1. Even under 40% ethanol conditions, 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 at all ethanol concentrations evaluated.

Table 1

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

hydromorphone Ethanol / water solution composition (% vol) 0% (Control) 4% 20% 40% T90 (h) 18 18 15 12 Cumulative% released in 2 hours (% of declared content) <1 <1 <1 4 Average release rate (% of declared content) 6 6 7 10 Average release rate versus 0% ethanol comparative 100 116 160

Example 3: Comparative in vitro release study

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

The dissolution parameters are as follows: Equipment: Varian VK7010 dissolution unit and VK8000 autosampler; medium: water and vodka (Pavlova, 40% (v / v) alcohol); volume: 900 ml; blade speed: 50 min ¹ ; withdrawal volume 5 ml; temperature 37 + 0.5 ° C; time points: T = 1, 2, 4, 6, 10, 14, 18 and hours. Note: the results of the test showed that the alcohol content of Pavlova vodka is only 27%.

Because of the chromatographic interference of vodka, solutions of the samples in vodka are evaporated before analysis. Using an automatic sample feeder, take 5 ml of the sample solution into the tube. After cooling to room temperature, 2 ml of the sample solution is added to the scintillation cuvette. The sample solution was evaporated to dryness at 45 ° C using an evaporator (SPC SpeecVac, SPD131DDA, RVT4104, OFP-400, Thermo Savant). 2 ml of water are again added to the scintillation vial. After thorough mixing, the sample solution is injected on HPLC. Solutions of the samples in water were cooled to room temperature and sprayed on HPLC.

The sample solutions in water are injected as they are, while the sample solutions in vodka are evaporated and reconstituted using water to prepare the sample. A short validation study shall be conducted to demonstrate that there is no difference between the two types of sample preparation. In the case of sample solutions in water, the two standards at 100.04 and 180.07 mg / ml are evaporated to dryness, 2 ml of water are separately added again to the evaporators and analyzed thoroughly by HPLC after thorough mixing. In the case of solutions of samples in vodka, the standard of 250,13 mg / ml in triplicate is diluted with vodka to a concentration of 50,03 mg / ml, the diluted samples are evaporated to dryness, 2 ml of water are again added to the residue and mixed 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 - 8 x 5) / 24 hours where 8x5 = 5 ml collection at 8 time points.

The dissolution profile calculations are corrected based on evaporation. For both water and vodka, the sample volume shall be verified as an independent experiment in triplicate.

HPLC conditions:

Column: Varian Inersil Phenyl-3, 5mm, 4.6x150mm

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

Flow rate: 1.5 ml / min

Temperature: 45 ° C

Injection volume: 100 ml

Wavelength: 280 nm

Cycle time: 6.5 min

The injection volume was increased to 100 ml because 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 FIG. 7th

Summary of the Liberation Properties of 32 mg Palladone Capsules

XL in vitro in ethanol-based solutions

Table 2

Palladone XL Ethanol / water solution composition (% vol) 0% (control) 27% T90 (h) > 24 1 Cumulative% released in 2 hours (% of declared content) 21 100

Example 4: Hydromorphone tablet, bilayer 16mg system

The hydromorphone sustained release dosage form of the present invention is prepared, formulated and shaped as an osmotic drug delivery device as follows: 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 K29-32 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. The wet granulate in the granulator is then dried to an acceptable moisture content and comminuted using a 7 mesh screen. The comminuted granulate is transferred to a mixer where it is mixed with 16 g of butylated hydroxytoluene as an antioxidant and lubricated with 0.20 kg of magnesium stearate.

An extrusion composition is then prepared as follows: 24.0 kg of sodium chloride and 0.32 kg of black iron oxide are 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 with 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 2910 hydroxypropylmethylcellulose with an average viscosity of 5 mPa.s is dissolved in 54.0 kg of water to obtain a binder solution. The dry materials are granulated in a fluid 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 is then transferred to a blender and mixed with 40 g of butylated hydroxytoluene and lubricated with 0.20 kg of magnesium stearate.

The bilayer cores are then 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.

The bilayer structures are coated with a semipermeable 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. gives a solution with a 6% solids concentration. The wall-forming composition is sprayed onto the bilayer structures in the coating drum so that about 33 mg of membrane is applied to each tablet,

Drilling the semipermeable membrane with a laser creates one 0.64mm outlet channel 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.

The dried tablets are then coated with a colored and clear coating. The Opadry II yellow colored coating is designated Y-3 012863-A. 14.4 kg of the yellow Opadry II mixture are mixed with 105.6 kg of water to give a colored suspension. The color suspension is spray-coated in the coating drum onto the dried tablets until about 18 mg of coating is applied to each tablet. A clear coating solution is then prepared by mixing 2.4 kg of a 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 drum until each tablet is coated.

1.5 mg of coating.

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

Example 5: In vivo study

The purpose of the Phase I study is to evaluate the effect of alcohol on the pharmacokinetic properties of hydromorionic 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 21-45 years (inclusive) weighing at least 70 kg and within 25% of normal weight in terms of height and body build. The study is conducted as a monocentric, 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 - 16mg hydromorphone tablets according to example 3 with 240 ml of 4% (v / v) alcohol in orange juice

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

Treatment D-16mg hydromorphone tablets 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 standard breakfast:

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

Treatment of the F - 16mg hydromorphone tablet according to Example 3 p

240 ml of 4% (v / v) alcohol in orange juice

Treatment of G-16mg hydromorphone tablets according to Example 3 with 240 ml of 20% (v / v) alcohol in orange juice

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

Alcohol administered in the treatment of B, C, D, F, GaHa is diluted with orange juice and is consumed for approximately 30 minutes without swallowing. Within each treatment, the subject is administered about 50 mg of naltrexone, as an opioid antagonist, which is administered about 14 hours prior to administration and twice daily during administration and for the first approximately 48 hours after administration. Between treatment periods there is an approximately 6 to 14 day elimination period beginning approximately 24 hours after administration.

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

Plasma samples are analyzed using the valdised liquid chromatography-tandem mass spectrometry (LC / MS / MS) method developed by CEDRA Corporation. Human plasma containing hydromorphone and hydromorphone-D ₃ as internal standard is extracted with ethyl acetate / hexane solution. The organic layer was separated, back extracted and evaporated to dryness. The extract is reconstituted and an aliquot is injected into a SCIEX API 4000 LC / MS / MS system equipped with an HPLC column. Positive ions are monitored in multi-reaction monitoring (MRM) mode.

This method is validated with a minimum quantifiable concentration of hydromorphone of 0.05 ng / ml. During validation, analyte calibration curves are plotted by plotting the ratio of analyte: internal standard against known analyte concentrations. Plot a calibration curve using peak area ratios of calibration standards using the inverse of the square of the concentration, a linear-weighted regression algorithm. The calibration curve of hydromorphone 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 the logarithms of plasma concentration during the terminal log-linear elimination phase

- apparent terminal half-life values, calculated as 0,693 / k

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

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

In the fasted and postprandial treated groups, plasma concentrations were close to the limit of quantitation at the first time point after administration, i.e. at 2 hours; then, for all 4 treatments, plasma concentrations increased slowly. There were some subjects in each group 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 for the three treatments involving alcohol were slightly higher than those for 0% alcohol at 117% at 4% alcohol, 131% at 20% alcohol and 128% at 40% fasting alcohol. For post-prandial administration, 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 (114% for 4% alcohol, 114% for 20% alcohol and 110% for 40% alcohol based on treatment results including 0% alcohol) was shown.

The AUCs of the three treatments involving alcohol relative to the treatment containing 0% alcohol met the 80-125% bioequivalence criterion for both fasting and postprandial confidence intervals. In FIG. 8 shows the mean concentration profile after four fasting treatments (group 1). The pharmacokinetic parameters are summarized in Table 3. FIG. 9 shows the mean concentration profile after four treatments in Group 2, in which all medications were performed after standard breakfast.

The pharmacokinetic parameters are summarized in Table 4.

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

0% alcohol 4% alcohol 20% alcohol 40% alcohol Cmax (ng / ml) 1.37 (0.32) 1.56 (0.39) 1.90 (0.66) 1.89 (0.85) Tmax (h) [median (Range)] 16 (6-7) 12 (6-7) 12 (5-16) 12 (6-7) T% (h) 12.4 (5.1) 12.6 (6.5) 12.4 (7.2) 11.1 (3.0) inf 40.6 (11.0) 39.9 (14.1) 43.7 (12.1) 42.2 (13.2) Ratio - Arithmetic mean (range) Cmax comparative 1.19 (0.8-1.7) 1.35 (0.7-2.4) 1.37 (0.7-2.5) Ratio -% Geometric Diameter (90% Cl) Cmax comparative 116.70 (104,48- 130.36) 131.16 (117,01- 147.02) 128.31 (114,18- 144.17) inf comparative 98.83 (87,48- 107,19) 103.21 (92,93- 114.62) 101.65 (91,32- 113.13)

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

0% alcohol 4% alcohol 20% alcohol 40% alcohol Cmax (ng / ml) 1.42 (0.50) 1.64 (0.60) 1.52 (0.32) 1.56 (0.56) Tmax (h) [median (Range)] 1S (6-7) 12 (7-24) 12 (6-7) 16 (6-7) (H) 11.6 (5.1) 11.6 (4.9) 10.4 (3.9) 10.8 (4.8) inf 37.1 (8.6) 36.7 (10.5) 36.6 (9.7) 34.8 (11.9) Ratio - Arithmetic mean (range) Cmax comparative 1.20 (0.7-1.8) 1.20 (0.8-1.9) 1.14 (0.6-2.0) Ratio -% Geometric Diameter (90% Cl) Cmax comparative 113.72 (99,97- 129.36) 114.36 (100,14- 130.61) 11,0,34 (97,08- 125.41) inf comparative 94,72 (88,44- 103.70) 106.21 (96,63- 116.73) 94.09 (85,91- 103.04)

Example 6: Comparison of Individual Ratios: Alcohol versus Repeat Study

The study is conducted 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 elimination periods are included in the treatment. The aim is to characterize the variability of pharmacokinetics between subjects and in 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. the following treatments:

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

Treatment B: Batch, with naltrexone hydrochloride, 50 mg

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

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

At each sampling time, 10 mm venous blood samples are collected in tubes containing anticoagulants. Samples are centrifuged for 1 hour after collection 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 form according to the present invention. Plasma samples are analyzed using validated liquid chromatography-tandem mass spectrometry (LC / M3 / 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. In FIG. Figures 10 and 11 show comparisons for groups 1 and 2 of Example 5. It can be seen from these figures that the range of the ratio C max observed in 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 (v / v)

Using a wet granulation process, 10 g of each formulation with and without stearyl alcohol are prepared. The necessary amounts of oxycodone hydrochloride, lactose and Eudragit® RS PO are mixed in a suitable container and mixed for 5 minutes. The powder mixture is granulated using water until a wet mass is formed. The wet mass is then passed through a 16 mesh screen and allowed to dry overnight under ambient conditions. In a small vessel, the required amount of stearyl alcohol is melted in a water bath. The stearyl alcohol is kept molten in a water bath and the necessary amount of dried granules is added. The resulting mixture is stirred until the granules are sufficiently coated with molten stearyl alcohol. The water bath was removed, the mixture was allowed to cool to ambient conditions and crushed using a 16 mesh screen. Talc and magnesium stearate are added to the coated granules and mixed in a suitable mixer. The granules are then compressed into 375 mg tablets using a suitable tableting machine, such as a Carver press. 300 mg tablets are compressed from granules not coated with stearyl alcohol.

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

component % by weight Oxycodone HCl 8.02 lactose 56.72 Eudragit RS PO 11.97 stearyl 20.29 talc 1.99 Magnesium stearate 1.00

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

component % by weight Oxycodone HCl 10.09 lactose 71,13 Eudragit RS PO 14.99 talc 2.49 Magnesium stearate 1.30

Example 8: A formulation containing hydromorphone hydrochloride with and without stearyl alcohol

The same manufacturing process as in Example 7 was used, but hydromorphone hydrochloride was used instead of oxycodone hydrochloride.

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 56.72 Eudragit RS PO 11.97 stearyl 20.29 talc 1.99 Magnesium stearate 1.00

Table 8: Formulation of tablets containing hydromorphone hydrochloride (30 mg) without stearyl alcohol dose = 30 mg / tablet; tablet = 300 mg each

component % by weight Hydromorphone HCl 10.09 lactose 71,13 Eudragit RS PO 14.99 talc 2.49 Magnesium stearate 1.30

100

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

Samples for this test come from Examples 7 and 8. Release from tablets is tested in a Type VII USP. The following liberation media will be used:

Ethanol: ethanol = 40% EtOH / 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, AAM1.773v1, AAM1.585v50).

Conclusion: Stearyl alcohol suppresses the effect of ethanol on opioid release, as shown in FIG. 12 and 13.

Example 10: Effect of Eudragit ⁹ 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 tablet weight is adjusted so that each tablet contains 30 mg opioids. The formulation of the formulations is shown in Tables 9 and 10.

101

Table 9: Formulation of tablets containing oxycodone hydrochloride (25 mg) without Eudragit RS dose = 25 mg / tablet; tablet = 310 mg each

component % by weight Oxycodone HCl 8.05 lactose 69.04 stearyl 19.92 talc 1.99 Magnesium stearate 1.00

Table 10: Formulation of tablets containing hydromorphone hydrochloride (25 mg) without Eudragit RS dose = 25 mg / tablet; tablet = 310 mg each

component % by weight Oxycodone HCl 7.99 lactose 69.03 stearyl 19.98 talc 2.00 Magnesium stearate ----.------- 1.00

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

102

Example 11: Relative effects of stearyl alcohol, hydrogenated polyoxyl 60 castor oil and carnauba 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 stearyl alcohol. The tablets to be 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 Water: water is used as medium at all intervals

Table 11: Oxycodone hydrochloride formulation, 30 mg, tablets

Ingredients (% by weight) stearyl Hydrogenated poly castor oil carnauba wax Oxycodone HCl 8.02 8.06 8.08 lactose 56.72 57,00 57.13 Eudragit RS PO 11.97 12,03 12.06 stearyl 20.29 19.92 19.76 talc 1.99 1.98 1.98 magnesium magnesium 1.00 0.99 0.99

Conclusion: As shown in FIG. 16, carnauba wax but not hydrogenated polyoxyl castor oil may be used in place of stearyl alcohol.

103

Example 12: Testing OxyContin dosage forms

Dissolution testing of OxyContin dosage forms is conducted essentially at these

Dissolution conditions:

Appliances:

Impeller stirrer speed:

Obj em:

Bath temperature:

Sample volume:

Dissolution media:

Sampling interval:

conditions:

Type II USP min ^-1

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 are analyzed on a C18 column with detection at a UV wavelength of 286 nm. Quantification is performed on the basis of 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 provided below.

HPLC conditions:

column:

Mobile phase.

flow rate:

Detection at wavelength:

Zorbax Extended 50 x 4.6mm THF ·. acetonitrile buffer (3:25:72, 1.2 mL / min)

286 nm

C18, 5 p,

34mM phosphate volume)

104

Injection volume: Column temperature: Cycle time:

The results are shown at μΐ 50 ° C min. 17th

Claims (50)

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 such that the ratio of the mean maximum plasma opioid concentration achieved with a single application achieved when the opioid sustained release dosage form is administered to a patient together with aqueous alcohol to the mean maximum plasma opioid concentration achieved with a single application a sustained-release opioid release dosage form to the patient without alcohol, that at the same time filed water is 1.8: 1 or less. 2. Oral application forma s extended release according to claim 1, characterized by is that the ratio is 1.6: 1 or lower, preferably 1.4: 1 or lower. 3. Oral application forma s extended release which contains an opioid and applicator structure extended characterized in that the sustained release delivery structure of the sustained release dosage form in the presence of an aqueous alcohol comprising 106 alcohol at concentrations of 20% v / v or more releases the opioid such that the ratio of the maximum opioid plasma concentration of an individual patient when administered as a single dose when the opioid sustained release dosage form is co-administered with aqueous alcohol to the patient the single opioid plasma concentration of a single dose achieved when the opioid sustained release dosage form is administered to the patient without concurrent administration of aqueous alcohol 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. 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% v / v or above, releases the opioid by releasing from the sustained release opioid dosage form 80% or less by weight of the opioid dose, measured (a) using an in vitro test method comprising a test medium, and (b) within 2 hours after initiation of the opioid. in vitro test method; wherein the test medium comprises aqueous alcohol which contains alcohol at concentrations that are 20% or greater by volume. 107 The sustained release oral dosage form of claim 5, wherein the release is 50% by weight or less of the opioid dose, preferably 25% by weight of the opioid dose or less. 7. An oral sustained release dosage form comprising an opioid and an extended release delivery structure, wherein the extended release delivery structure of the extended release dosage form is in the presence of an aqueous alcohol containing alcohol at concentrations of 20% by volume or above, releases the opioid such that the ratio of the median time of onset of the maximum plasma concentration in a single application when the dosage form is administered to a patient together with aqueous alcohol to the median of the time of onset of the maximum plasma concentration in a single application The sustained-release opioid for once-daily administration to a patient without concomitant administration of aqueous alcohol ranges from 0.5 to 1.0. The sustained release oral dosage form according to any one of claims 1 to 7, characterized in that it allows administration once a day or twice a day. The sustained release oral dosage form of any one of claims 1 to 8, wherein the opioid is selected from morphine, codeine, thebaine, diamorphine, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, nicomorphine, methadone, levometadylacetate. 108 hydrochloride, petidine, ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine and phenazocine, and pharmaceutically acceptable salts thereof 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 40% vol. by volume or more. The oral dosage form according to any one of claims 1 to 10, further comprising an opioid antagonist such as levallorphan, naloxone, naltrexone, buprenorphine, nalorphine, nalmefene diprenorphine, cyclazocine, metazocin or naxolone. by releasing naltrexone nalbuphine, etazocine, The extended release oral dosage form according to any one of claims 1 to 11, characterized in that 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, selected from a diffusion system, a dissolution system, a combined diffusion / dissolution system, an ion exchange resin based system, an osmotic system, a gastroretentive dosage form, a microparticle the sustained release formulations and the osmosis sustained release dosage form. 109 The sustained release oral dosage form of claim 13, wherein the diffusion system is selected from a reservoir device or a matrix device. The oral extended release 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. The oral dosage form of claim 13, wherein the form comprises a reservoir that is a semipermeable membrane. sustained release that the osmotic delivery at least partially formed The oral extended release dosage form of claim 16, wherein the semipermeable membrane is coated with a polyvinyl alcohol film. The sustained release oral dosage form of claim 16 or 17, comprising a medicament composition in the form of a suspension or solution, a small outlet orifice, and an expandable layer. 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. The extended release oral dosage form of any one of claims 16 to 19, wherein the osmosis sustained release dosage form is as follows: 110 comprises an enteric coating or a non-enteric coating. The sustained release oral dosage form of claim 20, wherein the enteric coating comprises a material selected from cellulose acetate phthalate, hydroxypropyl methylcellulose 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 containing a drug layer in which the drug is in admixture with one or more a plurality of 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 homopolymers and copolymers such as cellulose esters, cellulose ethers and cellulose ester-ethers. The extended release oral dosage form of any one of claims 22 to 24, further comprising a flow control agent, in particular selected from polyhydric alcohols, polyalkylene glycols, polyalkylene diols and polyesters of alkylene glycols. 111 The oral sustained release 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 swelling with liquid suction. The oral extended release 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 the second drug layer comprises an opioid in admixture with selected excipients that are adapted to achieve an osmotic activity gradient. The sustained release oral dosage form of claim 29, wherein the second drug layer does not contain osmotic active agents. The sustained release oral dosage form of any one of claims 26 to 30, further comprising an outlet. 112 The sustained release oral dosage form of any one of claims 26 to 31, wherein the first and second drug layers further comprise a hydrophilic polymeric carrier, in particular a carrier that erodes in the stomach environment. 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 oral extended release dosage form of any one of claims 26 to 33, further comprising a flow control agent, in particular a flow enhancing agent or a flow reducing agent selected from polyhydric alcohols, polyalkylene glycols, polyalkylene diols and polyesters of alkylene glycols. The sustained release oral dosage form of any one of claims 26 to 34, wherein the expandable layer comprises a hydroactive layer comprising osmopolymers or osmagents. 36. The extended release oral dosage form of claim 13, wherein the oral dosage form is a soft capsule or a hard capsule. The sustained release oral dosage form of claim 36, wherein the oral dosage form is a closed, unitary soft capsule in which the drug composition is encapsulated. 113 The sustained 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 includes an outlet. The sustained release oral dosage form of any one of claims 36 to 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 expandable layer is formed in discrete sections that do not surround the entire capsule coated with the 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. The sustained release oral dosage form of claim 41, wherein the capsule is encapsulated by a semipermeable coating. 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, when filled with the formulations, allow the slidable cap to be joined and fixed together 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. 114 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 45, wherein the semipermeable membrane surrounds and forms a reservoir comprising one or more layers, one of which is an expandable layer preferably comprising an osmotic agent. 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 are round and convex in shape, and the matrix is concentrically encircling strips formed from a material that is relatively insoluble in aqueous media. . The oral sustained release dosage form of claim 13, wherein the oral dosage form is a gastroretentive dosage form comprising a tablet or capsule containing a plurality of particles of a sparingly soluble drug dispersion in a hydrophilic water swellable crosslinked polymer that retains physical integrity for a period of time. drug release but then dissolves rapidly. The sustained release oral dosage form of claim 13, wherein the oral dosage form is a matrix dosage form comprising a gelling agent, a hydrophobic excipient, a medicament, and a diluent. 115 51. The extended release oral dosage form of claim 13, wherein the oral dosage form is in the form of osmotic beads comprising nonpareil beads or other substrates having sufficient osmotic activity, coated with a semi-permeable film having a wide film thickness distribution or a non-semipermeable film. water. The sustained release oral dosage form of claim 51, wherein the osmotic beads are present in a capsule.